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Kidney Int. 2017 Oct;92(4):953-963. doi: 10.1016/j.kint.2017.03.041. Epub 2017 Jun 19.

Elevated factor H-related protein 1 and factor H pathogenic variants decrease complement regulation in IgA nephropathy.

Author information

1
Department of Cellular and Molecular Medicine and Center for Biological Research and Center for Biomedical Network Research on Rare Diseases, Madrid, Spain.
2
Department of Nephrology, Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain.
3
Department of Immunology, Faculty of Medicine, Complutense University and Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain.
4
Division of Nephrology, Hospital Vall d'Hebron, Barcelona, Spain.
5
Department of Nephrology, Hospital Reina Sofía, Cordoba, Spain.
6
Department of Medicine, University of Barcelona, Hospital Clínic, Barcelona, Spain.
7
Pediatric Nephrology Unit, Hospital La Fe, Valencia, Spain.
8
Servicio de Nefrologia, Hospital German Trias i Pujol, Badalona, Barcelona, Spain.
9
Unidad de Inmunología, Hospital Universitario de La Paz and Center for Biological Research and Center for Biomedical Network Research on Rare Diseases, Madrid, Spain.
10
Department of Nephrology, Research Institute Hospital 12 de Octubre (imas12), Madrid, Spain; Department of Medicine, Complutense University, Madrid, Spain.
11
Department of Cellular and Molecular Medicine and Center for Biological Research and Center for Biomedical Network Research on Rare Diseases, Madrid, Spain. Electronic address: srdecordoba@cib.csic.es.

Abstract

IgA nephropathy (IgAN), a frequent cause of chronic kidney disease worldwide, is characterized by mesangial deposition of galactose-deficient IgA1-containing immune complexes. Complement involvement in IgAN pathogenesis is suggested by the glomerular deposition of complement components and the strong protection from IgAN development conferred by the deletion of the CFHR3 and CFHR1 genes (ΔCFHR3-CFHR1). Here we searched for correlations between clinical progression and levels of factor H (FH) and FH-related protein 1 (FHR-1) using well-characterized patient cohorts consisting of 112 patients with IgAN, 46 with non-complement-related autosomal dominant polycystic kidney disease (ADPKD), and 76 control individuals. Patients with either IgAN or ADPKD presented normal FH but abnormally elevated FHR-1 levels and FHR-1/FH ratios compared to control individuals. Highest FHR-1 levels and FHR-1/FH ratios are found in patients with IgAN with disease progression and in patients with ADPKD who have reached chronic kidney disease, suggesting that renal function impairment elevates the FHR-1/FH ratio, which may increase FHR-1/FH competition for activated C3 fragments. Interestingly, ΔCFHR3-CFHR1 homozygotes are protected from IgAN, but not from ADPKD, and we found five IgAN patients with low FH carrying CFH or CFI pathogenic variants. These data support a decreased FH activity in IgAN due to increased FHR-1/FH competition or pathogenic CFH variants. They also suggest that alternative pathway complement activation in patients with IgAN, initially triggered by galactose-deficient IgA1-containing immune complexes, may exacerbate in a vicious circle as renal function deterioration increase FHR-1 levels. Thus, a role of FHR-1 in IgAN pathogenesis is to compete with complement regulation by FH.

KEYWORDS:

CFH mutation; IgAN; complement alternative pathway; factor H; factor H-related proteins

PMID:
28637589
DOI:
10.1016/j.kint.2017.03.041
[Indexed for MEDLINE]

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