Clonal Hematopoiesis of Indeterminate Potential and Progression of CKD.

BACKGROUND Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. CHIP has been associated with incident AKI and kidney function decline in the general population, particularly mutations in CHIP genes other than DNMT3A (termed non-DNMT3A CHIP). Prior studies of CHIP in individuals with CKD had limited sample sizes and conflicting findings. METHODS We examined CHIP and CKD progression in four CKD cohorts (N = 5,654): the Chronic Renal Insufficiency Cohort (CRIC), the African American Study of Kidney Disease (AASK), individuals with CKD from the BioVU biorepository, and the Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT).Primary outcomes were incident CKD progression (50% eGFR decline or kidney failure), and eGFR slope over time. In addition, kidney function and pathology were assessed in a Tet2-CHIP mouse model of CKD induced by dietary adenine. RESULTS Across all cohorts the average age was 66 ± 11 years, with an average baseline eGFR of 43 ± 15 ml/min/1.73m2, and 24% had CHIP. After meta-analysis, non-DNMT3A CHIP was associated with a 64% higher relative risk of incident CKD progression (hazard ratio [HR] 1.64; 95% confidence interval [CI], 1.00-2.68), with the strongest effect observed in individuals with baseline eGFR 30-60 ml/min/1.73m2 (HR 1.85, 95% CI: 1.18-2.90). Non-DNMT3A CHIP carriers also exhibited a faster eGFR decline (β, -0.62 ± 0.28 ml/min/1.73m2 per year; P = 0.03). In a dietary adenine mouse model of CKD, Tet2-CHIP was associated with lower GFR as well as greater kidney inflammation, tubular injury, and tubulointerstitial fibrosis. CONCLUSIONS Non-DNMT3A CHIP was associated with CKD progression among individuals with CKD. Further, Tet2-CHIP mouse models support a causal role in kidney injury.