Suzuki, Yusuke

Background Nephritis is a common manifestation of IgA vasculitis and is morphologically indistinguishable from IgA nephropathy. While MEST-C scores are predictive of kidney outcomes in IgA nephropathy, their value in IgA vasculitis nephritis has not been investigated in large multiethnic cohorts. Methods Biopsies from 262 children and 99 adults with IgA vasculitis nephritis ( N =361) from 23 centers in North America, Europe, and Asia were independently scored by three pathologists. MEST-C scores were assessed for correlation with eGFR/proteinuria at biopsy. Because most patients ( N =309, 86%) received immunosuppression, risk factors for outcomes were evaluated in this group using latent class mixed models to identify classes of eGFR trajectories over a median follow-up of 2.7 years (interquartile range, 1.2–5.1). Clinical and histologic parameters associated with each class were determined using logistic regression. Results M, E, T, and C scores were correlated with either eGFR or proteinuria at biopsy. Two classes were identified by latent class mixed model, one with initial improvement in eGFR followed by a late decline (class 1, N =91) and another with stable eGFR (class 2, N =218). Class 1 was associated with a higher risk of an established kidney outcome (time to ≥30% decline in eGFR or kidney failure; hazard ratio, 5.84; 95% confidence interval, 2.37 to 14.4). Among MEST-C scores, only E1 was associated with class 1 by multivariable analysis. Other factors associated with class 1 were age 18 years and younger, male sex, lower eGFR at biopsy, and extrarenal noncutaneous disease. Fibrous crescents without active changes were associated with class 2. Conclusions Kidney outcome in patients with biopsied IgA vasculitis nephritis treated with immunosuppression was determined by clinical risk factors and endocapillary hypercellularity (E1) and fibrous crescents, which are features that are not part of the International Study of Diseases of Children classification.

AbstractIgA nephropathy (IgAN), an immune complex‐mediated process and the most common primary glomerulonephritis, can progress to end‐stage renal disease in up to 40% of patients. Accordingly, a therapeutic strategy targeting a specific molecular pathway is urgently warranted. Aided by structure characterisation and target identification, we predicted that a novel ring‐fused 6‐(2,4‐difluorophenyl)‐3‐(3‐(trifluoromethyl)phenyl)‐2H‐benzo[e][1,3]oxazine‐2,4(3H)‐dione (LCC18) targets the NLRP3 inflammasome, which participates in IgAN pathogenesis. We further developed biomarkers for the disease. We used two complementary IgAN models in C57BL/6 mice, involving TEPC‐15 hybridoma‐derived IgA, and in gddY mice. Moreover, we created specific cell models to validate therapeutic effects of LCC18 on IgAN and to explain its underlying mechanisms. IgAN mice benefited significantly from treatment with LCC18, showing dramatically improved renal function, including greatly reduced proteinuria and renal pathology. Mechanistic studies showed that the mode of action specifically involved: (1) blocking of the MAPKs/COX‐2 axis‐mediated priming of the NLRP3 inflammasome; (2) inhibition of ASC oligomerisation and NLRP3 inflammasome assembly by inhibiting NLRP3 binding to PKR, NEK7 and ASC; and (3) activation of autophagy. LCC18 exerts therapeutic effects on murine IgAN by differentially regulating NLRP3 inflammasome activation and autophagy induction, suggesting this new compound as a promising drug candidate to treat IgAN. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.