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Tissue expression of tubular injury markers is associated with renal function decline in diabetic nephropathy
Subin Hwang1, Jeeeun Park1, Jinhae Kim1
1Nephrology Division, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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) <30mL/min/1.73m2, 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 1.73m2, and median GFR decline slope was 15.6 (4.4-35.1) mL/min per 1.73m2 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 DKD in high-risk patients. Further studies are warranted to determine whether tubular injury could be a therapeutic target in DKD.