Morphometric Analysis of Different Nephron Segments in Patients with Diabetic Nephropathy and Overt Proteinuria

Background: Patients with diabetic nephropathy (DN) are characterized by kidney enlargement, and heavy proteinuria is associated with poor kidney function outcomes. The relationship between hypertrophic changes in single nephrons and the development of proteinuria has not been studied in DN patients. Methods: Glomerular volume (Vglom), proximal tubular diameter (Dprox) and distal tubular diameter (Ddist) were measured using biopsy specimens from DN patients with overt proteinuria. Nephron-related parameters were estimated using combination of computed tomography imaging and biopsy stereology. These include number of total non-globally sclerotic glomeruli (NNSG), number of globally sclerotic glomeruli (NGSG) and single-nephron GFR (SNGFR), which was estimated by deviding eGFR by NNSG of both kidneys. The proteinuria level at biopsy were compared among tertile groups based on Vglom, Dprox, and Ddist. Results: A total 78 patients were included in this study (median 56 [quartile 46-67] years, 82% male, eGFR 40.0 [27.4-53.5] ml/min/1.73m2, urinary protein 4.3 [2.0-6.9] g/day). Of the Vglom, Dprox, and Ddist tertiles, only Dprox showed a significant trend to correlate with urinary protein levels (Figure). Among the Dprox tertile, there were no differences in age, sex, hypertension, eGFR, and HbA1c among the groups, while body mass index showed an increasing trend with Dprox. NNSG, NGSG, and SNGFR were not statistically different among the Dprox tertile. Dprox showed an increasing trend with glomerular lesions characteristic of DN, but Vglom, and Ddist did not show such a trend. Conclusion: The present study is the first to morphologically demonstrate the involvement of proximal tubular hypertrophy in the pathophysiology of proteinuria in DN. Morphological findings of different nephron segments, as shown in this study, may provide clinically useful insights when combined with response to treatment and kidney function outcomes.Comparison of proteinuria levels according to morphological measurement of different nephron segments