Genetics of Immune-Mediated Glomerular Diseases: Focus on Complement

Semin Nephrol. 2017 Sep;37(5):447-463. doi: 10.1016/j.semnephrol.2017.05.018.

Abstract

The spectrum of immune-mediated glomerular diseases is wide, ranging from rare diseases with well-recognized genetic origins to more common and multifactorial diseases. Immune-mediated glomerular injury is complex and involves both the innate and the adaptive immune systems. In the past 20 years a huge effort has been undertaken to unravel the genetic basis of immune-mediated glomerular diseases. The discovery of abnormalities in genes encoding proteins of the alternative pathway of complement in more than 50% of patients with atypical hemolytic uremic syndrome (aHUS), and in approximately 20% of patients with membranoproliferative glomerulonephritis (MPGN), has highlighted the role of this complement pathway in the pathogenesis of immune-mediated glomerular diseases. aHUS-associated complement gene abnormalities mainly result in complement dysregulation restricted to the cell surface, whereas complement activation in the fluid phase prevails in most, but not all, genetic cases of MPGN. Results achieved in aHUS and MPGN have boosted interest in the impact of complement gene abnormalities and variations in the predisposition to more common, multifactorial kidney diseases, including IgA nephropathy and lupus nephritis. Emerging findings in these complex diseases have broadened our understanding of the fragile balance between the protective and harmful functions of the complement system.

Keywords: Genetics; IgA nephropathy; atypical hemolytic uremic syndrome; complement; glomerular diseases; lupus nephritis; membranoproliferative glomerulonephritis.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atypical Hemolytic Uremic Syndrome / etiology
  • Atypical Hemolytic Uremic Syndrome / genetics*
  • Atypical Hemolytic Uremic Syndrome / immunology
  • Complement System Proteins / genetics*
  • Glomerulonephritis, IGA / genetics*
  • Glomerulonephritis, Membranoproliferative / etiology
  • Glomerulonephritis, Membranoproliferative / genetics*
  • Glomerulonephritis, Membranoproliferative / immunology
  • Humans
  • Lupus Nephritis / genetics*

Substances

  • FHR5 protein, human
  • Complement System Proteins