Central American Institute for Studies on Toxic Substances (IRET-UNA) Program on Work, Environment and Health in Central America (SALTRA)

Serie SALUD, TRABAJO Y

International Research Workshop on MeN Workshop Research International AMBIENTE 33

Second

1 Report from the from Report MESOAMERICAN NEPHROPATHY Report from the Second International Research Workshop on MeN MESOAMERICAN NEPHROPATHY MESOAMERICAN

Programa Financiado por la Unión Europea MESOAMERICAN NEPHROPATHY Report from the Second International Research Workshop on MeN 616.61 I-61m International Workshop on Mesoamerican Nephropathy (2°: 2015 nov. 18-20 : San José, Costa Rica) Mesoamerican nephropathy: report from the second international research workshop on men / David Wegman …[et. al.]. -- 1 ed. – Heredia, C.R.: SALTRA / IRET- UNA, 2016. 200 p.: il.; 21.5 x 25.5 cm. -- (Serie Salud; Trabajo y Ambiente; n° 33).

Publicado también con la serie: Informe técnicos IRET, n° 34 ISBN 978-9968-924-33-7

1. RIÑONES. 2. ENFERMEDADES 3. NEFROLOGIA. 4. EPIDEMIOLOGIA 5. ENFERMEDADES OCUPACIONALES 6. ENFERMEDADES DEL APARATO URINARIO 7. ESTRÉS 8. HOMBRES 9. AGRICULTURA 10.MESOAMÉRICA I. Wegman, David… [et. al.]. II. Título. III. SALTRA. IV. IRET- UNA.

Program on Work, Environment and Health in Central America (SALTRA) (+)506-2263-6375 www.saltra.una.ac.cr

Central American Institute for Studies on Toxic Substances (IRET) (+)506-2277-3584 www.una.ac.cr/iret

EDITORS: David Wegman Jennifer Crowe Christer Hogstedt Kristina Jakobsson Catharina Wesseling

© SALTRA SALTRA and the editors of this report invite you to reproduce and otherwise use the material in this report to inform research, healthcare, prevention and policy efforts to lessen the effects of chronic kidney disease of unknown origin. There is no charge and you do not need permission. However, we ask that you please cite both the report as well as the individual authors of any part of the report you use.

CORRESPONDENCE TO: Jennifer Crowe IRET-SALTRA-UNA Email: [email protected] (+) 506-2277-3584

This publication has been created with assistance from the European Union. Its content is the exclusive responsibility of the SALTRA program and in no case should be considered to reflect the views of the European Union.

En colaboración con el Programa de Publicaciones e impresiones de la Universidad Nacional, Costa Rica. MESOAMERICAN NEPHROPATHY Report from the Second International Research Workshop on MeN

Bringing together knowledge, research questions, and initiatives related to Chronic Kidney Disease of unknown origin in Mesoamerica

NOVEMBER 18-20, 2015 HOTEL AUROLA HOLIDAY INN, SAN JOSÉ, COSTA RICA

Organized by Central American Program for Work, Editors: Environment and Health – SALTRA Central American Institute for David Wegman Studies on Toxic Substances (IRET) Universidad Nacional (UNA), Jennifer Crowe Costa Rica. Christer Hogstedt Kristina Jakobsson Technical Series SALTRA Catharina Wesseling Program for Work, Environment and Health in Central America (SALTRA) (+506) 2263-6375 / www.salta.una.ac.cr MAIN MESSAGE

different research groups in several countries that Mesoamerican NephropathyThere is general has a scientific predominantly consensus occupational based on multiplecomponent. studies There by is growing evidence for a causal role of strenuous work, heat and been made towards clarifying pathophysiological pathways for heatinsufficient stress leadingrehydration to chronic as risk kidney factors disease. in MeN, Intervention and progress studies has are warranted to reduce heat stress and dehydration in high risk workers. It is also quite possible that other factors also play a role in the disease, perhaps in combination with heat stress and dehydration. need further evaluation as possible risk factors related to disease initiationExposures or to progression. specific agrochemicals The roles ofor infectiousother yet-unknown agents, NSAIDs, toxins genetic susceptibility, gene-environment interactions and social determinants as contributors to disease onset and progression also

Social and economic drivers of the disease, including working conditions,need to be clarified. unemployment and precarious employment and poverty in general need to be analyzed both in community and workplace studies. There is a need for standardized studies (including simple prevalence studies) to enable valid comparisons between countries and regions. This is an important step in ascertaining whether the epidemic of CKDu in Central America that we have called MeN is pathophysiologically similar to what is occurring in other parts of the world. Coordinated regional approaches to study prevalence, causes of this disease and to seek viable solutions the challenges itetiology, presents. and to evaluate interventions are needed to find the Declaración de la Junta del CENCAM y el Comité Científico del 2do Taller Internacional sobre Nefropatía Mesoamericana referente a los hechos actualmente conocidos sobre la epidemia

l 2do Taller Internacional sobre la Epide- mia de Nefropatía Mesoamericana (MeN, Statement of the CENCAM Board E por su nombre en inglés) fue celebrado and the Scientific Committee of the en San José, Costa Rica, del 18 al 20 de noviem- 2nd International Workshop on bre del 2015, tres años después de realizar el Mesoamerican Nephropathy regarding primer taller. Un total de 75 expertos de 18 paí- currently known facts about the ses discutieron la evidencia sobre las posibles - epidemic cas, y las similitudes y diferencias con otras epi- demiascausas dede laenfermedad MeN, sus secuenciasrenal crónica fisiopatológi no relacio- he 2nd International Workshop on the nada con las causas de tradicionales de diabetes Epidemic of Mesoamerican Nephropa- e hipertensión (ERCu) en Sri Lanka y otras par- T thy (MeN) was held in San José, Costa tes del mundo. La discusión también incluyó los Rica, November 18-20, 2015, three years after métodos para evaluar diferentes aspectos de la epidemia, que abarcaron desde preguntas sobre 18 countries discussed the evidence regard- su etiología hasta las intervenciones dirigidas a ingthe firstpossible workshop. causes Aof total MeN, of pathophysiologic 75 experts from su prevención. Actualmente estamos preparan- pathways, and similarities and differences with do un informe técnico completo, pero conside- other epidemics of chronic kidney disease un- rando la urgencia de tomar medidas para hacer related to traditional CKD causes of diabetes - and hypertension (CKDu) in Sri Lanka and oth- vulgar esta declaración inicial con algunas de las er parts of the world. The discussion also ad- conclusionesfrente a esta enfermedadclaves sobre mortal,la MeN. se justifica di dressed methods to assess different aspects of Hubo consenso en que la Nefropatía Mesoa- the epidemic, ranging from etiologic questions mericana tiene un componente predominante- to interventions aimed at prevention. A compre- mente ocupacional. Dicha conclusión se basa en hensive technical report is in preparation, but los múltiples estudios con variedad de diseños an interim statement of some key conclusions realizados por múltiples grupos de investigación y en diferentes países. Hay evidencia creciente of taking action to address this fatal disease. sobre el papel causal del trabajo extenuante, el aboutThere MeN was is ajustified consensus considering that MeN the hasurgency pre- - dominantly an occupational component. This res de riesgo en la MeN; y se ha progresado en conclusion is based on multiple studies with calor y la rehidratación insuficiente como facto various designs by different research groups estrés por calor que conduce a la enfermedad in several countries. There is growing evidence la clarificación de las vías fisiopatológicas del- for a causal role of strenuous work, heat and tudios de intervención para reducir el estrés por calorrenal ycrónica. la deshidratación Por ende, seen justificatrabajadores realizar de alto es and progress has been made towards clarify- riesgo y, de hecho, ya se inició un importante es- insufficient rehydration as risk factors in MeN, ing pathophysiological pathways for heat stress tudio al respecto. Sin embargo, se considera que leading to chronic kidney disease. Intervention hay otros factores que también pueden jugar un studies to reduce heat stress and dehydration in papel importante, posiblemente en combina- high risk workers are warranted, and one ma- ción con el estrés por calor y la deshidratación. jor study has been initiated. However, it is quite - possible that other factors also play a role, per- cos o a otros agentes tóxicos aún desconocidos haps in combination with heat stress and dehy- requierenLa exposición ser evaluadosa algunos comoagroquímicos posibles específifactores de riesgo relacionados con el origen o la evolu- other yet-unknown toxins need further evalu- ción de la enfermedad. Con base en los estudios ationdration. as Exposurespossible risk to factorsspecific related agrochemicals to disease or realizados a la fecha, no existe evidencia sobre initiation or progression. Based on studies con- la exposición a metales pesados o alcohol como ducted to date, no evidence exists for exposure factor único o como factores de riesgo impor- to heavy metals or alcohol as sole or important risk factors for MeN. The roles of infectious el papel de los agentes infecciosos, los anti-in- agents, NSAIDs, genetic susceptibility, gene-en- tantes para la MeN. Además, se debe clarificar- vironment interactions and social determinants bilidad genética, las interacciones genético-am- as contributors to disease onset and progres- bientalesflamatorios y nolos esteroideosdeterminantes AINEs, sociales, la suscepti como factores contribuyentes para la aparición y la Social and economic drivers of the disease, evolución de la enfermedad. includingsion also need working to be conditions,clarified. unemployment Se deben analizar los factores sociales y econó- and precarious employment, and poverty in micos que promueven la enfermedad, incluyendo general need to be analyzed both in community las condiciones de trabajo, el desempleo, el em- and workplace studies. The need for alterna- pleo precario y la pobreza en general, a través de tive, improved work environments, particularly estudios tanto comunitarios como en lugares de concerning heat conditions and agrochemical trabajo. Se destacó la necesidad de proveer entor- exposures, was underlined as was the need for nos de trabajo alternativos y mejorados, particu- improved healthcare for the victims of the epi- larmente en ambientes con condiciones de altas demic. temperaturas y exposición a agroquímicos, así Coordinated regional approaches to study como como la necesidad para mejorar la atención prevalence, etiology, and to evaluate interven- de la salud de las víctimas de la epidemia. tions were given high priority. Emphasis was Se dio alta prioridad a los enfoques regiona- also given to a global focus on CKDu, for under- les coordinados para estudiar la prevalencia y standing of the similarities and differences of la etiología, y para evaluar las intervenciones. CKDu epidemics in different geographic areas. También se dio un gran énfasis al enfoque glo- In particular, there is a need for standardized bal de la ERCu, para entender las similitudes y studies (including simple prevalence studies) diferencias de la epidemia de ERCu en diferen- to enable valid comparisons between countries and regions. This is an important step in ascer- realizar estudios estandarizados (incluyendo taining whether the epidemic of CKDu in Central estudiostes áreas geográficas.sencillos de En prevalencia) particular, esque necesario permi- America that we have called MeN is pathophysi- tan hacer comparaciones válidas entre países y ologically similar to what is occurring in other regiones. Este es un paso muy importante para parts of the world. In turn, a better understand- determinar si la epidemia de ERCu en Centroa- ing of the extent to which CKDu is occurring mérica que hemos llamado MeN, es similar a las in multiple locations would provide important que están ocurriendo en otras partes del mun- information regarding the likely causes of this do. A su vez, el tener un mejor entendimiento fatal disease. sobre el grado en que la ERCu está ocurriendo en múltiples localizaciones, podría proporcio- nar información importante relacionada con las causas probables de esta enfermedad mortal. INAUGURAción INAUGURATION

Dr. Norman Solórzano Alfaro, Vice-Rector de Docencia en representación del Sr. Rector el Señor Rector de la Uni- versidad Nacional Dr. Alberto Salom Echeverría. Dra. Catharina Wesseling, Presidenta del CENCAM. Máster Pelayo Castro Zuzuarregui, embajador para Centroamérica de la Unión Europa. Dr. Mario Cruz, en representación de la Dra. Lilian Renau de la Organización Panamericana de la Salud. Dra. Aurora Aragón, en representación de la Máster Marianela Rojas Garbanzo, Coordinadora Regional de SALTRA.

hablar de casi todo sin saber de casi nada. Yo Opening remarks en esta ocasión particular sería muy osado por Palabras del Excelentísimo Pelayo Castro miprefiero parte, saltarme sin duda el improcedente, protocolo pues intentar en mi caso decir y Zuzuarregui algo inteligente en materia de nefropatías o ne- Embajador, Jefe de Delegación de la Unión frología. Les provocaría una piedra en el riñón. Europea para Costa Rica. Así es que les ahorraré ese atrevimiento y me li- mitaré a explicarles por qué yo, por qué la Unión Dra. Aurora Aragón Benavidez, Representación Coor- Europea, está hoy aquí. dinadora Regional SALTRA Lo haré compartiendo 3 mensajes muy senci- Dra. Catharina Wesseling, Presidenta Consorcio para llos. la epidemia de la Nefropatía en México y Centro América (CENCAM) Dra. Lilliam Renau-Vernon, Representante OPS en El primer mensaje Costa Rica es COOPERACION Dr. Norman Solórzano Alfaro, Representación Rec- La bandera de la UE está hoy aquí porque toría Universidad Nacional existe una enfermedad renal crónica de etiolo- gía que ustedes están tratando de determinar es agradezco que me permitan acompa- y que está devastando vidas de trabajadores y ñarles en la apertura de un taller como sus familias en múltiples rincones de Centroa- éste en el que participan 79 investiga- mérica. Ésta es una enfermedad silenciosa que dores de 18 países. Ustedes son los ver- satura los sistemas de salud y provoca muertes Ldaderos y únicos protagonistas. prematuras, tragedias personales, pero también Hay quienes sostienen que el trabajo de un una tragedia social. Esa enfermedad necesita embajador o un diplomático es ser capaz de ayuda. Esa enfermedad necesita cooperación internacional. Les necesita a ustedes. Por eso la comunitario y muy europeo: trabajar conjun- UE está hoy aquí. tamente, aprendiendo de los demás, compar- La UE ayuda a través de SALTRA en esta y en tiendo experiencias, apoyándonos en la ciencia, otras actividades de otros componentes del pro- uniendo a investigadores de 19 países por enci- grama. En el año 2011 la UE se unió a SALTRA ma de fronteras. (en su Fase II) apoyando con €1.161.886 la El tercer mensaje tiene que ver con el ri- “Acción para la incorporación de los principios ñón. No soy un experto como ustedes. Por eso de desarrollo sostenible en la gestión de salud me disculparán que diga que he leído que los ambiental y laboral desde las universidades riñones limpian el cuerpo de residuos, y que centroamericanas”, de la mano de la Universi- metafóricamente, algunos creen que limpian el dad Nacional de Costa Rica, lo que le ha permiti- cuerpo de toxinas e ideas negativas. Al riñón se do a SALTRA compartir experiencias y trasladar sus logros de salud ocupacional de la Fase I al la concentración de emociones de estrés, miedo, área de salud ambiental. ansiedad,le asocia conincertidumbre, la purificación terror, pero etc. también Llevando con Se trata, y quiero subrayarlo, de cooperación la metáfora un poco más lejos, y por deforma- regional. Y para nosotros tiene un valor añadido ción profesional, podríamos decir que el riñón fundamental. Creemos en ella. Es nuestra seña del mundo está enfermo. Sufre una nefropatía de identidad. La UE tiene un Acuerdo de Aso- muy grave. Me perdonarán que tenga muy pre- ciación con América Central – el único entre 2 sente los atentados de París, que se han clavado regiones de esta naturaleza en el mundo – y ha en el corazón de la familia europea. Pero no sólo reforzado su cooperación regional con Centroa- los de Paris. Los atentados de Beirut, de Túnez, mérica. Nuestra política de apoyo a la región si- del Sinaí, Nigeria, Ankara y tantos otros rinco- gue siendo un compromiso a largo plazo ya que nes del planeta. Fueron ataques contra la huma- la UE quiere seguir siendo un socio de referen- nidad. Contra todos nosotros. cia en la región Centroamericana: unos 120 mi- El riñón del mundo está enfermo. Pero el ta- llones de euros están ya previstos para la coope- ller que hoy se inaugura, ver a tantas naciona- ración regional durante el periodo 2014-2020. lidades juntas, saltando fronteras, cooperando El segundo mensaje es un mensaje social. para enfrentarse a una enfermedad es un pe- La salud ocupacional y ambiental es uno de los queño acto de esperanza. El riñón del mundo se focos fundamentales del desarrollo sostenible. Y es también una seña de identidad europea. Por falta una Europa unida y mucha cooperación eso esta la UE hoy aquí. Yo todavía lo llamo mo- internacional.puede curar. Va No a seres solamentedifícil. Y para una lograrlo cuestión hace de delo social europeo, porque creo en él. Porque diplomáticos, ni mucho menos. Es una cuestión creo que Europa debe seguir siendo sinónimo que nos interpela a todos, todos los días. Tam- de liderazgo en educación y sanidad, en políti- bién hoy aquí. cas sociales, asistencia sanitaria universal, in- Ustedes están hoy aquí para colaborar, para - aportar y trabajar duro, para dejarse los riño- nal. La OIT considera que cada año 2.3 millones nes y cambiar la vida de los miles de personas devestigación personas científica mueren pory cooperación accidentes internacioo enferme- afectadas en este momento por la epidemia de dades relacionadas con el trabajo. Aparte de las la nefropatía renal crónica, para descubrir su consecuencias dramáticas para sus familias, en causa. Para generar esperanza, para evitar en - pérdida del 4% de crecimiento del PIB mundial. medad sigan creciendo en Centroamérica, Asia Portérminos eso esté económicos, la UE hoy aquí. significa cada año una ydefinitiva posiblemente que las otras víctimas partes de del esta mundo. grave enfer Si lo resumimos de manera muy resumida, los éxitos durante el desarrollo de este evento. actividad para vencer a una enfermedad leja- Para finalizar, quisiera desearles los mejores nacontribuyentes y generar salud europeos y esperanza están financiando al otro lado esta del océano. Y lo están haciendo con un método muy Message of Welcome pacional y sobre todo, en la promoción de redes y alianzas con diferentes actores en los países centroamericanos. Es precisamente, debido a Palabras de Marianela Rojas Garbanzo la misión de SALTRA, que desde el 2003, bajo Directora del Programa Salud, Trabajo y la Dirección de la Dra. Catharina Wesseling co- Ambiente, Costa Rica locó en su agenda de trabajo, acciones para la investigación de la Enfermedad Renal dando Excelentísimo Señor Pelayo Castro Zuzuarregui, Em- lugar al primer encuentro Centroamericano con bajador para Centroamérica de la UE nefrólogos, y epidemiólogos que por referencia Dra. Catharina Wesseling, Presidente de CENCAM y habían escrito o tenían alguna experiencia que fundadora del programa SALTRA Dr. Cruz, OPS contar en torno a la enfermedad. De ahí surgie- Dr. Norman Solórzano, Representante de la Rectoría ron dos investigaciones hermanas en Nicaragua de la UNA (Vice-Rector de Docencia) y El Salvador, y en 2009 un segundo encuentro con nuevos actores en coordinación esa vez con el representante de la de la Sociedad Latinoa- n nombre de Marianela Rojas, Directo- mericana de Nefrología e Hipertensión Dr. Ri- ra del Programa Salud, Trabajo y Am- cardo Correa Rotter hasta dar lugar al primer biente, coordinado desde el IRET de la taller de CENCAM. Universidad Nacional, y de mis cole- Hoy, estamos aquí la mayoría de las personas Egas coordinadores nacionales de SALTRA des- que estuvimos en el Taller anterior, con nues- de Guatemala hasta Panamá, les damos la más tros aliados y colaboradores como la OPS que cordial bienvenida a Costa Rica y al II Taller In- declaró esta epidemia como un problema de sa- ternacional de Investigación sobre la Nefropatía lud pública, y también hay gente nueva que se Mesoamericana. ha ido sumando a esta iniciativa con ideas, in- De nuevo nos damos cita más de 75 profesio- vestigaciones, y acciones. A como lo veremos durante el taller, a pesar no sólo con seguir esclareciendo el enigma de que hemos avanzado sustancialmente en la in- lanales enfermedad y científicos renal de 15crónica países, de comprometidos causa desco- vestigación de esta enfermedad, algunas causas nocida, o Nefropatía Mesoamericana a como la y mecanismos que hacen que esta enfermedad hemos llamado, si no que también con la comu- progrese tan rápidamente, siguen siendo desco- nicación, la difusión y la incidencia. Quisiera destacar la presencia del Dr. Chris- necesidad de desarrollar acciones que permitan ter Hogstedt y la Dra. Catharina Wesseling, co- reducirnocidos, las y consecuencias que seguramente trágicas reafirmaremos de esta enfer la- fundadores del Programa SALTRA, quienes han medad. trabajado incansablemente en la región centro- SALTRA como programa académico tiene el americana para atender este asunto de impor- compromiso de continuar atendiendo este pro- tancia regional. blema y apoyar a los gobiernos para buscar El Programa SALTRA, para quienes no lo co- - nocen, es un programa que fue creado hace más lud, sociales y económicas. Sin embargo, ante de 12 años para avanzar en el desarrollo de la lasoluciones complejidad y la de definición este enigma, de políticas siguen siendo en sa salud de los trabajadores centroamericanos, absolutamente necesarias las alianzas interna- desde las universidades nacionales de los paí- ses centroamericanos. Hoy en día el programa, parte, y de nuevos actores de distintas discipli- gracias al trabajo de los colaboradores y el apo- nascionales de otras de los partes científicos del mundo. y expertos que ya son yo decidido de sus fundadores y contrapartes Exactamente 3 años despues del primer taller estratégicas, ha logrado enraizarse en cada uno MeN, SALTRA continua apoyando, ahora junto de los países y contribuir con investigación, di- a CENCAM, la convocatoria de socios y aliados ferentes modelos de educación, herramientas para continuar evaluando el problema y bus- para el registro y la vigilancia de la salud ocu- car la dirección hacia donde enfocar nuevos que estamos aquí sabemos que esta enferme- dad,esfuerzos no espera para nuestrosllegar a soluciones resultados eficaces. y que sigue Los afectando a muchos trabajadores quienes sin tratamiento fallecen a edades tempranas y que la atención médica sigue desbordando la capa- cidad de los sistemas de salud en varios países de la región. Es también la misión de SALTRA mantener el apoyo a través de sus representan- tes en los países para que se siga investigando problemas sociales y proponer soluciones. Finalmente quisiera enfatizar el objetivo del taller. Estamos hoy aquí con el propósito de co- laborar para lograr una diferencia para los miles de personas afectadas en este momento por la epidemia de enfermedad renal crónica de causa desconocida, para todas aquellas personas que caerán víctimas de esta grave enfermedad en el futuro, y también pensando en los miles de trabajadores ya fallecidos, en Centroamérica, y posiblemente otras partes del mundo. Tenemos una oportunidad única de revisar, reflexionar y deplanificar acción. como grupo, de integrar eficiencia y eficaciaUna vez en losmás futuros en nombre planes de de misinvestigación colegas de y SALTRA y particularmente de Marianela Rojas, les agradecemos su presencia y les decimos oportunidad con madurez y sabiduría. queGracias confiamos por venir que juntos y estar aprovecharemos aquí durante estos esta tres días. Que sean todos muy bienvenidos. TABLE OF CONTENTS

Prologue 14

Theme: What do we know? 19

Advances in knowledge of CKDu

· What has happened since the 1st Mesoamerican Nephropathy Workshop? 19 Catharina Wesseling, Jennifer Crowe, Christer Hogstedt, Kristina Jakobsson, Rebekah Lucas, David H. Wegman · In which countries and occupations has CKDnT been reported in excess and how well has it been studied where there are no reports? 23 Kristina Jakobsson · In which countries and occupations has CKDu been reported in excess and how well has it been studied where there are no reports? 31 Agnes Soares da Silva, José Escamilla, Lenildo Moura, Isaías Valente Prestes and Patricia Ruiz · Epidemic of CINAC in Sri Lanka (CKD in Sri Lanka) 39 Channa Jayasumana · Interventions, regulation and response of health care systems in Central America 45 Julietta Rodriguez Guzman

Reviews of evidence for CKDu in relation to hypotheses

· Heat stress and dehydration 58 Daniel Brooks, Jennifer Crowe, Rebekah Lucas · Does exposure to toxic metals have a role in the development of Mesoamerican Nephropathy (MeN)? 64 Carl-Gustaf Elinder · Chronic kidney disease of undetermined etiology and pesticide exposure: an update on recent data 71 Mathieu Valcke, Carlos M Orantes Navarro, Marie-Eve Levasseur · Proposed mechanisms for chronic kidney disease of uncertain etiology observed in Central America (Mesoamerican Nephropathy) 81 Richard J Johnson, Ramon García-Trabanino · Worker’s Health and Efficiency Program – Lessons learned from a pilot intervention in El Salvador 89 Theo Bodin, Emmanuel Jarquin, Ilana Weiss, Ramón Garcia-Trabanino, David H. Wegman · Boston University School of Public Health: Studies of occupational and non-occupational risk factors for chronic kidney disease 94 Michael D. McClean, Rebecca L. Laws, Juan José Amador, Damaris López-Pilarte, Madeleine K. Scammell, Oriana Ramírez-Rubio, David J. Friedman, James S. Kaufman, Daniel E. Weiner, Alejandro Riefkohl, Daniel R. Brooks · Gaining insights into the evolution of CKDnt from community-based follow up studies 100 Ben Caplin, Marvin Gonzalez-Quiroz, Neil Pearce

Clinical Conditions and Pathology

· What is known about the burden and clinical characteristics of Mesoamerican nephropathy? 106 Zulma Trujillo, Ricardo Correa-Rotter · Pathology and pathophysiology of Mesoamerican nephropathy and comparisons with hypertension/ diabetes CKD and CKD of unknown cause outside Mesoamerica 115 Annika Wernerson, Julia Wijkström Theme: What do we need to know and understand? 121

Working Groups - Next steps to address knowledge gaps

· Exploring biomarkers for early evidence of abnormal kidney function 121 · Exploring genetic and epigenetic susceptibility 123 · Assessing individual risk factors 124 · Assessing exposures to pesticides and metals 128 · Assessing exposure to environmental heat load/dehydration and workload 130 · Consideration on infectious agents 140 · Understanding the mechanism of Mesoamerican nephropathy - Theory 141 · Developing central elements for a core questionnaire 143 · Approaches to intervention 146 · Understanding macro factors 148 · Approaches to surveillance of MeN 153

Poster abstracts 158

Working Groups - Next steps to address knowledge gaps

· Chronic kidney disease in Guatemalan children 158 · Comprehensive approach to pediatric kidney diseases in Guatemala 159 · Applying qualitative research methodology to characterize young patients with chronic kidney disease of unknown cause in Argentina. Project Description. 160 · End-stage renal disease of unknown etiology in a sugarcane region in Argentina 162 · Prevalence of traditional and non traditional risk factors of chronic kidney disease in Roosevelt hospital, Guatemala 163 · Exposure to nephrotoxic pollutants in Las Brisas community, El Salvador 165 · Weather trends at a sugar mill in northwest Nicaragua, 1973-2013 166 · End-stage renal disease incidence, mortality, and prevalence in a hot spot of Mesoamerican nephropathy in El Salvador: a ten-year community registry 168 · National prevalence of end-stage renal disease patients under renal replacement therapy in El Salvador, 146 year 2014 169 · Heat exposure, volume depletion and acute kidney injury in California’s agricultural workers 170 · Cumulative incidence of acute kidney injury in California’s agricultural workers 171 · Urinary biomarkers KIM-1 and NGAL for early prediction of Chronic Interstitial Nephritis in Agricultural Communities in Sri Lanka. 172 · RO water plants: A successful short-term solution for CINAC in Sri Lanka 174 · Heat stress exposures on kidney dysfunction – An exploratory study in a steel industry. 175 · Pesticide exposure and chronic kidney disease 176

Acknowledgements 177

Workshop Objectives 178

Workshop Program 179

Participant list 188 PROLOGUE

14

PROLOGUE searchers became aware and convinced of the need to research this disease before the year his report is the result of the Second In- 2000. In November 2005, recognizing the need ternational Workshop of Mesoamerican for collaboration and a coordinated vision for T Nephropathy (MeN 2015) held Novem- research, SALTRA1 convened a Central American ber 18-20, 2015, which was part of an increas- workshop in León, Nicaragua about CKD (http:// ingly collaborative effort of researchers and www.saltra.una.ac.cr/index.php?option=com_co other actors to coordinate efforts to understand ntent&view=article&id=90&Itemid=260). Over the next 5 years, researchers from Cen- unknown etiology (CKDu) in Mesoamerica and tral America, North America and Sweden start- otherand find parts solutions of the world. for chronic kidney disease of ed to characterize the unique chronic kidney disease (CKD) that was occurring and explore hypotheses about its causes. In 2010, SALTRA History together with the Autonomoous University of Mexico (UNAM) to hold a second workshop – Workers in Mesoamerica have been aware of this time with aimed at increasing collaboration MeN for more than 20 years and only a few re- in the region and at bridging the gap between

1. In 2005 SALTRA was the Program on Work and Health, Phase I, a Central American-Swedish collaborative university-based research and action program to improve occupational health in the region. Phase I was funded by Sida and received also US and other international support. the disciplines involved ranging from occupa- The Statement goes on to say that “Global and tional health to epidemiology to nephrology. local interdisciplinary action and research are This led to the creation of RERCEM, the Network essential to address this urgent and tragic public for the Study of Mesoamerican Nephropathy health problem. As such, we offer our support to (http://www.saltra.una.ac.cr/index. governments to aid them in recognizing the dis- php?option=com_content&view=article&id=90 ease in Central America and to collaborate with &Itemid=260 ). local researchers and multi-sector actors to: Address this issue by pooling resources and MeN 2012 Workshop The epidemic continued to advance and suf- 2. Prevent premature deaths in the most affect- fering of patients and their families along with edusing populations existing scientific by intervening evidence, where possible.” the increasing inability of the healthcare sys- The participants also decided to form a re- tems to respond adequately, made it clear that search consortium, which came to be called broader international collaborations and fund- CENCAM (Consortium on the Epidemic of Ne- ing were needed to accelerate research. As re- phropathy in Central America and Mexico), to searchers in other part of the world starting facilitate collaboration between researchers becoming aware of the problem, some offered working on the disease. to become involved. In 2012, SALTRA convened an International Organizing Committee and set MeN 2015 a date for the First International Workshop of Mesoamerican Nephropathy (MeN 2012). For three days in Novembers 2012, a total of 51 re- andThe second work ofworkshops CENCAM areas well detailed as the in scientific this re- searchers from 15 different countries set out port,and political(see “What developments has happened between since the the 1st firstMe- to answer the questions, “What do we know?” soamerican Nephropathy Workshop?”). Simply 15 “What do we need to know?” and to come to consensus on 1) A prioritized research agenda - and 2) ways to collaborate, improve coherence cultput, tothe overstate scientific the and importance political contexts of the progresschanged between research initiatives and use scarce re- dramatically between 2012 and 2015. It is diffi political arenas. Nonetheless, it is also true that for the 51 participants, especially given the his- themade situation in these for three the individualsyears in the affected scientific by andthis sourcestoric tension more andefficiently. differences These between were lofty research goals disease and their families has not changed dra- groups and other actors in the region at that matically. This was the important reality guid- time. It must be said that the participants of the ing the participants of the 2015 workshop and 2012 workshop knew the task that they were will remain the reality that should guide our undertaking and believed in its importance – so current efforts. much so that each participant paid his or her The participants of MeN 2015 included 80 re- own expenses to attend the workshop. searchers from 19 different countries and many The participants in MeN 2012 held this meet- different specialties. Their names and institu- ing in a global context in which the very existence tions can be found at the end of this report. of Mesoamerican Nephropathy2. As such, one of the most important achievements of the MeN Objectives of MeN 2015 2012 was the signing of a statement(http:// The goals of the workshop were to: www.saltra.una.ac.cr/index.php?option=com_ 1. Update progress in understanding the epi- content&view=article&id=114) including the at First International Workshop. of a chronic kidney disease of undetermined ori- 2.demic Share and ongoing on the studiesresearch in questionsthe region identifiedand iden- gindeclaration (MeNu) affectingthat “…that Mesoamerica…” there is sufficient proof tify current knowledge gaps.

2. See note below regarding names for the disease. 3. Articulate key hypotheses and strength of posters were presented orally in a session dur- evidence to date with a view to focus future re- ing the workshop. The abstracts are included in search on the most promising hypotheses. this report. 4. Promote and establish new relationships and collaboration among researchers and clini- How can we advance? cians. 5. Identify data and data sources to inform the The workshop also included working groups public, clinicians, labor market partners, and led by 2-3 researchers familiar with the desig- policy makers in understanding the evidence nated topics. Each workshop attendee partici- base of interventions and solutions for the pre- pated in two working groups and the summa- vention and treatment of CKDnT. ries from each presented orally and discussed 6. Strengthen the communication and support in a plenary session with all participants. The structure for researchers in the region written summaries were updated by the work- 7. Publish proceedings, peer-review papers - summarizing progress and research gaps and host in-person CENCAM meeting. Sub-Committeeing group leaders before to reflect being the accepted plenary for discus inclu- Simply put, we aimed to answer the following sion inand this submitted report. for review by the Scientific questions, updating the answers we document- ed in the 2012 workshop: What are the top priority 1. What do we know? research initiatives? 2. What do we need to know and understand? 3. How can we advance? - 4. What are the top priority research initia- ting research priorities and including a summa- 16 tives? ryThe of the final proposals part of the set workshop forth by working focused groupson set - ing Committee. Suggestions for moving forward MeN 2015 Methods and Outcomes canand abe summary found in by each five working members group of the summary Organiz and a summary of the consensuses reached dur- What do we know? ing the workshop can be found in the Statement What do we need to know and understand? by the Board available online (http://repositorio.una.ac.cr/bitstream/han- The 2015 MeN workshop was designed to dle/11056/12869/Board%20Statement%20 obtain maximum participation from the par- MeN.pdf?sequence=1) as well as in this report. ticipants. Oral presentations were invited from researchers prior to the workshop with the This report aim to summarize recent research outcomes and update data relevant to etiologic hypoth- It is our hope that this report will serve as a eses disease. Their written submissions were useful tool for researchers interested in collab- - - vised accordingly. They were distributed to all ness of their work and by policy makers seeking workshopreviewed byparticipants the Scientific prior Sub-Committee, to the workshop re toorating address to increasechronic kidneythe efficiency disease and of unknowneffective and presented orally during the workshop. Fol- origin. We are increasingly aware of similar epi- lowing the workshop, authors were asked to up- demics in other parts of the world and hope to contribute to the worldwide efforts looking for data presented at the workshop and re-submit causes and solutions. date their papers to reflect discussions and new Thanks to a grant from the National Institute review and acceptance for this report. Posters of Environmental and Occupational Health Sci- werethem also to the solicited Scientific from Sub-Committee any participant forwishing final ences (NIEHS) in the United States awarded to inform about recent and ongoing work. All jointly to Boston University and the Universidad Nacional in Heredia, we were able to provide Notes simultaneous English-Spanish translation dur- ing the workshop and thanks to a generous of- · The workshop title used the term fer from the National Institute for Occupational ‘Mesoamerican Nephropathy’. The Safety and Health (NIOSH) in the United States, acronym ‘MeN’ (originally MEN with the we are able to translate the content of this re- “e” refering to “endemic” or “epidemic”, port to Spanish. We hope that this will add to was used before the 2012 workshop. the usability of this report. However, it was pointed out during the 2012 workshop, that ‘MeN’ is an acronym that might appear to exclude Heredia, May 15, 2016 attention to women as victims of the disease and that another name should be proposed. Since 2012, multiple The Organizing Committee names have been coined to refer to the Ricardo Correa-Rotter disease. CKDu (chronic kidney disease Jennifer Crowe (Secretary)* of unknown origin) was used during Ramón García-Trabanino the 2012 workshop and CKDnT (chronic Marvin González Quiroz kidney disease of non-traditional causes) Carolina Guzmán Quilo tends to be used by PAHO and Central Christer Hogstedt* American governments. In Sri Lanka, Kristina Jakobsson* the name Chronic Interstitial Nephritis Rebecka Lucas in Agricultural Communities (CINAC) is Madeleine Scammell used. The choice of the most appropriate Agnes Soares name for the disease was discussed David Wegman* at length in the General Assembly in Ineke Wesseling (Chair)* November 2015 and different opinions remain about the most appropriate 17 *Denotes Scientific Committee Members. name. This report generally uses CKDu to refer to the disease worldwide and MeN to refer to CKDu occurring in the Mesoamerican Region. However, the term used by each author was respected in this report. · Throughout the document there is an inconsistent use of the terms Mesoamerica and Central America. There are different definitions for delimitations regarding Middle America, depending on whether the focus is geographic, geological, historical, cultural, political or economic. Panama (the most southern country), Belize (the only ex-British colony of the isthmus), or the south of Mexico (Mexico is considered part of North-America) may be included or excluded. We must keep in mind that for the study of the MeN epidemic, we target from south to north: Panama, Costa Rica, Nicaragua, El Salvador, Honduras, Belize, Guatemala, and the south of Mexico. · We are grateful for the work done by the authors contributing the pre- workshop papers, the rapporteurs and facilitators from all the discussion groups and the abstract authors. We are also deeply grateful for the work done by those who worked behind the scenes to help assure the success of the workshop and the publication and translation of this document (see Acknowledgements). · The contents of all papers and posters remain the opinion and responsibility of the authors and, unlike the summaries of rotating table discussions and working group discussions, are not to be considered consented workshop conclusions. · The content of the publication is the responsibility of the authors and the SALTRA program. The content does not necessarily reflect the opinion of the European Union, which provided funding for SALTRA at the time the workshop was held nor does it represent the opinions of NIEHS which provided funding for layout design or NIOSH which generously translated the report.

18 CENCAM Board Dra. Aurora Aragón, Nicaragua. Dr. Dan Brooks, USA. Dra. Kristina Jakobsson, Suecia. Dr. Ricardo Correa-Rotter, México. Dr. Ricardo Leiva, El Salvador. Dra. Catharina Wesseling, Costa Rica. (Chair) PhD. Jennifer Crowe, Costa Rica (Secretary). Theme: What do we know?

nd International Workshop on 2 Mesoamerican Nephropathy November 18-20, 2015

Theme: What do we know?

Advances in knowledge of CKDu

edge gaps and knowledge that must be generated What has happened since the to clarify the causes and propose prevention and st 1 Mesoamerican Nephropathy mitigation measures. At the end of the workshop, Workshop? we reached consensus on concepts and priorities for research and action. The workshop concluded that MeN was well- - 19 The Organizing Committee of the dor and Costa Rica, but not universally observed 1st MeN workshop in 2012: throughoutidentified in these certain countries, parts of Nicaragua,and the absence El Salva of Catharina Wesseling, Chair CENCAM; Karolinska adequate prevalence studies in most of Meso- Institutet, Stockholm, Sweden america was a recognized concern. It was not Jennifer Crowe, SALTRA, IRET-UNA, Heredia, clear if the epidemics observed in Sri Lanka and Costa Rica India resulted from the same disease or were Christer Hogstedt, Karolinska Institutet, caused by the same factors as in Mesoamerica. Stockholm, Sweden The cause of MeN remained uncertain; however, Kristina Jakobsson, University of Gothenburg; the leading hypothesis was that the disease was University of Lund, Sweden linked to repeated episodes of occupational heat Rebekah Lucas, University of Birmingham, UK stress and water/solute loss, possibly in combi- David H. Wegman, University of Massachusetts nation with other potential risk factor(s) such Lowell, USA and other nephrotoxic medications, inorganic arsenic,as use of leptospirosis, nonsteroidal or anti-inflammatory pesticides. Although drug Background: 1st MeN workshop genetic susceptibility was discussed as a theo- Exactly three years ago, nearing the end of retically plausible risk factor, no studies explor- 2012, the Central American Program on Work, ing genetics were reported. It was emphasized Environment and Health (SALTRA) organized the that social factors, including work organization, 1st International Research Workshop on the Me- migration patterns, and other local and macro soamerican Epidemic Nephropathy (MeN) (Figure - ease occurrence. South America, Europe and Sri Lanka conducted socioeconomicTo maximize driversfuture research, strongly the influence workshop dis an1). in-depthFifty-five reviewresearchers of the from existing North, knowledge Central and on - clinical purposes and epidemiologic research, recommended to establish case definitions for the epidemic. The workshop identified knowl Advances in knowledge of CKDu

Figure 1. Participants in the 1st International Research Work- shop on the Mesoamerican Epidemic Nephropathy (MeN).

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the development and validation of biomark- ers of early and late disease, and methods for correct measurements of risk factors including phropathy (MeN) have been appearing at an in- a common questionnaire. The workshop also creasingly rapid pace, and to a somewhat lesser recommended more biopsy and prevalence degree, in relation to similar epidemics in other studies and, despite their high costs, prospec- geographical regions. Presentations about MeN tive cohort studies in occupational groups or and CENCAM have been given at major scien- contrasting communities. Intervention studies to reduce heat stress and improve hydration a provisional list of peer reviewed publications with adequate electrolyte replacement were startingtific conferences. from January The CENCAM2013, which Board includes has made ar- considered necessary. Finally, the workshop ticles related to MeN or CKD in Mesoamerica concluded with the establishment of a research and to CKDu or CKDnT in other regions, aiming consortium, which was later named the Consor- for periodic updating. It is clear that the current tium on the Epidemic of Nephropathy in Central number of research groups and individual re- America and Mexico (CENCAM), to facilitate col- searchers investigating topics related to MeN is laboration between researchers working on the considerably larger than at the time of the MeN disease. workshop in 2012. The program of the 2015 workshop includes What has happened since? presentations about most topics that have been proposed as potential causes or co-factors, and Scientific advances ongoing research by several research groups in In the past three years, publications directly Mesoamerica and Sri Lanka. For the purpose or indirectly related to the Mesoamerican ne- -

of this overview, it suffices to note that stud Advances in knowledge of CKDu ies in Central America have demonstrated the National Geographic, The Guardian, as well as occupational nature of the disease, albeit pos- many local newspapers and radio and television sibly with other contributing causes. Important programs. research results have been obtained quantify- ing the strenuous nature of work, the very hot Political developments climatic conditions, and potential pathophysi- in Mesoamerica ological pathways leading to CKD. Further- After the 1st MeN workshop in 2012, the al- more, animal experimental data has challenged ready long-existing awareness and concerns of the classical dogma that dehydration does not most governments of Central American coun- - tries and regional organizations translated into vent heat stress and dehydration among sug- arcanecause CKD. cutters The began first intervention in November study 2014. to Stud pre- outlined in detail in one of the introductory pre- ies of occupational cohorts in different worker sentationsspecific resolutions at the 2015 and workshop actions, (see which “Interven were- populations and at least one community cohort tions, regulations and response of health care sys- are underway. The hypothesis that pesticides tems in Central America” in this report). Several are a main cause of MeN has decreased in ur- key political meetings have yielded statements gency, but has not been abandoned since the highlighting Mesoamerican nephropathy as a etiologic nature of pesticides has not been ex- priority public health problem and urging gov- haustively investigated in Mesoamerica. Genetic susceptibility and leptospirosis hypotheses are Declaration of the Council of Ministers of Health at an initial stage of exploration. Other topics ofernments Central toAmerica act, specifically and the Dominican the San Salvador Repub- - lic (COMISCA) in April 2013, and Resolution clude the overall burden of MeN, clinical aspects CD52/8 of the Pan American Health Organiza- 21 ofthat accessibility, have not beenand success addressed rate sufficiently of treatments in tion (PAHO) Assembly in October 2013. In ad- and survival of MeN patients. Gender differenc- dition, the Latin American Society of Nephrol- es need to be better understood with remain- ogy and Hypertension (SLANH), PAHO and the ing uncertainties as to why rates among women US Center of Disease Control (CDC) organized have increased in affected areas, albeit in much a workshop in Guatemala in 2014 to develop a lesser degree than among men. Of note, there is increasing interest in exploring the similari- - ties and differences between MeN and similar mentalclinical definitionactions include for the the chronic efforts kidney of the disease Salva- epidemics, especially in Sri Lanka and India. In dorianepidemic Ministry in Central of Health America. to ban Specific nephrotoxic govern these Asian countries, pesticides continue to and other hazardous pesticides in 2013; the be an important hypothesis and research topic, establishment of interinstitutional committees whereas no investigations regarding heat stress on CKD in Guatemala in 2013 and Costa Rica in and dehydration have been published. 2014; a Decree of the Costa Rican government to regulate occupational heat exposure in 2015; Increased publicity of MeN and a PAHO meeting in Nicaragua to develop re- The international awareness of MeN has in- gional strategies to address the epidemic. creased also thanks to immense media public- At the start of this past three-year period, so- ity. During the last three years, articles about cial and economic issues related to Mesoameri- can nephropathy were highly sensitive and and political issues have been published by sci- in some parts of the region resulted in social the MeN epidemic and related scientific, social unrest. Research into the etiology of MeN has British Medical Journal. Press articles and radio struck ethical and political chords, in some cas- programsentific journalists have appeared in Science, in majorThe Lancet news and media the es negatively affecting researchers. There have including the New York Times, Center for Public Integrity, US Public Broadcasting System (PBS), to industry funding (both sugarcane and pes- been accusations of conflicts of interest due Advances in knowledge of CKDu

ticides) and industry has also interfered with (SALTRA/UNA) in Costa Rica. The secretariat data interpretation and publication as well as distributes the minutes of board meetings and plain research obstruction. Some of these issues regular communications about relevant topics have considerably improved in the last year to CENCAM members and a listserve allows for and a half, partly thanks to the increasing po- direct communication between all members. litical awareness of regional organizations and CENCAM has two websites. Membership in- national governments, pressure from affected creased from the initial 55 members from 15 parties, more interchange between research countries in November 2012 to 103 members groups (especially through CENCAM), and in from 22 countries in October 2015. SALTRA and general an improved collaborative attitude that CENCAM jointly organized the 2nd International results from increased research capacity. Also Workshop on Mesoamerican Nephropathy. The the CENCAM Board has contributed to a more - peaceful research environment by following day November 20, 2015, with the presentation the recommendations of a subcommittee es- firstof a detailed General Memberreport. Assembly was held on Fri tablished to provide guidance on how CENCAM Notable today is that researchers know each - other better than before, often as a result of CEN- ations in Central America. Of note is the gen- CAM. Increasing overlap of research groups on eralcan helpincreased solve politically willingness difficult among research sugarcane situ different publications can be seen as an indica- companies to respond to the epidemic through tor for evolving collaboration between groups. preventive actions. The earlier mentioned heat Several research collaborations developed stress and dehydration intervention study in El within CENCAM, one example being a grant giv- Salvador is conducted in full collaboration and en by the International Society of Nephrology 22 harmony with the second largest mill in the (ISN) to compare biopsies between MeN and Sri country. Also other sugar-related companies in Lanka CKDu patients, with participation of CEN- Central America are increasingly opening up to CAM members from Central American, Sweden implementation of heat stress prevention mea- and Sri Lanka. sures. In summary, in these three years, we have - achieved increased knowledge, a much larger cant gaps in our understanding of the mecha- international awareness, and a better research nismsDespite underlying these positive the disease developments, and the potential signifi environment with increased collaboration. However, there is still much to learn in theory The number of individuals suffering from MeN and in practice to prevent MeN, and researchers continuesinfluence ofto rise, different and will risk continue factors stillto do remain. so un- need to continue expanding collaborations and til appropriate interventions can be directed bringing together their expertise. to address major risk factors and related safe- guards are implemented.

CENCAM development - uting to knowledge generation and promoting andCENCAM’s facilitating mission activities was and defined policies as to contrib reduce CKDu occurrence in Central America and Mexi- co. The inaugural board was elected in July 2013 and CENCAM has slowly established itself as a solid and active organization. The board holds regular meetings (about 6 per year). The secre- tariat is run by the Central American Program on Work and Health of the Universidad Nacional Advances in knowledge of CKDu

data retrieval. The problems with mortality In which countries and occupations data quality are well known, but the most obvi- has CKDnT been reported in excess ous limitation is the lack of data. Many countries and how well has it been studied that have mortality registries have not reported where there are no reports? to the database. The same limitation holds for population statistics. The WHO Global burden of disease project has assembled data on non-communicable dis- Kristina Jakobsson, Department of Occupational eases including CKD from many available sourc- and Environmental Medicine es. These data are available on-line, with con- Gothenburg University, Sweden. venient modules for mortality, years of life lost (YLL) and disability-adjusted life year (DALY) mapping and time-trends.(1) Much of this in- What do we know? formation is based on scarce data, modeling and assumptions and has to be used with great cau- Sources of information and their tion. Moreover, data on a national scale will not limitations capture important regional variations. As seen in the map (Figure 1), Mexico, El Salva- The WHO mortality registry is available dor and Nicaragua are hot-spots. These countries on-line (http://www.who.int/healthinfo/mor- have also marked increases in YLLs (years of life tality_data/en/), with easy-to use modules for lost due to premature mortality) between 1990

23 Figure 1. Mapping of CKD mortality in males, aged 40-44, 2010. Accessed from www.healthdata.org/gbd Advances in knowledge of CKDu

and 2013. Several countries in North Africa are is strongly affected by health care access the in- cidence rates reported are not indicative of true not increased during the observation period. disease incidence between different countries Also,also identified Iraq has a ashigh hotspots, CKD mortality but here without YLLs have YLL and regions. increase between 1990 and 2013. The existing The proportion of ESRD cases where diabetes regional endemic in Sri Lanka is apparently not was listed as the primary cause was available affecting the national rates. Pakistan –a country for 46 of the 51 countries or regions. Figure 3 summarizes information available by country distinct hot-spot (see also further below). for all causes reported to the USRDS for 2013. withoutEnd-stage a mortality renal disease registry- (ES is R identifiedD) and renal as a (4) Approximately half to two-thirds of cases replacement therapy (RRT) registries are were associated with diabetes in Malaysia, Sin- available in some, but still too few countries. The gapore, Jalisco (Mexico), Hong Kong, New Zea- United States Renal Data System (USRDS) col- land and Rep. of Korea. At the other extreme, lects data each year for international compari- 15 to 20% were reported for Romania, Iceland, sons.(2) Countries report incidence and preva- Netherlands, and Norway. Belgium and Estonia. lence data according to a standardized format. In 34 countries incidence rates were reported Reports include, as possible, patient count data by sex. All countries reported higher incidence for the entire population, by sex (male, female), in males than females although the ratio varied between 1.2 in Malaysia to 2.2 in Denmark. 45-64, 65-74, 75+) for patients new to ESRD Kidney Disease Data Center. In 2005, the duringor by five the different year. Reports age categories also can include(0-19, 20-44, num- International Society of Nephrology (ISN) es- bers undergoing different types of treatment. tablished a program aimed at building global 24 Underlying risk factors (diabetes, hyperten- capacity for preventing CKD in developing na- sion) are reported most commonly as the cause tions. By 2009, more than 25 programs had of disease requiring RRT. However, in countries - with limited healthcare resources, the patients rolled more than 38,000 subjects. Publications included in such registries cannot be considered canbeen be established found searching on five for continents “Screening and and had Early en representative of the total diseased population Evaluation of Kidney disease – SEEK”. in the catchment areas. Moreover, population In 2007, the ISN funded the establishment of age distributions are not comparable between an electronic database (Kidney Disease Data countries. Thus, information from such reg- Center [KDDC]) in Bergamo, Italy, to support the istries is not informative on the CKDu disease collection and analysis of data. An analysis with burden, but can give interesting information on differences in the use of RRT between countries, South East Asia was recently published.(5) The and on diabetes as a risk factor for ESRD. investigatorsfocus on findings report from a widely screening varying programs prevalence in In 2013, reported rates of the incidence of with certain regions experiencing high preva- ESRD varied greatly across 51 countries (Figure lence of CKDu affecting younger populations in 2). Taiwan, Jalisco (Mexico), U.S. and Singapore poor communities. Caucasians generally have reported the highest rates of ESRD incidence lower rates than Asians but whether ethnicity ranging from 458 to 308 per million population. or environmental factors explain the differenc- (3) Below these areas, ESRD incidence rates of es is not known. Access to health care certainly nine other countries were reported between accounts for some differences that complicate 208 (Indonesia) and 286 (Japan) per million interpretation of CKD patterns. Nonetheless population. The lowest ESRD incidence rates improved health care apparently has resulted in were reported in 9 countries between 45 (Ban- increasing numbers of those receiving RTT. gladesh) and 96 (Scotland). In the remaining NGO and media reports are another source countries, incident ESRD rates ranged from 100 of information. An example: In eastern India, to 195 per million population. Since reporting certain coastal villages in the Uddanam area Advances in knowledge of CKDu

Figure 2. International comparison of incidence of ESRD/million population, 2013 (taken from Volume 2, Chapter 13 accessed at http://www.usrds.org/2015/view/Default.aspx)

25 Advances in knowledge of CKDu

Figure 3. International comparison of the distribution of causes of CKD where CGN=chronic glomerulo- nephritis; HT=hypertensive nephrosclerosis; CIN=chronic interstitial nephritis; and RVD=renovascular disease. (taken from Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker S, Plattner B, Saran R, Wang AY, Yang CW. Chronic kidney disease: global dimension and perspectives. Lancet. 2013 Jul 20;382(9888):260-72. doi: 10.1016/S0140-6736(13)60687-X. Epub 2013 May 31)

26 Advances in knowledge of CKDu in Andhra Pradesh have for several years wit- had been reported as an endemic disease.(9) nessed a massive increase of CKDu, with over In reports from the Indian CKD registry, it was 4000 deaths. Media have repeatedly reported noted that underprivileged patients at govern- the existence of the problem, and investigations mental hospitals were younger and more likely are ongoing. One of the investigation has fo- to present at late CKD stage, with undetermined cused on drinking water as a source of the CKDu etiology.(10). excess but inorganic contaminants appears un- The use of traditional herbs, with aristoloch- likely.(6) Also, there are other rural areas in In- ic acid as a known nephrotoxin, is reported in dia, where NGOs and local kidney foundations several studies from Taiwan (11-14) and China report an increase of CKD, especially in agricul- (12-14). Another contaminant, ochratoxin, is also considered to be a risk factor for CKD in North Africa (15). governmentaltural workers. reports.It has however been difficult to The potential effect of arsenic exposure on re- findPublished comprehensive scientific information papers. inOverall, scientific most or nal function has been explored in studies from original articles and review papers report an in- Bangladesh, Taiwan and Chile. There may be crease of CKD related to aging populations, and slight effects on eGFR, but seemingly not of a an increase of hypertension, diabetes and meta- magnitude that is comparable with clinical CKD bolic risk factors. Smoking as a risk factor is also disease. (16) often assessed, as is use of potentially nephro- From Australia, an increased prevalence of toxic pharmaceuticals and herbs. There is little CKD in the aboriginal population is well de- or no information on occupational and environ- scribed, attributed not only to socioeconomic mental factors, and seldom descriptions of the and life-style factors, but also to prenatal ad- natural and socioeconomic circumstances in the verse effects, resulting in a lower number of 27 populations studied, neither on an individual nephrons, and thus an increased susceptibility nor on an area level. A limited literature search, for future insults. (17) The importance of good childhood kidney was performed. This literature search is by no health, ranging from optimal fetal development waywith complete, focus on but identified may serve countries as an illustration of interest to absence of childhood urogenital infections, of the scarcity of information relevant for CKDu. which has profound implications especially in deprived populations, has also been clearly ad- spot, a series of papers describe results from vocated. (18) a Pakistan:national comprehensiveFrom Pakistan, identifiedhousehold as healtha hot- survey in 1990-1994, with more than 18 000 What do we need to know? participants. Interestingly, a more than six-fold increased risk of dip-stick proteinuria (adjusted · The spatial distribution of CKD and CKDu, for age, diabetes, hypertension, BMI, smoking at regional and sub-regional scale, including and some other potential confounders) was ob- changes over time served in the ethnic group of Sindhis.(7) This is · CKD prevalence in different age strata, in- also the population living in the lowland, with cluding changes over time agriculture as the dominant economy and in the · CKD prevalence in different population stra- hottest parts of the country. Notably, hyperten- ta, including changes over time sion was more prevalent in other ethnic groups. · CKD prevalence in different occupational (8) groups, including changes over time A marked difference in CKD prevalence be- · The distribution of known and suspected risk tween SEEK screening centers participating in factors in the general (non-diseased) popula- a nation-wide study in India 2005-2006 was tion observed, with the highest prevalence (40%) · The distribution of known and suspected risk among adults in Andhra Pradesh, where CKD factors in diseased populations Advances in knowledge of CKDu

How can we move forward? existing national data sources as well as from · More effective use of already existing data satellite data. In this way temporal and spatial variations in CKD mortality within a country In countries where mortality registries and can be visualized. population registries provide data on regional Such spatially distributed information may and district level, modern geographical infor- shed light not only on environmental but also mation system (GIS) tools can be used to com- on occupational exposures, but only when bine health and socioeconomic information such exposures are geographically distinctly with data on temperature, elevation, land use, localized, e.g. different types of agriculture, or and other spatially distributed data. Figure 4 mining activities. For other occupations, e.g. provides an example of this applied in Costa construction work, this approach is not feasible. Rica. Such additional data can be retrieved from

Figure 4. Mortality Rate Growth from 1980 to 2012 (Slope of change of the Mortality Rate)

28 Advances in knowledge of CKDu

Figure 5.

GWR coefficients for all independent variables

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A GIS analysis from Costa Rica – spatial co-lo- · New prevalence studies using a protocol cation of the highest mortality rate increase based on screening both for eGFR and protein- 1980-2012 with highest temperature, lowest uria, with information on former and present precipitation and land area with most perma- occupational activities, and with good descrip- nent crops. By courtesy from Ali Mansourian, tions of the environment in the study area. GIS center, Lund university, Sweden. From prevalence studies on kidney function in · Re-examination of existing prevalence stud- developed as well as developed countries, it is ies. Usually the existing publications have fo- well known that the majority of cases with de- creased kidney function were not previously factors – diabetes, hypertension and smoking, known. Unfortunately, low-budget prevalence withcused no on or identificationvery limited information of the traditional on occupa risk- studies in developing countries often have been tional and environmental conditions. For some of these prevalence studies, it might be possible followed by determination of S-Cr only in cases to go back and use existing knowledge of the withconditioned proteinuria. on dipstick Such a screening strategy will as a miss first earlystep, screened population and their living conditions and sometimes even advanced CKDu cases with (soft data, data on area level, or not yet analyzed a clinical picture similar to the disease entity or reported individual data) to describe the ”un- observed in Central America as well as in Sri known” risk factors for CKD. Lanka. Advances in knowledge of CKDu

· Feasible study designs to investigate renal Kirpalani AL, Abraham G, Agarwal SK, Almeida health in migrant workers (an intriguing ex- AF, Gang S, Gupta A, Modi G, Pahari D, Pisharo- ample is Nepalese construction workers return- dy R, Prakash J, Raman R, Rana DS, Sharma RK, ing from the Gulf states, anecdotally reported to Sahoo RN, Sakhuja V, Tatapudi RR, Jha V. What have an increased risk of CKD after return) do we know about chronic kidney disease in In-

References Nephrol 2012; 13:10. 1. www.healthdata.org/gbd 11.dia: Lai,first M-N,report Lai of theJ-N, Indian Chen CKDP-C, registry. Tseng BMCW-L, 2. http://www.usrds.org/adr.aspx Chen Y-Y, Hwang J-S, Wang JDW. Increased 3. 2015 Annual Data Report, Volume 2, Chap- Risks Of Chronic Kidney Disease Associated ter 13, United States Renal Data System ac- With Prescribed Chinese Herbal Products Sus- cessed at http://www.usrds.org/2015/view/ pected To Contain Aristolochic Acid. Nephrol- Default.aspx) ogy 2009; 14, 227–234 Doi:10.1111/J.1440- 4. http://www.usrds.org/2014/view/v2_10. 1797.2008.01061.X aspx 12. Yang CS, Lin CH, Chang SH, Hsu HC. Rapidly 5. Abraham G, Varughese S, Thandavan T, Iy- - engar A, Fernando E, Naqvi SA, Sheriff R, Ur- ciated with Chinese herbal drugs. Am J Kidney Dis.progressive 2000;35:313-8. fibrosing interstitial nephritis asso kidney disease hotspots in developing countries 13. Yang L, Su T, Li XM, Wang X, Cai SQ, Meng LQ, inRashid South H, Asia. Gopalakrishnan Clin Kidney J.N, 2016 Kafle Feb;9(1):135- RK. Chronic et al. Aristolochic acid nephropathy: variation 41. doi: 10.1093/ckj/sfv109. Epub 2015 Nov in presentation and prognosis. Nephrol Dial 17. Transplant. 2012;27:292-8. 30 6. Reddy DV, Gunasekar A. Chronic kidney dis- 14. Lai MN, Lai JN, Chen PC, Tseng WL, Chen YY, ease in two coastal districts of Andhra Pradesh, Hwang JS, et al. Increased risks of chronic kid- India: role of drinking water. Environ Geochem ney disease associated with prescribed Chinese Health. 2013 Aug; 35(4):439-54 herbal products suspected to contain aristolo- 7. Jafar TH, Chaturvedi N, Gul A, Khan AQ, chic acid. Nephrology (Carlton). 2009;14: 227- Schmid CH, Levey AS. Ethnic differences and 34. determinants of proteinuria among South 15. Zaied C, Bouaziz C, Azizi I, Bensassi F, Chour Asian subgroups in Pakistan. Kidney Int. 2003 A, Bacha H, Abid S Presence of ochratoxin A in Oct;64(4):1437-44. Tunisian blood nephropathy patients. Exposure 8. Jafar TH, Levey AS, Jafary FH, White F, Gul level to OTA. Exp Toxicol Pathol. 2011 Nov;63(7- A, Rahbar MH, Khan AQ, Hattersley A, Schmid 8):613-8. doi: 10.1016/j.etp.2010.05.001. Epub CH, Chaturvedi N. Ethnic subgroup differences 2010 Aug 12. in hypertension in Pakistan. J Hypertens. 2003 16. Ehlinder CG Does exposure to toxic metals May;21(5):905-12. have a role in the development of Mesoameri- 9. Singh AK, Farag YMK, Mittal BV, Subrama- can Nephropathy (MeN)? (this volume) nian KK, Reddy SRK, Acharya VN, Almeida AF, 17. Hoy WE, Kincaid-Smith P, Hughson MD, Channakeshavamurthy A, Ballal, HS, Gaccione Fogo, AB, Sinniah R, Dowling J, Samuel T, Mott P, Issacs R, Jasuja S, Kirpalani AL, Kher V, Modi SA, Douglas-Denton RN, Bertram JF. CKD in GK, Nainan G, Prakash J, Rana DS, Sreedhara R, aboriginal Australians. Am J Kidney Dis. 2010 Sinha DK, Shah BV, Sunder S, Sharma RK, Seeth- 56(5):983-93 aram S, Ruju TR, Rajapurkar MM. Epidemiol- 18. Jha V, Garcia-Garcia G, Iseki K, Li Z, Naicker ogy and risk factors of chronic kidney disease S, Plattner B, Saran R, Wang AY-M, Yang C-W. in India – results from the SEEK (Screening and Chronic kidney disease: global dimension and Early Evaluation of Kidney Disease) study. BMC perspectives. The Lancet 2013, Vol 382:260– Nephrology 2013, 14:114 272, 20 July 2013 10. Rajapurkar MM, Rajapurkar MM, John GT, Advances in knowledge of CKDu

2013 but El Salvador is only included through In which countries and occupations 2012.(2) Other limitations are coverage and has CKDu been reported in excess data quality. El Salvador and Paraguay report and how well has it been studied where there are no reports? unknown causes of death”.(2) Mortality under- registration19% and 10% can respectivelygo up to 39% of (Peru), “ill-defined being andap- South and Central America proximately 21% in El Salvador and 25% in Ni- caragua.(2) There are large differences in death

among other problems. It is not possible to sep- Agnes Soares da Silva*, José Escamilla*, aratecertificates CKDu withusing respect the mortality to how dataICD10 available, is used, Lenildo Moura*, Isaías Valente Prestes**, and but it is possible to explore differences on CKD Patricia Ruiz* mortality among countries in the Region, which *Pan American Health Organization, PAHO/WHO; will be presented. **Universidade Federal do Rio Grande do Sul - Programa de Pós-Graduação em Epidemiologia Population based prevalence and incidence studies A systematic search of published literature re- What do we know? veals few studies on national population prev- Prevalence studies that present data on alence or incidence of CKD in Central, South Chronic Kidney Diseases of unknown etiology America and the Caribbean. (CKDu) are rare, and registries of patients in One report explored prevalence and regional replacement therapy are voluntary, frequently variation of CKD among an older population 31 omitting the number or percentage of patients in Costa Rica. This study used data from the with CKDu. Very few countries have any infor- Costa Rican Longevity and Health Aging Study mation on the prevalence and distribution of CKDu within the country. Some countries have based on a measured eGFR<60 ml/min/1.73 means to estimate the incidence and prevalence m(CRELES)2.(3) An andestimated relied 20%on defining of older a personscase of CKD (60 of the population with end-stage renal disease (ESRD) that are in replacement therapy, when slightly more frequently among women (21%) access to health care services is high, and data thanor older) men met (17%). the case CKD definition. prevalence CKD among occurred el- on morbidity from different sources are avail- derly (adjusted for traditional CKD risk factors) able for analysis, as in Brazil, for example. We was higher at higher altitudes but also demon- will present some information collected from strated a striking regional variation with two peer-reviewed papers, a preliminary analysis of lowland provinces, Guanacaste and Limón, the within country variation of CKD incidence and former a known endemic CKDu region in Costa prevalence in Brazil, and estimates of CKDu in Rica, standing out for their high prevalence. some countries based on voluntary registries. In Peru, a population-based study (CRONI- Mortality data remain the most reliable infor- CAS) found an overall prevalence of CKD mation available from all countries. The PAHO (eGFR<60 ml/min/1.73 m2) of 16.8%. Similar to mortality registry database is available online, the population study from Costa Rica, but unlike with easy-to use modules for data retrieval and regional studies from Central America, preva- pre-set data visualization.(1) However, it is im- lence in women was higher (23.4%) than in men portant to note that there remain some prob- (10.3%). The authors also note that older age lems with the mortality data that should be and being diabetic were independent predictors taken in consideration in any analysis.(2) One of CKD. There is no mention of CKDu (4). limitation is the delay in reporting, most Cen- Some estimates of population-based incidence tral American countries are included through are available from Colombia, where 52% of the Advances in knowledge of CKDu

population is estimated to be covered by the so- ed to deterioration of eGFR, which the authors cial security system. Using 2004 data from that - system, it is estimated that the most important origines. causes of incident chronic renal failure are dia- report as similar to findings from Australian ab betes mellitus (33%), hypertension (29%), glo- populations within country is provided in the merulonephritis (8%), and other causes includ- paperA report by Trujillo of prevalence and Correa-Rotter of CKD for specific in this sub- re- ing unknown causes (30%). The average age of port. (7) the incident patients was 54 years. (5) Morbidity based on registry comes from Argentina. The adjusted (age and of treatment of ESRD and RRT gender)One report prevalence of CKD of in CKD a specific in Toba ethnic aborigines group from the Chaco province was estimated at 5.5% In most Latin American countries reporting is (CKD Stage 3); 9.5% of them had diabetes, and voluntary and few countries have information 76.2% arterial hypertension.(6) The authors do concerning chronic kidney disease of unknown not present the percentage that is unrelated to etiology (Table 1). The quality of the data from both risk factors. Proteinuria was highly preva- the regional registry is determined by that pro- lent in the age group >45 years, though unrelat- vided by the national registries. The heteroge-

Table 1. Prevalence and incidence of RRT in Latin America in year 2010.(8)

32 Prevalence (per Incidence Country % CKDu 106) (per 106) Nicaragua 37 ND - Guatemala 123.3 10.7 - Paraguay 148.7 33.3 - Bolivia 153.1 ND - Dominican Republic 165 ND - Honduras 187.2 197.1 - Cuba 303.9 99 - Peru 335.3 34.3 - Costa Rica 338.8 ND - Ecuador 405.9 127.7 - Venezuela 457.4 ND - Panama 517.3 ND - Colombia 533.1 141.9 - El Salvador 562.4 ND - Brazil 708.7 173.7 8-42% (9,10) Argentina 777.8 152.5 25% incident; (≥40% are >50 yo) (11) Uruguay 1,031.10 161 - Chile 1,136.70 174.9 22% in dialysis (12) Advances in knowledge of CKDu neity or even absence of registries in some Latin try, particularly in older age groups (10). American countries is congruent with the ineq- Assessment of unknown causes of CKD proved uities for ESRD patients in access to RRT in such - pared. Based on a self-assessment survey, Sesso personnel.(8) etdifficult al reported when these that twoonly data 8% sourcesof the cases were werecom countries, as well as the availability of qualified A study case: Brazil contrast Moura et al, using a much larger data Sesso et al surveyed RRT centers in 2013 on from ill defined or unknown etiology (9). By behalf of the Brazilian Society of Nephrology.(9) - Half of the 658 units registered by the Society setment recovered system, reporteddirectly from 42.3% the of notifications cases as unde of- and actively treating chronic CKD patients com- thetermined.(10). SUS (Brazilian A study Unified in São Health Paulo System) reports highpay pleted a survey of prevalent cases. The preva- rates of CKDu in patients in RRT who have never lence of RRT was reported as 499 patients per visited a nephrologist prior to RRT (24). It is million inhabitants, with large differences be- evident that, without complete and systematic tween the regions of the country: North (284); assessment of causes of CKD, the proportion of Northeast (358); Center-West (589); South-East patients without known causes will not be con- (597); and South (622). Patients were more sistently reported. commonly male (58%) and almost two-thirds (62.6%) were between 19 and 64 years of age. An exploratory study in Brazil Using a different data source, Moura et al evalu- Based on the same SUS database used by Moura et al (10), we have done an exploratory - analysis of the within country distribution of nancedated all patientsdialysis for(2000-2012) a minimum with of threeESRD monthsdefined 33 toas eliminatethose with cases reimbursement of acute renal from failure. publically A total fi the period between 2009-2012, which is pre- sentedthe 42.3% here of (unpublished the cases identified data). Details as CKDu of the for to account for 85% of all patients in RRT in Bra- methods used for the linkage of the databases zil.of 280,667The distribution patients wereof patients identified, based estimated on race and for the current estimates have been pub- was similar to the general population according lished by Moura et al (13). In the CKDu group, to the Brazilian census. Prevalence of ESRD in- approximately 60% of the study population was creased 47% in the period; incidence increased male, a proportion that did not vary by regions 20% in both sexes and in all regions of the coun- of the country. The distribution of the overall

Table 2. CKDu adjusted rates*, all ages, 2009-2012, Brazil

Region States 2009 2010 2011 2012 Center-West MT, MS, GO, DF 48 48 53 56 North-East MA, PI, CE, RN, PB, PE, AL, SE, BA 46 46 50 55 North AC, RO, AM, RR, PA, AM, TO 36 41 31 30 South-East MG, ES, RJ, SP 72 73 76 74 South PR, SC, RS 74 76 90 87

(*rates /106 adjusted for the Brazilian population) Advances in knowledge of CKDu

Figure 1. CKDnT incidence rates*, Federal Unities (States), Brazil, 2012 (* rates /106, unadjusted)

Table 3. CKD premature mortality (N17-N18) rates* male and female, Americas, 2001 and 2010 (Source: PAHO mortality database) 34

2001 2010 Rate Country Rate male/female Rate male/female Difference Argentina 10.62 1.7 9.87 1.6 -0.8 Bolivia 9 1.1 na NA - Brazil 6.33 1.6 5.93 1.6 -0.4 Chile 5.78 1.6 5.98 1.5 0.2 Colombia 5.8 1.5 6.29 1.4 0.5 Costa Rica 6.13 1.8 7.66 2.1 1.5 Cuba 3.28 1.1 3.41 1.2 0.1 Dominican Republic 4.38 1.6 3.68 2.0 -0.7 Ecuador 15.28 1.2 10.36 1.5 -4.9 El Salvador 47.2 3.1 66.6 3.3 19.4 Guatemala na NA 24.74 1.2 - Honduras na NA 2.75 1.5 - Mexico 12.36 1.2 10.66 1.5 -1.7 Nicaragua 24.15 3.6 44.7 4.4 20.6 Panama 8.26 1.9 10.86 2.7 2.6 Advances in knowledge of CKDu

2001 2010 Rate Country Rate male/female Rate male/female Difference Paraguay 8.59 1 12.08 1.4 3.5 Peru 10.4 1 11.32 1.1 0.9 Uruguay 3.71 1.4 4.69 1.3 1.0 Venezuela na NA 8.43 1.4 - Total 7.42 1.4 7.35 1.5 -0.1

* age-adjusted mortality rates

CKDu rates per regions of the country adjusted States (9th), and Uruguay (8th). However, only in for the Brazilian population is presented in Ta- some of these countries this group of diseases ble 2, and shows higher rates in the South-East and South regions. However, the states present- age group 30-69 years, the group of interest ing higher rates of CKDu are not only concen- forremains prevention within ofthe non-communicable first causes of deaths diseases. in the trated in these regions. Figure 1 shows the un- CKD mortality rates (N18) is > 10/100,000 in adjusted rates per million of the population by Nicaragua (42.8), El Salvador (41.9), Guatemala the Units of the Federation (states) for the year (13.6) and Panama (12.3). 2012, comparing the total rates, and those for Table 3 shows adjusted CKD premature mor- the age groups 20-44 and 45-64 years of age. tality rates for 2001 and 2010 (best available 35 data for comparison between countries) along group 45-64 years. There are large differences with the male/female rate ratios. For some inThis the figure population clearly size, shows age distribution, higher rates and in spe the- countries, the male/female ratio is more than cialized RRT services in different areas of the 2.0 in both periods. country, which may explain, at least in part the differences observed. More in depth analysis is CKDnT and occupation needed to understand this distribution. Although MeN is often described as an epi- demic of agricultural workers, in Central Amer- Mortality database ica sugarcane workers are clearly the most af- In the Americas as a region, the age-adjusted fected population (14). Several studies suggest rate from diseases of the urinary system is the that MeN may also occur among miners and 10th cause of death, and in the age group 30- construction workers (15,16), cotton workers 69, it is the 13th. In El Salvador during 2012, dis- (17), and subsistence farmers.(18) However, these are all cross-sectional studies and most mortality regardless of age, with highest rates collected data are on current occupation and amongease of thethose urinary in the system age group was the30-69 first years. cause Inof are therefore not conclusive. In addition, cane Nicaragua, it was the third and second respec- cutting is seasonal and many sugarcane work- tively in the same group ages, In the same year, ers are also subsistence farmers or work in con- in Peru, it was the 5th cause of death in all ages, but the 8th in the group 30-69 years. It was also risk among subsistence farmers (16, 17). Con- - trarystruction. to contract Two studies workers, did not independent find an increased small- lowing countries (rates not adjusted): Argen- scale farmers have control over their work tinaamongst (6th), the Brazil first 10(10 causesth), Colombia of death (9 inth), the Costa fol hours and are able to avoid the hottest tem- Rica (9th), Ecuador (9th), Guatemala (8th), Mex- peratures. Furthermore they are autonomous ico (8th), Panama (6th), Paraguay (9th), United on the decision about the use of agrochemicals. Advances in knowledge of CKDu

This group should be better studied to inform - targeted policy actions. force during the harvest season on the preva- In Brazil, from the 1980s to 2006, the amount lenceThe ofimpact CKDnT of withinthe migration and between flow of countries. the work a sugarcane harvester cuts has increased from four tons to 12 tons a day (19). Payment is re- How can we move forward? ceived by amount harvested, and the increased Focus future studies in places most likely to demand of this work was appointed as the cause present the same type of working conditions as of death of 21 manual sugarcane harvesters at in Central America, and explore patterns of the work in the interior of São Paulo between 2004 distribution of CKD within regions of the coun- and 2007. Among them were young migrant tries to identify potential areas and occupations workers from other regions of the country, es- where the prevalence rates are higher in young- pecially from the Northeast (20,21). There are er ages. We need more information on migrant estimates from a study performed in the begin- workforce. ning and in the end of a harvest season with As pointed by recent analysis from PAHO, 28 healthy sugarcane workers in São Paulo, health statistics bureaus in countries in the Brazil. At the end of the daily shift of the sea- Region of the Americas are implementing in- son, all individuals presented a decrease of the formation systems to produce reliable, timely, - valid and accurate data. Several countries have mately 20%. 18.5% presented serum creatinine improved their systems in the last years, mainly increases.estimated glomerularThe changes filtration were associatedrate by approxi with regarding mortality. However, challenges re- increase of CPK and other biomarkers of renal main regarding morbidity and epidemiological surveillance. Health information systems need 36 oxidative stress and rhabdomyolisis (22). to be strengthened in the region, including pro- damage, systemic inflammation, dehydration, visions for a national registry of patients in di- Migrant workers alysis. In Costa Rica there seasonal workers fre- We need an agreed list of “suspected causes” quently come from Nicaragua for the sugarcane that would support the improvement of the ICD harvest activities (23). There are a number of 10 codes for CKD, including “associated causes” other studies showing that internal migrant workers are an important part of the workforce This would help standardize information, and in sugarcane plantations in São Paulo (20). It is that could also be used in death certificates. necessary to understand and take into consid- Referenceswould facilitate the identification of CKDnT. between countries or regions within a country 1. (PAHO (2015). Mortality Data. Available at: duringeration thethe harvestmigration season, flow ofwhen the searchingworkforce for to https://hiss.paho.org/pahosys/ ). possible areas with high concentration of cases 2. (PAHO (2015). Health Situation in the Amer- of CKDnT. icas. Basic Indicators, 2014 (accessed 24 March 2016). Available at: http://www.paho.org/hq/ What do we need to know? index.php?option=com_content&view=categor More attention should be given to the reasons y&layout=blog&id=2394&Itemid=239 for high rates of CKD of unknown etiology in 3. Harhay MN, Harhay MO, Coto-Yglesias F Bix- some of the countries in the Region. by LR. Altitude and regional gradients in chron- Prevalence studies have been recommended ic kidney disease prevalence in Costa Rica: Data to assess exposure to CKD risk factors and kid- from the Costa Rican Longevity and Healthy Ag- ney dysfunction in different occupations. ing Study. Tropical Medicine and International There is an urgent need to review the evidence Health volume 21 no 1 pp 41–51 January 2016 and quantify the health risks that payment-for- doi:10.1111/tmi.12622 production represent for the workforce. 4. Francis ER, Kuo C-C, Bernabe-Ortiz A, et al. Advances in knowledge of CKDu

Burden of chronic kidney disease in resource- bsson K, Lucas R, Wegman DH. The epidemic limited settings from Peru: a population- of chronic kidney disease of unknown etiol- based study. BMC Nephrology. 2015;16:114. ogy in Mesoamerica: a call for interdisciplin- doi:10.1186/s12882-015-0104-7. ary research and action. Am J Public Health. 5. Gómez RA. Renal Disease in Colombia. Re- 2013 Nov;103(11):1927-30. doi: 10.2105/ nal Failure, 2006; 28:643–647, AJPH.2013.301594. 6. Bianchi ME1, Farías EF, Bolaño J, Massari 15. McClean MA, Amador JJ, Laws R, et al. Bio- PU. Epidemiology of renal and cardiovascu- logical sampling report: Investigating biomark- lar risk factors in Toba Aborigines. Ren Fail. ers of kidney injury and chronic kidney disease 2006;28(8):665-70. among workers in Western Nicaragua. 2012, 7. Trujillo Z and Correa-Rotter R. What is Boston University School of Public Health: known about the Burden and Clinical Charac- Compliance Advisor Ombudman. Available at teristics of Mesoamerican Nephropathy? (this http://www.cao-ombudsman.org/documents/ volume). Biological_Sampling_Report_April_2012.pdf. 8. Gonzalez-Bedat1M, Rosa-Diez G, Pecoits- Accessed January 2, 2016) Filho1 R, Ferreiro A, García-García G, Cusumano 16. Wesseling C, Aragón A, González M, Weiss A, Fernandez-Cean J, Noboa O, and Douthat W. I, Glaser J, Rivard CJ, Roncal-Jiménez C, Correa- Burden of disease: prevalence and incidence of Rotter R, Johnson RJ. Heat stress, hydration, uric ESRD in Latin America. Clinical Nephrology, Vol. acid and Mesoamerican nephropathy: a cross- 83 – Suppl. 1/2015 (S3-S6) sectional study in workers of three occupations. 9. Sesso RC, Lopes AA, Saldanha Thomé F, Lu- Submitted. gon JR, dos Santos DR. Brazilian Chronic Dialy- 17. Peraza S, Wesseling C, Aragón A, et al. sis Survey 2013 - Trend analysis between 2011 Decreased kidney function among agricul- 37 and 2013. J Bras Nefrol 2014;36(4):476-481. ture workers in El Salvador. Am J Kidney Dis DOI: 10.5935/0101-2800.20140068 2012;59:531-40 10. Moura, L. D., Prestes, I. V., Duncan, B. B., 18. Vela XF, Henríquez DO, Zelaya SM, et al. Saldanha Thome F & Schmidt, M. I. (2014) (a). Chronic kidney disease and associated risk fac- tors in two Salvadoran farming communities, through the Brazilian National Health System, 2012. MEDICC Rev 2014;16:55-60 2000Dialysis to 2012. for end BMC stage Nephrology, renal disease 2014, 15:111 financed 19. Alves FJC. [Why are the sugar cane harvest- 11. Marinovich S, Lavorato C, Bisigniano L, Sor- ers dying?] Saúde Soc 2006; 15(3):90-98. atti C, Hansen Krogh D, Celia E, Fernández V, 20. Nunes da Silva AJ, Rodrigues Corrêa Filho H, - Gronau Luz V, Oikawa Zangirolani LT, Fontana gentino de Diálisis Crónica SAN-INCUCAI 2012. de Laat E, Oliveira Catanho da Silva F, Andrade SociedadTagliafichi Argentina V, Rosa Diez de Nefrología G, Fayad A: e InstitutoRegistro NaAr- Gouveia Vilela R, Migrant labor and wear-out cional Central Único Coordinador de Ablación e in Manual sugarcane harvesting in São Paulo, Implante. Buenos Aires, Argentina. 2013. Brazil . Ciência & Saúde Coletiva 2012172831- 12. Poblete Badal H. XXXII Cuenta de Hemodiáli- 2840. Available at: . http://www.redalyc.org/ sis Crónica (HDC) en Chile. Sociedad Chilena de articulo.oa?id=63024360030 Nefrología. Registro de Diálisis, 2012 (accessed 21. Laat EF, Vilela RAG, Silva AJN, Luz VG. [Im- 30 March 2016) Available at: http://www.fmc- pact over the worn conditions: physical wear of sugarcane cutters]. In: Impactos da Indústria 13. Moura, L. D., Prestes, I. V., Duncan, B. B., & Canavieira no Brasil. Rio de Janeiro: Plataforma Schmidt,ag.cl/_file/file_2_cuentahemodialisis2013.pdf M. I. (2014). Construção de base de da- BNDES; 2008. p. 36-46 dos nacional de pacientes em tratamento dialíti- 22. Paula Santos U, Zanetta DM, Terra-Filho M, co no Sistema Único de Saúde, 2000-2012. Epi- Burdmann EA. Burnt sugarcane harvesting is demiologia e Serviços de Saúde, 23(2), 227-238 associated with acute renal dysfunction. Kid- 14. Wesseling C, Crowe J, Hogstedt C, Jako- ney Int. 2015 Apr;87(4):792-9. doi: 10.1038/ Advances in knowledge of CKDu

ki.2014.306. Epub 2014 Sep 17. 23. Crowe J, Nilsson M, Kjellström T, Wesseling C. Heat-related symptoms in sugarcane harvest- ers. Am J Ind Med 2015;58:541-8. 24. Cordeiro AC, Carrero JJ, Qureshi AR, et al. Study of the incidence of dialysis in São Paulo, the largest Brazilian city. Clinics. 2013;68(6):760- 765. doi:10.6061/clinics/2013(06)06.

38 Advances in knowledge of CKDu

Epidemic of CINAC in Sri Lanka Prevalence The underlying cause of renal failure was not (CKD in Sri Lanka) renal clinic at Anuradhapura teaching hospital betweenidentified 2000 in 82% and of 2002 CKD [4]. patients The WHO seen atstudy the Channa Jayasumana, Faculty of Medicine, group reported age-standardized prevalence Rajarata University of Sri Lanka. of CINAC higher in women 16.9% (95% CI = 15.5%–18.3%) than in men 12.9% (95% CI = 11.5%– 14.4%), but noted that more advanced Introduction stages of CINAC were seen more frequently in - men (stage 3, men 23.2% and women 7.4%; crease in the Chronic Kidney disease (CKD) stage 4 men 22% and women 7.3%; p <0.001) casesDuring has thebeen last observed two decades, in the adry significant zone of Sriin [5]. Lanka, especially in the North Central Province (NCP). Two main climatic zones are recognized Clinical profile in Sri Lanka: the wet zone that occupies the The CINAC is a disease that progresses slow- South, West and Central regions, and the dry ly. Patients are asymptomatic during the early zone, which occupies North, North Central and stages of the disease. Athuraliya and others re- Eastern regions of the country (Figure 1). In the dry zone average annual rainfall is 1000–1500 (n=109) was essentially normal, except for the mm that mainly occurs during the Northeastern raisedported serum the symptom creatinine profile (2.51±2.06 of CKDu mg/dl) patients and monsoon period [1]. NCP is a major rice culti- small bilateral echogenic kidneys (mean rela- vation area where two districts, Anuradhapura tive bipolar length 5.36±0.91 cm). Urine sam- 39 and Polonnaruwa, contribute 19–23% of the to- ples had no active deposits, few having hyaline tal rice production of the country. This unusual or granular casts [6]. The disease is character- ized by tubular proteinuria (alpha-1 and beta- aged paddy farmers in Padaviya region in the 2 microglobulin) and high urine Neutrophil NCPCKD [2].was In first this reported epidemic in the 1994 etiology among of themiddle- CKD Gelatinase-associated Lipocalin (NGaL) levels was unknown. Therefore, initially the term CKD (>300 ng/mg creatinine/dL) [7]. Nanayakkara of unknown origin (CKDu) to identify these pa- and others showed urinary excretion of alpha-1 tients was used. However, and considering the microglobulin was elevated in CINAC patients at early stage indicating that renal tubular damage the disease is now named as Chronic Interstitial and tubular epithelial dysfunction occurs early Nephritisepidemiological in Agricultural and histopathological Communities (CINAC).findings, in CINAC [8]. Slow progression, minimum urine proteinuria without active sediment, bilateral small echogenic kidneys and long-standing hy- NCPTwenty with moreyears thanafter 69,000 the first estimated report, CINAC patients is pertension in the absence of diabetes strong- andthe mostmany significantdeaths [3]. public The disease health is issue spreading in the ly favor a tubulointerstitial disease. Another in epidemic scale to other adjacent farming ar- eas in the Eastern, North Western and Uva prov- acid levels (7.83±1.32 mg/dL) in CINAC pa- inces of Sri Lanka. The affected area covers one tientsstudy showswhen significantcompared elevationto healthy of individualsserum uric third of Sri Lanka’s landmass. Interestingly only (5.14±2.87 mg/dL) [9]. very few patients were reported from Northern province of Sri Lanka which shares similar soil, Diagnosis climate, agriculture and occupational patterns In 2009, the Ministry of Health (MoH) of Sri with CINAC endemic regions (Figure 2). Lanka introduced three criteria to differentiate CINAC from usual CKD [10]: a. No past history of, or current treatment for, Advances in knowledge of CKDu

diabetes mellitus or chronic and/or severe hy- pertension, history of snakebite, urological dis- ease of known etiology or glomerulonephritis. any evidence of interstitial inflammation. Stage b. Normal Glycosylated Hemoglobin level IIIII disease disease had had moderate moderate interstitial and severe fibrosis interstitial with or without mild interstitial inflammation. Stage c. tubular atrophy and some glomerulosclerosis. (HbA1C˂6.5%). - fibrosis, moderate interstitial inflammation, siveBlood agents. Pressure ˂160/100 mmHg untreated - orWanigasuriya ˂ 140/90 mmHg and onothers up to have two usedantihyperten different ulosclerosis.Stage IV disease They had show severe that interstitialinitial renal fibrosis injury criteria for their published research. They re- and inflammation, tubular atrophy and glomer- cruited patients with a serum creatinine greater cording to them, a possible explanation is tu- than 2 mg/dl with no obvious underlying cause isbule interstitial epithelial fibrosis injury without due to inflammation.chronic low dose Ac [11]. Athuraliya and others have used protein- exposure to environmental toxins. The other uria detected on two out of three time points, explanation is episodic exposure to high con- (during a period of 3-4 months in early-morn- centrations of toxins giving rise to acute tubu- ing clean-catch spot urine sample) by dipstick - tool [6]. The WHO study group used albumin– thermore,lo-interstitial they nephritis have demonstrated then healing the by progres fibrosis- and confirmed by heat testing as a screening- sionshowing of the progressive pathological interstitial features associated fibrosis. with Fur failing GFR and argued that initial renal injury identifycreatinine CKD ratio patients. ≥30 mg/g They creatininealso used MoH’s in an criini- occurs at a young age. Tubulointerstitial disease teriatial urine to distinguish sample, confirmed patients with at a repeatCINAC. visit, to 40 and complement-3 are in more favor of exclud- Histopathology ingwith an negative infectious immunofluorescence origin [6]. for IgG, IgM Findings have shown tubular interstitial ne- - Etiology tration, glomerular sclerosis and tubular atro- Wanigasuriya and others described that be- phyphritis [12]. associated Athuraliya with and mononuclear others carried cell out infil 26 ing a farmer (P < 0.001), using pesticides (P < - 0.001), drinking well water (P < 0.001) and in merular sclerosis, tubular atrophy and active P < 0.036), a family history of renal kidney biopsies and found renal fibrosis, glo dysfunction (P < 0.001), taking ayurvedic treat- [6]. A retrospective analysis of 211 renal biop- mentthe field in the ( past (P < 0.001) and past history siesinterstitial in asymptomatic space with CINAC inflammatory patients infiltraterevealed of snake bite (P < 0.001) were risk factors for early disease among asymptomatic patients is CINAC [11]. Athuraliya and others found age more than 60 years (OR = 3.5, 95% CI = 1.6 to 7.4), being a farmer (OR = 2.1, 95% CI = 1.4 to sclerosischaracterized and preserved by interstitial glomerular fibrosis function. without 3.3), family history of CKD (OR = 2.9, 95% CI = Absencesignificant of interstitial hypertension inflammation, associated glomerular vascular 1.2 to 7.2) and exposure to agrochemicals (OR = changes in the early stages of the disease makes 5.6, 95% CI = 2.3 to 13.2) were risk factors for hypertension an unlikely etiological agent. In CINAC. Further, they mentioned CKDu is unlike- late cases, hypertension is probably second- ly to be due to analgesic use as the patients were ary to advanced renal damage [13]. In another not on long-term analgesics [6]. Bandara and retrospective study of 251 renal biopsies, Wije- others found elevated dietary cadmium (Cd) - as a possible causative factor for the disease [15]. They reported high Cd content in lotus rhi- Lankatunga and[14]. others The predominanthave identified feature histopatholog of stage zomes, rice and tobacco, and concluded that the Iical disease features was of mildfirst fourand stagesmoderate of CINAC interstitial in Sri provisional tolerable weekly intake of Cd, based

fibrosis while most cases did not demonstrate on extreme exposure through rice and fish, was Advances in knowledge of CKDu high in the area. Meharg and others demon- malaria (P < 0.027) are factors that lead to the strated the cadmium content in rice samples of development of CKDu [20]. However, the effect Sri Lanka is high and only rice from Bangladesh of heat stress and chronic repeated dehydration had a higher content, when cadmium levels in on CINAC has not been systematically studied rice grains from 12 countries in four continents in Sri Lanka. In a cohort study done by Senevi- were compared [16]. The WHO research group rathna and others, it was pointed out that the pointed out risk for CINAC was increased in in- proportion of early stage CINAC was greater in dividuals aged more than 39 years and those the younger patient group (66% of stage 1 pa- engaged in vegetable cultivation (OR = 1.926, tients are less than 30 years), while higher pro- 95% CI = 1.561 to 2.376 and OR = 1.195, 95% CI portion of advanced CINAC (68.8% of stage 5 = 1.007 to 1.418 respectively, P < 0.05). Further, patients are more than 50 years) were seen in they showed pesticide residues were above the older groups [21]. In the same study, they have reference levels in 31.6% of those with CINAC. Detection frequency of 2,4-D, 3,5,6-trichloro- disease progression. A study done in Padaviya pyridinol, p-nitrophenol, 1-naphthol, 2-naph- andidentified Medawacchchiya hypertension showed as the that main the factor major for- thol, glyphosate, and AMPA was 33%, 70%, ity of CINAC affected villages are located down- 58%, 100%, 100%, 65% and 28% respectively stream, far away from the reservoirs and irriga- [5]. They have also shown mean concentration tion canals [22]. Certain compounds present in ground water and soil in the disease endemic area have been controlsof Cadmium in the in endemicurine was and significantly non- endemic higher areas in postulated as possible etiological factors for those with CINACP (1.039 μg/g) comparedP <0.05) with CINAC. Chandrajith and others hypothesized el- - - 41 fect(0.646 relationship μg/g, <0.001 (P < and0.05) 0.345 between μg/g, the urine tain areas in Sri Lanka could be associated with Cdrespectively. concentration They and found stage a of significant the chronic dose-ef renal increasingevated levels prevalence of fluoride of in CINAC ground [23]. water Jayaward in cer- - ana and others revealed that the number of tion, USA. In the same study, authors reported CINAC patients is high in places where elevated urinefailure concentrations as defined by of National Selenium Kidney is low Foundain CKDu concentrations of soil vanadium were observed patients [5]. [24]. Further, they recorded vanadium levels in Jayasumana and others have shown that the nonagricultural soils of CKD-reported sites are CINAC epidemic among farmers in the dry zone of Sri Lanka is associated with drinking well wa- level recommended for soil (200 mg/kg). ter, with history of drinking water from a well significantlyDharma-wardana exceeding and theothers maximum in 2014 presentedthreshold that was abandoned and with spraying glypho- a new hypothesis based on “increased ionicity of drinking water due to fertilizer runoff into the riv- comprehensive hypothesis to explain the occur- er system, redox processes in the soil and features saterence in of paddy the disease. fields [17]. According They also to thisdeveloped hypoth a- of ‘tank’- cascades and aquifers. The consequent esis chemical nephrotoxicity due to herbicides, chronic exposure to high ionicity in drinking wa- herbicide surfactants, heavy metals, high ico- ter is proposed to debilitate the kidney via a Hof- nicity of the ground water and chronic repeated meister-type (protein-denaturing) mechanism” dehydration are the culprits of the epidemic [25]. [18,19]. Siriwardhana and others have shown Ocharatoxin A, a naturally occurring fungal in a study done in Medawachchiya, a CKDu en- toxin was also speculated as an etiological agent demic area in NCP, that working for more than for CINAC in Sri Lanka. However, a study showed P it is a natural contaminant of cereals and pulses < 0.003), drinking water only from well (P < cultivated in CINAC endemic area, and the levels 0.006),six hours consumption in the field ofper less day than under three the liters sun (of detected were below the toxic limits [26]. Dis- water per day (P < 0.04), and having a history of

sanayake and others identified cyanobacterial Advances in knowledge of CKDu

toxin as a potential nephrotoxin in the CINAC high-risk population and affected areas. endemic areas [27]. Nevertheless, contamina- · Promote collaborative basic and clinical re- tion of ground water in shallow wells and tube search in order to understand the pathogenesis wells by cyanobacterial toxin has not been re- of CINAC and identify protective strategies pre- ported yet. vents its development and slows the progres- sion. susceptibility as a risk factor for CINAC by using a genome-wideNanayakkara association and others study identified (GWAS) genetic [28]. References 1. Climate in Sri Lanka [Internet]. [cited 2014 association with CINAC for a single nucleotide Nov 25]. Available from: http://www.meteo. polymorphismThe GWAS yielded (SNP; a genome-widers6066043; p significant=5.23×10 gov.lk/index.php?option=com_content&view=a in quantitative trait locus analysis; p=3.73×10 rticle&id=106&Itemid=81& in dichotomous analysis) in SLC13A3 (sodium- 2. Jayasumana M, Paranagama P, Amarasinghe dependent dicarboxylate transporter member M, Wijewardane K, Dahanayake K, Fonseka S, et 3). For this SNP, population attributable fraction al. Possible link of Chronic arsenic toxicity with was 50% and odds ratio was 2.13. Chronic Kidney Disease of unknown etiology in The differences in the incidence of CKD among Sri Lanka. 2013;3(1):64–73. patients exposed to similar environmental con- 3. Data presented at the presidential taskforce ditions and risk factors suggest that a singu- for prevention of kidney diseases 06.06.2014 lar risk factor is unlikely to be responsible for Colombo Sri Lanka. Ministry of Health, Sri Lan- CINAC. It is more likely that an interaction be- ka. :2014. tween the proposed risk factors could contrib- 4. Athuraliya T, Abeysekera D, Amerasinghe 42 ute to the eventual development of the disease. P, Kumarasiri P, Dissanayake V. Prevalence of chronic kidney disease in two tertiary care hos- Prevention pitals: high proportion of cases with uncertain CINAC is a multifarious issue requiring multi- aetiology. Ceylon Med J. 2009 Apr 21;54(1):23–5. pronged, short, medium and long-term ap- 5. Jayatilake N, Mendis S, Maheepala P, Mehta proaches. The search for solutions to CINAC must FR. Chronic kidney disease of uncertain aetiol- go beyond the bio-medical model. As CINAC is an ogy: prevalence and causative factors in a devel- irreversible disease, identifying and implement- oping country. BMC Nephrol. BMC Nephrology; ing all the known strategies to slow down the 2013 Jan;14(1):180. progression is mandatory. The author recom- 6. Athuraliya NTC, Abeysekera TDJ, Ameras- mends the following measures to protect at risk inghe PH, Kumarasiri R, Bandara P, Karunara- populations: tne U, et al. Uncertain etiologies of protein- · Social and political measures to guarantee uric-chronic kidney disease in rural Sri Lanka. nephrotoxin-free drinking water and ensure Kidney Int. 2011 Dec;80(11):1212–21. adequate hydration 7. Jayasumana C. Sri Lankan Agricultural Ne- · Minimize the usage of glyphosate base herbi- phropathy. International workshop on Chronic cides and phosphate fertilizers. kidney disease of nontraditional causes. San · Minimize the usage of sugar and sugary Salvador: National Instiute of Health, El Salva- drinks by farmers. dor; 2012 Nov 27. · Promote cultivation and sale of traditional 8. Nanayakkara S, Senevirathna STMLD, Ka- varieties of rice, vegetables and fruits, which are runaratne U, Chandrajith R, Harada KH, Hitomi less dependent on agrochemicals. T, et al. Evidence of tubular damage in the very · Develop a screening method based on early early stage of chronic kidney disease of uncer- proximal tubular damage markers and extend tain etiology in the North Central Province of Sri community CINAC screening to detect early Lanka: a cross-sectional study. Environ Health loss in renal function and to better characterize Prev Med. 2012 Mar;17(2):109–17. Advances in knowledge of CKDu

9. Jayasumana C. PhD thesis, Rajarata Univer- als: Are they the culprits behind the epidemic of sity of Sri Lanka. 2015 chronic kidney disease of unknown etiology in 10. Ministry of Health SL. Chronic Kidney Dis- Sri Lanka? Int J Environ Res Public Health 2014, ease of Unknown Etiology, Circular no 01- 11:2125-47 10/2009. 2009. 19. Jayasumana MACS, Gunatilake S, Siribad- 11. Wanigasuriya KP, Peiris-john RJ, Wickrema- dana SH. Simultaneous Exposure to Multiple singhe R, Hittarage A. Chronic renal failure in Heavy Metals and Glyphosate May Contribute to - Sri Lankan Agricultural Nephropathy. BMC Ne- ronmentally induced disease. Trans R Soc Trop phrology 2015;16:103. MedNorth Hygine. Central 2007;101:1013–7. Province of Sri Lanka : an envi 20. Siriwardhana EARIE, Perera PAJ, Sivakane- 12. Nanayakkara S, Komiya T, Ratnatunga N, san R, Abeysekara T, Nugegoda DB. Dehydration Senevirathna STMLD, Harada KH, Hitomi T, et and malaria in augmenting the risk of develop- al. Tubulointerstitial damage as the major path- ing chronic kidney disease in Sri Lanka. Indian ological lesion in endemic chronic kidney dis- J Nephrol [Internet]. 2014;1–6. Available from: ease among farmers in North Central Province http://www.indianjnephrol.org/preprintarti- of Sri Lanka. Environ Health Prev Med. 2012 cle.asp?id=140712 May;17(3):213–21. 21. Senevirathna L, Abeysekera T, Nanayakkara 13. Wijetunge S, Ratnatunga NVI, Abeysekera S, Chandrajith R, Ratnatunga N, Harada KH, et DTDJ, Wazil AWM, Selvarajah M, Ratnatunga CN. al. Risk factors associated with disease progres- Retrospective analysis of renal histology in as- sion and mortality in chronic kidney disease of ymptomatic patients with probable chronic kid- uncertain etiology: a cohort study in Medawach- ney disease of unknown aetiology in Sri Lanka. chiya, Sri Lanka. Environ Health Prev Med. 2012 Ceylon Med J. 2013;2(September):142–7. May;17(3):191–8. 43 14. Wijetunge S, Ratnatunga NVI, Abeysekera 22. Jayasekara JMKB, Dissanayake DM, Ad- TDJ, Wazil AWM, Selvarajah M. Endemic chronic hikari SB, Bandara P. Geographical distribution kidney disease of unknown etiology in Sri Lan- of chronic kidney disease of unknown origin in - North Central Region of Sri Lanka. Ceylon Med J. es. Indian J Nephrol. 2014;24 (6):1–7. 2012;3(November):6–10. 15.ka : BandaraCorrelation JMRS, of pathology Senevirathna with clinical DMAN, stag 23. Chandrajith R, Nanayakkara S, Itai K, Atu- Dasanayake DMRSB, Herath V, Bandara JMRP, raliya TNC, Dissanayake CB, Abeysekera T, et al. Abeysekara T, et al. Chronic renal failure among Chronic kidney diseases of uncertain etiology farm families in cascade irrigation systems in (CKDue) in Sri Lanka: geographic distribution Sri Lanka associated with elevated dietary cad- and environmental implications. Environ Geo- chem Health. 2011 Jun;33(3):267–78. Environ Geochem Health. 2008 Oct;30(5):465– 24. Jayawardana DT, Pitawala HMTGA, Ishiga 78.mium levels in rice and freshwater fish (Tilapia). H. Geochemical evidence for the accumulation 16. Meharg A, Norton G, Deacon C, Williams P, of vanadium in soils of chronic kidney disease Adomako EE, Price A, et al. Variation in rice cad- areas in Sri Lanka. Environ Earth Sci. 2014 Oct mium related to human exposure. Environ Sci 29; DOI 10.1007/s12665-014-3796-2 Technol. 2013 Jun 4;47(11):5613–8. 25. Dharma-Wardana MWC, Amarasiri SL, Dhar- 17. Jayasumana C, Paranagama P, Agampodi S, mawardene N, Panabokke CR. Chronic kidney Wijewardane C, Gunatilake S, Siribaddana S. disease of unknown aetiology and ground-wa- Drinking well water and occupational exposure ter ionicity: study based on Sri Lanka. Environ to Herbicides is associated with chronic kidney Geochem Health. 2014 Aug 14; DOI 10.1007/ disease, in Padavi-Sripura, Sri Lanka. Environ- s10653-014-9641-4 mental Health. 2015; 14:6. 26. Wanigasuriya KP, Peiris H, Ileperuma N, 18. Jayasumana C, Gunatilake S, Senanayake P. Peiris-John RJ, Wickremasinghe R. Could och- Glyphosate, hard water and nephrotoxic met- ratoxin A in food commodities be the cause of Advances in knowledge of CKDu

chronic kidney disease in Sri Lanka? Trans R Soc 28. Nanayakkara S, Senevirathna S, Abeysekera Trop Med Hyg. 2008 Jul;102(7):726–8. T, Chandrajith R, Ratnatunga N, Gunarathne E, 27. Dissananyake DM, JM J, Ratnayake P, Wick- et al. An Integrative Study of the Genetic, Social ramasinghe W, YA R. The Short Term Effect of and Environmental Determinants of Chronic Cyanobacterial Toxin Extracts on Mice Kidney. Kidney Disease Characterized by Tubulointer- Peradeniya University Research Sessions. Per- stitial Damages in the North Central Region of adeniya: University of Peradeniya; 2011. p. 13. Sri Lanka. J Occup Health. 2014;56(1):28–38.

44

Figure 1. Climatic Zones of Sri Lanka Figure 2. Geographical distribution of CINAC in Sri Lanka (Northern province is encircled) Advances in knowledge of CKDu

are not yet conclusive but strongly suggest Interventions, regulations and known occupational causes, aggravating envi- response of health care systems in ronmental factors, and social inequities, empha- Central America sizing the multi-causal etiology of the disease (1). While research teams continue to conduct studies about exposures to factors that seem to cause the kidney damage, countries have issued Julietta Rodriguez Guzman, PAHO/WHO. public health policies to address the problem, and health systems have led actions to detect and provide treatment when possible and to Introduction mitigate the consequences of CKDu. One inter- The high incidence, prevalence and mortality vention aiming to control hazardous and pre- rates of Chronic Kidney Disease from Non-tradi- carious working conditions has been piloted in tional Causes (CKDu) in Central America, have an effort to document effectiveness and develop increasingly been reported in underprivileged improved work practices for the long term (5). populations during the last two decades (1), af- This article addresses the interventions, regula- fecting agricultural communities where poverty tions and responses of the healthcare sector at and working opportunities are limited. The em- sub-regional, regional and country levels to mit- ployment choices available in agricultural jobs igate and control the epidemics; address social occur in precarious working conditions and in- gaps and propose some policy recommenda- equitable employment conditions. The majority tions aiming to control the devastating human, of workers affected with CKDu are young men social and economic effects of the epidemic. ages 18 to 35, farm workers, immigrants, and 45 Political willingness translated coast of Mesoamerica (2). Recent research has to policies and agreements seasonalalso shown workers, early participation concentrated of inchildren the Pacific and addressing adolescents in the workforce ( ), as a conse- 3 the epidemic quence of the sugarcane monoculture, the en- demic poverty in the region, and the need to al- To better understand the breadth and the commitment of policy and decision makers death of a parent or family member caused by at sub-regional, regional and national levels, a CKDu.leviate These financial youth pressures are even often more resulting susceptible from to description of the actions carried out at these work under hazardous conditions, with low pay, three levels follows. and long hours, and uncertainty for their future (4). The high demand for tertiary level clinical a) Sub-regional level healthcare services, - nephrology services of- The regional health sector of Central America fering dialysis, hemodialysis and kidney trans- and Dominican Republic has a long standing plants -, has become a challenge for health care history of integrative efforts through the systems operating in the affected countries. creation of several political and governmental This burden on health systems with limited re- bodies: The Central American Integration sources has jeopardized the capacity to respond System (SICA3), the Council of Ministers of as well as the health and lives of the affected Health from Central America and the Dominican workers. Altogether, CKDu adds social and eco- Republic (COMISCA3), and the Executive nomic burdens to their families, communities, Secretariat for the COMISCA (SE-COMISCA3). health systems, and society as a whole (1,2). During the past decades these bodies have Etiologic studies done during the last decade designed and followed-up regional policies

1. From its name in Spanish Advances in knowledge of CKDu

Table 1. Sub-regional policy instruments of the health sector.

Year Policy instrument

Health Agenda for Central America and Dominican Republic; and, Health Plan for Central America and 2009 Dominican Republic (HPCA&DR), 2010-2015

2012 Preliminary mid-term report of the HPCA&DR, 2010-2015 2013 Amendments to the HPCA&DR, 2010-2015 2014 SICA Regional Health Policy 2015-2022 issued in 2014 2015 End-term report of the HPCA&DR, 2010-2015 New Health Plan for Central America and Dominican Republic 2016-2020 was issued in December 2015 2016 during the XLIII Meeting of the COMISCA

Source: Adapted from: Peña, R. Perspectiva de la CT con el SICA. Reunión inter-programática de OPS sobre Enfer- medad renal crónica de las comunidades agrícolas de Centroamérica. Managua, Nicaragua, September, 2015.

46 Figure 1. Operative model of the regional political framework

Source: Pena, R. Perspectiva de la CT con el SICA. Reunión inter-programática de OPS sobre Enfermedad renal crónica de las comunidades agrícolas de Centroamérica. Managua, Nicaragua, September, 2015. Advances in knowledge of CKDu

Figure 2. Operative components and cross-cutting themes

Source: Pena, R. Perspectiva de la CT con el SICA. Reunión inter-programática de OPS sobre Enfermedad renal crónica de las comunidades agrícolas de Centroamérica.

47 aimed to improve people’s lives and wellbeing in Figure 3. Advances in the implementation of the region. SICA advanced in building capacity, Agreement No. 2 of the XXX RESCAD 2014 organizing technical and functional structures, and developing political agendas addressed to

legal frameworks were developed to organize plans,specific strategies economic andsectors. agreements. In the case Therefore, of health, based on the Agenda of the Americas 2008-2017 (6), they developed several policy instruments for strengthening regional and national public health policies (7), as seen in Table 1. However, policy instruments to assemble and coordinate all the regional efforts for effective public regional management were still needed. Thus, SICA issued the Regional Health Policy 2015-2022, that was approved during the Summit of Chiefs of States in December 2014. It serves as a political instrument that Source: RESSCAD XXXI, Tegucigalpa, Honduras, guides and allows active regional integration, October, 2015. through strengthening national actions and solving regional processes with an inter-

actions to be developed at a regional level for complementingsectorial approach. national It also defines competencies governmental and responsibilities. It is based on a public health Advances in knowledge of CKDu

approach to achieving equity in health, addressing to carry out preventive and inter-sectorial ac- tions upon traditional and non-traditional risks gaps of the unfair and preventable health that could contribute to the origin and develop- differencessocial determinants observed ofin health,the health and situation filling the of ment of the disease. Emphasis was placed on the countries belonging to the region, with the the need to start individual and population in- (8). terventions immediately to prevent CKDu even In the Regional Health Policy 2015-2022, health inequitiesfinal purpose are ofaddressed improving based people’s on the health regional commission was created to address CKD led by political framework, inter-sectorial actions in theif etiology National is institute not yet fullyof Health, defined. of the Also, Ministry a sub- response to the situation analyses, political of health of El Salvador, in close cooperation with relevance of the topics, and opportunities for PAHO, CDC and SE-COMISCA (10). This way, all international technical cooperation. They aim agreements of COMISCA, RESSCAD and country to closing the gap of inequities in health, as efforts could lead to capacity building, and devel- shown in Figure 1. Each inter-sectorial setting oping actions to minimize and control the CKDu depicts operative components that include epidemics, as a sub-regional health priority. actions on environmental and occupational On October 2015, during the XXXI RESSCAD health, addressing social and environmental in Honduras, the balance of achievements on determinants of health; and, cross-cutting Agreement No. 2 showed that all countries topics that include human rights related to were interested in starting a research agenda health, as shown in Figure 2. With this public to characterize CKDu although the represented health policy, SICA envisions supporting countries had advanced at different levels; that regional interventions and regulations for the some countries had taken regulatory measures 48 time period 2015-2019. to control the disease; others had built capacity The Meeting of the Health Sector of Central and developed clinical protocols for providing America and Dominican Republic (RESSCAD1) comprehensive healthcare services to workers is a political forum of SICA that analyzes health and some regulations were issued too. Achieve- problems, coordinates actions to build regional ments between countries varied, with differ- policies, and promotes the exchange and de- ences ranging between 25 to 75% of completed velopment of experience and knowledge about actions, and an average of 61% as illustrated in common health problems. RESSCAD supports (11). and consolidates monitoring and assessment In December 2015, during the XLIII meeting processes carried out for complying with the offigure COMISCA, No. 3 the Health Action Plan for Central agreements done by Member States. However, it America and Dominican Republic 2016-2020 does not have enforcement capacity. It promotes was approved and launched. It contains a line of strategic alliances and supports searching for Action on Non-Communicable Diseases which will address CKD in general, but there is no spe- and solve health priorities under the integrated frameworktechnical and of financialSICA. It aims cooperation to using tobetter address the resources in each particular country and for the B)cific Regional mention of CKDulevel: (12). region, seeking for a better life quality for the The Directive Council of the Pan American population, and strengthening development for Health Organization (PAHO) recognized, in 2013, the health sector and the environment (9). that CKDu affecting agricultural communities During the XXX RESSCAD held in 2014, coun- in Central America was a serious public health tries recognized the complexity of the social problem that required urgent, effective, and determinants for CKDu, the need to close the concerted multi-sectorial actions. This decision gaps, strengthen healthcare systems, and to train was made in response to a call for action from the healthcare personnel. In Agreement No. 2, coun- Minister of Health of El Salvador, during PAHO’s tries committed to act with their health systems 52nd Directing Council (1). Consequently, PAHO Advances in knowledge of CKDu organized an inter-programmatic working group published many of their study results, includ- that includes staff members from different ing the Consortium for Nephropathy in Central departments involved in health services, health America and Mexico (CENCAM) (14). analysis, sustainable development and research e. Protocols for implementing preventive inter- at headquarters along with PAHO representatives ventions on occupational and environmental of each of the Central American countries. health are currently on going in El Salvador with The working group has focused on providing (NIOSH/CDC, IRET) the support of PAHO’s Col- technical assistance and support to the countries, laborating Centers on Occupational and Envi- and coordinating activities with different ronmental Health, employing recommendations stakeholders, namely delegates of the Ministries from the US Occupational Safety and Health Ad- of Health of the countries (Costa Rica, El Salvador, ministration (OSHA) regarding strenuous work Guatemala, Honduras, Nicaragua and Panama), professional medical societies (Latin American promising although further validation of inter- Society of Nephrology and Hypertension), SE- ventionsin hot climates. such as The Water. first Rest.Shade round of andresults Work seem Ef- COMISCA, and PAHO collaborating centers on ficiency will continue to be tested in 2016 (5). epidemiology, health analysis, and occupational f. PAHO set up and implemented an on-line and environmental health4. course on diagnosis, treatment and prevention Activities carried out at the regional level dur- of acute pesticide poisonings (15). ing the last two years were reported during the g. Advances in incorporating comprehensive 52nd Directive Council, September 2015(2), and care for CKD in health services, such as clinical can be summarized as follows: guidelines at a primary level of care, updating a. national standards, and developing preventive case of CKDu, epidemiological case and several and comprehensive care of CKD with emphasis 49 mechanisms Preparation for of improving a set definitions epidemiological for: clinical sur- on primary health care (PHC). El Salvador and veillance. The paper is still under discussion for Nicaragua established legal and regulatory reaching a consensus with all countries and all in- frameworks for organ and tissue donation and terested sub-regional parties, with support from transplantation. CDC, the Latin American Society of Nephrology h. PAHO reviewed essential drugs and technolo- and Hypertension (SLANH), SE-COMISCA and gies for CKD treatment with their possible in- delegates from member States; b. Improvement of CKD mortality statistics with Strategic Fund, although countries have not used the help of PAHO’s Latin American and Caribbean it.clusion PAHO in also the reviewed list of qualifications efforts to improve for the accessPAHO Network for Strengthening Information Systems and coverage of transplants as treatment for CKD. for Health (RELACSIS, from its name in Spanish); 1. PAHO recently issued the Action Plan on c. Countries and research groups incorporated Workers Health 2015-2015 CD52/10 Rev.1, CKDu in their research agendas, and carried out in which countries committed to strength- and published descriptive and analytical stud- en diagnostic capacity, information systems, ies (13, 14). epidemiological surveillance, and research d. Conducting a Delphi Survey to determine in the field of occupational diseases, injuries, and deaths. They aim to establish national Research Agenda for CKDu. This activity is cur- research agendas to determine working rentlyresearch ongoing, priorities, despite aiming the to fact define that a manyRegional ef- and employment conditions and related in- forts have been done by the countries and re- equalities; and generate practical solutions, search groups who have conducted studies and knowledge, and evidence for decision and

2. Regional Institute for study of Toxic substances (IRET from its name in Spanish), Costa Rica; the National Institute of Public health of Quebec (NIPH), Canada; and the US Centers of Disease Control and Prevention (CDC), and the National Institute on Oc- cupational Safety and Health (NIOSH). Advances in knowledge of CKDu

policy makers - Later, the Minister of Health of El Salvador pre- cator to tackle the epidemic was included sented the CKDu problems to the COMISCA and for having countries. In this develop sense, interventiona specific indi or SICA forums, and to the Pan American Sanitary action protocols to minimize the occurrence Conference, at the meetings of the Group of the of CKDu in Central America (16). Americas during the 2011 World Health Assem- i. Finally, a policy framework addressing the bly, and at preparatory meetings for the Region occupational nature of CKDu is under construc- of the Americas prior to the United Nations Gen- tion, also considering aggravating environ- eral Assembly High-level Meeting on Non-com- mental and social factors that enhance the oc- municable Diseases in 2011 (19). currence of CKDu. This is another reason why Member States belonging to SICA and COMISCA PAHO has prioritized actions to strengthen attended the “High-level Meeting on Chronic Kid- occupational and environmental health in the ney Disease from Non-traditional Causes () in Cen- countries involved to minimize or mitigate haz- tral America” in April 2013(20). They discussed ardous exposures, and prevent the disease. the gaps and challenges they had for addressing the clinical burdens of and the ways to prevent C) National policies and it, and issued the “Declaration of San Salvador” it regulations issued by countries - The countries affected by CKDu have been cant public health problem that required urgent addressing the problem with different levels of which they recognized that the disease is a signifi - the fact that it mainly affected agricultural com- tional action plans. Some have undertaken poli- munities;action. They described proposed it as a definitiona catastrophic highlighting disease cypublic actions policy based definitions, on existing national regulations and interna includ- and a major health problem. As a consequence, 50 ed in their Constitutional mandates, healthcare the member states committed to organize and systems, social security systems, sanitary and mobilize inter-sectorial resources needed at na- labor codes, environmental health regulations, tional and regional levels to control it (21). and occupational health and safety regulations. Following the agreements and policy man- In particular, those pertaining to occupation- dates of the health ministers and the PAHO al health and safety such as labor codes, OSH mandates aforementioned, countries have as- guidelines, Lists of Occupational Diseases, etc., sembled task forces and designed national ac- proved to be outdated and need to be brought tion plans, identifying their gaps and challenges to address the epidemics. While most countries decade (17, 18). During the last 10 years some focused on issuing regulations and strengthen- countriesup to date (Costa from the Rica, beginning El Salvador) of the did first update 2000 ing health systems, statistics and clinical ser- several regulations, and others have recently vices to increase the responsiveness of clinical advanced in a similar way (Guatemala and Nica- services for treatment of CKDu (dialysis), some ragua). However, structural limitations dealing countries issued regulations and organized na- with human resources, capacity building and tional action plans to address and control prob- enforcement of regulations for workers’ health able hazardous exposures and working condi- remain to be achieved. tions causing kidney damage. The Ministries of Health have taken actions Based on the reports made by SALTRA and to create awareness about CKDu, and triggered others gathered by PAHO’s inter-programmatic actions at national and international levels. The working group for following-up and providing technical assistance to the countries affected who called upon the needs for public health in- by the epidemics, Table No. 2 summarizes the tervention,first country and to raiseat the the end issue of 2009,was El requested Salvador, recent policy advances related to regulations, technical cooperation from PAHO to address national plans, comprehensive healthcare the disease that had been widely documented systems, research and major challenges to be in previous research and technical reports (5). addressed (18, 22, 23). Advances in knowledge of CKDu

Table 2. Summary of advances in policy and regulations, national plans, health services and challenges of countries affected by CKDu.

Country Regulations National Plans Healthcare Research Challenges services

Costa Rica Decree for National Council Costa Rican Social Survey done by Compliance protection and on Occupational Security Institution CCSS on CKD. of protective rehydration Health with MoH building measures and of persons discussing CKDu capacities to SALTRA/IRET in insurance for exposed to high register & follow- the Secretariat of workers. temperaturewas up CKDu cases CENCAM. issued. (on-line reporting), Having a and providing national dialysis services, program on institutional and occupational home services health to address CKDu.

El Salvador Regulations on • National Integrated National National OHS up-dated Research preventive and studies trying research agenda in 2004. Program for healthcare approach to determine on genetics, 51 CKD/CKDu, for CKD/CKDu. CKDu causes congenital Issued Diabetes with national disease and regulation Mellitus, Strengthening PHC and international cancer within forbidding High Blood services. research groups. people with 53 active Pressure, CVD, CKDu. ingredients of Obesity and Increase # of Registries of pesticides risk factors in nephrologists. CKDu cases and Intervention and the Salvadorian mortality. cost research. population Registry of Dialyses & Registry on Registries of transplants. dialysis. CKDu cases

Improve diagnostic Lab technologies. developments.

Implementation of Strengthening the Nefro Lempa national policies project (3 levels on OHS and of services) with toxicology PAHO, the Cuban National Institute of Nephrology and the Spanish AECID. Advances in knowledge of CKDu

Country Regulations National Plans Healthcare Research Challenges services

Guatemala Government Action Plan for Aiming to increase Participated in Implementation approved non-communi- coverage, access several regional and coordina- Agreement cable disease and quality studies with tion with PAHO No. 229-2014: (NCD) in Guate- of healthcare the support of to advance in National Regu- mala. services: the Guatema- the pending lation on Labor . Guidelines for lan Society of agenda Health and National Strate- addressing CKD Nephrology, Safety that gic Plan on Occu- & CKDu and SALTRA. includes issues pational Health. Lack of funding for preventing for medication, Needs to estab- CKD. Protocols for dialysis and trans- lish national re- epidemiologic plants. Follow- search agenda Regulation un- surveillance for up is being done der construc- CKD and CKDu through COMISCA tion modifying were revised and and RESSCAD management updated. of domestic pesticides.

52 Honduras National Regu- Template for MoH: establish- Secretary of Strengthening lation: Renal registering CKD ment of a Unit for Health: has 15 healthcare fa- Decree 200, for revision of Data Management research stra- cilities, informa- 2013, to guar- Nephrologists. to register patients tegic lines, one tion systems, antee dialysis under hemodialysis for NCDs that funding and processes, National Plan for in 2 cities. includes CKD. new healthcare improvement Water Safety. model. of healthcare Services provided Protocol to facilities, and Decree to “Acti- by the Honduran characterize Defining CKD re- special support vate Honduras” Institute of Social CKD in Hon- search agenda. services for for addressing Security (>14,892 duras is under patients. NCDs. 1st trimester 2015). construction. Inter-sectorial approach to ad- Coming: Law Research agenda U. of Kentucky: dress risk factors for Social on NCDs includes brigades for kidney and SDH. protection CKD. transplants. and National Health system Medications avail- able.

Sources: Carmenate Milian, L, et al. SALTRA 2014 (17) PAHO (2014) Country reports on advances for implementa- tion of PAHO Resolution CD52/8 (21). PAHO (2015) Country reports presented during PAHO’s Inter-programmatic meeting on CKDu, Managua, Nicaragua, September, 2015 (23). Advances in knowledge of CKDu

Country Regulations National Plans Healthcare Research Challenges services

Nicaragua Law No. 456: 2013: Working Law to donate and National stud- Patient associa- “Additional group for elabo- transplant organs, ies trying to tions in need of risks and oc- rating the Na- tissues and cells. determine social and emo- cupational tional Strategic Issued 9 October causes of CKDu tional support. diseases”. Plan for Kidney 2013. with national Health in Nicara- and interna- Improving oc- Law No. 185, gua. Text under Limited installed tional research cupational & “Labor Code “, revision. capacities for he- groups. environmental issued 15 June modialysis. policies and 2004, added Hosted recent regulations. Chronic kidney Medical education Latin American failure in Art. in nephrology is Congress of Ne- Cost analyses 111. required. phrology where is needed to advances on estimate in- MoU with the Lo- the prevalence vestments ad- cal health system and character- equately. of Chinandega to ization of the strengthen ser- disease were vices. brought by several research 53 groups.

Panama Executive de- National plan of Participation in Panamanian Advancing in cree No. 1510, NCDs included several workshops Nephrology As- pesticide ap- issued on Sep- surveillance of for surveillance sociation with plication and tember 2014, pesticides as a on CKDu in 2013, PAHO, UNEP, control established risk factor for and registration of INCAP, MoH National Stra- CKD. dialyses and trans- and The Pana- Proposal for tegic Plan for plants in 2014. ma University next RESSCAD: NCDs. 2011: National developed a to control pes- Plan of kidney Moving towards study about ticide applica- 2013: Interna- Health. Pilot expanding clinical risk of pesti- tions. tional meeting project in Coclé, healthcare service cides, mycotox- with COMISCA with early detec- for early detection ins and metals Implement sur- countries to tion of CKD yield and treatment of for CKD. veillance system develop a road decreased wait- CKD. for NCDs includ- map for CKD ing times, and Diagnosis of ing CKD, dialysis research. increased capac- CKD and risk and transplant ity building. To factors in Coclé registries. 2015: restric- be replicated in province, Pana- tions for ap- other parts of ma, 2014. Expand kidney plication of the country. clinics. pesticides. Strengthening OHS Advances in knowledge of CKDu

Conclusions strengthening occupational and environmental 1. Regional, sub-regional and national politi- health policies, regulations and programs will cal levels recognize that CKDu is a major public contribute to preventing or mitigating the con- health problem that needs multi-sectorial in- sequences of CKDu and to clarify its etiology. terventions to understand the dynamics of the 6. All countries need to build capacity both for disease, timely detection of workers at risk, and healthcare systems and occupational and envi- prevention and/or minimizing on-set of CKD. ronmental health teams, since actions carried 2. Strong political willingness at all decision out until now have not stopped the epidemics. Prevention should be enhanced at the work- advances shown in both the RESSCAD follow-up place to avoid increase in the number of cases. andlevels the to addressPAHO inter-programmatic the epidemic is reflected follow-up. in the 7. Evidence from research teams indicate a Nonetheless, information gaps about the mag- strong need to close other gaps such as those nitude and extension of the disease, as well as caused by the inequities of employment. Thus, actions to be taken by labor and agricultural still persist. Hence, efforts must continue at all authorities with a multi-sectorial approach. decisionabout efficacy levels ofin policythe affected and actions countries undertaken to deter- Research results supporting public workers’ mine the magnitude of the population affected, health and labor policies to improve these situ- implement effective preventive measures, and ations are strongly recommended. assess the impact of the clinical and preventive 8. Technical cooperation from regional and sub- interventions carried out until now. regional bodies play a key role to advance the 3. Regulations about health care systems, statis- settlement of research agendas, preventive in- tics and occupational and environmental health terventions and, lately, stop the epidemics. 54 - tween countries. This remains a challenge to be The way forward addressedservices seem by the to have countries significant at sub-regional differences level be 1. In response to the needs of the countries to for providing reliable data that can be utilized address the CKDu epidemics, the PAHO working by decision makers. group moves towards having a complete inter- 4. PAHO working inter-programmatic group programmatic project that will provide techni- agreed that despite the fact that etiologic stud- cal assistance to build capacity for comprehen- ies are not yet conclusive, evidence gathered sive health services that include: until now strongly suggest the occupational · Workers’ health promotion character of the disease, probably aggravated · Preventive occupational and environmen- by environmental factors and social inequities, tal interventions emphasizing the multi-causal etiology of the · Curative and clinical interventions through disease. Recognizing CKDu as an occupational strong healthcare systems at all levels of as- disease and making it a compulsory epidemio- sistance (PHC, institutional and highly spe- logical report, could help to understand the ex- cialized services) tent of the problem. · Social support for affected families and sur 5. Many isolated and joint efforts have been vivors done to address the CKDu epidemic and control 2. A research agenda on CKDu that involves eti- it at the country level. However, most of the in- terventions done are focused on strengthening clinical services for curative purposes including stronglyologic research on this and line, field and research currently at theconducts country a very costly interventions such as transplants, surveylevel should to determine soon be the defined. agenda PAHO in the is mid-working and rather than strengthening preventive occupa- long-term. tional and environmental interventions which 3. Need to enhance policy-making for are less costly and could decrease the occurrence of the disease. This is a major challenge. Thus, health, that should include: prevention, particularly in the field of workers’ Advances in knowledge of CKDu

a. partment of Law and Human Rights [Consulted diseases in the countries aiming to have CKDu October 20, 2015] Available on line at: https:// includedUpdating in it. the official lists of occupational laislafoundation.org/child-labor-report/ b. Implementing occupational and environ- 4. Wesseling C., Crowe,J., Hogstedt C., Jacobson mental surveillance systems at the agricultural K., Lucas R., Wegman D. Eds. Mesoamerican Ne- workplaces involved, or other sectors where the disease might appear. Research Workshop on MeN. 28-30 November, c. 2012,phropathy: San JoséReport (Costa from Rica).the first Heredia International (Costa in place good work practices such as those Rica): Organized by Central American Pro- proven Implementing to be effective field and research to improve and workers’ putting gram for Work, Environment and Health - SAL life quality and work performance (Water. TRA, Central American Institute for Studies on Toxic Substances (IRET), Universidad Nacional d. Enforcing compliance with child labor (UNA), Costa Rica 2013. Technical Series SAL- regulationsRest.Shade andat the the countryWork Efficiency level, and WE). for the TRA: No. 10 [consulted 13 June 2013]. Available eradication the worst forms of child labor as on line at: http://www.regionalnephropathy. conveyed in the II Global Meeting on Child org/wp-content/uploads/2013/04/Technical- Labor (Brasilia, 2013). Report-for-Website-Final.pdf 4. A policy statement regarding all PAHO 5. Bodin, T, Jarquin E, Weiss I, Garcia-Travan- recommendations is being drafted, and should - include all the policy recommendations at the ciency Program – Lessons learned from a pilot three decision-making levels. interventionino R, Wegman in ElDH. Salvador. Worker’s 2015. Health Proceedings, and Effi 2nd International Workshop on Mesoamerican References Nephropathy, San Jose, CR. 55 1. Pan American Health Organization. Prog- 6. Pan American Health Organization. Health ress report on: Chronic Kidney Disease in Ag- Agenda of the Americas. 2007-2017. Presented ricultural Communities in Central America by the Ministers of Health of the Americas in [Online]. 54th Directing Council of PAHO, 67th Panama City, June 2007 [On line] Panama, 2008. Session of the Regional Committee of WHO for [consulted 13 June 2013] Available on line at: the Americas; 2015 Sep 28-Oct 2; Washington http://new.paho.org/hq/dmdocuments/2009/ (DC), US. Washington (DC): PAHO; 2015 (Docu- Health_Agenda_for_the_Americas_2008-2017. ment CD54/INF/5). Available on line at: http:// pdf www.paho.org/hq/index.php?option=com_ 7. Peña, R. Perspectiva de la CT con el SICA. docman&task=doc_download&gid=31192&Ite Reunión inter-programática de OPS sobre En- mid=270&lang=en fermedad renal crónica de las comunidades 2. Pan American Health Organization. Chronic agrícolas de Centroamérica. Managua, Nicara- Kidney Disease in Agricultural Communities gua, September, 2015. in Central America [Internet]. 52nd Directing 8. Sistema de la Integración Centroameri- Council of PAHO, 65th Session of the Regional cana (SICA) Política Regional de Salud del SICA Committee of WHO for the Americas; 2013 2015-2022. Aprobada por el consejo d Min- Sep 30-Oct 4; Washington (DC), US. Washing- istros de salud de Centro América y república ton (DC): PAHO; 2013 (Document CD52/R10). Dominicana en Septiembre 2014. [On-line] Con- [Cited 2015 Jan 15]. Available from: http:// sejo de Ministros de Salud de Centroamérica y www.paho.org/hq/index.php?option=com_ República Dominicana (COMISCA) Secretaria docman&task=doc_download&gid=23347&Ite Ejecutiva del COMISCA (SE-COMISCA) (consul- mid=270&lang=en tado Septiembre 25 20150 disponible en línea 3. La Isla Foundation. Cycle of Sickness, A Sur- en: http://www.mcr-comisca.org/sites/all/ vey report on Child Labor in the Nicaraguan - Sugarcane Fields of Ingenio San Antonio. De- LITICA%20REGIONAL%20DE%20SALUD.pdf modules/ckeditor/ckfinder/userfiles/files/PO Advances in knowledge of CKDu

9. Reunión del Sector Salud de Centro Améri- collaboration network. Costa Rica: CENCAM; ca y República Dominicana RESSCAD. About 2012 [cited 2015 Jan 15]. Available from: http:// RESSCAD. What is RESSCAD? [Internet] Con- www.regionalnephropathy.org/ sulted October 20/2015. Available on line 15. Pan American Health Organization; Vir- at: http://www.paho.org/resscad/index. tual Campus for Public Health. Virtual course php?option=com_content&view=article&id=63 with regional experts in diagnosis, treatment &Itemid=191 and prevention of acute pesticide poisoning (in 10. Reunión del Sector Salud de Centro Améri- Spanish), 2015 version [Internet]. Washington ca y República Dominicana RESSCAD. Acu- (DC): PAHO and VCPH; 2015 cited 2015 Jan 15]. Available in Spanish from: http://www.cam- transmisibles, con énfasis en la enfermedad pusvirtualsp.org/?q=en/recent-completion- renalerdo No.crónica 2: Desafío de causas de lasno enfermedadestradicionales noen courses-area-pesticides-grade-methodology- los países de Centroamérica y República Do- and-english-version-virtual-course minicana. En: Acuerdos de la XXX Reunión del 16. Pan American Health Organization. Action Sector Salud de Centroamérica y República Plan on Workers’ Health 2015-2025 [Inter- Dominicana. San Salvador, El Salvador. XXX net]. 54th Directing Council of PAHO, 67th Ses- RESSCAD, Presidencia pro-tempore El Sal- sion of the Regional Committee of WHO for the vador, 17-18 de Octubre 2014. Disponible Americas; 2015 Sep 28-Oct 2; Washington (DC), en línea en: http://www.paho.org/resscad/ US. Washington (DC): PAHO; 2015 (Document index.php?option=com_docman&task=doc_ CD54/10 Rev.1). Available on line at: http:// download&gid=296&Itemid=192 www.paho.org/hq/index.php?option=com_ 11. Reunión del Sector Salud de Centro América docman&task=doc_download&gid=31686&Ite 56 y República Dominicana RESSCAD. Informe de mid=270&lang=en cumplimiento de los Acuerdos de la XXX RESS- 17. Rodríguez Guzmán, J., Moreno Díaz, LA, - Paredes Cubillos, N, & Gómez, GE. Plan e instru- dades no transmisibles, con énfasis en la enfer- mentos para fortalecer regionalmente la salud medadCAD. Acuerdo renal crónica No. 2: de Desafío causas deno tradicionales las enferme ocupacional y el aseguramiento de los riesgos en los países de Centroamérica y República asociados a la actividad laboral. Informe Re- Dominicana. XXXI RESSCAD, Tegucigalpa, gional. Banco Interamericano de desarrollo Honduras, 15-16 de Octubre 2015. Disponible BID (TC-01-08028). FISO. Bogotá, Colombia- en línea en: http://www.paho.org/resscad/ Diciembre, 2002. [Internet]. [Consultado Octu- index.php?option=com_docman&task=doc_ bre 20, 2015] Disponible en línea en: http:// download&gid=325&Itemid=192 idbdocs.iadb.org/wsdocs/getdocument. 12. Consejo de Ministros de Salud de Centro aspx?docnum=355108 América y República Dominicana (COMISCA) 18. Plan de Salud para Centro América y Repúbli- Ocupacional América Central, 1ed.- Serie Salud, ca Dominicana 2016-2020. Lanzamiento en la Trabajo Carmenate y Ambiente; - Milán, No. L. 20.et al. Informes Perfil de Técnicos la Salud Página web. Disponible por solicitud. http:// IRET No.21. Costa Rica: IRET-UNA, SALTRA. San comisca.net/content/comisca-aprueba- José, Costa Rica, 2014. plan-de-salud-de-centroam%C3%A9rica-y- 19. Pan American Health Organization/World rep%C3%BAblica-dominicana-2016-2020 Health Organization; Ministry of Health of 13. Enfermedad renal crónica azota comu- Mexico. Ministerial declaration for the preven- nidades agrícolas. MEDICC Review [Internet]. tion and control of noncommunicable chronic April 2014 [cited 2015 Jan 15];Selecciones diseases [Online]. Regional High-level Consulta- 2013, 2014 Apr. Available from: http://www. tion of the Americas against Noncommunicable medicc.org/mediccreview/index.php?issue=32 Chronic Diseases and Obesity; 2011 February 14. Consortium for the Epidemic of Nephropa- 24-25; Mexico City (Mexico): 2011 [cited 2013 thy in Central America and Mexico. CENCAM June 10]. Available at: http://new.paho.org/ Advances in knowledge of CKDu hq/index.php?option=com_docman&task=doc_ view&gid=13836&Itemid= 20. Council of Ministers of Health of Central America and the Dominican Republic; Ministry of Health of El Salvador; National Health Insti- tute. International Conference and High-Level Meeting on Chronic Kidney Disease from Non- traditional Causes (CKDu) in Central America; 2013 April 24-26; San Salvador (El Salvador). San Salvador: COMISCA; 2013. 21. Ministerio de Salud. Declaración de San Sal- vador: Abordaje integral de la enfermedad re- nal túbulo-intersticial crónica de Centroaméri- ca (ERTCC) que afecta predominantemente a las comunidades agrícolas. San Salvador, El Salvador. San Salvador: COMISCA; 2013 [In- ternet] [consultado Octubre 20 de 2015] Dis- ponible en línea en: http://www.salud.gob.sv/ archivos/comunicaciones/archivos_comunica- dos2013/pdf/Declaracion_San%20Salvador_ ERCnT_26042013.pdf 22. Organización Panamericana de la Salud. Grupo de trabajo interprogramático sobre En- 57 fermedad Renal Crónica de las Comunidades Agrícolas de Centro América. Productos y servi- cios para responder al mandato del Consejo Di- rectivo de la OPS. Avances reportados por país a Diciembre de 2014. Documento de trabajo. 23. Pan American Health Organization. Inter- programmatic working group. Country reports presented during PAHO’s Inter-programmatic meeting on CKDu, Managua, Nicaragua. Septem- ber, 2015. Working documents. Reviews of evidence for CKDu in relation to hypotheses

between self-reported occupational heat ex- Heat stress and dehydration posure and subsequent self-reported kidney disease diagnosis. In that study, neither the ex- posure nor kidney disease diagnosis was objec- tively determined. Daniel Brooks, Boston University, USA. The lack of evidence of CKDnT excess in many Jennifer Crowe, IRET-SALTRA, Universidad other areas of the world where HS/D conditions Nacional, Costa Rica. coupled with strenuous labor presumably exist. Rebekah Lucas, University of Birmingham, UK. excess of CKD was occurring in other countries inSpecifically, which sugarcane evidence was was an lacking important that cropa similar and Background largely harvested manually. At the 2012 workshop, heat stress and de- The lack of evidence for biologically plausible hydration (HS/D) was believed by a majority mechanisms for how HS/D causes CKDnT, par- of workshop attendees to be a key hypothesis ticularly in the absence of acute kidney injury based on the evidence available at that time, (AKI). primarily: Since the 2012 workshop, advances in three HS/D is an exposure that occurs over a wide main areas have provided new evidence regard- area, covering the areas of highest-reported in- ing the HS/D hypothesis. First, potential mech- cidence of CKDnT. anisms linking HS/D to CKDnT have been pro- - posed, and supported by animal data. [1]. (See 58 mographic characteristics of the disease, par- “Proposed mechanisms for chronic kidney disease ticularlyAn occupational its disproportionate exposure that occurrence best fit theamong de of uncertain etiology observed in Central Ameri- younger men, most notably in sugarcane work- ca (Mesoamerican Nephropathy)” in this report). ers. Of the variety of hypothesized occupational stress and health outcomes have been under- taken.Second, Third, field studiescohort thatand better case-control document studies heat ratesexposures, of elevated HS/D appearedcreatinine the in bestcross-sectional fit for the (some including exposure and outcome data) seroprevalencerange of industries studies identified pre-2012. as havingThese stud high- that provide further information on the poten- ies had found high rates of elevated creatinine tial association between HS/D and CKDnT have not only in agriculture but, importantly, also in been published. (Note: some of these studies other industries requiring strenuous manual la- have recently been summarized in a review by bor, yet without high exposure to agrichemicals Elinder and colleagues [2]). Herein we summa- (e.g., mining, construction, port work). HS/D, particularly combined with strenuous exertion, is a well-known cardiovascular and Workload,rize findings from heat the stress second and and third fluid areas. kidney stressor, which can lead to acute kidney balance in CKDnT-affected injury (AKI). populations In 2012, evidence was preliminary and in- complete, and there was consensus that more Workload knowledge was necessary to determine how Qualitative observational assessments of important HS/D was as a causal component of workload for sugarcane cutters have clearly CKDnT. The primary challenges facing the HS/D shown that cutters carry out labor-intensive hypothesis following the 2012 workshop were: work [3-6]. To date in Central America, only a The almost complete lack of epidemiological few job tasks in other industries, such as dig- studies linking HS/D to CKD of any kind. Just ging trenches or sack loading in warehouses one study from Thailand showed an association have been shown to be of a similar intensity as Reviews of evidence for CKDu in relation to hypotheses sugarcane harvesting and sugarcane seeding [13]. Further, in a study of sugar cane workers [7, 8](Luis Blanco Romero, personal commu- in Costa Rica, heat-related symptoms were re- nication). Within a recent pilot study from the ported more frequently by harvesters than by non-harvesters working in the same company El Salvador, 45 workers wore heart rate moni- [14]. torsWorker for oneHealth full and workday. Efficiency The majority(WE) Program of work in- ers (28/45) spent over half the shift working Fluid balance at and above 50% of their predicted heart rate Several studies have attempted to measure max [9]. Such heart rate intensities are higher than that maintained by soldiers during multi- markers of hydration status (osmolality and day operations (30-40% aerobic power/heart density)changes remain in fluid the status most commonly in workers. used, Urinary how- rate max)[10]. Similarly, one study demonstrat- ever, it was argued at the 2012 workshop that ed that a group of Brazilian sugarcane workers such urinary markers are relatively crude mea- (n=28) performed on average at 61% of their predicted heart rate max (estimated from an average daily work shift heart rate of 116 ± 11 sures of acute changes in fluid status. Change beats per min)[11]. in body mass has been difficult to measure and (evenhas given in workers inconsistent drinking results considerable in the field [5,liquid) 15]. Heat stress toUrine increase specific during gravity the workshift (USG) has in beencane cutters shown Sugarcane cutters work in hot and humid en- [5, 11, 16]. vironmental conditions. Wet bulb globe temper- ature (WBGT, a composite measure of environ- Epidemiological studies 59 mental parameters: air temperature, humidity, investigating wind speed and radiation) has been measured the association between HS/D during harvest periods in coastal sugarcane and CKDnT Pre-2012, epidemiological studies for CKDnT with highs reaching above 33°C WBGT in all in Mesoamerica were limited to two communi- casesfields andin Costa with averageRica, El maximumSalvador and air (dry)Nicaragua tem- ty-based seroprevalence studies in Nicaragua peratures during the hottest parts of the har- [17, 18] and one similar study in El Salvador vest season between 34.0°C and 42.0°C [3-5]. [19]. Since that time, a small number of epide- In Brazil, similarly high dry bulb temperatures miological studies have been undertaken that have been reported up to 35.0°C [11, 12]. Given have added to the working knowledge of CKDnT. the hot environmental conditions and strenu- One case-control study was conducted in a ous workload performed by sugarcane cutters, greatly-affected community in northwestern OSHA guidelines stipulate that cutters should Nicaragua [20]. Cases (n=78) were individuals only work at 100% effort for 15-45 minutes with a measurement of eGFR<60 mL/min/1.73 per% hour in order to avoid the ill effects of heat m2 obtained at a screening of community resi- exposure. In reality, workers rest infrequently dents; controls (n=205) had eGFR>90 mL/ in non-shaded area and therefore are exposed min/1.73 m2. Questions relevant to HS/D in- - cluded an assessment among those with a his- tion of the workday. Indeed, the WE pilot study tory of agricultural employment (48 cases, 69 into excessiveEl Salvador heat found stress that for overa significant the course propor of a controls) of the time spent conducting a vari- harvest, cutters in the coastlands spent 40% of ety of work tasks over their working lives, and their time working in environmental conditions self-reported daily water and boli (rehydration - erted for 25% per hour (calculated from hourly electrolytes) intake during the workday. After climate≥30°C WBGT, data whencollected full effortover should102 workshifts) only be ex adjustmentpacket consisting for sex of and water, age, sugar,any lifetime flavoring, work and as Reviews of evidence for CKDu in relation to hypotheses

a cane cutter was strongly associated with re- and urine samples were collected prior to be- duced eGFR. Daily bolis at work was also associ- ing hired for the harvest and near the end of the ated with reduced eGFR, while amount of water harvest. A questionnaire was administered in- consumption was unrelated. Limitations of the cluding questions on work history, symptoms, study include a limited number of high-risk in- medications, quantity of water and number of dividuals (women and non-agricultural work- bolis typically consumed at work. Both serum ers comprised the bulk of the population) and creatinine and urine biomarkers of kidney in- the potential for recall bias due to the retrospec- jury were measured and compared across job tive nature of the information on exposure. For and time. Factory workers were the reference example, as bolis are packaged in small discrete group for all analyses. Analyses were adjusted packets while water is carried in various-sized, for sex, age, and duration of employment. From beginning to late harvest, eGFR decreased a workers to recall accurately the volume of wa- further 5-9 mL/min/1.73 m2 in seed cutters, terrefillable consumed containers as compared it is likely to the more number difficult of bofor- irrigators, and cane cutters, as compared to fac- lis. Workers incorrectly estimating water con- tory workers [8]. These three jobs also reported sumption has been reported by other authors drinking the most water per day. Cane cutters (Jennifer Crowe, personal communication) and experienced the largest increases in NGAL and may help explain the lack of association seen IL-18 relative to factory workers during the with water consumption. harvest [22]. Water consumption was unrelated A second case-control study was conducted to eGFR or biomarker measures, but cane cut- in the Guanacaste region of Costa Rica by the ters who consumed a greater number of bolis 60 Costa Rican Health Care and Social Security had both a smaller decline in eGFR and less System [21]. Cases (n=192) were patients aged of an increase in NGAL than cane cutters who 18-59 with a diagnosis of CKD during 2005- consumed a smaller number. No association 2011 based on two consecutive measurements was seen for other job categories. The authors of eGFR<60 3 months apart. Controls (n=317) concluded that the greater decrement in eGFR were patients who were determined not to have - CKD as a result of normal renal function tests. ers, particularly cane cutters, along with the Controls were matched to cases based on sex protectiveand increases effect in biomarkersof greater boliamong consumption, field work and age. Eighteen percent of cases and 4% of was most consistent with the HS/D hypothesis. controls were persons of Nicaraguan national- While a strength of this study was the compari- ity living in Costa Rica, which was also adjusted son of different jobs within the same industry for in the analysis. Results of the study indicat- that had different potential HS/D exposures and ed that being an agricultural day laborer (peón other potential risk factors, HS/D was not di- agrícola), working in the sugarcane industry, rectly measured. Additional limitations includ- working between 10 AM – 2 PM, and greater use ed the fact that changes in eGFR were generally

aspirin) were associated with greater preva- that a pre-employment screening program par- lenceof anti-inflammatory of CKD. pain medications (AINES/ tiallysmall selectedand of uncertain out workers clinical with significance, elevated creati and- Additionally, three prospective cohort stud- nine [2]. As with the study by Raines et al [20], ies have been conducted in Nicaragua and El the apparent protective effect of greater boli - consumption compared to water consumption gion where workers were assessed at more than oneSalvador; time pointthese andstudies changes were over the firsttime in could the rebe Data analysis is ongoing for two additional prospectivecould be due cohort to misclassification. studies. One was conducted sugarcane company in northwestern Nicaragua among workers in a community setting in north- amongassessed. 284 The workers first studyin 7 job was tasks conducted [8, 22]. Blood at a western Nicaragua (Aurora Aragón, personal Reviews of evidence for CKDu in relation to hypotheses communication), and the second a component ies and then conduct a pooled or meta-analysis. of the WE intervention underway at a sugarcane The effectiveness of the latter strategy will be company in El Salvador (see “WE program pilot maximized if there is as much standardization intervention 2014-2015: Lessons learned”, in this as possible regarding methods, sample testing, report). and questionnaires. If the disease is in fact of multifactorial eti- Future considerations ology, incorporation of the assessment of oth- Current evidence makes the following con- er potential causal agents or conditions may siderations of particular importance in ongoing help lessen the time needed to clarify the role and future work: of HS/D. The risk will likely be most evident Water is the main element lost with sweat- among workers with both factors; if the inter- ing/dehydration and therefore should be an action is a strong one, analyses that account important component of a hydration program. for this interaction may be more powerful than - those that ignore it. garding the consumption of carbohydrate-elec- The timing of biological measures must be trolyteCurrently, drinks there to is determine insufficient how information they should re considered. Circadian rhythm is well-known to be incorporated into a hydration program and affect cardiovascular responses and body core it should be noted that these drinks typically temperature. Diet [24] and muscle damage [25] contain fructose, which emerging animal data can affect circulating creatinine levels in the suggest may be linked to kidney damage in the body. Also, the recovery of renal responses (i.e., context of dehydration [23]. Because of the nature of the exposure as- can take anywhere between 1-2 hours to 24-48 61 sessment (including collecting information on hoursrenal blooddepending flow on and the GFR) variable following of interest exercise (i.e., plausible potential confounders such as ag- proteinuria and muscle damage markers) and richemical exposure), case-control studies will recovery conditions [26, 27]. Urinary protein generally be limited for assessing the HS/D hy- excretion should be reported as a rate (i.e., ug/ pothesis, although a valid job-exposure matrix min) to correct for changes in urine concentra- that can broadly quantify various occupational tion/output throughout the day [26]. exposures may be able to overcome this prob- lem. Remaining questions for the If studies are instead prospective cohort by HS/D hypothesis design, then money and time are the main ob- stacles. The number of new diagnosed CKD HS/D hypothesis is the perception that many cases that would develop each year is not suf- peopleAs noted around above, the one world of thecarry difficulties out strenuous of the work in conditions of high ambient tempera- very large number of study participants, sub- - stantialficiently durationlarge to obviateof follow-up, the requirement or both. Use for of a roprevalence studies in other regions in which strongly predictive intermediate marker would conditionsture and with are insufficient similar but hydration.not currently Simple identi se- help address this problem. Advances are being made in this area (see working group report data. The question of “why here” is particularly “Exploring biomarkers for early evidence of ab- relevantfied with toCKD other epidemics regions would in which provide sugarcane useful normal kidney function,” in this report). production is an important industry. For exam- There are at least two strategies for collecting ple, sugarcane cutters in Brazil show decreas- the necessary evidence through prospective co- es in eGFR and increases in serum creatinine hort studies, which are not mutually exclusive. across shift, yet CKD has not been reported as an important problem in this population [11]. the second to conduct a number of smaller stud- However, this perhaps highlights the gap in un- The first is to conduct one or two large studies, Reviews of evidence for CKDu in relation to hypotheses

derstanding between acceptable kidney stress 4. McClean M, et al., Boston Biological Sam- due to strenuous activity and sub-clinical indi- pling Report: Investigating biomarkers of kid- cators of kidney injury. Determining the preva- ney injury and chronic kidney disease among lence of CKDnT in other settings and what fac- workers in Western Nicaragua. 2012, Boston tors might explain any differences would help University School of Public Health: http:// provide more clarity on those factors that may www.cao-ombudsman.org/cases/document- be important in Central America. Further work links/documents/Biological_Sampling_Report_ is also needed to establish appropriate kidney April_2012.pdf. biomarkers and normative ranges in order to 5. García-Trabanino, R., et al., Heat stress, de- differentiate a stress response from kidney in- hydration, and kidney function in sugarcane jury or disease. This would clarify the clinical cutters in El Salvador – A cross-shift study of - workers at risk of Mesoamerican nephropathy. markers. Environmental Research, 2015. 142: p. 746- significance of measured changes in kidney bio 755. Summary 6. Cortez, O.D., Heat stress assessment among In sum, studies to date have used proxy or workers in a Nicaraguan sugarcane farm. Global self-reported measures of HS/D and have main- Health Action, 2009. 2. ly not been able to adjust for other potential risk 7. McClean, M., et al., Industrial Hygiene/Oc- factors for CKDnT that may be associated with cupational Health Assessment: Evaluating Po- these proxy measures. A natural next step in tential Hazards Associated with Chemicals and evaluating the HS/D hypothesis epidemiologi- Work Practices at the Ingenio San Antonio (Chi- 62 cally would be to take advances made in mea- chigalpa, Nicaragua). Boston University School suring HS/D and apply them in studies with of Public Health, 2010. longer-term follow-up. It is important to note 8. Laws, R.L., et al., Changes in kidney function that this discussion applies to the question of among Nicaraguan sugarcane workers. Interna- obtaining the evidence to decide whether or not tional journal of occupational and environmen- HS/D is an important cause of CKDnT. Given the tal health, 2015. 21(3): p. 241-250. documented heat stress and strenuous work 9. Lucas, R.A.I., et al., Heat stress and workload conditions, interventions to reduce HS/D based associated with sugarcane cutting-an excessive- only on preliminary evidence or even regard- ly strenuous occupation! Extreme Physiology & less of its connection to CKDnT are appropriate Medicine, 2015. 4(Suppl 1): p. A23. and necessary. 10. Myles, W., J. Eclache, and J. Beaury, Self-pac- ing during sustained, repetitive exercise. Avia- References tion, space, and environmental medicine, 1979. 1. Roncal-Jimenez, C., et al., Mechanisms by 50(9): p. 921-924. Which Dehydration May Lead to Chronic Kidney 11. Santos, U.P., et al., Burnt sugarcane harvest- Disease. Annals of Nutrition and Metabolism, ing is associated with acute renal dysfunction. 2015. 66(Suppl. 3): p. 10-13. Kidney international, 2015. 87(4): p. 792-799. 2. Elinder, C., A. Wernerson, and J. Wijk- 12. Barbosa, C., et al., Burnt sugarcane harvest- ström, Mesoamerican Nephropathy (MeN): A ing-cardiovascular effects on a group of healthy ‘New’Chronic Kidney Disease related to Occu- workers, Brazil. PloS one, 2012. 7(9): p. e46142. pational Heat Exposure with Repeated Depri- 13. Bodin, T., et al., Intervention to reduce heat vation of Salts and Water. Int J Nephrol Kidney Failure, 2015. 1(2). workers in El Salvador – Phase 1. Occupation- 3. Crowe, J., et al., Heat exposure in sugarcane alstress and and Environmental improve efficiency Medicine, among 2016 sugarcane eprint harvesters in Costa Rica. American Journal of In- ahead of print. dustrial Medicine, 2013. 56(10): p. 1157-1164. 14. Crowe, J., et al., Heat-Related symptoms in Reviews of evidence for CKDu in relation to hypotheses sugarcane harvesters. American journal of in- kidney injury biomarkers and kidney function. dustrial medicine, 2015. 58(5): p. 541-548. American Journal of Physiology-Renal Physiol- 15. Crowe, J., et al., 0401 Repeated pre and ogy, 2013. 305(6): p. F813-F820. post-shift urinalyses show kidney dysfunction 26. Poortmans, J.R., Exercise and renal function. among Costa Rican sugarcane cutters exposed Sports Medicine, 1984. 1(2): p. 125-153. to heat stress. Occupational and environmental 27. Bellinghieri, G., V. Savica, and D. Santoro, Re- medicine, 2014. 71: p. A51-A51. nal alterations during exercise. Journal of Renal 16. Crowe, J., Heat exposure and health out- Nutrition, 2008. 18(1): p. 158-164. comes in Costa Rican sugarcane harvesters, in Department of Public Health and Clinical Medi- cine. 2014, Umeå University: Umeå, Sweden. 17. Torres, C., et al., Decreased kidney function of unknown cause in Nicaragua: a community- based survey. American Journal of Kidney Dis- eases, 2010. 55(3): p. 485-496. 18. O'Donnell, J.K., et al., Prevalence of and risk factors for chronic kidney disease in rural Ni- caragua. Nephrology Dialysis Transplantation, 2011. 26(9): p. 2798-2805. 19. Peraza, S., et al., Decreased kidney func- tion among agricultural workers in El Salvador. American Journal of Kidney Diseases, 2012. 63 59(4): p. 531-540. 20. Raines, N., et al., Risk factors for reduced - munity affected by Mesoamerican nephropathy. MEDICCglomerular review, filtration 2014. rate 16(2): in a p. Nicaraguan 16-22. com 21. Wong McClure, R., Factores asociados a En- fermedad Renal Crónica, Región Chorotega. In- forme Final de Resultados. Caja Costarricense de Seguro Social, 2014. 22. Laws, R.L., et al., Biomarkers of Kidney In- jury Among Nicaraguan Sugarcane Workers. American Journal of Kidney Diseases, 2015(Oct 6 [epub ahead of print]. doi:10.1053/j. ajkd.2015.08.022). 23. Roncal-Jimenez, C., et al., Heat Stress Ne- phropathy From Exercise-Induced Uric Acid Crystalluria: A Perspective on Mesoamerican Nephropathy. American Journal of Kidney Dis- eases, 2016. 67(1): p. 20-30. 24. Jacobsen, F., et al., Pronounced increase in serum creatinine concentration after eating cooked meat. BMJ, 1979. 1(6170): p. 1049- 1050. 25. Junglee, N.A., et al., Exercising in a hot envi- ronment with muscle damage: effects on acute Reviews of evidence for CKDu in relation to hypotheses

al meeting on Mesoamerican nephropathy (5). Does exposure to toxic metals Chapters with detailed descriptions of the tox- have a role in the development of icity of a series of metals of interest in relation Mesoamerican Nephropathy (MeN)? to human exposure and health are also available in Handbook on the Toxicology of Metals; Arse- nic (6), cadmium (7), mercury (8) and lead (9). There is also easily available and updated infor- , Unit for Renal medicine, Carl-Gustaf Elinder mation of what is known about human toxicity Department of Clinical Science, Technology of these metal in UpToDate; (10-14). and Intervention, Karolinska Institutet and Here we will shortly in tables summarize the Department of Evidence based Medicine, following. Do we have information or knowl- Stockholm County Council, Stockholm, Sweden. edge on; Evidence of nephrotoxicity in humans,

human nephrotoxicity, the existence of clear- Introduction cutspecific evidence clinical of nephrotoxicity and morphological in animal findings experi in- In this working paper we will examine the - possible role of exposure to toxic metals in the dose-effectments, specific and biochemicaldose response and/or relations morphologi between disease that have been given the name Mesoa- exposurecal findings and in animalrenal effects nephrotoxicity, in humans, established the pos- mericandevelopment nephropathy of a specific (MeN) type (1). of chronic In spite kidney of its sibility to use measurements in blood and or name MeN possible affects persons in several urine (biological monitoring) to assess exposure 64 parts of the world. Sometimes the MeN referred and the existence of established dose-effect and as chronic kidney disease of unknown cause dose response relations between results from bi- (CKDu) chronic kidney disease non-traditional ological monitoring and renal effects in humans cause (CKTnt) or sugar cane nephropathy (2). As starting point we will make reference to lead, lithium and mercury. the classical review by Austin Bradford Hill in for five non-essential metals; arsenic, cadmium,- 1965 (3) on the issue of The Environment and posure to these metals in MeN (CKDu) endemic Disease: Association or Causation? Subsequent- areasWe willfrom review environmental the evidence measurements, of significant from ex ly we will make an attempt to apply these prin- biological measurements in blood and/or urine. cipals to what we now about exposure to toxic Next we will examine to what extent the clini- metals and renal effects in general and in par- ticular to what we know from published reports CKD in endemic areas agree with those from concerning exposure to toxic metals and MeN. cal and renal morphology findings in cases with In fact these principles for judging on causality to metals. Are they similar or not? from Hill may well, as we see it, be useful for the confirmed cases of renal toxicity from exposure evaluation of causality of MeN in general, and of associations; - none, + limited or weak, ++ yes not only for metals. andWe +++ will strong. use the following crude classification Arsenic; Albeit inorganic arsenic overall is Evidence of exposure to toxic highly toxic to humans, a classical poison with metals and renal effects an acute lethal dose of about 1-3 mg/kg and with a series of chronic toxic effects there are A comprehensive review on this subject was remarkably few renal ones mentioned in ex- published by Barregård and Elinder in the re- tensive textbooks and reviews(6). There are cently updated two volume textbook Handbook merely a few cross-sectional studies on asso- the Toxicology of Metals in 2014 (4) and over- ciations between exposure to arsenic in drink- view was also given at the previous internation- ing water and proteinuria, but this may be due Reviews of evidence for CKDu in relation to hypotheses

Table 1. Metal exposure and renal effects: Agreement between morphology and renal toxicity from ex- posure to metals.

Metal Arsenic Cadmium Lead Lithium Mercury

Evidence of nephrotoxicity in + +++ ++ +++ +++ humans

Specific clinical and morphological findings in human - +++ + ++ ++ nephrotoxicity

Specific biochemical and/or morphological findings in animal - +++ ++ ++ ++ nephrotoxicity

Established dose-effect and 65 dose response relations between - +++ - + ++ exposure and renal effects in humans

The possibility to use measurements in blood and or + +++ +++ +++ +++ urine (biological monitoring) to assess exposure

The existence of established dose-effect and dose response relations between results from - +++ - ++ ++ biological monitoring and renal effects in humans. Reviews of evidence for CKDu in relation to hypotheses

to confounding from other exposures and in can be seen as result of excessive exposure, and particular reversed causality; i.e. proteinuria, this is nuclear inclusion bodies with a high con- which in turn is signalling glomerular damage, tent of lead(16). However this does not translate brings about increased urinary excretion of ar- in to renal damage but is more of a proof that ex- senic. One particular problem with arsenic is cessive exposure, which often may cause other the use (or misuse) of measurements of arsenic types of non-renal effects. The clinical and renal in urine to assess exposure and eliminating the morphological descriptions of cases with diag- pronounced effect from intake of seafood (10). Normal levels of arsenic in urine, in the order of 5-50 ug/l, may become increased more than nosed lead nephropathy are not very specific,- but rather non-specific with slightly decreased- arsenic’ (i.e. arsenobetaine). To avoid this ef- merularglomerular sclerosis(14). filtration (lowered Thorough eGFR) examination and inter of 20-times after ingestion of seafood contain ‘fish stitial inflammation, secondary fibrosis and glo lead exposure have, in large, been unable to re- infects different of seafood forms a ofstrict arsenic, fish- originand shellfish from expo free- lead exposed groups of adults with well-defined diet must be kept or the urine analysis specified tubular function. Measurements of lead in blood Cadmium; Renal effects from exposure to cad- haveveal morebeen proven specific to effects be very of useful the glomerular in assessing or miumsure to are inorganic well established or fish arsenic in humans (6). as well as exposure and different types of adverse health in animals. The earliest effects from cadmium effects, but not renal ones. Lead in urine can also are typical with signs of renal tubular dysfunc- tion with increased urinary excretion of tubu- use for assessment of exposure (9). 66 lar proteins and enzymes. The metabolism of beLithium; used but Exposure is less stable to this and metal more is widespread difficult to cadmium and its accumulation in the kidneys from worldwide from the use of lithium in the treatment and prophylaxis of manic-depressive protein – metallothionein – have been delin- disorders. Typical daily doses of lithium to reach eateddue to (7).the formation Later glomerular of a specific effects metal may binding come a therapeutic level in plasma of around 0,5-0,8 with a drop in the glomerular function and an mmol/l is around 1,500 mg of lithium carbonate increased risk for renal stones. Measurements which contain 282 mg of lithium. Daily intake of cadmium in blood and urine are useful as- from food and water normally range from 0.6 to sessing recent as well as long-term exposure. 3 mg/day. Drinking water in very lithium are- Dose-response curves for cadmium in urine and as may reach concentrations of 500-1000 ug/l renal effects from a large number of studies in (17). During medication intake of lithium is in- humans are in grossly good agreement and form creased with a factor of 100. Measurements of the basis for environmental and occupational lithium in blood and urine can be used to assess intake from water. In individuals using drink- in kidneys from human cases and animals with ing water rich in lithium (500-1000 ug/l) blood renalthreshold toxicity values agree (7, 12).well, Morphological tubular damage findings with or plasma levels of lithium may reach levels in - the order of 100 ug/l(18). This is far below the therapeutic range in plasma of 0.8 to 1.2 mmol/l interstitialLead; Lead inflammation is a classical nephrotoxicand fibrosis agentwith secand (5,550-8,330 ug/l). The therapeutic range for leadondary nephropathy glomerular has damage, been aredescribed not specific. in medi - lithium is narrow and symptoms and signs of cal report for more than 100 years. However, lithium intoxication may appear at plasma lev- when the evidence for nephrotoxicity from lead els exceeding 1.2 mmol/l and above 3 mmol/l is thoroughly scrutinized the evidence is not they may become life threatening. Neurological that impressive and hard to replicate in animal symptoms and signs dominate, often polyuria experiments(15). There is however one possibly with production diluted urine is seen and – in severe cases – EKG changes and risk for circular

pathognomonic finding in renal biopsies that Reviews of evidence for CKDu in relation to hypotheses

Table 2. Likelihood of association with MeN (CKDu) and exposure to metals.

Likelihood of association with MeN Arsenic Cadmium Lead Lithium Mercury (CKDu).

Evidence of significantexposure in MeN (CKDu) endemic areas from + - - - - environmental measurements or biological measurements.

Clinical concordance between cases with CKD in endemic areas with of - - + + - what has been reported from humans exposed to metals.

67 Renal pathology in concordance between cases with CKD in endemic - + + - - areas with of what has been reported from humans exposed to metals.

collapse. Also in the therapeutic range lithium has been reported to display a certain type tu- affects the renal handling of sodium and concen- bule-interstitial changes with microcyst forma- trating capacity of the kidneys, and decreased tion in the tubulus (20). These tubular cysts, ability to concentrate the urine and polyuria is which are typically seen during lithium treat- common during treatment with lithium. Wheth- ment, are comprised of glycogen containing er long term use lithium may produce CKD has vacuoles. Occasionally lithium treatment may been long debated. Most patients on long-term also precipitate a nephrotic syndrome in certain treatment with lithium (decades!) will retain susceptible individuals. We have not found any their renal function but some may eventually report suggesting that environmental or occu- develop CKD and end stage renal disease, not pational exposure to lithium may cause any of always clear if caused by lithium or not. Major the above mentioned renal effects. risk factors for nephrotoxicity appear to be the Mercury; Exposure to inorganic mercury duration of lithium exposure, the cumulative may cause early subtle tubular effects with in- dose, and advanced age(19). The degree of re- creased urinary excretion tubular enzymes in groups of occupationally exposed workers, and may occasionally progress to end-stage renal occasionally, in individuals with very high expo- diseasenal insufficiency (ESRD). isNevertheless generally relatively renal mild,biopsies but sure to inorganic mercury from various sourc- from patients with long-term lithium treatment es such as for example skin-lightning mercury Reviews of evidence for CKDu in relation to hypotheses

containing moistures and creams, a nephrotic but in the normal range (25). Likewise the con- syndrome with heavy proteinuria. Renal biop- centration of a series of potentially nephrotoxic sies in cases with mercury induced nephrotic metals, including arsenic, cadmium, lead and syndrome often reveal glomerulonephritis of lithium has recently been measured in drinking minimal change or membranous type. As a rule water and urine from patients with and CKDu, the nephrotic syndrome is reversible when ex- and individuals without CKDu in CKD endemic posure to the inadvertent exposure has ceased. and non-endemic areas of Sri Lanka. Overall the Measurements of mercury in urine is useful in concentrations were low and water as well as in assessing exposure and in diagnosing cases of urine and there was nothing indicating a caus- poisoning (21). ative association between exposure to metals There is no robust data (without analytical and CKDu (26). problems or, in the case of mercury speciation problems) providing evidence of excessive ex- Overall summary posure to toxic metals in MeN/CKDu endemic When scrutinizing available knowledge on areas of Central America. The histopathological renal effects and exposure to toxic metals (ar- senic, cadmium, lead, lithium and mercury) and from endemic areas do not resemble those seen information about exposure to these metals in infindings cases fromwith classical renal biopsies cases of so metal far presented poison- MeN/CKDu endemic area, the clinical presenta- ing(22), although one could argue that non-spe- that it is unlikely that this epidemic is primarily with cadmium and lead nephropathy, thus one causedtion and by morphological exposure to these findings, metals. we conclude 68 +.cific Clinically sclerotic MeN changes is characterized are seen also by inlowered cases eGFR and no, or limited, proteinuria. This is References clearly different from cadmium and mercury, 1. Wesseling C, Crowe J, Hogstedt C, Jako- but weakly compatible with lead. Patients with bsson K, Lucas R, Wegman D. Report from the MeN, working and living in hot climates, often First International Research Workshop on MeN. - Costa Rica: Program on Work, Environment ceeding 8 l/day. Albeit this has similarities with and Health in Central America (SALTRA) and thereport polyuria high daily commonly intake experienced of fluids sometimes by patients ex CentralAmerican Institute for Studies on Toxic treated with lithium there are no data suggest- Substances (IRET) Universidad Nacional (UNA), ing excessive exposure to lithium on Men/CKDu Costa Rica; 2013 2013-04-25. 239 p. endemic populations. In addition the typical tu- 2. Elinder CG, Wernerson A, Wijkstrom J, bular cyst in patients under lithium treatment cartographers. Mesoamerican Nephropathy has not been reported in biopsies from patients (MeN): A 'New' Chronic Kidney Disease related in MeN/CKDu endemic areas. to Occupational Heat Exposure with Repeated In Sri Lanka it has been shown that people Deprivation of Salts and Water. Int J Nephrol who live in disease endemic region may be ex- Kidney Failure2015. posed to arsenic, cadmium, and some other 3. Hill AB. The Environment and Disease: As- metals, through drinking water, food and to- sociation or Causation? Proceedings of the Roy- bacco to a greater extent than in people living al Society of Medicine. 1965;58:295-300. in non-endemic regions (23, 24). However, the 4. Barregard L, Elinder C-G. Renal Effects from clinical picture and renal pathology is not com- Exposure to Metals In: Nordberg GF, Fowler BA, patible with metal poisoning. Nordberg M, editors. Handbook on the Toxicol- Measurement of arsenic, cadmium and lead ogy of Metals I General Considerations. 4th edi- in biological media from populations with CKD tion ed. Amsterdam: Academic Press/Elsevier; of unknown cause in Central America has not 2014 p. 333-50. shown potentially toxic levels of these metals, 5. Elinder CG, editor Renal effects from expo- Reviews of evidence for CKDu in relation to hypotheses sure to lead, cadmium and mercury. First In- MH. Renal ultrastructure, renal function, and ternational Research Workshop on MeN; 2012; parameters of lead toxicity in workers with Heredia, Costa Rica: Program on Work, Environ- different periods of lead exposure. Br J Ind ment and Health in Central America (SALTRA), Med. 1974 Apr;31(2):113-27. PubMed PMID: Costa Rica. 4830763. Epub 1974/04/01. eng. 6. Fowler BA, Chou C-HSJ, Jones RL, Sullivan JR 17. Harari F, Ronco AM, Concha G, Llanos M, DW, Chen C-J. Arsenic. In: Nordberg GF, Fowler Grander M, Castro F, et al. Early-life exposure BA, Nordberg M, editors. Handbook on the Toxi- to lithium and boron from drinking water. Re- productive toxicology. 2012 Dec;34(4):552-60. ed. Amsterdam: Academic Press/Elsevier; 2014 PubMed PMID: 23017911. p.cology 581-653. of Metals II Specific Metals. 4th edition 18. Harari F. Maternal and fetal health i rela- 7. Nordberg GF, Nogawa K, Nordberg M. Cad- tion to lithium in drinking water [Academic Ph mium. In: Nordberg GF, Fowler BA, Nordberg M, D]. Stockholm, Sweden: Karolinska Instututet; editors. Handbook on the Toxicology of Metals 2015. 19. Rej S, Elie D, Mucsi I, Looper KJ, Segal M. Academic Press/Elsevier; 2014 p. 667-716. Chronic kidney disease in lithium-treated old- 8.II SpecificBerlin M, Metals. Zalups 4th RK, edition Fowler ed.BA. Amsterdam:Mercury. In: er adults: a review of epidemiology, mecha- Nordberg GF, Fowler BA, Nordberg M, editors. nisms, and implications for the treatment of Handbook on the Toxicology of Metals II Specif- late-life mood disorders. Drugs Aging. 2015 ic Metals. 4th edition ed. Amsterdam: Academic Jan;32(1):31-42. PubMed PMID: 25519823. Press/Elsevier; 2014 p. xxx-xyy. 20. Battle D, Lerma EV, Naaz P, Hakkapakki S. 9. Skerfving S, Bergdahl IA. Lead. In: Nordberg Lithium-associated kidney effects. In: De Broe 69 GF, Fowler BA, Nordberg M, editors. Handbook ME, Porter GA, editors. Clinical Nephrotoxins Renal Injury from Drugs and Chemicals. Third 4th edition ed. Amsterdam: Academic Press/El- Edition ed. New York, NY Springer; 2008. p. sevier;on the 2014 Toxicology p. 911-67. of Metals II Specific Metals. 725-48. 10. Goldman RH. Arsenic exposure and poison- 21. Fowler BA, Whittaker MH, Elinder C-G. ing. 2015. In: UpToDate [Internet]. Waltham, Mercury-induced renal effects. In: De Broe ME, MA: UpToDate. Porter GA, editors. Clinical Nephrotoxins Renal 11. Lerma EV. Renal toxicity of lithium. 2015. In: Injury from Drugs and Chemicals. Third Edition UpToDate [Internet]. Waltham, MA, 2015.: Up- ed. New York, NY Springer; 2008. p. 811-26. ToDate. 22. Wernerson A, Wijkstrom J, Elinder CG. Up- 12. Elinder C-G. Epidemiology and toxic- date on endemic nephropathies. Curr Opin ity of cadmium. 2015. In: UpToDate [Internet]. Nephrol Hypertens. 2014 May;23(3):232-8. Waltham, MA: UpToDate. PubMed PMID: 24717833. 13. Elinder C-G. Epidemiology and toxic- 23. Jayatilake N, Mendis S, Maheepala P, Mehta ity of mercury. 2015. In: UpToDate [Internet]. FR, Team CKNRP. Chronic kidney disease of Waltham, MA, 2015.: UpToDate. uncertain aetiology: prevalence and causative 14. Weaver VM, Jaar BG. Lead nephropathy and factors in a developing country. BMC Nephrol. lead-related nephrotoxicity. 2015 July 7, 2015. 2013;14:180. PubMed PMID: 23981540. In: UpToDate [Internet]. Waltham, MA: UpTo- Pubmed Central PMCID: 3765913. Date. 24. Jayasumana C, Gunatilake S, Siribaddana 15. Evans M, Elinder CG. Chronic renal failure S. Simultaneous exposure to multiple heavy from lead: myth or evidence-based fact? Kid- metals and glyphosate may contribute to Sri ney Int. 2011 Oct 13;79:272-9. PubMed PMID: Lankan agricultural nephropathy. BMC Nephrol. 20944550. Epub 2010/10/15. Eng. 2015;16:103. PubMed PMID: 26162605. 16. Cramer K, Goyer RA, Jagenburg R, Wilson Pubmed Central PMCID: 4499177. 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25. McClean M, Amador JJ, Laws R, Kaufman JS, Weiner DE, Rodríguez JMC, et al. Investigating biomarkers of kidney injury and chronic kidney disease among workers in Western Nicaragua. 2012 April 26, 2012. Report No. 26. Rango T, Jeuland M, Manthrithilake H, Mc- Cornick P. Nephrotoxic contaminants in drink- ing water and urine, and chronic kidney disease in rural Sri Lanka. Sci Total Environ. 2015 Jun 15;518-519:574-85. PubMed PMID: 25782025.

70 Reviews of evidence for CKDu in relation to hypotheses

that must be thoroughly addressed (1, 7 – 9). Chronic kidney disease of Although the precise etiology of the epidemics undetermined etiology and remains unknown, it is generally well recognized pesticide exposure: an update on that multiple causes are likely involved, with recent data two main hypotheses being put forward. First, a striking male/female ratio of 3:1 or higher docu- mented in Central America countries strongly suggests that the occurrence of CKDnt in this Mathieu Valcke, WHO/PAHO Collaborating region is associated with an occupational expo- Centre in Environmental and Occupational sure experienced primarily by men (1, 8, 10). In Health, Quebec’s National institute of Public particular, strenuous agricultural work in hot cli- Health and University Hospital Centre (INSPQ- matic conditions, often in sugarcane plantations, CHUQ), Québec, Canada and Department leading to heat stress with repeated episodes of Environmental and Occupational Health, of dehydration (and, hypothetically, rhabdomy- Université de Montréal, Montreal, Canada. olysis), combined with excessive consumption of Carlos M Orantes Navarro, National Health NSAIDS to relieve muscular pain, have been sug- Institute, Ministry of Health (MINSAL), San gested as important risk factors (1, 5, 8, 9, 11 – Salvador, El Salvador. 14). Second, the gender disparity of CKDnt cases Marie-Eve Levasseur WHO/PAHO Collaborating in Central America is also compatible with occu- Centre in Environmental and Occupational pational exposure to pesticides, which are han- Health, Quebec’s National Institute of Public dled preferentially by men in this region. In El Health and University Hospital Centre (INSPQ- Salvador and Sri Lanka agrochemicals have been 71 CHUQ), Québec, Canada. targeted by national policies (15, 16). Although

exposure was considered an unlikely cause of Introduction CKDntin the first based International on regional Workshop data available on MeN prior such to For more than two decades, various regions 2012 (8), this review is prompted by persisting of the world including Central America (1), Sri concerns of scientists, policy makers and the Lanka (2), India (3-4), and Egypt (5) have expe- general society raised by a series of recent pub- rienced an excess of chronic kidney disease un- lications that could shed new light on the issue. related to traditional causes as hypertension and The current short paper thus aims to provide an diabetes. As such, it is often referred to “CKDu”, update on the state of knowledge regarding this for “undetermined etiology”, as well as “MeN” issue, and strictly focuses on articles published for “Mesoamerican nephropathy” for the cen- since 2012. troamerican and mexican epidemic. Since PAHO - Approach followed ing on its “non traditional (nt)” causes (6), this Much of this paper is based on an ongoing termofficially will refers be used to thehereafter disease and as “CKDnt”,account forfocus all thorough retrospective literature review (man- uscript in preparation) of original epidemiologic CKDnt emerges disproportionally in patients studies looking into chronic kidney disease and fromthree oftendenominations disadvantaged unless communities specified otherwise. with the considering associations with pesticide expo- resulting psychosocial consequences; it is thus sure.5 recognized as a serious public health problem the study was conducted, study design and pop- Briefly, data on geographical area where

1. literature published since 2000 and is co-authored by M Valcke, ME Levasseur, L Revez, A Soares and C Wesseling, to be submit- tedThis in early review, 2016. carried out under the auspices of PAHO, is based on a manuscript in preparation that focuses on the scientific Reviews of evidence for CKDu in relation to hypotheses

farming or agricultural-related activities in gen- or outcome(s) and statistical methods used to eral (10, 22, 25), which includes but is not limited examineulation, exposurepotential assessment,associations casebetween definition pesti- to pesticide exposure, and certainly also involves cides and CKD in general or end-stage renal dis- strenuous workload at some level. ease (ESRD) were extracted. Reported results were qualitatively evaluated based on the valid- likely confounding effect of such heavy work- ity of the studies and strength of associations. loadThe in lackintense of heat specific experiences consideration in any forkind the of agricultural work but in particular cutting in Relevant recent evidence sugarcane plantations, on the observed associa- A total of 16 peer-reviewed papers published tions between CKD and pesticide exposure, is a since 2012 have formally examined pesticide critical issue that needs to be further examined. (or so-called “agrochemical”) exposure by some This would contribute to isolate and appreciate direct or indirect means, although often quite the true magnitude of the potential causal factor of pesticides to the “CKDnt/agricultural work” relation between pesticide exposure and CKDnt relation. It may contribute to further investi- issuperficially not obvious (Table based I). on Overall, negative the or evidence inconclusive of a results in quite few studies (17 - 22) for which bivariate OR of CKDu with virtually every agri- the exposure assessments realized were, in gen- culturalgate surprising pesticide results considered such asby theJayasumana significant et eral, limited. Except for Jayasumana et al. (23), al. (23): organophosphates (OR=1.77 [95% CI Lebov et al. (24) and Raines et al. (25), the stud- 1.10-2.86]), paraquat (2.51 [1.56-4.04]), MCPA ies reviewed generally relied solely on question- (1.80 [1.12-2.88]), bispyribac (2.00 [1.25- 72 naire/interview data with qualitative questions 3.18]), carbofuran (1.47 [0.91-2.40]), mancozeb such as “ever/never used pesticides?”, or indi- (1.94 [1.21-3.13]) and glyphosate (4.33 [2.66- rect, qualitative occupational characteristics 7.05]). Among these, only paraquat is a known such as “applicator, sprayer, preparing pesticide human nephrotoxicant, although some of the formulation”. Besides, being mostly cross-sec- other agents have shown nephrotoxicity in ani- mal models (27, 28). This Sri Lankan study ob- the temporality of potential pesticide exposure served an increased risk if the source of drink- withintional, the studieswork or retrieved residential could history not withconfirm re- ing water was a serving well (2.52 [1.12 – 5.7]) gard to onset of CKDnt cases (e.g: 15, 25, 26). and a higher risk for abandoned wells (5.43 Such limited exposure assessment may have [2.88 – 10.26]), the latter with higher levels of - glyphosate residues. This strong association is sure status that, if non-differential, may have coherent with the fact that this herbicide has biasedresulted the in resultsimportant towards misclassification the null with of correexpo- been hypothetically linked with ESRD, although sponding underestimation of the true risk. The participants were generally aware of the CKDnt (29), is the most widely used in the disease en- epidemics in their region as well as the fact that demicin a very region superficial and exhibs caveat-full an amphotericecological study and it is thought to be associated, at least in part, zwitterion structure capable of chelating met- with working in sugarcane plantations and cor- als, including nephrotoxic ones (e.g. cadmium). responding pesticide use; thus over- reporting Whether resulting from either an occupational such potential exposure may have occurred. exposure or not, the resulting glyphosate-metal - complex would exhibit a half-life that is hundred tions were measured, appear unlikely since most fold higher than for individual substances (14). subjectsHowever, involved recall bias, in the when reviewed significant studies associa did not Besides, ingestion of water containing 0.1 ppb even know the outcome of their kidney function of glyphosate-based herbicide resulted in kid- tests when they were interviewed. Still, positive ney damage in a two years follow-up rat model associations were obtained in some studies for (30), whereas concentrations measured in the Reviews of evidence for CKDu in relation to hypotheses

Jayasumana et al. study were above 1 µg/l (23). in eGFR were observed over a harvesting sea- Dose-response patterns were observed among son (19), and markers of early tubular kidney a cohort of more than 55 000 US licensed pes- injury did not change over the harvest season ticide applicators, reported by Lebov et al. (24). (31). Finally, a study in three Salvadorian com- Applicators hospitalized for any pesticide expo- munities (10) reports that exposure to methyl- sure had an elevated Cox proportional hazard parathion in one of them, being suburban agri- ratios (HR) for ESRD (3.05 [1.67, – 5.58]). Also, cultural community adjacent to an abandoned ESRD was related to the number of times medical - assistance was sought due to pesticide exposure creased CKD probability (OR 2.6 [1.24-5.45]), warehouse agrochemicals, significantly in (max. HR 2.13 = [1.17 – 3.89], ptrend = 0.0384). but the paper’s methods section only refers Increased HR were also obtained for applica- to self-reported “contact with agrochemicals” tors exposed in the highest intensity-weighted without further characterization . lifetime exposure category as compared to non- In view of Table I, there seem to be a tendency towards positive association between pesticide were obtained, for the following pesticides: atra- exposure and CKD in general being observed in users, and significant exposure-response trends zine (1.52 [1.11 – 2.09], ptrend = 0.008), paraquat recent studies outside Central America. A role (2.15 [1.11 – 4.15], ptrend = 0.016), pendimethalin of pesticides in the etiology of CKDnt can still (HR = 2.13 [1.2 – 3.78], ptrend = 0.0057), alachlor be hypothesized physiopathologically in harsh (HR = 1.51 [1.08-2.13], ptrend = 0.015), metola- working conditions, either due to exposure to chlor (HR = 1.53 [1.08 – 2.18], ptrend = 0.0084) and highly concentrated renal-excreted toxins in permethrin (2 [1.08 – 3.68], ptrend = 0.031). There were associations without exposure – response intake, or increased intake due to greater con- 73 trend for petroleum oil and imazethapyr, and sumptionsituations of of contaminated profuse sweating drinking and lowwater fluid or - inhalation and dermal contact rates resulting phos, parathion, phorate, aldicarb, chlordane and from high cardio-respiratory rhythm and der- metalaxyl.non-significantly No increased increased risks HR were (>1.6) observed for couma for mal vasodilatation. The lack of sound exposure the remaining 25 pesticides. assessment with only crude self-reported bi- Siddharth et al., (3, 4), found higher organo- nary measures of ever exposure to pesticides, a chlorine (OC) pesticide blood concentrations in very large and heterogeneous group of agents, urban CKD patients than in controls, and eGFR and the lack of taking temporality into account in most studies hitherto performed is apparent. hexachlorocyclohexane, aldrin and total OC pes- Along with continued characterization of the in- ticidewas significantlyblood concentrations. negatively Associations correlated were with volved physiopathology, robust and consistent particularly strong among subjects with null exposure assessment throughout the different Glutathione S-transferase (GST) genotypes - and parts of the world affected by CKDnt could in- hence lack of detoxifying enzymes - (4), which form on whether we are facing one global dis- reduces the possibility of reverse causality, i.e. - reduced kidney function and corresponding ex- nal outcomes. Not only workers with repeated cretory capacity resulting in higher blood lev- occupationalease or region-specific pesticide diseasesexposure with but similar also low re els. In a cross-shift study in sugarcane cutters, chronic environmental exposure in the general García-Trabanino et al. (26) observed that ever population should be studied in well-designed prospective studies that accurately accounts for reduced eGFR in sugarcane cutters, whereas potential confounders in order to shed further nousing association carbamate was was observeda significant for predictorglyphosate, of insight on possible causal factors of the disease, paraquat, 2-4 D, organophosphates, triazines, - pyrethroids or captan. In Nicaraguan pesticide aallowing possible the role scientific of pesticides community in CKDnt. to better un derstand, and maybe either confirm or discard, sprayers in a sugar mill, no significant changes Reviews of evidence for CKDu in relation to hypotheses

Conclusion use of agrochemicals, temperature) but also on poverty conditions that could interact with conclusions on the role of pesticides in the any other etiologic factor including toxic expo- etiologyThe results of CKDnt. of this However, review dodespite not allow frequent firm sure. This could bring out regional discrepan- - cies/similarities of CKDnt, clarify the disease’s sulting trend towards absence of risk, positive causes and contribute to the implementation of resultssevere exposurehave been misclassification obtained in several with studies the re measures that will help reduce its serious pub- published in the more recent years, in particu- lic health burden in the affected countries. lar those with better exposure assessments and References to raise questions that should be further inves- 1. Wesseling C, Crowe J, Hogstedt C, Jako- strongertigated before designs. discarding To our view, any causativethis is sufficient role of bsson K, Lucas R, Wegman DH. The epidemic these chemicals known to be toxic to humans in of chronic kidney disease of unknown etiology variable conditions. Arguments in favor of the in Mesoamerica: a call for interdisciplinary re- hypothesis of an etiological role of pesticides in search and action. Am J Public Health 2013 the CKDnt epidemic include 1) CKDnt appears Nov;103(11):1927-30. more frequently in agricultural populations, 2. Chandrajith R, Nanayakkara S, Itai K, Atu- raliya TN, Dissanayake CB, Abeysekera T, et al. areas ;2) those areas all exhibit high pesticide Chronic kidney diseases of uncertain etiology usage,including including women some (32), with in identified likely nephrotoxic high-risk (CKDue) in Sri Lanka: geographic distribution properties (6, 27, 28, 33); 3) a possible chelat- and environmental implications. Environ Geo- 74 ing effect of some pesticides, the prime candi- chem Health 2011 Jun;33(3):267-78. date hypothesized in the literature as being 3. Siddarth M, Datta SK, Mustafa M, Ahmed glyphosate (14, 34), on nephrotoxic metals RS, Banerjee BD, Kalra OP, et al. Increased level present in hard drinking water, which thus may of organochlorine pesticides in chronic kidney accumulate more heavily in renal tissues. Argu- disease patients of unknown etiology: role of ments against pesticide as a cause include that GSTM1/GSTT1 polymorphism. Chemosphere 1) there are hundreds of different active ingre- 2014 Feb;96:174-9. dients of pesticides/agrochemicals, with dis- 4. Siddharth M, Datta SK, Bansal S, Mustafa M, tinct toxicities, that cannot really be grouped all Banerjee BD, Kalra OP, et al. Study on organo- together as if they were one single nephrotoxin, chlorine pesticide levels in chronic kidney dis- as proposed elsewhere (33), without generat- ease patients: association with estimated glo-

in order to point out a single or limited num- Biochem Mol Toxicol 2012 Jun;26(6):241-7. ing a huge misclassification of exposure; 2) that 5.merular Kamel filtration EG, El-Minshawy rate and oxidativeO. Environmental stress. J factor, a truly universal nephrotoxic pesticide factors incriminated in the development of end withber ofnumerous pesticides men as exposed a significant would contributing need to be stage renal disease in El-Minia Governorate, Up- per Egypt. Int J Nephrol Urol 2010 occurred yet. Further investigations should fo- 6. Pan American Health Organization. Chronic identified; however, such identification has not Kidney Disease in Agricultural Communities in exposure measures within a framework that Central America [Online]. 52nd Directing Coun- considerscus on specific a wide agrochemicals range of public and usehealth adequate deter- cil of PAHO, 65th Session of the Regional Com- minants and corresponding actions. Indeed, mittee of WHO for the Americas; 2013 Sep 30- causal hypotheses about CKDnt are not neces- Oct 4; Washington (DC), US. Washington (DC): sarily mutually exclusive, and require equal at- PAHO; 2013 (Resolution CD52.R10) tention. Therefore, future studies should focus 7. Herrera R, Orantes CM, Almaguer M, Alfonso not only on environmental determinants (e.g. P, Bayarre HD, Leiva IM, et al. Clinical character- Reviews of evidence for CKDu in relation to hypotheses istics of chronic kidney disease of nontradition- gel-Ascencio R, Preciado-Martinez V, Munoz-Is- al causes in Salvadoran farming communities. las L, Beltran-Miranda C, et al. Effect of chronic MEDICC Rev 2014 Apr;16(2):39-48. pesticide exposure in farm workers of a Mex- 8. Wesseling C, Crowe J, Hogstedt C, Jakobsson ico community. Arch Environ Occup Health K, Lucas R, Wegman DH. Resolving the enigma 2012;67(1):22-30. of the mesoamerican nephropathy: a research 18. Laux TS, Bert PJ, Barreto Ruiz GM, Gonzalez workshop summary. Am J Kidney Dis 2014 M, Unruh M, Aragon A, et al. Nicaragua revisited: Mar;63(3):396-404. evidence of lower prevalence of chronic kidney 9. Correa-Rotter R, Wesseling C, Johnson RJ. disease in a high-altitude, coffee-growing vil- CKD of unknown origin in Central America: The lage. J Nephrol 2012 Jul;25(4):533-40. case for a Mesoamerican nephropathy. Am J 19. Laws RL, Brooks DR, Amador JJ, Weiner DE, Kidney Dis 2014 Mar;63(3):506-20 Kaufman JS, Ramirez-Rubio O, et al. Changes in 10. Orantes CM, Herrera R, Almaguer M, Brizu- kidney function among Nicaraguan sugarcane ela EG, Nunez L, Alvarado NP, et al. Epidemiol- workers. Int J Occup Environ Health 2015 Jul- ogy of chronic kidney disease in adults of Sal- Sep;21(3):241-50. vadoran agricultural communities. MEDICC Rev 20. Mejia R, Quinteros E, lopez A, Ribo A, Ce- 2014 Apr;16(2):23-30. dillos H, Orantes CM, et al. Pesticide-handling 11. Sanoff SL, Callejas L, Alonso CD, Hu Y, Colin- practices in agriculture in El Salvador: an exam- dres RE, Chin H, et al. Positive association of re- ple from 42 patient farmers with chronic kidney disease in the Bajo Lempa region. Occup Dis En- and unregulated alcohol consumption in Nica- viron Med 2014 Aug;2:56-70. ragua.nal insufficiency Ren Fail 2010;32(7):766-77. with agriculture employment 21. Vela XF, Henriquez DO, Zelaya SM, Granados 75 12. Soderland P, Lovekar S, Weiner DE, Brooks DV, Hernandez MX, Orantes CM. Chronic kidney DR, Kaufman JS. Chronic kidney disease associ- disease and associated risk factors in two Salva- ated with environmental toxins and exposures. doran farming communities, 2012. MEDICC Rev Adv Chronic Kidney Dis 2010 May;17(3):254- 2014 Apr;16(2):55-60. 64. 22. Jayatilake N, Mendis S, Maheepala P, Mehta 13. Wanigasuriya K. Update on uncertain eti- FR. Chronic kidney disease of uncertain aetiol- ology of chronic kidney disease in Sri Lanka's ogy: prevalence and causative factors in a devel- north-central dry zone. MEDICC Rev 2014 oping country. BMC Nephrol 2013;14:180. Apr;16(2):61-5. 23. Jayasumana C, Paranagama P, Agampodi S, 14. Jayasumana C, Gunatilake S, Senanayake P. Wijewardane C, Gunatilake S, Siribaddana S. Glyphosate, hard water and nephrotoxic met- Drinking well water and occupational exposure als: are they the culprits behind the epidemic of to Herbicides is associated with chronic kidney chronic kidney disease of unknown etiology in disease, in Padavi-Sripura, Sri Lanka. Environ Sri Lanka? Int J Environ Res Public Health 2014 Health 2015;14:6. Feb;11(2):2125-47. 24. Lebov JF, Engel LS, Richardson D, Hogan 15. Shavkin S. Countries target pesticides as SL, Hoppin JA, Sandler DP. Pesticide use and suspected link to rare kidney disease. 2013. The risk of end-stage renal disease among licensed Global Mockraker. Sept 19. Available at: http:// pesticide applicators in the Agricultural Health www.icij.org/blog/2013/09/countries-target- Study. Occup Environ Med 2015 Jul 15. pesticides-suspected-link-rare-kidney-disease. 25. Raines N, Gonzalez M, Wyatt C, Kurzrok M, 16. Gorry C. Sounding the alarm on chronic Pool C, Lemma T, et al. Risk factors for reduced kidney disease in farming communities: María - Isabel Rodríguez MD. Minister of health, El Sal- munity affected by Mesoamerican nephropathy. vador, 2013. MEDICC Rev 2013 Jul;15(3):8-10. MEDICCglomerular Rev filtration 2014 Apr;16(2):16-22. rate in a Nicaraguan com 17. Payan-Renteria R, Garibay-Chavez G, Ran- 26. Garcia-Trabanino R, Jarquin E, Wesseling C, Reviews of evidence for CKDu in relation to hypotheses

Johnson RJ, Gonzalez-Quiroz M, Weiss I, et al. Heat stress, dehydration, and kidney function in sugarcane cutters in El Salvador - A cross- shift study of workers at risk of Mesoameri- can nephropathy. Environ Res 2015 Jul 23. doi: 10.1016/j.envres.2015.07.007 27. Kataria A, Trasande L, Trachtman H. The ef- fects of environmental chemicals on renal func- tion. Nature Rev Nephrol. 2015 Oct; 11:610-625 28. Van Vleet TR, Schnellmann RG. Toxic ne- phropathy: environmental chemicals. Sem Nephrol 2003 Sept; 23(5):500-508 29. Samsel A, Seneff S. Glyphosate, pathways to modern diseases II: Celiac sprue and glu- ten intolerance. Interdiscip Toxicol 2013 Dec;6(4):159-84 30. Mesnage R, Arno M, Costanzo M, Malat- esta M, Séralini GE, Antoniou MN. Transcrip- - ney damage following chronic ultra-low dose Rounduptome profile exposure. analysis Environ reflects Health.rat liver 2015 and kidAug 76 25;14(1):70 31. Laws RL, Brooks DR, Amador JJ, Weiner DE, - mell MK, López-Pilarte D. Biomarkers of Kidney InjuryKaufman Among JS, Ramírez-Rubio Nicaraguan Sugarcane O,Riefkohl Workers.A, Scam Am J Kidney Dis. 2016 Feb;67(2):209-17 32. Orantes CM, Herrera R, Almaguer M, Calero DJ, Fuentes de Morales J, Alvarado Ascencio NP, , et al. Epidemiological characteristics of chron- ic kidney disease of non-traditional causes in women of agricultural communities of El Sal- vador.Clinical Nephrology 2015 Jul;83(7 Suppl 1):24-31 33. Jayasinghe S. Chronic kidney disease of unknown etiology should be renamed chronic agrochemical nephropathy. MEDICC Rev 2014 Apr;16(2):72-4 34. Rango T, Jeuland M, Manthritilake H, McCor- nick P. Nephrotoxic contaminants in drinking water and urine, and chronic kidney disease in rural Sri Lanka. Sci Tot Env. 2015; 518-519(6): 574-85 Reviews of evidence for CKDu in relation to hypotheses

Table 1: Studies of interest for exploring the role of pesticides in the etiology of CKD and ESRD published in 2012 and after.

Reference & General Method Outcomea) Association main country findingsb)

Payan-Renteria • Cross-sectional study based on 25 exposed male SCr and serum Negative, but unclear et al., 2012 farmworkers and 21 unexposed workers uric acid description of the Mexico • Exposure assessment: the exposed group had statistical method, sprayed pesticides last season i.e. suggest cluster • Spearman correlations and more multivariate analysis but do not present the corresponding results.

Laux et al., 2012 • Community-based cross-sectional survey on 267 Proteinuria Negative Nicaragua adults (120 ♂) adjusted for • Exposure assessment: face to face questionnaire - DB and HT “Work with pesticides ‘yes/no’” • Univariate and multivariate logistic regressions

77 Siddharth et al., • Hospital-based case-control in 246 adults (128♂), CKD Weak positive 2012 incl. 150 cases (77♂) correlations with India • Exposure assessment: organochlorine pesticide some organochlorine residue levels in blood pesticides • Spearman correlation; 2-way ANOVA with Bonfer- roni analysis

Jayatilake et al., • Cross-sectional population-based prevalence sur- CKD and CKDu Negative, but hardly 2013 vey in 4777 adults (1991 ♂) with case-control analy- interpretable Sri Lanka ses (733 cases, 520 ♂) • Exposure assessment: face to face questionnaire (protection from agrichemicals, all subjects) + uri- nary biomonitoring (57 CKDu patients) • Logistic regressions of risk factors, adjusted for age and sex Reviews of evidence for CKDu in relation to hypotheses

Reference & General Method Outcomea) Association main country findingsb)

Siddharth et al., • Hospital-based case-control in 540 patients (270 CKDu Strong positive 2014 cases, 140 ♂) association with India • Exposure assessment: biomonitoring of organo- HCH, endosulfan, chlorine (OC) pesticide residues in blood; glutathi- DDT and total one S-transferase (GST) genotyping OCs, especially in • Mann-Whitney U-test; multivariate logistic regres- presence of GSTM(-) sions / GSTT(-) genotype, discarding in part the possibility of reverse causality.

Mejia et al., • Descriptive survey of 42 CKDu male farmer cases CKDu Not measurable 2014 • Exposure assessment: face to face questionnaire - El Salvador past exposures conditions to various types of pesticides • Descriptive statistics only

Raines et al., • Cross-sectional population-based survey (424 eGFR Weak positive, 2014 adults, 166 ♂); nested case-control analysis non significant 78 Nicaragua • Exposure assessment: researcher-administered association with questionnaire - detailed conditions and frequen- lifetime days cies of past exposure working with • Uni- and multivariate analyses pesticide (univariate analysis) Significant association with nondeliberate pesticide inhalation (multivariate analysis)

Vela et al., 2014 • Descriptive survey in 223 age ³ 15 (111 ♂) CKD Not measurable El Salvador • Exposure assessment: face to face questionnaire - “contact with agrichemicals ‘yes/no’” • No statistical testing

Orantes et al., • Cross-sectional population-based survey in 2388 CKD Positive association, 2014 adults (876 ♂ ) with methyl- El Salvador • Exposure assessment: face to face questionnaire parathion only, « general/specific contact with agrichemicals” in one of 3 • Uni- and multivariate analyses communities. No information on exposure assessment. Reviews of evidence for CKDu in relation to hypotheses

Reference & General Method Outcomea) Association main country findingsb)

Herrera et al., • Case series (46 individuals age 18-59, incl. 36 ♂) CKD Not measurable 2014 • Exposure assessment: personal interview by soci- El Salvador ologist with tailored questionnaire - Farming, con- tact with agrichemicals • Descriptive statistics only

Laws et al., • Cohort of 284 sugarcane workers (251♂), incl. SCr, eGFR, Negative 2015 and Laws agrochemical applicators proteinuria, et al., 2016 • Exposure assessment: Field worker vs non-field tubular Nicaragua worker; agrichemical applicator vs factory worker markers of • t-tests, paired t-test, multivariate regressions, pre- kidney injury post harvesting season

Orantes et al., • Cross-sectional population-based survey in 1412 CKD and Not measurable 2015 women aged ³ 18 CKDnt El Salvador • Exposure assessment: face to face questionnaire - agricultural worker, contact with general/specific agrichemicals • Descriptive statistics only 79 García- • Cross-sectional study in 189 sugarcane cutters (168 eGFR adjusted Positive association, Trabanino et al., ♂) for HT with “ever used 2015 • Exposure assessment: face to face questionnaire - carbamate” El Salvador general and specific pesticide use ever • Logistic regressions

Jayasumana et • Case-control in 305 adults (187 ♂), incl. 125 cases CKDu Strong positive al., 2015 (89♂) associations in Sri Lanka • Exposure assessment: face to face questionnaire bivariate (exposure detailing pesticide use up to 10 years back in time; to multiple specific drinking from serving wells and abandoned wells; pesticides) and analyses of glyphosate, metals, and hardness re- multivariate lated parameters in water from serving and aban- analyses (drinking doned wells well water • Bi- and multivariate logistic regression contaminated with pesticides, applying pesticide and use of glyphosate). Some dose-response pattern Reviews of evidence for CKDu in relation to hypotheses

Reference & General Method Outcomea) Association main country findingsb)

Rango et al. • Cross-sectional study in 109 adults and 25 children Albumin / Use of herbicides 2015 aged 10-<18. 82♂. creatinine significantly higher Sri Lanka • Exposure assessment: Concentration of As, Cd, ratio in regions of Pb, Mo and U in urine. Household survey data on endemic CKDu. reported past pesticide use • Logit regressions

Lebov et al., • Cohort of 55 580 licensed pesticide applicators ESRD Strong positive 2015 (320 ESRD) association for USA • Exposure assessment: self-administered question- medical assistance naire regarding past use of 39 specific pesticides, due to pesticide accounting for a 5-years post enrolment lag time exposure; significant (to prevent healthy worker effect). Take-home exposure response questionnaire (n=24 565, 130 ESRD cases) for addi- trends for tional pesticide information intensity-weighted • Cox proportional hazards models, adjusted for age lifetime use of and state; sensitivity analyses alachlor, atrazine, metolachlor, paraquat, 80 pendimethalin, and permethrin.

Abbreviations: disease; GST, glutathione-S-transferase; HT, hypertension; SCr, serum creatinine a) CKD name as usedCKD, bychronic the authors kidney (i.e.disease; “CKD”, DB, “CKDnt” diabetes; or “CKDu”)eGFR, glomerular filtration rate; ESRD, end-stage renal b) Association between the outcome indicated in the previous column and pesticide exposure as assessed in the study. Reviews of evidence for CKDu in relation to hypotheses

As a result, the combination of the effects of Proposed mechanisms for chronic low kidney perfusion, high tubular reabsorption kidney disease of uncertain etiology demands, high urine uric acid with the pres- observed in Central America ence of urate crystals, and vasopressin effects, (Mesoamerican Nephropathy) could be producing daily, recurrent kidney dam- age that accumulates over time. This proposed mechanism: a) is supported by the recently published evidence, b) matches the histological Richard J Johnson, Division of Renal Diseases lesions, and d) explains the clinical features of and Hypertension, University of Colorado Denver, the disease, including the dysuria often report- Anschutz Medical Campus, Aurora CO, USA. ed by patients (passing of sandy urine). Ramon García-Trabanino, Association of This hypothesis opens the way for clinical tri- Nephrology and Hypertension of El Salvador, San als focused on the use of drugs blocking the de- Salvador, El Salvador. scribed pathways, possibly leading to treatment options in early stages, and ways to prevent the disease from developing in high-risk popula- tions. Summary A wide variety of etiologies have been pro- Main Text posed to explain the cause of Mesoamerican The majority of patients with Mesoamerican Nephropathy in Central America, including ex- nephropathy (MeN)[1-3] are male, working posure to herbicides, pesticides, heavy metals manually outdoors in hot tropical environments. 81 (cadmium, arsenic, lead), toxins (Aristolochia), [4-7] Apart from the occasionally reported dys- drugs (NSAIDs), infections (Leptospirosis, Hanta uria, patients are mostly asymptomatic, typi- virus), metabolic causes (hypokalemia, hyperuri- cally presenting low-grade proteinuria (< 300 cemia), and the effects of strenuous physical la- mg/day) and elevated serum creatinine. Hypo- bor in the presences of heat stress and recurrent kalemia and hyperuricemia are common. Blood dehydration. pressure is normal or mildly elevated, and dia- - betes is absent. Some have crystalluria with di- clic daily uricosuria induced by heat stress and hydrate urate crystals and occasional subjects strenuousRecent findings work as support a plausible the cause.hypothesis Serum of uric cy have microhematuria.[8] Kidney biopsies show acid levels rise during the workday due to the in- - creased release of substrate (purines) as a prod- mation, often with ischemic changes and glo- uct of the intense muscle activity associated with merulosclerosis.[9]chronic tubulointerstitial fibrosis with inflam strenuous labor and heat stress, leading to uri- cosuria. Simultaneously, physical activity gener- On the Etiology of ates endogenous heat, which adds up to the high Mesoamerican Nephropathy environmental heat stress, increasing body core Chronic tubulointerstitial disease may have temperature. A transient state of volume deple- multiple etiologies and has led to several poten- tion ensues, producing a fall in kidney perfusion tial hypotheses for what might be causing the and high demands on tubular reabsorption, with - the consequent activation of several compensa- cuss the major hypotheses. tory mechanisms (systemic vasopressin and local epidemicHerbicides (Table and 1).[1,2,8]Other Pesticides We will. brieflyThe initial dis activation of the aldose reductase-fructokinase observation that CKD was common in pathway in the renal tubule). Then, uricosuria in agricultural workers led to the hypothesis that it might relate to exposure to herbicides (such formation of urate crystals. as glyphosate and 2,4-D) or insecticides (such the concentrated and acidified urine leads to the Reviews of evidence for CKDu in relation to hypotheses

as chlorpyrifos and cypermethrin).[10,11] Glyphosate ingestion can be associated with not yet been determined. acute kidney injury (AKI), and has been linked gion,Inorganic affecting arsenic specifically species malemay also workers, be poten has- to a similar epidemic in Sri Lanka.[12] Since tially nephrotoxic and have been linked with glyphosate is a chelating compound that forms proteinuria,[20,21] biomarkers of kidney in- complex molecules with metals present in hard jury,[22] and hyperuricemia.[23] However, ar- senic poisoning is also associated with many molecules could cause damage. However, in Mesoamericawater, when filtered a primary through role forthe agrichemicals kidney these such as hyperkeratosis on the palms and soles, seems unlikely. First, because workers at high leukonychiaother findings striata not (Mee’s present nail in lines), MEN liver patients, and altitude have a lower frequency of disease than gastrointestinal dysfunction. those working at low altitude, despite similar Silica exposure, which is released from burn- pesticide exposure.[6,13] Second, studies of ing sugarcane, has also been suggested as a sugarcane workers show that cutters, not potential mechanism to explain the epidemic. agrichemical sprayers, have the greatest risk Some studies suggest that individuals with high [14,15]. Epidemiological studies of the general silica exposure, such as those working in con- population also do not show an association with struction or agriculture, have a higher frequen- pesticides.[5] Furthermore, the observation cy of CKD.[24] However, inhaled silica is usually that MeN also occurs in other occupations is associated with pulmonary symptoms and sili- not consistent with a pesticide mechanism. - Finally, the toxicity of most agrichemicals ing in MeN patients. 82 involves neurological, respiratory, hepatic, cosis,Chronic which lead does toxicity not appearis also possible, to be a usual as it can find be and gastrointestinal signs, symptoms and associated with CKD and hyperuricemia,[25-27] syndromes, which are absent from the clinical and can induce and accelerate tubulointerstitial presentation of MeN. Heavy Metals and Toxins. Heavy metal poi- would occur primarily in the men working in the soning from contaminated ground water has disease,[28] but it is difficult to explain why it also been proposed, and at least one study has Aristolochic acid. Accidental ingestion of plants suggested cadmium toxicity may be involved in containingfields, as opposed aristolochic to the acid, general a carcinogenic population. com- the CKD epidemic occurring in Sri Lanka.[12] pound, produces a rapidly progressive chronic Cadmium was the cause of a major outbreak of tubulointerstitial disease (aristolochic acid as- kidney disease in the early 20th century in the sociated nephropathy) and is the cause of the Jinzu River Basin, Toyama Prefecture, Japan, due Balkan Endemic Nephropathy and the Chinese to contamination from a mine.[16] However, Herbs Nephropathy.[29] Kidney biopsies gener- the disease (itai-itai) presented more as a Fan- coni syndrome with severe hypophosphatemia appear to distinguish this from MeN, where fo- and a vitamin D-resistant rickets. Nevertheless, ally show very little inflammation, which might cadmium poisoning has been associated with hypertension and hyperuricemia,[17] possibly aristolochiccal inflammation acid nephropathy is common. is However, because recentbiop- due to stimulation of xanthine oxidase by cad- siesstudies are suggestoften collected that the inlack the of late inflammation phase of the in mium.[18] Low grade cadmium nephrotoxicity disease, and some studies suggest that its early is still possible, as some studies suggest chronic renal injury is indeed associated with a pro- toxicity is associated with elevated urinary bio- - markers of tubular damage and a slow decline in kidney function over time,[19] although a populationnounced inflammatory would be exposed infiltrate.[30] to this toxin. Neverthe source for a hypothetical broad cadmium con- less,Nonsteroidal it seems unlikely agents that. A suchpotential a large, iatrogenic specific tamination throughout the Mesoamerican re- cause is the frequent use of nonsteroidal an- Reviews of evidence for CKDu in relation to hypotheses

The Role of Dehydration and known cause of AKI, especially in the setting Heat Stress as a Cause of ofti-inflammatory volume depletion. analgesics NSAIDs, (NSAIDs), which are awidely well- Mesoamerican Nephropathy available, are commonly taken with and with- out prescription by workers for the aches and history of working in hot environment where muscle pains they suffer from the demands of theyA common are at findingrisk for in recurrentpatients with dehydration MeN is a their work. The possibility that chronic use of [13,37-39]. Some studies show that heat indices NSAIDs may be an aggravating factor in the CKD - epidemic seems plausible.[10] It is known that cupational Safety and Health Administration, by recurrent analgesic use (primarily compounds midmorningcross into the on unsafe a typical zone, work defined day.[38] by the Work Oc- containing paracetamol, but NSAIDs may fall ers not uncommonly develop signs of dehydra- into this category as well) can result in chron- tion during the workday, as noted by symp- ic tubulointerstitial disease, occasionally with toms (lightheaded, fainting) and signs (urinary papillary necrosis, [31] a feature not observed concentration with a rise in urine osmolarity). in the MeN biopsies. [13,37-39] Metabolic Causes. Chronic hypokalemia is com- Recurrent heat stress and dehydration mon in patients with MeN, possibly induced by may promote kidney damage via several chronic volume depletion. Chronic hypokalemia mechanisms. First, sugarcane workers are prone to developing subclinical rhabdomyolysis. part by stimulating intrarenal angiotensin and [40] While frank rhabdomyolysis is a classic endothelinis known to production.[32] cause tubulointerstitial Subjects fibrosis, may also in cause of AKI, there is concern that recurrent develop nephrogenic diabetes insipidus, and subclinical rhabdomyolysis might also result 83 over time may show a loss of kidney function. in repeated and subtle damage to the kidney Also, dehydration can be a source of volume over time. Second, dehydration (loss of water - greater than salt) is known to stimulate both ing in subjects with MeN is hyperuricemia.[13] the aldose reductase and vasopressin systems. Hyperuricemiadepletion. Another has been common shown metabolic experimentally find There is evidence that chronic vasopressin to cause both glomerulosclerosis and tubuloin- stimulation may induce and accelerate CKD. terstitial disease.[33-35] The role of uric acid in [41] Furthermore, we found that activation of MeN is discussed in more detail below. the aldose reductase-fructokinase enzymes in Infectious causes. Leptospirosis causes acute the proximal tubule of chronically dehydrated interstitial nephritis, often with fevers, conjunc- mice also develop CKD with tubulointerstitial tivitis, muscle pains, and liver dysfunction, and is passed by skin exposure to rodent urine, a presence of urate crystalluria in sugarcane - workersfibrosis.[42] in El Finally, Salvador we recentlythat approach identified levels the bility that severe or recurrent leptospirosis may similar to what is observed in the tumor lysis leadfrequent to CKD plague has inbeen sugarcane entertained, fields. but The the possi lack syndrome.[8] Thus, we have hypothesized that of other features (liver disease, meningitis, etc.) dehydration and/or subclinical rhabdomyolysis makes this possibility less likely.[36] Likewise, might lead to a rapid rise in serum uric acid while some Hanta viral infections may cause and uricosuria, crystallizing in the acidic, acute or chronic tubulointerstitial disease, no concentrated urine.[8] In turn, crystals might induce local injury via binding to toll-like patients to date. receptors or other mechanisms.[43,44] It specific pathogen has been identified in these is interesting that many sugarcane workers complain of dysuria, possibly a symptom of passing sand in their urine, locally referred to as chistata in Nicaragua and mal de orín in El Reviews of evidence for CKDu in relation to hypotheses

Figure 1. Proposed mechanism of chronic kidney injury in Mesoamerican nephropathy.

84

Salvador.[13,45] As a result, the combination of tions. Currently there is a major ongoing study the effects of low kidney perfusion, high tubular to determine if improved hydration and proper reabsorption demands, urine urate crystals, and rest in shady spots can reduce the development vasopressin effects could be producing kidney of CKD. Results of this study might provide key damage on a daily basis. Figure 1 presents insights into how to reverse the epidemic and the proposed mechanism for Mesoamerican provide better health for those living in the re- nephropathy. gion. In summary, while the etiology of the epi- demic of CKD in Central America remains un- Table 1. Proposed Causes of Mesoamerican known, the strongest evidence to date suggests Nephropathy that heat stress and recurrent dehydration play an important role, if not the dominant mecha- Agrichemicals and Pesticides nism, in the development of MeN (Figure 1). Glyphosate (herbicide, metal chelator) This hypothesis opens the way for clinical tri- 2,4-D (herbicide 2,4-dichlorophenoxy- als focused on the use of drugs blocking the de- acetic acid and dioxin) scribed pathways, possibly leading to treatment Chlorpyrifos (insecticide, a cholinester- options in early stages, and ways to prevent the ase inhibitor) disease from developing in high-risk popula- Cypermethrin (insecticide, a nerve so- Reviews of evidence for CKDu in relation to hypotheses

dium channel modulator) 4. Torres C, Aragon A, Gonzalez M, Lopez I, Paraquat (herbicide, reactive oxygen Jakobsson K, Elinder CG, Lundberg I, Wessel- species => acute tubular necrosis) ing C: Decreased kidney function of unknown Heavy metal and toxin exposure cause in nicaragua: A community-based survey. Cadmium - Arsenic cial journal of the National Kidney Foundation Lead 2010;55:485-496.American journal of kidney diseases : the offi Silica (from burning of sugarcane) 5. O'Donnell JK, Tobey M, Weiner DE, Stevens Aristolochic acid LA, Johnson S, Stringham P, Cohen B, Brooks DR: Nonsteroidal agents (iatrogenic) Prevalence of and risk factors for chronic kidney disease in rural nicaragua. Nephrology, dialysis, Metabolic Causes - Hypokalemia pean Dialysis and Transplant Association - Euro- Hyperuricemia peantransplantation Renal Association : official 2011;26:2798-2805. publication of the Euro 6. Peraza S, Wesseling C, Aragon A, Leiva R, Infectious Causes Garcia-Trabanino RA, Torres C, Jakobsson K, Leptospirosis Elinder CG, Hogstedt C: Decreased kidney func- Hanta virus tion among agricultural workers in el salvador. - Recurrent Dehydration and Heat Stress cial journal of the National Kidney Foundation Subclinical rhabdomyolysis 2012;59:531-540.American journal of kidney diseases : the offi Dehydration with stimulation of vaso- 7. McClean MA, Amador JJ, Laws R, Kaufman 85 pressin JS, Weiner DE, Sanchez-Rodriguez JM, Ramirez- Dehydration with activation of aldose Rubio O, Brooks DR: Biological sampling report: reductase and fructokinase in the renal Investigating biomarkers of kidney injury and tubule chronic kidney disease among workers in west- Uricosuria ern nicaragua Heat stroke 8. Roncal-Jimenez CA, Garcia-Trabanino R, Barregard L, Lanaspa MA, Wesseling C, Harra T, References Aragon A, Grases F, Jarquín E, Gonzalez M, Weiss 1. Wesseling C, Crowe J, Hogstedt C, Jakobsson I, Glaser J, Sanchez-Lozada LG, Johnson RJ: Heat K, Lucas R, Wegman D: Mesoamerican nephropa- stress nephropathy from exercise-induced uric acid crystalluria: A perspective on mesoameri- workshop on men. Http://www.Regionalne- can nephropathy American journal of kidney phropathy.Org/wp-content/uploads/2013/04/thy: Report from the first international research preprint-technical-report.Pdf. Heredia, Costa Kidney Foundation 2015;submitte Rica, SALTRA / IRET-UNA, 2013. 9.diseases Wijkstrom : the J, official Leiva journalR, Elinder of theCG, NationalLeiva S, 2. Correa-Rotter R, Wesseling C, Johnson Trujillo Z, Trujillo L, Soderberg M, Hultenby RJ: Ckd of unknown origin in central america: K, Wernerson A: Clinical and pathological The case for a mesoamerican nephropathy. characterization of mesoamerican nephropa- - thy: A new kidney disease in central america. cial journal of the National Kidney Foundation - 2014;63:506-520.American journal of kidney diseases : the offi cial journal of the National Kidney Foundation 3. Weiner DE, McClean MD, Kaufman JS, Brooks 2013;62:908-918.American journal of kidney diseases : the offi DR: The central american epidemic of ckd. Clini- 10. Orantes CM, Herrera R, Almaguer M, Bri- cal journal of the American Society of Nephrol- zuela EG, Hernandez CE, Bayarre H, Amaya JC, ogy : CJASN 2013;8:504-511. Calero DJ, Orellana P, Colindres RM, Velazquez Reviews of evidence for CKDu in relation to hypotheses

ME, Nunez SG, Contreras VM, Castro BE: Chronic medicine : eCAM 2012;2012:548430. kidney disease and associated risk factors in the 19. Wallin M, Sallsten G, Lundh T, Barregard bajo lempa region of el salvador: Nefrolempa L: Low-level cadmium exposure and effects on study, 2009. MEDICC review 2011;13:14-22. kidney function. Occupational and environmen- 11. Vela XF, Henriquez DO, Zelaya SM, Granados tal medicine 2014;71:848-854. DV, Hernandez MX, Orantes CM: Chronic kidney 20. Zheng LY, Umans JG, Tellez-Plaza M, Yeh disease and associated risk factors in two sal- F, Francesconi KA, Goessler W, Silbergeld EK, vadoran farming communities, 2012. MEDICC Guallar E, Howard BV, Weaver VM, Navas-Acien review 2014;16:55-60. A: Urine arsenic and prevalent albuminuria: Evi- 12. Jayasumana C, Gunatilake S, Siribaddana S: dence from a population-based study. 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The American journal of medicine Kong LD: Quercetin protects against cadmium- 2002;113:563-568. induced renal uric acid transport system al- 27. Sanchez-Fructuoso AI, Torralbo A, Arroyo teration and lipid metabolism disorder in rats. M, Luque M, Ruilope LM, Santos JL, Cruceyra Evidence-based complementary and alternative A, Barrientos A: Occult lead intoxication as a Reviews of evidence for CKDu in relation to hypotheses cause of hypertension and renal failure. Ne- cemia causes glomerular hypertrophy in the rat. American journal of nephrology 2003;23:2-7. publication of the European Dialysis and Trans- 35. Mazzali M, Hughes J, Kim YG, Jefferson JA, plantphrology, Association dialysis, - European transplantation Renal Association : official Kang DH, Gordon KL, Lan HY, Kivlighn S, John- 1996;11:1775-1780. son RJ: Elevated uric acid increases blood pres- 28. 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44. - tory reaction to crystals. Rheum Dis Clin North Am Terkeltaub1988;14:353-364. RA, Ginsberg MH: The inflamma 45. Ramirez-Rubio O, Brooks DR, Amador JJ, Kaufman JS, Weiner DE, Scammell MK: Chron- ic kidney disease in nicaragua: A qualitative analysis of semi-structured interviews with physicians and pharmacists. BMC public health 2013;13:350.

Acknowledgments. We thank our numerous collaborators on this project, including, Aurora Aragon, Lars Barregard, Ricardo Correa-Rotter, Marvin Gonzalez, Annika Werneson, Tamara Harra, Emmanuel Jarquín, Miguel Lanaspa, Car- los Roncal-Jimenez, Laura G Sanchez-Lozada, David Wegman, Sandra Peraza, Ilana Weiss, Ja- son Glaser, Catharina Wesseling and others. Disclosures. Dr R Johnson is on the Scien-

Department of Defense, VA Administration, Na- 88 tionaltific Board Institute of Amway, of Health, and Amway, has grants Danone, from andthe La Isla Foundation. He has patents and patent applications related to blocking uric acid and fructose metabolism, and he is a member of Col- orado Research Partners LLC that is developing inhibitors of fructose metabolism. Dr Johnson - peutics and has stock in this company that is de- velopingis also on novel the Scientificxanthine oxidaseBoard of inhibitors. XORT Thera Reviews of evidence for CKDu in relation to hypotheses

cía-Trabanino et al 2015)6 which represented Worker’s Health and Efficiency two distinct environments; the coastal area at Program – Lessons learned from a sea level (coastlands) and an inland area at 350- pilot intervention in El Salvador 450 masl altitude (inlands). The intervention: The intervention adapted OSHA’s Water.Rest.Shade program in Theo Bodin, Karolinska Institutet, Sweden Emmanuel Jarquin, AGDYSA, El Salvador. · A rest schedule was developed adapted Ilana Weiss, La Isla Foundation, Nicaragua. conjunctionfrom the USwith Army efficiency Research training. on Environmen - Ramón Garcia-Trabanino, Association of tal Health (USARIEM) Heat Strain Decision Nephrology and Hypertension of El Salvador. Aid7 - David H. Wegman, University of Massachusetts ting. Lowell, USA · All, breaksmodified took for place feasibility in the in shade this work of a por set- table canopy built by the mill. Mill staff man- aged the Canopies moving them with the Rational for the study cane cutting teams throughout each work- We undertook an intervention study designed day. to prevent heat stress and dehydration among · Potable water was provided by the mill, de- sugarcane cutters of a mill in El Salvador as a means to improve working conditions and to » The water was stored in 40 Liter cool- prevent CKD. Since sugar cane cutting is piece- livereders dailyunder by each water shade truck canopy. to the field. 89 work, measures of maintaining or increasing » Each worker was supplied with a 3 productivity was a key part of the intervention. Liter backpack-mounted bladder with The study design has three phases: Phase 1 - a from CamelBak® to permit continuous each of the study elements; Phase 2 - an expan- connected flexible tube and mouthpiece pilot study to examine feasibility by field-testing- at rest breaks with water from the cooler. ine feasibility and cost of a large-scale interven- Workershydration. were The urged CamelBaks to continue were rehydra refilled- tionsion asto wella sufficiently as examine large the population effectiveness to examof the tion while returning to their community. intervention in preventing heat stress and dehy- - dration; Phase 3 - an expansion of the interven- perienced Australian cane-cutting experts. It tion beyond a single mill to demonstrate gener- consistedEfficiency of trainingtwo parts: was conducted by two ex alizability of the intervention. We are reporting 1. A new design of the machete improved the on the feasibility studied in the pilot effort. ergonomics of repetitive movement of cutting cane, and Methods 2. Fewer rows cut to reduce lateral carrying dis- tance and consequently metabolic load. Study population: Two groups (cutting fronts), cutting for Ingenio Data collection: At a meeting before the El Angel (the mill), were selected to take part in harvest began, the study design and purpose was the intervention. We had had an earlier positive explained. At baseline all volunteers provided experience working with these two fronts (Gar- their signed informed consent for the following:

1. García-Trabanino R, Jarquín E, Wesseling C, Johnson RJ, González-Quiroz M, Weiss I, Glaser J, José Vindell J, Stockfelt L, Roncal C, Harra T, Barregard L. 2015. 2. Laurie Blanchard, USARIEM – personal communication. Reviews of evidence for CKDu in relation to hypotheses

· Blood and urine samples on four sampling Concerning the individual components we days [pre- and post-shift at baseline, imme- learned: diately before, during and at the end of the · Blood and urine samples were successfully intervention] collected at beginning and end of shift. · Urine samples pre-post-shift every second » There were some nervous moments in week [8 additional times] Blood pressure, heart rate and weight appropriate coolers to protect the sam- · Baseline questionnaire on a) socio-demo- plesmaking to transport sure that to we the had laboratory sufficient to and be graphics, b) past and present work history, frozen and shipped. c) use of tobacco, alcohol and recreational » The general cooperation of all partici- drugs, d) general health and medications, e) family history of CKD and f) past and present time taken to clearly explain what we symptoms of heat stress and dehydration. neededpants in and sample why. collection justified the · Brief questionnaires every second week on · heat stress or dehydration symptoms, esti- sameUrine next analysis year. Thein the key field is identifying worked quite and well hir- and shade [12 times] and we are confident that this will prove the- ·mated A sub-study total fluid of ingestion,10-11 who use wore of rest heart breaks rate cians to carry out this work responsibly. monitors and accelerometers for 7 days to ing· Collection qualified ofand weight committed and heart research rate technibefore estimate workload. work started was reasonably successful. Baseline measurement of BP was possible 90 with the requisite 5-minute rest period, but andMicroscopy, hemogram specificwas performed gravity the by same microscopy day. All this could not be done successfully in the otherand dip-stick samples ofwere urine shipped were to done Sweden in the and field an- alyzed in an accredited laboratory in one single likely not include BP after baseline in the fu- run to avoid variability. Weather information ture.field before Body aweight regular after working baseline, day. similarly We will and Wet Bulb Globe Temperature (WBGT) was will also not be considered next year since measured continuously on a daily basis using a there are to many errors due to water and QUESTemp® 34. food intake in an uncontrolled environment. · Our baseline questionnaire worked well Lessons learned but was too long. We learned about some Preparations important confusions and ambiguities (e.g.,

Study Objectives: The pilot study was to certain time-frames (i.e. “During the last designed to test the intervention, to assure that threefamily, weeks, income) have as wellyou...”) as difficultiesthat made thisrelated pi- participants would volunteer, and to test data lot effort all the more valuable. We plan to - correct these areas of confusion, better tar- mined to test study and intervention feasibility get questions on some items and shorten the andcollection acceptance in the rather field. than Sample to achieve size was an detereffect questionnaires. - · To our pleasant surprise the sub-study of fectiveness. workload worked out quite well and coop- size for significance testing of intervention ef eration was excellent. We will try this again The Protocol: Overall, we tried to do too in the next zafra selecting participants who much. We want to emphasize that each piece of represented a range of work production as well as trying some improved technology for to a study question to justify its inclusion to lim- heart rate monitoring. itdata data collection collection should and reduce be specifically risk of error. matched · We determined it necessary to send the Reviews of evidence for CKDu in relation to hypotheses

frozen samples to a collaborating laboratory in Sweden. While this was less than ideal in spokesperson(s) to communicate effectively withming the primarily target population. from a failure to find the best went smoothly and all samples were received Despite this failure with this second group andterms logged of efficiency without problem. the process The ultimatelycomplete we continued to engage with that group. By laboratory data are just now becoming avail- the end of the zafra we believe we successful- able to us. ly addressed the miscommunication and par- We wish to offer the following general advice ticipants asked to be included in the end-zafra measurements as well as volunteered interest in being part of the full study in the following about· Has developing to be decided a protocol upon for at suchleast a three field year. study.months We concludebefore the a finalstart studyof the protocol. study to allow all stakeholders to make appropriate prepa- Risk management El Salvador is a violent and partly unsafe en- related delays. rations· Should and be providetranslated sufficient into a detailedtime for to-do IRB- history of violence and exploitation of workers list and by counting backwards appropriate vironment in which to conduct field studies. Its deadlines should be assigned to all items many uncertainties and risks. We needed to ar- with a substantial safety-margin. Err on the rangemakes for it aa difficultsecurity taskescort to toachieve accompany goals ourdue re to- side of too much detail. It is almost impos- - sible to overthink what needs to be planned for. followedsearch team by aduring coordinated each field approach visit. The to reduceidenti 91 · Planning ahead is especially important for thefication, probability assessment, and/or and impact prioritization of unfortunate of risks all types of equipment that cannot be bought events is crucial to success. Building a team of or rented in the country but has to be im- local staff and continuous dialogue with part- ported. ners, workers, the local community and security · Items requiring engagement of multiple forces are a good approach. stakeholders and other complex processes should be given priority. Communication A communication strategy should be devel- Health Problems that Arise: A plan oped on the basis of the needs of all parties. on how to report results to workers and han- Written communication using email is highly dle participants with possible health problems recommended, even when importance seems should be developed beforehand. Informing small. Although the existing, complexities of local healthcare providers and reaching agree- work organization and relationships among ments on referrals is important. While we made personnel can be formally described to investi- sure to make such plans, we found that there gators all organizations include informal struc- were barriers to easy access to necessary health tures and power relationships. These are only care. revealed to outsiders as they become impor- tant. We learned that we needed to assume that Gaining Participation: Reaching out and everyone wants to be copied on everything, and - ticipants before the study starts is of utmost once. importance.starting a sufficient This was dialogue not as straight-forward to potential par as that we needed to re-confirm everything at least we had hoped it would be. In our pilot we had communication with the workforce throughout to withdraw from one group due to security theOne study. of theUnless more we difficultwere careful, tasks communica is effective- concerns as well as a lack of participation stem- tion to the workforce occurred only in groups Reviews of evidence for CKDu in relation to hypotheses

or through workforce leadership. We were able that are developed for each process or mea- to address the problem with reasonable success

(sunrise to end of work) on regular occasions. evensurement an untrained in the field. assistant The lead should theme be ableshould to Weby havingbecame our known investigators and workers in the were field able all to day in- succeed.be “make it easy to do it right” sufficient that teract with us over the course of a workday. Managing resources Intervention roll-out The complex dynamics of a project such as the Intervention studies in work settings are not WE program, which was implemented in a short common. There is a very good reason for this. time frame and with participation of multiple Hardly anyone likes change. For that reason local and foreign partners, require the estab- alone, it was critical that we engaged partici- lishment of a clear budget with ongoing discus- pants at all levels from the earliest possible mo- ment. Everyone was going to be impacted by the confusion, establish study constraints, and fa- changes we were implementing. As we initiat- cilitatesions of necessaryflexible expenditure adjustments spending as the toproject avoid ed our intervention we made certain to take a evolves. This way, the limitations of the study step back and allow the engineers, agronomists, in regards to sample size, work team size, num- cane-cutters and caporales take part in planning and decision-making. An intervention, espe- managed as effectively as possible. cially on a larger scale, is costly, time-consum- ber of field visits, lab tests selection, etc., can be ing and induces a great deal of uncertainty. To Implications for future studies 92 achieve the necessary long-term commitment We conclude that a pilot study in advance of to the change it is essential to establish a notion any effort to implement a full-scale intervention of ownership by all actors and a willingness to study is invaluable. Had we attempted to imple- assume responsibility for the different compo- ment a full-scale study from the beginning, the nents of the intervention. We had to be as clear number of problems and complications that we as possible about the intended intervention, the confronted would likely have caused the effort to fail. There is no question that a pilot effort these into the existing work practices and work of this scale is costly, time consuming and de- environment.objectives we hadWe incannot mind overemphasize and the need to the fit lays the implementation of an intervention that is strongly believed to be necessary and appro- to achieve this. For example, we developed a priate. Nonetheless, in the interests of achiev- Water.Rest.Shadeneed to be flexible schedule and open that to different was based routes on laboratory studies in a normal population in a to convince skeptics, we believe a pilot effort of temperate climate. The schedule design, while someing broad sort is acceptance essential. and We evidencestill have sufficientthe chal- lenges ahead to carry out the expanded inter- vention study and to demonstrate intervention Opengenerally discussion appropriate, with didthe not key fit personnelas well as were- effectiveness. We are looking forward to those sultedhad hoped in an toacceptable the work compromise, practices in which the field. was challenges. then implemented. One last comment that is particularly ger- mane to the objectives of this workshop. Since Data collection these studies are costly and time-consuming, Fieldwork is time-consuming and subject to a study populations are usually small. We believe lot of potential errors. Developing a “fool-proof” it is important to start coordinating studies plan while recognizing nothing is truly “fool- wherever possible and to share protocols and proof” is of utmost importance. The protocol questionnaires to enable future pooled analysis must include detailed, step-by-step instructions

of data within this field. Reviews of evidence for CKDu in relation to hypotheses

References 1. García-Trabanino R, Jarquín E, Wesseling C, Johnson RJ, González-Quiroz M, Weiss I, Gla- ser J, José Vindell J, Stockfelt L, Roncal C, Harra T, Barregard L. Heat stress, dehydration, and kidney function in sugarcane cutters in El Sal- vador - A cross-shift study of workers at risk of Mesoamerican nephropathy. Environ Res. 2015 Jul 23. pii: S0013-9351(15)30028-1. doi: 10.1016/j.envres.2015.07.007. 2. Laurie Blanchard, USARIEM – personal communication.

93 Reviews of evidence for CKDu in relation to hypotheses

is to identify the cause(s) of the epidemic to in- Boston University School of Public form intervention studies and minimize risk of Health: Studies of occupational and chronic kidney disease (CKD). non-occupational risk factors for - chronic kidney disease tween 2008 and 2012 and was presented at the 2012The Mesoamerican first phase of our Nephropathy work was conducted Workshop be in San José, Costa Rica. This phase included the fol- lowing activities: · A Scoping Study, summarizing the avail- Michael D. McClean, Boston University, USA. able information on CKD in the region, identi- Rebecca L. Laws, Boston University, USA. fying data gaps, and recommending research Juan José Amador, Boston University, USA. activities to address those gaps (BUSPH 2009; Damaris López-Pilarte, Boston University, USA. Ramirez-Rubio et al. 2013b; Soderland et al. Madeleine K. Scammell, Boston University, USA. 2010; Weiner et al. 2013); Oriana Ramírez-Rubio, Boston University, USA. · An Investigation of CKD Prevalence and David J. Friedman, Boston University, USA. Risk Factors in Rural Nicaragua, involving a James S. Kaufman, Boston University, USA. partnership with the Brookline-Quezalguaque Daniel E. Weiner, Boston University, USA. Sister City Committee to characterize the extent Alejandro Riefkohl, Boston University, USA. and nature of CKD in Quezalguaque, Nicaragua Daniel R. Brooks, Boston University, USA. (O’Donnell et al. 2011); · An Industrial Hygiene/Occupational 94 Health Assessment, evaluating the potential hazards associated with chemicals and work Introduction practices at a sugarcane company in northwest- The research group at the Boston University ern Nicaragua and providing recommendations School of Public Health (BUSPH) has been in- for improving working conditions (McClean et vestigating Mesoamerican Nephropathy (MeN) al. 2010); in Central America since 2008. Given that the · A Preliminary Investigation of Water Qual- disease likely has a multifactorial etiology, our ity, assessing approximately 200 contaminants broad research program includes multiple stud- in water samples collected from six locations ies designed to investigate the role of occupa- selected by representatives of the affected com- tional and non-occupational risk factors experi- munity (Atkins et al. 2010); enced along the lifespan. At birth, there may be · A Qualitative Analysis of Interviews with important differences in susceptibility to such Physicians and Pharmacists, using data from exposures, including genetics. During critical semi-structured interviews with health profes- stages of physiological development through sionals in Nicaragua to assess their perceptions adolescence, factors such as diet, medication, regarding renal disease in the region (Ramirez- and environmental exposures may play a role in Rubio et al. 2013a; Ramirez-Rubio and Scam- disease and/or susceptibility. Finally, once old mell 2011); enough to join the workforce, occupational ex- · A Pilot Cohort Study, assessing the feasibil- posures play a key role in disease onset either ity of conducting a complete retrospective co- hort study on the relationship between sugar- Importantly, though we are conducting mul- cane work practices and CKD based on medical tipledirectly studies or as to modifiers investigate of risk other factors risk factors.across records in a sugarcane company (Aschengrau et the lifespan, these are not ‘separate’ studies al. 2012); but rather multiple components of a single re- · An Investigation of Biomarkers in Work- search program. The common goal of our work ers, evaluating biological markers of kidney in- Reviews of evidence for CKDu in relation to hypotheses jury and CKD in sugarcane workers in multiple tance, the CDC Foundation serves as the central jobs at pre-harvest and late-harvest, as well as administrative and coordinating lead, and an miners, construction workers, and port work- External Advisory Board has been convened to ers (Laws et al. 2015a, b; McClean et al. 2012); review our protocols and provide strategic di- · An Investigation of Urinary Biomarkers in rection and guidance. Adolescents, evaluating evidence of subclinical kidney damage among adolescents in different Follow-up study of MeN in areas of Nicaragua, suggested by the very young Quezalguaque, Nicaragua age at diagnosis among many affected workers Since 1985, the Brookline-Quezalguaque Sis- and community residents (Ramirez-Rubio et al. ter City Committee (BQSCC) has had a close rela- 2015; Ramirez-Rubio et al. 2012). tionship with the municipality of Quezalguaque, We have concluded from this work that one located in the northwest region of Nicaragua. In or more risk factors are occupational. We found that (a) sugarcane workers in northwestern the BQSCC of a number of excess deaths due Nicaragua experienced a decline in kidney tothe chronic early 2000s, kidney town disease. health In officials2008, the informed BQSCC function and an increase in kidney injury dur- worked in partnership with BUSPH to conduct ing the harvest, (b) measures of kidney func- a seroprevalence study and found an elevated tion and kidney injury were different by job, prevalence of reduced eGFR, which is found dis- with greatest risk observed among those in the proportionately among younger males. heaviest manual labor jobs, (c) decreased kid- During the summer of 2015, we again worked ney function was associated with longer dura- in partnership with BQSCC to conduct a study tion of employment, (d) in the most high risk in Quezalguaque designed to revisit partici- 95 jobs, hydrating with electrolyte solution during pants from the 2008 study. Our team contacted the workday was protective against kidney in- approximately 200 of the 321 participants (or jury, and (e) decreased kidney function was also proxies) from the case-control component of observed among other heavy manual laborers the original study to determine mortality, pro- such as miners, port workers, and construc- gression, and regression among participants tion workers. Our results add to the growing who had an eGFR<60, as well as new cases evidence that heat stress and dehydration play a whose creatinine had previously been within role, possibly in combination with one or more normal limits. We collected questionnaire data other occupational or non-occupational factors and obtained blood, urine, and saliva samples. (Brooks et al. 2012). Our work also suggests Testing for serum creatinine and other clinical that early kidney damage may be occurring in adolescents, suggesting a possible role of genet- Centro Nacional de Diagnóstico y Referencia ics or early life exposures (i.e. environmental, (CNDR,measures a division was conducted within the at Nicaragua the ISO-certified Ministry diet, medication). of Health). In February 2016, we plan to attempt The ongoing research of the BUSPH team to enroll those 2008 participants who we did builds on this early work and continues to fo- not have time to contact during summer 2015. cus on occupational and non-occupational fac- First, and most importantly, we aim to char- tors across the lifespan. These research efforts acterize factors associated with more rapid include collaborations with Chirag Parikh at progression among cases, and incidence of new Yale University, Sandra Peraza at the University disease among those previously unaffected. of El Salvador, and Kate Applebaum at George Second, we will assess the proportion of par- Washington University. Additionally, for most ticipants who had reduced eGFR in the original of the studies described below, subject matter study but no longer test in that range, as an es- experts at US Centers for Disease Control and timate of the potential effect of using one creati- Prevention (CDC) are providing technical assis- nine measure as an outcome in epidemiological Reviews of evidence for CKDu in relation to hypotheses

studies. Finally, we are also assessing the accu- that are enriched in the local population. Our team has recruited approximately 300 mem- a point-of-care device via a comparison with bers of 25 families with high burdens of kidney laboratory-basedracy of a field measurement creatinine of creatininemeasurements. using disease, including both men and women over There have been almost no studies that have the age of 18. These families include members characterized the effect of the CKD epidemic in of ASOCHIVIDA, a community organization of communities over a period of time; this study individuals with CKD, and other families known will contribute to an understanding of the natu- in the community to have multiple family mem- ral history of the disease and hopefully identify bers with CKD. We interviewed family members factors (e.g. work history, agrichemical use, hy- to construct family trees that include the rela- dration, etc.) that can inform future interven- tionships between family members (e.g., child, tions to slow progression of disease and pre- parent, spouse, brother), CKD diagnosis, and vent new cases. The study is supported by funds whether the person is alive or dead. Samples from BQSCC and Santander scholarships. of urine, serum, and saliva have been collected from nearly all participants. In addition, partici- Investigating genetic pants responded to a questionnaire detailing susceptibility to MeN occupational history (job and duration), medi- We are currently conducting multiple studies cal problems, medications, herbal remedies, to explore the potential role of genetic suscep- and diet. tibility in MeN. While we believe that occupa- The early phase of the project included DNA tional and environmental exposures are the pri- extraction from either saliva or whole blood col- 96 mary cause(s), it is possible that some exposed lected from approximately 200 participants, as individuals are more prone to develop kidney disease than others. Finding genetic variants - that increase risk of kidney disease may be help- itywell for as next-generation DNA quantification genetic and rigoroustesting. To quality date, ful in several ways. First, the genes involved in wholecontrol exome assays sequencing to ensure sufficienthas been performed DNA qual susceptibility may tell us about the nature of the for more than 50 samples. In the near future, occupational/environmental factor (e.g. a liver genotype-array based linkage will also be per- detoxifying enzyme may point toward a toxin formed. While we are still analyzing our data, whereas a variant in a salt or water handling - gene would implicate dehydration). Second, latedness between many of our independently studies of occupational/environmental factors recruitedone finding families. has been For aexample, high degree eight of of interre our ex- focusing on those individuals with an underly- tended families are connected by intermarriage, ing genetic susceptibility may have consider- representing a “superfamily” with 65 individu- ably more power in some instances than studies als affected with kidney disease. Also of note are where non-susceptible individuals are also con- highly elevated uric acid levels in family cases. sidered. These studies include a family pedigree To determine whether these high levels are out study and a case-control study. These comple- of proportion to the degree of kidney dysfunc- tion, we compared uric acid levels between variants with a wide range of frequency, pen- cases in this cohort and similar CKD patients in etrancementary (power), studies areand designeddependence to findon both genetic oc- the NHANES cohort. We found individuals with cupational and non-occupational environmental MeN had 2.0 mg/dL higher uric acid levels than factors. These studies are summarized below. NHANES CKD cases after correction for age, GFR, and use of uric acid lowering medications. Family Pedigree. The family-based study is - optimal for identifying strong genetic variants tabolism could be important in the pathogene- sisThis of finding MeN. suggests that elevated uric acid me Reviews of evidence for CKDu in relation to hypotheses

Case-Control Study. The case-control study producers in Nicaragua, as well as funds from the Doris Duke Foundation and Beth Israel Dea- modify the effect of an occupational or environ- coness Medical Center in Boston. mentalis optimal exposure. for finding We are geneticrecruiting variants 360 former that sugarcane workers who have been diagnosed Biomarkers and risk factors - for MeN among children and cial Security renal clinic, which is administered adolescents in Nicaragua bywith the CKD, Ministry identified of Health. through Controls the Institute will include of So Building on our preliminary investigation of 360 healthy members of the same community adolescents, we were able to locate, re-enroll, matched to cases by age and job description, and collect new samples from greater than drawn from current workers at the sugarcane 80% of the students who participated in the company. Because 97.5% of patients at the so- 2011 study to assess whether kidney injury has cial security clinic are men, the study will be changed during the 4 year period and whether limited to males. this differs by school, or subsequent occupa- Starting in 2015, we have recruited 331 ac- tional factors. tive sugarcane workers as controls during the We are also preparing to conduct a new cross- harvest season. These workers included pri- sectional study to determine whether children marily cane cutters, irrigators, pesticide appli- and adolescents aged 7-17 from 8 schools locat- cators, and seed cutters with several years of ed in 4 different geographical areas of Nicara- experience in sugar cane agriculture. From each gua (chosen based on different population CKD worker, we collected blood and saliva for DNA, mortality rates, climate, altitude, and primary as well as serum and urine. More than 200 cas- industry of the region, as well as parents’ occu- 97 es have been recruited from the social security pation) show signs of kidney injury, and wheth- clinic to date. We will use whole genome geno- er the extent of injury varies by school. We will typing arrays to identify genetic variants that also explore potential factors (e.g. dehydration, exposure to arsenic and other metals, nephro- and controls, followed by more detailed stud- toxic drugs, infections, and work history) that differ significantly in frequency between cases might lead to kidney damage. Compared to the causing variant. 2011 study, the current study will be larger, cov- iesPreliminary (“fine-mapping”) data indicateto determine that asthe manydisease- as er a broader geographic area, wider age range, 10% of subjects recruited as controls have el- use a lower-risk reference group, and collect evated creatinine values during the zafra. In fol- information on potential causes of early kidney low-up assessments of these workers with high damage, which was not part of the prior study. creatinine values after the harvest, we found The funds for this study have been donated by that most had substantial improvement in cre- CNPA, an association of sugar producers in Ni- atinine level, suggesting that AKI may be more caragua. frequent than expected. In addition, we found that CKD cases are more likely to have a brother Longitudinal investigation (3-fold increase) or father (nearly 4-fold in- of MeN among Central American crease) with CKD than controls, supporting the workers study idea that MeN may have a genetic component. We have planned a large-scale longitudinal This family study is funded by the Doris Duke study to investigate the role of heat stress and Foundation, the Satellite Healthcare Founda- pesticide exposure on risk of MeN among Cen- tion, and Beth Israel Deaconess Medical Center. - The case-control study has been supported by tigation has not yet been funded, we intend to funds donated by Comité Nacional de Produc- recruittral American a study workers.population While of 780 the workers field inves from tores de Azúcar (CNPA), an association of sugar multiple industries in Nicaragua and El Salva- Reviews of evidence for CKDu in relation to hypotheses

dor. At Baseline (Round 1), we will conduct an We are currently pursuing the funds necessary extensive exposure characterization during three consecutive workdays. We plan to then could potentially include donations from indus- follow this cohort of workers over time and tries,to proceed foundations, with the and field grant investigation, funding from which the National Institutes of Health. six-month intervals (30 month period). In the conduct five additional rounds of sampling at MeN progression of exposure to heat and agrichemicals (expo- The MeN progression study aims to identify sure/dose),first round, volume we will depletion obtain repeated and muscle measures dam- age (physiologic response), tubular damage progression of MeN, which may assist physi- (subclinical acute kidney damage), and eGFR ciansmodifiable and patients risk factors to slow that the may rate relate of disease to the (CKD). In later rounds (Rounds 2-6), we will progression. The study is being conducted in primarily monitor tubular damage and eGFR to conjunction with the case component of the characterize the progression of change in eGFR. genetic case-control study. Questionnaire and Monitoring workers on-site during the workday biological samples are shared between the two will provide the opportunity to obtain quanti- studies. Medical records will also be abstracted tative exposure measures. Additionally, revisit- and provide additional data regarding deter- ing workers at six-month intervals will provide minants of progression. Funding for this study the opportunity to investigate the potential for comes from George Washington University. repeated subclinical acute kidney damage to progress to CKD, a process that may be uniquely Summary 98 observable in this population. We will evaluate The BUSPH studies represent multiple com- occupational exposures with acute kidney in- ponents of a single research program designed jury and/or chronic kidney disease while also to investigate occupational and non-occupa- exploring the potential role of alcohol consump- tional risk factors across the lifespan. Our work tion, medication use, and dietary factors. to date provides evidence that one or more risk As part of planning for this study, we con- factors are occupational and we have made rec- ducted a pilot study of 50 Nicaraguan sugar- ommendations for improving work practices. cane workers to obtain preliminary data on ag- Given that the disease likely has a multifacto- richemicals, metals, and arsenic (speciated and rial etiology, our primary goal is to identify the total). These 50 workers had previously partic- occupational and non-occupational cause(s) of ipated in our study from four years earlier. At the epidemic to inform intervention studies and the end of the workday, we collected blood and minimize risk of MeN. urine samples to be analyzed for agrichemicals, heavy metals, and arsenic at the laboratories References of the CDC. Serum creatinine and other clinical 1. Aschengrau A, et al. 2012. Cohort Pilot parameters were analyzed at CNDR, and bio- Study Report: Evaluation of the Potential for an markers of kidney injury were measured at the Epidemiologic Study of the Association between Division of Nephrology and Hypertension at Work Practices and Exposure and Chronic Kid- Cincinnati Children’s Hospital Medical Center ney Disease at the Ingenio San Antonio (Chi- in the US. Analyses are on-going and we plan chigalpa, Nicaragua). Boston University School of Public Health. Available: http://www.cao- study at the workshop in November, after which ombudsman.org/cases/document-links/docu- weto present can update preliminary this summary. findings from this pilot ments/BU_CohortPilotStudyReport_Jan2012_ ENGLISH.pdf Azucareros del Istmo Centroamericano, an as- 2. Atkins D, McClean MD, Brooks DR. 2010. sociationThe first of years sugar of producers funding was in Central donated America. by the Phase I Environmental Monitoring: April 2010 Reviews of evidence for CKDu in relation to hypotheses

Assessment of Water Samples. Boston Univer- biomarkers of kidney injury among adolescents sity School of Public Health. Available: http:// in Nicaragua, a region affected by an epidemic www.cao-ombudsman.org/cases/document- of chronic kidney disease of unknown aetiology. links/documents/Water_sampling_report_Au- Nephrol Dial Transplant. Published on-line Au- gust2010.pdf. gust 25, 2015. 3. Brooks DR, Ramirez-Rubio O, Amador JJ. 11. Ramirez-Rubio O, Brooks DR, Amador JJ, 2012. CKD in Central America: A Hot Issue. Am J Kaufman JS, Weiner DE, Parikh CR, et al. 2012. Kidney Dis 59(4): 481-484. Biomarkers of early kidney damage in Nicara- 4. Brooks DR, et al. 2009. Final Scoping Study guan adolescents, September-November 2011. Report: Epidemiology of Chronic Kidney Dis- Available: http://www.cao-ombudsman.org/ ease in Nicaragua. Boston, MA. Boston Univer- cases/document-links/documents/Adolescen- sity School of Public Health. Available: http:// tReportJune252012.pdf www.cao-ombudsman.org/cases/document- 12. Ramirez-Rubio O, Brooks DR, Amador JJ, links/documents/03H_BU_FINAL_report_ Kaufman JS, Weiner DE, Scammell MK. 2013a. scopestudyCRI_18.Dec.2009.pdf Chronic kidney disease in Nicaragua: a qualita- 5. Laws RL, Brooks DR, Amador JJ, Weiner DE, tive analysis of semi-structured interviews with Kaufman JS, Ramirez-Rubio O, et al. 2015a. Bio- physicians and pharmacists. BMC Public Health markers of kidney injury among Nicaraguan 13(350). sugarcane workers. American Journal of Kidney 13. Ramirez-Rubio O, McClean MD, Amador JJ, Diseases. In press. Brooks DR. 2013b. An epidemic of chronic kid- 6. Laws RL, Brooks DR, Amador JJ, Weiner ney disease in Central America: an overview. DE, Kaufman JS, Ramirez-Rubio O, et al. 2015b. Journal of epidemiology and community health 99 Changes in kidney function among Nicaraguan 67(1): 1-3. sugarcane workers. Int J Occup Environ Health. 14. Ramirez-Rubio O, Scammell MK. 2011. Published on-line January 28, 2015. Chronic Kidney Disease in Nicaragua: A Qualita- 7. McClean M, Laws R, Ramirez-Rubio O, tive Analysis of Semi-Structured Interviews with Brooks D. 2010. Industrial hygiene/occupa- Physicians and Pharmacists. Boston University tional health assessment: evaluating potential School of Public Health. Available: http://www. hazards associated with chemicals and work cao-ombudsman.org/cases/document-links/ practices at the Ingenio San Antonio. Available: documents/BU_Interviews_Report_FEB_2012_ http://www.caoombudsman.org/documents/ Eng.pdf FINALIHReport-AUG302010-ENGLISH.pdf 15. Soderland P, Lovekar S, Weiner DE, Brooks 8. McClean MD, Amador JJ, Laws RL, Kaufman DR, Kaufman JS. 2010. Chronic kidney disease JS, Weiner DE, Sanchez Rodriguez JM, et al. associated with environmental toxins and expo- 2012. Biological Sampling Report: Investigating sures. Adv Chronic Kidney Dis 17(3): 254-264. biomarkers of kidney injury and chronic kidney 16. Weiner DE, McClean MD, Kaufman JS, Brooks disease among workers in Western Nicaragua. DR. 2013. The Central American Epidemic of Available: http://www.cao-ombudsman.org/ CKD. Clin J Am Soc Nephrol 8(3): 504-511. cases/document-links/documents/Biological_ Sampling_Report_April_2012.pdf 9. O’Donnell JK, Tobey M, Weiner DE, Stevens LA, Johnson S, Stringham P, et al. 2011. Preva- lence of and risk factors for chronic kidney dis- ease in rural Nicaragua. Nephrol Dial Transplant 26(9): 2798-2805. 10. Ramirez-Rubio O, Amador JJ, Kaufman JS, Weiner DE, Parikh CR, Khan U, et al. 2015. Urine Reviews of evidence for CKDu in relation to hypotheses

natural history of disease is not well enough Gaining insights into the evolution understood to inform sufferers how quickly of CKDnt from community-based their kidney function will decline, and whether follow up studies remaining in intensive agricultural occupations will alter this trajectory. This information is clearly critical to those with CKDnt and it is only by performing representative community based Ben Caplin, UCL Centre for Nephrology and longitudinal studies that the necessary data can Department of Non-Communicable Disease be collected. Epidemiology, LSHTM. Funded by the UK Colt Foundation in partner- Marvin Gonzalez-Quiroz, Department of Non- ship with the La Isla Foundation we recently Communicable Disease Epidemiology, LSHTM, commenced a community based follow-up and Research Center for Health, Work and study in Leon and Chinandega departments, Ni- Environment, (CISTA), National Autonomous caragua. 350 participants aged 18-30 without University of Nicaragua, León. known CKD (M:F 3:1) were recruited follow- ing local community censuses. This represents Neil Pearce, Department of Non-Communicable >95% of the men in these communities and a Disease Epidemiology, LSHTM. random sample of women. Study visits, which take place twice a year, have been arranged for the weeks prior to, and again in the weeks fol- Summary lowing, the zafra. Conducting a follow up study 100 Chronic Kidney Disease (CKD) is a clinical syn- in a rural area has been, and remains, a major drome that is usually without symptoms until the challenge and several issues have had to be condition is at an advanced stage. CKD is often - frequently remain unknown (or recorded as due nalovercome migration. during Achieving the first follow-up year of thestudy study. visits A toidentified hypertension), late, and as the renal underlying biopsy aetiology in advanced will insignificant this group obstacle has requiredhas been internalthe investment and exter of - and atrophy of renal tubules (scarred kidneys). munity engagement has been key. A high pro- TheCKD situationwill usually is further reveal complicatedonly interstitial by thefibrosis pro- portionsignificant of timestudy and subject resources. retention Continuing appears com to gressive nature of CKD, with continuing decline be based on the development of good relation- in kidney function even after the withdrawal or ships with both the participants and also with adequate treatment of an initial insult. Together the community leaders. - In summary, community based follow-up al factors is extremely challenging. studies have several advantages over cross- theseWe attributeshave recently mean commenced that identification a community- of caus sectional studies in the community or research based longitudinal study examining CKDnt in designs based in healthcare or occupational Leon and Chinandega departments, Nicaragua. settings. These include generalizability, reduc- Although perhaps logistically more challenging, tion in selection bias, better handling of reverse study designs of this type have the potential to causation and recall bias, along with the ability provide important insights that cross-sectional to utilize an outcome measure (within-person survey, case-control or occupationally based cohorts cannot. In particular, community based follow-up studies are likely to provide informa- kidneychange injury. in eGFR) We that hope allows our study the identification along with tion on the rate of progression of disease. Cur- othersof those of sustaining similar design the most will providesignificant important chronic rently, although those with CKDnt are often told insights into the aetiology of CKDnt. that they have abnormal kidney function, the Reviews of evidence for CKDu in relation to hypotheses

Introduction healthcare services. As renal replacement ther- Chronic Kidney Disease (CKD) is a clinical apy is often not a treatment option amongst af- syndrome that is usually without symptoms un- fected communities, sufferers of CKDnt, in par- til the condition is at an advanced stage. Even ticular, may not engage with medical services at in countries with highly developed healthcare all. These issues mean that healthcare system systems, in the absence of known risk factors based studies may not be optimal for identify- for kidney disease such as diabetes, CKD is of- ing cases as participants may only represent a subset of those with CKDnt, i.e. those with aetiology will frequently remain unknown (or advanced disease who choose and are able to recordedten identified as due late. to In hypertension)(1), these cases the underlying as renal engage with the health services. Furthermore, biopsy in advanced CKD will usually reveal only choosing appropriate controls is also likely to also be challenging because it may not be clear (scarred kidneys). The situation is further com- what the appropriate ‘catchment population’ of plicatedinterstitial by fibrosisthe progressive and atrophy nature of renal of CKD, tubules with the health system is. continuing decline in kidney function even af- As CKDnt is thought to be, at least partly, an oc- ter the withdrawal or adequate treatment of an initial insult.(2) Together these attributes mean sugar cane production companies, are a logical placecupational to conduct disease(4), studies. workplaces, This has the specifically advantage challenging. These problems are particularly of easier capture of both data and samples relat- relevantthat identification when considering of causal the factors aetiology is extremely of CKD ed to work-based exposures. In addition, partic- of non-traditional causes (CKDnt) where the ipants recruited in the workplace are likely to be at relatively high risk of CKDnt; thus, the power 101 We have recently commenced a community- to detect associations is likely to be maximized basedcause(s) longitudinal remain to bestudy firmly examining established. CKDnt in for any given sample size. However, there are Leon and Chinandega departments, Nicaragua. several disadvantages to workplace studies that Although perhaps logistically more challenging, must also be considered. It is clear that CKDnt in study designs of this type have the potential to provide important insights that cross-sectional working in sugar cane production, with women survey, case-control or occupationally based co- andCentral agricultural America isworkers not entirely growing confined other to cropsthose horts cannot. This contribution will outline the also being affected. Perhaps more importantly, rationale underlying our approach. It will discuss however, increasing awareness of the epidemic some of the theoretical advantages as well as amongst employers now means that those with practical challenges associated with conducting impaired kidney function are either no longer this type of investigation. employed at the beginning of the zafra or are excluded from follow-up visits in longitudinal Where should we conduct our studies encompassing the harvest period. studies? Generalizability and rep- Community cohorts have several advantages. resentativeness of occupational Firstly this type of cohort represents the entire and community cohorts at-risk population. Workers from all occupations As noted above, CKD in its early stages re- and both men and women can be recruited as mains asymptomatic. Therefore, unless identi- study participants. Assuming that the commu- - nities chosen to take part are appropriate, and ly only present to healthcare services when they generally support the study objectives, there is fiedbecome on routine unwell, blood i.e. with tests, late those disease. affected Advanced usual - ease risks(3), so patients may die from stroke or assess,unlikely environmental to be significant exposures selection bias.in close Although prox- cardiacCKD also causes carries before significant coming cardiovascular to the attention dis of imityoccupational to participants’ exposures homes may be can more be difficultmeasured to Reviews of evidence for CKDu in relation to hypotheses

relatively easily. One general disadvantage of lenges when trying to determine the cause of community-based studies is that they typical- disease. The initial response to any injury will ly need to be large if disease prevalence is not not necessarily immediately manifest in a bio- high. However, given the epidemic proportions chemical deterioration in kidney function (and of CKDnt, this may not be such a problem when in some cases such as diabetes, initially leads to studying the disease in Central America. Finally, when considering longitudinal studies loss to This means that a clearly abnormally low eGFR hyperfiltration, an increase in eGFR; Figure 2).- is likely to be less of challenging in community- tion of the kidney is scarred. Indeed, the initial basedfollow-up, studies although than in stilloccupational a significant cohorts. concern, maysource not of be the present injury until may ahave significant resolved/been propor removed before the eGFR falls to the level that Dealing with reverse-causation – would be used to diagnose CKD clinically. longitudinal studies Given this background, attempts to identify Several risk factors associated with CKDnt in causal factors when using questionnaires, as cross-sectional studies, although possibly re- part of a cross-sectional (usually case-control) - - sequence of impaired kidney function. For exam- call bias if an eGFR threshold of <60mL/minute ple,flecting several a causal studies relationship, have reported may analso association be a con approach, is likely to be prone to significant re biological and environmental samples obtained This association could represent a causal effect atis usedthe time for caseof a definition.clinical diagnosis Furthermore, of CKD both are ofbetween high levelshigh volumes of exposure of fluid to intake a water-soluble and CKDnt. likely to have limited utility in these circum- 102 toxin, it could be a surrogate for general work in- stances. The proposed research threshold of an tensity/heat-stress, or alternatively could be the eGFR of <90mL/minute, although less prone to consequence of impaired kidney function where this problem, may still occur long after the oc- participants with pre-existing kidney injury are currence of important exposures in the natural unable to concentrate their urine. Other exam- history of the disease. ples where it is similarly challenging to untangle A further challenge in epidemiological CKD causation from reverse causation and confound- research surrounds the measurement of kidney ing include the associations of CKDnt with higher function. Between-person variation in GFR is serum/urinary uric acid levels and increased al- large, even amongst those without any underly- cohol intake. ing kidney disease, i.e. normal kidney function is Although confounding can obviously only be highly variable. In addition there are consider- dealt with by appropriate measurement and ad- able sources of variation when using the equa- justment, reverse causation can usually be ad- tions used to estimate the GFR (the eGFR) from dressed by using a longitudinal study design. the serum creatinine(6). Table 1 outlines some

Measuring kidney function. where it is calculated from the creatinine (e.g. Overcoming the issues with usingof the the factors MDRD that or CKD-EPI might influence equations). the Newer eGFR definition of CKD, historic markers of kidney function such as cystatin-C exposures and between-subject are less prone to some of these problems. variability in GFR. Taken together, the above factors may mean - that the absolute eGFR may not be the most use- sis of the presence of an eGFR<60mL/minute ful outcome measure for research studies trying forClinical more than CKD 3 is months(5). usually defined Although on there the ba is to establish the causes of nephron loss in CKDnt. - For example, a low-normal eGFR in a healthy atic when conducting aetiological research. As subject may be similar to another subject with describedclinical utility above, in CKD this definition,provides particular it is problem chal- impending CKDnt (Figure 2). Another possible Reviews of evidence for CKDu in relation to hypotheses

Figure 1. Hypothetical timing of injury and decline in eGFR.

103

Table I.

Factors influencing variation in eGFR calculated from the serum creatinine.

Within-person factors unrelated to Within-person factors due to Between-person factors kidney clearance changes in kidney clearance

Functional decrease in eGFR Muscle mass (i.e. reduced glomerular blood flow) (although this can also change Animal protein meal Due to volume depletion or vasoactive within a person) drugs. Loss of nephrons Strenuous exercise leading to muscle (functional units of the kidney) Ethnicity breakdown Due to tubular or glomerular cell damage.

Drugs that alter creatinine handling Sex (e.g. trimethoprim)

Changes in plasma volume (impacts all solutes in the plasma) Genetic background e.g. short term dehydration or overhydration Reviews of evidence for CKDu in relation to hypotheses

outcome measures might be the development of Figure 2. Theoretical example of use of within- low molecular weight (tubular) proteinuria, if a person change in eGFR as the outcome measure protein that accurately predicts progression to in research.

subject change in eGFR(6). This latter outcome isCKDnt advantageous can be identified, in that theor alternatively measure will within- be in- dependent of between-person factors and if cal- culated across a number of time points will re-

that are not related to nephron loss. duce the influence of the within-person factors Insight into the rate of progression of disease Community based follow-up studies are also likely to provide information on the rate of pro- gression of disease. Currently, although those with CKDnt are often told that they have abnor- mal kidney function, the natural history of dis- ease is not well enough understood to inform function that declines slowly. Depending on the sufferers how quickly their kidney function will timing of a cross sectional study subject B may decline, and whether remaining in intensive ag- - 104 ricultural occupations will alter this trajectory. ject C has normal kidney function which never This information is clearly critical to those with orfalls may below not bethe classified research as threshold having CKDnt. for CKDnt Sub CKDnt and it is only by performing representa- during the study period however they appear tive community based longitudinal studies that the necessary data can be collected. kidney injury. Straight lines represent the slope ofto within-personhave sustained change the most in eGFRsignificant and are chronic more Loss to follow-up informative than absolute values. Loss to follow-up is one potential weakness of any longitudinal design. For cohort studies Early experience of conducting such as the one we describe here, failure to ob- a community follow-up study in tain follow-up eGFR measurements from each Leon and Chinandega departments, subject will substantially reduce the power of Nicaragua the study to detect associations. Continuous Funded by the UK Colt Foundation in partner- engagement with study communities including ship with the La Isla Foundation we recently holding village meetings, ensuring that study commenced a community based follow-up study visits are conducted at appropriate times, feed- in Leon and Chinandega departments, Nicaragua. back of results of kidney tests, and exploring 350 participants aged 18-30 without known CKD causes of disease felt to be important by the lo- (M:F 3:1) were recruited following local commu- cal community, will all be critical to the success nity censuses. This represents >95% of the men of the study. in these communities and a random sample of Subject A has normal kidney function but sus- women. Study visits, which take place twice a tains a single acute kidney injury at 6-months year, have been arranged for the weeks prior to, which then recovers. Depending on the timing and again in the weeks following, the zafra. De- of a cross sectional study subject A could be tailed questionnaires were conducted by trained interviewers and baseline clinical data, biologi- og <90mL/min). Subject B has impaired kidney cal and environmental samples collected. A total classified as having CKDnt (using a threshold Reviews of evidence for CKDu in relation to hypotheses

tion bias, better handling of reverse causation took place in May/June 2015 and the third visit and recall bias, along with the ability to utilize isof plannedfive study for visits October are 2015.planned. Participants The second receive visit an outcome measure (within-person change their kidney test results within a fortnight of the study visits. Additionally participants receive re- imbursement of expenses and any lost income injury.in eGFR) We that hope allows our studythe identification along with others of those of they have incurred to attend the study visit. Ap- similarsustaining design the mostwill provide significant important chronic insights kidney proximately 90% of the initial cohort attended into the aetiology of CKDnt. for the second study visit. Conducting a follow up study in a rural area has References been, and remains, a major challenge and several 1. Haynes R, Staplin N, Emberson J, Her- rington WG, Tomson C, Agodoa L, et al. Evalu- ating the contribution of the cause of kidney internalissues have and hadexternal to be migration. overcome At during the end the of first the disease to prognosis in CKD: results from the harvestyear of thearound study. 30% A significant of the study obstacle population has been had Study of Heart and Renal Protection (SHARP). left their communities, to go to Costa Rica or oth- - er departments in Nicaragua, to look for alterna- cial journal of the National Kidney Foundation. tive employment during the non-harvest period. 2014;64(1):40-8.American journal of kidney diseases : the offi Achieving follow-up study visits in this group has 2. Chawla LS, Kimmel PL. Acute kidney in- jury and chronic kidney disease: an integrat- resources. ed clinical syndrome. Kidney international. requiredSecondly, the the investment small number of significant of participants time and 2012;82(5):516-24. 105 who were working during the pre-harvest has 3. Hallan SI, Matsushita K, Sang Y, Mahmoodi been an issue. As the workday starts very early BK, Black C, Ishani A, et al. Age and association of kidney measures with mortality and end- stage renal disease. JAMA. 2012;308(22):2349- conductin the morning the data and collection. finishes late in the afternoon 60. it Finally,has been the difficult real or to perceived identify suitable fear of timesjob loss to 4. Correa-Rotter R, Wesseling C, Johnson RJ. is ever present. Participants have reported that CKD of unknown origin in Central America: employers have told them that they will not be the case for a Mesoamerican nephropathy. allowed to work if they participate in research - projects. Although study visits have been time- cial journal of the National Kidney Foundation. tabled to occur outside of the zafra, employees American2014;63(3):506-20. journal of kidney diseases : the offi still express the concern they will be sacked and 5. Stevens PE, Levin A, Kidney Disease: Im- permanently lose their livelihoods. proving Global Outcomes Chronic Kidney Dis- Continuing community engagement has been ease Guideline Development Work Group M. key. A high proportion of study subject reten- Evaluation and management of chronic kidney tion appears to be based on the development of disease: synopsis of the kidney disease: im- good relationships with both the participants proving global outcomes 2012 clinical prac- and also with the community leaders. tice guideline. Annals of internal medicine. 2013;158(11):825-30. Conclusions 6. Padala S, Tighiouart H, Inker LA, Contreras Community based follow-up studies have G, Beck GJ, Lewis J, et al. Accuracy of a GFR esti- several advantages over cross-sectional stud- mating equation over time in people with a wide ies in the community or research designs based range of kidney function. American journal of in healthcare or occupational settings. These - include generalizability, reduction in selec- tional Kidney Foundation. 2012;60(2):217-24. kidney diseases: the official journal of the Na Clinical Conditions and Pathology

Burden of disease in Central What is known about the burden America: and clinical characteristics of Mesoamerican nephropathy? El Salvador There are four reports on the prevalence of MeN in different parts of El Salvador, ranging from 10 to 18%, with prevalence predominat- Zulma Trujillo, Servicio de Nefrología, Hospital ing in males. Nacional Rosales, El Salvador. In 2005, García--Trabanino and coworkers re- Ricardo Correa-Rotter, Instituto Nacional de ported a cross-sectional study that explored the Ciencias Médicas y Nutrición Salvador Zubirán, prevalence of CKD among males in eleven com- Departamento de Nefrología y Metabolismo munities at different geographic altitude (me- Mineral, Mexico. ters above sea level = masl); eight villages were located at the coast (n=291) and three at an al- titude above 500 masl (n=62). This investiga-

he prevalence and burden imposed by were performed and tests for albuminuria Chronic Kidney Diseases (CKD) in Cen- (dipsticktion included +) performed two phases; in inall the 253 first persons. interviews The T tral America is mostly unknown as no na- study found proteinuria in 46% of the coastal tional or regional registries are in place and no area subjects vs 13% at higher altitude. Those national prevalence studies are available. While positive for albuminuria at the coast were in- 106 CKD causes are diverse and some associated cluded in the second phase where samples for with known chronic non-communicable diseas- serum creatinine (SCr) were collected success- es (diabetes mellitus, hypertension) as happens fully from 80 of 133 with albuminuria. CKD elsewhere, the emergence of a major CKD epi- (SCr >1.5 mg/Dl) occurred in 37 cases (13%) demic known as Mesoamerican Nephropathy with only 14 (38%) with a history of diabetes (MeN) or CKD of unknown origin (CKDu), has or hypertension. The remaining (62%) did not drawn the attention of health authorities and appear to have a clear-cut cause for CKD. (1) international organizations that have made ef- In 2009, Orantes and coworkers, conducted a forts to understand the magnitude of this public study in the Bajo Lempa Region in search of MeN health problem. Here we review the situation cases. They recruited a total of 375 families and in four Central American countries (El Salvador, 775 individuals (343 men, 432 women, average Nicaragua, Guatemala, and Costa Rica) where age 39) were studied (88% of the total resident some data are available. Then we present an population in the region). Elevated prevalence overview of what we know currently about Me- of risk factors was observed: diabetes melli- soamerican Nephropathy in this region. tus, 10%; hypertension, 17%; family history Current data for a review of each country’s of chronic kidney disease, 22%; dyslipidemias, MeN experience are obtained from scarce pub- 63%; overweight, 34%; obesity, 22% (twice as lished articles, hospital records, and verbal common in women); metabolic syndrome, 29%; communications and only allow crude and frag- mented estimates of the burden of this disease. 75%; infectious diseases, 87%; agricultural oc- Table 1 summarizes the status of MeN in the re- cupation,use of non-steroidal 41% (81% in anti-inflammatory men); and contact drugs, with gion and is described in detail below. agrochemicals, 50% (83% in men). Prevalence of renal damage markers was 16% (greater in men): microalbuminuria 6%; proteinuria 6%; hematuria 4%; proteinuria–hematuria 0.3%. Proteinuria of <1 g/L predominated. Prevalence Clinical Conditions and Pathology of chronic kidney disease (persistent abnormal- ity during 3 months) was 18% (26% in men; - 12% in women). sociatedcroalbuminuria with male 7%;proteinuria sex, older age, (≥0.3 hypertension, g/L) 2%; Distribution by stages: stage 1, 5%; stage 2, agriculturaland hematuria, occupation, 1.5%. CKD and was family significantly history asof 4%; stage 3, 6%; stage 4, 3%; stage 5, 0.6%. Of chronic kidney disease. (4) the cases of CKD stage 1-5 86% did not have diabetes mellitus, and 55% of the CKD cases Nicaragua were associated with neither diabetes nor hy- While there are some reports from this country pertension. Prevalence of chronic renal failure the burden of the disease is unknown. In 2010 (CKD stage 3+) was 10% (17% in men; 4% in a cross-sectional study of 1096 subjects from women). (2) 5 communities, four at sea level and 1 at high In 2012, Peraza and coworkers performed a study of 256 men and 408 women from 5 com- eGFR of <60ml/min/1.73 m2 - nityaltitude, included was individuals performed. working CKD was in mining defined and as min/1.73m2. Two communities, one rural and subsistence farming; low eGFR. The was first observed commu in themunities. other semi-rural, They defined were CKD located as eGFR at the <60 coast ml/ 19% of men and 5% of women. A community at less than 500 masl communities was sug- of workers from banana and sugar cane plan- arcane agriculture. Differences in CKD by sex tations displayed the highest CKD prevalence: were similar in the two communities: in the - rural community, 19% men and 8% of women munity had a CKD prevalence of 13% men and and in the semi-rural community 18% and 8%, 4%22% women. in men Aand fourth 6% in community women. A withfishing service com respectively. In a third community located at workers (street vendors for example) had no 107 more than 500 masl, sugarcane agriculture pre- dominated but only 2% of the men and 3% of high altitude, 8% of men and no women had low the women had CKD. A fourth community of cof- eGFR.CKD cases, (5) and in the fifth coffee community, at fee growers located at 1650 masl had CKD in no In the rural municipality of Quezalguaque, - 771 members from 300 randomly selected nity was urban and located at 650 masl. In this households were studied: 13% had eGFR of <60 communitymen and only no 1% men of and women. just 2%The of fifth the commu women ml/min/1.73m². Of those with reduced eGFR, had eGFR below 60 ml/min/1.73m2 CKD, al- 89% lived in the lowlands (<500 masl) with a though 9% of men and 11% women had abnor- mean age of 55; 61% were male. Among young mal SCr, probably not related to MeN. The high people between 18 and 30 years, 3% of the 278 prevalence of eGFR <60 mL/min/1.73 m2 in the participants had eGFR <60 ml/min/1.73m². (6) coastal communities - 19% of men aged 20-60 Another study near the town of Chichigalpa years, indicates the severity of the epidemic in recruited 424 individuals of whom 151 were ag- region where there is little to offer to patients ricultural workers. The prevalence of low eGFR and where CKD often progresses to ESRD and was 42% in men and 10% in women and mi- death.(3) croalbuminuria was present in <10%. CKD was The last study published in 2014 by Orantes not associated with diabetes, NSAIDs or hyper- et al was performed in 3 communities: Bajo Lempa, Guayapa Abajo, and Las Brisas. The development were amount of sugarcane cutting prevalence of all stages of CKD was 18% among (ORtension. 5.9), Among inhalation risk offactors pesticides identified (OR 3.3), for CKDand 2388 adults, men and women. The prevalence chewing sugar cane (OR 3.2). (7) of CKD with neither diabetes nor hypertension A recent cross sectional study among 2275 in- dividuals aged 18-70 in the Municipality of León in men and 7% in women). Prevalence of renal (64% urban population) showed that the over- damagenor proteinuria markers ≥1 was g/L 13% (51.9%) (higher was in 11% men): (17% mi- all prevalence of eGFR <60ml/min/1.73m² was Clinical Conditions and Pathology

9%, 14% men and 6% women. Rural areas had with a male/female ratio of 7/6, and increased a higher prevalence than urban areas, 13% vs to 9.6/100000 for 2010. In 2008, the highest - ing age; living and working in rural areas, low particular in the Department of Retalhuleu with education,7%. Significant and CKDincreasing risk factors years were:of agriculture increas 30.9/100,000mortality occurred inhabitants, along thefollowed Pacific by coast, Santa in work. (8) Rosa with 20.36/100,000 inhabitants.(11) Recently an investigation was conducted of Costa Rica 3,105 patients with ESRD in renal replacement A study published in 2005 reports a national therapy (RRT). Dialysis enrollment was posi- prevalence of 193 ESRD patients/million inhab- tively correlated with the Human Development itants. The main causes were diabetic nephrop- Index and with literacy rates overall suggesting athy and hypertension, but a different pattern better access to dialysis services in higher socio- of ESRD appeared in the Guanacaste province economic regions. But the same data showed where the number of new cases has reached that dialysis rates were highest in the poor south- epidemic proportions, all affected being young west coastal region where both peritoneal dialy- men working as sugar cane cutters and between sis and hemodialysis were more common in men the ages of 20 and 40 years. The clinical picture was concordant with what is usually seen in peritoneal dialysis (58% male). This geographic chronic tubular interstitial nephritis and a few areathan womenis where – significantlysugar cane plantations different for are those locat on- ed and where higher daytime temperatures are pattern. (9) recorded. The etiology of cases of ESRD is not 108 biopsiedDuring cases1970-2012, confirmed age-adjusted this histopathological CKD related described in this study but many cases could be mortality increased in the province of Guana- MeN as the geographic distribution of dialysis caste, among men from 4.4 to 38.5/100 000 vs cases resembles the situation in Nicaragua and El 3.6 to 8.4 in the rest of Costa Rica, and among Salvador: i.e. higher in the high temperature and women from 2.3 to 10.7/100 000 vs 2.6 to 5.0 in sugar cane growing regions. Therefore, it is likely the rest of Costa Rica. During the period 2008- that the epidemic of CKDu extends throughout 2012, the mortality rate among males was al- the Mesoamerican region. (12) most 9 times higher than in the rest of Costa Rica but also among females twice as high as Mortality due to CKD chronic compared to the rest of the country. (10) kidney disease and renal failure in Central America Guatemala PAHO reports that in the past two decades, There are only scarce data about the preva- a disconcerting increase in CKD has been ob- lence of CKD or end-stage renal disease (ESRD) served in Central America, causing thousands of or CKD mortality in this country. Guatemala pre- deaths. According to the available data, the mor- sented data on CKD in a 2013 meeting sponsored tality rates >10 deaths/100,000 from chronic by COMISCA/PAHO. PAHO reported CKD and end kidney failure (ICD 10, N-18) in the Americas stage renal disease (ESRD) incidence of 1069 are, in descending order, Nicaragua (42.8), El new cases in 2009 and 1422 in 2012. Prevalence Salvador (41.9), Peru (19.1), Guatemala (13.6), of CKD/ESRD in the year 2012 was highest in and Panama.(12.3) Canada and Cuba have re- the capital city (1468 cases), followed by the Es- ported the lowest mortality rates in the Region. cuintla (231 cases), Santa Rosa (173) and Jutiapa Mortality in Nicaragua and El Salvador was 17 (154) departments, all located on the Southwest times higher compared to Cuba, and in these countries three times higher for men than for PAHO meeting CKD associated mortality rates women, but rates among women were also inPacific 2007 coastwere reported of Guatemala. as 6/100,000 At the inhabitants COMISCA/ higher than in other countries. (13) Clinical Conditions and Pathology

Clinical and laboratory male gender; increasing age, low socio-econom- characteristics: ic status; use of NSAIDs and herbal medicines The development of MeN in agricultural and exposure to agrochemicals.(24) - cal manifestations. Some of the most frequent Diagnosis and treatment of MeN symptomsworkers is reported accompanied by workers by non-specific are related cliniwith As discussed, MeN is a tubulointerstitial ne- heat stress and physical effort: muscle spasms, phropathy that in most instances evolves to cramps, arthralgia, dysuria, nausea, vomiting, headache, asthenia, profuse sweating, and short- This behavior is similar to most other tubuloin- ness of breath, distal edema and lumbar pain; terstitialESRD without nephropathies, abundant therefore specific symptoms.there is a yet these symptoms are not direct manifesta- strong need to have a high suspicion level in in- tions of MeN (14,15). Often affected individuals dividuals exposed to risk factors. It is mandato- employ NSAIDS, antibiotics, diuretics or herbal ry to perform periodic clinical and biochemical medicines by self-prescription, or prescribed by evaluations for those at risk to identify, as early general practitioners or non-physicians, which as possible, a disease pattern that suggests the may add to the renal injury (15). At later stages presence of MeN (16,18,22,23,24) of CKD the clinical scenario is identical to that Prevention is the best possible action, yet seen in most other causes of advanced uremia there is a lack of precise knowledge of causal or ESRD. - Patients are usually normotensive (1,3,16) or provement in working conditions, including slightly hypertensive (2,4,5,17) and most rele- lessspecific continuous factors. sun We exposure, strongly believeshaded areas that imfor rest, and optimal rehydration would reduce the 109 hyponatremia (16,17,18), hypermagnesuria magnitude of this epidemic. While pesticides andhypophosphaturiavant biochemical findings (17), are: andhypokalemia hyperurice and- have not been proven as causal of CKD, there is no doubt that they are harmful to health; we proteinuria but microalbuminuria has been re- strongly encourage elimination of those banned portedmia(19, (1,2,3,16,17,18). 20). Patients do Somenot present studies significant have re- in other environments given their toxicity and ported increased biomarkers of tubular injury: proper protection for those exposed to agro- chemicals. Education in relation to avoidance (16,17,18,21). of excessive alcohol, NSAIDS abuse and herbal NAG,A common IL-18 (16,17,18) pattern of behavior and β2 is microglobulin usually slow medicine exposure is also relevant. Finally, it is yet progressive decline of renal function. Imag- of upmost importance to view this in a holistic ing studies are scarce yet some have revealed ul- way. Improvement of sanitary, economic, and trasound images with loss of cortico-medulary educational conditions will lead to a better en- relation and small kidneys (22). Early pathol- vironment to reduce the risk of development of ogy studies demonstrate chronic glomerular MeN and other diseases. damage with widespread glomerulosclerosis Once the disease is present, treatment is not and mild to moderate chronic tubulointerstitial different to what is offered to other patients changes. (16,18,23) with tubulointerstitial diseases, including cor- rection of hyperuricemia and/or hypertension Risk factors if present. Dietary measures need to be individ- ualized yet once the disease has progressed to work and warm weather in coastal areas less Stages 3-4, there will be a need to reduce pro- thanIdentified 500 masl risk with factors repeated are: strenuous daily dehydration, physical tein intake and possibly potassium and sodium. agricultural work, in particular sugarcane, and Avoidance of exposure to nephrotoxic agents is other crops like banana (5,22) and subsistence of upmost importance. When the patient devel- ops ESRD, RRT is required with hemodialysis, farming (5,16,23). Other identified factors are: Clinical Conditions and Pathology

peritoneal dialysis, and ideally transplantation. Rica. Occup Environ Med. 2015 Oct;72(10):714- Unfortunately in most of the countries, the avail- 21. doi: 10.1136/oemed-2014-102799. Epub ability of proper follow up of RRT is profoundly 2015 Jul 21. limited as discussed above. 11. Data presented at COMISCA meet- ing, April 2013, El Salvador. http://www. References paho.org/els/index.php?option5com_ 1. García-Trabanino R, Dominguez J, Jansá JM, content&task5view&id5778. Accessed to the Oliver A. Proteinuria and chronic renal failure presentation 22/7/14. In the present is not in the coast of El Salvador: detection with low available. cost methods and associated factors. Nefrología 12. Laux TS, Barnoya J, Guerrero DR, Rothstein 2005; 25:31. M. Dialysis enrollment patterns in Guatemala: 2. Orantes CM, Herrera R, Almaguer M, et al. evidence of the chronic kidney disease of non- Chronic kidney disease and associated risk fac- traditional causes epidemic in Mesoamerica. tors in the Bajo Lempa region of El Salvador: Ne- BMC Nephrol 2015; 16:54. frolempa study, 2009. MEDICC Rev 2011; 13:14. 13. Pan American Health Organization/ World 3. Peraza S, Wesseling C, Aragon A, et al. De- Health Organization; 52nd directing council creased kidney function among agricultural 65th session of the regional committee; Wash- workers in El Salvador. Am J Kidney Dis 2012; ington, DC, USA, 30 september – 4 october 2013. 59: 531. cd52/8 (eng.); 17 july 2013. 4. Orantes CM, Herrera R, Almaguer M, et al. Ep- 14. Crowe J, Nilsson M, Kjellstrom T, Wesseling idemiology of chronic kidney disease in adults C. Heat-related symptoms in sugarcane harvest- 110 of Salvadoran agricultural communities. MED- ers. Am J Ind Med 2015; 58:541 ICC Rev 2014; 16:23 15. Ramírez Rubio O, Brooks D, Amador JJ, 5. Torres C, Aragón A, González M, et al. De- Kaufman J, Weiner D, Kangsen Scammell M. creased kidney function of unknown cause in Chronic Kidney disease in Nicaragua: a qualita- Nicaragua: a community-based survey. Am J tive analysis of semi-structured interviews with Kidney Dis 2010; 55:485. physicians and pharmacists. BMC Public Health 6. O’Donnell JK, Tobey M, Weiner DE, et al. Prev- 2013, 13:350 p1-9. alence of and risk factors for chronic kidney 16. Wijkström J, Leiva R, et al. Clinical and disease in rural Nicaragua. Nephrol Dial Trans- pathological characterization of Mesoamerican plant 2011; 26:2798. nephropathy; a new kidney disease in Central 7. Raines N, González M, Wyatt C, et al. Risk fac- America. Am J Kidney Dis 2013; 62: 908. 17. Herrera R, Orantes CM et al..Clinical charac- Nicaraguan community affected by Mesoameri- teristics of chronic kidney disease of nontradi- cantors nephropathy.for reduced glomerularMEDICC Rev filtration 2014; 16:16. rate in a tional causes in Salvadoran farming communi- 8. Lebov JF, Valladares E, Peña R, et al. A popula- ties. MEDICC Rev 2014; 16:2, 39-48. tion-based study of prevalence and risk factors 18. Wernerson A., Wijkström J, Gonzalez M, et of chronic kidney disease in León, Nicaragua. - Can J Kidney Health Dis 2015; 2:6. american Nephropathy - A kidney biopsy study 9. Cerdas M. Chronic kidney disease in Costa ofal. sugarConfirmation cane workers of renal in morphologyNicaragua. ISN in WorldMeso Rica. Kidney International, Vol. 68, Supplement Congress of Nephrology. Cape Town, 2015. ISN: 97 (2005), pp. S31–S33. SUN-476. 10. Wesseling C, van Wendel de Joode B, Crowe 19. Correa-Rotter R, Wesseling C, Johnson RJ. J, Rittner R, Sanati NA, Hogstedt C, Jakobsson K. CKD of unknown origin in Central America: the Mesoamerican nephropathy: geographical dis- case for a Mesoamerican nephropathy. Am J tribution and time trends of chronic kidney dis- Kidney Dis 2014; 63: 506. ease mortality between 1970 and 2012 in Costa 20. Carlos A. Roncal Jimenez, Richard J. Johnson, Clinical Conditions and Pathology

Fructokinase activity mediates dehydration- induced renal injury. Kidney Int. 2014 Aug; 86 (2):294-302. doi: 10.1038/ki.2013.492. Epub 2013 Dec 11. 21. Michael McClean Juan José Amador Rebecca Laws BIOLOGICAL SAMPLING REPORT: Investi- gating biomarkers of kidney injury and chronic kidney disease among workers in Western Ni- caragua. Boston University School of Public Health, April 26, 2012 22. Carl-Gustaf Elinder, MD, Annika O Werner- son MD, Mesoamerican nephropathy Uptoday reviewed 9/3/16 23. López-Marín L, Chávez Y, García XA, et al. Histopathology of chronic kidney disease of un- known etiology in Salvadoran agricultural com- munities. MEDICC Rev 2014; 16:49. 24. Mesoamerican Nephropathy: Report from the First International Research Workshop on MeN. http://www.regionalnephropathy.org/ wp-content/uploads/2013/04/Technical-Re- port-for-Website-Final.pdf. Pag 24. 111 Clinical Conditions and Pathology

Appendix Data for Guatemala CKD/ERDS. COMISCA/PAHO meeting, San Salvador, El Salvador. April 20, 2013.

112 Clinical Conditions and Pathology

113 Clinical Conditions and Pathology

114 Clinical Conditions and Pathology

Pathology and pathophysiology of and aristolochic acid nephropathy (Balkan ne- phropathy or Chinese herb nephropathy). For Mesoamerican nephropathy and comparison, we also display the typical biopsy comparisons with hypertension/ - diabetes CKD and CKD of unknown sive nephrosclerosis, being the two most com- cause outside Mesoamerica monfindings causes in diabetic of end stage nephropathy renal disease and hyperten in the US, Europe and Latin America.

Morphology in Mesoamerican Annika Wernerson, Division of Renal Medicine, nephropathy (Figure 1A) Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet, Stockholm, on the renal morphology in patients with MeN Sweden. (1).In 2013Kidney our biopsies group publishedfrom eight the male first agricul study- Julia Wijkström, Division of Renal Medicine, tural workers with suspected MeN in El Salva- Department of Clinical Sciences, Intervention dor were analyzed. The included patients had an and Technology, Karolinska Institutet, Stockholm, eGFR 27-79 (mean 46) ml/min/1.73m² and the Sweden. morphology was similar in all eight patients. The changes seen were chronic glomerular damage with widespread glomerulosclerosis (29-78%), hypertrophy of the remaining glomeruli, signs Background of glomerular ischemia with wrinkling of glo- Kidney biopsies are an important and often merular capillaries or thickening of Bowman’s 115 routinely performed procedure in the clinical capsule and mild to moderate chronic tubuloin- investigation of patients with newly diagnosed terstitial changes (tubular atrophy, interstitial chronic kidney disease (CKD). The morphology in the kidney biopsies usually reveals the un- changes were only mild. Immune complex dis- derlying renal disease, i.e. the diagnosis. It also fibrosis and interstitial inflammation). Vascular provides the nephrologist with information re- electron microscopy podocytic changes were garding the severity of the disease, the degree of ease was excluded by immunofluorescence. By chronic vs active disease and subsequently how the widespread glomerulosclerosis was not only the disease should be treated and the prognosis. secondaryshown. Our to group the tubulointerstitial suggested from changesfindings seenthat In many Central American countries kidney and that mechanisms that could cause primary biopsies are not routinely done due to short- glomerular damage should be further investigat- age of health care resources and/or of renal ed. A similar study has recently been performed pathologists. Consequently, only a few biopsies in Nicaragua (manuscript in preparation). from patients with Mesoamerican Nephropathy López-Marín et al published in 2014 a study (MeN) are available and only two studies on the of renal biopsies from 46 participants (36 males morphology have been published. In Sri Lanka, and 10 females) in El Salvador with chronic kid- a few published studies have described the re- ney disease of unknown cause (2). eGFR of the nal morphology of the chronic kidney disease of included participants ranged between 30-89 unknown cause (CKDu) affecting rural inhabit- ml/min/1.73m². They reported that 59% of ants, but a direct comparison with the biopsy the participants (67% of the males) had global - to different inclusion criteria. eruli and 40% of the participants displayed glo- studies done in Central America is difficult due- glomerulosclerosis in ≥25% of included glom- opsy studies from three endemic kidney diseas- sis was reported in 26% (33% of males) of the es:We MeN here in present Central an America, overview CKDu of findings in Sri Lanka in bi merular hypertrophy. Severe interstitial fibro

cases and tubular atrophy was ≤25% in 87% Clinical Conditions and Pathology

of the participants. López-Marín et al conclude ence in inclusion criteria makes it hard to do

nephropathy with secondary glomerular and studies performed hitherto. their findings show chronic tubulointerstitial comparisons between the findings in the biopsy were negative, but electron microscopy was not Aristolochic acid nephropathy performed.vascular damage. Immunofluorescence studies (Balkan nephropathy or Chinese - herb nephropathy) ings with regards to the glomerular and tubu- A high incidence of CKD was described in larThese changes two but biopsy the studystudies by report López-Marín similar findet al certain villages on the Balkan peninsula in the reports a higher prevalence of severe intersti- 1950’s and later a close association with up- per urinary tract carcinomas became evident these two studies may be due to difference in (5). The endemic was named Balkan Endemic thetial selectionfibrosis. The of participants somewhat different or difference findings in the in Nephropathy (BEN) and the renal morphol- evaluation by the pathologists. tubular atrophy while glomeruli are relatively Sri Lanka sparedogy displays (6). However, extensive some interstitial secondary fibrosis vascular and Around year 2000, an increasing number of and glomerular lesions may be present (7). For CKD without traditional risk factors was report- many years the etiology behind the disease was ed from the North Central Province in Sri Lanka. unknown. In 1993 a report from Belgium was In 2011, Athuraliya et al (3) presented a prev- published describing nine women developing alence study of CKD in three rural communi- 116 ties in the North Central, Central and Southern of slimming herbs containing aristolochic acid Provinces. They showed that in one community, (8).interstitial The renal fibrosis morphology and renal was failure found after to be intake simi- Medawachchiya in the north, dry region, 87% of lar with BEN cases and the Belgian patients also CKD cases did not have a clear cause or risk fac- developed urothelial carcinoma (7). Aristolo- tor. Of these participants 26 underwent kidney chic acid had been proposed as a possible etiol- ogy in BEN in the 1970’s, because an aristolo- tubulointerstitial disease. A more detailed de- chic acid containing plant was found growing in scriptionbiopsy with of themorphological renal morphology findings was reported provided as by Nanayakkara et al (4) who examined 64 re- forwheat many fields years in endemicforgotten areasuntil theand reportmight fromhave light microscopy represented a tubulointersti- contaminated the flour. But this hypothesis was- nal biopsies and concluded that the findings by - atrophy. However, they also reported a high per- tationsBelgium. in Furtherrenal tissue studies of patients have identified with BEN aris (9) centagetial disease of globalwith interstitial glomerular fibrosis sclerosis and tubular(37%), andtolactam-DNA also in patients adducts with and urothelial specific TP53malignan mu- glomerular enlargement (37%) and wrinkling cies, associated with the use of herbal medicines containing aristolochic acid in Taiwan. Thus, the also have been reported from kidney biopsies diseases are regarded to have the same etiology. inof MeN-patients.the glomerular In capillaries, both studies e.g. from findings Sri Lanka that Hypertensive nephrosclerosis electron microscopy was not performed. (Figure 1B) immunofluorescenceIn most studies from studies Sri Lankawere negativeproteinuria but Kidney damage due to hypertension can by or albuminuria have been used for screening of divided into “benign/chronic” nephrosclerosis CKD and inclusion in the studies. This contrasts and “malignant” nephrosclerosis. In malignant to the studies of MeN patients who have been hypertensive nephrosclerosis the patient pres- screened by serum creatinine and often lack or ents with very high blood pressure and in the only have low grade of proteinuria. The differ- kidneys petechial hemorrhage can be found on Clinical Conditions and Pathology the subcapsular surface and sometimes areas of Diabetic nephropathy (Figure 1C) infarct are seen. A typical lesion for malignant Diabetic nephropathy is the most common hypertension is thrombotic microangiopathy cause of chronic kidney disease worldwide (12,

by Gellman et al 1959 (14), is similar in type I In(thrombosis “benign” or in chronic arterioles), nephrosclerosis arteriolar fibrinoidthe typi- and13). typeThe IImorphological diabetes and maypicture, include first changes described in calnecrosis lesions and are arteries thickening with intimalof the tunicafibrosis media (10). the glomerular, vascular and tubulointerstitial (i.e. the smooth muscle layer) in the vascular compartments. The earliest lesion is thickening - of the glomerular basement membrane which ferent arterioles. The vascular changes cause a only can be detected by electron microscopy. narrowingwall, intimal of the fibrosis afferent and arterioli hyalinization and a subse of af- Later, there is a mesangial expansion in the quent increase in vascular resistance (11). The glomerulus which is found by light microscopy. vascular lesions result in ischemic changes of The mesangial expansion, caused by an increase the glomeruli with glomerulosclerosis and/or in mesangial matrix and or mesangial cells, wrinkling of the glomerular basement mem- could be diffuse or nodular (so called Kimmel- brane. Focal segmental sclerosis may be present in some cases. Tubular atrophy and interstitial glomerulosclerosis. Typically, the glomerular changesstiel Wilson are lesions)accompanied and finally by hyalinosis results in globalin the podocyte foot process effacement and widening efferent arterioli. The latter lesion can be used offibrosis lamina is raraalso present.interna inBy the electron glomerular microscopy base- to distinguish between diabetic and hyperten- - cence studies are negative. - 117 mentThe membranediagnosis ofmay hypertensive be seen. Immunofluores nephrosclero- brosissive nephropathy. and sometimes In thehyperplasia arteries, of nonspecific the tunica sis is made when a combination of these lesions media.arteriosclerosis The tubulointerstitial is often seen withchanges, intimal which fi is present and no other lesions indicating pri- - mary glomerular disease are found. are not specific for diabetic nephropathy, in- clude tubular atrophy and interstitial fibrosis,- often with an inflammatory component. Immu nofluorescence for immunoglobulins, comple Table 1: Morphological features by nephropathy

Chronic Glomerular Glomerular Tubular Interstitial Inflam- vascular ischemia sclerosis atrophy fibrosis mation changes

MeN ++ ++ - + + +

CKDu in Sri Lanka ? +(+?) + + + +

Aristolochic acid - - + ++ ++ + nephropathy (+ late) (+ late) Hypertensive ++ ++ ++ + + + nephrosclerosis

Diabetic nephropathy - + ++ + + + Clinical Conditions and Pathology

ment and light chains should be performed to exclude diabetes or uncontrolled hypertension rule out other causes of renal disease. An inter- when performing biopsy studies of patients with CKD of unknown cause in other parts of the world. progressive glomerular changes with a separate A key question that still remains unanswered scoringnational ofconsensus the vascular classification and tubulointerstitial system for the is if MeN and CKDu in Sri Lanka have the same lesions was published 2010 (15). At present, renal morphology and subsequently a possible renal biopsy in diabetes is only indicated when there is suspicion of another glomerular disease in renal biopsies from Central America and Sri than diabetic nephropathy. However, several au- Lankajoint etiology. cannot Asanswer of today, this the question. reported To findingsinvesti- thors suggest that the indications for renal bi- gate the renal morphology in possible cases of opsies should be broadened in order to rule out MeN/CKDu in Sri Lanka, patients with diabetes treatable non diabetic renal disease (16, 17). and uncontrolled hypertension should be ex- The pathogenesis of diabetic nephropathy is not cluded. Finally, we want to emphasize the im- understood. It has been considered as a micro- portance of performing a thorough evaluation vascular disease, but lately an important role of of the biopsies by combining light microscopy, the podocyte has been suggested involving loss of cells and alterations in signaling pathways. In a recent review by Reidy et al, interrelated Referencesimmunofluorescence and electron microscopy. changes in podocytes, mesangial- and endothe- 1. Wijkstrom J, Leiva R, Elinder CG, Leiva S, lial cells are suggested (18). Trujillo Z, Trujillo L, et al. Clinical and patho- logical characterization of Mesoamerican ne- 118 Conclusion phropathy: a new kidney disease in Central We here demonstrate the morphology of three America. American journal of kidney diseases : endemic chronic kidney diseases from Central - America, Sri Lanka and the Balkans and also the dation. 2013 Nov;62(5):908-18. PubMed PMID: morphology in the two most common causes of 23850447.the official journal of the National Kidney Foun CKD with changes in the glomeruli; hyperten- 2. Lopez-Marin L, Chavez Y, Garcia XA, Flores sive nephrosclerosis and diabetic nephropathy. WM, Garcia YM, Herrera R, et al. Histopathology These diseases share some morphologic char- of chronic kidney disease of unknown etiology in Salvadoran agricultural communities. ME- (Table 1). In diabetic nephropathy, nodular glo- DICC review. 2014 Apr;16(2):49-54. PubMed merulosclerosisacteristics, but they is typical also have and specificnot seen features in the PMID: 24878649. other diseases. Aristolochic acid nephropathy 3. Athuraliya NT, Abeysekera TD, Amerasinghe PH, Kumarasiri R, Bandara P, Karunaratne U, et often with spared glomeruli. Signs of glomeru- al. Uncertain etiologies of proteinuric-chronic laris characterized ischemia with by wrinklingextensive interstitialof the glomerular fibrosis kidney disease in rural Sri Lanka. Kidney inter- basement membrane are seen in hypertensive national. 2011 Dec;80(11):1212-21. PubMed nephrosclerosis but also in the Sri Lankan and PMID: 21832982. Central American CKD epidemics. However, in 4. Nanayakkara S, Komiya T, Ratnatunga N, - Senevirathna ST, Harada KH, Hitomi T, et al. cular changes are seen, but in MeN and CKDu Tubulointerstitial damage as the major patho- inhypertensive Sri Lanka, most nephrosclerosis cases show significantminor vascular vas logical lesion in endemic chronic kidney disease changes. among farmers in North Central Province of Sri Since some of the morphological features seen Lanka. Environmental health and preventive in diabetic nephropathy and hypertensive neph- medicine. 2012 May;17(3):213-21. PubMed rosclerosis also are found in the CKD epidemic PMID: 21993948. Pubmed Central PMCID: in Central America, we believe it is important to 3348245. Clinical Conditions and Pathology

5. Grollman AP. Aristolochic acid nephrop- tem 2014 Annual Data Report: Epidemiology of athy: Harbinger of a global iatrogenic dis- Kidney Disease in the United States. American ease. Environmental and Molecular Muta- genesis. 2013 Jan;54(1):1-7. PubMed PMID: the National Kidney Foundation. 2015 Jun;65(6 WOS:000312991300001. Suppljournal 1):A7. of kidney PubMed diseases PMID: : the 26111994. official journal of 6. Pozdzik AA, Berton A, Schmeiser HH, Mis- 14. Gellman DD, Pirani CL, Soothill JF, Muehrcke soum W, Decaestecker C, Salmon IJ, et al. Aris- RC, Kark RM. Diabetic nephropathy: a clinical tolochic acid nephropathy revisited: a place for and pathologic study based on renal biopsies. innate and adaptive immunity? Histopathol- Medicine. 1959 Dec;38:321-67. PubMed PMID: ogy. 2010 Mar;56(4):449-63. PubMed PMID: 13827229. 20459552. 15. Tervaert TW, Mooyaart AL, Amann K, Co- 7. Gokmen MR, Cosyns JP, Arlt VM, Stiborova M, hen AH, Cook HT, Drachenberg CB, et al. Patho- Phillips DH, Schmeiser HH, et al. The Epidemiol- ogy, Diagnosis, and Management of Aristolochic Journal of the American Society of Nephrology Acid Nephropathy A Narrative Review. Annals of :logic JASN. classification 2010 Apr;21(4):556-63. of diabetic PubMed nephropathy. PMID: internal medicine. 2013 Mar;158(6):469-U132. 20167701. PubMed PMID: WOS:000316565100015. 16. Gonzalez Suarez ML, Thomas DB, Barisoni L, 8. Vanherweghem JL, Depierreux M, Tiele- Fornoni A. Diabetic nephropathy: Is it time yet mans C, Abramowicz D, Dratwa M, Jadoul M, for routine kidney biopsy? World journal of dia- - betes. 2013 Dec 15;4(6):245-55. PubMed PMID: brosis in young women: association with slim- 24379914. Pubmed Central PMCID: 3874483. minget al. regimen Rapidly including progressive Chinese interstitial herbs. renal Lancet. fi 17. Espinel E, Agraz I, Ibernon M, Ramos N, 119 1993 Feb 13;341(8842):387-91. PubMed PMID: Fort J, Seron D. Renal Biopsy in Type 2 Dia- 8094166. betic Patients. Journal of clinical medicine. 9. Jelakovic B, Karanovic S, Vukovic-Lela I, Mill- 2015;4(5):998-1009. PubMed PMID: 26239461. er F, Edwards KL, Nikolic J, et al. Aristolactam- Pubmed Central PMCID: 4470212. DNA adducts are a biomarker of environmental 18. Reidy K, Kang HM, Hostetter T, Susztak K. exposure to aristolochic acid. Kidney interna- Molecular mechanisms of diabetic kidney dis- tional. 2012 Mar;81(6):559-67. PubMed PMID: ease. The Journal of clinical investigation. 2014 22071594. Pubmed Central PMCID: 3560912. Jun;124(6):2333-40. PubMed PMID: 24892707. 10. Fogo AB. Fundamentals of renal pathology. Pubmed Central PMCID: 4089448. New York: Springer; 2006. vi, 221 p. p. 11. Rosario RF, Wesson DE. Primary hyperten- sion and nephropathy. Curr Opin Nephrol Hy- pertens. 2006 Mar;15(2):130-4. PubMed PMID: 16481878. 12. Stengel B, Billon S, Van Dijk PC, Jager KJ, Dekker FW, Simpson K, et al. Trends in the in- cidence of renal replacement therapy for end- stage renal disease in Europe, 1990-1999. publication of the European Dialysis and Trans- plantNephrology, Association dialysis, - European transplantation Renal :Associa official- tion. 2003 Sep;18(9):1824-33. PubMed PMID: 12937231. 13. Saran R, Li Y, Robinson B, Ayanian J, Balkrish- nan R, Bragg-Gresham J, et al. US Renal Data Sys- Clinical Conditions and Pathology

Figure legend: Figure 1, A-C: A: Light microscopy, MeN (Peri- odic Acid Schiff staining, PAS): Global glomerulosclerosis is seen (white arrow). Non-scle- rosed glomeruli show signs of chronic ischemia with thicken- ing of Bowman’s capsule and wrinkling of capillaries (black star), despite normal arteries (long black arrow). B: Light microscopy, Benign nephrosclerosis (PAS): In addi- tion to global glomerulosclero- sis (white arrow), severe intimal

black arrow). Non-sclerosed glomerulifibrosis is seenshow in signs an artery of chronic (long ischemia with collapse of the glomerular tuft and wrinkling of 120 capillaries (black star). C: Light microscopy, Diabetic nephropathy (PAS): The typi- cal nodular glomerulosclerosis (black star) is seen in addition to global glomerulosclerosis (white arrow). An arteriolus show hyalinosis (long black ar- row). A-C: Varying degrees of tubular atrophy (short black arrow) and

seen in all biopsies. interstitial fibrosis (blue star) is Theme: What do we need to know and understand?

Working Groups - Next steps to address knowledge gaps

be used to diagnose CKD, biomarkers that can Exploring biomarkers for early be used to identify and assess or diagnose expo- evidence of abnormal kidney sure to a chemical/pollutant or infectious agent function (e.g. using an antibody test) and those that can predict outcome, or serve as risk factors for dis- ease, such as proteinuria. However, biomarkers do not need to have a physiological role. Group Leaders: Ricardo Correa Rotter, The use of biomarkers in clinical care, surveil- National Medical Science and Nutrition Institute, lance/prevalence and research studies is vast. Mexico. Carl-Gustaf Elinder, Karolinska Institutet, disease or abnormality are key features when Sweden. assessingSensitivity the and usefulness specificity of to a correctlybiomarker´s diagnose diag- Rapporteur: James Kaufman, New York nostic potential. University School of Medicine, USA. For assessing renal function, the use of cre- Participants: atinine measurements in plasma (or serum) to Magnus Abrahamson Jenny Appelquist currently the standard. However it is necessary Cynthia Bonilla toestimate use IDMS the glomerularcalibrated methodsfiltration forrate creatinine (eGFR) is Ben Caplin determinations to get comparable and reason- 121 Zulma Cruz ably accurate results. Cystatin C is another use- Ulf Ekström ful marker of eGFR, in particular when the mus- Dorien Fabier cles mass of examined individuals is abnormal Randall Gutierrez or subject to change, as this may bias the eGFR Wendy Hoy from creatinine. To analyse both creatinine and Rebecca Laws cystatin C in plasma, and to use a combined Julieta Rodriguez equation for eGFR increases precision (1) (2), Madeleine Scammel but also the cost. Mathieu Valcke The urine albumin to creatinine ratio (ACR) is another, independent and very useful biomark- er for detecting presence of CKD and estimating prognosis. When using spot or morning urine Desired output: The best possible consensus samples, adjustment for dilution using the cre- of which biomarkers to use for early detection atinine concentration in urine is recommended. of abnormal kidney function. Priority of single, In research studies on MeN/CKDnT the use of or combinations of biomarkers to serve as study a number of other biomarkers in urine may be helpful and informative. What one chooses de- Mesoamerican nephropathy (MeN) or Chronic pends on the hypothesis to be tested. Following kidneyendpoints disease in field (CKD) and of laboratorynon-traditional studies causes on serve as examples. (CKDu). · For early detection of tubular injury: Report: A biomarker is an analyte in a bio- » neutrophil gelatinase-associated lipo- calin (NGAL) disease, presence of an exposure, or to predict » protein HC outcome/prognosis.logic fluid that that can Examples be used of as biomarkers a marker of » beta-2 microglobulin disease are plasma/serum creatinine which can ·

for inflammation Working Groups - Next steps to address knowledge gaps

» C-reactive protein (CRP) » IL-6m · for oxidative stress » superoxide dismutase (SOD) » reduced glutathione (GSH) » oxidized low density lipoprotein (ox- LDL) · » angiopoietin 1 and 2. A fewfor fibrosisof these urinary biomarkers have been used, but not validated, in the context of Meso- american Nephropathy. Finding biomarkers for recurrent subclini- cal acute kidney injury and progression to CKD would be of great value. Unfortunately, the avail- able biomarkers, other than ACR and those used to estimate GFR, have not yet been shown to predict the development or progression of CKD.

Working group recommendations regarding biomarkers for diagnosing and surveillance 122 of MeN/CKDnT · Measure plasma/serum creatinine using a validated method for estimating GFR. · Analyze urine for albumin to creatinine ratio (ACR) to help assess type/cause of CKD · Measure cystatin C combined with creatinine for more accurate eGFR in research setting if re- sources allow. · As yet, no other well-validated biomarkers for early detection and prognosis of CKD are avail- able. Future research to identify such biomark- ers is encouraged, but will require longitudinal studies.

References 1. Elinder CG, Ahlberg M, Allander SV, Alves- trand A, Asker-Hagelberg C, Bell M, et al. Meth- ods to Estimate and Measure Renal Function (Glomerular Filtration Rate). A Systematic Re- view. In: (SBU). SCoHTA, editor. Stockholm2013. 2. Elinder CG, Barany P, Heimburger O. The use

adjustment of medications in the elderly. Drugs Aging.of estimated 2014 glomerularjune 2014;31(7):493-9. filtration rate PubMedfor dose PMID: 24902935. Working Groups - Next steps to address knowledge gaps

Exploring genetic and epigenetic susceptibility

(This working group was not held).

123 Working Groups - Next steps to address knowledge gaps

Assessing individual risk factors Group Leader: Joaquin Barnoya Aurora Aragón, Willy Carrillo UNAN-León, Nicaragua. Channa Jayasumana Rapporteur: Randall Lou Manuel Cerdas, Sally Moyce Hospital México, San Gary Noonan José, Costa Rica. Reyna Pacheco Participants: Rafael Porras Hildaura Acosta Clemens Ruepert Cynthia Bonilla

Table 1. Summary of risk factors that should be assessed in studies, potential limitations and suggestions for best collection of each risk factor.

Potential What do we need to know How can we advance 124 limitations

NSAIDs -Local suppliers -Recall bias -Frequency of use Mostly subject to A way of getting more -Way of using them (like diluted in self medication, information before deciding fluids: water, juice etc or in addition -Possibility of what and how to ask is doing to vitamin B complex) not getting the community based participatory -Prescriptions. information research together with key -When do they take them (before, because of fear of people from the communities during or after work; before having being connected (qualitative/anthropological pain or after) to the disease research) to create a good -Why do they take them, for environment for getting the “prevention” as a surrogate of information vitamins, or as pain killers -Providers (companies, local sellers/ distributors) To understand exposure levels it is advisable to use some qualitative methods before hand, in order to get ideas of type, frequency, ways, if it is work related and reasons for taking, Working Groups - Next steps to address knowledge gaps

Potential What do we need to know How can we advance limitations

Nutrition -We must take into account that If we want to know nutrient we have disadvantaged populations current consumption then with potential low birth weight which we should focus on what we means reduce numbers of nephrons want to know, i.e, soft drinks -Follow up studies since delivery, consumption for fructose (other options, feasibility could be a intake, and not the entire food hindrance) having access to registries, frequency ----Questionnaire to get info of weight at birth. -Another option is a study of stunting as a surrogate of low birth weight.

If we want to know about general aspects of dietary intake -It is not adequate to ask of dietary intake the day before or the week before due to a recall bias. -Body Mass Index information to know nutritional status is safely 125 obtained in the fieldwork with a proper scale. The measurement in this case should be in the morning. Working Groups - Next steps to address knowledge gaps

Potential What do we need to know How can we advance limitations

Alcohol -Information about suppliers There is a Group interviews, key -Type of alcohol, (legal or illegal) social stigma informants interviews, -Pattern of alcohol consumption reporting alcohol anthropological studies through ethnographic study and consumption, using participatory action research underreporting to involve the community to first due to connection understand the habits, alcohol use with the CKDu frequency, times, if they drink during work (lunch time, after work) -Register information to calculate grams of alcohol to allow comparison -Consumption of homemade alcohol

Other Exposures

Smoking -Habits with the usual questions and calculating pack years -Measure urinary cotinine could also 126 include exposure to secondhand smoke.

Drug use Illegal Drug consumption among -Safety problem Tests of urinary metabolites exposed population, use and abuse of especially in areas for cocaine, marihuana, legal drugs with high risk with amphetamines, when is feasible drug dealers -Subject to selection and information bias

Exposure to The potential as a contaminant to -Time for Performing a study proposal for sugarcane affect the kidneys, both for workers measuring the a community study that includes ashes in the and the neighborhood. Important the contaminant and workers and their families during environment content evaluation of the ashes. exposure zafra (harvest) season distributed in the -Appropriate vicinity methods for lab analysis Dioxins and silica

Use of Habits of home remedies and Using observation through homemade medication to keep up their anthropologist specialists remedies (herbs) performance, and treat dehydration and medication or heat stroke Working Groups - Next steps to address knowledge gaps

Potential What do we need to know How can we advance limitations

Habits to handle Self-medication, home remedies, Using qualitative methods heat stroke visit to doctors, or health units

Habits to keep Hours working, resting time, drinking Using qualitative methods themselves able water, energizers, alcohol especially to work beer drinking, playing baseball or football, coffee to keep themselves awake or to “treat” dehydration or heat stroke

Child labor History of child labor using a question Include this type of questions of age starting work paid or unpaid, in a questionnaire, a population duration and intensity study that includes the all possible age groups

Important: To perform a regional study to allow comparison among countries.

127 Working Groups - Next steps to address knowledge gaps

port. In brief, Cadmium (Cd), lead (Pb) and ura- Assessing exposures to nium (U) exposure are potential risk factors for pesticides and metals decreased renal function and may at high expo- sure levels also cause acute clinical disease. On population level, the margin between dietary Cd exposure and subtle tubular effects may not be Group Leader: Kristina Jakobsson, Gothenburg University, Sweden. high consumption of rice. There is, however, a Rapporteur: Berna van Wendel de lacksufficient, of base-line especially data onnot cadmium, in populations lead and with ura a- Joode, Universidad Nacional, Costa Rica. nium exposure levels in Central America, both Participants: in the general population and in occupational Vivek Bhalla populations at risk of CKD. For inorganic arse- Sarath Gunatilake nic (As), which in contrast to organic As has a Brian Curwin Carolina Guzman nephrotoxicity has been established. wellThe -known present toxicity sparse profile, data nofrom firm populations evidence of Channa Jayasumana at risk for MeN, emanating from the Boston Jill Lebov University investigations in Nicaraguan cane Carlos Manuel Orantes workers and unpublished data from sugarcane Clemens Ruepert cutters in El Salvador presented during the Rolvin Salas workshop, have not indicated exposure to Pb Virginia Weaver 128 and Cd at levels compatible with renal damage, taking existing dose-response relations into account. Similarly, the hitherto published data from Sri Lankan investigations do not indicate Objectives heavy metals as probable risk factors for the a. Consider the evidence for exposure to pes- epidemic of CKDnT. ticides and to metals to explain epidemics of However, there is clearly a need for an ex- CKDnT tended monitoring of heavy metal exposure, b. Identify the best methods to measure and quantify these for use in population and ex- risk groups for CKD. This is especially the case perimental studies and how to assure validity forboth Cd, in Pb the and general inorganic population As. Also, and monitoring in defined of metal levels in drinking water is needed, espe- setting. cially in locations where the bedrock may con- of measures in the field and in an experimental tain metals that can be dissolved in the ground Output water. The primary reason for this recommen- a. Identify which pesticides and which metals dation is precautionary, since exposure to Cd, are a priority for consideration in studies of Pb and inorganic As have well-known extra-re- CKDnT: nal adverse effects. b. Identify how to quantify exposures. How to assess exposure Metals to metals? Environmental monitoring should be per- Which metals are a priority formed to understand sources and routes of ex- for studies of CKDnT? posure, in particular via drinking water and food The present knowledge of the nephrotoxicity (e.g. rice, and other important dietary compo- of metals is summarized elsewhere in this re- nents). The use of biomarkers for heavy metals in Working Groups - Next steps to address knowledge gaps

active ingredients, but also the pesticide formu- in occupational as well as environmental expo- lations and the toxicity of additives and possible surebody monitoring.fluids and other We heretissues refer has to a longthe extensive tradition contaminants such as cadmium. biomonitoring literature for information on the consideration of suitable matrices and the corre- How to assess exposure lated kinetics (i.e. which time period of exposure to pesticides? - Historical and current pesticide use should be dling of samples to avoid contamination, and the studied by constructing pesticide crop use ma- accuracyis reflected of differentby the selected analytical tissue), methods. correct Notably, han trices. Such matrices can be constructed using international control programs exist for quality e.g. pesticide import data and by interviewing control, and should be adhered to. agronomists and farm managers. IRET has long- In cross-sectional investigations measuring standing experience that can be shared. It is also exposure and effect simultaneously, not only likely that large farms have registers of pesticide the understanding of the biomarker kinetics but use. Collaboration with governmental agencies also the concept of reverse causation has to be should also be used for data collection. By map- considered. This may also be a problem in case- ping crops, and pesticide use by crop, in relation control studies. However, such studies can be to the prevalence of CKD, contrasts over time and valuable for base-line exposure monitoring, and space can be assessed. for time-trend investigations. On group and individual level, the use of ques- tionnaires is common, but often the results are Pesticides of limited quality, and not possible to compare between studies. 129 Which pesticides are a priority Environmental pesticide monitoring of air, for studies of CKD? dust, biomaterials, and water should be per- Workgroup participants agreed that it is un- formed taking the timing of sampling in rela- likely that pesticides can explain the epidemic of tion to agricultural activities into consideration. MeN in Mesoamerica. Pesticide and agrochemi- Proper sampling and good analytical quality is a cal exposures may possibly play a role in the prerequisite. CKDu epidemic observed in Sri Lanka, but there Personal airborne and dermal exposure as- is a need to investigate other potential risk fac- sessment can be performed in occupational set- tors related to agricultural work, such as heat tings. For a very limited number of pesticides stress. Pesticide intoxications may be associ- there are also biomarkers of exposure (e.g. me- ated with acute as well as chronic CKD, possibly - - ing or recent exposures. Thus, the same con- tion, but cannot explain the current epidemics. cernstabolites about in urine), timing usually of sampling reflecting and onlybiomarker ongo becauseYet, it isdue necessary to non-specific to study mechanisms pesticide use of and ac kinetics as for the metal biomarkers are valid. exposure in historical and current context. Based In summary, life-time exposures to pesticides on the results of recently performed studies, should be assessed using mixed data collection herbicide exposure should be studied in more methods (registry data, interviews and question- detail, in particular, glyphosates, paraquat, and naires, environmental monitoring, biomonitor- 2,4-D. The past use of toxaphene should also be ing). Finally, to answer the questions whether taken into account. Also, in sugarcane produc- pesticides play a role in CKD, research priorities tion, glyphosates have been aerially sprayed to should be set at a regional and international lev- mature cane, and may have caused relevant en- el. It is recommended to develop a core module vironmental exposures. As pesticides from dif- for assessment on pesticide exposure that can ferent producers may vary in quality and added be used for regional, national and international substances, it is necessary to study not only the comparisons. Working Groups - Next steps to address knowledge gaps

Assessing exposure to environmental heat load/ dehydration and workload

Group leaders: Rebekah Lucas, University of Birmingham, UK. Esteban Arias Monge, Costa Rican Technol. Institute, Costa Rica. Rapporteur: Jennifer Crowe Participants: Willy Carrillo Randall Gutierrez Rebecca Laws Magdalena Madero Michael McClean Sally Moyce Sandra Peraza Rafael Porras Oriana Ramírez Rubio 130 Andrés Robles Julieta Rodríguez Pedro Vinda

Objectives a.

and Consider workload the in essentials both short of field and assessmentlong-term studiesand quantification and how to assure of heat validity load/dehydration of measures

b. Propose priority measures of heat/ dehydrationin the field and and in of an workload experimental that are setting necessary to include in population studies or to examine in laboratory investigations.

Heat exposure The following methods were discussed for

challenges that should be evaluated based on theassessing study question,heat exposure. design Each and haspopulation. benefits and Working Groups - Next steps to address knowledge gaps

Table 1. Heat Exposure Factors and Methods.

Factor Method Validity Appropriateness Comments/Recommendations

Expensive May be unacceptable to some individuals/ Gastro populations. Any field studies using gastrointestinal A valid and intestinal Consider pills might also measure tympanic reliable measure temperature contraindications for temperature and report their findings of body core (via an safe use of the pill. widely to explore validity of tympanic temperature ingestible These include reusing measurements and modeled estimates for field-based telemetry pill a pill, having a MRI of body core temperature (Buller et al measurements. system) with a pill ingested, 2013). choking hazard for small children and Internal heat chewing the pill. production

131

Less invasive than Infrared tympanic Tympanic a gastrointestinal At this stage, tympanic temperature temperature temperature pill, although more should not be used in isolation to measurements (via infrared difficult to get describe body core temperature, but are not currently thermometer reliable readings (i.e. could be used in addition to other accepted as a valid or tympanic due to the shape of methods in an attempt to further measure of body thermistor) the ear and ear canal, validate this measure. core temperature. user technique etc.). Working Groups - Next steps to address knowledge gaps

Factor Method Validity Appropriateness Comments/Recommendations

Humidex and Heat index are user-friendly WBGT is one of and can be more the most widely It is important to know and report easily understood used heat indexes, the assumptions being made when by workers and but is expensive calculating heat stress based on an employers. WBGT is to measure and index: i.e. clothing, wind velocity. It is appropriate for initial requires being also valuable to have an estimate of Modeled studies, but not onsite. the metabolic rate for the particular job estimates practical for day-to- Existing data from task being examined. (Heat stress day monitoring long previous studies indexes such term. Local Climate makes data easily Interpretation of WBGT should be done as WBGT, comparable to according to standard protocol (i.e. not Humidex, In all cases, it is other countries/ interpreted only on an hourly basis) NIOSH Heat obligatory to measure job tasks. index) as a minimum “Permissible” Acclimatization, acclimation and temperature heat exposure cardiovascular fitness are important and humidity. threshold limit factors influencing heat tolerance and 132 Dry temperature values are often are potentially accounted for in some measures alone published using heat stress indexes. are not sufficient WBGT. to calculate a meaningful heat stress index. Working Groups - Next steps to address knowledge gaps

Factor Method Validity Appropriateness Comments/Recommendations

Some technically “portable” weather stations are Relatively small scale studies to cumbersome and compare local field assessments Having complete generally expensive to airport weather data could be weather data is and therefore not useful. helpful in initial Portable weather always appropriate These data are relevant both from assessments of stations for field monitoring. a historical and future perspective heat exposure in If the possibility in relation to understanding worker a specific working exists to have the health in relation to climate change. population. station in place for a Studies that map heat index change long period of time, it over time would be useful. could provide helpful data. Local Climate

Would provide data There are on temperature and limitations to only humidity conditions 133 Small portable using temperature during transport to Personal-level data can be temperature/ and humidity to and from the field compared to field-level WBGT humidity loggers estimate heat and also during data and publically available (eg: HOBO data exposure, but the night. These geographical grid level weather loggers) individual-level data might be data. data can be very important for fully useful. understanding heat exposure.

Airport weather stations data can be accurate and Attractive because readily available, Airport weather data should be they are readily Airport weather but they do not compared to locally collected data available and would stations necessarily reflect in a workplace before using it to enable larger spatial General the specific calculate heat exposure. and temporal Climate conditions of comparisons (i.e., a particular across decades, workplace. between countries or around the globe.) Studies to compare general climate Global climate Generally accurate data to locally collected data would databases (NOAA) and detailed data. be useful. Working Groups - Next steps to address knowledge gaps

Dehydration/fluid balance -

Understanding the amount of fluid consumed by workers affected by heat and heavy workload is es- sential, yet quite difficult to assess accurately. Some experience and insight has been gained by recent studies that have attempted to measure fluid consumption. Difficulties and potential solutions to mea Tablesuring 2.dehydration and fluid balance were discussed.

Dehydration/fluid balance measures. Measure Difficulty Possible solutions

Using a questionnaire with pictures of cup and water bottle sizes.

Workers are generally able to recall a number of something consumed. For example, they are Worker recall about the volume of fluid they more likely to accurately remember that they Fluid have consumed is notoriously inaccurate and consumed 2 “bolis” than to know how many liters consumption workers often have trouble knowing how of water they consumed. If workers use a standard much their cups or water bottles hold. size water bottle, they may be more accurate in 134 reporting how many bottles they have consumed. For increased accuracy, the bottles can be visually inspected or weighed pre and post shift; and fluid distributed during the shift can be observed and recorded. Working Groups - Next steps to address knowledge gaps

Measure Difficulty Possible solutions

Changes in body mass is a reliable and valid measure of sweat loss and dehydration (i.e., % change in body mass is used to describe level of dehydration in literature). However, weighing scales can fail in the field due to heat, uneven terrain or direct sun. More expensive scales are reported to perform better in the heat. Researchers should plan to calibrate scales regularly in the field.

Workers must be weighed wearing the same clothes pre and post shift. Ideally, workers are weighed nude or in underwear, but cultural and field conditions often make this impossible.

Fluid balance - weight loss Food and fluid consumption during a shift must be accurately recorded for all participants in order to interpret changes in body mass data. Researchers should also Workers generally do not recall or self-report food 135 ideally know how many times and how much and fluid consumption accurately enough for participants urinated. Some of the Central study purposes. Direct observation is much more American studies that have tried this report effective. workers who were unable to urinate at the end of the shift.

In the case of sugarcane cutters, soot, dirt and sweat in clothing will add to weight post- shift. Working Groups - Next steps to address knowledge gaps

Measure Difficulty Possible solutions

USG is debated as a valid measure of hydration, but remains a rather easy and Pooling data and “lessons learned” from field inexpensive indicator. USG should be studies could allow us to create a “living” shared interpreted with other biomarkers. It is also protocol for measuring fluid balance. unclear whether USG is valid in workers with reduced kidney function.

It is useful to measure pre-shift, post-shift and the morning following the shift when looking for Changes in plasma volume can be estimated biomarkers until more research confirms the ideal from changes in haemoglobin concentration timing of measurements. Existing data suggests Fluid balance - and hematocrit using the previously biomarkers may be most informative the morning biomarker established calculations (Dill & Costill 1974) after a shift (after sleep).

Urine and serum/plasma osmolality is worth testing. Serum/plasma osmolality reference values can be used to quantify hydration status and water-loss dehydration.

Some relatively new options such as postural 136 Creating a standard protocol and validating it in blood pressure might be helpful. The US Army different study populations might help determine has data on the expected blood pressure whether this is an appropriate and valid measure. changes from laying, sitting and standing.

Electrolyte loss remains relatively understudied for working populations. One possibility might be to measure electrolytes in Salt loss Of note, endurance training and heat sweat. This has not been done yet by any research acclimation/acclimatization dilutes sweat and groups. preserves electrolytes in extracellular fluid. Working Groups - Next steps to address knowledge gaps

Workload It is essential to understand workload in CKDnT affected populations; however the methods for achiev- are summarized below. ing this are varied. The pros, cons and possible solutions to common difficulties were discussed. These Table 3. Measures of workload.

Remaining Common difficulties and Measure Pros Cons questions and possible solutions future steps

Purchasing the correct equipment (eg. Polar watches) can be very confusing. It is The US Army important to know whether has a model Cardiac drift the equipment is coded or that uses heart occurs with heat encoded and whether there will A very useful rate to estimate stress, i.e., heart be logger interference when tool in measuring changes in core rate increases workers are close together. It workload temperature. This 137 beyond metabolic is also essential to know how objectively might be worth demand due to a often it will log data and for how investigating temperature effect. long. Many models will only further (Buller et al give a minimum, maximum and 2013). average, but ideally, researchers should be able to log heart rate at least hourly.

Heart rate A recent US army model (Buller This model is To date, this model has not been 2013) estimates relatively new and validated in sugarcane cutters change in body has not yet been against more direct measures of core temperature widely validated. body core temperature. from heart rate.

Can be expensive and may be Monitors with a interference wristwatch and between workers, chest band easily especially if used in the field. researcher wears the wrist monitor. Working Groups - Next steps to address knowledge gaps

Remaining Common difficulties and Measure Pros Cons questions and possible solutions future steps

Placement of accelerometers It might be for tasks such as interesting to cutting sugarcane experiment with is not standard. For placement of two example, placement accelerometers might determine Relatively on the machete whether they can Sharing experiences would be Accelerometers inexpensive and and one on the accurately be used helpful to standardize protocols. objective tool. worker’s trunk/ to measure cutting wrist to determine versus walking. more specific

information about ActiGraph the task of cutting equipment seems cane. to be the most commonly used.

Workload Inexpensive 138 classifications method that does are very general, not require the Observational leading to many job purchasing of tasks with the same equipment. metabolic load. Working Groups - Next steps to address knowledge gaps

Remaining Common difficulties and Measure Pros Cons questions and possible solutions future steps

When observing cane cutting, the following considerations are important: How tangled was the cane? Assumptions must (Workers are generally able to be made to be say whether the cane was good able to compare (easy), normal or bad (difficult)). Theoretically, different days Variation in cane weight (The productivity within the same workers will be paid by meters should decrease Productivity (ie work group and to cut and the weight of the cane with increased number of feet compare different once it is taken to the mill. The heat exposure and cut, baskets working groups or weight can vary considerably dehydration. In collected or tons different jobs. (i.e. depending on the variety of cane tasks paid by the cut). if cane is hard to cut as well as how long it was in the piece/weight, this one day and easy field. can be relatively to cut the next day, It is necessary to know the easy to measure. using “productivity” age, weight and body mass of as an indicator may workers to interpret metabolic 139 be misleading. load. Videotaping the work is recommended to help with the interpretation of accelerometer data.

Priority research and actions References The following actions and research initiatives 1. Buller, et al., Estimation of human core tem- are recommended as top priority: perature from sequential heart rate observa- 1. Creating shared protocols and reporting tions. Physiological measurement 2013, 34, 781 quickly on data and lessons learned, especially [see also: http://www.usariem.army.mil/index. with regard to validating (or developing a cor- cfm/modeling/cbt_algorithm] rection model for) less expensive and less inva- 2. Dill and Costill. Calculation of percentage sive methods. changes in volumes of blood, plasma, and red 2. Whenever possible, researchers should use cells in dehydration. J Appl Physiol 1974, 37, more than one measurement to help with vali- 247-248. dation (eg. report both individual-level heat monitors as well as WBGT and airport data or report both gastrointestinal pill and tympanic temperature). Working Groups - Next steps to address knowledge gaps

kidney disease. Agents thought most likely to Consideration on infectious agents contribute to the worsening are Leptospira, Hantavirus, Dengue, and West Nile virus. More research is required to improve understanding. This research would be facilitated by targeted Leader: Reina Turcios-Ruiz, CDC, Atlanta, studies of blood samples of those with CKD USA. (both serum and whole blood) and of tissue Rapporteur: Juan José Amador, Boston samples (kidney and bone marrow biopsies). University, USA. For these studies to be a success it is critical that Participants: good comparison groups be selected and evalu- Vivek Bhalla ated in the same manner. David Friedman Ana Leonor Rivera Recommendations to move Gary Noonan forward 1. The primary recommendations from the workgroup · Strengthen collaborations among groups of he Working Group on Infectious Agents researchers both those investigating infectious was charged to consider evidence for agents and those directing attention to etiologic T infectious (bacterial, parasitic or viral) studies of CKDu etiologies for CKDu and how these might be as- · Studies of infectious agents require testing 140 - of blood, serum, urine and tissue samples with ations the group was asked to: careful attention to proper standardization of sessedPropose in field which, studies. if any, Based infectious on these agents consider are collection, management and examination of the important to further assess in population or biologic materials laboratory studies of CKDnT · It will be necessary to coordinate with hospi- tals and families in order to obtain proper tis- Knowledge and knowledge gaps sues and samples to be tested The group discussed the evidence base for an · The use of antibody testing remains a main- infectious agent role in the etiology of CKDu and stay of this research but there is a need to con- gaps in that evidence base. In advance of the tinue efforts to develop and apply new tools for working group a literature review in PubMed biological testing and detecting agents that can - improve upon or expand the information avail- ing the following key words in the search: in- able from antibody testing alone fection,identified “chronic 462 articles kidney/renal (39 non-English) failure/disease”; by us · Case studies continue to offer insights but a cause, etiology and adult. A summary of the priority should be place on establishing re- search based in cohorts to understand burden are infectious complications of persons with es- and natural history of the role of infectious findingstablished from kidney that failure search as indicates a consequence that a) ofthere im- agents in CKDu. munosuppression, b) there are renal manifesta- tions of infectious disease, and c) that infectious diseases are associated with (a consequence of) kidney failure. In sum the group judged that infectious dis- eases should be considered an unlikely cause of CKDu but could contribute to the worsening of clinical progression for those with chronic Working Groups - Next steps to address knowledge gaps

Understanding the mechanism renal biopsies; chronic tubulointersitial chang- es and glomerular ischemia with glomeruloscle- of Mesoamerican nephropathy - rosis. Theory However, several mechanisms could indeed contribute to the ischemic renal damage (Fig- Group Leaders: Richard J Johnson, ure 1); University of Colorado, USA. · Increase in body temperature: Physical activ- Annika Östman Wernerson, Karolinska ity generates endogenous heat and higher body Institutet, Sweden. temperature, which adds to the heat from the Rapporteurs: Ramon García-Trabanino high environmental temperatures. Participants: · Uric acid: Serum uric acid levels rise during Magnus Abrahamson the workday due to the increased release of Ben Caplin substrate (purines) as a product of the intense Ulf Ekström muscle activity associated with strenuous la- bor. Coupled with the heat stress experienced, Sarath Gunatilake this may lead to uricosuria. A transient state Claudio Mascheroni of volume depletion ensues, producing a fall in Carlos Manuel Orantes kidney perfusion and high demands on tubular Madeleine Scammel reabsorption, with the consequent activation of Agnes Soares several compensatory mechanisms (systemic Elizabeth Whelan vasopressin and local activation of the aldose 141 Emily Wright reductase-fructokinase pathway in the renal tu- bule). Then, uricosuria in the concentrated and

Output · Salt depletion and RAAS activation: Strenu- Characterize the most promising hypotheses ousacidified work urine in high may ambient form urate temperature crystals. results in sweating and loss of salts that, in combina- tion with dehydration, may activate the RAAS and propose laboratory and/or field studies to system and result in intrarenal vasoconstriction Reportconfirm or refute. and hypokalemia. Activation of RAAS is sup- A wide variety of etiologies have been pro- ported by the low sodium and potassium levels posed to explain the cause of Mesoamerican often found in MeN patients and may also pres- Nephropathy in Central America, including ex- ent in workers doing strenuous work in these posure to herbicides, pesticides, heavy metals environments.. (cadmium, arsenic, lead), toxins (Aristolochia), · Intake of pain killers: In dehydrated patients, drugs (NSAIDs), infections (Leptospirosis, intake of NSAIDs could further impair renal Hanta virus), metabolic causes (hypokalemia, - hyperuricemia), and the effects of strenuous nal injury. physical labor in the presences of heat stress blood flow and may further contribute to the re and recurrent dehydration. Studies recommended to confirm To date, heat stress due to high ambient tem- the hypothesis perature and strenuous work have been identi- Experimental studies: Are important to evalu- - ate the role of uric acid and heat exposure as bination with dehydration may lead to reduced mechanisms for the development of CKD. renalfied as perfusion important and factors. renal Theseischemia factors, which in couldcom Intervention studies: To optimize water intake (ongoing studies in El Salvador), to optimize re- explain the histopathological findings found in Working Groups - Next steps to address knowledge gaps

hydration (water, salt and glucose) and to opti- Studies needed to find out if CKDu mize rehydration and treat with urine alkaliza- found in other endemic areas rep- tion and xanthine oxidase blockage. Heat control resent MeN by “rest and shade” should be recommended in The group discussed possible causes of CKDu all studies. The ultimate outcome is stable eGFR. in Sri Lanka where the researchers in Sri Lanka Monitoring of the following parameters would have considered a combination of toxic chemi- be valuable: Medication, heat stress symptoms, cals and heavy metal as the most relevant con- hydration status, plasma electrolytes , plasma tributing factors to the CKD found in that area. and urine uric acid, and RAAS, biomarkers for tubular injury. other endemic areas, e.g., Sri Lanka, is the same If possible, studies of urine; volume, osmolal- diseaseTo find as outMeN if it CKDis important of unknown to perform etiology renal in ity electrolytes / 24 h would be informative. biopsies on carefully selected patients. Reduced Biopsy studies: Biopsy studies in early stag- eGFR (and not proteinuria) should be used as es of the renal disease, if possible in the acute inclusion criteria and patients with diabetes phase, would add valuable information about and hypertension should be excluded. Clinical the acute injury and the possible presence of urate crystals in the tissue. and urine samples should be collected at the timecharacteristics of biopsy. should Standardized be identified questionnaires and blood would be of great value (see summary of Work- ing Group on Developing Central Elements for a Core Questionnaire. 142 Figure 1. Proposed mechanism of chronic kidney injury in Mesoamerican nephropathy. Working Groups - Next steps to address knowledge gaps

and questions where possible, and Developing central elements c. for a core questionnaire and evaluation, with special attention paid to importantA centralized, topics efficient for which process good ofdata testing have

Cited examples included agrichemical Group Leaders: Daniel Brooks, Boston exposure,been difficult heat to stress obtain and by hydration, questionnaire. and University, USA. medications (pharmaceutical and herbal). Rapporteur: Marvin González, National At the same time, working group participants Autonomous University of Nicaragua at León. noted that researchers might be interested in Participants: different populations and questionnaires might Hildaura Acosta be administered in different settings, both of Joaquín Barnoya which could impact the types of topics that Jessica Cardanedo might be considered most relevant. Community Dorien Faber residents, workers, and patients were the main Carolina Guzmán Emmanuel Jarquín differ for these groups, but the amount of time Jill Lebov availablegroups identified. to ask questions Not only mightcould therange questions greatly Mathew Lozier depending on the setting. For example, ques- Ándres Robles tionnaires administered at a worksite might Vidhya Venugopa need to be limited to 10-15 minutes or less, Roy Wong while community-based questionnaires admin- 143 istered at participants’ homes might extend for an hour or more. Working group participants also noted that uring its discussions, the Working Group the design of the study also could have an im- covered the following areas: pact on the type of information gathered, par- D ticularly whether only a single (cross-sectional, 1. Rationale for a core questionnaire case-control, or retrospective cohort study) or 2. Topics to consider for inclusion multiple (prospective cohort study) encounters 3. Methods for testing and evaluation were anticipated. 4. Next steps While recognizing this variability, there was agreement that certain topics would be of com- Rationale mon interest across groups and that a core - questionnaire would be a useful template, un- es of developing a core questionnaire, including: derstanding that different researchers would Participants identified a number of advantag want to add or modify certain questions. Rather 1. than try to consider different uses, the working across different populations, including allowing group participants agreed that it would be most forEnhancing pooling of data comparisons across studies. of study findings useful to start with the elements of a question- 2. Encouraging the conduct of studies in areas naire that would be used in a cross-sectional/ where there are reports of MeN but little data. case-control study of community residents in 3. Initiating a process that would produce a which the assessment of factors associated with higher-quality questionnaire because it would elevated creatinine levels was of primary inter- a. Allow for a systematic consideration of est. topics that should be prioritized, b.

Identification of validated instruments Working Groups - Next steps to address knowledge gaps

Topics It was also recognized that a core question- Working group participants struggled with naire would still need to be adapted based on the balance between the desire for brevity and the knowledge of the researchers in consulta- tion with the study participants to account for differences in terminology and culture between ofat thetopics same and time the fornumber sufficient of questions information. for eachThis and within different countries. topic.conflict An manifested example of itselfthe latter in both concern the numberwas the issue of work history, which everyone agreed Next steps was an important topic. Discussion centered on The working group participants suggested the question of how much detail was needed to the following steps: get a measure of work history that would pro- vide useful information for assessment of an 1. Set up a CENCAM task force association with elevated creatinine level. Par- 2. First focus on one common scenario: base- ticipants did not reach a conclusion, but this line/one-time questionnaire of adults at work question was recognized as an important issue or in community. Consider longer and shorter for future consideration. versions. Given time limitations and the fact that this 3. Inventory questionnaires used to date in study of MeN, and obtain input from research- participants had the opportunity to consider ers regarding more or less successful questions. themeeting idea ofwas the the core first questionnaire, time most working it was decidgroup- 4. Search more broadly for questionnaires that ed that it would be most useful for participants can provide assistance for topics that have prov- 144 to focus on suggesting a range of possible topics and not try to narrow down the list. The list of 5. - suggested topics is included in the table at the poseden to be core difficult elements to obtain for questionnaire good data. end of this summary. Develop, circulate, field test, and revise pro

Testing and evaluation Working group participants recognized that formal validation studies were unlikely to be undertaken, but that efforts should be made to make the questions as accurate and useful as possible. Suggestions included:

1. Use validated questions when possible, while recognizing that it is important to consider the population in which the questions have been

2. Circulate draft questions within CENCAM, validated,so that the as experience validity can and be population-specific. perspective of the broader community of researchers has a chance to be incorporated into the questionnaire. 3. The questionnaire should be piloted with community members in different locations to test reliability. In addition, the technique of in- terview probing should be used to assess how community participants’ understood the ques- tion in order to identify problems with wording. Working Groups - Next steps to address knowledge gaps

Table 1. Suggestions for elements of a core questionnaire.

Topic Potential Elements Considerations

What are appropriate SEP measures? USAID Sex, age, height, weight, socioeconomic Demographics questionnaire uses index of running water, position (SEP), access to medical care roof materials

Years, migration, water source, sanitation Residential facilities, agrichemical use

Industry/crop/job/tasks (current, past), age started working, labor migration, Occupation years, hours, days per week, employment relationship, form of compensation (hourly, piece rate), personal protective equipment

Level of exertion/sweating, symptoms 145 Heat stress (timing, duration, frequency, episodic vs. chronic)

Visual aids would help for amounts. What is Hydration Type (at work/not at work, amount) an appropriate recall period?

Location (Work/not at work); years, days/ Focus only on agrichemicals already identified Agrichemicals year, age started; ever intoxication; planes as potentially nephrotoxic? spraying

Medical history/ CKD (personal and family), diabetes, symptoms hypertension

Visual aids would help for pharmalogical medications. What is the appropriate recall period? Are herbal medications important NSAIDS, other pain relievers nephrotoxic Medications for etiology of MeN? How can they be antibiotics, pyridium; chronic vs. episodic use ascertained in a brief questionnaire (Y/N question, followed by open-ended response for specific names)?

Behaviors Smoking, alcohol Working Groups - Next steps to address knowledge gaps

Approaches to intervention

Group Leaders: Theo Bodin, Karolinska Institutet, Sweden. Rapporteur: Ilana Weiss, La Isla Foundation, Nicaragua. Participants: Brian Curwin Randall Gutierrez Christer Hogstedt Emmanuel Jarquin Michael McClean Sandra Peraza Oriana Ramírez Rubio etc. that could change the working live for many Andres Robles workers across several countries at the same David Rodriguez time. On a national or industry-wide level, poli- Vidya Venugopa cy regulations, engagement of national govern- mental bodies such as the min. Labor, Health, 146 Environment etc. could result in intervention through legislation regarding work practices, Introduction child labor, pesticides, minimum wage, etc. As we come closer to identifying the under- The national and regional sugar industry could lying cause of the Mesoamerican nephropathy also be target for business model interventions epidemic, we have reached the point where it aimed at identifying the competitive edge and is beyond reasonable doubt that the issue lies investing in modernization. If changes are not within the occupational setting. Irrespectively achieved industry-wide, individual companies all agree that manual cane-cutting is a high-risk could take the lead and show how moderniza- job with environmental and occupational haz- tion, interventions along the value chain, vo- ardous exposures that could be tackled through cational training for workers during transition interventions. Participants in this workshop process and other interventions could increase agreed that we do not have to wait for research productivity and revenues. Finally, on a worker- to come out to improve working conditions. level, there are several interventions that could Interventions can take place at several levels be of great value if proven successful and dis- in society and business. They could also have seminated to a wider audience. Education and long-term as well as short-term objectives. It is sensitization regarding pesticides, heat and er- important to try to stop the epidemic as soon as gonomics could be important although individ- ualizing these problems won’t have big impact. tackle implications in the long run. Structural re- formpossible of business and we alsois under need way to figure and intervention out how to Intervention priorities strategies have to address several levels of soci- ety. Figure 1 depicts the macro, meso and micro 1. Mitigate Heat Stress level of intervention and its potential impact. A further development and evaluation of Wa- On an international level, interventions could be ter.Rest.Shade components and different modes aimed at trade agreements, fair trade programs of the program in order to evaluate best prac- Working Groups - Next steps to address knowledge gaps tices in each situation. Also a need to develop 4. Re-inventing business models and econom- suitable re-hydration formulas and develop ic impact. common protocols for evaluation of heat stress CENCAM lacks health and business econo- and hydration. - ventions on both company and societal level. 2. Innovation and education mists who can evaluate the cost-benefit of inter Pesticides—how and when to apply, good Key components for successful practices interventions · Good planning and communication with all Heat Stress/Dehydration - Intelligent tex- stakeholders. tiles—fabricErgonomics—bring that cools in field engineers · Intervention on multiple sites to protect from Total worker health—medications, nutrition- unforeseen events such as bankruptcy or sud- al interventions den changes of heart in individual companies or governments. 3. Policy intervention · Testing methodology. Development of a living Comprehensive legislation on import/export lab where interventions could be tested and in- of pesticides. terested parties could test live intervention. Education and training programs to ease the · Build on knowledge from other disciplines transition when mechanization happens. such as sports medicine, engineering, sociology etc. Interdisciplinary research is key.

147 Table 1. Possible interventions at several different levels in society. Working Groups - Next steps to address knowledge gaps

Macro factors Understanding macro factors The working group considered various factors that could be considered as macro factors. Here, they are grouped from the most proximal to the worker to the most distal or global. Because of Group Leaders: Donna Mergler, University the high prevalence of MeN among sugar cane of Quebec in Montreal (UQAM). workers, we use this as an example, but it can Rapporteur: Neil Pearce, London School of apply to other occupations and/or environmen- Hygiene & Tropical Medicine. tal conditions where MeN may develop. Participants: · The worker: While most of the work- Jessica Candanedo ers are men, there is a growing number of Jason Glaser women that are working in sugar cane. In Christer Hogstedt addition to the biologic differences that Wendy Hoy Reyna Lizette Pacheco women and men have different social roles Claudio Mascheroni andmay possiblyinfluence different the development co-exposures, of the life MeN, tra- Julietta Rodriguez-Guzmán jectories and medical history that may be David Saúl relevant to MeN. Emily Wright · The workers’ home environment: The worker’s home constitutes the most im- mediate physical and social environment. 148 The proximal physical environment can Objectives - Since epidemics exist in a social context, we ing construction materials, its situation in considered how we can study the social context anbe beneficialarea conducive or harmful to insect to healthbreeding depend or to in which MeN occurs, including socio-economic heavy smoke during sugar cane burning, as status, migrant labour patterns, and other fac- well as access to potable water and healthy tors affecting community health. food. The immediate social determinants of health likewise play an important role Summary in the capacity to recuperate from work- Exposures and the development of MeN occur place stress and to overcome developing in a context that involves working conditions, illness: these include family psychological and the biogeochemical environment, as well as and physical support, crowding, gender re- the immediate, local and global context and the lations, income and lifestyle. For example, economic and political realities. Understanding after a day’s hard labour, having another of the context and the interaction of the differ- person care for your needs - usually but not always, a women (mother, daughter, sister) MeN can lead to improved study designs, inter- who cares for both men and women work- pretationsent factors and that recommendations influence the development for change. of ers - may mitigate, at least partially, the For example, knowledge of the particular social harm done to the body’s attempt to adapt to - extreme conditions. ing conditions and/or the evolution of MeN can · Worker status: Workers may be regular helpand economicus to ask the pressures most appropriate that influence questions work or contractual employees of a company, self- with respect to causes, and with respect to pol- employed or in a cooperative, with regular icy. or migrant status. In some instances work- ers are hired by a foreperson on a daily or weekly basis from a group seeking employ- Working Groups - Next steps to address knowledge gaps

Agricultural Service8 contains the following: “A national sugar law for commercialization, ·ment. Work Those organization who are most and fitco-exposures: or appear to production, and distribution of sugar is an beWork most organization fit are more includes likely to thebe selected. work pace important component to the reengineering - often determined by the means of remu- process that the industry has undergone. neration (piece work, quota system and/or In addition, assisted by (mostly) attractive salary) - the area allotted for water, rest and prices and additional access to the U.S. shade, as well as the physical dimensions market, the sector seems to be recovering and organisation of the working area, which financially after facing debt complications for sugar cane, can facilitate, or not, as the due to natural disasters, high transportation ease of cutting. Pollution from pesticide costs and lack of government policies to assist sugarcane growers. Ultimately the success overall health and renal functioning. In- of the industry will depend on compliance deed,use, silica both and direct burning and indirect can further work-related influence with the sugar law by all the stake holders, factors can potentially contribute to or ac- continued improvement in sugarcane and celerate the development of disease. sugar yields, and increased diversification · Local ecosystem: For outdoor work, the into additional energy co-generation local ecosystem, which depends on the projects and an ethanol law that encourages global ecosystem, is affects the ambient investment. However, increased crime rates temperature and humidity. Global climate including extortions are of major concern to change, which in local tropical coastal areas the sector.” Knowing how a local industry translates into increasing mean and maxi- complies with the laws and regulation, and 149 how they are implemented, can help us to particularly when the body is functioning understand the working conditions and atmum its limitstemperatures, of adaptation intensifies and internal heat stress, heat improve ergonomic observations and/or production is high from physical exertion. questionnaire design. · Health services and access: In many ar- · Economic and political forces: The eco- eas, health services are minimal and some- nomic and political forces that drive the lo- times absent. Local health personnel may cal, national and global economies likewise not be knowledgeable about MeN, but may have useful information about the type of like sugar cane are subject to market pres- signs and symptoms that they observe. In influence workers’ health. Commodities,- some instances, there may be traditional fect prices, production and working condi- medicine providers, who may also have tions.sures andFor fluctuations,example, the which,report cited in turn, above af knowledge of ailments and the use of tra- indicates: “Higher yielding sugarcane vari- eties, diversification of the industry into the services often translates into waiting before production of energy and alcohol/ethanol, oneditional can remedies.no longer Difficultwork before access consulting to health investment in milling equipment to improve with the health services. sugar yields, and additional access to the U.S. · Local laws, regulation and market due to CAFTA-DR will all continue implementation: These also shape to benefit El Salvador’s sugar industry over working conditions and health outcomes. the next 3 to 5 years. Declining international The Global Agricultural Information prices and an expected El Nino weather pat- Network (GAIN) report of the USDA Foreign tern might bring stormy conditions.”

1. http://gain.fas.usda.gov/Recent%20GAIN%20Publications/Sugar%20Annual_San%20Salvador_El%20 Salvador_4-18-2015.pdf Working Groups - Next steps to address knowledge gaps

· International agreements: International · Study designs that are iterative and incor- agreements bring in voices from around the porate space for interventions and evalua- world, including consumers that consider working conditions and workers health as rest/shade and cost-effective treatments). part of “fair trade” policies. For example, in ·tion Gender of acceptance and sex sensitiveand efficiency. approaches (eg water/ that November 2013, Central America, signed identify issues such as co-exposures, roles, a Trade Association Agreement with the living and working conditions, health status, European Union that provides access to up to 100,000 MT of duty-free sugar from similar for men and women. the region1. Furthermore, Central America ·home Participatory and outside research care that where are specific we can or is negotiating a free trade agreement with learn from communities’ and stakehold- Canada that could also affect the sugar ers’ knowledge and provide them with the industry1. Knowledge of the factors in play means of changing their situation (empow- can be useful in thinking about how these erment) factors affect working conditions (and thus · An ecosystem approach, based on systems inform our questionnaires on working analysis, can be helpful in mapping out the conditions) and demands on production levels (and thus interpretation of results · We need to develop: (i) an overview of and possible recommendations). For sugar thevarious essential influences elements and their of theinteractions. social con- cane cutters, the international agreements text which should be taken into account in on climate change mitigation may have a 150 direct effect on their working conditions. researchers can play in their amelioration ; · History: An understanding of the differ- (iii)field recommendations studies ; (ii) an overviewon how to of move the rolefor- ent histories, including the history of the worker, the community, the region, and the country, as well as the history of the disease Understandingward to fill those contextknowledge gaps. in this and other areas can further contrib- Since MeN is primarily an occupational ill- ute to better a better comprehension of ness, here, we place the worker in the center. The - worker’s home constitutes the most immediate opment of MeN. physical and social environment. The proximal macro-factors that may influence the devel - Recommendations ful to health depending construction materi- The workshop proposed the following recom- als,physical its situation environment in an can area be conducive beneficial orto harminsect mendations: breeding or to heavy smoke during sugar cane · More inter-disciplinary focussed research, burning, as well as access to potable water and which incorporates on a non-hegemonic healthy food. The immediate social determi- basis, the natural sciences, social sciences, nants of health likewise play an important role in policy and economic research, as well as the the capacity to recuperate from workplace stress health sciences into on-going and proposed and to overcome developing illness: family psy- chological and physical support, crowding, gen- · An ecosystem approach, based on systems der relations, income and lifestyle. For example, fieldanalysis, and canclinical be helpfulstudies inon mapping MeN. out the after a day’s hard labour, having another person pathways of how the various macro factors care for your needs, usually but not always, a - women (mother, daughter, sister) who cares for velopment of the disease at different points both men and women workers, can counteract, inand the their continuum interactions from may health influence to diseasethe de at least partially, the harm done to the body’s at- state. tempt to adapt to extreme conditions. Working Groups - Next steps to address knowledge gaps

A good portion of the waking day is spent in the workplace, where the primary determinant next 3 to 5 years. Declining international prices of MeN is the work situation and work organi- andto benefit an expected El Salvador’s El Nino sugar weather industry pattern over might the zation. Workers may be regular or contractual bring stormy conditions.” Knowledge of the fac- employees of a company, self-employed or in a tors in play can be useful in thinking about how cooperative, with regular or migrant status. In these factors affect working conditions (and some instances workers are hired by a foreper- thus questionnaires on working conditions) son on a daily or weekly basis from a group and demands on production levels (and thus in- terpretation of results and possible recommen- dations). selected.seeking employment. Work organization Those includes who are the most work fit International agreements bring in voices pace,or appear often todetermined be most fit by are the more means likely of remu to be- from consumer countries, including consumers neration (piece work, quota system and/or sal- that consider working conditions and workers ary), the area allotted for water, rest and shade, health as part of “fair trade” policies. as well as the physical dimensions and organ- In November 2013, Central America, signed a isation of the working area, which for sugar Trade Association Agreement with the Europe- cane, can facilitate, or not, as the ease of cutting. an Union that provides access to up to 100,000 Pollution from pesticide use, silica and burning MT of duty-free sugar from the region1. Fur- thermore, Central America is negotiating a free functioning. Indeed, both direct and indirect trade agreement with Canada that could also work-relatedcan further influence factors can overall contribute health to and or accel renal- 1. erate the development of disease. Local laws, regulation and implementation 151 For outdoor work, the local ecosystem, which benefitalso shape the sugarworking industry conditions and health out- is dependant on the global ecosystem is cen- comes. The report for the El Salvador sugar in- tral to the ambient temperature and humidity. dustry sited above indicates : “A national sugar Global climate change, which in local tropical law for commercialization, production, and dis- coastal areas is producing increasing mean and tribution of sugar is an important component to the reengineering process that the industry has particular when the body is functioning at its undergone. In addition, assisted by (mostly) at- limitmaximum of adaptation. temperatures, intensifies heat stress, tractive prices and additional access to the U.S. The economic and political forces that drive - the local, national and global economies like- nancially after facing debt complications due to naturalmarket, disasters, the sector high seems transportation to be recovering costs and fi like sugar cane are subject to market pressures lack of government policies to assist sugarcane wise influence workers’ health. Commodities, growers. Ultimately the success of the industry production and working conditions. For ex- will depend on compliance with the sugar law ample,and fluctuations, the Global Agricultural which, in turn, Information affect prices, Net- by all the stake holders, continued improvement work (GAIN) report of the USDA Foreign Agri- in sugarcane and sugar yields, and increased di- cultural Service9, states that “Higher yielding - - tion projects and an ethanol law that encourag- try into the production of energy and alcohol/ esversification investment. into However, additional increased energy crime co-genera rates ethanol,sugarcane investment varieties, diversificationin milling equipment of the industo im- including extortions are of major concern to the prove sugar yields, and additional access to the sector.” Knowing how a local industry complies U.S. market due to CAFTA-DR will all continue with the laws and regulation and how they are

2. http://gain.fas.usda.gov/Recent%20GAIN%20Publications/Sugar%20Annual_San%20Salvador_El%20 Salvador_4-18-2015.pdf Working Groups - Next steps to address knowledge gaps

implemented can help to understand the work- ing conditions and improve ergonomic observa- tions and/or questionnaire design.

History · Gender roles and relations · Health services and access · Social security

152 Working Groups - Next steps to address knowledge gaps

portantly, surveillance carries with it a responsi- Approaches to surveillance of MeN bility for public health action. While the precise boundary between surveillance and interven- tion is subject to debate, it is widely accepted

Group Leaders: David Wegman, University application of the data to prevention. of Massachusetts Lowell, USA. that the final link in the surveillance chain is the Rapporteur: Ineke Wesseling, Karolinska In the setting related to MeN, surveillance was Institutet. seen as essential to: Participants: » Document the overall magnitude of the Lars Barregård problem Randall Lou » Mathew Lozier by age, gender, race/ethnicity) at risk that Ana Leonor Rivera meritCharacterize special attention the populations (defined Agnes Soares » Identify the work or jobs where inter- Virginia Weaver vention is most needed Identify individual Elizabeth Whelan workplaces (or areas within workplaces) Roy Wong where intervention is warranted » Characterize the illnesses, its causes and known risk factors that need to be ad- dressed he Working Group on Surveillance was » Identify potential, previously undocu- 153 charged to prepare the following output: mented risk factors that require further T etiologic research Propose administrative, hospital, or commu- nity-based measures for case- based and pop- Surveillance across countries, particularly ulation-based measurement of MeN and poten- those with limited resources, is often very dif- tial ways to collaborate between governments - and between government and academia. tablished cases or it might include those where The group discussed the objectives of sur- thereficult. isSurveillance only a suspicion might of be a case.focused Depending only on eson veillance in general and as applied to the CKD problem present in Central America. The CDC on different levels of information ranging from - suspicionspecified objectives,of a case (doessurveillance not require can be clinical based ing systematic collection, analysis, and interpre- - tationdefinition of health of surveillance data essential was accepted:to the planning, “ongo implementation, and evaluation of public health thenconfirmation) these can to be certainty used selectively of a medical as needed diagno to practices, closely integrated with the timely dis- estimatesis. If surveillance burden, report definitions characteristics are well specified of cas- semination of these data to those who need to know (CDC, 1988)”. It can be seen as the “cor- populations likely to be at risk, follow-up of in- nerstone of public health practice” that pro- dividuales according cases, to or different identify definitions,“hotspots” describewhere a vides the foundation on which to build success- disease of interest is unusually concentrated. ful prevention programs. Where possible surveillance information can be Surveillance is systematic; it is carried out using consistent methods over time. It is often cases meet ranging from possible and probable continuous but may also be periodic. However, stratified according to the specific criteria that it should not be confused with one-time survey research efforts. Second, and perhaps most im- to definite. Working Groups - Next steps to address knowledge gaps

Knowledge gaps tainly could include more complete information The working group discussed knowledge gaps about work. It was suggested, however, that this and determined that the primary problem with promise of greater detail about cases recorded undertaking surveillance of CKD was not due to by attending physicians is not necessarily so, knowledge gaps. Rather there are critical sys- especially in outpatient care. And there is the tems gaps that interfere with successful collec- added problem of variability in diagnosis as tion, collation and analysis of what information physicians may not be well trained in diagnosis is available in different data systems. There was or staging of CKD, especially in earlier stages. general agreement that passive surveillance It does not appear that any of hospital or out- (utilizing existing data systems) was much more patient records are in electronic form yet in feasible than developing and maintaining active Central America. This could be anticipated as surveillance that requires original data collec- an area for development as electronic health re- tion required for the surveillance purposes. The passive systems discussed (Table) were: Mortality: This is the clearest endpoint but Householdcords find their or wayequivalent into the health surveys: care system.These the completeness of reporting of deaths and the sources have potential to provide a broad pop- quality of mortality records are known to vary ulation-based understanding of CKD. If well de- by country and even within country. One special signed, these could account for different causes problem highlighted is the absence of a CKDu of CKD and be used to estimate the burden of MeN. Such surveys are labor intense and quite - expensive to organize and manage. One exam- 154 betescategory or hypertension within the ICD/CIE or other 10 conditions classification. such ple is the Central American Survey of Working asDeaths systemic caused lupus by CKD if these are codedare associated first under condi dia- tions. While there is a sub-series of codes (N18) - that can be used to assign CKD stage, this series tributeConditions to surveillance and Health. ofThe MeN. first The survey 2nd didsurvey, not ininclude planning sufficiently stages, is specificexpected questions to improve to infor con- on CKD diagnosis and recording should be im- mation about hot occupations as well as CKD. proveddoes not for indicate both physicians any specific and cause.medical Training record This survey is region-wide. Without country- personnel. provided will be at a fairly general level. Renal Replacement Therapy (RRT) Centers: specific surveys it is likely that the information There are increasing numbers of RRT centers Occupation or other risk information: As far that, using a common format, could provide in- as is known there is no systematic collection of formation to serve as a registry for pre-mortal individual data that can be used to attribute oc- cases and selected risk factors. Here there is cupation or other types of risk information to greater opportunity to identify CKDu/CKDnT. individual cases useful for passive surveillance. However there is no standard reporting or re- The obvious advantage of such data would be to cording forms so collection of case details is examine patterns of CKD by different occupa- likely to be quite cumbersome if comparisons tional groups. are to be made. Actual RRT registries in Central America are in the very early stages of develop- Miscellaneous: Mention was made of data ment or absent. systems that might be adapted to surveillance

Hospital or Ambulatory Care Records: These information systems (GIS) designed to collect, analyzeuse. Specifically and present mentioned all types were of spatial i) geographic or geo- detailed data about cases of CKD that might graphical data, and ii) health care or disability sources could provide much more specific and- payment systems. Either or both of these sys-

permit a better specification of cause and cer Working Groups - Next steps to address knowledge gaps tems might be linked electronically to health- nities should be sought, where possible, through - add-ons to existing surveys. Keep in mind that derstanding of the patterns of MeN. surveys beyond those directly related to health specific information above to provide new un may prove helpful (routine household surveys, Recommendations to move payment systems, employment systems, dis- forward ability systems, etc.) (see table) 4. Consider innovative use of GIS by taking ad- 1. The primary recommendation from the vantage of environmental and occupational da- tabases that might lend themselves to GIS analy- in each country. This will establish a clear base- sis that targets CKD or CKD risk factors. lineworkgroup of surveillance was to find practices. out what Emphasis was being should done 5. Examine surveillance “hot spot” signals by be placed on the quality and potential for pas- an active effort to follow-up these signals to en- sive surveillance systems since resources are hance understanding wherever and whenever scarce. Lessons learned in each country can be possible. shared so that mistakes are not duplicated and clever methods can be well documented. The group noted that a range of electronic data systems are likely to be designed in the near future to serve a variety of purposes in the different institutions. As these are devel- oped and adopted in each of the Mesoamerican countries, it is important that a baseline census 155 of systems be available so that components of new electronic systems critical to inform un- derstanding of CKD and MeN can be taken into account. The following should be included in a census of country surveillance capacities: » Mortality data quality and timely re- porting » Hospital discharge quality and degree

» Central RRT centers considering a stan- dardof specificity case report in the format diagnoses » » National household and other surveys existingClusters or planned of CKD or MeN identified » Insurance coverage for CKD » Current resources for surveillance tasks

2. Intensive passive surveillance efforts im- mediately by selecting the data systems that are most reliable and accurate. These can be expanded and improved upon as resources be- come available. 3. While active surveillance has many theoreti- cal advantages, these are very resource inten- sive and expensive. Active surveillance opportu- Working Groups - Next steps to address knowledge gaps

Table 1. Summary of relevant issues for CKDu surveillance.

Resource Target Advantages Disadvantages Priority Actions Needed Requirements

• No CKDu/ • Address • Clear endpoint CKDnT disadvantages • Ease of access • Incomplete • Train physicians • Subnational Mortality • Quality Lowest Highest and medical possible questions registry personnel • Basic • Limited • ICD10 recoding demographics demographics needed

• Coverage limited • Registry? • Depending on • CENCAM • Clear endpoint RRT capacity subcommittee RRT Low High options for with SLANH treatment could take this 156 may be forward limited.

More complete Establish systems Hospital/ Variability in Moderate- diagnoses may be Medium of electronic Ambulatory care diagnosis Intensive available records

• Target Household questions • Begin discussions Unlikely or equivalent specifically Intensive Low • Link to existing subnational survey • Nationally surveys representative

Occupation Exposure or job Access Ministry or other risks information to Few relevant Low Medium of Labor & related information link to health resources sources systems system data Working Groups - Next steps to address knowledge gaps

Figure 1. Schematic Overview of CKDu Surveillance.

157 Poster abstracts

Chronic kidney disease in Guatemalan children Alejandro Cerón, Meredith P. Fort, Chris M. Morine and Randall Lou-Meda

Background: Epidemiological were 4.9 and 4.6 per million age information on pediatric related population. Incidence chronic kidney disease (CKD) was higher for the Pacific coast is limited internationally. This and Guatemala City. The cause study analyzed the registry of CKD was undetermined in at Guatemala’s only Pediatric forty three percent of patients. Nephrology center. The aim was . Average time to progress to to describe the distribution ESRD was 21.9 months; factors of pediatric CKD, estimate associated with progression 158 incidence and prevalence of were: older age, diagnosis of pediatric end stage renal disease glomerulopathies, and advanced- (ESRD), and estimate time to stage CKD at consultation. progress to ESRD. Conclusions: Prevalence and Methods: Incidence and incidence of ESRD are lower than prevalence were calculated for in other countries. This may annual periods. Moran’s index reflect poor access to diagnosis. for spatial autocorrelation was Areas with higher incidence used to determine significance and a large proportion of CKD of geographic distribution of of undetermined cause are incidence. Time to progress compatible with other studies to ESRD and associated risk from the region. factors were calculated with multivariate Cox regression. Keywords: Chronic kidney disease, End-stage renal Results: Of 1545 patient disease, Epidemiology, Risk records, 432 patients had CKD. factors, Pediatric nephrology, Prevalence and incidence of ESRD FUNDANIER. Poster abstracts

Comprehensive approach to pediatric kidney diseases in Guatemala Randall Lou-Meda, M.D., M.Sc., M.A. Servicio de Nefrología, Hipertensión, Diálisis y Trasplante. Hospital Roosevelt/Fundación para el Niño Enfermo Renal –FUNDANIER- Guatemala.

Abstract: The Foundation for Children with Kidney Disease (FUNDANIER) has been the driving force that has facilitated changes in the Guatemalan health system in order to establish a comprehensive pediatric nephrol- 159 ogy program. We previously described the creation and early phases of the FUNDANIER project. This article describes the recent accomplishments of the project with the intention of sharing a model that might be applicable in other developing countries.

Key words: Chronic kidney disease – preven- tion - kidney foundation - FUNDANIER - pedi- atric nephrology. Poster abstracts

Applying qualitative research methodology to characterize young patients with chronic kidney disease of unknown cause in Argentina. Project Description.

Claudio Mascheroni1, Adriana Dawidowsky2, Adriana Peñalba1, Natalia Pereiro3, Jimena Vicens2, Gustavo Greloni1, Analia Ferloni3, Flavia Vidal4, Guillermo Rosa Diez1. 1Argen- tine Society of Nephrology; 2Department of Research, 3Area of Epidemiology and 4Area of Toxicology of the Hospital Italiano de Buenos Aires.

Introduction: Chronic kidney new CKD cases (20 women and disease (CKD) is a serious global 40 men) of unknown cause in the 160 public health problem. The etiol- population between 20 and 44. ogy of this disease has been at- This projection requires further tributed to “traditional factors”, study of these cases deepen such as diabetes and hyperten- their causal knowledge. sion, as well as “non-traditional factors”, many of which are Objective: To characterize categorized as CKD of unknown clinical, environmental and social cause. In recent years several determinants of the population publications have reported a under 45 years with chronic kid- high prevalence of CKD of un- ney disease of unknown cause known cause in Central American who enter dialysis in the province countries, mainly in rural areas of Tucuman in Argentina affecting men farmers under 60 years, which led the study of its Methods causes by different research Methodological approach: An ex- groups. In Argentina, data ob- ploratory study of a case series tained from the National Reg- of patients with chronic kidney istry of Dialysis, showed a high disease of unknown cause from prevalence of CKD in Tucuman qualitative methodology using province compared to the rest of biographical-narrative research. the country, with high frequency of unknown cause. In this prov- Population: People under 45 ince, by 2016, are expected 60 years with chronic kidney disease Poster abstracts

of unknown cause who enter di- guidelines written in the Declara- alysis during 2016 in the province tion of Helsinki. It shall conform of Tucuman in Argentina. to the legislation of National Law Personal Data Protection Data Source: In-depth inter- No. 25,326 (Law of Habeas Data) views individually to investigate to protect the identity, ensuring socio-environmental history of anonymity and confidentiality patients. of information. For conducting Analysis: Qualitative materials interviews informed consent will collected during interviews are be required. liberalized verbatim and process 161 information using content analy- Expected results: To facilitate sis to generate a list of factors a systemic understanding of and dimensions explanatory non-traditional risk factors power of the health situation for chronic kidney disease of of the population and non- tra- unknown cause involving the ditional risk factors and the stakeholders themselves in an relationships postulated among iterative process for contextual these factors. knowledge.

Ethical issues: The project will comply with international ethical Poster abstracts

End-stage renal disease of unknown etiology in a sugarcane region in Argentina

Claudio Mascheroni1, Silvana Figar2, Adriana Peñalba1, Ana Gomez Saldaño3, Gustavo Greloni1, Soledad Aragone3, Valeria Aliperti3, Guillermo Rosa Diez1. 1Argentine Society of Nephrology; 2Department of Research and 3Area of Epidemiology of the Hospital Italiano de Buenos Aires.

Introduction: In the last years, a Preliminary results: For year growing incidence of end-stage 2013, ESRD total adjusted IR renal disease (ESRD) affect- for Tucuman was 225 (CI 95% ing young agricultural workers 201-252) vs 160 (CI 95% 156- in several countries has been 164) for national rate (p 0.001). observed. Unknown etiology (UE) In Tucuman, ESRD crude rate in young people is considered a for women was 167 (vs overall 162 faulty of preventive measures 128) and 237 for men (vs overall in controlling risk factors and 193). The UE is 17% of the total in surveillance of early damage. incidental cases, and it appears In Argentina, dialysis and trans- to be the main etiology among plant records are compulsory as younger people (20 to 44 years the state finances these prac- old). The national UE-ESRD tices, thus the argentinian public rate for 2011-2013 was 25 while registry has a coverage of more for Tucuman it was 31.4 being than 95% of ESRD population. Tucuman the second largest province in crude incidence. This Methods: In this ongoing study study is in process to calculate we aim to describe the incident UE and other etiologies adjusted rate (IR) of UE-ESRD in men rate by age and sex and regions between 20 and 44 years old for Argentina. in the last 10 years comparing a sugarcane main production Conclusion: The preliminary region (Tucuman) to national IR. results show that sugarcane Crude and adjusted rates are region in Argentina is one of the expressed per million of inhabit- higher region of UE in incident ants and with 95% confidence dialysis patients. Final results Interval. Time trend will be anal- will help us understand if in some ysed using joint point. region of Argentina there also exists an epidemic of UE-ESRD in young people. Poster abstracts

Prevalence of traditional and non traditional risk factors of chronic kidney disease in Roosevelt hospital, Guatemala Dr. José Loaiza1, Dr. Joaquín Barnoya2, Licda. Violeta Chacón2, Dr. Pablo García1 1Internal Medicine Department, Roosevelt Hospital, Guatemala. 2Research Department Cardio- vascular Unit of Guatemala, Guatemala.

Introduction: Chronic Kidney Methods: Cross-sectional study Disease (CKD) is considered by at Roosevelt Hospital in Guate- the World Health Organization mala City. All CKD patients were (WHO) as a worldwide epidemic. interviewed, regardless of time The traditional causes of CKD are since diagnosis. Patients over diabetes mellitus (DM) (40%) and 12 years and of both sexes were hypertension (HT) (30%). In Cen- included. We used a previously tral America, in the last 20 years validated suvery that includes 83 163 it has been reported an increase questions evaluating demograph- in CKD prevalence not associated ic and occupational factors, and with traditional causes (CKDnT). traditional and non-traditional CKDnT has been reported in young CKD risk factors. Diabetes and men and farmers in several com- hypertension were considered as munities of southern Nicaragua traditional risk factors. Non-tra- and El Salvador. Possible causes ditional risk factors include oc- of CKDnT include exposure to cupation and time of the workday pesticides, heat-induced stress, and hydration during the day, use indiscriminate use of nonsteroidal of NSAIDs and antibiotics, birth anti-inflammatory drugs (NSAIDs) weight, home remedies, and the and infections. At Roosevelt source of water for consumption. Hospital, the largest referral hospital in Guatemala, CKD is the Results: We interviewed 249 leading cause of hospitalization. patients, 128 (51%) were male. However, it is yet unknown the The age range was 12-84 years characteristics of CKD patients old. The average age by sex and the prevalence of CKDnT. was 48±17.91 male and 46±19.36 female. Fifty-four percent were Objectives: To determine the from Guatemala City, followed by prevalence of traditional CKD risk the southern state of Escuintla factors and CKDnT in Roosevelt (20%). Consequently, most of Hospital in Guatemala. the patients live in a mild weather Poster abstracts

and over 1000 meters above sea quently reported activity in both level. Less than half (103, 41%) groups and most had contact are newcomers and the rest with pesticides. Working hours already had a previous diagnosis in the no-traditional risk fac- (p=0.004). Among those who tor group were between 8 and 16 had traditional risk factors 170 hours and water consumption (68%) were hypertensive and during working hours was 2 to 5 103 (41%) diabetics (p<0.001). liters (not significantly different One-quarter (61) patients had from those with traditional risk no traditional risk factors. Four factors). The largest source of (1.5%) were excluded due to water of all CKD patients is well, co-morbidities that lead to the pipeline and river. CKD. Of the 57 patients without 164 traditional risk factors or co- Conclusion: In the largest public morbidities, they were, on aver- referral hospital in Guatemala, age, significantly younger com- one quarter of the patients lack pared to those with traditional traditional CKD risk factors. Of risk factors (35±18.5 years vrs. the proposed possible risk fac- 50±17.3 years old, p <0.001). The tors, we did not find any higher frequency of use of NSAIDs and prevalence in those with no home remedies was significantly traditional risk factors compared (p<0.05) higher among those with to those with traditional ones. non-traditional risk factors com- The possible etiology of CKDnT pared to their counterparts with deserves further research before traditional ones. The percentage the diagnosis of CKD is made. of patients working in agricul- ture was not different between Keywords: Chronic Kidney Dis- those with non-traditional and ease, Occupational Disease, traditional risk factors (33% Epidemiology, Central America. and 37%, respectively). Corn cultivation was the most fre- Poster abstracts

Exposure to nephrotoxic pollutants in Las Brisas community, El Salvador

Alejandro López1, Alexandre Ribó1, Roberto Mejía1, Edgar Quinteros1, Wilfredo Beltetón3, Carlos M. Orantes1, Dina L. López2. 1Instituto Nacional de Salud, Ministerio de Salud de El Salvador. 2Departamento de Ciencias Geológicas, Universidad de Ohio, EUA. ³Laboratorio Nacional de Referencia, Instituto Nacional de Salud.

Introduction: In the former formulator pes- absorption) and paraquat (Spectrophotom- ticide factory AGROJELL S.A. de C.V., located eter UV-VIS) were carried out by the National in the municipality of San Miguel of El Salva- Reference Laboratory of Ministry of Health dor, 92 barrels of toxaphene, an obsolete of El Salvador. pesticide with nephrotoxic properties, were improperly stored since early 90s until 2010. Results: According the sampling analysis San Miguel is a city located close Chapar- carried out in this study, surface and ground- rastique volcano and west of Río Grande de waters of Las Brisas communities can be de- San Miguel one of the major rivers of the scribed as hard and very hard waters (136-419 165 country. Around the former factory there are mg/L) with Arsenic content reaching maximum Las Brisas communities where some fami- values of 0.01 mg/L (0.01 is the standard lies are supplied by shallow wells, some of proposed by Salvadoran Consumption Water them with presence of toxaphene according Quality Guidelines) and with some wells with analysis carried out in 2011 by the Ministry of paraquat pollution reaching maximum val- Enviroment. Las Brisas community has a high ues of 1.69 mg/L (0.62 mg/L is the standard prevalence of Chronic Kidney Disease non- proposed by Salvadoran Consumption Water traditional causes (CKDnt), a disease whose Quality Guidelines). main risk factors are related to work condi- tions of agricultural workers and to exposure Conclusion Through water intake form to toxics as pesticides and heavy metals. We domestic wells, Las Brisas population has examined the presence of common neph- been exposed to a nephrotoxic load formed rotoxic pollutants in water in El Salvador as mainly by toxaphene, arsenic and paraquat. arsenic (volcanic materials and hydrothermal This chronic exposure could explain the high water are important sources of arsenic in El prevalence of CKDnt of Las Brisas community, Salvador) and paraquat (the most widely used whose inhabitants, in general, are not related pesticide in El Salvador). to agriculture. Identified high hardness of water in serving wells also could be considered Methods: Waters from community wells as risk factor of CKDnt according recent hy- (groundwater) and surrounding rivers (sur- pothesis proposed by Sri Lanka researchers. face water) were sampled during dry season in 2014. Physicochemical water parameters Keywords: CKD of nontraditional causes, were obtained in situ and chemical analysis Obsolete pesticides, Arsenic, Toxaphene, to identify, arsenic (Graphite furnace atomic Paraquat, Water hardness, El Salvador.

Poster abstracts

Weather trends at a sugar mill in northwest Nicaragua, 1973-2013

Oriana Ramírez-Rubio1, Kai Zhang2, Xiao Li2, Rebecca L. Laws1, Michael D. Mcclean1, Madeleine K. Scammell1, Juan Jose Amador1, Daniel R. Brooks1 1Boston University School of Public Health. 2School of Public Health, University of Texas Health Science Center at Houston.

Background: Over the past two Methods: We used daily weather decades an epidemic of chronic data collected from 1973 to 2013 kidney disease of non-traditional at a weather station located etiology (CKDnT), also termed at sugar mill of the region of Mesoamerican Nephropathy Chinandega, in northwest Nica- (MeN), has been identified as ragua (at the epicenter of MeN 166 a public health emergency in epidemic), including minimum, Central America. Sugar cane average, and maximum tempera- workers are among the most af- ture (°C); minimum, average, and fected populations. Although the maximum relative humidity (%); causes of MeN remain unknown, hours of sunlight per day; wind heat stress, a growing concern speed (km/24 hours); evapora- in a warming climate, has been tion (inches); and precipita- identified as one potential cause, tion (inches). We used extreme or an effect modifier of other weather indicators based both nephrotoxic exposures, including on daily absolute mean values, agrichemicals, heavy metals and percentile based values and infectious agents. threshold indicators, developed We analyzed weather conditions by the World Climate Research over four decades in a region of Programme’s Expert Team on high incidence of CKDnT to as- Climate Change Detection and sess average changes in annual Indices. We fit linear regres- temperature, changes in tem- sion models for each extreme perature variability, and related weather variable as a function climate data. of calendar year, and calculated

Poster abstracts

decadal trends as changes per decade based on above derived Conclusion: We found evidence regression coefficients. that both average maximum and long-term variability of tempera- Results: Preliminary results tures has increased over the past show that in each decade three decades. This is particu- the annual average maximum larly important during dry sea- temperature increased 0.26 sons (when the harvest occurs). ºC (p=0.04) and the average These changes can be a potential maximum temperature during burden for workers’ capability to the dry season (November to adapt to climate conditions. If April approx.) increased 0.30 ºC heat stress does play a key role (p=0.01). It also increased by a in the MeN epidemic as hypoth- 167 quarter of a degree in April, the esized, the at-risk population will hottest month of the year. The continue to grow with predicted minimum temperature in a given increases in both temperature year decreased per decade 0.46 and frequency and intensity ºC (p=0.005) both on an an- of heat waves due to climate nual and dry season basis. We change. Furthermore, climate found a statistically significant models have shown that tropical, increased standard deviation of low-latitude regions display the daily mean temperatures both on earliest significant warming, and an annual and dry season basis, are also the most vulnerable due an indicator of long-term tem- to low adaptive capacity. perature variability, which results in hotter days and/or cooler nights. Analyses are ongoing.

Poster abstracts

End-stage renal disease incidence, mortality, and prevalence in a hot spot of Mesoamerican nephropathy in El Salvador: a ten-year community registry

Ramón García-Trabanino1,2 MD, Carolina Hernández2,3 MD, Adrián Rosa2,4 MD, Jesús Domín- guez Alonso2,5 MD. On behalf of the Emergency Social Fund for Health of Tierra Blanca, Usu- lután, El Salvador. 1Association of Nephrology and Hypertension of El Salvador, San Salva- dor, El Salvador. 2Emergency Social Fund for Health of Tierra Blanca, Usulután, El Salvador. 3Integral Health Basic System (SIBASI) Usulután, Ministry of Health, Usulután, El Salvador. 4Medic Unit Puerto El El Triunfo, Salvadoran Institute of Social Security (ISSS), Usulután, El Salvador. 5Primary care, Northwest Jaén sanitary area, Andalucía, Spain.

Abstract: The Bajo Lempa is an im- Results: In 10 years we registered poverished, rural coastal region of 271 new cases (annual average 27,1; 168 El Salvador affected by a chronic 11% female, 89% male; mean age kidney disease epidemic named the 55,6 years, four <18 years). Average Mesoamerican nephropathy. The annual ESRD incidence rate: 1409,8 emergency social fund for health per million population (pmp). Ninety- (ESFH), a local communal organiza- four patients received RRT (34,7%): tion, helps to fight the epidemic in 58 in the Ministry of health, 9 in 42 communities (N=19223; mean age the social security, 1 in the military 26,7 years; 51,5% female, 48,5% health, and 26 in private services. male; 40,2% <18 years) of the re- Two hundred forty-six patients died gion. (annual average 24,6; 10,6% female, 89,4% male; mean age 56,1 years; Aims: To report annual rates of 92,3% at their home). Average an- end-stage renal disease (ESRD) in- nual mortality rate: 128/100000 cidence and patient mortality in population. Prevalence of patients these communities during a 10 year receiving RRT at year 2013: 1300.5 period (2004-2013), and the preva- pmp (N=25; 16% female, 84% male; lence of patients receiving renal mean age 51 years). replacement therapy (RRT) at year 2013. Conclusions: This region has a high incidence of ESRD. Few receive RRT. Methods: The ESFH registered new Patient mortality is high with or ESRD cases, their basic past his- without RRT. Most are male (9:1). tory, RRT modality if received, and Social determinants influence the their deaths. high mortality.

Poster abstracts

National prevalence of end-stage renal disease patients under renal replacement therapy in El Salvador, year 2014

Ramón García-Trabanino1,2, Zulma Trujillo3, Ana Verónica Colorado4, Salvador Magaña Mer- cado5 y Carlos Atilio Henríquez6. On behalf of the association of nephrology and hyperten- sion of El Salvador (ANAHES). 1 Asociación de Nefrología e Hipertensión de El Salvador, San Salvador, El Salvador. 2Fondo Social de Emergencia para la Salud, Usulután, El Salvador. 3Servicio de Nefrología, Hospital Nacional Rosales, San Salvador, El Salvador. 4Servicio de Nefrología, Hospital General de Especialidades, Instituto Salvadoreño del Seguro Social, San Salvador, El Salvador. 5Servicio de Nefrología, Hospital Nacional San Juan de Dios, San Miguel, El Salvador. 6Servicio de Ne- frología, Hospital Nacional de niños Benjamín Bloom, San Salvador, El Salvador. En nombre de la Asociación de Nefrología e Hipertensión Arterial de El Salvador (ANAHES).

Abstract: With 21041 km2 and RRT provider attending 49.7% of pa- 6401240 inhabitants for 2014, El tients. National prevalence 2014 was: Salvador suffers the epidemic called total RRT 595 per million population 169 Mesoamerican nephropathy (MeN) (pmp), peritoneal dialysis (PD) 289 and has the highest renal failure pmp, haemodialysis 233 pmp, kidney mortality rate of the Americas. Five transplantation 74 pmp (living donor healthcare providers offer renal re- only). Generally, coastal and low- placement therapy (RRT). The exact lands municipalities showed higher national RRT prevalence has never prevalence. Only 4.8% haemodialy- been reported. Aims: report RRT sis patients receive it thrice weekly. prevalence during the third trimester Only 40.9% PD patients belong to a 2014, and patients’ basic character- continuous ambulatory or automa- istics. Methods: The association of tized program, and 25.4% still use nephrology coordinated a standard- rigid catheter. Discussion: Despite ized instrument, registering patients the significant increase in RRT ser- in all 31 RRT centres from all health- vices in recent years the national care providers nationwide. Results: RRT prevalence is still insufficient, during 2014, 3807 patients were lower than the Latin American aver- undergoing RRT, mean age 50.42 age (660 pmp). Three fourths of hae- years old, 67.5% male. Etiology of modialysis and PD patients are infra- end-stage renal disease was: not re- dialyzed. Old RRT techniques are still ported or undetermined 50%, hyper- used. RRT patients are younger than tension 21.1%, diabetes 18.9%, glo- expected and male gender predomi- merulonephritis 6.7%, obstructive nates, matching the epidemiological causes 1.2%, tubulointerstitial 0.9%, pattern of MeN. polycystic 0.4%, congenital and oth- ers 0.7%. Social security is the main

Poster abstracts

Heat exposure, volume depletion and acute kidney injury in California’s agricultural workers Moyce, S., Joseph, J. Tancredi, D., Mitchell, D., Armitage, T. Schenker, M. University of California, Davis

Objective: Chronic kidney disease in Results: In 295 agricultural workers, Central America suggests agricultural AKI after a work shift was detected work is potentially harmful to in 35 participants (11.8%). Prelimi- the kidneys. We investigated the nary analyses show weight loss to cumulative incidence of acute kidney be associated with twice the odds of injury (AKI) over one work shift incident AKI (adjusted odds ratio 2.11, agricultural workers in California 95% confidence interval 1.15-3.90). 170 and estimated associations of heat (Heat exposure results pending, but exposure and volume depletion on will be presented in final poster.) incident AKI. Conclusions: The cumulative inci- Methods: Serum creatinine measure- dence of AKI after a single day of ments were collected both before agricultural work is alarming due to and after a work shift to estimate increased risk of long-term kidney AKI. Heat exposure was estimated damage and mortality. The associa- via the physiologic strain index us- tion with volume depletion suggests ing core body temperature and heart AKI may be prevented with proper re- rate measurements. Volume deple- hydration during a work shift. These tion was estimated via change in results also indicate AKI in Califor- body mass after a work shift. As- nia’s workers may be linked to Meso- sociations of incident AKI with heat american Nephropathy. exposure and volume depletion were tested using logistic regression.

Poster abstracts

Cumulative incidence of acute kidney injury in California’s agricultural workers Sally Moyce, Jill Joseph, Daniel Tancredi, Diane Mitchell, Marc Schenker University of California, Davis.

Objective: Chronic kidney dis- was detected in 35 participants ease in Central America suggests (11.8%). Piece-rate work was as- agricultural work is potentially sociated with 4.52 adjusted odds harmful to the kidneys. We inves- of AKI (95% confidence interval tigated the cumulative incidence 1.61-12.70). of acute kidney injury (AKI) over one work shift among agricultural Conclusions: The cumulative in- workers in California. cidence of AKI after a single day 171 of summer agricultural work is Methods: Serum creatinine was alarming due to increased risk measured both before and after of long-term kidney damage and a work shift to estimate AKI. As- mortality. sociations of incident AKI with traditional and occupational risk Moyce, S., Joseph, J., Tancredi, factors were tested using chi- D., Mitchell, D., & Schenker, M. square and trend tests and logis- (2016). Cumulative Incidence of tic regression. Acute Kidney Injury in California’s Agricultural Workers. Journal of Results: In 295 agricultural work- Occupational and Environmental ers, AKI after a summer work shift Medicine, 58(4), 391-397.

Poster abstracts

Urinary biomarkers KIM-1 and NGAL for early prediction of Chronic Interstitial Nephritis in Agricultural Communities in Sri Lanka. K.S. Mohammed Abdul1, C. Jayasumana2, S.H.Siribaddana2, S.S. Jayasinghe3, H.B. Asanthi4, G.G.T. Chaminda5, E.P.S. Chandana1, P. Mangala C.S. De Silva1 1Faculty of Science, University of Ruhuna, Matara, Sri Lanka. 2Faculty of Medicine, Raja- rata University, Saliyapura, Sri Lanka. 3Faculty of Medicine, University of Ruhuna, Galle, Sri Lanka. 4Faculty of Fisheries and Marine Sciences and Technology, University of Ruhuna, Matara, Sri Lanka. 5Faculty of Engineering, University of Ruhuna, Hapugala, Sri Lanka.

High incidence of Chronic Interstitial marker of tubule-epithelial cell dam- Nephritis in Agricultural Communities age (KIM-1 & NGAL) for early CINAC di- (CINAC) is reported in rural Sri Lanka. agnosis in Sri Lanka. 172 Victims do not exhibit common caus- For determination of KIM-1 and NGAL ative factors such as hypertension, levels, urine and blood samples were diabetes or glomerulonephritis. Pre- collected from non endemic controls vious studies have identified agri- living in wet zone (Matara-M) and in cultural activities (usage of herbi- two study locations representing cides and phosphate fertilizers), farming communities located in dry repeated dehydration, and genetic zone (i.e. Angunakolapelessa ─ (H-A) susceptibility as potential risk fac- and Bandagiriya ─ (H-B). Urine cre- tors. Although CINAC is a tubular dis- atinine and serum creatinine were ease, urine albumin or albumin–cre- measured using Jaffe rate-blanked atinine ratio is still being used as the creatinine assay and eGFR was cal- screening tool. culated using both CKD-EPI and MDRD Proximal tubular epithelial cells ex- equation. Urinary KIM-1 and NGAL press Kidney Injury Molecule (KIM-1) levels were measured using specific and Neutrophil Gelatinase-Associ- KIM-1 (Cusabio, P.R. China) and NGAL ated Lipocalin (NGAL) in response to (Ray Biotech, USA) Enzyme Linked renal injury. KIM-1 and NGAL are con- Immuno Sorbent Assay (ELISA) kits. sidered urinary biomarkers for early H-A and H-B subjects were further prediction of tubular injuries. Never- subdivided into two groups depend- theless, they have not been used for ing on their albumin–creatinine ratio early perdition of CINAC in Sri Lanka. (ACR) and serum creatinine levels. In present study, we report the use Subjects with ACR ≥ 30 mg/g and se- of non-invasive, rapid and sensitive rum creatinine level > 1.3 mg/dl was

Poster abstracts

considered as CINAC patients af- N=15, p<0.05) and (2.310 ± 0.586 ter excluding other risk factors Mean ± SEM; Min=0.136; Max= and the rest were considered as 8.785; N=15, p<0.05). endemic controls. Urinary KIM-1 and NGAL concen- In M group (N=27) CINAC was not trations in H-B endemic control reported. Creatinine adjusted group were (10.507 ± 2.477 Mean urinary KIM-1 (μg/g Cr) and NGAL ± SEM; Min=0; Max= 42.903; N=26) (ng/mg Cr) concentrations in M and (1.158 ± 0.14 Mean ± SEM; Min= group were (2.885 ± 0.524, Mean 0.179; Max= 2.78; N=26) respec- ± SEM; Min=0.208; Max= 8.943) tively. Urinary KIM-1 concentra- and (0.568 ± 0.108 Mean ± SEM; tions in H-B CINAC group (43.881 Min=0.024; Max=2.234) respec- ± 9.589 Mean ± SEM; Min= 1.961; tively. Max= 87.476; N=10; p<0.05) were Creatinine adjusted urinary KIM- 15 times higher than the non- 173 1 (μg/g Cr) concentrations in H-A endemic M control group where- endemic control group (16.852 ± as Urinary NGAL concentrations 4.766, Mean ± SEM; Min= 0; Max= (6.297 ± 2.284 Mean ± SEM; Min= 73.391; N= 20; p<0.05) were 5 times 0.394; Max= 24.123; N=10; p<0.05) higher than the non-endemic con- were 11 times higher than non- trols. However, NGAL concentra- endemic M control group. Urinary tions in H-A endemic control group KIM-1 and NGAL concentrations (0.797 ± 0.161 Mean ± SEM; Min= 0; were also significantly higher in Max= 2.499; N=20; p>0.05) were CINAC cases in H-B with compared not significantly different from to the control groups (p<0.05) the non-endemic control group. indicating that urinary KIM-1 and When compared to the control NGAL concentrations may be used groups (M and H-A) creatinine ad- as early predictive biomarkers for justed urinary KIM-1 (μg/g Cr) and CINAC patients in Sri Lanka. NGAL (ng/mg Cr) concentrations Acknowledgement: This project were significantly higher in H-A was funded by TURIS grant (RU/ CINAC group (60.165 ± 11.414 Mean TURIS/PhD/02). ± SEM; Min= 2.552; Max= 176.113;

Poster abstracts

RO water plants: A successful short-term solution for CINAC in Sri Lanka Sarath Gunatilake, Channa Jayasumana and Sisira Siribaddana

Chronic interstitial nephritis in agricultural increasingly hard and distasteful. This could communities (CINAC) is a rapidly progressing have led to a reduction in the water intake as health issue in the dry zone of the Sri Lanka. well. Later analysis of this well water at the Synergistic chemical nephrotoxicity caused by California State University, Long Beach labs glyphosate, paraquat, herbicide surfactants showed the presence of agrochemical resi- and heavy metals, heat stress and chronic re- dues. peated dehydration are hypothesized as main Although we do not have data to compare wa- etiological factors of the disease. It is very ter intake prior to the 1960s and now, there likely that a combination of these factors is is anecdotal evidence to show that it was re- involved in the pathogenesis of the disease, duced mainly due to distaste resulting from rather than a single factor acting alone. CINAC high Ca, Mg and F levels. Hence, it was impera- is an irreversible disease. Therefore, identify- tive to introduce a strategy to purify and en- ing the risk factors and implementing all of hance the quality of ground water in order to 174 known strategies to slow down the progres- regularize the amount of water consumed by sion of the epidemic is mandatory. farmers. The solution was Reverse Osmosis One of the main preventive strategies pushed technology. Reverse Osmosis, commonly re- by us was social and political measure to guar- ferred to as RO, is a process of demineralizing antee nephrotoxin free drinking water and en- or deionizing water by pushing it under pres- sure adequate hydration. Providing adequate sure through a semi-permeable RO membrane clean water addresses both possible etiolo- which allows the passage of water molecules gies. but not the majority of inorganic ions, organic Large man-made reservoirs were the main molecules, bacteria and pyrogens. sources of drinking and irrigation water in the Although maintaining RO machine in rural set- dry zone, Sri Lanka. These reservoirs belong tings is an enormous challenge, more than 25 to cascade irrigation system and was initial- large scale machines (> 10000 L/day, cost- $ ly built during the time of ancient kingdoms 20000), 250 middle scale machines (500- (3BC-12 AC) and renovated during the last cen- 10000 L/day, cost-$ 2000) and 25000 domes- tury. However, with the introduction of chemi- tic machines (100 L/day, cost- $ 300) have cal farming in 1960s and 70s, it was commonly been established in CINAC endemic regions believed that the reservoir water is contami- for the last 5 years. The majority of large nated with agrochemicals including the pesti- and middle scale plants were funded by gov- cides and the triple phosphate fertilizer. This ernment and private donors and established situation prompted many farming families to through community-based organizations. use shallow wells as the main source of drink- Domestic machines are self-funded. Our ex- ing water. However, when the monsoonal rains perience up to now has shown that this may flooded the terrain of these shallow wells year be a viable temporary measure in dealing with after year these wells became contaminated drinking water supply issues in CINAC affected with agrochemicals as well. The water became areas.

Poster abstracts

Heat stress exposures on kidney dysfunction – An exploratory study in a steel industry. Vidhya Venugopal, Rekha. S, Latha. P.K.,Manikandan.K. Department of Environmental Health Engineering, Sri Ramachandra University, Chennai, India.

Background & Purpose: Raised tem- in CBT above 1°C in about 14% of the peratures and shifting humidity condi- workers (n=48) and SwRs higher than tions due to Climate Change are likely 1.0 L/hr in 15% of workers was recorded. to increase the heat stress for work- USGs >1.02 in 8.8% of the workers ers in physically exerting and high heat indicated moderate dehydration. Of occupations like in steel manufactur- the 91 workers with a clinical history of ing, with potential risks of adverse reported symptoms of burning sensa- kidney function. We have conducted tion, hesitant urination & pain in loins an exploratory study in a steel manu- and flanks, 39 workers were positive facturing in Southern India to test this for some kidney anomaly in Ultrasound 175 hypothesis. of Kidney. 70% of these workers were employed in high heat zones like in fur- Methodology - We conducted a cross- nace areas with high exposures to heat sectional study with 342 steel work- over 5 years. ers working in high heat environments engaged in heavy labor for more than Conclusion: The preliminary results 5 years in the industry. Area WBGTs of this study points at heat stress, (n=218) were assessed to evaluate heavy manual workload and chronic the heat exposures and physiological dehydration as the major risk factors parameters like Core body temperature for the disease development in the (CBT), Sweat Rates (SwR) & Urine spe- study population. Periodic surveillance cific gravity (USG) were assessed as using urinary biomarkers and enhancing indicators of heat strain. Ultra sound welfare facilities for the workers are of kidney was conducted in a subset imperative to avert adverse health con- of participants (n=91) based on clinical sequences as climate change proceeds. history and symptoms. Keywords: Sweat rate, heat stress, Findings – Workplace heat exposures urine specific gravity, kidney dysfunc- exceeded the threshold limit value tion. for safe manual work in 156 locations (Avg.WBGT of 33.4°C±3.76°C). Increase

Poster abstracts

Pesticide exposure and chronic kidney disease Jill Lebov, Research Epidemiologist, RTI International, Research Triangle Park, NC

Experimental studies suggest a the United States, in which elevated relationship between pesticide risk of end‐stage renal disease exposure and renal impairment, (ESRD) was associated with long- but epidemiological research on term use of the herbicides alachlor, 176 the long-term effects of chronic atrazine, metolachlor, paraquat, and low-level and short-term high‐level pendimethalin, and the insecticide pesticide exposure on renal dis- permethrin. Additionally, more than ease risk is limited. The poster one medical visit due to pesticide provides a brief outline of the use (hazard ratio (HR)=2.13; 95%CI existing evidence for a relationship 1.17-3.89) and hospitalization due between pesticide exposure and to pesticide use (HR=3.05; 95% CI kidney disease, including results 1.67‐5.58) were significantly associ- from a population‐based study in ated with ESRD. Our findings support Nicaragua, in which we observed a a possible association between higher prevalence of chronic kidney ESRD risk and chronic exposure to disease with increasing years of certain pesticides and suggest that work in agriculture. This poster also pesticide exposures requiring medi- describes findings from a recent cal attention may increase the risk study of pesticide applicators in of ESRD. Acknowledgements

The workshop was organized by SALTRA in collaboration with Raquel Campos Calvo the CENCAM Board and the MeN 2015 Organizing Committee. Marta Castillo Sevilla It was made possible thanks to the dedication of many Fabio Chaverri Fonseca individuals, including those who participated. We extend Leo Córdoba Gamboa our most profound thanks to the following individuals who Noemy Gómez Castro Sara González Bonilla dedicated their time and talents: Diego Gutiérrez Herrera Karen Herrera Benavides Diego Hidalgo Barrantes Claudio Monge Hernández Laura Ortiz Cubero Marianela Rojas Garbanzo Marianela Sibaja Quesada Scholarships Adriana Umaña Vargas Scholarship funds for some participants were provided by: Additional support • Universidad Nacional (Costa Rica) (Visiting Professor The SALTRA program Of Environmental Health provided logistical support, Sciences of the National Program) 177 infraestructura and Institutes of Health • National Institute Of Environmental Health Sciences of funding for the workshop (USA) under Award Number the National Institutes of Health organization. R13ES026050. The content (USA) The Vice-Rectory for is solely the responsibility Academics at the of the authors and does • Pan American Health Organization (PAHO) Universidad Nacional not necessarily represent in Costa Rica provided the official views of the • The International Society of Nephrology (ISN) support for the National Institutes of organization of the Health. All other participants either workshop. The National Institute paid their own way or obtained IRET provided of Occupational Safety external funding to attend. We administrative and and Health (NIOSH) (USA) know many participants went academic support for provided the translation of to great lengths to be able the organization of the this document to Spanish. to attend, and that this is a workshop. The Pan American reflection of their willingness to The Second Health Organization work toward finding the causes International Workshop (PAHO) contributed of and solutions for MeN. on Mesoamerican with professional time Nephropathy and this and support for the publication were supported organization of the by the National Institute workshop.

nd International Workshop on 2 Mesoamerican Nephropathy November 18-20, 2015

Workshop Objectives 1 Update progress in understanding the epidemic and on the research questions identified at First International Chronic Kidney Disease of Workshop. non-traditional causes is a public health problem 2 Share ongoing studies in the region and identify current of such a magnitude and knowledge gaps. severity in Mesoamerica that the Central American 3 Articulate key hypotheses and strength of evidence to Council of Ministries of date with a view to focus future research on the most Health recently called for promising hypotheses. 178 urgent action. MeN 2015 is a response to this call 4 Promote and establish new relationships and collaboration for action and will result among researchers and clinicians. in the most exhaustive and up-do-date review of 5 Identify data and data sources to inform the public, the science, elucidating clinicians, labor market partners, and policy makers in the potential causes of understanding the evidence base of interventions and the epidemic, research solutions for the prevention and treatment of CKDnT. recommendations, as well as possible solutions for 6 Strengthen the communication and support structure for prevention and mitigation. researchers in the region. The workshop has a number of ambitious 7 Publish proceedings, peer-review papers summarizing aims. These are: progress and research gaps and host in-person CENCAM meeting.

The Workshop brings together researchers from around the world who are working on the epidemic to share knowledge, techniques, data and hypotheses and plans to translate research into practice.

More information about CENCAM is available here: http://www.regionalnephropathy.org/?page_id=141 Workshop Program

Wednesday, 18 November

08:00-9:00 Registration 09:00-10:00 Inauguration 10:00-10:15 Coffee Break

Theme: What do we know?

10:15-12:15 Advances in Knowledge of CKDnT Chair: Daniel Brooks, Boston University, USA

• What has happened since the 1st Mesoamerican Nephropathy Workshop? Catharina Wesseling, Chair CENCAM, Karolinska Institutet, Sweden

• In which countries and occupations has CKDnT been reported in excess and how well has it been studied where there are no reports? Agnes Soares da Silva, PAHO/WHO, Washington DC Kristina Jakobsson, Gothenburg University, Sweden

• CKD in Sri Lanka 179 Channa Jayasumana, Rajarata University, Sri Lanka

• Government and health care systems response in Central America Julietta Rodríguez-Guzmán, PAHO/WHO, Washington DC

• Moderated Discussion

12:15-13:30 Lunch

13:30-15:30 Reviews of Evidence for CKDnT in Relation to Hypotheses

Chair: Kristina Jakobsson, Gothenburg University, Sweden

• Heat and dehydration Daniel Brooks, Boston University USA Jennifer Crowe, Universidad Nacional, Costa Rica Rebekah Lucas, University of Birmingham, UK

Programa Financiado por la Unión Europea • Does exposure to toxic metals have a role in the development of Mesoamerican Nephropathy (MeN)? Carl-Gustav Elinder, Karolinska Institutet, Sweden Channa Jayasumana, Rajarata University, Sri Lanka

• Chronic kidney disease of undetermined etiology and pesticide exposure: an update on recent data Mathieu Valcke, National Institute of Public Health, Canada Carlos Orantes, Instituto Nacional de Salud Pública, El Salvador

• Proposed mechanisms for chronic kidney disease of uncertain etiology observed in Central America (Mesoamerican Nephropathy) Richard J. Johnson, University of Colorado, USA Ramón García-Trabanino, Assoc. of Nephrology and Hypertension of El Salvador

Moderated Discussion

15:30-16:00 Coffee Break

16:00-17:30 Experiences from Ongoing Studies Chair: Catharina Wesseling, Chair CENCAM, Karolinska Institutet, Sweden 180 • WE program pilot intervention 2014-2015: Lessons learned Theo Bodin, Karolinska Institutet, Sweden Ramón García-Trabanino, Assoc. of Nephrology and Hypertension of El Salvador David H. Wegman, University of Massachusetts Lowell, USA

• Boston University School of Public Health: Studies of Occupational and Non-Occupational Risk Factors for Chronic Kidney Disease Michael McClean, Boston University, USA David Friedman, Boston University, USA

• Gaining insights into the evolution of CKDnt from community-based follow up studies Ben Caplin, London School of Hygiene and Tropical Medicine, UK Neil Pearce, London School of Hygiene and Tropical Medicine, UK Marvin González, National Autonomous Univ. of Nicaragua at León (UNAN- León)

• Moderated Discussion

Programa Financiado por la Unión Europea 17:30-18:00 • Summary of the Day Carolina Guzmán Quilo, San Carlos University Guatemala Madeleine Scammell, Boston University, USA

Thursday, 19 November

08:00-8:30 Announcements and Explanation of the Day´s Activities

08:30-09:30 • Clinical Conditions and Pathology Chair: Ramón García-Trabanino, Association of Nephrology and Hypertension of El Salvador

• What is known about the Burden and Clinical Characteristics of Mesoamerican Nephropathy? Ricardo Correa Rotter, National Medical Science and Nutrition Institute, Mexico Zulma Cruz de Trujillo, Hospital Nacional Rosales, El Salvador

• Pathology and pathophysiology of Mesoamerican nephropathy and comparisons with hypertension/diabetes CKD and CKDnT outside Mesoamerica Annika Östman Wernerson, Karolinska Institutet, Sweden Julia Wijkström, Karolinska Institutet, Sweden 181

• Moderated Discussion

9:30-9:45 Coffee Break

Theme: What do we need to know and understand?

9:45- 11:15 Working Groups (A) - Next Steps to Address Knowledge Gaps At registration, each participant will be asked, to prioritize (highest 5) the eleven Working Groups that are of most interest. The Organizing Committee will use these priorities to assign participants to one Working Group (A) and a different Working Group (B) to balance participant interests and number of participants in each group.

Programa Financiado por la Unión Europea 1. Exploring biomarkers for early evidence of abnormal kidney function a. Objectives: Discuss strengths and limitations of biomarkers, the time course of their appearance in non-diseased populations and the priority of

laboratory studies. b.single Output: or combinations The best possible of biomarkers consensus to ofserve which as studybiomarkers endpoints should in fieldbe and considered priority. i. Group Leaders: Carl-Gustaf Elinder, Karolinska Institutet, Sweden; Ricardo Correa Rotter, National Medical Science and Nutrition Institute, Mexico. ii. Rapporteur: James Kaufman, Boston University, USA.

2. Exploring genetic and epigenetic susceptibility a. Objectives: Discuss evidence for susceptibility, measurement of genetic

b. Output: Propose markers of susceptibility that might be appropriate or epigenetic markers, potential for use in field and laboratory studies. priority focus for laboratory investigation. to usei. G inroup field L eader:studies David whenever Friedman, possible Harvard and/or University, markers thatUSA should be a ii. Rapporteur: Joseph Kupferman, Beth Israel Deaconess Hospital, Boston, USA

182 3. Assessing individual risk factors a. Objectives: Discuss evidence for importance of factors such as NSAIDs, nutrition, alcohol and exposure, the potential for estimating exposure

an experimental setting b.levels Output: and approaches The best possible to assuring consensus validity of ofwhich measures factors in are the most field and in

i. Group Leader: Aurora Aragón, UNAN-León, Nicaragua importantii. Rapporteur: to consider Manuel in field Cerdas, studies Mexico Hospital, San Jose, Costa Rica

4. Assessing exposures to pesticides and metals a. Objectives: Consider the evidence for exposure to pesticides and to metals to explain epidemics of CKDnT, the best methods to measure and quantify these for use in population and experimental studies and how to

b. Output: Identify which pesticides and which metals are a priority for considerationassure validity in of studies measures of CKDnT in the field and howand into an quantify experimental exposures. setting i. Group Leader: Kristina Jakobsson, Gothenburg University, Sweden ii. Rapporteur: Berna van Wendel de Joode, Universidad Nacional, Costa Rica

Programa Financiado por la Unión Europea 5. Assessing exposure to environmental heat load/dehydration and workload a. Objectives:

Consider the essentials of field assessment and inquantification an experimental of heat setting load/dehydration and workload in both short and b.long-term Output: studies Propose and priority how to measures assure validity of heat/dehydration of measures in and the offield and workload that are necessary to include in population studies or to examine in laboratory investigations i. Group Leaders: Rebekah Lucas, University of Birmingham, UK; Esteban Arias Monge, Costa Rican Technol. Institute, Costa Rica ii. Rapporteur: Jennifer Crowe, Universidad Nacional, Costa Rica

6. Consideration of infectious agents a. Objectives: Consider evidence for infectious (bacterial, parasitic or

studies b.viral) Output: etiologies Propose for CKDnTwhich, ifand any, how infectious these might agents be are assessed important in field to further assess in population or laboratory studies of CKDnT i. Group Leader: Reina Turcios-Ruiz, CDC, Atlanta, USA ii. Rapporteur: Juan José Amador Velázquez, Boston University, USA

183 Thursday, 19 November (continued)

7. Understanding the mechanism of MeN – Theory a. Objectives: Examine proposed mechanisms for etiology of MeN and CKDnT and consider both epidemiologic and laboratory evidence in support of these b. Output: Characterize the most promising hypotheses and propose

i. Group Leaders: Rick Johnson University of Colorado, USA; Annika laboratoryÖstman and/orWernerson, field Karolinskastudies to confirm Institutet, or refuteSweden ii. Rapporteur: Catharina Wesseling, Chair CENCAM, Karolinska Institutet, ii. Sweden

Programa Financiado por la Unión Europea 8. Developing central elements for a Core Questionnaire a. Objectives: populations, prioritize common core questions that could be agreed on to include in futureEnhance studies comparison of study findings across different b. Output: Propose a core questionnaire using questions from already standardized instruments (if available) and questions that need validation for use studying MeN i. Group Leader: Daniel Brooks, Boston University, USA ii. Rapporteur: Marvin González, National Autonomous Univ. of Nicaragua at León (UNAN-León)

9. Approaches to intervention a. Objectives: Discuss approaches to intervention in light of current knowledge, discuss those that warrant immediate action and propose feasible study designs to assess their value in preventing MeN b. Output – Propose interventions that should be implemented now and

i. Group Leader: Theo Bodin, Karolinska Institutet, Sweden howii. best Rapporteur: to assess efficacyIlana Weiss, and effectivenessLa Isla Foundation, in the shortNicaragua and long-term.

10. Understanding macro factors 184 a. Objectives: Since the epidemic(s) exists in a social context how can we study the context with respect to socio-economic status, migrant labor patterns, community health, etc. a. Output: Propose the essential elements of the social context to account

i. Group Leader: Donna Mergler, University of Quebec in Montreal for (UQAM)in field studies and the role researchers can play in their amelioration. ii. Rapporteur: Neil Pearce, London School of Hygiene & Tropical Medicine

11. Approaches to surveillance of MeN a. Objectives: How best assess the cross-national burden of MeN, identify geographic or demographic “hot spots,” and track the trends in MeN over time. a. Output: Propose administrative, hospital, or community-based measures for case-based and population-based measurement of MeN and potential ways to collaborate between governments and between government and academia. i. Group Leader: David H. Wegman, University of Massachusetts Lowell ii. Rapporteur: Ramón García-Trabanino, Hospital Nacional Rosales, El Salvador

Programa Financiado por la Unión Europea Thursday, 19 November (continued)

11:15-12:30 Poster Exhibition 3-minute presentations, questions and time for individual review of posters

12:30-14:00 Lunch

Theme: How can we advance?

14:00-15:30 Working Groups (B) on Next Steps to Address Knowledge Gaps Participants will attend their other assigned Working Group for this second period of meetings. Group Leaders and Rapporteurs will remain the same for both sessions of the Working Groups.

15:30-16:30 Coffee Break (+ poster discussion)

16:30-17:30 Observations on the Context of the MeN Epidemic Chair: Donna Mergler, University of Quebec in Montreal (UQAM)

185 • Precarious Populations: Impacts of the political and socio- economic context of the MeN epidemic Ilana Weiss, La Isla Foundation, Nicaragua Jason Glaser, La Isla Foundation, Nicaragua

Friday, 20 November

08:15-08:30 Announcements and Explanation of the Day´s Activities

Theme: What are the top priority research initiatives?

08:30-10:30 Working group reports and discussions on concrete proposals for each theme Chair: Christer Hogstedt, Karolinska Institutet, Sweden

Programa Financiado por la Unión Europea Reports from each of the Working Group Leaders

Moderated Discussion

10:30-10:45 Coffee break

10:45-12:00 Moving forward – Priorities for a Research Agenda Workshop summary and framework introducing a general discussion of a research agenda Chair: David Wegman, University of Massachusetts Lowell, USA Agnes Soares, PAHO/WHO, Washington DC Christer Hogstedt, Karolinska Institutet, Sweden Catharina Wesseling, Chair CENCAM, Karolinska Institutet, Sweden Ricardo Correa-Rotter, National Medical Science and Nutrition Institute, Mexico

• Moderated Discussion

12:00-12:15 Workshop Closing 186 Catharina Wesseling, Chair CENCAM, Karolinska Institutet, Sweden

12:15-13:30 Lunch

*****************

13:30-15:00 CENCAM General Assembly

he organizers of this workshop would like to recognize and thank the many institutions and or- T ganizations that have contributed both time and funds so generously to make the event possible. American Institute for Studies on Toxic Substances (IRET) Central American Program on Work, Environment and Health (SALTRA) Consortium on the Epidemic of Nephropathy in Central America and Mexico (CENCAM) International Society of Nephrology Pan American Health Organization Universidad Nacional, Costa Rica U.S. National Institute for Environmental Health Sciences U.S. National Institute for Occupational Safety and Health

Funding for this conference was made possible (in part) by 1R13ES026050-01 from the National Insti- tute of Environmental Health Sciences. The views expressed in written conference materials or publica-

tions and by speakers and moderators do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the U.S. Government. Partial support for this workshop and workshop participants was provided by Universidad Nacional, Costa Rica Partial support for workshop participants was provided by the Pan American Health Association and the International Society of Nephrology.

187 Participant list

Magnus Abrahamson - Sweden Joseph Kupferman - United States Hildaura Acosta - Panama Rebecca Laws - United States Juan José Amador - Nicaragua Jill Lebov - United States Jenny Apelqvist - Sweden Randall Lou - Guatemala Aurora Aragón - Nicaragua Matthew Lozier - United States Esteban Arias - Costa Rica Rebekah Lucas - United Kingdom Joaquín Barnoya - Guatemala Michael McClean - United States Lars Barregard - Sweden Magdalena Madero - Mexico Vivek Bhalla - United States Claudio Mascheroni - Argentina Theo Bodin - Sweden Donna Mergler - Canada Daniel Brooks - United States Sally Moyce - United States Jesica Candanedo - Panama Carlos Manuel Orantes - El Salvador Ben Caplin - England Gary Noonan - United States Willy Carrillo - Costa Rica Annika Östman Wernerson - Sweden Cinthya Castillo - Honduras Reyna Lizette Pacheco - Mexico Manuel Cerdas - Costa Rica Neil Pearce - England Fabio Chaverri - Costa Rica Sandra Peraza - El Salvador Ricardo Correa Rotter - Rafael Porras - 188 Mexico Costa Rica Jennifer Crowe - Costa Rica David Rodríguez - El Salvador Zulma Cruz - El Salvador Oriana Ramírez Rubio - Spain Mario Cruz Peñate - Costa Rica Ana Leonor Rivera - Costa Rica Brian Curwin - United States Andrés Robles - Costa Rica Ulf Ekstrom - Sweden Julietta Rodríguez - United States Carl-Gustaf Elinder - Sweden Clemens Ruepert - Costa Rica Dorien Faber - Nicaragua Madeleine Scammell - United States David Friedman - United States Agnes Soares - United States Ramón García Trabanino - El Salvador Reina Turcios Ruiz - United States Jason Glaser - United States Mathieu Valcke - Canada Marvin González - Nicaragua Berna Van Wendel - Costa Rica Sarath Gunatilake - United States Vidhya Venugopa - Sri Lanka Randall Gutiérrez - Costa Rica Pedro Vinda - Panama Carolina Guzmán - Guatemala Virginia Weaver - United States Christer Hogstedt - Sweden David Wegman - United States Wendy Hoy - Australia Ilana Weiss - United States Kristina Jakobsson - Sweden Ineke Wesseling - Costa Rica Emmanuel Jarquín - El Salvador Elizabeth Whelan - United States Channa Jaysumana - Sri Lanka Paul Wise - United States Richard Johnson - United States Roy Wong - Costa Rica James Kaufman - United States Emily Wright - United States Central American Institute for Studies on Toxic Substances (IRET-UNA) Program on Work, Environment and Health in Central America (SALTRA)

Serie SALUD, TRABAJO Y

International Research Workshop on MeN Workshop Research International AMBIENTE 33

Second

1 189 Report from the from Report MESOAMERICAN NEPHROPATHY Report from the Second International Research Workshop on MeN MESOAMERICAN NEPHROPATHY MESOAMERICAN

Programa Financiado por la Unión Europea