Plasma Biomarkers of Kidney Health and Mortality in Diabetes and Chronic Kidney Disease in the REGARDS Study

Key Points In diabetes and CKD, creatinine- and cystatin C–based eGFR has a strong inverse correlation with plasma TNF receptor 1, TNF receptor 2, and soluble urokinase-type plasminogen activator receptor. Higher plasma soluble TNF receptors 1 and 2 and soluble urokinase-type plasminogen activator receptor were each individually associated with mortality, independent of baseline kidney measures. Background Several plasma biomarkers of kidney health have been associated with CKD progression in persons with diabetes, but their associations with mortality risk have been largely unexplored. Methods In a random sample of 594 participants with diabetes and creatinine-based eGFR <60 ml/min per 1.73 m 2 from the REGARDS cohort study, Cox proportional hazards regression was used to determine hazard ratios of mortality by plasma concentrations of soluble TNF receptors 1 and 2 (TNFR1 and TNFR2), soluble urokinase-type plasminogen activator receptor (suPAR), kidney injury molecule 1 (KIM-1), chitinase 3–like 1 (YKL-40), and monocyte chemotactic protein 1 (MCP-1). Covariates included sociodemographic and clinical factors, urine albumin-to-creatinine ratio (UACR), and creatinine- and cystatin C–based eGFR (eGFRcr-cys). Results At baseline, the mean age was 70 years, 47% were male, 53% self-identified as Black, mean±SD eGFRcr-cys was 41±13 ml/min per 1.73 m 2 , and median (interquartile range) UACR was 32 (9–224) mg/g. Correlations with eGFRcr-cys were stronger for TNFR1, TNFR2, and suPAR ( r =−0.72 to −0.76) than for KIM-1, YKL-40, and MCP-1 ( r =−0.10 to −0.40). With a median follow-up of 7 years, 332 participants died. In models adjusted for sociodemographic and clinical factors, each SD higher baseline concentration of plasma TNFR1 (hazard ratio [HR], 1.28; 95% confidence interval [CI], 1.20 to 1.38), TNFR2 (HR, 1.61; 95% CI, 1.42 to 1.82), suPAR (HR, 1.33; 95% CI, 1.22 to 1.44), KIM-1 (HR, 1.20; 95% CI, 1.08 to 1.33), and YKL-40 (HR, 1.23; 95% CI, 1.11 to 1.38) was associated with higher risk of all-cause mortality, whereas MCP-1 was not. Upon further adjustment for baseline eGFRcr-cys and UACR, only the associations for TNFR1 (HR, 1.16; 95% CI, 1.04 to 1.29), TNFR2 (HR, 1.34; 95% CI, 1.12 to 1.60), and suPAR (HR, 1.23; 95% CI, 1.11 to 1.36) persisted. Conclusions Among adults with diabetes and CKD, higher plasma TNFR1, TNFR2, and suPAR were associated with all-cause mortality, independent of baseline kidney function.