Associations Between Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Disease in Three Prospective CKD Patient Cohorts

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Background: Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by the clonal expansion of blood cells carrying somatic mutations to specific driver genes. Although CHIP has been established as an important contributor to cardiovascular diseases (CVD) in the general population, its association with CVD in a pro-inflammatory chronic kidney disease (CKD) setting has not been examined. Methods: We examined prospective associations between CHIP status and CVD events in three cohorts that included a total of 3,414 CKD patients: the Chronic Renal Insufficiency Cohort (CRIC), the African American Study of Kidney Disease (AASK), and the Canadian study of prediction of death, dialysis and interim cardiovascular events (CanPREDDICT). Primary analyses tested associations between CHIP status and a composite CVD endpoint of myocardial infarction (MI), stroke, congestive heart failure (CHF), or peripheral artery disease (PAD). Cox proportional hazards regression models were used, adjusting for demographic, lifestyle, and clinical covariables, including cardiovascular risk factors. Secondary analyses investigated individual CVD endpoints. Random-effect meta-analyses were employed to combine effects across studies. Results: Study participants had an average age of 68.8 years and a mean eGFR of 40.2 ml/min/1.73m2. As expected, participants had a high frequency of hypertension (95%) and diabetes (49%), with CHIP identified in 25% of participants. Those with large CHIP clone size (VAF≥10%) and a non-DNMT3A CHIP gene mutation exhibited 38% (95% CI:2%-85%) and 42% (95% CI: 6%-90%) higher risks of the composite CVD endpoint, respectively, compared to noncarriers. Compared to non-CHIP status, large clone size was further associated with incident CHF (HR: 1.53, 95% CI: 1.13-2.00). Conclusions: CHIP carrier status may be an important risk factor for CVD among CKD patients, with associations mirroring those observed in the general population. Funding: NIDDK Support, Government Support - Non-U.S.

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