Single-Nephron Dynamics Across Chronic Kidney Disease Stages in Overt Diabetic Nephropathy

Background: Single-nephron glomerular filtration rate (GFR) represents a nephron-level functional index that may reveal key pathophysiological mechanisms driving progression in patients with diabetic nephropathy. However, its clinical relevance remains incompletely understood. This cross-sectional study assessed single-nephron estimated GFR (eGFR) across different chronic kidney disease (CKD) stages in patients with advanced diabetic nephropathy. Methods: Nephron number was estimated as the number of nonglobally sclerotic glomeruli per kidney using computed tomography-derived cortical volume combined with biopsy stereology. Single-nephron eGFR was calculated by dividing eGFR by the nephron number of both kidneys. Patients were stratified according to CKD stage at kidney biopsy. Associations between CKD stages and single-nephron eGFR were evaluated using multivariable linear regression models adjusted for age, sex, urinary protein excretion, and eGFR. Results: The study included 105 patients with biopsy-proven diabetic nephropathy and overt proteinuria (median age 59 years, 83% male, HbA1c 6.6%, 57% had nephrotic range proteinuria). The percentage of globally sclerotic glomeruli, mesangial expansion score, and prevalence of nodular lesions increased significantly with advancing CKD stage. Median nephron number declined from 529,178 to 224,458 per kidney, whereas glomerular volume remained constant. Single-nephron eGFR decreased markedly with CKD stage and remained significantly inversely associated with CKD stage after adjustment for clinicopathologic covariates (P for trend <0.001). Conclusion: In overt diabetic nephropathy, single-nephron eGFR decreased with advancing CKD stage, despite relatively preserved glomerular volume. At this stage of disease, structural alterations specific to diabetic nephropathy may impair effective single-nephron filtration capacity.