High sensitivity C-reactive protein and the risk of cardio-kidney outcomes in adults with moderate to severe chronic kidney disease: a nationwide study

BACKGROUND AND HYPOTHESIS: The burden and prognostic significance of inflammation in chronic kidney disease (CKD) remains poorly characterized, with prior studies yielding conflicting estimates of the association between elevated high-sensitivity C-reactive protein (hsCRP) and cardio-kidney outcomes. METHODS: Observational nationwide study of 23,008 adults with CKD stages 3-5 attending nephrology care and enrolled in the Swedish Renal Registry (2008-2023). Inflammation was assessed longitudinally via 94,500 repeated hsCRP registrations. Time-varying, cause-specific Cox models accounting for competing risks estimated associations with study outcomes, which included major adverse cardiovascular events (MACE), heart failure (HF) hospitalization, acute kidney injury (AKI), kidney failure requiring replacement therapy (KFRT) and all-cause mortality. Pre-defined stratifiers were atherosclerotic cardiovascular disease (ASCVD) history and CKD stage. RESULTS: Mean age was 71 years, 65% were male, and median estimated glomerular filtration rate was 25 mL/min/1.73 m². Median hsCRP was 4.0 (IQR 1.9-7.0) mg/L, and 75% of participants had hsCRP≥2. Over median 3.9 (IQR 2.0-6.7) years, hsCRP ≥2 mg/L was associated with higher rates of all outcomes: hazard ratio 1.20 (95% confidence interval 1.12-1.28) for MACE (n=5,480 events); 1.29 (1.22-1.37) for HF hospitalization (n=8,173); 1.28 (1.18-1.38) for AKI (n=3,943); 1.09 (1.02-1.15) for KFRT (n=6,177); and 1.43 (1.37-1.50) for mortality (n=12,645). In spline analyses, associations were steeper at lower hsCRP levels and flatter thereafter for all outcomes except KFRT, where the hsCRP-response relationship was relatively flat. Associations with MACE, HF, AKI and mortality were consistent regardless of ASCVD status and CKD stage. Associations with KFRT were inconsistent across CKD stages. CONCLUSION: In this nationwide cohort of adults with moderate to severe CKD receiving nephrology care, inflammation was common, and higher hsCRP levels were associated with adverse cardiovascular and kidney outcomes, as well as mortality. Although associations were less consistent for KFRT, these findings collectively support the utility of hsCRP monitoring in this population.