Top

Published in:

01-01-2014 | Original Article

Long-term remission of atypical HUS with anti-factor H antibodies after cyclophosphamide pulses

Authors: Gwenaëlle Sana, Marie-Agnès Dragon-Durey, Marina Charbit, Karim Bouchireb, Caroline Rousset-Rouvière, Etienne Bérard, Rémi Salomon, Véronique Frémeaux-Bacchi, Patrick Niaudet, Olivia Boyer

Published in: Pediatric Nephrology | Issue 1/2014

Abstract

Background

Anti-complement factor H (CFH) autoantibody (Ab)-associated atypical hemolytic uremic syndrome (aHUS) has a poor prognosis, but no consensus exists on its treatment.

Methods

We report the follow-up of four children with anti-CFH Ab (8,000 to >32,000 arbitrary units)-associated aHUS after plasma exchanges (PEs), prednisone, and cyclophosphamide pulse therapy with the evolution of anti-CFH Ab titers and kidney function.

Results

Patient 1 received PEs + prednisone + cyclophosphamide pulses after two relapses following PEs and then PEs + rituximab. The other three patients were treated with PEs + prednisone + cyclophosphamide pulses as a first-line therapy. In our four patients, the induction protocol combining PEs + prednisone + cyclophosphamide pulses led to a rapid and sustained remission up to 6 years, 4 years and 4 months without any maintenance therapy. Kidney function was normal and anti-CFH Ab titer decreased, but remained detectable during remission without any clinical or biological signs of relapse.

Conclusions

We demonstrate the long-term efficiency and safety of cyclophosphamide pulses combined with PEs and prednisone in anti-CFH Ab-associated aHUS leading to a prolonged decrease in anti-CFH Ab titers and prevention of relapses without the need for maintenance therapy.

Dragon-Durey MA, Loirat C, Cloarec S, Macher MA, Blouin J, Nivet H, Weiss L, Fridman WH, Frémeaux-Bacchi V (2005) Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 16:555–563PubMedCrossRef

Skerba C, Józsi M, Zipfel PF, Dragon-Durey MA, Frémeaux-Bacchi V (2009) Autoantibodies in haemolytic uraemic syndrome. Thromb Haemost 101:227–232

Józsi 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 110:1516–1518PubMedCrossRef

Strobel S, Hoyer PF, Mache CJ, Sulyok E, Liu WS, Richter H, Oppermann M, Zipfel PF, Józsi M (2010) Functional analyses indicate a pathogenic role of factor H autoantibodies in atypical haemolytic uraemic syndrome. Nephrol Dial Transplant 25:136–144PubMedCrossRef

Blanc C, Roumenina LT, Ashraf Y, Hyvärinen S, Sethi SK, Ranchin B, Niaudet P, Loirat C, Gulati A, Bagga A, Fridman WH, Sautès-Fridman C, Jokiranta TS, Frémeaux-Bacchi V, Dragon-Durey MA (2012) Overall neutralization of complement factor H by autoantibodies in the acute phase of the autoimmune form of atypical hemolytic uremic syndrome. J Immunol 185:3528–3537CrossRef

Dragon-Durey MA, Blanc C, Marliot F, Loirat C, Blouin J, Sautes-Fridman C, Fridman WH, Frémeaux-Bacchi V (2009) The high frequency of complement factor H related CFHR1 gene deletion is restricted to specific subgroups of patients with atypical haemolitic uraemic syndrome. J Med Genet 46:447–450PubMedCrossRef

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 111:1512–1514PubMedCrossRef

Hughes AE, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, Chakravarthy U (2006) A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet 38:1173–1177PubMedCrossRef

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

10.

Lee BH, Kwak SH, Shin JI, Lee SH, Choi HJ, Kang HG, Ha IS, Lee JS, Dragon-Durey MA, Choi Y, Cheong HI (2009) Atypical hemolytic uremic syndrome associated with complement factor H autoantibodies and CFHR1/CFHR3 deficiency. Pediatr Res 66:336–340PubMedCrossRef

11.

Boyer O, Balzamo E, Charbit M, Biebuyck-Gougé N, Salomon R, Dragon-Durey MA, Frémeaux-Bacchi V, Niaudet P (2010) Pulse of cyclophosphamide therapy and clinical remission in atypical hemolytic uremic syndrome with anti-complement factor H autoantibodies. Am J Kidney Dis 55:923–927PubMedCrossRef

12.

Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637PubMedCrossRef

13.

Sellier-Leclerc AL, Frémeaux-Bacchi V, Dragon-Durey MA, Macher MA, Niaudet P, Guest G, Boudailliez B, Bouissou F, Deschenes G, Gie S, Tsimaratos M, Fischbach M, Morin D, Nivet H, Alberti C, Loirat C, French Society of Pediatric Nephrology (2007) Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 18:2392–2400PubMedCrossRef

14.

National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (2004) The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 114:555–576CrossRef

15.

Hofer J, Janecke AR, Zimmerhackl LB, Riedl M, Rosales A, Giner T, Cortina G, Haindl CJ, Petzelberger B, Pawlik M, Jeller V, Vester U, Gadner B, Van Husen M, Moritz ML, Jungraithmayr T (2013) Complement factor H-related protein 1 deficiency and factor H antibodies in pediatric patients with atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol 8:407–415PubMedCrossRef

16.

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 5:1844–1859PubMedCrossRef

17.

Kwon T, Belot A, Ranchin B, Baudouin V, Frémeaux-Bacchi V, Dragon-Durey MA, Cochat P, Loirat C (2009) Varicella as a trigger of atypical haemolytic uraemic syndrome associated with complement dysfunction: two cases. Nephrol Dial Transplant 24:2752–2754PubMedCrossRef

18.

Nürnberger 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 Eng J Med 360:542–544CrossRef

19.

Abarrategui-Garrido C, Martinez-Barricarte R, Lopez-Trascasa M, de Cordoba SR, Sanchez-Corral P (2009) Characterization of complement factor H-related proteins in plasma reveals novel genetic variations of CFHR1 associated with atypical hemolytic uremic syndrome. Blood 114:4261–4271PubMedCrossRef

20.

Geerdink LM, Westra D, van Wijk JA, Dorresteijn EM, Lilien MR, Davin JC, Kömhoff M, Van Hoeck K, van der Vlugt A, van den Heuvel LP, van de Kar NC (2012) Atypical hemolytic uremic syndrome in children: complement mutations and clinical characteristics. Pediatr Nephrol 27:1283–1291PubMedCrossRef

21.

Moore I, Strain L, Pappworth I, Kavanagh D, Barlow PN, Herbert AP, Schmidt CQ, Staniforth SJ, Holmes LV, Ward R, Morgan L, Goodship TH, Marchbank KJ (2010) Association of factor H autoantibodies with deletion of CFHR1, CFHR3, CFHR4 and with mutations in CFH, CFI, CD46, and C3 in patients with atypical haemolytic uraemic syndrome. Blood 115:379–387PubMedCrossRef

22.

Roumenina LT, Loirat C, Dragon-Durey MA, Halbwachs-Mecarelli L, Sautes-Fridman C, Frémeaux-Bacchi V (2011) Alternative complement pathway assessment in patients with atypical HUS. J Immunol Methods 365:8–26PubMedCrossRef

23.

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, European Paediatric Study Group for HUS (2009) Guidelines for the investigation and initial therapy of diarrhea negative haemolytic uraemic syndrome. Pediatr Nephrol 24:687–696PubMedCrossRef

24.

Taylor CM, Machin S, Wigmore SJ, Goodship TH (2010) Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. Br J Haematol 148:37–47PubMedCrossRef

25.

Kwon T, Dragon-Durey MA, Macher MA, Baudouin V, Maisin A, Peuchmaur M, Fremeaux-Bacchi V, Loirat C (2008) Successful pre-transplant management of a patient with anti-factor H autoantibodies-associated haemolytic uraemic syndrome. Nephrol Dial Transplant 23:2088–2090PubMedCrossRef

26.

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

27.

Barbour T, Johnson S, Cohney S, Hughes P (2012) Thrombotic micorangiopathy and associated renal disorders. Nephrol Dial Transplant 27:2673–2685PubMedCrossRef

28.

Larrea CF, Cofan F, Oppenheimer F, Campistol JM, Escolar G, Lozano M (2010) Efficacy of eculizumab in the treatment of recurrent atypical hemolytic-uremic syndrome after renal transplantation. Transplantation 89:903–904PubMedCrossRef

Title: Long-term remission of atypical HUS with anti-factor H antibodies after cyclophosphamide pulses
Authors: Gwenaëlle Sana
Marie-Agnès Dragon-Durey
Marina Charbit
Karim Bouchireb
Caroline Rousset-Rouvière
Etienne Bérard
Rémi Salomon
Véronique Frémeaux-Bacchi
Patrick Niaudet
Olivia Boyer
Publication date: 01-01-2014
Publisher: Springer Berlin Heidelberg
Published in: Pediatric Nephrology / Issue 1/2014
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-013-2558-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Long-term remission of atypical HUS with anti-factor H antibodies after cyclophosphamide pulses

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 1/2014

High serum phosphorus and FGF 23 levels are associated with progression of coronary calcifications

Efficacy and safety of intermittent hemodialysis in infants and young children with inborn errors of metabolism

Early detection of acute kidney injury by serum cystatin C in critically ill children

Recovery of native erythropoietin in a patient with erythropoietin-associated pure red cell aplasia

Renal tubular dysgenesis

Eculizumab long-term therapy for pediatric renal transplant in aHUS with CFH/CFHR1 hybrid gene