Anti-Factor H Autoantibody–Associated Hemolytic Uremic Syndrome: Review of Literature of the Autoimmune Form of HUS

ABSTRACT

Non-Shiga toxin-associated hemolytic uremic syndrome (atypical HUS) is a rare form of thrombotic microangiopathy that associates hemolytic anemia, thrombocytopenia, and acute renal failure. The disease has been demonstrated to be linked with a complement alternative pathway dysregulation due to genetic defects but also to development of autoantibodies to factor H (FH), the main plasmatic alternative pathway regulatory protein. In this review, we summarize the more recent data of this autoimmune form of HUS at the level of epidemiology and its clinical and biological features. We propose the performance of anti-FH autoantibodies screening at the very onset of the disease in all cases of HUS to first make the proper diagnosis as early as possible, and second to support an appropriate therapy including early plasma exchanges and immunosuppressive treatments.

Atypical hemolytic uremic syndrome - complement factor H - autoantibodies - complement factor H–related proteins

REFERENCES

• 1 Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome.  N Engl J Med. 2009;  361(17) 1676-1687
• 2 Caprioli J, Noris M, Brioschi S International Registry of Recurrent and Familial HUS/TTP et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome.  Blood. 2006;  108(4) 1267-1279
• 3 Noris M, Brioschi S, Caprioli J International Registry of Recurrent and Familial HUS/TTP et al. Familial haemolytic uraemic syndrome and an MCP mutation.  Lancet. 2003;  362(9395) 1542-1547
• 4 Goodship T H, Liszewski M K, Kemp E J, Richards A, Atkinson J P. Mutations in CD46, a complement regulatory protein, predispose to atypical HUS.  Trends Mol Med. 2004;  10(5) 226-231
• 5 Frémeaux-Bacchi V, Dragon-Durey M A, Blouin J et al. Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome.  J Med Genet. 2004;  41(6) e84
• 6 Dragon-Durey M A, Frémeaux-Bacchi V, Loirat C et al. Heterozygous and homozygous factor H deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases.  J Am Soc Nephrol. 2004;  15(3) 787-795
• 7 Frémeaux-Bacchi V, Moulton E A, Kavanagh D et al. Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome.  J Am Soc Nephrol. 2006;  17(7) 2017-2025
• 8 Goicoechea de Jorge E, Harris C L, Esparza-Gordillo J et al.. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome.  Proc Natl Acad Sci U S A. 2007;  104(1) 240-245
• 9 Frémeaux-Bacchi V, Miller E C, Liszewski M K et al.. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome.  Blood. 2008;  112(13) 4948-4952
• 10 Roumenina L T, Jablonski M, Hue C et al.. Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome.  Blood. 2009;  114(13) 2837-2845
• 11 Delvaeye M, Noris M, De Vriese A et al.. Thrombomodulin mutations in atypical hemolytic-uremic syndrome.  N Engl J Med. 2009;  361(4) 345-357
• 12 Venables J P, Strain L, Routledge D et al.. Atypical haemolytic uraemic syndrome associated with a hybrid complement gene.  PLoS Med. 2006;  3(10) e431
• 13 Zipfel P F, Edey M, Heinen S et al.. Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome.  PLoS Genet. 2007;  3(3) e41
• 14 Abarrategui-Garrido C, Martínez-Barricarte R, López-Trascasa M, de Córdoba S R, Sánchez-Corral P. Characterization of complement factor H-related (CFHR) proteins in plasma reveals novel genetic variations of CFHR1 associated with atypical hemolytic uremic syndrome.  Blood. 2009;  114(19) 4261-4271
• 15 Moore I, Strain L, Pappworth I et al.. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome.  Blood. 2010;  115(2) 379-387
• 16 Dragon-Durey M A, Loirat C, Cloarec S et al.. Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome.  J Am Soc Nephrol. 2005;  16(2) 555-563
• 17 Jokiranta T S, Hellwage J, Koistinen V, Zipfel P F, Meri S. Each of the three binding sites on complement factor H interacts with a distinct site on C3b.  J Biol Chem. 2000;  275(36) 27657-27662
• 18 Józsi M, Strobel S, Dahse H M et al.. Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome.  Blood. 2007;  110(5) 1516-1518
• 19 Strobel S, Hoyer P F, Mache C J et al.. Functional analyses indicate a pathogenic role of factor H autoantibodies in atypical haemolytic uraemic syndrome.  Nephrol Dial Transplant. 2010;  25(1) 136-144
• 20 Józsi M, Licht C, Strobel S et al.. Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency.  Blood. 2008;  111(3) 1512-1514
• 21 Dragon-Durey M A, Blanc C, Marliot F et al.. The high frequency of complement factor H related CFHR1 gene deletion is restricted to specific subgroups of patients with atypical haemolytic uraemic syndrome.  J Med Genet. 2009;  46(7) 447-450
• 22 Sethi S, Dragon-Durey M A, Dinda A, Hari P, Baaga A. Autoantibodies to complement factor H are an important cause of atypical hemolytic uremic syndrome (HUS).  Pediatr Nephrol. 2009;  24(3) 627-685
• 23 Le Quintrec M, Zuber J, Noel L H et al.. Anti-Factor H autoantibodies in a fifth renal transplant recipient with atypical hemolytic and uremic syndrome.  Am J Transplant. 2009;  9(5) 1223-1229
• 24 Kwon T, Belot A, Ranchin B et al.. Varicella as a trigger of atypical haemolytic uraemic syndrome associated with complement dysfunction: two cases.  Nephrol Dial Transplant. 2009;  24(9) 2752-2754
• 25 Lee B H, Kwak S H, Shin J I et al.. Atypical hemolytic uremic syndrome associated with complement factor H autoantibodies and CFHR1/CFHR3 deficiency.  Pediatr Res. 2009;  66(3) 336-340
• 26 Kwon T, Dragon-Durey M A, Macher M A et al.. Successful pre-transplant management of a patient with anti-factor H autoantibodies-associated haemolytic uraemic syndrome.  Nephrol Dial Transplant. 2008;  23(6) 2088-2090
• 27 Sánchez-Corral P, González-Rubio C, Rodríguez de Córdoba S, López-Trascasa M. Functional analysis in serum from atypical hemolytic uremic syndrome patients reveals impaired protection of host cells associated with mutations in factor H.  Mol Immunol. 2004;  41(1) 81-84
• 28 Blanc C, Roumenina L T, Hue C et al.. Co-precipitation of CFHR proteins by anti-factor H IgG purified from atypical hemolytic uremic syndrome [FC6]. Presented at: International Workshop of Current Diagnosis and Therapy of Hemolytic Uremic Syndrome (HUS) 2009 Innsbruck, Austria;
• 29 Barbosa R E, Córdova S, Cajigas J C. Coexistence of systemic lupus erythematosus and myasthenia gravis.  Lupus. 2000;  9(2) 156-157
• 30 Morita S, Arima T, Matsuda M. Prevalence of nonthyroid specific autoantibodies in autoimmune thyroid diseases.  J Clin Endocrinol Metab. 1995;  80(4) 1203-1206
• 31 Wigger M, Drückler E, Jozsi M et al.. Course of atypical HUS due to factor H autoantibodies and CFHR1/CFHR3 deficiency during 1 year treatment with mycophenolate mofetil.  Pediatr Nephrol. 2009;  24 1777-1899 , Abstract FRI-M-1117