Associations of Kidney Tubular Biomarkers With Incident Macroalbuminuria and Sustained Low eGFR in DCCT/EDIC

Abstract

Objective: Tubulointerstitial injury contributes to diabetic kidney disease (DKD) progression. We tested tubular biomarker associations with DKD development in type 1 diabetes (T1D).

Research design and methods: We performed a case-cohort study examining associations of tubular biomarkers, measured across seven time points spanning ∼30 years, with incident macroalbuminuria ("severely elevated albuminuria," urinary albumin excretion rate [AER] ≥300 mg/day) and sustained low estimated glomerular filtration rate (eGFR) (persistent eGFR <60 mL/min/1.73 m2) in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. Biomarkers included KIM-1 and sTNFR1 in serum/plasma, MCP-1 and EGF in urine, and a composite tubular secretion score reflecting secreted solute clearance. We assessed biomarkers using single values, as mean values from consecutive time points, and as change over consecutive time points, each as time-updated exposures.

Results: At baseline, mean diabetes duration was 5.9 years, with mean HbA1c 8.9%, eGFR 125 mL/min/1.73 m2, and AER 16 mg/day. There were 4.8 and 3.5 cases per 1,000 person-years of macroalbuminuria and low eGFR, respectively. Assessed according to single biomarker values, KIM-1 was associated with risk of subsequent macroalbuminuria and low eGFR (hazard ratio [HR] per 20% higher biomarker 1.11 [95% CI 1.06, 1.16] and 1.12 [1.04, 1.21], respectively) and sTNFR1 was associated with subsequent macroalbuminuria (1.14 [1.03, 1.25]). Mean KIM-1 and EGF-to-MCP-1 ratio were associated with subsequent low eGFR. In slope analyses, increases in KIM-1 and sTNFR1 were associated with subsequent macroalbuminuria (per 20% biomarker increase, HR 1.81 [1.40, 2.34] and 1.95 [1.18, 3.21]) and low eGFR (2.26 [1.65, 3.09] and 2.94 [1.39, 6.23]).

Conclusions: Serial KIM-1 and sTNFR1 are associated with incident macroalbuminuria and sustained low eGFR in T1D.

Graphical abstract

Figure 1

Schematic of analyses used to examine associations of longitudinal tubular biomarker measurements with incident macroalbuminuria and sustained low eGFR. Time points (TP) at which biomarkers were measured over the duration of DCCT/EDIC are depicted on the x-axis. Biomarker measurements were performed median 3.9 (interquartile range 3.0, 4.2) years apart. Blue square, biomarker measurements; purple X, kidney outcomes; dark-blue arrow, time interval between biomarker measurements and kidney outcomes. A and B: Depiction of time-varying exposure analyses. We used single biomarkers to test associations of biomarkers from the start of each interval with outcomes occurring at the end of the interval. Using consecutive biomarkers for analyses, we tested the association of the mean of and slope between biomarkers from the start and end of each interval with subsequent outcomes. C: Depiction of fixed exposure analyses. We tested associations of biomarkers measured at DCCT baseline or year 1 with kidney outcomes over the entirety of the DCCT/EDIC follow-up period. We tested for associations of biomarkers measured at the final time point (TP 7) with kidney outcomes occurring through the end of EDIC follow-up.