Kidney Proximal Tubular Ultrastructural Changes Precede Albuminuria in Type 1 Diabetes

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Background: Kidney proximal tubular epithelial cells (PTEC) are mitochondria-rich and metabolically active. Abnormalities in PTEC mitochondria and other ultrastructural elements have been described in diabetes but detailed characterization is lacking. Methods: Wedeveloped and validated novel methods to quantify PTEC ultrastructure in kidney biopsies from 15 adults with type 1 diabetes (T1D) and without clinical evidence of kidney disease from the Renin-Angiotensin System Study. We performed electron microscopy imaging of S1/S2 proximal tubular segments and developed and validated unbiased stereology protocols for quantifying morphology of ultrastructural features: PTEC volume, brush border thickness, and basolateral infoldings; fractional volume of mitochondria per PTEC; surface area of mitochondrial outer and inner membranes; mitochondrial ribosome density. We compared measurements between T1D and age- and sex-matched healthy controls (n=4) and examined correlations with glomerular features and tubular biomarkers. Results: T1Dparticipants had mean age 30 years, 47% male, diabetes duration 12 years, hemoglobin A1c 7.8%, GFR 119 ml/min/1.73m2, AER 5 µg/min. Fractional volume of mitochondria and basolateral infoldings per PTEC were significantly higher in T1D versus controls (p<0.05; Figure). Several other measures, including brush border thickness and mitochondrial ribosome density, trended higher in T1D but were not significant. Basolateral infolding density correlated with mesangial fractional volume and mitochondrial cristae surface density correlated with glomerular basement membrane surface density (r=0.7, p<0.01 for both). Plasma arginine-citrulline ratio was positively correlated with PTEC nucleus volume and mitochondrial cristae metrics (p<0.05). Conclusion: Analysis of PTEC ultrastructure shows increased mitochondrial volume density and early structural changes in T1D, which are apparent before GFR decline or albuminuria onset. Funding: NIDDK Support

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