Tissue Expression of Tubular Injury Markers is Associated with Renal Function Decline in Diabetic Nephropathy

Aims: The pathogenesis of diabetic kidney disease (DKD) is complex and multifactorial; increasing evidence suggests that tubular injury and inflammatory process are involved in disease progression. We investigated the potential association of renal expression of tubular injury markers, neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and inflammatory markers, tumor necrosis factor receptor (TNFR) 1 and 2 with renal progression in pathologically proven diabetic nephropathy (DN). Methods: We identified 122 patients with confirmed DN. After excluding patients with other coexisting renal disease or estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m(2), 35 patients were included. Annual decline of (GFR decline slope) was calculated using linear regression analysis. Tissue tubular and glomerular expressions of NGAL, KIM-1, TNFR1, and TNFR2 were assessed using immunohistochemistry. Results: Median baseline urinary protein to creatinine ratio (uPCR) was 6.76 (2.18-7.61) mg/mg Cr, median baseline eGFR was 50 (43-66) mL/min per 1.73 m(2), and median GFR decline slope was 15.6 (4.4-35.1) mL/min per 1.73 m(2) per year. Positive correlations were observed between tubular expressions of NGAL and KIM-1, and GFR decline slopes (r = 0.601, p < 0.001; r = 0.516, p = 0.001, respectively), and between tubular expressions of KIM -1 and uPCR (r = 0.596, p < 0.001), and between NGAL and interstitial fibrosis and tubular atrophy (IFTA) score (r = 0.391, p = 0.024). No correlations were found between glomerular or tubular expressions of TNFRs, and clinical parameters including GFR decline slopes. On multivariate analysis, the association between tubular expressions of KIM-1 and GFR decline slopes was dependent on uPCR. Tubular expressions of NGAL were independently associated with GFR decline slopes, with an adjusted coefficient factor of 0.290 (95% confidence interval, 0.009-0.202, p = 0.038). Conclusions: These findings suggest that tubular injury plays a key role in the pathogenesis of DIM in high-risk patients. Further studies are warranted to determine whether tubular injury could be a therapeutic target in DKD. (C) 2017 Elsevier Inc. All rights reserved.