Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a common inflammatory condition of aging that causes myriad end-organ damage. We have recently shown associations for CHIP with acute kidney injury and with kidney function decline in the general population, with stronger associations for CHIP driven by mutations in genes other than DNMT3A (non-DNMT3A CHIP). Longitudinal kidney function endpoints in individuals with pre-existing chronic kidney disease (CKD) and CHIP have been examined in two previous studies, which reported conflicting findings and were limited by small sample sizes. Methods: In this study, we examined the prospective associations between CHIP and CKD progression events in four cohorts of CKD patients (total N = 5,772). The primary outcome was a composite of 50% kidney function decline or kidney failure. The slope of eGFR decline was examined as a secondary outcome. Mendelian randomization techniques were then used to investigate potential causal effects of CHIP on eGFR decline. Finally, kidney function was assessed in adenine-fed CKD model mice having received a bone marrow transplant recapitulating Tet2-CHIP compared to controls transplanted wild-type bone marrow. Results: Across all cohorts, the average age was 66.4 years, the average baseline eGFR was 42.6 ml/min/1.73m2, and 24% had CHIP. Upon meta-analysis, non-DNMT3A CHIP was associated with a 59% higher relative risk of incident CKD progression (HR 1.59, 95% CI: 1.02-2.47). This association was more pronounced among individuals with diabetes (HR 1.29, 95% CI: 1.03-1.62) and with baseline eGFR >= 30 ml/min/1.73m2 (HR 1.80, 95% CI: 1.11-2.90). Additionally, the annualized slope of eGFR decline was steeper among non-DNMT3A CHIP carriers, relative to non-carriers (Beta -0.61, SE 0.31 ml/min/1.73m2, p = 0.04). Mendelian randomization analyses suggested a causal role for CHIP in eGFR decline among individuals with diabetes. 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. Conclusion: Non-DNMT3A CHIP is a potentially targetable novel risk factor for CKD progression.

The authors have declared no competing interest.

Funding for the CRIC Study was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK; grants U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902 and U24DK060990). Funding for the ancillary CHIP study in CRIC was supported by R01DK125782. In addition, this work was supported in part by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award (National Institutes of Health/National Center for Advancing Translational Sciences [NIH/NCATS] UL1TR000003), Johns Hopkins University (UL1 TR-000424), University of Maryland (GCRC M01 RR-16500), Clinical and Translational Science Collaborative of Cleveland (UL1TR000439 from the NCATS component of the NIH and NIH roadmap for Medical Research), Michigan Institute for Clinical and Health Research (MICHR; UL1TR000433), University of Illinois at Chicago (CTSA UL1RR029879), Tulane COBRE for Clinical and Translational Research in Cardiometabolic Diseases (P20 GM109036), Kaiser Permanente (NIH/National Center for Research Resources [NCRR] UCSF-CTSI UL1 RR-024131), Department of Internal Medicine, University of New Mexico School of Medicine (R01DK119199). A portion of the data reported here have been supplied by the United States Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government. The dataset(s) used for the BioVU analyses described were obtained from Vanderbilt University Medical Centers BioVU which is supported by numerous sources: institutional funding, private agencies, and federal grants. These include the NIH funded Shared Instrumentation Grant S10RR025141, S10OD025092, and S10OD017985; and CTSA grants UL1TR002243, UL1TR000445, and UL1RR024975. Genomic data are also supported by investigator-led projects that include U01HG004798, R01NS032830, RC2GM092618, P50GM115305, U01HG006378, U19HL065962, R01HD074711; and additional funding sources listed at https://victr.vumc.org/biovu-funding/. This research was also supported by the National Institute of Diabetes and Digestive and Kidney Diseases (Grant R01DK132155 to C.R.C., B.K., R.H. and A.B.).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The ethics committees of Vanderbilt University Medical Center (#240462), University of Illinois Chicago (#STUDY2022-0735), and McMaster University (#2024-11298-AP) gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The CHIP calls for the observational cohorts will be released via Zenodo alongside publication of the paper.