Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2021 Mar 23;3(3):CD012862.
doi: 10.1002/14651858.CD012862.pub2.

Interventions for atypical haemolytic uraemic syndrome

Dan Pugh  1 , Eoin D O'Sullivan  1   2 , Fiona Ai Duthie  1 , Philip Masson  3 , David Kavanagh  4
Affiliations
Meta-Analysis

Interventions for atypical haemolytic uraemic syndrome

Dan Pugh et al. Cochrane Database Syst Rev. .

Abstract

Background: Atypical haemolytic uraemic syndrome (aHUS) is a rare disorder characterised by thrombocytopenia, microangiopathic haemolytic anaemia, and acute kidney injury. The condition is primarily caused by inherited or acquired dysregulation of complement regulatory proteins with ~40% of those affected aged < 18 years. Historically, kidney failure and death were common outcomes, however, improved understanding of the condition has led to discovery of novel therapies.

Objectives: To evaluate the benefits and harms of interventions for aHUS.

Search methods: We searched the Cochrane Kidney and Transplant Register of Studies for randomised controlled studies (RCTs) up to 3 September 2020 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. MEDLINE(OVID) 1946 to 27 July 2020 and EMBASE (OVID) 1974 to 27 July 2020 were searched for non-RCTs.

Selection criteria: All randomised and non-randomised clinical trials comparing an intervention with placebo, an intervention with supportive therapy, or two or more interventions for aHUS were included. Given the rare nature of the condition in question, prospective single-arm studies of any intervention for aHUS were also included.

Data collection and analysis: Two authors independently extracted pre-specified data from eligible studies and evaluated risk of bias using a newly developed tool based on existing Cochrane criteria. As statistical meta-analysis was not appropriate, qualitative analysis of data was then performed.

Main results: We included five single-arm studies, all of which evaluated terminal complement inhibition for the treatment of aHUS. Four studies evaluated the short-acting C5 inhibitor eculizumab and one study evaluated the longer-acting C5 inhibitor ravulizumab. All included studies within the review were of non-randomised, single-arm design. Thus, risk of bias is high, and it is challenging to draw firm conclusions from this low-quality evidence. One hundred patients were included within three primary studies evaluating eculizumab, with further data reported from 37 patients in a secondary study. Fifty-eight patients were included in the ravulizumab study. After 26 weeks of eculizumab therapy there were no deaths and a 70% reduction in the number of patients requiring dialysis. Complete thrombotic microangiopathic (TMA) response was observed in 60% of patients at 26 weeks and 65% at two years. After 26 weeks of ravulizumab therapy four patients had died (7%) and complete TMA response was observed in 54% of patients. Substantial improvements were seen in estimated glomerular filtration rate and health-related quality of life in both eculizumab and ravulizumab studies. Serious adverse events occurred in 42% of patients, and meningococcal infection occurred in two patients, both treated with eculizumab.

Authors' conclusions: When compared with historical data, terminal complement inhibition appears to offer favourable outcomes in patients with aHUS, based upon very low-quality evidence drawn from five single-arm studies. It is unlikely that an RCT will be conducted in aHUS and therefore careful consideration of future single-arm data as well as longer term follow-up data will be required to better understand treatment duration, adverse outcomes and risk of disease recurrence associated with terminal complement inhibition.

Trial registration: ClinicalTrials.gov NCT01194973 NCT01193348 NCT00838513 NCT00844428 NCT00844545 NCT00844844 NCT02949128 NCT02222545 NCT01757431 NCT03131219 NCT03205995.

PubMed Disclaimer

Conflict of interest statement

  1. D Pugh has declared that they have no conflict of interest

  2. ED O'Sullivan has declared that they have no conflict of interest

  3. FAI Duthie has declared that they have no conflict of interest

  4. P Masson has declared that they have no conflict of interest

  5. D Kavanagh: Newcastle University has received funding from Biomarin, Gyroscope Therapeutics and Alexion Pharmaceuticals for consultancy work undertaken by DK. DK is scientific advisor to Gyroscope Therapeutics, London.

Figures

1
1
Study flow diagram.
See this image and copyright information in PMC

Update of

  • doi: 10.1002/14651858.CD012862

References

References to studies included in this review

Fakhouri 2016 {published data only}
    1. Fakhouri F, Bedrosian C, Ogawa M, Kincaid J, Loirat C. Eculizumab safety and efficacy in adult patients with aHUS, with or without baseline dialysis [abstract no: SA-PO507]. Journal of the American Society of Nephrology 2014;25(Abstracts):751A.
    1. Fakhouri F, Hourmant M, Campistol JM, Cataland S, Espinosa M, Gaber AO, et al. Eculizumab inhibits thrombotic microangiopathy, and improves renal function in adult atypical hemolytic uremic syndrome patients: 1-year update [abstract no: SA-PO508]. Journal of the American Society of Nephrology 2014;25(Abstracts):751A.
    1. Fakhouri F, Hourmant M, Campistol JM, Cataland SR, Espinosa M, Gaber AO, et al. Terminal complement inhibitor eculizumab in adult patients with atypical hemolytic uremic syndrome: a single-arm, open-label trial. American Journal of Kidney Diseases 2016;68(1):84-93. [MEDLINE: ] - PubMed
    1. Fakhouri F, Hourmant M, Cataland S, Espinosa M, Gaber AO, Menne J, et al. Eculizumab (ECU) inhibits thrombotic microangiopathy (TMA) and improves renal function in adult patients (pts) with atypical hemolytic uremic syndrome (aHUS) [abstract no: 2179]. Blood 2013;122(21). [EMBASE: 71265761]
    1. Loirat C, Legendre C, Ogawa M, Bedrosian C, Kincaid J, Fakhouri F. Safety and efficacy of eculizumab in adult aHUS patients, with or without a history of renal transplant [abstract no: SA-PO511]. Journal of the American Society of Nephrology 2014;25(Abstracts):752A.
Greenbaum 2016 {published data only}
    1. Ariceta G, Greenbaum LA, Wang J, Kincaid J, Licht C. Safety of eculizumab in pediatric patients with atypical hemolytic uremic syndrome [abstract no: TH-PO460]. Journal of the American Society of Nephrology 2015;26(Abstracts):191A.
    1. Greenbaum L, Fila M, Ardissino G, Al-Akash S, Evans J, Henning P, et al. Eculizumab (ECU) inhibits Thrombotic Microangiopathy (TMA) and improves renal function in pediatric patients (Pts) with atypical Hemolytic Uremic Syndrome (aHUS) [abstract]. Blood 2013;122(21). [EMBASE: 71265773]
    1. Greenbaum L, Fila M, Ardissino G, Al-Akash S, Evans J, Lieberman K, et al. Eculizumab inhibits Thrombotic Microangiopathy and improves renal function in pediatric patients with Atypical Hemolytic Uremic Syndrome: 1-year update [abstract no: 4986]. Blood 2014;124(21). [EMBASE: 71756929]
    1. Greenbaum LA, Fila M, Ardissino G, Al-Akash SI, Evans J, Henning P, et al. Eculizumab is a safe and effective treatment in pediatric patients with atypical hemolytic uremic syndrome. Kidney International 2016;89(3):701-11. [MEDLINE: ] - PubMed
    1. Van De Kar N, Greenbaum LA, Fila M, Tsimaratos M, Ardissino G, Al-Akash SI, et al. Evaluation of eculizumab treatment of paediatric patients with atypical haemolytic uraemic syndrome: a prospective clinical trial [abstract]. Pediatric Nephrology 2014;29(9):1670-1. [EMBASE: 71662350]
Legendre 2013 {published data only}
    1. Ariceta G, Greenbaum LA, Wang J, Kincaid J, Licht C. Safety of eculizumab in pediatric patients with atypical hemolytic uremic syndrome [abstract no: TH-PO460]. Journal of the American Society of Nephrology 2015;26(Abstracts):191A.
    1. Bedrosian C, Babu S, Furman R, Sheerin N, Cohen D, Gaber O, et al. Eculizumab is effective in patients resistant to plasma exchange/infusion with atypical hemolytic uremic syndrome (AHUS) [abstract no: P-WE-419]. Journal of Thrombosis & Haemostasis 2011;9(Suppl 2):651-2. [EMBASE: 70614363]
    1. Davin JC, Sheerin N, Legendre C, Greenbaum L, Furman R, Gaber AO, et al. Long-term improvements in outcomes with eculizumab in aHUS patients with progressing TMA [abstract]. Acta Clinica Belgica 2013;68(4):318. [EMBASE: 71518311]
    1. Goodship T, Smith RJ, Legendre C, Muus P, Rodig N, Al-Akash SI, et al. Eculizumab (ECU) is effective in patients (pts) with atypical hemolytic uremic syndrome (aHUS) regardless of underlying genetic mutations or complement factor H (CFH) auto-antibodies [abstract no: TH-PO442]. Journal of the American Society of Nephrology 2012;23(Abstracts):199A.
    1. Goodship TH, Muus P, Legendre C, Douglas K, Hourmant M, Delmas Y, et al. Interim analysis of phase II efficacy and safety data for eculizumab in patients with atypical hemolytic uremic syndrome (aHUS) receiving chronic plasma exchange/infusion [abstract]. Molecular Immunology 2011;48(14):1712. [EMBASE: 70969332]
Licht 2015 {published data only}
    1. Ariceta G, Greenbaum LA, Wang J, Kincaid J, Licht C. Safety of eculizumab in pediatric patients with atypical hemolytic uremic syndrome [abstract no: TH-PO460]. Journal of the American Society of Nephrology 2015;26(Abstracts):191A.
    1. Douglas K, Sheerin N, Legendre C, Greenbaum L, Furman R, Cohen D, et al. Progressing thrombotic microangiopathy in atypical haemolytic uraemic syndrome patients: long term improvements in outcomes with eculizumab [abstract no: P212]. Haematologica 2013;98(Suppl 1):91-2. [EMBASE: 71696065]
    1. Greenbaum L, Delmas Y, Fakhouri F, Kincaid J, Licht C, Minetti E, et al. Eculizumab prevents thrombotic microangiopathy: long-term follow-up study of patients with atypical hemolytic uremic syndrome [abstract no: 2252]. Blood 2016;126(23):2252. [EMBASE: 72172548]
    1. Legendre C, Greenbaum LA, Babu S, Furman R, Sheerin N, Cohen D, et al. Eculizumab (ECU) in atypical hemolytic uremic syndrome (aHUS) patients (pts) with progressing TMA: continued improvements at 2-year follow-up [abstract no: SA-OR101]. Journal of the American Society of Nephrology 2012;23(Abstracts):88-9.
    1. Licht C, Greenbaum LA, Muus P, Babu S, Bedrosian CL, Cohen DJ, et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney International 2015;87(5):1061-73. [MEDLINE: ] - PMC - PubMed
Rondeau 2020 {published data only}
    1. Rondeau E, Scully M, Ariceta G, Barbour T, Cataland S, Heyne N, et al. The long-acting C5 inhibitor, Ravulizumab, is effective and safe in adult patients with atypical hemolytic uremic syndrome naive to complement inhibitor treatment [Erratum in: Kidney Int. 2020 Dec;98(6):1621; PMID: 33276869]. Kidney International 2020;97(6):1287-96. [MEDLINE: ] - PubMed

References to studies excluded from this review

Aigner 2018 {published data only}
    1. Aigner C, Bohmig G, Eskandary F, Gaggl M, Kain R, Sunder-Plassmann R, et al. Preemptive plasma therapy and eculizumab (ECU) rescue for atypical hemolytic uremic syndrome (AHUS) relapse following kidney transplantation (KTX) [abstract no: C76]. American Journal of Transplantation 2018;18(Suppl 4):793-4. [EMBASE: 622280126]
    1. Aigner C, Bohmig G, Eskandary F, Gaggl M, Kain R, Sunder-Plassmann R, et al. Preemptive plasma therapy and eculizumab rescue for atypical hemolytic uremic syndrome relapse following kidney transplantation [abstract no: SP730]. Nephrology Dialysis Transplantation 2018;33(Suppl 1):i592-3. [EMBASE: 622606849]
Aigner 2020 {published data only}
    1. Aigner C, Bohmig GA, Eskandary F, Herkner H, Prohaszka Z, Csuka D, et al. Preemptive plasma therapy prevents atypical hemolytic uremic syndrome relapse in kidney transplant recipients. European Journal of Internal Medicine 2020;73:51-8. [MEDLINE: ] - PubMed
Al‐Akash 2012 {published data only}
    1. Al-Akash SI, Goodship TH, Smith RJ, Legendre CM, Licht C, Muus P, et al. Eculizumab is an effective treatment for atypical hemolytic uremic syndrome in patients with or without identified genetic complement mutations or complement factor H auto-antibodies [abstract no: 2085]. Blood 2012;120(21):2085. [EMBASE: 70964820]
Alpay 2019 {published data only}
    1. Alpay N, Ozcelik U. Renal transplantation in patients with atypical hemolytic uremic syndrome: a single center experience. Transplantation Proceedings 2019;51(7):2295-7. [MEDLINE: ] - PubMed
Alsakran 2019 {published data only}
    1. Alsakran A, Ibrahim A, Alshareef T, Saadeh S, Alsabban E. Eculizumab for the treatment of atypical hemolytic uremic syndrome in pediatric patients, a tertiary care hospital experience [abstract]. Nephrology Dialysis Transplantation 2019;34(Suppl 1). [EMBASE: 631305535]
Bhalla 2019 {published data only}
    1. Bhalla A, Alasfar S, Alachkar N. Eculizumab in kidney transplant recipients with atypical hemolytic uremic syndrome-single center experience [abstract no: A232]. American Journal of Transplantation 2019;19(Suppl 3):682-3. [EMBASE: 628454026]
Bohl 2016 {published data only}
    1. Bohl SR, Harsdorf S, Schoensteiner S, Schwarzwaelder P, Scholl K, Wais V, et al. Eculizumab therapy of adult TA-TMA: A high response rate is associated with a high infection-related mortality [abstract no: 2255]. Blood 2016;128(22). [EMBASE: 614309788]
Cao 2018 {published data only}
    1. Cao M, Leite BN, Ferreiro T, Calvo M, Fernandez C, Alonso A, et al. Eculizumab modifies outcomes in adults with atypical hemolytic uremic syndrome with acute kidney injury. American Journal of Nephrology 2018;48(3):225-33. [MEDLINE: ] - PubMed
Cataland 2014 {published data only}
    1. Cataland SR, Feldkamp T, Bedrosian CL, Kincaid J, Minetti EE. Eculizumab Is an effective treatment for atypical hemolytic uremic syndrome in pediatric and adult patients with or without identified genetic complement mutations or complement factor H autoantibodies [abstract no: 2789]. Blood 2014;124(21). [EMBASE: 71760434]
Cofiell 2015 {published data only}
    1. Cofiell R, Kukreja A, Bedard K, Yan Y, Mickle A, Ogawa M, et al. Biomarkers of complement and endothelial activation, inflammation, thrombosis and renal injury in patients (pts) with aHUS treated with eculizumab (ECU) [abstract no: 2184]. Blood 2013;122(21). [EMBASE: 71265766]
    1. Cofiell R, Kukreja A, Bedard K, Yan Y, Mickle A, Ogawa M, et al. Eculizumab reduces terminal complement (TC) and complement alternative pathway (CAP) activation, inflammation, endothelial damage, thrombosis and renal injury in atypical hemolytic uremic syndrome (aHUS) patients [abstract no: MP035]. Nephrology Dialysis Transplantation 2014;29(Suppl 3):iii339-40. [EMBASE: 71492439]
    1. Cofiell R, Kukreja A, Bedard K, Yan Y, Mickle AP, Ogawa M, et al. Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS. Blood 2015;125(21):3253-62. [MEDLINE: ] - PMC - PubMed
    1. Cofiell R, Kukreja A, Bedard K, Yan Y. Eculizumab reduces terminal complement, complement alternative pathway activation, inflammation, endothelial damage, thrombosis and renal injury markers in patients with atypical hemolytic uremic syndrome [abstract no: SA-PO506]. Journal of the American Society of Nephrology 2014;25(Abstracts):750A.
Escribano 2017 {published data only}
    1. Escribano TC, Praga M, De Cordoba SR. Eculizumab in secondary atypical hemolytic uremic syndrome [abstract]. Nephrology Dialysis Transplantation 2017;32(Suppl 3):iii58. [EMBASE: 617291197]
Favi 2018 {published data only}
    1. Favi E, Ardissino G, Cresseri D, Brocca J, Testa S, Tel F, et al. Thirty-six consecutive kidney transplants in recipients with atypical hemolytic uremic syndrome: a single-centre experience [abstract]. American Journal of Transplantation 2018;18(Suppl 4):286. [EMBASE: 622279700]
Fremeaux‐Bacchi 2015 {published data only}
    1. Fremeaux-Bacchi V, Legendre CM. The emerging role of complement inhibitors in transplantation. Kidney International 2015;88(5):967-73. [MEDLINE: ] - PubMed
Frykman 2016 {published data only}
    1. Frykman A, Swerkersson S, Westphal Ladfors S, Hansson S. Long-term outcome after hemolytic uremic syndrome in childhood [abstract no: PO-332]. Pediatric Nephrology 2016;31(10):1871. [EMBASE: 612479657]
Galbusera 2019 {published data only}
    1. Galbusera M, Noris M, Gastoldi S, Bresin E, Mele C, Breno M, et al. An ex vivo test of complement activation on endothelium for individualized eculizumab therapy in hemolytic uremic syndrome. American Journal of Kidney Diseases 2019;74(1):56-72. [MEDLINE: 30851964] - PubMed
Gavriilaki 2015 {published data only}
    1. Gavriilaki E, Yuan X, Ye Z, Ambinder AJ, Shanbhag SP, Streiff MB, et al. Modified ham test for atypical hemolytic uremic syndrome. Blood 2015;125(23):3637-46. [MEDLINE: ] - PMC - PubMed
Gomez‐Alvarez 2016 {published data only}
    1. Gomez-Alvarez S, Llopis-Salvia P, Avila-Bernabeu A, Pallardo-Mateu L, Climente-Marti M. Effectiveness and safety of eculizumab in atypical haemolytic uraemic syndrome and thrombotic microangiopathy [abstract]. European Journal of Hospital Pharmacy 2016;23(Suppl 1):A88. [EMBASE: 614325739]
Gruppo 2011 {published data only}
    1. Gruppo R , Rodig N, Vilalta R, Hernandez J, Camacho Diaz J, Lapeyraque A-L, et al. Eculizumab (ECU) therapy for atypical hemolytic uremic syndrome (AHUS) in pediatric patients: efficacy and safety outcomes from a retrospective study [abstract no: P-WE-444]. Journal of Thrombosis & Haemostasis 2011;9(Suppl 2):660. [EMBASE: 70614387]
Han 2019 {published data only}
    1. Han H, Alagusundaramoorthy S, Swanson K, Gardezi AI, Chan MR. Acute candida albicans peritonitis in a patient with atypical hemolytic uremic syndrome treated with eculizumab. Peritoneal Dialysis International 2019;39(6):575-6. [MEDLINE: ] - PubMed
Hanes 2019 {published data only}
    1. Hanes V, Pan J, Mytych DT, Chien D, Chow V. Relationship between pharmacokinetics and antidrug antibody status of ABP 959, a biosimilar candidate to eculizumab: results from a pharmacokinetic similarity study [abstract no: 128621]. Blood 2019;134(Suppl 1). [EMBASE: 630317971]
Ito 2019 {published data only}
    1. Ito S, Hidaka Y, Inoue N, Kaname S, Kato H, Matsumoto M, et al. Safety and effectiveness of eculizumab for pediatric patients with atypical hemolytic-uremic syndrome in Japan: interim analysis of post-marketing surveillance. Clinical & Experimental Nephrology 2019;23(1):112-21. [EMBASE: 623239057] - PMC - PubMed
Jozsi 2007 {published data only}
    1. Jozsi M, Strobel S, Dahse HM, Liu WS, Hoyer PF, Oppermann M, et al. Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome. Blood 2007;110(5):1516-8. [MEDLINE: ] - PubMed
Kant 2020 {published data only}
    1. Kant S, Bhalla A, Alasfar S, Alachkar N. Ten-year outcome of eculizumab in kidney transplant recipients with atypical hemolytic uremic syndrome- a single center experience. BMC Nephrology 2020;21(1):189. [MEDLINE: ] - PMC - PubMed
Kato 2019 {published data only}
    1. Kato H, Miyakawa Y, Hidaka Y, Inoue N, Ito S, Kagami S, et al. Safety and effectiveness of eculizumab for adult patients with atypical hemolytic-uremic syndrome in Japan: interim analysis of post-marketing surveillance. Clinical & Experimental Nephrology 2019;23(1):65-75. [EMBASE: 622799582] - PMC - PubMed
Khandelwal 2016 {published data only}
    1. Khandelwal P, Sinha A, Hari P, Bagga A. Multicenter cohort of atypical hemolytic uremic syndrome (aHUS) in Indian children [abstract no: PO-378]. Pediatric Nephrology 2016;31(10):1886. [EMBASE: 612479699]
Khandelwal 2019 {published data only}
    1. Khandelwal P, Thomas CC, Rathi BS, Hari P, Tiwari AN, Sinha A, et al. Membrane-filtration based plasma exchanges for atypical hemolytic uremic syndrome: audit of efficacy and safety. Journal of Clinical Apheresis 2019;34(5):555-62. [MEDLINE: ] - PubMed
Khursigara 2014 {published data only}
    1. Khursigara G, Johnson S, Harvey E, Kincaid J, Bedrosian C. Time to end-stage renal disease in patients with atypical hemolytic uremic syndrome receiving supportive care and eculizumab [abstract no: SA-PO509]. Journal of the American Society of Nephrology 2014;25(Abstracts):752A.
Kumar 2019 {published data only}
    1. Kumar G, Al-Masri O, Alismaili Z, Tawfik E, Al-Ghabra MK, Ilyas SH, et al. Eculizumab in paediatric atypical haemolytic uraemic syndrome: lessons learned from a single-centre experience in the United Arab Emirates. Journal of Paediatrics & Child Health 2019;55(10):1237-40. [MEDLINE: ] - PubMed
Lappegard 2015 {published data only}
    1. Lappegard KT, Bjerre A, Tjonnfjord GE, Mollnes TE. Therapeutic complement inhibition - from experimental to clinical medicine. Tidsskrift for Den Norske Laegeforening 2015;135(19):1745-9. [MEDLINE: ] - PubMed
Legault 2009 {published data only}
    1. Legault DJ, Boelkins MR. Successful treatment of aHUS recurrence and arrest of plasma exchange resistant TMA post-renal transplantation with the terminal complement inhibitor eculizumab [abstract no: 2421]. Blood 2009;114(22). [EMBASE: 70247442]
Levi 2016 {published data only}
    1. Levi C, Rabant M, Fremeaux-Bacchi V, Scemla A, Zuber J, Legendre C, et al. Outcome after eculizumab therapy to prevent recurrence of atypical hemolytic uremic syndrome: experience in twelve renal transplant recipients [abstract no: 550.9]. Transplantation 2016;100(7 Suppl 1):S325. [EMBASE: 613004527]
Mazo 2017 {published data only}
    1. Mazo A, Ananin P, Pushkov A, Savostianov K, Zrobok O, Tsygin A. Efficacy of treatment with eculizumab in children with aHUS [abstract no: P-338]. Pediatric Nephrology 2017;32(9):1788. [EMBASE: 618119670]
Menne 2019 {published data only}
    1. Menne DJ, Delmas Y, Kincaid JF, Licht C, Minetti EE, Mix C, et al. Ongoing eculizumab (ECU) prevents thrombotic microangiopathy (TMA) in patients (pts) with atypical hemolytic uremic syndrome (aHUS): final long-term observational study data [abstract no: FR-PO136]. Journal of the American Society of Nephrology 2017;28(Abstracts):435. [EMBASE: 633699768]
    1. Menne J, Delmas Y, Fakhouri F, Kincaid JF, Licht C, Minetti EE, et al. Eculizumab prevents thrombotic microangiopathy in patients with atypical haemolytic uraemic syndrome in a long-term observational study. Clinical Kidney Journal 2019;12(2):196-205. [MEDLINE: ] - PMC - PubMed
    1. Menne J, Delmas Y, Fakhouri F, Licht C, Lommelé Å, Minetti EE, et al. Outcomes in patients with atypical hemolytic uremic syndrome treated with eculizumab in a long-term observational study. BMC Nephrology 2019;20(1):125. [MEDLINE: ] - PMC - PubMed
    1. Menne J, Delmas Y, Rondeau E, Licht C, Wang J, Mix C, et al. Eculizumab prevents thrombotic microangiopathy in atypical hemolytic uremic syndrome patients: long-term follow-up [abstract no: FR-PO446]. Journal of the American Society of Nephrology 2015;26(Abstracts):458A.
    1. Menne J, Greenbaum L, Licht C, Mix C, Kincaid J, Wang J, et al. Long-term safety and effectiveness of eculizumab for patients with atypical haemolytic uraemic syndrome: Outcomes from a prospective observational clinical trial [abstract]. Nephrology Dialysis Transplantation 2017;32(Suppl 3):iii572-3. [EMBASE: 617290186]
Monet‐Didailler 2020 {published data only}
    1. Monet-Didailler C, Chevallier A, Godron-Dubrasquet A, Allard L, Delmas Y, Contin-Bordes C, et al. Outcome of children with Shiga toxin-associated haemolytic uraemic syndrome treated with eculizumab: a matched cohort study. Nephrology Dialysis Transplantation 2020;35(12):2147-53. [MEDLINE: ] - PubMed
Nayer 2016 {published data only}
    1. Nayer A, Asif A. Atypical hemolytic-uremic syndrome: a clinical review. American Journal of Therapeutics 2016;23(1):e151-8. [MEDLINE: ] - PubMed
Nester 2013 {published data only}
    1. Nester CM, Brophy PD. Eculizumab in the treatment of atypical haemolytic uraemic syndrome and other complement-mediated renal diseases. Current Opinion in Pediatrics 2013;25(2):225-31. [MEDLINE: ] - PubMed
Nilsson 2007 {published data only}
    1. Nilsson SC, Karpman D, Vaziri-Sani F, Kristoffersson AC, Salomon R, Provot F, et al. A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation. Molecular Immunology 2007;44(8):1835-44. [MEDLINE: ] - PubMed
Noris 2014 {published data only}
    1. Noris M, Galbusera M, Gastoldi S, Macor P, Banterla F, Bresin E, et al. Dynamics of complement activation in aHUS and how to monitor eculizumab therapy. Blood 2014;124(11):1715-26. [MEDLINE: ] - PMC - PubMed
Pape 2016 {published data only}
    1. Pape L, Mix C, Wang J, Greenbaum L, Lapeyraque A-L. Outcomes from an observational clinical trial evaluating the long-term safety and effectiveness of eculizumab use in paediatric patients with atypical haemolytic uraemic syndrome (aHUS) [abstract no: FP-S30-2]. Pediatric Nephrology 2016;31(10):1757. [EMBASE: 612479810]
Pape 2017 {published data only}
    1. Pape L, Mix C, Wang J, Greenbaum L, Lapeyraque A-L. Improved outcomes for paediatric patients with atypical haemolytic uraemic syndrome (AHUS) receiving long-term eculizumab treatment during on-treatment periods compared with off-treatment periods [Abstract no: O-46]. Pediatric Nephrology 2017;32(9):1662. [EMBASE: 618120141]
Picard 2015 {published data only}
    1. Picard C, Burtey S, Bornet C, Curti C, Montana M, Vanelle P. Pathophysiology and treatment of typical and atypical hemolytic uremic syndrome. Pathologie Biologie 2015;63(3):136-43. [MEDLINE: ] - PubMed
Raina 2018 {published data only}
    1. Raina R, Chauvin A, Fox K, Kesav N, Ascha M, Vachharajani TJ, et al. Effect of immunosuppressive therapy on the occurrence of atypical hemolytic uremic syndrome in renal transplant recipients. Annals of Transplantation 2018;23:631-8. [MEDLINE: ] - PMC - PubMed
Siedlecki 2019 {published data only}
    1. Siedlecki AM, Isbel N, Vande Walle J, James Eggleston J, Cohen DJ, Global aHUS Registry. Eculizumab use for kidney transplantation in patients with a diagnosis of atypical hemolytic uremic syndrome. KI Reports 2019;4(3):434-46. [MEDLINE: ] - PMC - PubMed
Simonetti 2011 {published data only}
    1. Simonetti G, Gruppo R , Rodig N, Hernandez J, Lapeyraque A, Sherwinter J, et al. Eculizumab therapy for atypical hemolytic uremic syndrome (aHUS) in pediatric patients: efficacy and safety outcomes from a retrospective study [abstract no: PS2-FRI-288]. Pediatric Nephrology 2011;26(9):1663. [EMBASE: 70530739]
Socie 2019 {published data only}
    1. Socie G, Caby-Tosi MP, Marantz JL, Cole A, Bedrosian CL, Gasteyger C, et al. Eculizumab in paroxysmal nocturnal haemoglobinuria and atypical haemolytic uraemic syndrome: 10-year pharmacovigilance analysis. British Journal of Haematology 2019;185(2):297-310. [MEDLINE: ] - PMC - PubMed
Taylor 2010 {published data only}
    1. Taylor CM, Machin S, Wigmore SJ, Goodship TH, Working Party from the Renal Association the British Committee for Standards in Haematology and the British Transplantation Society. Clinical practice guidelines for the management of atypical haemolytic uraemic syndrome in the United Kingdom. British Journal of Haematology 2010;148(1):37-47. [MEDLINE: ] - PubMed
Ubago 2014 {published data only}
    1. Ubago Perez R, Castillo Munoz MA, Galvan Banqueri M, Abdel-Kader L, Vega Coca MD, Romero Tabares A, et al. Efficacy of eculizumab in adult patients with atypical hemolytic uremic syndrome resistant to plasma treatment [abstract]. European Journal of Hospital Pharmacy 2014;21(Suppl 1):A99. [EMBASE: 611784993]
Uriol 2018 {published data only}
    1. Uriol M, Cabello S, Allende N, Ballester C, Mas A, Perez A, et al. Efficacy and safety of the eculizumab on haemolytic uremic syndrome [abstract]. Nephrology Dialysis Transplantation 2018;33(Suppl 1):i97. [EMBASE: 622605278]
Vakiti 2019 {published data only}
    1. Vakiti A, Singh D, Pilla R, Alhaj-Moustafa M, Fitzpatrick KW. Bevacizumab-induced atypical hemolytic uremic syndrome and treatment with eculizumab. Journal of Oncology Pharmacy Practice 2019;25(4):1011-5. [MEDLINE: ] - PubMed
Vilalta 2012 {published data only}
    1. Vilalta R, Al-Akash S, Davin J, Diaz J, Gruppo R , Hernandez J, et al. Eculizumab therapy for pediatric patients with atypical hemolytic uremic syndrome: Efficacy and safety outcomes of a retrospective study [abstract]. Haematologica 2012;97(Suppl 1):479. [EMBASE: 71724689]
Vivarelli 2014 {published data only}
    1. Vivarelli M, Emma F. Treatment of C3 glomerulopathy with complement blockers. Seminars in Thrombosis & Hemostasis 2014;40(4):472-7. [EMBASE: 53127391] - PubMed
Volokhina 2016 {published data only}
    1. Volokhina E, Wijnsma K, Sweep F, Bruggemann R, Wetzels J, Van De Kar N, et al. Pharmacokinetics and pharmacodynamics of eculizumab in individualized treatment of atypical hemolytic uremic syndrome [abstract]. Immunobiology 2016;31(10):1141. [EMBASE: 613695985]
Volokhina 2016a {published data only}
    1. Volokhina E, Wijnsma K, Sweep F, Bruggemann R, Wetzels J, Van De Kar N, et al. Pharmacokinetics and pharmacodynamics of eculizumab in individualized treatment of atypical HUS [abstract no: FP-S30-1]. Pediatric Nephrology 2016;31(10):1757. [EMBASE: 612479791]
Walle 2017 {published data only}
    1. Walle JV, Siedlecki A, Isbel N, Kupelian V, Cohen D. Timing of eculizumab initiation and the need for dialysis in patients with atypical haemolytic uraemic syndrome undergoing kidney transplantation [abstract]. Nephrology Dialysis Transplantation 2017;32(Suppl 3):iii85. [EMBASE: 617289751]
Walle 2017a {published data only}
    1. Walle JV, Delmas Y, Ardissino G, Wang J, Kincaid JF, Haller H. Improved renal recovery in patients with atypical hemolytic uremic syndrome following rapid initiation of eculizumab treatment. Journal of Nephrology 2017;30(1):127-34. [MEDLINE: ] - PMC - PubMed
Weston‐Davies 2013 {published data only}
    1. Weston-Davies W, Westwood JP, Nunn M. Phase 1 clinical trial of novel complement C5 inhibitor coversin [abstract]. Molecular Immunology 2013;56(3):264. [EMBASE: 71684209]
Wijnsma 2016 {published data only}
    1. Wijnsma KL, Volokhina E, Van Den Heuvel LP, Wetzels JF, de Kar NC. Safety and effectiveness of restricted eculizumab regimen in atypical HUS [abstract no: PO-371]. Pediatric Nephrology 2016;31(10):1883-4. [EMBASE: 612479611]
Wong 2015 {published data only}
    1. Wong EK, Kavanagh D. Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Translational Research: The Journal Of Laboratory & Clinical Medicine 2015;165(2):306-20. [MEDLINE: ] - PubMed
Wuhl 2020 {published data only}
    1. Wuhl E, Adams B, Cheong HI, Constantinescu A, Denker A, Dixon B. The long-acting complement inhibitor ravulizumab in children with atypical hemolytic uremic syndrome (interim analysis) [abstract]. Nieren und Hochdruckkrankheiten 2020;40(3):112. [EMBASE: 631397518]

References to ongoing studies

EUCTR2017‐001082‐24 {published data only}
    1. EUCTR2017-001082-24. An international study at different study sites providing a drug called cemdisiran (ALN-CC5) to patients with atypical hemolytic uremic syndrome by a subcutaneous injection. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... 2017.
EudraCT2014‐001032‐11 {published data only}
    1. EudraCT2014-001032-11. A study to investigate the safety, pharmacokinetics, pharmacodynamics, immunogenicity, and clinical activity of study drug OMS721 in adults with thrombotic microangiopathies. www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:201... (first received 25 June 2014).
NCT01757431 {published data only}
    1. NCT01757431. The safety and efficacy of eculizumab in Japanese patients with atypical hemolytic uremic syndrome (aHUS). www.clinicaltrials.gov/show/NCT01757431 (first received 31 December 2012).
NCT03131219 {published data only}
    1. NCT03131219. Study of ravulizumab in children and adolescents with atypical hemolytic uremic syndrome (aHUS). www.clinicaltrials.gov/show/NCT03131219 (first received 27 April 2017).
NCT03205995 {published data only}
    1. Leifke E. Safety and efficacy study of OMS721 in patients with atypical hemolytic uremic syndrome (aHUS). www.clinicaltrials.gov/show/NCT03205995 (first received 2 July 2017).
UMIN000014869 {published data only}
    1. Nangaku M. Observational study of atypical hemolytic uremic syndrome in Japan. upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000017280 (first received 1 September 2014).

Additional references

Ariceta 2009
    1. Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, et al. Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Pediatric Nephrology 2009;24(4):687–96. [MEDLINE: ] - PubMed
Besbas 2006
    1. Besbas N, Karpman D, Landau D, Loirat C, Proesmans W, Remuzzi G, et al. A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders. Kidney International 2006;70(3):423-31. [MEDLINE: ] - PubMed
Constantinescu 2004
    1. Constantinescu AR, Bitzan M, Weiss LS, Christen E, Kaplan BS, Cnaan A, et al. Non-enteropathic hemolytic uremic syndrome: causes and short-term course. American Journal of Kidney Diseases 2004;43(6):976-82. [MEDLINE: ] - PubMed
Coppo 2016
    1. Coppo R, Bonaudo R, Peruzzi RL, Amore A, Brunati A, Romagnoli R, et al. Liver transplantation for aHUS: still needed in the eculizumab era? Pediatric Nephrology 2016;31(5):759-68. [MEDLINE: ] - PubMed
Fakhouri 2017
    1. Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C. Haemolytic uraemic syndrome [Erratum in: Lancet. 2017 Aug 12;390(10095):648; PMID: 28438379]. Lancet 2017;390(10095):681-96. [MEDLINE: ] - PubMed
Fremeaux‐Bacchi 2013
    1. Fremeaux-Bacchi V, Fakhouri F, Garnier A, Bienaimé F, Dragon-Durey MA, Ngo S, et al. Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults. Clinical Journal of The American Society of Nephrology: CJASN 2013;8(4):554-62. [MEDLINE: ] - PMC - PubMed
GRADE 2008
    1. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924-6. [MEDLINE: ] - PMC - PubMed
Higgins 2003
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327(7414):557-60. [MEDLINE: ] - PMC - PubMed
Higgins 2011
    1. Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Hillmen 2013
    1. Hillmen P, Muus P, Röth A, Elebute MO, Risitano AM, Schrezenmeier H, et al. Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. British Journal of Haematology 2013;162(1):62–73. [MEDLINE: ] - PMC - PubMed
Kanakura 2011
    1. Kanakura Y, Ohyashiki K, Shichishima T, Okamoto S, Ando K, Ninomiya H, et al. Safety and efficacy of the terminal complement inhibitor eculizumab in Japanese patients with paroxysmal nocturnal hemoglobinuria: the AEGIS clinical trial. International Journal of Hematology 2011;93(1):36-46. [MEDLINE: ] - PubMed
Kaplan 2014
    1. Kaplan BS, Ruebner RL, Spinale JM, Copelovitch L. Current treatment of atypical hemolytic uremic syndrome. Intractable & Rare Diseases Research 2014;3(2):34–45. [MEDLINE: ] - PMC - PubMed
Kulasekararaj 2019
    1. Kulasekararaj AG, Hill A, Rottinghaus ST, Langemeijer S, Wells R, Gonzalez-Fernandez FA, et al. Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study. Blood 2019;133(6):540-9. [MEDLINE: ] - PMC - PubMed
Lai 2007
    1. Lai JS, Cella D, Kupst MJ, Holm S, Kelly ME, Bode RK, et al. Measuring fatigue for children with cancer: development and validation of the pediatric Functional Assessment of Chronic Illness Therapy-Fatigue (pedsFACIT-F). Journal of Pediatric Hematology/Oncology 2007;29(7):471-9. [MEDLINE: ] - PubMed
Lara 1999
    1. Lara PN Jr, Coe TL, Zhou H, Fernando L, Holland PV, Wun T. Improved survival with plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. American Journal of Medicine 1999;107(6):573-9. [MEDLINE: ] - PubMed
Lee 2019
    1. Lee JW, Sicre de Fontbrune F, Wong Lee Lee L, Pessoa V, Gualandro S, Fürender W, et al. Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood 2019;133(6):530-9. [MEDLINE: ] - PMC - PubMed
Loirat 2016
    1. Loirat C, Fakhouri F, Ariceta G, Besbas N, Bitzan M, Bjerre A, et al. An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Pediatric Nephrology 2016;31(1):15-39. [MEDLINE: ] - PubMed
Michael 2009
    1. Michael M, Elliott EJ, Ridley GF, Hodson EM, Craig JC. Interventions for haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No: CD003595. [DOI: 10.1002/14651858.CD003595.pub2] - DOI - PMC - PubMed
Noris 2005
    1. Noris M, Remuzzi G. Hemolytic uremic syndrome. Journal of the American Society of Nephrology 2005;16(4):1035-50. [MEDLINE: ] - PubMed
Noris 2009
    1. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. New England Journal of Medicine 2009;361(17):1676-87. [MEDLINE: ] - PubMed
Noris 2010
    1. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clinical Journal of The American Society of Nephrology: CJASN 2010;5(10):1844-59. [MEDLINE: ] - PMC - PubMed
Rathbone 2013
    1. Rathbone J, Kaltenthaler E, Richards A, Tappenden P, Bessey A, Cantrell A. A systematic review of eculizumab for atypical haemolytic uraemic syndrome (aHUS). BMJ Open 2013;3(11):e003573. [MEDLINE: ] - PMC - PubMed
Remuzzi 2005
    1. Remuzzi G, Ruggenenti P, Colledan M, Gridelli B, Bertani A, Bettinaglio P, et al. Hemolytic uremic syndrome: a fatal outcome after kidney and liver transplantation performed to correct factor H gene mutation. American Journal of Transplantation 2005;5(5):1146-50. [MEDLINE: ] - PubMed
Saland 2009
    1. Saland JM, Ruggenenti P, Remuzzi G, Consensus Study Group. Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. Journal of the American Society of Nephrology 2009;20(5):940-9. [MEDLINE: ] - PubMed
Schunemann 2011a
    1. Schünemann HJ, Oxman AD, Higgins JP, Vist GE, Glasziou P, Guyatt GH. Chapter 11: Presenting results and 'Summary of findings' tables. In: Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Schunemann 2011b
    1. Schünemann HJ, Oxman AD, Higgins JP, Deeks JJ, Glasziou P, Guyatt GH. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JP, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.
Sheerin 2016
    1. Sheerin NS, Kavanagh D, Goodship TH, Johnson S. A national specialized service in England for atypical haemolytic uraemic syndrome-the first year’s experience. QJM 2016;109(1):27-33. [MEDLINE: ] - PubMed
Sterne 2016
    1. Sterne JAC, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: a tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016;355:i4919. [MEDLINE: ] - PMC - PubMed
Van De Kar 2014
    1. Van De Kar N, Greenbaum LA, Fila M, Tsimaratos M, Ardissino G, Al-Akash SI, et al. Evaluation of eculizumab treatment of paediatric patients with atypical haemolytic uraemic syndrome: a prospective clinical trial [abstract]. Pediatric Nephrology 2014;29(9):1670-1. [EMBASE: 71662350]

References to other published versions of this review

Pugh 2017
    1. Pugh D, O'Sullivan ED, Duthie FAI, Masson P, Kavanagh D. Interventions for atypical haemolytic uraemic syndrome. Cochrane Database of Systematic Reviews 2017, Issue 11. Art. No: CD012862. [DOI: 10.1002/14651858.CD012862] - DOI - PMC - PubMed

MeSH terms

Associated data