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Prevalence and Risk Factors for CKD in the General Population of Southwestern

Ryan Ferguson,1 Sarah Leatherman,2 Madeline Fiore,3 Kailey Minnings,4 Martha Mosco,5 James Kaufman,6 Eric Kerns,7 Juan Jose Amador,8 Daniel R. Brooks,8 Melissa Fiore,9 Rulan S. Parekh,4,10 and Louis Fiore8

Due to the number of contributing authors, the affiliations are listed at the end of this article.

ABSTRACT Background Studies have described Mesoamerican nephropathy among agricultural workers of El Salva- dor and northwestern Nicaragua. Data on prevalence and risk factors for CKD beyond agricultural workers and in other regions in Nicaragua are sparse. Methods We recruited participants from 32 randomly selected communities in the Department of Rivas’s ten municipalities in two phases. In phase 1, we screened participants using a field-based capillary creat- inine measuring system and collected self-reported information on lifestyle and occupational, exposure, and health histories. Two years later, in phase 2, we enrolled 222 new participants, performing serum creatinine testing in these participants and confirmatory serum creatinine testing in phase 1 participants. Results We enrolled 1242 of 1397 adults (89%) living in 533 households (median age 41 years; 43% male). We confirmed CKD (eGFR,60 ml/min per 1.73 m2) in 53 of 1227 (4.3%) evaluable participants. In multivari- able testing, risk factors for prevalent CKD included age (odds ratio [OR], 1.92; 95% confidence interval [95% CI], 1.89 to 1.96) and self-reported history of hypertension (OR, 1.95; 95% CI, 1.04 to 3.64), diabetes (OR, 2.88; 95% CI, 1.40 to 5.93), or current or past work in the sugarcane industry (OR 2.92; 95% CI, 1.36 to 6.27). Conclusions Adjusted CKD prevalence was about 5% with repeat confirmatory testing in southwest Nicar- agua, lower than in the northwest region. Risk factors included diabetes, hypertension, and current or prior work in the sugarcane industry but not in other forms of agricultural work. Formal CKD surveillance programs in Nicaragua are needed to assess the overall burden of CKD nationally, with a focus on agri- cultural workers.

JASN 31: ccc–ccc, 2020. doi: https://doi.org/10.1681/ASN.2019050521

There is an increased awareness of a recently recog- specimens from persons affected with Mesoamer- nized form of CKD of unknown origin in Central ican nephropathy in El Salvador and Nicaragua America over the past decade.1,2 The disease, also show chronic tubulointerstitial damage with11 or termed Mesoamerican nephropathy, dispropor- without8 evidence of glomerular ischemia and tionately affects young male agricultural workers glomerulosclerosis. living in the Pacific lowlands of Central America with hotspots identified in El Salvador and north- west Nicaragua.3,4 Mesoamerican nephropathy is Received May 21, 2019. Accepted March 24, 2020. typically not associated with the traditional risk fac- Published online ahead of print. Publication date available at tors for CKD such as diabetes and hypertension. www.jasn.org. Putative causes of the disease include heat stress Correspondence: Dr. Louis Fiore, Department of Epidemiology, and dehydration,5 occupational or environmental Boston University School of Public Health, Boston, MA. Email: exposures,6,7 fructose toxicity, infectious disease,8,9 Lfi[email protected] and genetic susceptibility.10 Kidney biopsy Copyright © 2020 by the American Society of Nephrology

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A lack of health care information in other regions in Nicar- Significance Statement agua makes it difficult to estimate national CKD prevalence. Most studies in these hotspots are cross-sectional and include Most studies of Mesoamerican nephropathy have focused on re- predominantly young adults. The proportion of decreased gions in El Salvador and northwest Nicaragua and on agricultural – workers, but information regarding prevalence and risk factors for eGFR has widely divergent prevalence, from 9% 42% in ’ – CKD in Nicaragua s general population is sparse. In a study of men to 1% 10% in women. Published cross-sectional studies community-dwelling individuals in southwestern Nicaragua, the were executed with important design differences, even in geo- authors screened 1242 participants for CKD (defined as ,60 ml/min graphically proximate communities. Study differences include per 1.73 m2). Risk factors for prevalent CKD included age, diabetes, classification of participants with CKD on the basis of deter- and hypertension. Current or former workers in the sugarcane in- mination of eGFR at a single time point, selected study pop- dustry (but not other types of agriculture) had a twofold-increased odds of CKD. CKD prevalence in southwestern Nicaragua is about 12213 ulations, and varying measurements of creatinine and 5% among the general population but is not consistent across Ni- definitions of CKD.14,15 Almost all studies of CKD prevalence caragua. Formal CKD surveillance programs in Nicaragua are in Nicaraguan communities12,13,15–17 were conducted in the needed to assess the overall burden of CKD nationally, with a focus Pacific northwest region, where sugarcane is the primary ag- on agricultural workers. ricultural crop and which is a presumed hotspot for Mesoa- 4 merican nephropathy. One study conducted in the central in July and August, before the sugarcane harvest period. The interior of Nicaragua found lower rates of CKD and differed Institutional Review Board of the Dirección General de Do- . from other studies in both altitude of the region ( 1000 m cencia e Investigaciónes of the Ministry of Health of Nicaragua above sea level) and having coffee farming as the main agri- approved the protocol and granted permission to enroll par- 14,18–20 cultural crop. An important question facing health ticipants from these municipalities (, Belén, Buenos care providers and administrators is whether CKD is limited Aires, Cárdenas, Moyogalpa, Potosí, Rivas, San Jorge, San Juan fi to identi ed geographic hotspots or is more ubiquitous del Sur, and Tola) for phase 1 of the study. Phase 2 of the study throughout Nicaragua. Despite a lack of more robust and was approved by the Institutional Review Board of the Centro geographically distributed studies, Mesoamerican nephrop- Nacional de Diagnostico y Referencia of the Ministry of Health athy was widely publicized and characterized as an epi- of Nicaragua. All participants gave informed consent, and the demic,10,21 with a call made for additional research22 and study was performed in adherence with the Declaration of intervention.23,24 Helsinki. It is important to assess the burden of CKD across Nicar- To facilitate recruitment and screening in phase 1, partic- agua with important health service implications as well as to ipants were initially screened using a point-of-care capillary address risk factors leading to CKD specific to Nicaragua. The creatinine–measuring system, the StatSensor Express (Nova Department of Rivas borders the Pacific Ocean in the south- Biomedical, Waltham, MA),26 and then follow-up of those west of Nicaragua and shares many of the features of the with elevated creatinine by venous blood sampling for creat- northwestern regions that are associated with Mesoamerican inine was carried out, using standard laboratory procedures to nephropathy, including low altitude and similar occupations, fi agricultural crops, climate, and population demographics. In con rm the presence of CKD. In phase 1, 1020 participants 2012, health care providers and administrators in Rivas were consented and were screened for CKD (Figure 1, Strengthen- concerned about CKD in their region and supported studying ing the Reporting of Observational studies in Epidemiology of the Rivas region.25 The aim of this project was to create a diagram). Of the 1016 evaluable participants, 400 had an , 2 representative geographic-based cohort to estimate prevalence eGFR of 60 ml/min per 1.73 m calculated with the Modi- fi of CKD in the Department of Rivas. cation of Diet in Renal Disease (MDRD) equation. Phase 2 allowed for repeat testing of participants to confirm CKD and also enrollment of new participants from the same commu- METHODS nities as well as from four additional communities not visited during phase 1 that make-up the Department of Rivas. All Study Design and Data Collection enrolled participants in both phases had a urine dipstick test Detailed descriptions of study design and population are avail- performed and completed a questionnaire to ascertain expo- able in a published methods paper25 and important design sures relevant to CKD and Mesoamerican nephropathy. features are summarized here. The initial phase conducted point-of-care testing with par- The study was conducted in two phases. Subject recruit- ticipants due to cost and transport issues, and serum samples ment was designed to minimize the potential for recruitment were not routinely collected. Participants visited in phase 2 bias regarding CKD status and involved randomization at the had height and weight measured for body mass index deter- community level. Within each randomly selected community, mination using a portable mechanical scale and measuring participants were recruited from sequential households and an tape. Blood samples were obtained by trained phlebotomists. attempt was made to enroll all eligible members of each house- Blood samples were placed on ice immediately after collection; hold. Both phase 1 (2012) and phase 2 (2014) were conducted centrifuged at 3000 3 g for 15 minutes within 3 hours;

2 JASN JASN 31: ccc–ccc,2020 www.jasn.org CLINICAL EPIDEMIOLOGY refrigerated at 4°C until weekly transport to the International Or- (or Fisher’s exact test) for categoric measures. Stratum- ganization for Standardization-certified Centro Nacional de Diag- specific prevalence was calculated for those with and without nostico y Referencia in Managua, a division of the Ministry of CKD (eGFR,60 versus eGFR$60 ml/min per 1.73 m2)and Health (Ministerio de Salud); and then stored at 280°C. Serum compared by chi-squared test. Crude and adjusted (for sex, creatinine was measured using a kinetic-rate Jaffe method and age, self-reported high BP, and self-reported diabetes deter- calculations were made to calibrate to an isotopic dilution mass mined apriori) prevalence odds ratios (ORs) were calculated spectrometry standard. Urine dipstick testing was done immedi- using simple and multivariable logistic regression and presen- ately on voided specimens using Rapid Response 10 Parameter ted with their corresponding 95% confidence intervals (95% (10SG) Urinalysis Reagent TestStrips (BTNX Inc., Markham, ON). CIs). Participants with only serum creatinine in phase 2 and a Although the MDRD method was used for screening partic- single time point of assessment were included in a sensitivity ipants, all statistical analyses reported use the eGFR calculated analysis of CKD prevalence estimates. with the Chronic Kidney Disease Epidemiology Collaboration equation.27 CKD stage is defined only on the basis of eGFR determinations using the Kidney Disease: Improving Global RESULTS Outcomes definition, when the eGFR,60 ml/min per 1.73 m2 separated by at least 3 months was used to define CKD.28 The age distribution (mean 40.4 years, range 17.4–101.8) of the study population is similar to that of the Department of Statistical Analyses Rivas as determined in the 2005 census29 (Table 1). Of the 400 Comparisons between groups were performed with use of the participants with eGFR,60 ml/min per 1.73 m2 (MDRD) in t test for continuous measures and the chi-squared test phase 1, 316 had confirmatory serum creatinine determined

1659 potential participants (533 Households) 262 unable to contact

1397 invited to participate 155 refused consent

1242 consented 1020 consented 222 consented in Phase I in Phase II (2012) (2014)

211 evaluable 1016 evaluable Phase II Phase I samples samples

400 capillary CR elevated on screening

84 confirmatory 316 confirmatory serum samples serum samples NOT drawn drawn

1659 potential 273 normal 43 depressed 201 normal 10 depressed participants eGFR eGFR on eGFR eGFR on (533 Households) on retesting retesting on testing testing

Figure 1. Study population of the Rivas Cohort Study, Nicaragua.

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Table 1. Comparison of demographics among Nicaragua 2005 census,29 Rivas went unobserved. When combined with 2005 census,29 and the Rivas Cohort Study participants the observed cases, the “adjusted CKD Nicaragua 2005 Census Rivas 2005 Census Study Participants prevalence” was5.3%(54casesof1016 Indicator N % N % Na % screened participants). Proteinuria (.30 mg/dl) was found by dipstick in Total 2,627,737 51.1 84,944 54.4 1080 Age 6.2% of tested participants, but was 20–29 951,701 36.2 28,088 33.1 336 31.1 more common in CKD cases (26.0%; 30–39 632,253 24.1 19,178 22.6 275 25.5 13 of 50 participants tested) than in 40–49 451,622 17.2 14,935 17.6 181 16.8 non-CKD cases (5.2%; 53 of 1023 par- 50–59 278,984 10.6 9844 11.6 135 12.5 ticipants tested; P,0.001). 60–69 165,848 6.3 6110 7.2 81 7.5 Prevalence estimates differed signifi- 70–79 96,194 3.7 4243 5.0 50 4.6 cantly by diabetes and hypertension sta- 801 51,135 1.9 2546 3.0 22 2.0 tus(Table3).Therewerenosignificant Sex differences by sex, alcohol intake, water Male 1,255,294 47.8 41,581 49.0 472 43.8 intake, or agricultural work. In univari- Female 1,372,443 52.2 43,363 51.0 608 56.3 able and multivariable testing (Table 4), aExcludes 84 participants enrolled in phase 1 and not retested in phase 2; 63 enrolled individuals whose age is ,20 years as comparable census data are not available. risk factors for CKD included age (OR, 1.92; 95% CI, 1.89 to 1.96), self-reported history of hypertension (OR, 1.95; 95% via venipuncture during phase 2. A total of 84 participants CI, 1.04 to 3.64), and diabetes (OR, 2.88; 95% CI, 1.40 to were not retested; ten had died since the initial visit in phase 5.93). There was a strong association (OR, 2.9; 95% CI, 1.36 1 and the remainder refused to participate, had moved, or to 6.27, adjusted for sex, age, diabetes, and hypertension) of werenotathome—but were known to be alive and well current or past work in the sugarcane industry and CKD in the with no known kidney disease by family members and neigh- 174 participants who reported work in this sector. bors. Among those participants who could not be recontacted in phase 2, there was no significant difference in age, preva- lence of self-reported hypertension, or proportion male. The DISCUSSION only difference was that rates of self-reported diabetes were lower in those that were not available for recontact. In a population sampling of southwestern coastal Nicaragua, CKD was confirmed in 43 of the 316 participants that were in the Department of Rivas, we report that the prevalence of retested 2 years later. Observed prevalence of CKD in the co- CKD is about 5% and is typically associated with older age, hort was 4.2% (43 cases of 1016 screened participants), but diabetes, and hypertension. There was also a higher CKD this estimate excludes consideration of the 84 participants prevalence among those who had current or past work in who screened positive by capillary creatinine in phase 1 but the sugarcane industry; however, other agricultural work were not available for retesting (Table 2). If the same rate of was not associated with increased odds of CKD. This study em- CKD was observed, then it is estimated that there would be an ployed geographic sampling techniques with recruitment of ran- additional 11 cases of CKD (13.6% 3 84 participants) that dom households in specific sampling tracts and the logistics of

Table 2. Prevalence of CKD in Rivas, Nicaragua from 2012 to 2014 Variable Phase 1, 2012a Phase 2, 2014b Combined Total evaluable (n) 1016 211 1227 Screened with CKD by MDRD (n) 400 (39%) Not retested (n)84–– Retested (n) 316 –– Confirmed CKD by serum creatinine (n)431053 Stage 3A (eGFR 45–59) (n)21526 Stage 3B (eGFR 30–44) (n)12416 Stage 4 (eGFR 15–29) (n)819 Stage 5 (eGFR,15) (n)202 Confirmed not CKD (n) 273 CKD observed prevalence 4.2% (43 of 1016) 4.7% (10 of 211) 4.3% (53 of 1227) CKD adjusted prevalencec 5.3% (54 of 1016) 4.7% (10 of 211) 5.2% ([54110] of 1227) –,notapplicable. aCKD defined as eGFR,60 ml/min per 1.73 m2 using the Chronic Kidney Disease Epidemiology Collaboration equation. bNew participants enrolled. cAdjusted for participants who were screened positive for CKD in phase 1 but were not available for retesting in phase 2.

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Table 3. Stratum-specific prevalence of CKD by demographic characteristics and potential risk factors in Rivas, Nicaragua Stratum-Specific Prevalence (95% CI) Characteristic N (%) P Value eGFR<60 ml/min per 1.73 m2 eGFR‡60 ml/min per 1.73 m2 Study population 1143 n553 n51090 Mean eGFR6SD 42.0613.2 95.6619.6 Demographic characteristics Sex 0.4 Female 642 (56.2) 50.9 (36.8 to 64.9) 56.4 (53.4 to 59.4) Male 501 (43.8) 49.1 (35.1 to 63.2) 43.6 (40.6 to 46.6) Age (continuous) 1143 (100) 62.2613.3 38.7616.0 ,0.001 Age (categoric) ,0.001 ,20 63 (5.5) 0 5.8 (4.5 to 7.3) 20–29 336 (29.4) 0 30.8 (28.1 to 33.7) 30–39 275 (24.1) 7.6 (2.1 to 18.2) 24.9 (22.3 to 27.5) 40–49 181 (15.8) 11.3 (4.3 to 23.0) 16.1 (13.9 to 18.4) 50–59 135 (11.8) 28.3 (13.2 to 35.6) 11.0 (9.2 to 13.0) 60–69 81 (7.1) 24.5 (13.8 to 38.3) 6.2 (4.9 to 7.8) 70–79 50 (4.4) 18.9 (9.4 to 32.0) 3.7 (2.7 to 5.0) 801 22 (1.9) 9.4 (3.1 to 20.7) 1.6 (0.9 to 2.5) Municipalities 0.1 Altagracia 41 (3.6) 1.9 (0.05 to 10.1) 3.7 (2.6 to 5.0) Belen 136 (11.9) 11.3 (4.3 to 23.0) 11.9 (10.1 to 14.0) Buenos Aires 97 (8.5) 3.8 (0.5 to 13.0) 8.7 (7.1 to 10.6) Cardenas 104 (9.1) 11.3 (4.3 to 23.0) 9.0 (7.4 to 10.9) Moyogalpa 40 (3.5) 1.9 (0.05 to 10.1) 3.6 (2.6 to 4.9) Potosi 143 (12.5) 15.1 (6.8 to 27.6) 12.4 (10.5 to 14.5) Rivas 167 (14.6) 17.0 (8.1 to 29.8) 14.5 (12.5 to 16.7) San Jorge 145 (12.7) 11.3 (4.3 to 23.0) 12.8 (10.8 to 14.9) San Juan 124 (10.9) 1.9 (0.05 to 10.1) 11.3 (9.5 to 13.3) Tola 146 (12.8) 24.5 (13.8 to 38.3) 12.2 (10.3 to 14.3) Water sourcea Well 543 (47.5) 43.4 (29.8 to 57.7) 47.8 (44.8 to 50.9) 0.5 Piped 523 (45.8) 54.7 (40.5 to 68.4) 45.5 (42.5 to 48.5) 0.2 Potential risk factors Alcohol consumption No 998 (87.3) 92.3 (81.5 to 97.9) 89.1 (87.1 to 90.9) 0.5 Yes 120 (10.5) 7.7 (2.1 to 18.5) 10.9 (9.1 to 12.9) Alcohol consumption volume 0.8 0 drinks/d 998 (87.3) 92.3 (81.5 to 97.9) 89.1 (87.1 to 90.9) 1–2 drinks/d 44 (3.9) 1.9 (0.05 to 10.3) 4.0 (2.9 to 5.4) 3–4 drinks/d 18 (1.6) 1.9 (0.05 to 10.3) 1.6 (0.9 to 2.5) 51 drinks/d 58 (5.1) 3.9 (0.5 to 13.2) 5.3 (4.0 to 6.8) Ever smoked 0.1 No 751 (65.7) 64.4 (48.8 to 78.1) 75.4 (72.6 to 78.1) Yes 251 (22.0) 35.6 (21.9 to 51.2) 24.6 (21.9 to 27.4) Self-reported diabetes ,0.001 No 1063 (93.0) 75.5 (61.7 to 86.2) 93.9 (92.4 to 95.3) Yes 79 (7.0) 24.5 (13.8to 38.3) 6.1 (4.7 to 7.7) Self-reported high BP ,0.001 No 840 (73.5) 41.5 (28.1 to 55.9) 75.1 (72.4 to 77.7) Yes 302 (26.4) 58.5 (44.1 to 71.9) 24.9 (22.3 to 27.6) Number of years worked in agricultureb 0.1 Never 590 (51.6) 52.4 (36.4 to 68.0) 59.2 (56.0 to 62.3) 0–4 135 (11.8) 11.9 (4.0 to 25.6) 13.5 (11.4 to 15.9) 5–9 60 (5.3) 2.4 (0.1 to 12.6) 6.2 (4.7 to 7.9) 10–14 69 (6.0) 4.8 (0.6 to 16.2) 7.0 (5.5 to 8.8) $15 148 (13.0) 28.6 (15.7 to 44.6) 14.2 (12.0 to 16.5)

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Table 3. Continued

Stratum-Specific Prevalence (95% CI) Characteristic N (%) P Value eGFR<60 ml/min per 1.73 m2 eGFR‡60 ml/min per 1.73 m2 Daily water consumption 0.8 #1 L water/d 451 (39.5) 36.5 (23.6 to 51.0) 40.2 (37.3 to 43.3) 2–3 L water/d 533 (46.6) 48.1 (36.8 to 63.2) 47.3 (44.3 to 50.3) 4–5 L water/d 126 (11.0) 15.4 (6.9 to 28.1) 11.0 (9.2 to 13.0) 6–7 L water/d 12 (1.1) 0 1.1 (0.6 to 1.9) 8–9 L water/d 4 (0.4) 0 0.4 (0.1 to 1.0) Sample sizes (N) for some risk factor subgroups vary due to missing data. aCategories are not mutually exclusive. bMissing duration of agricultural work in 141 individuals. subject recruitment in the community, to maximize enrollment agricultural (specifically sugarcane) workers, for example, and retention in a rural region of Nicaragua and to ensure that andsoitismorereflective of the general population. Recent the study population was reflective of the general population. studies in artisanal brick layers from Las Paz Centro,30 agri- Additionally, there was a very small loss to follow-up of 6% over cultural workers, young adults under age 30, and other re- 2 years; yet, key information on mortality and report of kidney gional populations in the northwest report higher prevalence disease were available from other household members. of CKD,31,32 reflective of the higher-risk region and occupa- In a random general population of southwestern Nicara- tions at risk and not reflective of the general population. Al- gua, the observed prevalence of CKD was 4.3% and in contrast ternatively, the prevalence of CKD found in Rivas may reflect a with most previous studies that show a higher prevalence of true geographic difference from other studies conducted in CKD in population samples from Nicaragua and El Salvador. northwestern coastal Nicaragua and El Salvador. Indeed, a Planned recruitment strategies reduced the likelihood of over- low prevalence of CKD is reported in a high-altitude coffee- sampling or enrichment of the study population with growing village of central Nicaragua.14 The Department of

Table 4. Multivariable model of associations between CKD and potential risk factors in Rivas, Nicaragua Covariates Unadjusted POR (95% CI) P Value Adjusted POR (95% CI)a P Value Sex Female Referent Referent Male 1.25 (0.72 to 2.16) 0.4 1.40 (0.76 to 2.58) 0.2 Age (continuous, 10-yr increase) 2.04 (2.00 to 2.07) ,0.001 1.92 (1.89 to 1.96) ,0.001 Self-reported diabetes No Referent Referent Yes 5.04 (2.57 to 9.88) ,0.001 2.88 (1.40 to 5.93) 0.04 Self-reported high BP No Referent Referent Yes 4.25 (2.42 to 7.47) ,0.001 1.95 (1.04 to 3.64) 0.004 Worked in sugarcane No Referent Referent Yes 2.95 (1.61 to 5.43) 0.0005 2.92 (1.36 to 6.27) 0.006 Worked in agricultureb No Referent Referent Yes 1.53 (0.88 to 2.68) 0.1 1.53 (0.76 to 3.09) 0.2 Number of years worked in agriculture Never Referent Referent 0–4 0.99 (0.37 to 2.67) 0.9 1.47 (0.49 to 4.47) 0.5 5–9 0.44 (0.06 to 3.31) 0.4 0.65 (0.08 to 5.37) 0.7 10–14 0.77 (0.18 to 3.35) 0.7 0.97 (0.20 to 4.76) 0.9 $15 2.28 (1.10 to 4.72) 0.03 1.49 (0.59 to 3.74) 0.4 Ever smoked No Referent Referent Yes 1.70 (0.91 to 3.18) 0.09 1.46 (0.63 to 3.39) 0.4 POR, prevalence odds ratio. aLogistic regression model adjusted for sex, continuous age, self-reported high BP, and diabetes. bDefined as any of the following: current work in agriculture, ever worked in agriculture, or ever worked in sugarcane.

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Rivas shares many of the features of the Northwestern regions Dr. Minnings, and Ms. Mosco. Validation of capillary creatinine that are associated with Mesoamerican nephropathy including devices was performed by Ms. Melissa Fiore, Dr. L. Fiore, and low altitude inhabitant occupations, agricultural crops, cli- Dr. Kerns. Dr. Amador communicated with Nicaraguan authorities mate and population demographics. These shared features and institutional review boards. Dr. Leatherman did the statistical argue against the CKD prevalance differences reported in analysis. All authors contributed to editing of the manuscript. Dr. L. Fiore each region. and Dr. Parekh wrote the first and final drafts of the manuscript. An important feature of this study, and one that makes it Data collected for the study, including deidentified individual unique in relation to other studies in this region, is that kidney participant data and a data dictionary defining each field in the set, function was assessed twice and 2 years apart. This is critical will be made available to researchers with an institutional review because we identified 400 participants initially with possible board–approved protocol. A signed data access agreement that CKD and, upon retesting after 2 years, almost 70% no longer specifies how the data may be used is required. Generally, data are had advanced CKD. The high number of participants no available without cost and publications that result from data analyses longer having CKD could be due to false-positive findings, must acknowledge the original work. Data will be available indefinitely likely from the lack of precision of the point-of-care testing26 from the time of publication and can be obtained by contacting the or resolution of AKI. Nonetheless, frequent surveillance of corresponding author. Additional, related documents, including study high-risk agricultural workers is important to screen for the procedures and data collection forms, are published and available true burden of CKD in Nicaragua. Additionally, participants elsewhere25 or will be supplied by the corresponding author. were enrolled in July and August, before the sugarcane harvest season, in order to minimize this potential bias. Another crit- ical feature of the study methods is that creatinine values used DISCLOSURES for subject classification were determined at a central labora- tory and were not reliant on field-based measurements using All authors have nothing to disclose. capillary testing devices. The main limitations of this study include the inability to classify participants with milder forms FUNDING of CKD with eGFR from 60 to 90 ml/min per 1.73 m2 and that proteinuria was not available in all participants. Proteinuria by This project was funded primarily by small private contributions managed dipstick was more common among those with CKD and by the “Newton- Sister City Project” (http:// should be added to any screening program. A further limita- sanjuandelsursistercityproject.wordpress.com/). Additional support was pro- tion was that less than half of the study cohort worked within vided by the Medical Alumni Association at the University of Toronto Faculty an agricultural industry, with the majority having only a mild- of Medicine and the American Society of Nephrology (Dr. Minnings and Dr. to-moderate yearly exposure. Lastly, we were unable to retest Parekh). Dr. Parekh is funded by the Canada Research Chair in CKD Epide- miology. The funders had no role in the design, conduct, analysis, or writing 84 of the 400 participants who screened positive in phase 1, ten up of the study. The corresponding author had full access to the data and took of whom had died, and they may have suffered from kidney the decision to submit for publication. disease; however, reports from household members denied any kidney disease. Due to this lack of retesting, an adjusted model presuming similar CKD prevalence was incorporated as SUPPLEMENTAL MATERIAL the clinical characteristics were similar. This may have in- creased the overall prevalence reported. This article contains the following supplemental material online at CKD prevalence is 5% in southwestern Nicaragua among the http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2019050521/-/ general population and is associated with diabetes and hyperten- DCSupplemental. sion. Prior or current work in the sugarcane industry was also Supplemental Table 1. Published epidemiologic studies of Meso- independently and significantly associated with CKD; however, american nephropathy. the overall prevalence remained low. Rates of CKD are not con- Supplemental Figure 1. Map of Nicaragua showing Department of sistent across Nicaragua or among high-risk agricultural workers. Rivas; location of participant recruitment. The Rivas cohort established in southwest Nicaragua33 reflects a growing awareness for CKD surveillance programs in countries REFERENCES with emerging economies,34 where a lack of reliable health care data is a major obstacle to understanding CKD burden. 1. Cohen J: Mesoamerica’s mystery killer. Science 344: 143–147, 2014 2. Johnson RJ, Sánchez-Lozada LG: Chronic kidney disease: Mesoamer- ican nephropathy--new clues to the cause. Nat Rev Nephrol 9: 560–561, 2013 ACKNOWLEDGMENTS 3. Brooks DR, Ramirez-Rubio O, Amador JJ: CKD in Central America: A hot issue. Am J Kidney Dis 59: 481–484, 2012 4. Martín-Cleary C, Ortiz A: CKD hotspots around the world: Where, why Dr. Ferguson, Dr. Amador, Dr. Brooks, Dr. Kaufman, and Dr. L. Fiore and what the lessons are. A CKJ review series. Clin Kidney J 7: 519–523, conceived the study. Field work was managed by Dr. Madeline Fiore, 2014

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8 JASN JASN 31: ccc–ccc,2020 www.jasn.org CLINICAL EPIDEMIOLOGY

AFFILIATIONS

1Boston University, School of Public Health, Boston, Massachusetts 2Boston Cooperative Studies Program Coordinating Center, Veterans Affairs, Boston Healthcare System, Boston, Massachusetts 3University of Massachusetts, School of Medicine, Worcester, Massachusetts 4University of Toronto, Faculty of Medicine, Toronto, Ontario, Canada 5New York Presbyterian Hospital, Weill Cornell, New York, New York 6Division of Nephrology, Veterans Affairs New York Harbor Healthcare System and New York University School of Medicine, New York, New York 7Division of Nephrology, Lahey Hospital and Medical Center, Burlington, Massachusetts 8Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts 9Cornell University, Ithaca, New York 10Division of Nephrology, Department of Pediatrics and Medicine, Hospital for Sick Children, University Health Network, Toronto, Ontario, Canada

JASN 31: ccc–ccc, 2020 CKD Prevalence and Risk Factors in Nicaragua 9 Table of Contents

Supplemental Table 1. Published Epidemiological Studies of Mesoamerican Nephropathy…………………………………………………………………………2

Supplemental Figure 1. Map of Nicaragua showing Department of Rivas; Location of Participant Recruitment…………………………………………………....3

Supplemental Table 1. Published Epidemiological Studies of Mesoamerican Nephropathy

Age eGFR <60/ml/mg/1.73m2 Study Study Location Male (%) Range Creatinine Assay Measurement eGFR Equation (%) Population Mean Age Male Female 20-60 Torres17 Leon, Nicaragua 1096 44 IDMS Traceable Serum Creatinine MDRD 14.2 3.2 34 20-60 Peraza33 El Salvador 664 38 IDMS Traceable Serum Creatinine MDRD 8.6 4.7 37 20-60 Laux15 Matagalpa, Nicaragua 267 45 Capillary Creatinine MDRD 0 1.4 34 >18 O’Donnell16 Leon, Nicaragua 771 39 IDMS Traceable Serum Creatinine MDRD 20.1 8.0 39 >18 Serum Creatinine Orantes32 El Salvador 2388 44 (15% > MDRD 17.0 6.8 (Method not reported) age 60) Leon and Chinandega, >18 Serum Creatinine Sanoff14 997 85 MDRD 14.0 3.4 Nicaragua 39 (Method not reported) >20 Raines13 Chinandega, Nicaragua 401 39 IDMS Traceable Serum Creatinine, CKD-EPI 41.9 9.8 33 18-70 Lebov12 Leon, Nicaragua 2275 42 IDMS Traceable Serum Creatinine MDRD 13.8 5.8 38 18-60 mGallo-Ruiz27 Leon, Nicaragua 224 86 IDMS Traceable Serum Creatinine CKD-EPI 12.1 0 34 18-60 Serum Creatinine Kupferman34 Chinandega, Nicaragua 326 100 (median; CKD-EPI 34.5 0 (Method not reported) 34) Leon and Chinandega, 18-30 Gonzalez-Quiroz29 350 75 IDMS Traceable Serum Creatinine CKD-EPI 9.5 3.4 Nicaragua 24 18-59 MDRD 1.9* Fischer28 Chinandega, Nicaragua 586 90 (median; IDMS Traceable Serum Creatinine CKD-EPI 1.5* 28) Cockcroft-Gault 1.5* 18-63 Laws6 Chinandega, Nicaragua 284 88 IDMS Traceable Serum Creatinine CKD-EPI 0^ 4.2 34

Leon and Chinandega, Wesseling7 194 100 17-39 IDMS Traceable Serum Creatinine CKD-EPI 10.3+ - Nicaragua * No male/female breakdown – combined (%) ^ Male group used as reference + eGFR <80/ml/mg/1.73m2 Supplemental Figure 1. Map of Nicaragua showing Department of Rivas; Location of Participant Recruitment

Adapted from a publicly available map: https://upload.wikimedia.org/wikipedia/commons/4/4b/Rivas_Department%2C_Nicaragua.svg