Novel Renal Biomarkers for Early Detection of Cardio-Renal Syndrome in Heart Failure

Introduction: Acute kidney injury (AKI) complicates up to one-third of acute decompensated heart failure (ADHF) admissions, defining cardio-renal syndrome type 1 (CRS-1). Serum creatinine detects AKI with significant delay. NGAL, KIM-1, cystatin C, sST2, and galectin-3 are candidate early-detection biomarkers, yet their comparative diagnostic accuracy in CRS-1 remains unestablished. Methods: PubMed, Embase, and Cochrane Library were searched for studies published 2010-2026 enrolling adults (≥18 years) with ADHF or CRS-1, with an index biomarker measured within 24 hours and diagnostic accuracy reported against a KDIGO or creatinine-based reference standard. Pooled sensitivity, specificity, and AUC were computed using a DerSimonian-Laird random-effects model. Heterogeneity was assessed by I 2 and τ 2 , and threshold effect by Spearman correlation. Results: Fifteen study arms across 14 studies (N=3,447) were included: NGAL (k=5, n=1,346), KIM-1 (k=3, n=251), cystatin C (k=4, n=696), sST2 (k=1, n=189), and galectin-3 (k=2, n=965). All biomarkers outperformed creatinine (AUC 0.652). Pooled AUCs were: NGAL 0.741 (95% CI 0.662-0.807; I 2 =68.9%), KIM-1 0.739 (0.646-0.814; I 2 =0%), cystatin C 0.738 (0.674-0.793; I 2 =46.4%), sST2 0.740 (0.670-0.810), and galectin-3 0.662 (0.624-0.697; I 2 =0%). Overall pooled AUC was 0.721 (0.687-0.752; I 2 =50.9%), sensitivity 84.7%, specificity 80.3% (LR+ 4.30; LR– 0.191). Cystatin C achieved the highest individual specificity (74.4%). Galectin-3 showed marginal superiority over creatinine (ΔAUC +0.010) with negative net benefit at 30% prevalence. The NGAL + cystatin C + NT-proBNP panel achieved the highest accuracy (AUC 0.842; sensitivity 78%, specificity 100%). No threshold effect was detected (Spearman ρ=–0.079, p=0.78). Sensitivity analysis excluding a high-risk KIM-1 outlier did not materially alter estimates (overall AUC 0.720). Conclusion: NGAL, KIM-1, cystatin C, and sST2 demonstrate moderate but consistent superiority over creatinine for early AKI detection in CRS-1 (ΔAUC 0.086-0.089). Galectin-3 offers no meaningful advantage as a single biomarker. Multi-biomarker panels yield the highest accuracy and warrant prospective multicentre validation using standardised KDIGO criteria.