The P.K56M Variant and Risk of Heart Failure in Chronic Kidney Disease: the Chronic Renal Insufficiency Cohort Study

Background: Intercellular adhesion molecule-1 (ICAM-1) is a cell-surface protein that facilitates inflammation through leucocyte adhesion. Approximately 35% of Black individuals carry at least one copy of an missense variant (rs5491; p.K56M), which has been associated with increased risk of heart failure (HF) with preserved ejection fraction (HFpEF). Whether the risk of HFpEF conferred by rs5491 extends to individuals with chronic kidney disease (CKD), a cohort at high risk for HF, is unknown.

Aims: We investigated the association between rs5491 and the incidence of HF in CKD.

Methods: We estimated associations of rs5491 with incident HF and HF subtypes among Black individuals who were free from HF at baseline in the Chronic Renal Insufficiency Cohort (CRIC). The CRIC study recruited individuals who were 21-74 years old with estimated glomerular filtration rate (eGFR) of 20-70 mL/min/1.73 m at baseline.

Results: Among 1267 Black participants (mean age 57±11 years, 51% female, mean eGFR 45±15 mL/min/1.73 m), 464 (37%) had at least one copy of rs5491. During a median follow-up of 10.3 years (IQR: 4.7-15.0 years), there were 309 incident overall HF hospitalisations (160 HFpEF, 111 HF with reduced ejection fraction (HFrEF) and 38 HF with unknown ejection fraction). Each additional rs5491 allele was significantly associated with incident HFpEF (HR 1.35, 95% CI 1.03 to 1.76, p=0.029). The rs5491 variant was not associated with incident overall HF (HR 1.14, 95% CI 0.93 to 1.39, p=0.20) or incident HFrEF (HR 0.76, 95% CI 0.53 to 1.10, p=0.15).

Conclusion: The p.K56M variant is specifically associated with increased risk of incident HFpEF among individuals with CKD.