Elsevier

Molecular Immunology

Volume 46, Issue 7, April 2009, Pages 1405-1408
Molecular Immunology

Is complement factor H a susceptibility factor for IgA nephropathy?

https://doi.org/10.1016/j.molimm.2008.12.002Get rights and content

Abstract

There is substantial evidence to suggest that complement activation plays a pivotal role in the pathogenesis of IgA nephropathy. Mesangial C3 deposition is seen in ∼90% of patients and polymeric IgA has been shown to activate the alternative and lectin pathways. In addition there have been reports of deficiency and mutations in the serum complement regulator factor H (CFH) in association with IgA nephropathy. In this study we have examined the hypothesis that CFH is a susceptibility factor for IgA nephropathy. In 46 IgA nephropathy patients we undertook genotyping of three CFH SNPS (rs3753394, rs3753396 and rs1065489). There was no significant difference in the allele frequency of these 3 SNPs between the patients and normal controls. In the same group of patients we undertook mutation screening of CFH exons 18–23 using direct sequencing and found no abnormalities. All the patients had a normal serum factor H concentration. In this small cohort of IgA nephropathy patients we have not found evidence to support the hypothesis that factor H is a major susceptibility factor for the disease.

Introduction

There is substantial evidence to suggest that complement plays a pivotal role in the pathogenesis of IgA nephropathy (reviewed in Oortwijn et al. (2008)). Glomerular deposition of a variety of complement components including C3, properdin, the membrane attack complex, factor H, C4 binding protein and mannan-binding lectin is seen in 60–90% of patients (Bene and Faure, 1987, D’Amico et al., 1985, Endo et al., 1998, Endo et al., 2001, Ibels and Gyory, 1994, Lhotta et al., 1999, Matsuda et al., 1998, Miyazaki et al., 1984, Rauterberg et al., 1987). It has been shown that human polymeric IgA activates the alternative pathway (Hiemstra et al., 1987, Zwirner et al., 1997) and lectin pathways (Roos et al., 2001, Roos et al., 2006) but not the classical (Lucisano Valim and Lachmann, 1991). There is also evidence of in situ activation of the alternative pathway (Tomino et al., 1981) with up-regulation of local C3 production (Abe et al., 2001). Whilst serum levels of complement proteins have been reported to be normal in the majority of IgA nephropathy patients there are anecdotal reports of deficiencies in individuals and families (Wyatt et al., 1981). In 1982, Wyatt et al. reported two families with partial factor H deficiency associated with glomerulonephritis (Wyatt et al., 1982). In one of these families five members over three generations had low levels of complement factor H. Two of the factor H-deficient individuals, a brother and sister, had biopsy-proven IgA nephropathy. In 2004 we reported the case of a female infant with atypical haemolytic uraemic syndrome (Filler et al., 2004). There was a strong family history of renal disease. The paternal grandfather had end-stage renal failure and a renal biopsy 2 years previously had shown membranoproliferative glomerulonephritis. His younger brother had died in his twenties of ‘Bright's disease’ and another brother had hypertension, diabetes and progressive renal failure. His daughter (a paternal aunt of the index patient) had been found to have hypertension, renal impairment and urinary abnormalities whilst being worked-up as a potential kidney donor. A renal biopsy showed membranoproliferative glomerulonephritis, but with glomerular IgA deposition on immunofluorescence. Mutation screening of the gene encoding factor H (CFH) in this family showed a novel mutation (c.3546_3581dup36) in CFH exon 23. This mutation leads to the insertion of 12 additional amino acids after codon 1176. The serum factor H level in all individuals found to carry this mutation was normal. The mutation was found in the index case, the paternal grandfather and the paternal aunt with IgA deposition. In 1999 a Japanese group reported a case of atypical HUS in a 35-year-old man (Morita et al., 1999). Renal biopsy showed changes consistent with HUS but also mesangial IgA deposition on immunofluorescence in association with mesangial proliferation on light microscopy. C3 levels were at the lower end of the normal range. Neither factor H levels or CFH mutation screening results were available.

This evidence led us to examine the hypothesis that CFH was a susceptibility factor for the development of IgA nephropathy To do this we examined the allele frequency of three CFH SNPs and undertook mutation screening of CFH in a cohort of IgA nephropathy patients.

Section snippets

Subjects

46 patients with biopsy-proven IgA nephropathy were studied. They were recruited from patients attending a general nephrology clinic. Date of birth, gender, year of presentation, age at presentation, year of biopsy, presenting clinical features, comorbidity, and current clinical status were recorded. Venous blood samples were collected in sodium EDTA tubes and the DNA extracted manually and stored at −40 °C. Serum C3 and C4 concentrations were measured by rate nephelometery (Beckman Array 360).

Clinical features

There were 32 males and 14 females. The age at presentation and presenting clinical features were not available for 11 patients. One patient had been lost to follow up and the current clinical status was not available. The mean age at presentation for the remaining 35 patients was 40.8 years (range 17–77). There was no significant difference in the mean age at presentation between males and females (males, 38.9 vs female, 45.7). Information on the presentation was available for 35 patients. 14

Discussion

In this study we have examined the hypothesis that CFH is a susceptibility factor for aHUS. The evidence that led us to undertake this study included reports of an association between factor H deficiency and IgA nephropathy, a case report documenting both aHUS and IgA nephropathy in the same patient, and the presence of a C-terminal factor H mutation in a patient with IgA deposition on a background of membranoproliferative glomerulonephritis. We examined the allele frequency of 3 CFH SNPs which

Acknowledgement

This study was supported by a grant for the Northern Counties Kidney Research Fund.

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