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The pathogenesis of IgA nephropathy and implications for treatment

Nature Reviews Nephrology (2024)Cite this article

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Abstract

IgA nephropathy (IgAN) is a common form of primary glomerulonephritis and represents an important cause of chronic kidney disease globally, with observational studies indicating that most patients are at risk of developing kidney failure within their lifetime. Several research advances have provided insights into the underlying disease pathogenesis, framed by a multi-hit model whereby an increase in circulating IgA1 that lacks galactose from its hinge region — probably derived from the mucosal immune system — is followed by binding of specific IgG and IgA antibodies, generating immune complexes that deposit within the glomeruli, which triggers inflammation, complement activation and kidney damage. Although treatment options are currently limited, new therapies are rapidly emerging that target different pathways, cells and mediators involved in the disease pathogenesis, including B cell priming in the gut mucosa, the cytokines APRIL and BAFF, plasma cells, complement activation and endothelin pathway activation. As more treatments become available, there is a realistic possibility of transforming the long-term outlook for many individuals with IgAN.

Key points

  • IgA nephropathy (IgAN) is an important cause of progressive kidney disease and kidney failure globally, with most patients being at risk of developing kidney failure within their lifetime.

  • Advances in the understanding of the pathogenesis of IgAN have highlighted an (auto)immune basis for the disease, with increased circulating levels of galactose-deficient IgA1 (Gd-IgA1) being associated with the presence of IgA and IgG antibodies specific to these IgA1 O-glycoforms.

  • The circulating Gd-IgA1 that forms immune complexes and is deposited within the glomeruli in IgAN is probably mucosal in origin.

  • The presence of elevated levels of Gd-IgA1 alone is insufficient to trigger IgAN; genetic and epigenetic factors contribute to the susceptibility of developing IgAN and the risk of progressive disease.

  • Several therapies that target mucosal B cell priming, B cell production of Gd-IgA1, complement activity and the endothelin system are in development for the treatment of IgAN.

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Fig. 1: Geographical variation in the prevalence of IgA nephropathy.
Fig. 2: Long-term outcomes in IgA nephropathy.
Fig. 3: Pathogenesis of IgAN.
Fig. 4: IgA1 structure and glycosylation.
Fig. 5: Pathological consequences of IgA immune complex deposition in IgAN.

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Authors and Affiliations

  1. Mayer IgA Nephropathy Laboratories, Department of Cardiovascular Sciences, University of Leicester, Leicester, UK

    Chee Kay Cheung, Haresh Selvaskandan & Jonathan Barratt

  2. John Walls Renal Unit, University Hospitals of Leicester NHS Trust, Leicester, UK

    Chee Kay Cheung, Haresh Selvaskandan & Jonathan Barratt

  3. Department of Nephrology, Christian Medical College, Vellore, India

    Suceena Alexander

  4. Department of Medicine, Division of Nephrology, University of Toronto, University Health Network, Toronto, ON, Canada

    Heather N. Reich

  5. Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, P. R. China

    Hong Zhang

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All authors researched data for the article, made substantial contributions to discussions of the content and wrote, reviewed or edited the manuscript before submission.

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Competing interests

C.K.C. reports receiving consulting and speaker fees from Alexion, Alpine Immune Sciences, Calliditas, Chinook, CSL Vifor, George Clinical, Novartis, Otsuka, Stada, Travere Therapeutics, Vera Therapeutics; receiving grant support from Travere Therapeutics; and being on data-monitoring committees for Roche and Alpine Immune Sciences. H.N.R. has provided consultation for Calliditas, Chinook, Novartis and Omeros, and provided a conference lecture supported by Travere Therapeutics; serves on the steering committee of IgA studies for Calliditas and Chinook (a Novartis company); has attended advisory meetings for Otsuka, Pfizer and Eledon; is a clinical trial site investigator for Calliditas, Omeros and Alnylam; and directs the Louise Fast Foundation fellowship. H.Z. is employed by Peking University First Hospital and reports receiving consultancy fees for being a Steering Committee member from Novartis, Omeros, Calliditas, Chinook and Otsuka; and having participated in symposia or panel discussions and received honoraria for scientific presentations from Omeros and Novartis. J.B. reports consultancy for Alebund, Alnylam, Alpine, Argenx, Astellas, BioCryst, Calliditas, Chinook, Dimerix, HiBio, Kira, Novartis, Omeros, Otsuka, Q32 Bio, Roche, Sanofi, Takeda, Travere Therapeutics, Vera Therapeutics, Vifor and Visterra; research funding from Argenx, Calliditas, Chinook, Galapagos, GlaxoSmithKline, Novartis, Omeros, Travere Therapeutics and Visterra; a role on the Editorial Boards of CJASN, Clinical Science, Glomerular Diseases and Kidney International; and an advisory or leadership role as Treasurer of the International IgA Nephropathy Network. The other authors declare no competing interests.

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Cheung, C.K., Alexander, S., Reich, H.N. et al. The pathogenesis of IgA nephropathy and implications for treatment. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00885-3

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