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Current Understanding of Complement Proteins as Therapeutic Targets for the Treatment of Immunoglobulin A Nephropathy

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Abstract

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a frequent cause of kidney failure. Currently, the diagnosis necessitates a kidney biopsy, with routine immunofluorescence microscopy revealing IgA as the dominant or co-dominant immunoglobulin in the glomerular immuno-deposits, often with IgG and sometimes IgM or both. Complement protein C3 is observed in most cases. IgAN leads to kidney failure in 20–40% of patients within 20 years of diagnosis and reduces average life expectancy by about 10 years. There is increasing clinical, biochemical, and genetic evidence that the complement system plays a paramount role in the pathogenesis of IgAN. The presence of C3 in the kidney immuno-deposits differentiates the diagnosis of IgAN from subclinical glomerular mesangial IgA deposition. Markers of complement activation via the lectin and alternative pathways in kidney-biopsy specimens are associated with disease activity and are predictive of poor outcome. Levels of select complement proteins in the circulation have also been assessed in patients with IgAN and found to be of prognostic value. Ongoing genetic studies have identified at least 30 loci associated with IgAN. Genes within some of these loci encode complement-system regulating proteins that can interact with immune complexes. The growing appreciation for the central role of complement components in IgAN pathogenesis highlighted these pathways as potential treatment targets and sparked great interest in pharmacological agents targeting the complement cascade for the treatment of IgAN, as evidenced by the plethora of ongoing clinical trials.

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Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Arun Rajasekaran, Bruce A. Julian & Dana V. Rizk

  2. Department of Microbiology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Todd J. Green & Jan Novak

  3. Department of Biochemistry and Molecular Genetics, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    Matthew B. Renfrow

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  1. Arun Rajasekaran
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  4. Bruce A. Julian
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  6. Dana V. Rizk
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Correspondence to Dana V. Rizk.

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Funding

The authors of this manuscript have been supported in part by Grants AI149431, DK078244, and DK082753 from the National Institutes of Health, and a gift from the IGA Nephropathy Foundation.

Conflict of interest

JN is a co-founder and co-owner of and consultant for Reliant Glycosciences, LLC. JN is a co-inventor on US patent application 14/318,082 (assigned to UAB Research Foundation). JN has a sponsored research agreement with Travere Therapeutics. BAJ is a co-founder and co-owner of Reliant Glycosciences, LLC and a co-inventor on US patent application 14/318,082 (assigned to UAB Research Foundation). MBR is a co-founder and co-owner of and consultant for Reliant Glycosciences, LLC. MBR is a co-inventor on US patent application 14/318,082 (assigned to UAB Research Foundation). DVR received research funding from Reata Pharmaceuticals, Travere Therapeutics (Retrophin), Pfizer Pharmaceuticals, Calliditas Therapeutics (Pharmalink), Otsuka Pharmaceuticals (Visterra), Vertex Pharmaceuticals, Chinook Pharmaceuticals, consultancy fees from Novartis, GSK, George Clinical, Eledon Pharmaceuticals, Otsuka Pharmaceuticals (Visterra), Calliditas Therapeutics (Pharmalink), Chinook Pharmaceuticals. DVR is co-founder and co-owner of Reliant Glycosciences, LLC. None of the listed commercial entities contributed to this study. AR and TJG have nothing to disclose.

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DVR was responsible for conceptualization; DVR, BAJ were responsible for supervision; AR, TJG, MBR, JN and DVR wrote the different sections of the initial draft of the manuscript; all authors edited the manuscript. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work before and after publication.

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Rajasekaran, A., Green, T.J., Renfrow, M.B. et al. Current Understanding of Complement Proteins as Therapeutic Targets for the Treatment of Immunoglobulin A Nephropathy. Drugs 83, 1475–1499 (2023). https://doi.org/10.1007/s40265-023-01940-2

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