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  • Review Article
  • Published:

Anti-complement-factor H-associated glomerulopathies

Nature Reviews Nephrology volume 12, pages 563–578 (2016)Cite this article

Subjects

Key Points

  • Anti-complement factor H (FH)-associated haemolytic uraemic syndrome (HUS) is characterized by onset at 5–15 years of age, severe illness and marked extrarenal features

  • Anti-FH antibodies are mainly directed against the carboxy-terminal part of FH, thereby inhibiting cell surface protection from complement; they are associated with a deficiency in FH-related protein 1 (FHR1) in >80% of cases

  • Plasma exchange is the preferred therapy as it reduces levels of anti-FH antibodies; eculizumab, which blocks the terminal complement pathway, is also effective particularly in refractory cases

  • The combined use of immunosuppression is encouraged as it inhibits the production of antibodies and enables discontinuation of plasma exchange and/or treatment with eculizumab

  • The risk of post-transplantation recurrence is determined by the anti-FH antibody titre and coexisting defects in complement regulation

  • Patients with C3 glomerulopathy might show anti-FH antibodies with amino-terminal specificity, often associated with C3 nephritic factor or monoclonal gammopathy, and without FHR1 deficiency

Abstract

Atypical haemolytic uraemic syndrome (aHUS), an important cause of acute kidney injury, is characterized by dysregulation of the complement pathway, frequent need for dialysis, and progression to end-stage renal disease. Autoantibodies against complement factor H (FH), the main plasma regulatory protein of the alternative pathway of the complement system, account for a considerable proportion of children with aHUS. The autoantibodies are usually associated with the occurrence of a homozygous deletion in the genes encoding the FH-related proteins FHR1 and FHR3. High levels of autoantibodies, noted at the onset of disease and during relapses, induce functional deficiency of FH, whereas their decline, in response to plasma exchanges and/or immunosuppressive therapy, is associated with disease remission. Management with plasma exchange and immunosuppression is remarkably effective in inducing and maintaining remission in aHUS associated with FH autoantibodies, whereas terminal complement blockade with eculizumab is considered the most effective therapy in other forms of aHUS. Anti-FH autoantibodies are also detected in a small proportion of patients with C3 glomerulopathies, which are characterized by chronic glomerular injury mediated by activation of the alternative complement pathway and predominant C3 deposits on renal histology.

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Figure 1: Anti-FH antibodies in atypical HUS.
Figure 2: CFH and related genes at the RCA gene cluster on chromosome 1q32.
Figure 3: Strategies for peri-transplant management of patients with anti-factor H (FH)-associated haemolytic uraemic syndrome (HUS).

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Authors and Affiliations

  1. INSERM UMRS1138, Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, 15 rue de l'ecole de medecine, 75006, Paris, France

    Marie-Agnes Dragon Durey & Shambhuprasad Kotresh Togarsimalemath

  2. Université Paris Descartes, Paris, France

    Marie-Agnes Dragon Durey & Shambhuprasad Kotresh Togarsimalemath

  3. Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, APHP, 20 rue Leblanc, 75015, Paris, France

    Marie-Agnes Dragon Durey

  4. Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, 110029, New Delhi, India

    Aditi Sinha & Arvind Bagga

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  1. Marie-Agnes Dragon Durey
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All authors contributed to researching data for the article, discussion of the article's content, writing and reviewing or editing the manuscript before submission.

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Correspondence to Arvind Bagga.

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Supplementary information

Supplementary information S1 (table)

Frequencies of autoimmune HUS and FHR1 protein deficiency in large series of patients with atypical HUS and healthy controls (PDF 142 kb)

Supplementary information S2 (figure)

Age distribution of patients with anti-FH-associated HUS in various cohorts. (PDF 313 kb)

Supplementary information S3 (figure)

Epitope specificity of anti-FH antibodies in patients with atypical HUS. (PDF 789 kb)

Supplementary information S4 (table)

Concomitant inherited defects in patients with anti-FH-associated HUS, other than deletions of CFHR1 and CFHR3 (PDF 206 kb)

Supplementary information S5 (table)

Outcomes of anti-FH-associated HUS in relation to therapies (PDF 220 kb)

Supplementary information S6 (table)

Clinical features and outcome in patients with anti-FH antibody associated HUS managed with eculizumab (PDF 170 kb)

Supplementary information S7 (table)

Clinical characteristics of patients with C3 glomerulopathy with anti-FH antibodies* (PDF 204 kb)

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Durey, MA., Sinha, A., Togarsimalemath, S. et al. Anti-complement-factor H-associated glomerulopathies. Nat Rev Nephrol 12, 563–578 (2016). https://doi.org/10.1038/nrneph.2016.99

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