PFAS Exposure and Diabetic Kidney Disease in Youth with Type 2 Diabetes: A Multi-Omic Approach for Prevention and Treatment - PROJECT SUMMARY / ABSTRACT Over 50% of youths with type 2 diabetes (Y-T2D) develop diabetic kidney disease (DKD) during adolescence, increasing the risk of early dialysis and death. Latinx and African American youth are disproportionately affected but under-studied, and current treatment options for T2D in adolescents, projected to dramatically increase over the coming decades, are limited. Thus, it is critically important to identify modifiable risk factors and novel therapeutic approaches for preventing DKD in youth. Our strong preliminary data links per- and polyfluoroalkyl substances (PFAS), a group of ubiquitous artificial chemicals used for more than 60 years in consumer and industrial products, with kidney injury in proximal tubules in Y-T2D, a key component of DKD. PFAS toxicity in proximal tubules may be partly due to organic anion transporters (OATs) localized to these cells; Tubular OATs reabsorb PFAS from urine filtrate, concentrate PFAS in tubular cells, and decrease renal PFAS clearance, potentially amplifying PFAS associated nephrotoxicity. Our overarching biological hypothesis, supported by our preliminary data, is that PFAS increases tubular injury and DKD risk and that decreasing OAT reabsorption in proximal tubules may mitigate this risk. This first of its kind study will examine this hypothesis by building on existing data in two independent, meticulously phenotyped, longitudinal cohorts of youth with T2D of predominantly Latinx or African American race/ethnicity. To identify associations and potential therapeutic targets, we will leverage the NIDDK-funded Renal Hemodynamics, Energetics, and Insulin Resistance in Youth Onset Type 2 Diabetes Study (Renal-HEIR/HEIRitage). This study has existing measures of OAT activity measured using single cell RNA sequencing from kidney biopsies at baseline and gold-standard PAH clearance, a measure of tubular OAT function, in addition to existing outcome data, including tubular injury biomarkers, albuminuria, and hyperfiltration at both visits. To examine associations in a larger cohort with annual visits and longer follow-up duration, we will leverage the NIH/NIDDK funded TODAY/TODAY2 study, the largest longitudinal cohort of youth with T2D with comprehensive measures of kidney function (e.g., annual visits for 15 years) with the same outcomes as Renal-HEIR. In both cohorts, we will assess PFAS exposure and clearance by measuring longitudinal serum PFAS and urine PFAS at baseline; we will assess biomarkers of OAT function in urine and plasma and address reverse causality using pharmacokinetic (PK) models. We will use innovative statistical approaches, including a latent unknown factor analysis to identify how OAT activity associates with changes in PFAS over time, and a novel causal inference and mediation framework based on latent factors to examine whether decreases in OAT activity, induced by sodium/glucose cotransporter-2 inhibitors, decrease the risk of DKD via alterations in renal PFAS clearance. This groundbreaking study will deepen our understanding of the interplay between OATs, PFAS, and DKD in youth with T2D and inform targeted clinical interventions to prevent PFAS associated DKD, particularly in marginalized communities.
