The NINOS cohort: Children's Kidney Health in a High-Risk Region for CKDu

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PROJECT SUMMARY/ABSTRACT MesoAmerican Nephropathy (MeN) is a leading cause of death in Central America, resulting in more than 20,000 deaths in the last 20 years. Despite a decade of research on risk factors, including heat and subsequent dehydration, infectious diseases, chemical exposures, medications and diet, the causes of this devastating disease remain unclear. The majority of affected individuals are young men working in agricultural industries, notably sugarcane. Unlike chronic kidney disease (CKD) in other parts of the world, MeN is characterized by early onset, with patients diagnosed in the 20s or younger. Our Boston University research team, which has led MeN research in Central America since 2009, has identified evidence of kidney injury and renal function decline among youth in the region, including elevated prevalence of low eGFR and evidence of hyperfiltration and urinary biomarkers of kidney injury, both of which may indicate early kidney disease. Our preliminary data leads us to hypothesize that early life, nephrotoxic exposures contribute to kidney injury and renal function decline, and that these exposures increase susceptibility to MeN following occupational exposures later in life. In 2016 (baseline), our team recruited and enrolled over 800 youth in Nicaragua, ages 7-18 years, to set the foundation for a longitudinal cohort of children, adolescents and young adults (the “NIÑOS” cohort). In this R01, we propose to initiate follow up with these youth, who will be 12-28 years of age at the start of the study, for a 36-month period. The goals of this study are to: 1) characterize renal function during youth and young adulthood (annualized change in eGFR) in Nicaragua, a region of high-risk for MeN; 2) use high-throughput proteomic analysis, including >180 proteins, to develop a predictive biomarker of elevated annualized decline in eGFR over time; 3) establish the association between a broad spectrum of chemicals and heavy metals with annualized change in eGFR, using standard and “mixtures” analytic techniques; 4) conduct a multichemical exposome analysis, including >1500 chemicals, using silicone wristbands to broadly evaluate the association between personal chemical exposure and renal function; and 4) assess the association between exposure to heat and renal function in youth using personal heat exposure monitoring. This project would provide the most comprehensive account to date of renal function and environmental exposures among a population at high risk of MeN before disease onset, providing critically important etiologic inferences. Chronic kidney disease of unknown origin is a global public health crisis, with concurrent epidemics in Sri Lanka, Egypt, and India, as well as throughout Central America. This study will inform international efforts to understand this phenomenon and reduce incidence.