Associations of Biomarkers of Tubular Injury and Inflammation with Biopsy Features in Type 1 Diabetes

Abstract

Background Whether biomarkers of tubular injury and inflammation indicate subclinical structural kidney pathology early in type 1 diabetes remains unknown. Methods We investigated associations of biomarkers of tubular injury and inflammation with kidney structural features in 244 adults with type 1 diabetes from the Renin Angiotensin System Study, a randomized, placebo-controlled trial testing effects of enalapril or losartan on changes in glomerular, tubulointerstitial, and vascular parameters from baseline to 5-year kidney biopsies. Biosamples at biopsy were assessed for: kidney injury molecule 1 (KIM-1), soluble tumor necrosis factor receptor 1 (sTNFR1), and arginine-to-citrulline ratio in plasma; uromodulin (UMOD) and epidermal growth factor (EGF) in urine. We examined cross-sectional correlations between biomarkers and biopsy features and baseline biomarker associations with 5-year change in biopsy features. Results Participants’ mean age was 30 years (SD 10) and diabetes duration 11 years (SD 5); 53% were female. Mean iohexol-GFR was 128ml/min/1.73m2 (SD 19) and median urinary albumin excretion was 5μg/min (IQR 3,8). KIM-1 was associated with most biopsy features: higher mesangial fractional volume (0.5% [95% CI 0.1,0.9] greater per SD KIM-1), glomerular basement membrane width (14.2nm [95% CI 6.5,22.0] thicker), cortical interstitial fractional volume (1.1% [95% CI 0.6,1.6] greater), fractional volume of cortical atrophic tubules (0.6% [95% CI 0.2,0.9] greater), and arteriolar hyalinosis index (0.03 [95% CI 0.1,0.05] higher). sTNFR1 was associated with higher mesangial fractional volume (0.9% [95% CI 0.5,1.3] greater) and glomerular basement membrane width (12.5nm [95% CI 4.5,20.5] thicker), and lower glomerular basement membrane surface density (0.003μm2/μm3 [95% CI 0.005,0.001] lesser). EGF and arginine-to-citrulline ratio correlated with severity of glomerular and tubulointerstitial features. Baseline sTNFR1, UMOD, and EGF concentrations were associated with 5-year glomerular and tubulointerstitial feature progression. Conclusions Biomarkers of tubular injury and inflammation were associated with kidney structural parameters early type 1 diabetes and may be indicators of kidney disease risk.