IgA Nephropathy

Abstract

IgA nephropathy (IgAN) is a leading cause of CKD and renal failure. Recent international collaborative efforts have led to important discoveries that have improved our understanding of some of the key steps involved in the immunopathogenesis of IgAN. Furthermore, establishment of multicenter networks has contributed to rigorous design and execution of clinical trials that have provided important insights regarding immunotherapy in IgAN. In this article, we review emerging developments in clinical and translational IgAN research and describe how these novel findings will influence future strategies to improve the outcome of patients with IgAN.

Keywords: IGA; IgA nephropathy; chronic; corticosteroids; crescents; glomerulonephritis; humans; immunosuppression; immunotherapy; kidney; pathology; renal insufficiency; review; translational medical research.

Figure 1.

Understanding the pathogenesis of IgA nephropathy reveals therapeutic targets. (A) Mucosal IgA production by plasma cells occurs by T cell–dependent and –independent processes. T cell cytokines such as APRIL promote B cell class switch to IgA1-producing plasma cells. Inhibitors of these cytokines are potential therapeutic targets. B cell and plasma cell inhibitors (e.g., rituximab, bortezomib) may result in decreased IgA production. (B) The IgA1 produced in patients with IgA nephropathy is underglycosylated (Gd-IgA1). Susceptible individuals will also produce anti–Gd-IgA1 autoantibodies (auto-Ab), reviewed in (9). Antiproliferative drugs may affect production of anti-glycan autoantibodies. The Gd-IgA1–auto-Ab immune complexes activate the alternative pathway of complement. Complement inhibitors may prevent formation of immune complexes. (C) The immune complexes are nephritogenic, contributing to local inflammation, cellular proliferation, and ultimately fibrosis. Broad-based targeting of processes implicated in glomerular and tubulo-interstitial injury (e.g., inflammation, fibrosis) target these final common pathways of kidney damage. Anti-Gd-IgA1-auto Ab, autoantibody directed at galactose-deficient IgA1.

Figure 2.

A novel addition to the MEST classification system identifies patients at increased risk of poor outcome based on crescents: C0 (no crescents), C1 (<25% left panel), and C2 (≥25% right panel). The biopsy specimen represented in the left panel had 21 total glomeruli of which two had segmental crescents; of the six complete glomeruli represented in the photomicrograph one shows a fibrocellular crescent with segmental solidification of the tuft adjacent to the crescent. There is also mild mesangial hypercellularity, and the MEST scores are M1, E0, S1, T0. The biopsy represented in the right panel contained 14 total glomeruli, of which five had segmental cellular crescents; two of the latter glomeruli are represented in the photomicrograph. The glomeruli also show mesangial hypercellularity, and the biopsy also showed focal and segmental endocapillary hypercellularity (not shown in the photomicrograph); the MEST scores are M1, E1, S0, T0. Periodic acid–Schiff stain; original magnification, ×100 (left panel), and original magnification, ×200 (right panel).