Pre-emptive Eculizumab and Plasmapheresis for Renal Transplant in Atypical Hemolytic Uremic Syndrome

Nester, Carla; Stewart, Zoe A.; Myers, David T.; Jetton, Jennifer G.; Nair, Ramesh; Reed, Alan; Thomas, Christie P.; Smith, Richard J.H.; Brophy, Patrick D.

doi:10.2215/cjn.10181110

Cited by 117 publications

(86 citation statements)

References 37 publications

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“…The two subjects with renal function that worsened during therapy had very long histories of disease before eculizumab exposure (more than 27 years for DDD2 and more than 13 years for C3GN1), whereas the other subjects received the drug early in the disease course (range=0.5-25 months). Indeed, in appropriately screened patients, eculizumab may have its greatest use in transplant recipients with recurrent disease, employed either immediately after recognition of recurrence or, potentially, as prophylactic therapy initiated immediately post-transplantation, which has been done with aHUS (15). We cannot conclude whether the benefits of therapy experienced by our subjects will be sustained and whether continued therapy with the drug will be needed for such sustenance; thus far, two subjects have shown evidence of relapsing disease and have been restarted on therapy.…”

Section: Discussionmentioning

confidence: 99%

Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

Bomback

Smith

Barile

et al. 2012

Clinical Journal of the American Society of Nephrology

310

259

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SummaryBackground and objectives The principle defect in dense deposit disease and C3 glomerulonephritis is hyperactivity of the alternative complement pathway. Eculizumab, a monoclonal antibody that binds to C5 to prevent formation of the membrane attack complex, may prove beneficial. Design, setting, participants, & measurementsIn this open-label, proof of concept efficacy and safety study, six subjects with dense deposit disease or C3 glomerulonephritis were treated with eculizumab every other week for 1 year. All had proteinuria .1 g/d and/or AKI at enrollment. Subjects underwent biopsy before enrollment and repeat biopsy at the 1-year mark. ResultsThe subjects included three patients with dense deposit disease (including one patient with recurrent dense deposit disease in allograft) and three patients with C3 glomerulonephritis (including two patients with recurrent C3 glomerulonephritis in allograft). Genetic and complement function testing revealed a mutation in CFH and MCP in one subject each, C3 nephritic factor in three subjects, and elevated levels of serum membrane attack complex in three subjects. After 12 months, two subjects showed significantly reduced serum creatinine, one subject achieved marked reduction in proteinuria, and one subject had stable laboratory parameters but histopathologic improvements. Elevated serum membrane attack complex levels normalized on therapy and paralleled improvements in creatinine and proteinuria.Conclusions Clinical and histopathologic data suggest a response to eculizumab in some but not all subjects with dense deposit disease and C3 glomerulonephritis. Elevation of serum membrane attack complex before treatment may predict response. Additional research is needed to define the subgroup of dense deposit disease/C3 glomerulonephritis patients in whom eculizumab therapy can be considered.

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Section: Discussionmentioning

confidence: 99%

Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

Bomback

Smith

Barile

et al. 2012

Clinical Journal of the American Society of Nephrology

310

259

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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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“…Nester ve ark. atipik HÜS öyküsü olan ve transplantasyon sonrası rekürrens nedeniyle böbreğini kaybeden hastaya ikinci defa nakil planlandığında preemptif plazmaferez ve Eculizumab başlamış ve ilk dört aylık izlemde herhangi bir nüks bulgusuna rastlamadıklarını bildirmişlerdir (15 İlk kez 2004 yılında humoral rejeksiyon tedavisinde donör spesifik antikor (DSA)'ların uzaklaştırılması için plazmafereze zaman sağlamak, komplemanı fikse eden antikorların neden olduğu doku hasarını önlemek veya minimalize etmek gerekçesiyle bir olguda denenmiştir. Çalışma hastası dördüncü ayda allograft fonksiyon görür durumda iken masif pulmoner hemoraji nedeniyle kaybedilmiştir (7).…”

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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Pre-emptive Eculizumab and Plasmapheresis for Renal Transplant in Atypical Hemolytic Uremic Syndrome

Cited by 117 publications

References 37 publications

Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

Eculizumab for Dense Deposit Disease and C3 Glomerulonephritis

Atypical Hemolytic Uremic Syndrome

Böbrek Naklinde Kullanılan Yeni İmmünsupresif İlaçlar

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