Abstract
KEY POINTS: The presence of cellular segmental sclerosis and crescents predicts a favorable response to glucocorticoid therapy in patients with IgA nephropathy. Glucocorticoid therapy was associated with lower risk of kidney failure across histologic subtypes, with the greatest benefit in cellular segmental sclerosis. The study highlights that there is a need for further subclassification of segmental sclerosis lesions that may guide therapeutic decisions. BACKGROUND: The Oxford Classification is widely accepted as a histopathology tool to predict kidney outcomes in IgA nephropathy. However, it remains unclear whether the mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and crescents (C) scores can predict therapeutic response. This study aims to determine the predictive value of mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), tubular atrophy/interstitial fibrosis (T), and crescents (C) scores on the efficacy of glucocorticoid therapy using the Therapeutic Effects of Steroids in IgA Nephropathy Global trial. METHODS: Three hundred and seventy-nine Chinese participants were enrolled in the Therapeutic Effects of Steroids in IgA Nephropathy Global trial, of whom 279 had kidney biopsy slides available for central pathology review. The primary outcomes were a composite of ≥40% reduction in eGFR, kidney failure, or death due to kidney disease. Multivariable Cox regression analysis was used to determine the effects of glucocorticoid therapy across pathologic subgroups, and the interaction between glucocorticoid therapy and pathology scores was evaluated. RESULTS: Among 279 participants selected for this study, the median (interquartile range) time from kidney biopsy to randomization was 4 (3–7) months. The median (interquartile range) follow-up was 4.7 (3.0–6.4) and 5.1 (3.1–6.8) years for the placebo and glucocorticoid-treated group. Glucocorticoid therapy showed benefits across all histologic subtypes. Participants with crescents (C1/C2) showed a trend toward greater benefit from glucocorticoid therapy (C1/2: hazard ratio [HR], 0.05 [95% confidence interval (CI), 0.008 to 0.3]; C0: HR, 0.6 [95% CI, 0.4 to 0.9]; P for interaction = 0.4). Participants with hypercellularity within segmental sclerosis lesions (cellular segmental sclerosis) demonstrated a significant reduction in the risk of kidney failure compared with those without (HR, 0.2 [95% CI, 0.07 to 0.4] versus HR, 0.6 [95% CI, 0.4 to 1.0]; P for interaction = 0.03). Analysis of local pathologists' scores of all 379 Chinese participants demonstrated a significantly greater benefit from glucocorticoid therapy in participants with crescents (C0: HR, 0.7 [95% CI, 0.4 to 1.2]; C1: HR, 0.3 [95% CI, 0.2 to 0.6]; C2: HR, 0.2 [95% CI, 0.08 to 0.7]; P for interaction = 0.05). CONCLUSIONS: The presence of crescents and cellular segmental sclerosis in patients with IgA nephropathy was associated with a favorable response to glucocorticoid therapy.