Developmental Origins of Kidney Function in Early Life and Environmental Risks

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Project Summary NYU School of Medicine, Rush University Medical Center and New York State Department of Health respond to PA-19-056, proposing to study developmental origins of kidney function in early life and environmental risks. The incidence of chronic kidney disease (CKD) is steadily rising and synthetic chemicals are increasingly understood to contribute to acute and chronic kidney injury. Case-control studies of populations with high incidence rates have identified pesticide and herbicide exposures as risks, raising the question whether developmental exposures may be even more impactful. Our own studies of children with CKD (R01DK100307) have revealed modest declines in kidney function with increasing phthalate and bisphenol exposures, accompanied by increases in oxidative stress. However, these findings do not contribute to our understanding of the origin of CKD. A major limitation is the failure of our and other studies to account for the developmental biology of the kidney and strong influence of perinatal/infant factors. The premise of the present proposal is that intrauterine inflammatory processes disrupt nephrogenesis and that environmental chemicals also impair renal parenchymal growth longitudinally during gestation and postnatal development via oxidant stress. We further interrogate this hypothesis by examining phthalates, bisphenols, glyphosate and organophosphate (OP) pesticides as modifiable risks. We will test these hypotheses in the New York University Children's Health and Environment Study, one of the participating cohorts in the NIH Environmental Influences and Child Health Outcomes Program (UH3OD023305). The proposed work builds upon our experience with postnatal renal sonographic measurement, which we will add prospectively to the existing, funded follow up. The approach is cost-efficient, leveraging existing measures for three exposure categories in pregnancy and infancy and available biospecimens to measure soluble urokinase-type plasminogen activator receptor, an emerging marker of kidney injury and development, and glyphosate. The MPIs (Trasande and Trachtman) are highly complementary, coupling experts in children's environmental health with nephrology who have a track record of productive MPI partnership in R01DK100307, which produced preliminary data in support of the proposed work. Analyses will be performed by K. Kannan at Wadsworth Laboratories of the New York State Department of Health, who has deep experience with precise measurement of glyphosate and metabolites in urine. In contrast to many known CKD risks which are not amenable to modification or avoidance, pesticides and herbicides can be reduced by consuming organic foods while phthalates and bisphenols can be reduced by avoiding canned and processed foods. The proposed work has the potential to shift the paradigm of origins of CKD to focus needed attention on its developmental origins.