Prophylactic Eculizumab after Renal Transplantation in Atypical Hemolytic–Uremic Syndrome

Zimmerhackl, Lothar Bernd; Hofer, Johannes; Cortina, Gérard; Märk, Walter; Würzner, Reinhard; Jungraithmayr, Therese; Khursigara, Gus; Kliche, Kay Oliver; Radauer, Wolfgang

doi:10.1056/nejmc1001060

Cited by 141 publications

(102 citation statements)

References 6 publications

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“…At present, 17 patients have been published and reported in congresses (abstracts available on the net) who received eculizumab either for aHUS on their native kidneys (Table 9) [155][156][157][158][159][160][161] or to rescue [121,131,137,[162][163][164][165][166] or prevent [167][168][169] post-transplant recurrence (Table 10). Of the 17 patients, 8 were children (aged from 19 months to 18 years) and 6 had CFH mutation, 2 had C3 mutation, 1 had CFI mutation, 4 had no mutation identified and genetic was not documented in 2.…”

Section: Clinical Experience With Eculizumab In Ahusmentioning

confidence: 99%

Atypical Hemolytic Uremic Syndrome

Loirat¹,

Frémeaux‐Bacchi²

2016

Pediatric Kidney Disease

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Hemolytic uremic syndrome (HUS) is defined by the triad of mechanical hemolytic anemia, thrombocytopenia and renal impairment. Atypical HUS (aHUS) defines non Shiga-toxin-HUS and even if some authors include secondary aHUS due to Streptococcus pneumoniae or other causes, aHUS designates a primary disease due to a disorder in complement alternative pathway regulation. Atypical HUS represents 5 -10% of HUS in children, but the majority of HUS in adults. The incidence of complement-aHUS is not known precisely. However, more than 1000 aHUS patients investigated for complement abnormalities have been reported. Onset is from the neonatal period to the adult age. Most patients present with hemolytic anemia, thrombocytopenia and renal failure and 20% have extra renal manifestations. Two to 10% die and one third progress to end-stage renal failure at first episode. Half of patients have relapses. Mutations in the genes encoding complement regulatory proteins factor H, membrane cofactor protein (MCP), factor I or thrombomodulin have been demonstrated in 20-30%, 5-15%, 4-10% and 3-5% of patients respectively, and mutations in the genes of C3 convertase proteins, C3 and factor B, in 2-10% and 1-4%. In addition, 6-10% of patients have anti-factor H antibodies. Diagnosis of aHUS relies on 1) No associated disease 2) No criteria for Shigatoxin-HUS (stool culture and PCR for Shiga-toxins; serology for anti-lipopolysaccharides antibodies) 3) No criteria for thrombotic thrombocytopenic purpura (serum ADAMTS 13 activity > 10%). Investigation of the complement system is required (C3, C4, factor H and factor I plasma concentration, MCP expression on leukocytes and anti-factor H antibodies; genetic screening to identify risk factors). The disease is familial in approximately 20% of pedigrees, with an autosomal recessive or dominant mode of transmission. As penetrance of the disease is 50%, genetic counseling is difficult. Plasmatherapy has been first line treatment until presently, without unquestionable demonstration of efficiency. There is a high risk of post-transplant recurrence, except in MCP-HUS. Case reports and two phase II trials show an impressive efficacy of the complement C5 blocker eculizumab, suggesting it will be the next standard of care. Except for patients treated by intensive plasmatherapy or eculizumab, the worst prognosis is in factor H-HUS, as mortality can reach 20% and 50% of survivors do not recover renal function. Half of factor I-HUS progress to end-stage renal failure. Conversely, most patients with MCP-HUS have preserved renal function. Anti-factor H antibodies-HUS has favourable outcome if treated early.

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Section: Clinical Experience With Eculizumab In Ahusmentioning

confidence: 99%

Atypical Hemolytic Uremic Syndrome

Loirat¹,

Frémeaux‐Bacchi²

2016

Pediatric Kidney Disease

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“…The FDA has approved eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. It was used in the prevention and treatment of atypical hemolytic-uremic syndrome after transplantation (8,9).…”

Section: Complement Inhibitorsmentioning

confidence: 99%

Desensitization Protocols and Their Outcome

Marfo

Ling

et al. 2011

Clinical Journal of the American Society of Nephrology

235

184

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SummaryIn the last decade, transplantation across previously incompatible barriers has increasingly become popular because of organ donor shortage, availability of better methods of detecting and characterizing anti-HLA antibodies, ease of diagnosis, better understanding of antibody-mediated rejection, and the availability of effective regimens. This review summarizes all manuscripts published since the first publication in 2000 on desensitized patients and discusses clinical outcomes including acute and chronic antibody-mediated rejection rate, the new agents available, kidney paired exchange programs, and the future directions in sensitized patients. There were 21 studies published between 2000 and 2010, involving 725 patients with donor-specific anti-HLA antibodies (DSAs) who underwent kidney transplantation with different desensitization protocols. All studies were single center and retrospective. The patient and graft survival were 95% and 86%, respectively, at a 2-year median follow-up. Despite acceptable short-term patient and graft survivals, acute rejection rate was 36% and acute antibody-mediated rejection rate was 28%, which is significantly higher than in nonsensitized patients. Recent studies with longer follow-up of those patients raised concerns about long-term success of desensitization protocols. The studies utilizing protocol biopsies in desensitized patients also reported higher subclinical and chronic antibody-mediated rejection. An association between the strength of DSAs determined by median fluorescence intensity values of Luminex single-antigen beads and risk of rejection was observed. Two new agents, bortezomib, a proteasome inhibitor, and eculizumab, an anti-complement C5 antibody, were recently introduced to desensitization protocols. An alternative intervention is kidney paired exchange, which should be considered first for sensitized patients.

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“…Zimmerhackl ve ark. atipik HÜS öyküsü olan bir pediatrik hastaya nakil sonrası erken dönemde plazmaferez başlamış ve Eculizumab tedavisi ile devam etmiş ve bir yıllık süre sonunda nüks görmemişlerdir (14). Nester ve ark.…”

Section: Eculizumabunclassified

Böbrek Naklinde Kullanılan Yeni İmmünsupresif İlaçlar

Güngör¹,

Alp²,

Pembegül³

et al. 2017

Turk Neph Dial Transpl

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ÖzSon dönem böbrek yetmezliğinin en seçkin tedavi yöntemi böbrek naklidir. Ne yazıkki akut-kronik rejeksiyonlar ve ilaç toksisiteleri nakil sonrası dönemde organ sağ kalımını kısaltmaktadır. Bu yüzden son yıllarda rejeksiyonları ve ilaç toksisitelerini azaltabilecek yeni ilaçların bulunması amaçlanmıştır. Biz bu derlemede son yıllarda böbrek naklinde kullanıma girmiş yeni immünsupresif ilaçların başlı-calarını özetlemeyi amaçladık. AnAhTAR sÖzcükleR: Böbrek nakli, Yeni, İmmünsupresif ilaçlar AbsTRAcTRenal transplantation is the most prominent treatment of end-stage renal failure. Unfortunately, acute and chronic rejections and drug toxicities reduce graft survival in the post-transplantation period. An attempt has therefore been made in recent years to develop new drugs that can reduce rejections and drug toxicities. In this review, we intended to summarize the new immunosuppressive drugs that have entered use in recent years. GİRİŞSon dönem böbrek yetmezliğinin en seçkin tedavi yöntemi böbrek naklidir. Başarılı bir böbrek nakli için, gerek indüksiyon, gerekse idame immünsupresif tedavinin hasta bazında bireyselleştirilmesi gerekir. Halen dünyada indüksiyon tedavisi için en sık Antitimosit globulin (ATG), idame tedavide ise kortikosteroid-kalsinörin inhibitörü-antimetabolit ilaç kombinasyonu tercih edilmektedir. Günümüzde halen akut hücresel ve humoral rejeksiyonlar ne yazıkki böbrek sağ kalımını olumsuz etkileyen önemli sorunlar olarak karşımıza çıkmaya devam etmektedir. bir yıllık graft sürveyi %90'ların üzerinde iken beş yıllık sürvey %72 civarındadır. Uzun süreli kullanımda ilaçların toksik etkilerinin ortaya çıkması son 10 yıl içerisinde böbrek naklinde indüksiyon ve idame tedavide farklı ajanların bulunması için bir gereklilik doğurmuştur. Özellikle böbrek nakli tedavisinin köşetaşı ilacı olan kalsinörin inhibitörlerinin iki yıldan uzun süre kullanımında yüksek oranda toksisite gelişimi bu ihtiyacı zorunlu hale getirmiştir. Biz bu yazıda böbrek nakli hastalarında son yıllarda deneme aşamasında olan ve/veya kullanılmaya başlanan yeni immünsupresif ilaçların genel özelliklerini ve böbrek naklindeki deneyimlerini sunmayı amaçladık. eculizumabEculizumab insanlaştırılmış bir monoklonal IgG2/4 antikordur. Kompleman C5 proteinine bağlanarak C5 konvertaz ile C5a ve C5b'ye yıkımını önleyerek membran atak kompleksi oluşumunu engeller ve kompleman aracılı hücre hasarına engel olur (1). Eculizumab temelde terminal kompleman kaskadını hedefler, ancak proksimal kompleman yolaklarının etkisini ortadan kaldıramayabilir.

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Prophylactic Eculizumab after Renal Transplantation in Atypical Hemolytic–Uremic Syndrome

Cited by 141 publications

References 6 publications

Atypical Hemolytic Uremic Syndrome

Atypical Hemolytic Uremic Syndrome

Desensitization Protocols and Their Outcome

Böbrek Naklinde Kullanılan Yeni İmmünsupresif İlaçlar

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