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

Key Points:

1. 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.

2. 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 m² 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 m², 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.