Clonal Hematopoiesis of Indeterminate Potential and Progression of CKD

Key Points Non- DNMT3A clonal hematopoiesis of indeterminate potential was associated with CKD progression in a meta-analysis of 5654 individuals with CKD. In an adenine-induced CKD mouse model, Tet2 -clonal hematopoiesis of indeterminate potential was linked to lower GFR, increased kidney inflammation, tubular injury, and fibrosis. 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). Previous 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 =5654): the Chronic Renal Insufficiency Cohort, the African American Study of Kidney Disease, individuals with CKD from the BioVU biorepository, and the Canadian Study of Prediction of Death, Dialysis and Interim Cardiovascular Events. 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 per 1.73 m 2 , and 24% had CHIP. After meta-analysis, non- DNMT3A CHIP was associated with a 64% higher relative risk of incident CKD progression (hazard ratio, 1.64; 95% confidence interval, 1.00 to 2.68), with the strongest effect observed in individuals with baseline eGFR 30–60 ml/min per 1.73 m 2 (hazard ratio, 1.85; 95% confidence interval, 1.18 to 2.90). Non- DNMT3A CHIP carriers also exhibited a faster eGFR decline ( β , −0.62±0.28 ml/min per 1.73 m 2 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. Furthermore, Tet2 -CHIP mouse models support a causal role in kidney injury.

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Publication Details

Journal
Journal of the American Society of Nephrology
Published
2025-04-09
DOI
https://doi.org/10.1681/asn.0000000680
Citations
14
Primary Topic
Myeloproliferative Neoplasms: Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
22.76
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article

Clonal Hematopoiesis of Indeterminate Potential and Progression of CKD

Yang Pan, Do-Kyun Kim, Md Mesbah Uddin, Alexander G. Bick et al.
14 citations
Journal of the American Society of Nephrology
Myeloproliferative Neoplasms: Diagnosis and Treatment
22.76
article

Clonal Hematopoiesis of Indeterminate Potential and Progression of CKD

Yang Pan, Do-Kyun Kim, Md Mesbah Uddin, Alexander G. Bick, Caitlyn Vlasschaert, Changwei Li, Dawei Xie, Zhi Yu, Shirong Cao, Bryan Kestenbaum, Jing He, Manjula Kurella Tamura, Raymond Clement Harris, Adeera Levin, Fenfen Peng, Matthew B. Lanktree, Pradeep Natarajan, Tanika N. Kelly, Debbie L. Cohen, Elvis A. Akwo, James E. Hixson, Guillaume Paré, Adriana M. Hung, James Phillip Lash, Jianchun Chen, Y. Wang, Michael J. Rauh, Michael Chong, Zeenat Bhat, Cassianne Robinson‐Cohen, Panduranga S. Rao, Ming‐Zhi Zhang, Jiang He, Mengdi Jiang, Varun Rao
article en
14 citations

Abstract

Key Points Non- DNMT3A clonal hematopoiesis of indeterminate potential was associated with CKD progression in a meta-analysis of 5654 individuals with CKD. In an adenine-induced CKD mouse model, Tet2 -clonal hematopoiesis of indeterminate potential was linked to lower GFR, increased kidney inflammation, tubular injury, and fibrosis. 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). Previous 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 =5654): the Chronic Renal Insufficiency Cohort, the African American Study of Kidney Disease, individuals with CKD from the BioVU biorepository, and the Canadian Study of Prediction of Death, Dialysis and Interim Cardiovascular Events. 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 per 1.73 m 2 , and 24% had CHIP. After meta-analysis, non- DNMT3A CHIP was associated with a 64% higher relative risk of incident CKD progression (hazard ratio, 1.64; 95% confidence interval, 1.00 to 2.68), with the strongest effect observed in individuals with baseline eGFR 30–60 ml/min per 1.73 m 2 (hazard ratio, 1.85; 95% confidence interval, 1.18 to 2.90). Non- DNMT3A CHIP carriers also exhibited a faster eGFR decline ( β , −0.62±0.28 ml/min per 1.73 m 2 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. Furthermore, Tet2 -CHIP mouse models support a causal role in kidney injury.

Journal of the American Society of NephrologyVol. 36(9)
Broad Institute (US), Tulane University (US), University of British Columbia (CA), University of Illinois Urbana-Champaign (US), Illinois College (US), University of Washington (US), Queen's University (CA), Population Health Research Institute (CA), University of Illinois Chicago (US), Massachusetts General Hospital (US), Michigan Medicine (US), Thrombosis and Atherosclerosis Research Institute (CA), Impact (CA), University of Pennsylvania (US), Vanderbilt University Medical Center (US), The University of Texas Health Science Center at Houston (US), Stanford University (US), McMaster University (CA)
Good health and well-being
Openalex Percentile: Top 0%
Myeloproliferative Neoplasms: Diagnosis and Treatment
22.76
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