Clonal Hematopoiesis of Indeterminate Potential and Kidney Function Decline in the General Population

Abstract

Rationale & objective: Clonal hematopoiesis of indeterminate potential (CHIP), defined by the age-related ontogenesis of expanded leukemogenic variants indicative of a genetically distinct clonal leukocyte population, is associated with risk of hematologic malignancy and cardiovascular disease. In experimental models, recapitulation of CHIP promotes kidney interstitial fibrosis with direct tissue infiltration of donor macrophages. We tested the hypothesis that CHIP is associated with kidney function decline in the general population.

Study design: Cohort study.

Setting & participants: 12,004 individuals from 3 community-based cohorts in the TOPMed Consortium.

Exposure: CHIP status from whole-genome sequences obtained from DNA extracted from peripheral blood.

Outcome: Risk of 30% decline in estimated glomerular filtration rate (eGFR) and percent eGFR decline per year during the follow-up period.

Analytical approach: Cox proportional hazards models for 30% eGFR decline end point and generalized estimating equations for annualized relative change in eGFR with meta-analysis. Study-specific estimates were combined using fixed-effect meta-analysis.

Results: The median baseline eGFR was 84mL/min/1.73m². The prevalence of CHIP was 6.6%, 9.0%, and 12.2% in persons aged 50-60, 60-70, and>70 years, respectively. Over a median follow-up period of 8 years, for the 30% eGFR outcome 205 events occurred among 1,002 CHIP carriers (2.1 events per 100 person-years) and 2,041 events in persons without CHIP (1.7 events per 100 person-years). In meta-analysis, CHIP was associated with greater risk of a 30% eGFR decline (17% [95% CI, 1%-36%] higher; P=0.04). Differences were not observed between those with baseline eGFR above or below 60mL/min/1.73m², of age above or below 60 years, or with or without diabetes.

Limitations: Small number of participants with moderate-to-advanced kidney disease and restricted set of CHIP driver variants.

Conclusions: We report an association between CHIP and eGFR decline in 3 general population cohorts without known kidney disease. Further studies are needed to investigate this novel condition and its potential impact among individuals with overt kidney disease.

Keywords: Albuminuria; DNMT3A; TET2; cancer driver genes; chronic kidney disease (CKD); clonal hematopoiesis of indeterminate potential (CHIP); eGFR decline; estimated glomerular filtration rate (eGFR); mutation; older adults; renal function; whole-genome sequencing.