Perfluoroalkyl substances exposure and kidney function decline in a community-based prospective cohort

Per- and polyfluoroalkyl substances (PFAS) are a large class of synthetic chemicals widely used in industrial and consumer applications, known for their environmental persistence, bioaccumulation, and potential toxicity. Mounting toxicological evidence suggests that the kidney is a primary target organ for PFAS accumulation, yet human data regarding compound-specific renal effects remain limited. In this community-based prospective cohort study, we investigated the associations between serum PFAS concentrations and renal outcomes in 257 adults, including 48 with chronic kidney disease (CKD) and 209 with normal kidney function at baseline. Baseline serum levels of eight PFAS were quantified: perfluorobutanesulfonic acid; perfluorohexanoic acid; perfluoroheptanoic acid; perfluorohexanesulfonic acid (PFHxS); perfluorooctanoic acid (PFOA); perfluorononanoic acid (PFNA); branched perfluorooctanesulfonic acid (Br-PFOS); and linear perfluorooctanesulfonic acid. Participants were followed for four years, with kidney outcomes assessed at three time points. The primary outcomes were: (1) incident chronic CKD, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m² or urinary albumin-to-creatinine ratio > 30 mg/g at any time during follow-up; and (2) kidney function decline, defined as a ≥ 15 % or ≥ 30 % reduction in eGFR from baseline. Key statistical analyses included multivariable regression and restricted cubic spline modeling to evaluate longitudinal associations. In baseline cross-sectional analysis, PFNA and Br-PFOS were significantly associated with lower eGFR (β = -23.7 and -34.9 mL/min/1.73 m² per log unit) and higher odds of CKD (OR, 6.2; 95 % CI, 1.57-24.83 and OR,2.3; 95 % CI, 1.13-4.60), while PFOA showed an inverse association (OR, 0.44; 95 % CI, 0.22-0.89). Over four years, Br-PFOS and PFHxS predicted greater eGFR decline. Spline and latent class analyses revealed a dose-dependent, compound-specific association. These findings underscore the importance of isomer-specific PFAS evaluation in human nephrotoxicity and support the integration of PFAS monitoring into environmental health surveillance and regulatory policy.