Abstract
Atypical hemolytic uremic syndrome (aHUS) has been associated with defective regulation of the alternative complement pathway. Although the use of plasma therapy is recommended, there is little consensus on the optimal treatment regimen. The outcome in many cases remains poor despite an improvement in our understanding of the pathology of aHUS. We have followed a female patient with aHUS associated with heterozygous complement Factor H (CFH) mutation (S1191L) over a period of 15 years. She has been plasma dependent since infancy and has subsequently progressed to end stage kidney disease (ESKD) requiring dialysis treatment. Despite ESKD she still depends on regular plasma infusions to prevent thrombocytopenia. The long-term treatment plan for this patient is challenging. Renal transplantation in patients with the S1191L mutation of the CFH gene carries a high risk of failure due to recurrence of aHUS in the renal graft. Thus, the only available curative treatment seems to be combined liver–kidney transplantation, covered by intensive plasma therapy, which comes with a high risk of morbidity and mortality. Antibodies against key activating components of the complement cascade may provide a promising alternative therapeutic strategy in the future. Eculizumab, a monoclonal humanized anti-C5 antibody, has recently been shown to be effective and well-tolerated in patients with paroxysmal nocturnal hemoglobinuria by preventing complement-mediated lysis of affected erythrocytes. Treatment of our patient with eculizumab is supported by recent reports on its successful use in two (pediatric and adult) patients with complement-based aHUS.
References
Gasser C, Gautier E, Steck A, Siebenmann RE, Oechslin R (1955) Hemolytic-uremic syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia. Schweiz Med Wochenschr 85:905–909
Zipfel PF, Misselwitz J, Licht C, Skerka C (2006) The role of defective complement control in hemolytic uremic syndrome. Semin Thromb Hemost 32:146–154
Loirat C, Noris M, Fremeaux-Bacchi V (2008) Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol 23:1957–1972
Jokiranta TS, Zipfel PF, Fremeaux-Bacchi V, Taylor CM, Goodship TJ, Noris M (2007) Where next with atypical hemolytic uremic syndrome? Mol Immunol 44:3889–3900
de Cordoba SR, de Jorge EG (2008) Translational mini-review series on complement factor H: genetics and disease associations of human complement factor H. Clin Exp Immunol 151:1–13
Zipfel PF, Edey M, Heinen S, Jozsi M, Richter H, Misselwitz J, Hoppe B, Routledge D, Strain L, Hughes AE, Goodship JA, Licht C, Goodship TH, Skerka C (2007) Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome. PLoS Genet 3:e41
Heinen S, Hartmann A, Lauer N, Wiehl U, Dahse HM, Schirmer S, Gropp K, Enghardt T, Wallich R, Halbich S, Mihlan M, Schlotzer-Schrehardt U, Zipfel PF, Skerka C (2009) Factor H related protein 1 (CFHR-1) inhibits complement C5 convertase activity and terminal complex formation. Blood. doi:https://doi.org/10.1182/blood-2009-02-205641
Fremeaux-Bacchi V, Dragon-Durey MA, Blouin J, Vigneau C, Kuypers D, Boudailliez B, Loirat C, Rondeau E, Fridman WH (2004) Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet 41:e84
Kavanagh D, Kemp EJ, Mayland E, Winney RJ, Duffield JS, Warwick G, Richards A, Ward R, Goodship JA, Goodship TH (2005) Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. J Am Soc Nephrol 16:2150–2155
Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, Porrati F, Gamba S, Remuzzi G (2003) Familial haemolytic uraemic syndrome and an MCP mutation. Lancet 362:1542–1547
Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, Decorte R, Muslumanoglu MH, Kavukcu S, Filler G, Pirson Y, Wen LS, Atkinson JP, Goodship TH (2003) Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci USA 100:12966–12971
Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, Lopez-Trascasa M, Sanchez-Corral P, Morgan BP, Rodriguez de Cordoba S (2007) Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci USA 104:240–245
Fremeaux-Bacchi V, Miller EC, Liszewski MK, Strain L, Blouin J, Brown AL, Moghal N, Kaplan BS, Weiss RA, Lhotta K, Kapur G, Mattoo T, Nivet H, Wong W, Gie S, Hurault de Ligny B, Fischbach M, Gupta R, Hauhart R, Meunier V, Loirat C, Dragon-Durey MA, Fridman WH, Janssen BJ, Goodship TH, Atkinson JP (2008) Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 112:4948–4952
Pickering MC, Cook HT (2008) Translational mini-review series on complement factor H: renal diseases associated with complement factor H: novel insights from humans and animals. Clin Exp Immunol 151:210–230
Jozsi M, Licht C, Strobel S, Zipfel SL, Richter H, Heinen S, Zipfel PF, Skerka C (2008) Factor H autoantibodies in atypical hemolytic uremic syndrome correlate with CFHR1/CFHR3 deficiency. Blood 111:1512–1514
Jozsi M, Strobel S, Dahse HM, Liu WS, Hoyer PF, Oppermann M, Skerka C, Zipfel PF (2007) Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome. Blood 110:1516–1518
Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, Loirat C, Pecoraro C, Taylor CM, Van de Kar N, Vandewalle J, Zimmerhackl LB (2009) Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatr Nephrol 24:687–696
Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F, Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G (2006) Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108:1267–1279
Zimmerhackl LB, Scheiring J, Prufer F, Taylor CM, Loirat C (2007) Renal transplantation in HUS patients with disorders of complement regulation. Pediatr Nephrol 22:10–16
Loirat C, Fremeaux-Bacchi V (2008) Hemolytic uremic syndrome recurrence after renal transplantation. Pediatr Transplant 12:619–629
Dragon-Durey MA, Blanc C, Marliot F, Loirat C, Blouin J, Sautes-Fridman C, Fridman WH, Fremeaux-Bacchi V (2009) 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 46:447–450
Heinen S, Jozsi M, Hartmann A, Noris M, Remuzzi G, Skerka C, Zipfel PF (2007) Hemolytic uremic syndrome: a factor H mutation (E1172Stop) causes defective complement control at the surface of endothelial cells. J Am Soc Nephrol 18:506–514
Martinez-Barricarte R, Pianetti G, Gautard R, Misselwitz J, Strain L, Fremeaux-Bacchi V, Skerka C, Zipfel PF, Goodship T, Noris M, Remuzzi G, de Cordoba SR (2008) The complement factor H R1210C mutation is associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 19:639–646
Olie KH, Florquin S, Groothoff JW, Verlaak R, Strain L, Goodship TH, Weening JJ, Davin JC (2004) Atypical relapse of hemolytic uremic syndrome after transplantation. Pediatr Nephrol 19:1173–1176
Olie KH, Goodship TH, Verlaak R, Florquin S, Groothoff JW, Strain L, Weening JJ, Davin JC (2005) Posttransplantation cytomegalovirus-induced recurrence of atypical hemolytic uremic syndrome associated with a factor H mutation: successful treatment with intensive plasma exchanges and ganciclovir. Am J Kidney Dis 45:e12–e15
Davin JC, Strain L, Goodship TH (2008) Plasma therapy in atypical haemolytic uremic syndrome: lessons from a family with a factor H mutation. Pediatr Nephrol 23:1517–1521
Lapeyraque AL, Wagner E, Phan V, Clermont MJ, Merouani A, Fremeaux-Bacchi V, Goodship TH, Robitaille P (2008) Efficacy of plasma therapy in atypical hemolytic uremic syndrome with complement factor H mutations. Pediatr Nephrol 23:1363–1366
Richards A, Buddles MR, Donne RL, Kaplan BS, Kirk E, Venning MC, Tielemans CL, Goodship JA, Goodship TH (2001) Factor H mutations in hemolytic uremic syndrome cluster in exons 18–20, a domain important for host cell recognition. Am J Hum Genet 68:485–490
Saland JM, Ruggenenti P, Remuzzi G (2009) Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol 20:940–949
Hill A, Richards SJ, Hillmen P (2007) Recent developments in the understanding and management of paroxysmal nocturnal haemoglobinuria. Br J Haematol 137:181–192
Hillmen P, Hall C, Marsh JC, Elebute M, Bombara MP, Petro BE, Cullen MJ, Richards SJ, Rollins SA, Mojcik CF, Rother RP (2004) Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria. N Engl J Med 350:552–559
Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P, Roth A, Szer J, Elebute MO, Nakamura R, Browne P, Risitano AM, Hill A, Schrezenmeier H, Fu CL, Maciejewski J, Rollins SA, Mojcik CF, Rother RP, Luzzatto L (2006) The complement inhibitor eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 355:1233–1243
Gruppo RA, Rother RP (2009) Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med 360:544–546
Nurnberger J, Witzke O, Opazo Saez A, Vester U, Baba HA, Kribben A, Zimmerhackl LB, Janecke AR, Nagel M, Kirschfink M (2009) Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med 360:542–544
Remuzzi G, Ruggenenti P, Codazzi D, Noris M, Caprioli J, Locatelli G, Gridelli B (2002) Combined kidney and liver transplantation for familial haemolytic uraemic syndrome. Lancet 359:1671–1672
Cheong HI, Lee BS, Kang HG, Hahn H, Suh KS, Ha IS, Choi Y (2004) Attempted treatment of factor H deficiency by liver transplantation. Pediatr Nephrol 19:454–458
Dragon-Durey MA, Fremeaux-Bacchi V, Loirat C, Blouin J, Niaudet P, Deschenes G, Coppo P, Herman Fridman W, Weiss L (2004) 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 15:787–795
Filler G, Radhakrishnan S, Strain L, Hill A, Knoll G, Goodship TH (2004) Challenges in the management of infantile factor H associated hemolytic uremic syndrome. Pediatr Nephrol 19:908–911
Dragon-Durey MA, Loirat C, Cloarec S, Macher MA, Blouin J, Nivet H, Weiss L, Fridman WH, Fremeaux-Bacchi V (2005) Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 16:555–563
Licht C, Weyersberg A, Heinen S, Stapenhorst L, Devenge J, Beck B, Waldherr R, Kirschfink M, Zipfel PF, Hoppe B (2005) Successful plasma therapy for atypical hemolytic uremic syndrome caused by factor H deficiency owing to a novel mutation in the complement cofactor protein domain 15. Am J Kidney Dis 45:415–421
Nathanson S, Fremeaux-Bacchi V, Deschenes G (2001) Successful plasma therapy in hemolytic uremic syndrome with factor H deficiency. Pediatr Nephrol 16:554–556
Nathanson S, Ulinski T, Fremeaux-Bacchi V, Deschenes G (2006) Secondary failure of plasma therapy in factor H deficiency. Pediatr Nephrol 21:1769–1771
Remuzzi G, Ruggenenti P, Colledan M, Gridelli B, Bertani A, Bettinaglio P, Bucchioni S, Sonzogni A, Bonanomi E, Sonzogni V, Platt JL, Perico N, Noris M (2005) Hemolytic uremic syndrome: a fatal outcome after kidney and liver transplantation performed to correct factor h gene mutation. Am J Transplant 5:1146–1150
Saland JM, Emre SH, Shneider BL, Benchimol C, Ames S, Bromberg JS, Remuzzi G, Strain L, Goodship TH (2006) Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation. Am J Transplant 6:1948–1952
Cho HY, Lee BS, Moon KC, Ha IS, Cheong HI, Choi Y (2007) Complete factor H deficiency-associated atypical hemolytic uremic syndrome in a neonate. Pediatr Nephrol 22:874–880
Davin JC, Olie KH, Verlaak R, Horuz F, Florquin S, Weening JJ, Groothoff JW, Strain L, Goodship TH (2006) Complement factor H-associated atypical hemolytic uremic syndrome in monozygotic twins: concordant presentation, discordant response to treatment. Am J Kidney Dis 47:e27–e30
Jalanko H, Peltonen S, Koskinen A, Puntila J, Isoniemi H, Holmberg C, Pinomaki A, Armstrong E, Koivusalo A, Tukiainen E, Makisalo H, Saland J, Remuzzi G, de Cordoba S, Lassila R, Meri S, Jokiranta TS (2008) Successful liver-kidney transplantation in two children with aHUS caused by a mutation in complement factor H. Am J Transplant 8:216–221
Saland JM, Shneider BL, Bromberg JS, Shi PA, Ward SC, Magid MS, Benchimol C, Seikaly MG, Emre SH, Bresin E, Remuzzi G (2009) Successful split liver-kidney transplant for factor H associated hemolytic uremic syndrome. Clin J Am Soc Nephrol 4:201–206
Sethi SK, Marie-Agnes DD, Thaker N, Hari P, Bagga A (2009) Hemolytic uremic syndrome due to homozygous factor H deficiency. Clin Exp Nephrol. doi:https://doi.org/10.1007/s10157-009-0205-3
Watt T, Warshaw B, Katzenstein HM (2009) Atypical hemolytic uremic syndrome responsive to steroids and intravenous immune globulin. Pediatr Blood Cancer 53:90–91
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
De, S., Waters, A.M., Segal, A.O. et al. Severe atypical HUS caused by CFH S1191L—case presentation and review of treatment options. Pediatr Nephrol 25, 97–104 (2010). https://doi.org/10.1007/s00467-009-1306-7
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-009-1306-7