Top

Pediatric Nephrology

Published in:

01-05-2015 | Original Article

Eculizumab hepatotoxicity in pediatric aHUS

Authors: Wesley Hayes, Sibylle Tschumi, Simon C. Ling, Janusz Feber, Michael Kirschfink, Christoph Licht

Published in: Pediatric Nephrology | Issue 5/2015

Abstract

Background

Eculizumab is a humanized anti-C5 antibody approved for the treatment of atypical hemolytic uremic syndrome (aHUS). Its use is increasing in children following reports of its safety and efficacy.

Methods

We reviewed biochemical and clinical data related to possible drug-induced liver injury in 11 children treated with eculizumab for aHUS in a single center.

Results

Elevated aminotransferases were observed in 7 children aged 6 to 11 years following eculizumab treatment for aHUS. Internationally accepted liver enzyme thresholds for drug-induced liver injury were exceeded in 5 cases. In all cases, liver injury was classified as mixed hepatocellular and cholestatic. Infectious and other causes were excluded in each case. One patient with no pre-existing liver disease developed tender hepatomegaly and liver enzyme derangement exceeding 20 times the upper limit of normal following initiation of eculizumab. Recurrent liver injury following re-challenge with eculizumab necessitated its discontinuation and transition to plasma therapy.

Conclusions

Hepatotoxicity in association with eculizumab is a potentially important yet previously unreported adverse event. We recommend monitoring liver enzymes in all patients receiving eculizumab. Further research is required to clarify the impact of this adverse event, to characterize the mechanism of potential hepatotoxicity, and to identify which patients are most at risk.

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 350:552–559CrossRefPubMed

Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, Gaya A, Coyle L, de Castro C, Fu CL, Maciejewski JP, Bessler M, Kroon HA, Rother RP, Hillmen P (2008) Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood 111:1840–1847CrossRefPubMed

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 355:1233–1243CrossRefPubMed

Schmidtko J, Peine S, El-Housseini Y, Pascual M, Meier P (2013) Treatment of atypical hemolytic uremic syndrome and thrombotic microangiopathies: a focus on eculizumab. Am J Kidney Dis 61:289–299CrossRefPubMed

Hodgkins KS, Bobrowski AE, Lane JC, Langman CB (2012) Clinical grand rounds: atypical hemolytic uremic syndrome. Am J Nephrol 35:394–400CrossRefPubMed

Gruppo RA, Rother RP (2009) Eculizumab for congenital atypical hemolytic-uremic syndrome. N Engl J Med 360:544–546CrossRefPubMed

Nurnberger J, Philipp T, 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 360:542–544CrossRefPubMed

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

Gleesing J, Chiwane S, Rongkavilit C (2012) Gonococcal septic shock associated with eculizumab treatment. Pediatr Infect Dis J 31:543CrossRefPubMed

10.

Balagula Y, Newman SB, Lacouture ME (2010) Photodermatosis associated with eculizumab (Soliris): a novel monoclonal antibody directed against the complement protein C5. Am J Hematol 85:392–393PubMed

11.

Manganoni AM, Pavoni L, Facchetti F, Farisoglio C, Sereni E, Calzavara-Pinton P (2012) Melanoma in a patient in treatment with eculizumab. Ann Hematol 91:135–136CrossRefPubMed

12.

Knoll BM, Letendre L, Steensma DP (2008) Life-threatening desquamating rash and hyperammonemia following administration of eculizumab for paroxysmal nocturnal hemoglobinuria. Am J Hematol 83:881–883CrossRefPubMed

13.

Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, Hunt CM, Wilke RA, Avigan M, Kaplowitz N, Bjornsson E, Daly AK (2011) Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther 89:806–815CrossRefPubMed

14.

Unizony S, Arias-Urdaneta L, Miloslavsky E, Arvikar S, Khosroshahi A, Keroack B, Stone JR, Stone JH (2012) Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica. Arthritis Care Res 64:1720–1729CrossRef

15.

Navarro-Millan I, Singh JA, Curtis JR (2012) Systematic review of tocilizumab for rheumatoid arthritis: a new biologic agent targeting the interleukin-6 receptor. Clin Ther 34:788–802CrossRefPubMedCentralPubMed

16.

Hassan R, Cohen SJ, Phillips M, Pastan I, Sharon E, Kelly RJ, Schweizer C, Weil S, Laheru D (2010) Phase I clinical trial of the chimeric anti-mesothelin monoclonal antibody MORAb-009 in patients with mesothelin-expressing cancers. Clin Cancer Res 16:6132–6138CrossRefPubMedCentralPubMed

17.

Langenberg MH, Witteveen PO, Lankheet NA, Roodhart JM, Rosing H, van den Heuvel IJ, Beijnen JH, Voest EE (2010) Phase 1 study of combination treatment with PTK 787/ZK 222584 and cetuximab for patients with advanced solid tumors: safety, pharmacokinetics, pharmacodynamics analysis. Neoplasia 12:206–213PubMedCentralPubMed

18.

Trarbach T, Moehler M, Heinemann V, Kohne CH, Przyborek M, Schulz C, Sneller V, Gallant G, Kanzler S (2010) Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer. Br J Cancer 102:506–512CrossRefPubMedCentralPubMed

19.

Ierardi E, Valle ND, Nacchiero MC, De Francesco V, Stoppino G, Panella C (2006) Onset of liver damage after a single administration of infliximab in a patient with refractory ulcerative colitis. Clin Drug Invest 26:673–676CrossRef

20.

Menghini VV, Arora AS (2001) Infliximab-associated reversible cholestatic liver disease. Mayo Clin Proc 76:84–86CrossRefPubMed

21.

Saleem G, Li SC, MacPherson BR, Cooper SM (2001) Hepatitis with interface inflammation and IgG, IgM, and IgA anti-double-stranded DNA antibodies following infliximab therapy: comment on the article by Charles et al. Arthritis Rheum 44:1966–1968CrossRefPubMed

22.

Germano V, Picchianti Diamanti A, Baccano G, Natale E, Onetti Muda A, Priori R, Valesini G (2005) Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis. Ann Rheum Dis 64:1519–1520CrossRefPubMedCentralPubMed

23.

Tobon GJ, Canas C, Jaller JJ, Restrepo JC, Anaya JM (2007) Serious liver disease induced by infliximab. Clin Rheumatol 26:578–581CrossRefPubMed

24.

Soto-Fernandez S, Gonzalez-Carro P, De Pedro-Esteban A, Legaz-Huidobro ML, Perez-Roldan F, Roncero Garcia-Escribano O, Valbuena-Gonzalez M, Ruiz-Carrillo F (2006) Infliximab-induced hepatitis in a patient with Crohn’s disease. Gastroenterol Hepatol 29:321–322CrossRefPubMed

25.

Ozorio G, McGarity B, Bak H, Jordan AS, Lau H, Marshall C (2007) Autoimmune hepatitis following infliximab therapy for ankylosing spondylitis. Med J Aust 187:524–526PubMed

26.

Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L (2007) Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol 25:1256–1264CrossRefPubMed

27.

Brodsky A, Mazzocchi O, Sanchez F, Khursigara G, Malhotra S, Volpacchio M (2012) Eculizumab in paroxysmal nocturnal hemoglobinuria with Budd-Chiari syndrome progressing despite anticoagulation. Exp Hematol Oncol 1:26CrossRefPubMedCentralPubMed

28.

Dragon-Durey MA, Sethi SK, Bagga A, Blanc C, Blouin J, Ranchin B, Andre JL, Takagi N, Cheong HI, Hari P, Le Quintrec M, Niaudet P, Loirat C, Fridman WH, Fremeaux-Bacchi V (2010) Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome. J Am Soc Nephrol 21:2180–2187CrossRefPubMedCentralPubMed

29.

Loriot Y, Perlemuter G, Malka D, Penault-Llorca F, Boige V, Deutsch E, Massard C, Armand JP, Soria JC (2008) Drug insight: gastrointestinal and hepatic adverse effects of molecular-targeted agents in cancer therapy. Nat Clin Pract Oncol 5:268–278CrossRefPubMed

30.

McKoy JM, Angelotta C, Bennett CL, Tallman MS, Wadleigh M, Evens AM, Kuzel TM, Trifilio SM, Raisch DW, Kell J, DeAngelo DJ, Giles FJ (2007) Gemtuzumab ozogamicin-associated sinusoidal obstructive syndrome (SOS): an overview from the research on adverse drug events and reports (RADAR) project. Leuk Res 31:599–604CrossRefPubMed

31.

Maniecki MB, Hasle H, Friis-Hansen L, Lausen B, Nielsen OJ, Bendix K, Moestrup SK, Moller HJ (2008) Impaired CD163-mediated hemoglobin-scavenging and severe toxic symptoms in patients treated with gemtuzumab ozogamicin. Blood 112:1510–1514CrossRefPubMed

32.

Mastellos D, Papadimitriou JC, Franchini S, Tsonis PA, Lambris JD (2001) A novel role of complement: mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration. J Immunol 166:2479–2486CrossRefPubMed

33.

Schieferdecker HL, Schlaf G, Jungermann K, Gotze O (2001) Functions of anaphylatoxin C5a in rat liver: direct and indirect actions on nonparenchymal and parenchymal cells. Int Immunopharmacol 1:469–481CrossRefPubMed

34.

Cao Y, Marks JD, Huang Q, Rudnick SI, Xiong C, Hittelman WN, Wen X, Marks JW, Cheung LH, Boland K, Li C, Adams GP, Rosenblum MG (2012) Single-chain antibody-based immunotoxins targeting Her2/neu: design optimization and impact of affinity on antitumor efficacy and off-target toxicity. Mol Cancer Ther 11:143–153CrossRefPubMed

35.

Herlitz LC, Bomback AS, Markowitz GS, Stokes MB, Smith RN, Colvin RB, Appel GB, D’Agati VD (2012) Pathology after eculizumab in dense deposit disease and C3 GN. J Am Soc Nephrol 23:1229–1237CrossRefPubMedCentralPubMed

36.

Hillebrandt S, Wasmuth HE, Weiskirchen R, Hellerbrand C, Keppeler H, Werth A, Schirin-Sokhan R, Wilkens G, Geier A, Lorenzen J, Kohl J, Gressner AM, Matern S, Lammert F (2005) Complement factor 5 is a quantitative trait gene that modifies liver fibrogenesis in mice and humans. Nat Genet 37:835–843CrossRefPubMed

37.

Andrade RJ, Lucena MI, Kaplowitz N, Garcia-Munoz B, Borraz Y, Pachkoria K, Garcia-Cortes M, Fernandez MC, Pelaez G, Rodrigo L, Duran JA, Costa J, Planas R, Barriocanal A, Guarner C, Romero-Gomez M, Munoz-Yague T, Salmeron J, Hidalgo R (2006) Outcome of acute idiosyncratic drug-induced liver injury: Long-term follow-up in a hepatotoxicity registry. Hepatology 44:1581–1588CrossRefPubMed

Title: Eculizumab hepatotoxicity in pediatric aHUS
Authors: Wesley Hayes
Sibylle Tschumi
Simon C. Ling
Janusz Feber
Michael Kirschfink
Christoph Licht
Publication date: 01-05-2015
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 5/2015
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-014-2990-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Eculizumab hepatotoxicity in pediatric aHUS

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 5/2015

Short-term survival of hyperammonemic neonates treated with dialysis

Viral surveillance and subclinical viral infection in pediatric kidney transplantation

Does obesity or hyperuricemia influence lithogenic risk profile in children with urolithiasis?

Healthcare burden of venous thromboembolism in childhood chronic renal diseases

An unusual cause of gross hematuria: Answers

Comparison between adults and children with Henoch–Schönlein purpura nephritis