Abstract 4362955: Polygenic Risk Score Associated With Kidney Disease Progression In Patients With Cardiometabolic Risk Factors

Background: Chronic kidney disease (CKD) is associated with significant morbidity and mortality, especially in patients with concurrent heart disease who share many similar risk factors. Recent studies support a polygenic contribution to CKD, suggesting that a polygenic risk score (PRS) may have utility in predicting clinically significant progression of kidney disease. Methods: All patients who consented for genetic testing in 3 large TIMI clinical trials (SAVOR, FOURIER, DECLARE) were included in the study. Pts were binned as high (top 20%), intermediate, or low (bottom 20%) genetic risk using a genome-wide PRS developed to predict CKD in a diverse population (Mandla et al., 2024, Wuttke et al., 2019). A Cox model was used to calculate adjusted hazard ratios (aHR) across genetic risk groups for a 3-point renal composite outcome (eGFR decrease ≥40%, end-stage renal disease, or renal death). HRs were adjusted for age, sex, genetic ancestry, HTN, DM, CAD, PAD, smoking, and hyperlipidemia. Results: Of 35,182 pts across the 3 trials, 514 (1.46%) had a composite renal outcome over 2.5-yrs median follow-up with Kaplan-Meier event rates for those in low, intermediate, and high genetic risk groups of 0.83% (n=76), 1.05% (n=283), 1.59% (n=147), respectively ( p-trend <0.001). After adjustment for clinical risk factors, the PRS was independently associated with an aHR (per 1-SD) for the composite renal outcome of 1.17 (95% CI, 1.10-1.26, p<0.001). The PRS predicts risk of the composite renal outcome across the range of baseline eGFRs (Fig. 1). Notably, the PRS was associated with an enhanced ability to predict for the renal composite outcome in patients with eGFR <60 (aHR per 1-SD of 1.23 [1.10-1.38], p <0.001) compared to 1.11 [1.02-1.22, p =0.0196] in patients with eGFR≥60 ( p-heterogeneity =0.03). Indeed, in patients with at least CKD stage 3B (eGFR <45), the absolute excess risk of the renal composite outcome in patients with high vs. low genetic risk over 2.5 yrs was 4.36% compared to 0.30% in high vs. low genetic risk patients with CKD stage 2B or better (eGFR ≥60). Conclusions: A kidney disease PRS, when added to clinical risk factors, improves the prediction of developing clinically significant renal disease. The absolute risk excess was largest in patients with pre-existing CKD and therefore may be a useful risk marker for disease progression.