Nephron Number as a Structural Determinant of Kidney Functional Decline in IgAN: A Retrospective Cohort Study

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Background: We previously identified substantial inter-individual variability in nephron number among patients with IgA nephropathy (IgAN). However, the clinical significance of this structural parameter has not been systematically evaluated. In this retrospective cohort study, we investigated whether nephron number at the time of diagnostic biopsy is independently associated with long-term kidney outcomes in patients with IgAN. Methods: Nephron number was defined as the total count of non-globally sclerotic glomeruli per kidney, estimated by integrating computed tomography-based cortical volume assessment and biopsy-based stereological analysis. Patients were categorized into tertiles according to nephron number. The primary outcome was the annual decline in estimated glomerular filtration rate (eGFR), and the secondary outcome was the initiation of kidney replacement therapy (KRT). Results: A total of 222 Japanese adults with biopsy-confirmed IgAN were included. During a median follow-up of 7.6 years, a progressive decline in eGFR was observed. Multivariable linear regression models adjusting for baseline eGFR, proteinuria, Oxford classification lesions, and therapeutic interventions during the first year demonstrated a significantly steeper annual decline in eGFR in the lowest nephron tertile compared to the highest (–1.35, –1.11, and –0.97 mL/min/1.73 m2/year, respectively; P for trend < 0.001). The cumulative incidence of KRT initiation was 32.4%, 10.8%, and 0% across the lowest to highest tertiles (P for trend < 0.001). Cox proportional hazards analysis adjusted for age and sex confirmed a stepwise increase in the risk of KRT with decreasing nephron number. Conclusion: This study provides the first robust evidence that nephron number, quantified as the total number of non-globally sclerotic glomeruli per kidney, is independently and inversely associated with the trajectory of kidney functional decline in IgAN. These findings suggest the potential clinical utility of incorporating nephron number into routine diagnostic evaluation to enhance risk stratification and inform individualized therapeutic strategies.

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