Abstract
IgA nephropathy (IgAN), the most prevalent primary glomerulonephritis worldwide, carries a considerable lifetime risk of kidney failure. Clinical manifestations of IgAN vary from asymptomatic with microscopic or intermittent macroscopic haematuria and stable kidney function to rapidly progressive glomerulonephritis. IgAN has been proposed to develop through a ‘four-hit’ process, commencing with overproduction and increased systemic presence of poorly O-glycosylated galactose-deficient IgA1 (Gd-IgA1), followed by recognition of Gd-IgA1 by antiglycan autoantibodies, aggregation of Gd-IgA1 and formation of polymeric IgA1 immune complexes and, lastly, deposition of these immune complexes in the glomerular mesangium, leading to kidney inflammation and scarring. IgAN can only be diagnosed by kidney biopsy. Extensive, optimized supportive care is the mainstay of therapy for patients with IgAN. For those at high risk of disease progression, the 2021 KDIGO Clinical Practice Guideline suggests considering a 6-month course of systemic corticosteroid therapy; however, the efficacy of systemic steroid treatment is under debate and serious adverse effects are common. Advances in understanding the pathophysiology of IgAN have led to clinical trials of novel targeted therapies with acceptable safety profiles, including SGLT2 inhibitors, endothelin receptor blockers, targeted-release budesonide, B cell proliferation and differentiation inhibitors, as well as blockade of complement components.
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Introduction (R.K. and E.S.); Epidemiology (R.K., C.S. and E.S.); Mechanisms/pathophysiology (E.S., J.B. and J.F.); Diagnosis/screening/prevention (E.S., C.S., S.C.W.T., V.T., J.B., J.F. and P.B.); Management (E.S., C.S., S.C.W.T., V.T. and J.F.); Quality of life (J.B.); Outlook (J.F.); Overview of the Primer (R.K.).
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S.C.W.T. has acted as a consultant for Boehringer Ingelheim, Eledon Pharmaceuticals and Travere, and has received speaker’s honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, GSK and Novartis. He is an Executive Committee member of KDIGO. P.B. has received consulting fees from Bristol Myers Squibb, lecture fees from Novo Nordisk, Novartis, Astellas and research funding from Ergonex Pharma GmbH and Affiris AG, but none in association with this work. V.T. has acted as a consultant for or has received honoraria from AstraZeneca, Bayer, Boehringer-Ingelheim, Calliditas, GSK, Novartis, Omeros, Otsuka and Travere. J.F. has acted as a consultant for or has received honoraria from AstraZeneca, Boehringer, Calliditas, Chinook, Novartis, Omeros, Roche, Stadapharm, Travere and Vifor. He was also chair of the data safety monitoring committee of a trial by Visterra. J.B. has acted as a consultant for or has received honoraria from Alnylam, Argenx, Astellas, BioCryst, Calliditas, Chinook, Dimerix, Galapagos, Novartis, Omeros, Travere Therapeutics, Vera Therapeutics and Visterra; has received grant support from Argenx, Calliditas, Chinook, Galapagos, GlaxoSmithKline, Novartis, Omeros, Travere Therapeutics and Visterra; and has been involved in the following clinical trials: ADU-CL-19 & ALIGN (Chinook), APPLAUSE (Novartis), ARTEMIS-IGAN (Omeros), ENVISION (Visterra), NefIgARD (Calliditas) and ORIGIN (Vera Therapeutics). His research projects include Argenx, Calliditas, Chinook, Galapagos, GlaxoSmithKline, Novartis, Omeros, Travere Therapeutics, Visterra. R.K. is a founder, shareholder and board member of Sequantrix GmbH, a member of the scientific advisory board of Hybridize Therapeutics, has received honoraria for advisory boards and talks from Bayer, Chugai, Pfizer, Roche, Genentech, Lilly and GSK and has research funding from Travere Therapeutics, Galapagos, Novo Nordisk and Ask Bio. R.K. was supported by grants from the German Research Foundation (DFG; SFBTRR219: CRU344 428857858 and CRU5011 445703531), by two grants from the European Research Council (ERC-StG 677448, ERC-CoG 101043403), a grant from the Else Kroener Fresenius Foundation (EKFS), the Dutch Kidney Foundation (DKF), TASKFORCE EP1805 and Kolff Grant no. 113351, the NWO VIDI 09150172010072 and a grant from the Leducq Foundation, and the BMBF eMed Consortium Fibromap and the BMBF Consortium CureFib. C.S. has received honoraria from Stadapharm and is supported by the clinical research unit InteraKD consortium CRU5011 (project ID 45703531) of the DFG and by the Dr. Werner Jackstädt Stiftung. E.S. is supported by the clinical research unit InteraKD consortium CRU5011 (project ID 45703531) of the DFG and by STOP-FSGS by the German Ministry for Science and Education (STOP-FSGS-01GM2202C).
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Nature Reviews Disease Primers thanks J.-C. Lv; R. Monteiro, who co-reviewed with J. Gleeson; L. Peruzzi; and H. Suzuki for their contribution to the peer review of this work.
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Glossary
- Alternative complement pathway
-
The evolutionarily oldest of the three complement pathways. It undergoes constant low-level self-activation, which is rapidly amplified in the presence of a microorganism, a damaged host cell, or a deficiency in complement regulatory proteins.
- BAFF
-
A key cytokine and member of the TNF family of ligands that regulates B cell survival, maturation and differentiation through binding with its receptors: BAFF receptor (BAFF-R), transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI), and B cell maturation antigen (BCMA).
- Class switch recombination
-
A process by which a mature B cell switches from the production of IgM to the production of IgG, IgE or IgA in response to antigen stimulation and costimulatory signals.
- Complement C3
-
A pivotal protein in the activation of the complement system, with its processing and activation by C3 convertase being essential for both the classic and alternative pathways of complement activation.
- Crescent
-
Inflammatory collection of cells in Bowman’s space resulting from severe glomerular injury and localized rupture of the capillary wall or Bowman’s capsule, which enables entry of plasma proteins and inflammatory material into Bowman’s space.
- eGFR
-
The estimated overall rate at which fluid is filtered through the kidney; it is commonly measured using renal clearance techniques and typically averages around 120 ml/min per 1.73 m2 of surface area.
- Glomerulosclerosis
-
Scarring of glomeruli that disrupts the filtration process and leads to leakage of protein from the blood into the urine.
- Lectin pathway
-
One of the three complement pathways. It is activated by pattern recognition molecules of two major protein families, the ficolins and the collectins. This pathway has a crucial role in innate immunity and host defence against microbial infections.
- Minimal change disease
-
A podocytopathy that is characterized by the absence of histological abnormalities except for ultrastructural evidence of podocyte foot process fusion and, clinically, by the manifestation of nephrotic syndrome.
- Nephrotic syndrome
-
A clinical syndrome characterized by the presence of heavy proteinuria (>3.5 g per 24 h), hypoalbuminaemia, hypercholesterolaemia and peripheral oedema due to increased filtration of macromolecules across the glomerular capillary wall.
- TLRs
-
Cell surface and intracellular molecules of eukaryotic cells that recognize structurally conserved molecules derived from microorganisms, activating innate immunity serving as a first line of defence against foreign pathogens.
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Stamellou, E., Seikrit, C., Tang, S.C.W. et al. IgA nephropathy. Nat Rev Dis Primers 9, 67 (2023). https://doi.org/10.1038/s41572-023-00476-9
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DOI: https://doi.org/10.1038/s41572-023-00476-9
