Defining Kidney Health Dimensions and their Associations with Adverse Outcomes in Persons with Diabetes and Chronic Kidney Disease.

Abstract

Background: Individual kidney tubule biomarkers are associated with risks for chronic kidney disease (CKD) progression and mortality in persons with diabetes. Integrating multiple kidney biomarkers using a latent variable method of exploratory factor analysis could define distinct dimensions of kidney health, and their associations with adverse outcomes.

Methods: We conducted a factor analysis of 17 candidate urine and plasma biomarkers in 1,256 participants with diabetes and estimated glomerular filtration rate (eGFR) <60ml/min/1.73 m2 from the Chronic Renal Insufficiency Cohort (CRIC; N=701) and the Reasons for Geographic and Racial Differences in Stroke (REGARDS; N=555) studies. We used Cox proportional hazards models to evaluate the associations of identified factors with CKD progression and mortality, adjusting for baseline clinical risk factors, eGFR and albuminuria.

Results: Three factor scores comprising 10 biomarkers were identified: systemic inflammation and filtration (plasma tumor necrosis factor receptor-1 [TNFR-1] and -2 [TNFR-2], plasma soluble urokinase plasminogen activator receptor (suPAR), plasma symmetric dimethylarginine [pSDMA]) ), tubular function (Urine epidermal growth factor [uEGF], Urine asymmetric dimethylarginine [uADMA], Urine symmetric dimethylarginine [uSDMA]), and tubular damage (Urine α-1 microglobulin [α1m], Urine kidney injury molecule-1 [uKIM-1], Urine monocyte chemoattractant protein-1 [uMCP-1]). In CRIC, there were 244 incident end stage kidney disease (ESKD) events, 102 with ≥40% eGFR decline from baseline, and 259 deaths; in REGARDS, there were 121 incident ESKD events and 462 deaths. In CRIC, lower tubular function (hazard ratio per 1-standard deviation, 0.36; 95% confidence interval, 0.25-0.52) and higher tubular damage scores (1.45; 1.18-1.78) were independently associated with higher CKD progression risk. Associations in REGARDS were weaker but directionally consistent (tubular function [0.81; 0.47-1.39] and tubular damage scores [1.12; 0.73-1.72]). Higher tubular damage (1.47; 1.15-1.87) scores were associated with higher mortality risk in CRIC, but not REGARDS ( [1.15; 0.96-1.38]. Higher systemic inflammation and filtration factor scores were associated with higher mortality risk in both cohorts [CRIC: 1.35; 1.07-1.71; REGARDS: 1.41; 1.20-1.65].

Conclusions: Three distinct kidney health dimensions were identified, and each associated with CKD progression and/or all-cause mortality in persons with diabetes and CKD.