Variability in Glomerular Area and Adverse Kidney Outcomes in IgA Nephropathy

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a leading cause of chronic kidney disease (CKD). Histopathological systems such as the Oxford classification assess lesion severity but mainly reflect localized injury patterns, potentially missing broader structural heterogeneity or the burden of remaining functional nephrons. Our recent study identified total nephron number as a key determinant of kidney prognosis in IgAN, with fewer nephrons predicting faster CKD progression (Marumoto H and Sasaki T, Kidney360, 2025, Epub ahead of print). Reduced nephron number leads to compensatory hypertrophy of remaining nephrons, which, if excessive, promotes glomerulosclerosis and function loss. Variation in glomerular size may thus indicate compensatory stress. The coefficient of variation of glomerular area (CV of GA) quantifies this heterogeneity, reflecting the coexistence of hypertrophic and shrunken glomeruli. This study examined whether CV of GA is independently associated with kidney prognosis in IgAN, accounting for both histopathology and nephron number.

We retrospectively analyzed a Japanese cohort of biopsy-proven IgAN (N = 222). The original data on nephron number and kidney outcomes were originally reported elsewhere (Marumoto H and Sasaki T, Kidney360, 2025). CV of GA was calculated from diagnostic biopsies as the standard deviation of glomerular area divided by its mean, excluding sclerotic glomeruli. The primary endpoint was the annual eGFR slope, analyzed using a linear mixed-effects model adjusted for age, sex, baseline eGFR, proteinuria, Oxford classification scores, and use of RAAS inhibitors or corticosteroids. Nephron number was derived from estimated cortical volume on CT and glomerular density in biopsy specimens. Subgroup analyses were performed based on histopathological parameters. The secondary endpoint was initiation of kidney replacement therapy (KRT).

At biopsy, mean age was 42.7 years, 61.7% were male, mean eGFR was 60.6 mL/min/1.73 m2, and median proteinuria was 814 mg/day. Mean CV of GA was 49.4% ± 10.4 (range 18.0–81.8%). Across increasing CV of GA tertiles, age, proteinuria, hypertension, systolic blood pressure, and RAAS inhibitor use rose significantly, while eGFR declined. Higher CV of GA was not linked to Oxford scores or histological arterio- and arteriolosclerosis, but was associated with lower nephron number and larger mean GA. Over a median 7.6-year follow-up, higher CV of GA was independently associated with faster eGFR decline ( for trend < 0.001; Figure 1). Subgroup analyses confirmed consistent associations, except for mean GA (Figure 2). KRT incidence increased significantly across CV of GA tertiles (P for trend = 0.002).

In this retrospective cohort, higher CV of GA, a novel index reflecting imbalance between hypertrophic and atrophic nephrons, was independently associated with faster kidney function decline and greater KRT risk. These findings suggest that CV of GA captures structural vulnerability beyond traditional risk factors. Monitoring this metric may enhance risk stratification and guide therapy in IgAN, particularly in patients with smaller average glomeruli.