<b>Associations of kidney tubular biomarkers with incident macroalbuminuria and sustained low eGFR in DCCT/EDIC</b>

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: A case-cohort study examined associations of tubular biomarkers, measured across 7 time points spanning ~30 years, with incident macroalbuminuria (‘severely elevated albuminuria’, urinary albumin excretion rate ≥300mg/day) and sustained low eGFR (persistent eGFR<60ml/min/1.73m2) in DCCT/EDIC. Biomarkers included: KIM-1, sTNFR1 in serum/plasma; MCP-1, EGF in urine; a composite tubular secretion score reflecting secreted solute clearance. Biomarkers were assessed 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 125ml/min/1.73m2, and AER 16mg/day. 4.8 and 3.5 cases per 1000 person-years of macroalbuminuria and low eGFR were observed, respectively. Assessed as single biomarker values, KIM-1 was associated with risk of subsequent macroalbuminuria and low eGFR (hazard ratio [HR] per 20% higher biomarker, HR=1.11 [95% CI 1.06,1.16] and HR=1.12 [95% CI 1.04,1.21], respectively); sTNFR1 was associated with subsequent macroalbuminuria (HR=1.14 [95% CI 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 [95% CI 1.40,2.34] and HR=1.95 [95% CI 1.18,3.21], respectively) and low eGFR (HR=2.26 [95% CI 1.65,3.09] and HR=2.94 [95% CI 1.39,6.23], respectively). Conclusions: Serial KIM-1 and sTNFR1 are associated with incident macroalbuminuria and sustained low eGFR in T1D.