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Autoantibodies in Kidney Diseases

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Front. Immunol. | doi: 10.3389/fimmu.2019.00504

The Emerging Role of Complement Proteins as a Target for Therapy of IgA Nephropathy

  • 1Department of Medicine, School of Medicine, University of Alabama at Birmingham, United States
  • 2Department of Nephrology, Dialysis, Transplantation, CHU de Saint-Etienne, Université Jean Monnet, France
  • 3Department of Microbiology, School of Medicine, University of Alabama at Birmingham, United States
  • 4Department of Immunology, Faculty of Medicine and Dentistry, Palacky University and 12 University Hospital, Czechia
  • 5Department of Pediatrics, University of Tennessee Health Sciences Center, United States

IgA nephropathy is the most common form of primary glomerulonephritis worldwide and a common cause of end-stage renal disease. Evaluation of a kidney biopsy is necessary for diagnosis, with routine immunofluorescence-microscopy revealing dominant or co-dominant IgA immunodeposits usually with complement C3 and sometimes IgG and/or IgM. IgA nephropathy reduces life expectancy by more than 10 years and leads to kidney failure in 20-40% of patients within 20 years of diagnosis.
There is accumulating clinical, genetic, and biochemical evidence that complement plays an important role in the pathogenesis of IgA nephropathy. The presence of C3 differentiates the diagnosis of IgA nephropathy from the subclinical deposition of glomerular IgA. Markers for the activation of the alternative and mannan-binding lectin pathways in renal-biopsy specimens are associated with disease activity and portend a worse renal outcome. Complement proteins in the circulation have also been evaluated in IgA nephropathy and found to be of prognostic value. Recently, genetic studies have identified IgA nephropathy-associated loci. Within these loci are genes encoding products involved in complement regulation and interaction with immune complexes. Put together, these data identify the complement cascade as a rational treatment target for this chronic kidney disease. Recent case reports on the successful use of humanized anti-C5 monoclonal antibody eculizumab are consistent with this hypothesis, but a better understanding of the role of complement in IgA nephropathy is needed to guide future therapeutic interventions.

Keywords: IgA nephropathy, complement, therapy, immune complexes, Alternative complement pathway, Mannan binding lectin pathway

Received: 11 Dec 2018; Accepted: 25 Feb 2019.

Edited by:

Bradley P. Dixon, Children's Hospital Colorado, United States

Reviewed by:

Jonathan Barratt, University of Leicester, United Kingdom
Licia Peruzzi, Regina Margherita Hospital, Italy
Richard J. Glassock, UCLA David Geffen School of Medicine, United States  

Copyright: © 2019 Rizk, Maillard, Julian, Knoppova, Green, Novak and Wyatt. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
MD. Dana V. Rizk, Department of Medicine, School of Medicine, University of Alabama at Birmingham, Birmingham, AL 35233, Alabama, United States, drizk@uab.edu
MD. RobertRobert J. Wyatt, Department of Pediatrics, University of Tennessee Health Sciences Center, Memphis, 38103, Tennessee, United States, rwyatt@uthsc.edu