Defining Kidney Health Dimensions and Their Associations with Adverse Outcomes in Persons with Diabetes and CKD

Abstract

Key Points:

1. We identified three kidney health dimensions using 17 urine and plasma biomarkers across two cohorts of persons with diabetes and CKD.

2. Worse scores for tubule injury, tubule function, and systemic inflammation/filtration were associated with a higher risk of CKD progression and death.

3. A multibiomarker approach could help capture tubulointerstitial health in persons with diabetes and CKD.

Background: Individual kidney tubule biomarkers are associated with risks of 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 1256 participants with diabetes and eGFR <60 ml/min per 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 ten biomarkers were identified: systemic inflammation and filtration (plasma TNF receptor-1 and TNF receptor-2, plasma soluble urokinase plasminogen activator receptor, and plasma symmetric dimethylarginine), tubular function (urine EGF, urine asymmetric dimethylarginine, and urine symmetric dimethylarginine), and tubular damage (urine α-1 microglobulin, urine kidney injury molecule-1, and urine monocyte chemoattractant protein-1). In CRIC, there were 244 incident 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-SD, 0.36; 95% confidence interval, 0.25 to 0.52) and higher tubular damage (1.45; 1.18 to 1.78) scores were independently associated with higher CKD progression risk. Associations in REGARDS were weaker but directionally consistent (tubular function score [0.81; 0.47 to 1.39] and tubular damage score [1.12; 0.73 to 1.72]). Higher tubular damage (1.47; 1.15 to 1.87) scores were associated with higher mortality risk in CRIC, but not REGARDS (1.15; 0.96 to 1.38). Higher systemic inflammation and filtration factor scores were associated with higher mortality risk in both cohorts (CRIC: 1.35; 1.07 to 1.71; REGARDS: 1.41; 1.20 to 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.

Keywords: CKD; biomarkers; chronic diabetic complications; cohort studies; diabetes mellitus; epidemiology and outcomes; kidney dysfunction; kidney tubule; tubular physiology; tubulointerstitial disease.