Urinary biomarkers of kidney tubule health and mortality in individuals with chronic kidney disease and diabetes mellitus.

BACKGROUND: Kidney disease assessed by serum creatinine and albuminuria are strongly associated with mortality in diabetes. These markers primarily reflect glomerular function and injury. Urine biomarkers of kidney tubule health were recently associated with the risk of kidney failure in individuals with chronic kidney disease (CKD) and diabetes. Associations of these biomarkers with risk of death are poorly understood.

METHODS: In 560 individuals with diabetes and estimated glomerular filtration rate (eGFR) ≤60 ml/min/1.73m2 from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study (47% male, 53% Black), we measured urine biomarkers of kidney tubule health at baseline: monocyte chemoattractant protein-1 [MCP-1], alpha-1-microglobulin [α1m], kidney injury molecule-1 [KIM-1], epidermal growth factor [EGF], chitinase-3-like protein 1 [YKL-40], and uromodulin [UMOD]. Cox proportional hazards regression was used to examine the associations of urine biomarkers with all-cause and cause-specific mortality in nested models adjusted for urine creatinine, demographics, mortality risk factors, eGFR, and urine albumin.

RESULTS: The mean (SD) age was 70 (9.6) years and baseline eGFR was 40 (3) ml/min per 1.73m2. There were 310 deaths over a mean follow-up of 6.5 (3.2) years. In fully adjusted models, each 2-fold higher urine concentration of KIM-1 and YKL-40 were associated with all-cause mortality: hazard ratio (HR) 1.15, 95% CI 1.01,1.31 and 1.13, 95% CI 1.07,1.20, respectively. When examining cause-specific mortality, higher UMOD was associated with a lower risk of cardiovascular death (adjusted HR per 2-fold higher concentration 0.87, 95%CI 0.77,0.99), and higher MCP-1 was associated with higher risk of cancer-related death (HR per two-fold higher concentration 1.52, 95%CI 1.05,2.18).

CONCLUSION: Among persons with diabetes and CKD, higher urine KIM-1 and YKL-40 were associated with a higher risk of all-cause mortality independently of established risk factors. Urine UMOD and MCP-1 were associated with cardiovascular- and cancer-related death, respectively.