Supplemental Material for: High-sensitivity C-Reactive Protein as a Risk-Enhancing Biomarker in Patients with Chronic Kidney Disease and Atherosclerotic Cardiovascular Disease: A Narrative Review

Abstract

Background: Patients with chronic kidney disease (CKD) have a >10-fold higher risk of cardiovascular mortality than the general population, influenced by both traditional and non-traditional risk factors. Residual cardiovascular risk persists despite effective lipid lowering and antihypertensive treatment, suggesting that inflammation-driven mechanisms have been neglected. High-sensitivity C-reactive protein (hs-CRP) as a sensitive marker of systemic low-grade inflammation is a recognized risk-enhancing biomarker in atherosclerotic cardiovascular disease (ASCVD), but its precise role, optimal thresholds, and therapeutic relevance in concomitant CKD-ASCVD remain poorly synthesized.Summary: PubMed/MEDLINE, Scopus and EMBASE (January 1989–March 2026) were searched to consolidate evidence on hs-CRP in CKD-ASCVD from mechanistic, epidemiological, and clinical trials. Data supports a bidirectional cardiorenal axis: progressive CKD elevates hs-CRP by uremic toxin-induced interleukin-6 (IL-6), nuclear factor kappa-B (NF-κB) activation, atherosclerosis, while high hs-CRP aggravates renal deterioration by CD32b-Smad3-transforming growth factor beta 1 (TGF-β1) related tubulointerstistial fibrosis. hs-CRP >3 mg/L nearly doubles heart failure risk in CKD. Cumulative exposure increases the risk of developing CKD by 70% (hazard ratio [HR] 1.70) and cardiovascular mortality by up to three-fold. CKD-specific recalibration needed for standard thresholds (<1, 1–3, >3 mg/L). Novel anti-inflammatory agents, colchicine and ziltivekimab, reduce hs-CRP by 77–92% and lower cardiovascular events in general ASCVD populations, but advanced CKD evidence remains limited with outcome trials ongoing. Key Messages: hs-CRP is a marker of a pathogenic bidirectional cardiorenal loop, independently associated with cardiovascular events, CKD progression, and death, beyond LDL-cholesterol and traditional risk factors. Serial hs-CRP monitoring as a continuous measure may be superior to threshold-based categorization, pending CKD-specific validation. IL-1β/IL-6 pathway inhibitors and colchicine are promising for residual inflammatory risk but hs-CRP itself is not validated as a direct therapeutic target.