Variability in the estimated glomerular filtration rate 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). Identifying factors associated with kidney outcomes in IgAN is essential for risk stratification and management. In CKD more broadly, variability in kidney function, measured as the coefficient of variation (CV) of estimated glomerular filtration rate (eGFR), has been associated with adverse kidney outcomes. Whether such initial kidney function variability is relevant in IgAN, which involves both chronic and inflammatory processes, remains unclear.

We analyzed a Japanese retrospective cohort of patients with biopsy-proven IgAN who were followed for at least 2 years, had eGFR >30 mL/min/1.73 m2, and non-nephrotic range proteinuria. For each patient, the CV of eGFR was calculated over the first 2 years after diagnosis to quantify initial variability in kidney function. The CV of eGFR was calculated as the standard deviation divided by the mean value of all available eGFR measurements during the first 2 years. The primary endpoint was defined as the subsequent annual eGFR slope. The annual eGFR slope was analyzed using a linear mixed-effects model with repeated measures, including a random intercept for each patient and an autoregressive covariance structure to account for correlations between repeated measurements. The model adjusted for age, sex, baseline eGFR, proteinuria, Oxford classification scores, use of renin-angiotensin-aldosterone system inhibitors or corticosteroids, and the annual eGFR slope during the CV of eGFR calculation period. The secondary endpoint was defined as the initiation of KRT, which was selected as a definitive kidney outcome. Due to the limited number of events, only univariable analyses were performed for this endpoint.

A total of 153 patients were included in the present study, with a mean age of 41.5 years and 60.1% male. Baseline clinical characteristics, including age, sex, eGFR, and proteinuria, did not differ significantly across tertiles of CV of eGFR. In terms of histopathological findings, patients with higher CV of eGFR tended to have a slightly lower prevalence of crescents (P = 0.048), as shown in Figure A. Over a mean follow-up of 6.3 years, higher CV of eGFR was associated with a faster subsequent decline in eGFR, even after adjusting for baseline covariates including histopathological findings and initial annual eGFR decline (Figure B). Log-rank trend analysis showed a stepwise increase in KRT incidence across CV tertiles, with 0, 4, and 5 events in the lowest, middle, and highest tertiles, respectively (P for trend = 0.017).

In this retrospective cohort of Japanese patients with biopsy-proven IgAN, higher initial eGFR variability was independently associated with faster subsequent decline in kidney function and higher incidence of kidney replacement therapy, even after adjusting for baseline histopathology and initial annual eGFR slope. Unlike the eGFR slope, which reflects average decline, CV of eGFR captures fluctuations in kidney function that may indicate subclinical disease activity or increased susceptibility to kidney injury. These findings highlight the potential utility of monitoring initial eGFR variability for risk stratification in IgAN.