Nephron Number and Kidney Outcomes in IgA Nephropathy: A Retrospective Cohort Study

Background We previously reported substantial variability in the number of nephrons in patients with IgA nephropathy (IgAN), even among patients with similar risk factor profiles. This retrospective cohort study aimed to evaluate the clinical significance of nephron number at diagnostic biopsy for subsequent kidney outcomes in patients with IgAN.

The number of nephrons, defined as the total number of non-globally sclerotic glomeruli per kidney, was estimated using computed tomography imaging and biopsy-based stereology. Kidney outcomes were compared based on tertiles of nephron number. The primary endpoint was the annual slope of the estimated glomerular filtration rate (eGFR), and the secondary endpoint was the initiation of kidney replacement therapy.

A total of 222 Japanese adults with IgAN were included. Among the entire cohort, eGFR exhibited a gradual decline over time during a median follow-up of 7.6 years. Annual eGFR slopes, adjusted for baseline eGFR, baseline proteinuria, Oxford classification scores, and therapies during the first year after biopsy, were -1.35, -1.11, and -0.97 mL/min/1.73 m2/year for the lowest to highest nephron number tertiles, respectively (P for trend < 0.001). Kidney replacement therapy was initiated in 32.4%, 10.8%, and 0% of patients in the lowest, middle, and highest tertiles, respectively (P for trend < 0.001). A significantly higher risk of kidney replacement therapy initiation with decreasing number of nephrons was confirmed using age- and sex-adjusted Cox proportional hazards models.

The total number of non-globally sclerotic glomeruli per kidney identified at diagnostic biopsy was independently and inversely associated with the rate of future kidney function decline in IgAN patients. As a readily quantifiable marker, it offers additional information beyond conventional clinical and histopathological risk factors. Incorporating this metric into routine evaluation may enhance risk stratification and inform more personalized, targeted treatment strategies for patients with IgAN. Key points No prior studies have examined the clinical significance of nephron number in patients with IgA nephropathy (IgAN). This study provides the first robust evidence that the number of non-globally sclerotic glomeruli per kidney is significantly and inversely associated with the rate of subsequent decline in kidney function in patients with IgAN, independent of established risk factors. These findings highlight the potential utility of incorporating this metric into diagnostic evaluations to help assess risk and tailor treatment for IgAN. Competing Interest Statement The authors have declared no competing interest. Funding Statement This work was supported by JSPS KAKENHI grant numbers 21K08238 and 25K11551. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of the Jikei University School of Medicine gave ethical approval for this work [30-385 (9406)]. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data availability statement All data produced in the present study are available upon reasonable request to the authors.