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. 2025 Apr 9;36(9):1775-1785.
doi: 10.1681/ASN.0000000671.

Association of Clonal Hematopoiesis of Indeterminate Potential with Cardiovascular Events in Patients with CKD

Yang Pan  1 , Caitlyn Vlasschaert  2 , Varun Rao  1 , Elvis A Akwo  3 , James E Hixson  4 , Md Mesbah Uddin  5 , Zhi Yu  5   6 , Do-Kyun Kim  4 , Alexander Bick  7 , Bryan Kestenbaum  8 , Michael Chong  9   10 , Guillaume Paré  9   10 , Michael Rauh  11 , Adeera Levin  12 , James P Lash  1 , Manjula Kurella Tamura  13 , Debbie L Cohen  14 , Jiang He  15 , Lee Hamm  15 , Rajat Deo  16 , Zeenat Bhat  17 , Panduranga Rao  17 , Dawei Xie  18 , Pradeep Natarajan  5   6 , Tanika N Kelly  1 , Cassianne Robinson-Cohen  3   19 , Matthew B Lanktree  10   20   21 ; Canadian Study of Prediction of Death, Dialysis and Interim Cardiovascular Events (CanPREDDICT) and Chronic Renal Insufficiency Cohort (CRIC) Study Investigators
Collaborators, Affiliations

Association of Clonal Hematopoiesis of Indeterminate Potential with Cardiovascular Events in Patients with CKD

Yang Pan et al. J Am Soc Nephrol. .

Abstract

Key Points:

  1. In patients with CKD, non-DNMT3A clonal hematopoiesis of indeterminate potential (CHIP) was associated with higher risk of cardiovascular events.

  2. There was no significant difference in the CHIP–cardiovascular disease association based on baseline eGFR, diabetes status, or race.

  3. The protective effect of IL6R p.Asp358Ala on non-DNMT3A CHIP cardiovascular risk was similar to the general population.

Background: Patients with CKD are at higher risk of cardiovascular disease. Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with cardiovascular disease in the general population, with a causal role observed in animal models. In the general population, the effect of CHIP is greater for somatic mutations in predefined CHIP driver genes other than DNMT3A (referred to as non-DNMT3A CHIP). We sought to assess the prospective association between CHIP and cardiovascular events in patients with CKD.

Methods: CHIP was measured by high-depth targeted sequencing. The primary analysis tested the association of somatic mutations in non-DNMT3A CHIP driver genes with a composite cardiovascular disease end point of myocardial infarction, stroke, congestive heart failure, and peripheral artery disease in 5043 patients with CKD in four prospective cohorts. Sensitivity analyses examined the effect of CHIP subtypes, race, baseline comorbidities, APOL1 risk alleles, and IL6R p.Asp358Ala genotype.

Results: At baseline, patients had a mean age of 66±12 years and eGFR of 43±18 ml/min per 1.73 m2. CHIP was present in 24% of patients, with 13% of all patients carrying acquired non-DNMT3A mutations. Non-DNMT3A CHIP was associated with a 36% higher risk of the composite cardiovascular end point (95% confidence interval [CI], 6% to 76%). Among composite components, non-DNMT3A CHIP was associated with a higher risk of stroke (hazard ratio, 1.65; 95% CI, 1.10 to 2.47). Baseline eGFR, diabetes status, or race did not alter the association of non-DNMT3A CHIP with cardiovascular risk. Those without genetically reduced IL-6 signaling (noncarriers of IL6R p.Asp358Ala) had worse disease (hazard ratio, 1.46; 95% CI, 1.17 to 1.83; Psubgroup difference = 0.05).

Conclusions: In patients with CKD, non-DNMT3A CHIP was associated with cardiovascular disease with an effect size similar to that reported in the general population.

Keywords: biomarkers; cardiovascular disease; cardiovascular events; chronic inflammation; clinical epidemiology; epidemiology and outcomes; human genetics; risk factors.

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Conflict of interest statement

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/F159.

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