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01-05-2016 | Original Article

Liver transplantation for aHUS: still needed in the eculizumab era?

Authors: Rosanna Coppo, Roberto Bonaudo, R. Licia Peruzzi, Alessandro Amore, Andrea Brunati, Renato Romagnoli, Mauro Salizzoni, Miriam Galbusera, Eliana Gotti, Erica Daina, Marina Noris, Giuseppe Remuzzi

Published in: Pediatric Nephrology | Issue 5/2016

Abstract

Background

The risk of disease recurrence after a kidney transplant is high in patients with atypical hemolytic uremic syndrome (aHUS) and mutations in the complement factor H (FH) gene (CFH). Since FH is mostly produced by the liver, a kidney transplant does not correct the genetic defect. The anti-C5 antibody eculizumab prevents post-transplant aHUS recurrence, but it does not cure the disease. Combined liver–kidney transplantation has been performed in few patients with CFH mutations based on the rationale that liver replacement provides a source of normal FH.

Methods

We report the 9-year follow-up of a child with aHUS and a CFH mutation, including clinical data, extensive genetic characterization, and complement profile in the circulation and at endothelial level. The outcome of kidney and liver transplants performed separately 3 years apart are reported.

Results

The patient showed incomplete response to plasma, with relapsing episodes, progression to end-stage renal disease, and endothelial-restricted complement dysregulation. Eculizumab prophylaxis post-kidney transplant did not achieve sustained remission, leaving the child at risk of disease recurrence. A liver graft given 3 years after the kidney transplant completely abrogated endothelial complement activation and allowed eculizumab withdrawal.

Conclusions

Liver transplant may definitely cure aHUS and represents an option for patients with suboptimal response to eculizumab.

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Noris M, Remuzzi G (2009) Atypical hemolytic-uremic syndrome. N Engl J Med 361:1676–1687CrossRefPubMed

Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, Daina E, Fenili C, Castelletti F, Sorosina A, Piras R, Donadelli R, Maranta R, van der Meer I, Conway EM, Zipfel PF, Goodship TH, Remuzzi G (2010) Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol 5:1844–1859CrossRefPubMedPubMedCentral

Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, Goodship TH, Remuzzi G (2006) Outcome of renal transplantation in patients with non-Shiga toxin-associated hemolytic uremic syndrome: prognostic significance of genetic background. Clin J Am Soc Nephrol 1:88–99CrossRefPubMed

Loirat C, Fremeaux-Bacchi V (2008) Hemolytic uremic syndrome recurrence after renal transplantation. Pediatr Transplant 12:619–629CrossRefPubMed

Le Quintrec M, Zuber J, Moulin B, Kamar N, Jablonski M, Lionet A, Chatelet V, Mousson C, Mourad G, Bridoux F, Cassuto E, Loirat C, Rondeau E, Delahousse M, Fremeaux-Bacchi V (2013) Complement genes strongly predict recurrence and graft outcome in adult renal transplant recipients with atypical hemolytic and uremic syndrome. Am J Transplant 13:663–675CrossRefPubMed

Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, Bingham C, Cohen DJ, Delmas Y, Douglas K, Eitner F, Feldkamp T, Fouque D, Furman RR, Gaber O, Herthelius M, Hourmant M, Karpman D, Lebranchu Y, Mariat C, Menne J, Moulin B, Nurnberger J, Ogawa M, Remuzzi G, Richard T, Sberro-Soussan R, Severino B, Sheerin NS, Trivelli A, Zimmerhackl LB, Goodship T, Loirat C (2013) Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med 368:2169–2181CrossRefPubMed

Noris M, Remuzzi G (2013) Managing and preventing atypical hemolytic uremic syndrome recurrence after kidney transplantation. Curr Opin Nephrol Hypertens 22:704–712CrossRefPubMed

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 359:1671–1672CrossRefPubMed

Saland JM, Ruggenenti P, Remuzzi G (2009) Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol 20:940–949CrossRefPubMed

10.

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 5:1146–1150CrossRefPubMed

11.

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 6:1948–1952CrossRefPubMed

12.

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 8:216–221PubMed

13.

Loirat C, Noris M, Fremeaux-Bacchi V (2008) Complement and the atypical hemolytic uremic syndrome in children. Pediatr Nephrol 23:1957–1972CrossRefPubMed

14.

Saland J (2014) Liver-kidney transplantation to cure atypical HUS: still an option post-eculizumab? Pediatr Nephrol 29:329–332CrossRefPubMed

15.

Noris M, Galbusera M, Gastoldi S, Macor P, Banterla F, Bresin E, Tripodo C, Bettoni S, Donadelli R, Valoti E, Tedesco F, Amore A, Coppo R, Ruggenenti P, Gotti E, Remuzzi G (2014) Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood 124:1715–1726CrossRefPubMedPubMedCentral

16.

Valoti E, Alberti M, Tortajada A, Garcia-Fernandez J, Gastoldi S, Besso L, Bresin E, Remuzzi G, Rodriguez de Cordoba S, Noris M (2015) A novel atypical hemolytic uremic syndrome-associated hybrid CFHR1/CFH gene encoding a fusion protein that antagonizes factor H-dependent complement regulation. J Am Soc Nephrol 26:209–219CrossRefPubMedPubMedCentral

17.

Schwartz GJ, Haycock GB, Edelmann CM Jr, Spitzer A (1976) A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 58:259–263PubMed

18.

Schwartz GJ, Work DF (2009) Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol 4:1832–1843CrossRefPubMed

19.

Lara PN Jr, Coe TL, Zhou H, Fernando L, Holland PV, Wun T (1999) Improved survival with plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Am J Med 107:573–579CrossRefPubMed

20.

Heinen S, Sanchez-Corral P, Jackson MS, Strain L, Goodship JA, Kemp EJ, Skerka C, Jokiranta TS, Meyers K, Wagner E, Robitaille P, Esparza-Gordillo J, Rodriguez de Cordoba S, Zipfel PF, Goodship TH (2006) De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome. Hum Mutat 27:292–293CrossRefPubMed

21.

Pickering MC, de Jorge EG, Martinez-Barricarte R, Recalde S, Garcia-Layana A, Rose KL, Moss J, Walport MJ, Cook HT, de Cordoba SR, Botto M (2007) Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains. J Exp Med 204:1249–1256CrossRefPubMedPubMedCentral

22.

Caprioli J, Castelletti F, Bucchioni S, Bettinaglio P, Bresin E, Pianetti G, Gamba S, Brioschi S, Daina E, Remuzzi G, Noris M (2003) Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease. Hum Mol Genet 12:3385–3395CrossRefPubMed

23.

Esparza-Gordillo J, Goicoechea de Jorge E, Buil A, Carreras Berges L, Lopez-Trascasa M, Sanchez-Corral P, Rodriguez de Cordoba S (2005) Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum Mol Genet 14:703–712CrossRefPubMed

24.

Remuzzi G, Galbusera M, Noris M, Canciani MT, Daina E, Bresin E, Contaretti S, Caprioli J, Gamba S, Ruggenenti P, Perico N, Mannucci PM (2002) von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Blood 100:778–785CrossRefPubMed

25.

Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH (1994) Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 369:64–67CrossRefPubMed

26.

Sibani S, Leclerc D, Weisberg IS, O'Ferrall E, Watkins D, Artigas C, Rosenblatt DS, Rozen R (2003) Characterization of mutations in severe methylenetetrahydrofolate reductase deficiency reveals an FAD-responsive mutation. Hum Mutat 21:509–520CrossRefPubMed

27.

Herbert AP, Kavanagh D, Johansson C, Morgan HP, Blaum BS, Hannan JP, Barlow PN, Uhrin D (2012) Structural and functional characterization of the product of disease-related factor H gene conversion. Biochemistry 51:1874–1884CrossRefPubMed

28.

Zimmerhackl LB, Hofer J, Cortina G, Mark W, Wurzner R, Jungraithmayr TC, Khursigara G, Kliche KO, Radauer W (2010) Prophylactic eculizumab after renal transplantation in atypical hemolytic-uremic syndrome. N Engl J Med 362:1746–1748CrossRefPubMed

29.

Zipfel PF, Skerka C (1994) Complement factor H and related proteins: an expanding family of complement-regulatory proteins? Immunol Today 15:121–126CrossRefPubMed

30.

Assinger A (2014) Platelets and infection - an emerging role of platelets in viral infection. Front Immunol 5:649CrossRefPubMedPubMedCentral

31.

Bresin E, Rurali E, Caprioli J, Sanchez-Corral P, Fremeaux-Bacchi V, Rodriguez de Cordoba S, Pinto S, Goodship TH, Alberti M, Ribes D, Valoti E, Remuzzi G, Noris M (2013) Combined complement gene mutations in atypical hemolytic uremic syndrome influence clinical phenotype. J Am Soc Nephrol 24:475–486CrossRefPubMedPubMedCentral

32.

Noris M, Remuzzi G (2013) Overview of complement activation and regulation. Semin Nephrol 33:479–492CrossRefPubMedPubMedCentral

33.

Licht C, Greenbaum LA, Muus P, Babu S, Bedrosian CL, Cohen DJ, Delmas Y, Douglas K, Furman RR, Gaber OA, Goodship T, Herthelius M, Hourmant M, Legendre CM, Remuzzi G, Sheerin N, Trivelli A, Loirat C (2015) Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int 87:1061–1073CrossRefPubMedPubMedCentral

34.

Nishimura J, Yamamoto M, Hayashi S, Ohyashiki K, Ando K, Brodsky AL, Noji H, Kitamura K, Eto T, Takahashi T, Masuko M, Matsumoto T, Wano Y, Shichishima T, Shibayama H, Hase M, Li L, Johnson K, Lazarowski A, Tamburini P, Inazawa J, Kinoshita T, Kanakura Y (2014) Genetic variants in C5 and poor response to eculizumab. N Engl J Med 370:632–639CrossRefPubMed

35.

Peffault de Latour R, Fremeaux-Bacchi V, Porcher R, Xhaard A, Rosain J, Castaneda DC, Vieira-Martins P, Roncelin S, Rodriguez-Otero P, Plessier A, Sicre de Fontbrune F, Abbes S, Robin M, Socie G (2015) Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Blood 125:775–783CrossRefPubMed

36.

Schalk G, Kirschfink M, Wehling C, Gastoldi S, Bergmann C, Hoppe B, Weber LT (2015) A complicated case of atypical hemolytic uremic syndrome with frequent relapses under eculizumab. Pediatr Nephrol 30:1039–1042CrossRefPubMed

37.

Goyette P, Sumner JS, Milos R, Duncan AM, Rosenblatt DS, Matthews RG, Rozen R (1994) Human methylenetetrahydrofolate reductase: isolation of cDNA, mapping and mutation identification. Nat Genet 7:195–200CrossRefPubMed

38.

Frosst P, Blom HJ, Milos R, Goyette P, Sheppard CA, Matthews RG, Boers GJ, den Heijer M, Kluijtmans LA, van den Heuvel LP, Rozen R (1995) A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet 10:111–113CrossRefPubMed

39.

Goyette P, Rozen R (2000) The thermolabile variant 677C-->T can further reduce activity when expressed in cis with severe mutations for human methylenetetrahydrofolate reductase. Hum Mutat 16:132–138

40.

Morita H, Taguchi J, Kurihara H, Kitaoka M, Kaneda H, Kurihara Y, Maemura K, Shindo T, Minamino T, Ohno M, Yamaoki K, Ogasawara K, Aizawa T, Suzuki S, Yazaki Y (1997) Genetic polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) as a risk factor for coronary artery disease. Circulation 95:2032–2036CrossRefPubMed

41.

Jakubowski H, Boers GH, Strauss KA (2008) Mutations in cystathionine beta-synthase or methylenetetrahydrofolate reductase gene increase N-homocysteinylated protein levels in humans. FASEB J 22:4071–4076CrossRefPubMed

42.

Forbes TA, Bradbury MG, Goodship TH, McKiernan PJ, Milford DV (2013) Changing strategies for organ transplantation in atypical haemolytic uraemic syndrome: a tertiary case series. Pediatr Transplant 17:E93–E99CrossRefPubMed

43.

Tran H, Chaudhuri A, Concepcion W, Grimm PC (2014) Use of eculizumab and plasma exchange in successful combined liver-kidney transplantation in a case of atypical HUS associated with complement factor H mutation. Pediatr Nephrol 29:477–480CrossRefPubMed

44.

Luzzatto L, Hollak CE, Cox TM, Schieppati A, Licht C, Kaariainen H, Merlini G, Schaefer F, Simoens S, Pani L, Garattini S, Remuzzi G (2015) Rare diseases and effective treatments: are we delivering? Lancet 385:750–752CrossRefPubMed

Title: Liver transplantation for aHUS: still needed in the eculizumab era?
Authors: Rosanna Coppo
Roberto Bonaudo
R. Licia Peruzzi
Alessandro Amore
Andrea Brunati
Renato Romagnoli
Mauro Salizzoni
Miriam Galbusera
Eliana Gotti
Erica Daina
Marina Noris
Giuseppe Remuzzi
Publication date: 01-05-2016
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 5/2016
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-015-3278-0

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Liver transplantation for aHUS: still needed in the eculizumab era?

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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