Urine Biomarkers for Diabetic Kidney Disease Progression in Participants of the Chronic Renal Insufficiency Cohort Study

Key Points Higher urine levels of kidney injury molecule-1 and monocyte chemoattractant protein-1 were associated with higher risk of CKD progression. Higher urine levels of EGF were associated with lower risk of CKD progression. Urine kidney injury molecule-1, monocyte chemoattractant protein-1, and EGF may noninvasively assess tubule and interstitial health in diabetes and identify those at higher risk of CKD progression. Background Urine biomarkers of kidney tubular health and inflammation may provide a noninvasive way to identify individuals with diabetes at higher risk for CKD progression given that the extent of tubulointerstitial pathology is related to progression of diabetic kidney disease. Methods We performed a case-cohort study among 898 participants in the Chronic Renal Insufficiency Cohort with diabetes and eGFR <60 ml/min per 1.73 m 2 . Of these individuals, the subcohort ( N =599) was randomly selected from participants with urine samples available 1 year or less after enrollment to assay for urine proteins. Cases were participants who developed CKD progression (incident ESKD, or eGFR decline of 40% or greater from baseline). The median follow-up was 7.35 years. We studied urinary biomarkers of tubulointerstitial inflammation (monocyte chemoattractant protein-1 [MCP-1]), proximal tubular injury (kidney injury molecule-1 [KIM-1]), tubular resorptive capacity ( α 1-microglobulin), and tubular synthetic capacity (EGF and uromodulin). Weighted Cox regression models related urine biomarkers, standardized to urine creatinine (Cr), with CKD progression and were adjusted for CKD risk factors, including eGFR, and urine albumin-to-creatinine ratio. Results In fully adjusted models, higher urine KIM-1/Cr was associated with higher risk of CKD progression (hazard ratio [HR], 1.16 per two-fold higher; 95% confidence interval [CI], 1.05 to 1.29) and the highest quartiles of urine KIM-1/Cr and urine MCP-1/Cr, compared with the lowest quartile, were associated with higher risk of CKD progression (HR, 1.71; 95% CI, 1.15 to 2.55, and HR, 1.65; 95% CI, 1.10 to 2.47, respectively). Higher urine levels of EGF/Cr were associated with lower risk of CKD progression (HR, 0.81 per two-fold higher; 95% CI, 0.71 to 0.93), and the highest quartile of urine EGF/Cr, compared with lowest, associated with less CKD progression (HR, 0.57; 95% CI, 0.40 to 0.81). Conclusions Urine MCP-1, KIM-1, and EGF may provide noninvasive ways to assess tubule and interstitial disease in diabetes and identify those at higher risk of CKD progression.