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

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


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.

Publication types

  • Comparative Study

MeSH terms

  • Adult
  • Blood Proteins / genetics
  • Cohort Studies
  • Complement C3b Inactivator Proteins / analysis*
  • Complement C3b Inactivator Proteins / genetics
  • Complement Factor H / analysis
  • Complement Factor H / genetics
  • Complement Pathway, Alternative / genetics*
  • Disease Progression
  • Female
  • Glomerular Filtration Rate
  • Glomerulonephritis, IGA / blood*
  • Glomerulonephritis, IGA / genetics
  • Humans
  • Male
  • Middle Aged
  • Polycystic Kidney, Autosomal Dominant / blood*
  • Polycystic Kidney, Autosomal Dominant / genetics
  • Renal Insufficiency, Chronic / blood*
  • Renal Insufficiency, Chronic / genetics
  • Young Adult


  • Blood Proteins
  • CFH protein, human
  • CFHR1 protein, human
  • CFHR3 protein, human
  • Complement C3b Inactivator Proteins
  • Complement Factor H