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Title Averting the legacy of --focus on childhood.

Permalink https://escholarship.org/uc/item/7hm5797h

Journal Kidney international, 89(3)

ISSN 0085-2538

Authors Ingelfinger, Julie R Kalantar-Zadeh, Kamyar Schaefer, Franz et al.

Publication Date 2016-03-01

DOI 10.1016/j.kint.2015.10.014

License https://creativecommons.org/licenses/by/4.0/ 4.0

Peer reviewed

eScholarship.org Powered by the California Digital Library University of California editorial www.kidney-international.org

Averting the legacy of —focus on childhood

World Kidney Day 2016 focuses on kidney disease in childhood and the antecedents of adult kidney disease that can begin in earliest childhood. in childhood differs from that in adults, as the largest diagnostic group among children includes congenital anomalies and inherited disorders, with glomerulopathies and kidney disease in the setting of being relatively uncommon. In addition, many children with will fi 1 Julie R. Ingel nger , ultimately develop sequelae that may lead to and chronic kidney disease in later Kamyar Kalantar-Zadeh2 childhood or in adult life. Children born early or who are small-for-date newborns have a and Franz Schaefer3; for relatively increased risk for the development of chronic kidney disease later in life. Persons with the World Kidney Day Steering Committee4 a high-risk birth and early childhood history should be watched closely in order to help detect 1Professor of Pediatrics, early signs of kidney disease in time to provide effective prevention or treatment. Successful Harvard Medical School, Senior therapy is feasible for advanced chronic kidney disease in childhood; there is evidence that Consultant in Pediatric children fare better than adults if they receive kidney replacement therapy including and Pediatrician, and transplant, whereas only a minority of children may require this ultimate intervention. Mass General Hospital for Children at Massachusetts Because there are disparities in access to care, effort is needed so that those children with General Hospital, Boston, kidney disease, wherever they live, may be treated effectively, irrespective of their geographic Massachusetts, USA; 2Chief, or economic circumstances. Our hope is that World Kidney Day will inform the general public, Division of Nephrology & policy makers, and caregivers about the needs and possibilities surrounding kidney disease in Hypertension, Professor of childhood. Medicine, Pediatrics and Public Health, University of California Kidney International (2016) 89, 512–518; http://dx.doi.org/10.1016/j.kint.2015.10.014 Irvine, School of Medicine; Staff ª World Kidney Day 2016 Steering Committee Physician and Principal Investigator, Veterans Affairs (VA) Long Beach Healthcare System, Long Beach, CA, USA; “For in every adult there dwells the child long list of communicable are inex- Adjunct Professor of Epidemiology, Department of that was, and in every child there lies the tricably linked to kidney involvement. For Epidemiology, UCLA Fielding adult that will be.” example, children who succumb to cholera and School of Public Health, Los —John Connolly, The Book of Lost Things other diarrheal often die, not from Angeles, CA, USA; and the , but because of AKI induced by 3 Professor of Pediatrics, he 11th World Kidney Day will be cele- volume depletion and shock. In addition, a University of Heidelberg, Head, Division of Pediatric brated on March 10, 2016, around the substantial body of data indicates that hyper- Nephrology, Center for T globe. This annual event, sponsored jointly tension, proteinuria, and CKD in adulthood Pediatrics and Adolescent by the International Society of Nephrology have childhood antecedents—from as early as Medicine Heidelberg, Germany (ISN) and the International Federation of Kid- in utero and perinatal life (see Table 1 for Correspondence : World ney Foundations, has become a highly successful definitions of childhood). World Kidney Day Kidney Day, International Society of Nephrology, in effort to inform the general public and policy 2016 aims to heighten general awareness that collaboration with International makers about the importance and ramifications much adult renal disease is actually initiated in Federation of Kidney of kidney disease. In 2016, World Kidney Day childhood. Understanding high-risk diagnoses Foundation, Rues de Fabriques will be dedicated to kidney disease in childhood and events that occur in childhood have the 1B, 1000, Brussels, Belgium. and the antecedents of adult kidney disease, potential to identify and intervene pre- E-mail: myriam@ worldkidneyday.org which can begin in earliest childhood. emptively in those people at higher risk for Children who endure acute kidney injury CKD during their lifetimes. 4See Appendix for list of committee members. (AKI) from a wide variety of conditions may Worldwide epidemiologic data on the spec- have long-term sequelae that can lead to chronic trum of both CKD and AKI in children are This article is being published 1–4 in Kidney International and kidney disease (CKD) many years later. currently limited, though increasing in scope. reprinted concurrently in Furthermore, CKD in childhood, much of it The prevalence of CKD in childhood is rare— several journals. The articles congenital, and complications from the many and has been variously reported at 15 to 74.7 are identical except for minor nonrenal diseases that can affect the kidneys per million children.3 Such variation is likely stylistic and spelling changes secondarily, not only lead to substantial because data on CKD are influenced by in keeping with each journal’s style. Any of these versions morbidity and mortality during childhood, but regional and cultural factors, as well as by the may be used in citing this also result in medical issues beyond childhood methodology used to generate them. The article. (Figure 1). Indeed, childhood deaths from a World Health Organization has recently added

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Figure 1 | The types and risks of kidney disease change across the life cycle. The contribution of number increases over the life cycle, in concert with events that provide direct insults and challenges to kidney health.

kidney and urologic disease to mortality in- Assessment of Worldwide Acute Kidney Injury, formation tracked worldwide and should be a Renal Angina and Epidemiology (AWARE) valuable source of such data over time, but the study, a 5-nation study of AKI in children are World Health Organization does not post the awaited.13 Single-center studies, as well as information by age group.5 Databases such as meta-analyses indicate that both AKI and CKD the North American Pediatric Renal Trials and in children account for a minority of CKD Collaborative Studies (NAPRTCS)6 the U.S. worldwide.2,3 However, it is increasingly Renal Data System (USRDS)7 and the Euro- evident that kidney disease in adulthood often pean Dialysis and Transplant Association springs from a childhood legacy. (EDTA) registry8 include data on pediatric end- stage renal disease (ESRD), and some on CKD. SPECTRUM OF PEDIATRIC KIDNEY DISEASES Projects such as the ItalKid9 and Chronic The conditions that account for CKD in child- Kidney Disease in Children (CKiD)10 studies, hood, with a predominance of congenital and the Global Burden of Disease Study 2013, as hereditary disorders, differ substantially from well as registries that now exist in many those in adults. To date, mutations in >150 genes countries provide important information, and 11 have been found to alter kidney development or more is required. 14 specific glomerular or tubular functions. Most of AKI may lead to CKD, according to selected these genetic disorders present during childhood, adult population studies.12 The incidence of andmanyleadtoprogressiveCKD.Congenital AKI among children admitted to an intensive anomalies of the kidney and urinary tract account care unit varies widely—from 8% to 89%.1 for the largest category of CKD in children (see The outcome depends on the available re- Table 2) and include renal hypoplasia/dysplasia sources. The results from projects such as the and obstructive uropathy. Important subgroups among the renal dysplasias are the cystic kidney Table 1 | Definitions of stages of early life diseases, which originate from genetic defects of ’ Perinatal period 22 Completed weeks of gestation to the tubuloepithelial cells primary cilia. Many pe- day 7 of postnatal life diatric glomerulopathies are caused by genetic or Neonatal period Birth to day 28 of postnatal life acquired defects of the podocytes, the unique cell Infancy Birth to 1 year of age type lining the glomerular capillaries. Less com- Childhood 1 Year of age to 10 years of age Adolescence 10 Years of age to 19 years of age mon but important causes of childhood CKD are The data in this table are as defined by the World Health Or- inherited metabolic disorders such as hyper- ganization. The perinatal period is defined as 22 completed oxaluria and cystinosis, and atypical hemolytic weeks of gestation to day 7 of life; the neonatal period as up to uremic syndrome, a thrombotic microangiopathy 28 days of life; infancy as up to 1 year of age; childhood as years 1 to 10; and adolescence from 10 years to age 19. related to genetic abnormalities of complement, There is variation worldwide in how these stages of early life are coagulation, or metabolic pathways. defined. Some would define “young people” as those age 24 or fi younger. In the , childhood is as a whole defined as In various classi cations, it is not clear how going to age 21. to categorize children who have suffered AKI

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Table 2 | Etiology of chronic kidney disease in children CKD ESRD etiology Percentage range etiology Percentage range

CAKUT 48–59 CAKUT 34–43 GN 5–14 GN 15–29 HN 10–19 HN 12–22 HUS 2–6 HUS 2–6 Cystic 5–9 Cystic 6–12 Ischemic 2–4 Ischemic 2 CAKUT, congenital anomalies of the kidney and urinary tract; CKD, chronic kidney disease; ESRD, end-stage renal disease; GN, glomerulonephritis; HN, hypertension; HUS, hemolytic uremic syndrome. Rare causes include congenital , meta- bolic diseases, and cystinosis. Miscellaneous causes depend on how such entities are classified. Adapted from Harambat et al.2 CKD data are from North American Pediatric Renal Trials and Collaborative Studies NAPRTCS, the Italian Registry, and the Belgian Registry. ESRD data are from Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), Eu- ropean Society of Pediatric Nephrology/European Renal Association–European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry, U.K. Renal Registry, and the Japanese Registry.

and apparently recovered, or how and whether abnormalities are identified antenatally, which to include those children who have had peri- permits early intervention. However, in much natal challenges, likely resulting in a relatively of the world, children with structural abnor- low nephron number. malities are not identified until much later, Among children with childhood-onset when symptoms develop. Although generalized ESRD, glomerulopathies are slightly more and screening for proteinuria, , and congenital anomalies less common (Table 2) urinary tract infections are carried out in due to the typically more rapid nephron loss in some countries and regions, there is a lack of glomerular disease. However, recent evidence consensus as to its effectiveness. However, there suggests that many patients with milder forms is general agreement that children with ante- of congenital anomalies of the kidney and natal ultrasonogram studies that indicate urinary tract may progress to ESRD during possible genitourinary anomalies; children adulthood, peaking in the fourth decade of with a family history of kidney disease; and life.15 children with signs such as failure to thrive or a There are national and regional differences in history of , voiding the types and course of both AKI and CKD dysfunction, or an abnormal appearing during childhood and beyond. Death from should be examined. Initial screening would kidney disease is higher in developing nations, include a focused physical examination and a and national and regional disparities in care and urine dipstick, formal urinalysis, and a basic outcome must be addressed. Furthermore, ac- chemistry panel, followed by a more focused cess to care is variable, depending on the region, evaluation if indicated. the country and its infrastructure. By focusing Depending on the diagnosis, definitive ther- on kidney disease in childhood, cost-effective apy may be indicated. However, the evidence solutions may be reached, as treating disease that therapy will slow progression of CKD in early and pre-emptively may prevent later, more childhood remains limited. Angiotensin- advanced CKD. Expectations depend on the converting enzyme inhibitors, angiotensin availability of care and management. Treating receptor blockers, antioxidants, and, possibly, children, even from infancy, who have AKI and dietary changes may be indicated, depending on CKD that requires renal replacement therapy the diagnosis. However, dietary changes need to (RRT) can be effective in mitigating the burden permit adequate growth and development. The of kidney disease in adulthood. Doing so Evaluation Study of Congestive Heart Failure requires resources that focus on the most and Pulmonary Artery Catheterization Effec- expeditious and cost-effective ways to deliver tiveness (ESCAPE) trial provided evidence that acute RRT in childhood. strict blood pressure control retards progression of CKD in children irrespective of the type of 16 CONGENITAL KIDNEY DISEASE AND underlying kidney disease. DEVELOPMENTAL ORIGINS OF HEALTH Some very young children may require RRT AND DISEASE, RENAL ENDOWMENT, AND in early infancy. Recent data pooled from reg- IMPLICATIONS istries worldwide indicate good survival, even In regions where antenatal fetal ultrasonograms when dialysis is required from neonatal age.2,17 are routine, many children with urologic , the preferred RRT in

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children, is generally suitable after 12 months treat AKI when it occurs. This ongoing project of age, with excellent patient and allograft in Sub-Saharan Africa and South East Asia, survival, growth, and development. in which 4 kidney foundations participate Evidence is accumulating that childhood- equally (International Pediatric Nephrology onset CKD leads to accelerated cardiovascular Association, ISN, International Society for morbidity and shortened life expectancy. Peritoneal Dialysis, Sustainable Kidney Care Ongoing large prospective studies such as the Foundation), focuses on establishing and Cardiovascular Comorbidity in Children with maintaining centers for the care of AKI, CKD (4C) study are expected to inform about including the provision of acute peritoneal the causes and consequences of early cardio- dialysis. It links with the ISN’s0by25project, in children with CKD.18 which calls on members to ensure by 2025 In addition to those children with congen- that nobody dies from preventable and acute ital kidney disease, it is now known that kidney injury. perinatal events may affect future health in the In view of the preponderance of congen- absence of evident kidney disease in early ital and hereditary disorders, therapeutic life.19 Premature infants appear to be partic- resources for children with CKD have his- ularly at risk for kidney disease long after they torically been limited to a few immunolog- are born, based both on observational cohort ical conditions. Very recently, progress in studies, as well as on case reports. Increasingly drug development in concert with advances premature infants survive, including many in genetic knowledge and diagnostic capa- born well before nephrogenesis is complete.20 bilities has begun to overcome the long- Thelimiteddataavailableindicatethatinthe standing “therapeutic nihilism” in pediatric process of neonatal intensive care unit care, kidney disease. Atypical hemolytic uremic such babies receive many nephrotoxins, and syndrome, long considered ominous, with a that those dying prior to discharge from the high likelihood of progression to ESRD and nursery have fewer and larger glomeruli.21 posttransplantation recurrence, has turned Additionally, those surviving have evidence into a treatable condition—with the advent of renal impairment that may be subtle.22 Even of a monoclonal antibody that specifically more concerning, abundant epidemiologic blocks C5 activation.24 Another example is data indicate that persons born at term but the use of vasopressin receptor antagonists to with relatively low birth weights may be at retard cyst growth and preserve kidney high risk for hypertension, albuminuria, and function in polycystic kidney disease.25 First CKD in later life.23 When direct measurements proven efficacious in adults with autosomal are pursued, such persons, as adults, may dominant polycystic kidney disease, therapy have fewer , thus a low cardiorenal with vaptans holds promise also for the endowment. recessive form of the disease, which presents In focusing on children for World Kidney and often progresses to ESRD during Day, we would note that it is key to follow childhood. kidney function and blood pressure throughout However, patient benefit from pharmaco- life in those persons born early or small-for- logical research breakthroughs is jeopardized date. By doing so, and avoiding nephrotoxic on a global scale by the enormous cost of some throughout life, it may be possible of the new therapeutic agents. The quest for to avert CKD in many people. affordable innovative therapies for rare diseases will be a key issue in pediatric nephrology in RESOURCES AND THERAPEUTICS FOR the years to come. CHILDREN—DIFFERENCES FROM The identification of children likely to THERAPEUTICS IN ADULTS benefit from novel therapeutic approaches will Disparities exist in the availability of resources be greatly facilitated by the development of to treat AKI in children and young people; clinical registries that inform about the natural consequently, too many children and young disease course, including genotype-phenotype adults in developing nations succumb if AKI correlations. Apart from disease-specific data- occurs. To address the problem, the ISN has bases, there is also a need for treatment-specific initiated the Saving Young Lives Project, which registries. These are particularly relevant in aims both to prevent AKI with prompt treat- areas where clinical trials are difficult to ment of infection and/or delivery of appro- perform due to small patient numbers and priate fluid and electrolyte therapy, and to lacking industry interest, as well as for therapies

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in need of global development or improve- Importantly, transition may need to be ment. For instance, there is currently a large slowed, paused, or even reversed temporarily international gradient in the penetration and during crises such as disease flares or progres- performance of pediatric dialysis and trans- sion, or if family or societal instability occurs. A plantation. Whereas pediatric patient and recent joint consensus statement by the ISN technique survival rates are excellent and even and International Pediatric Nephrology Asso- superior to those of adults in many industri- ciation proposed steps consistent with the alized countries, it is estimated that almost one- points just outlined, aiming to enhance the half of the world’s childhood population is not transition of care in kidney disease in clinical offered chronic RRT at all. Providing access to practice.29,30 RRT for all children will be a tremendous future challenge. To obtain reliable information CALL FOR GENERATING FURTHER on the demographics and outcomes of pediat- INFORMATION AND ACTION ric RRT, the International Pediatric Nephrology Given vulnerabilities of children with kidney Association is about to launch a global disease including impact on growth and population-based registry. If successful, the development and future life as an adult, and International Pediatric Nephrology Association given the much greater proportion of children RRT registry might become a role model for in developing nations facing resource con- global data collection. straints educating everyone involved is imperative in order to realign communica- TRANSITION FROM PEDIATRIC TO ADULT CARE tions and actions.31,32 These efforts should Transition of care for adolescents with kidney foster regional and international collabora- disease into an adult setting is critical both tions and exchange of ideas among local for patients and their caregivers. Nonadherence kidney foundations, professional societies, is a too-frequent hallmark of transition from other not-for-profit organizations, and states pediatric to adult care for young patients with and governments, so as to help empower all – chronic disease states.26 28 Hence, considered stakeholders to improve the health, well- steps combined with systematically defined being, and quality of life of children with procedures supported by validated pathways kidney diseases and to ensure their longevity and credible guidelines must be in place to into adulthood. ensure successful outcomes. Until recently, however, the World Health In the process of change from pediatric to Organization consensus statement on non- adult care, “transition,” which should occur communicable diseases (NCDs) included car- gradually, must be distinguished from “trans- diovascular disease, , diabetes, and fer,” which is often an abrupt and mechanistic chronic respiratory disease, but not kidney change in provider setting. Introducing the disease.33,34 Fortunately, due, in part, to a global concept of transition should be pre-emptive, campaign led by the ISN, the Political Decla- starting months to years prior to the targeted ration on NCDs from the U.N. Summit in 2011 time, as children move into adolescence and mentioned kidney disease under Item 19.35 adulthood. The ultimate goal is to foster a Increasing education and awareness about strong relationship and individualized plan in renal diseases in general and kidney disease in the new setting that allows the patient to feel childhood in particular is consistent with the comfortable enough to report nonadherence objectives of the World Health Organization to and other lapses in care. reduce mortality from NCD with a 10-year A transition plan must recognize that the target population–level initiatives focusing on emotional maturity of children with kidney changes in lifestyle (including tobacco use disease may differ widely. Assessment of the reduction, salt intake control, dietary energy caregiver and the family structure as well as control, and alcohol intake reduction) and cultural, social, and financial factors at the time effective interventions (including blood pres- of transition are key, including a realistic sure, cholesterol, and glycemic control). assessment of caregiver burden.4 The appro- Heightened efforts are needed to realign and priate timing and format of transition may vary expand these multidisciplinary collaborations widely among different patients and in different with more effective focus on early detection settings; therefore, a flexible process without a and management of kidney disease in children. set date and even without a delineated format Whereas the issues related to kidney disease may be preferred. may be overshadowed by other NCDs with

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apparently larger public health implications with congenital malformations of the kidney and urinary tract. Clin J Am Soc Nephrol. 2013;8:67–74. such as diabetes, cancer, and cardiovascular 16. Wuhl E, Trivelli A, Picca S, et al., for the ESCAPE Trial diseases, our efforts should also increase edu- Group. Strict blood-pressure control and progression cation and awareness on such overlapping of renal failure in children. N Engl J Med. 2009;361: – conditions as cardiorenal connections, the 1639 1650. 17. van Stralen KJ, Borzych-Duzalka_ D, Hataya H, et al. global nature of the CKD and ESRD as major Survival and clinical outcomes of children starting NCDs, and the role of kidney disease as the renal replacement therapy in the neonatal period. – multiplier disease and confounder for other Kidney Int. 2014;86:168 174. 18. Querfeld U, Anarat A, Bayazit AK, et al., for the 4C NCDs. White papers including consensus arti- Study Group. The Cardiovascular Comorbidity in cles and blueprint reviews by world class Children with Chronic Kidney Disease (4C) study: experts can serve to enhance these goals.36 objectives, design, and methodology. Clin J Am Soc Nephrol. 2010;5:1642–1648. 19. Hoy WE, Ingelfinger JR, Hallan S, et al. The early REFERENCES development of the kidney and implications 1. Goldstein SL. Acute kidney injury in children and its for future health. JDevOrigHealthDis. 2010;1: potential consequences in adulthood. Blood Purif. 216–233. 2012;33:131–137. 20. Flynn JT, Ng DK, Chan GJ, et al., for the Chronic Kidney 2. Harambat J, van Stralen KJ, Kim JJ, Tizard EJ. Disease in Children Study. The effect of abnormal birth Epidemiology of chronic kidney disease in children. history on ambulatory blood pressure and disease Pediatr Nephrol. 2012;27:363–373. progression in children with chronic kidney disease. 3. Warady BA, Chadha V. 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factors and progression to chronic kidney disease. APPENDIX J Paediatr Child Health. 2010;46:504–509. Members of the World Kidney Day Steering 33. Zarocostas J. Need to increase focus on non- Committee are Philip Kam Tao Li, Guillermo Garcia- communicable diseases in global health, says WHO. fi BMJ. 2010;341:c7065. Garcia, William G. Couser, Timur Erk, Julie R Ingel nger, 34. Gulland A. WHO agrees to set up body to act on non- Kamyar Kalantar-Zadeh, Charles Kernahan, communicable diseases. BMJ. 2013;346:f3483. Charlotte Osafo, Miguel C. Riella, Luca Segantini, and 35. Feehally J. Chronic kidney disease: health burden of Elena Zakharova. The 4 partners are (in alphabetical kidney disease recognized by UN. Nat Rev Nephrol. order) the IPNA (International Pediatric Nephrology – 2011;8:12 13. Association), ISN (International Society of 36. Couser WG, Remuzzi G, Mendis S, Tonelli M. The contribution of chronic kidney disease to the global Nephrology), ISPD (International Society for Perito- burden of major noncommunicable diseases. Kidney neal Dialysis), and SKCF (Sustainable Kidney Care Int. 2011;80:1258–1270. Foundation).

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