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Journal ArticleDOI

Atypical Hemolytic Uremic Syndrome

01 Nov 2013-Seminars in Nephrology (Elsevier)-Vol. 33, Iss: 6, pp 508-530
TL;DR: HUS is a triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure that predicts the prognosis both in native kidneys and after renal transplantation.
About: This article is published in Seminars in Nephrology.The article was published on 2013-11-01 and is currently open access. It has received 258 citations till now. The article focuses on the topics: Atypical hemolytic uremic syndrome & Eculizumab.
Citations
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Journal ArticleDOI
TL;DR: 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.
Abstract: 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.

505 citations

Journal ArticleDOI
TL;DR: Recommendations for best treatment strategies were discussed at length, providing the evidence base underpinning current treatment options, and knowledge gaps were identified and a prioritized research agenda was proposed to resolve outstanding controversial issues.

462 citations

Journal ArticleDOI
TL;DR: The need for prospective studies to establish evidence-based criteria for the continuation or cessation of anticomplement therapy in patients with and without identified complement mutations is discussed.
Abstract: Atypical hemolytic uremic syndrome (aHUS) emerged during the last decade as a disease largely of complement dysregulation. This advance facilitated the development of novel, rational treatment options targeting terminal complement activation, e.g., using an anti-C5 antibody (eculizumab). We review treatment and patient management issues related to this therapeutic approach. We present consensus clinical practice recommendations generated by HUS International, an international expert group of clinicians and basic scientists with a focused interest in HUS. We aim to address the following questions of high relevance to daily clinical practice: Which complement investigations should be done and when? What is the importance of anti-factor H antibody detection? Who should be treated with eculizumab? Is plasma exchange therapy still needed? When should eculizumab therapy be initiated? How and when should complement blockade be monitored? Can the approved treatment schedule be modified? What approach should be taken to kidney and/or combined liver-kidney transplantation? How should we limit the risk of meningococcal infection under complement blockade therapy? A pressing question today regards the treatment duration. We discuss the need for prospective studies to establish evidence-based criteria for the continuation or cessation of anticomplement therapy in patients with and without identified complement mutations.

421 citations

Journal ArticleDOI
TL;DR: The history, current landscape and future directions for anti-complement therapies are described, which include infectious, inflammatory, degenerative, traumatic and neoplastic disorders.
Abstract: The complement system is a key innate immune defence against infection and an important driver of inflammation; however, these very properties can also cause harm. Inappropriate or uncontrolled activation of complement can cause local and/or systemic inflammation, tissue damage and disease. Complement provides numerous options for drug development as it is a proteolytic cascade that involves nine specific proteases, unique multimolecular activation and lytic complexes, an arsenal of natural inhibitors, and numerous receptors that bind to activation fragments. Drug design is facilitated by the increasingly detailed structural understanding of the molecules involved in the complement system. Only two anti-complement drugs are currently on the market, but many more are being developed for diseases that include infectious, inflammatory, degenerative, traumatic and neoplastic disorders. In this Review, we describe the history, current landscape and future directions for anti-complement therapies.

315 citations

Journal ArticleDOI
11 Sep 2014-Blood
TL;DR: Results point to efficient complement inhibition on endothelium for aHUS treatment, including C5b-9 endothelial deposits, which might help monitor eculizumab effectiveness, avoid drug overexposure, and save money considering the extremely high cost of the drug.

268 citations

References
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Journal ArticleDOI
TL;DR: An updated view of the function, structure and dynamics of the complement network is described, its interconnection with immunity at large and with other endogenous pathways is highlighted, and its multiple roles in homeostasis and disease are illustrated.
Abstract: Nearly a century after the significance of the human complement system was recognized, we have come to realize that its functions extend far beyond the elimination of microbes. Complement acts as a rapid and efficient immune surveillance system that has distinct effects on healthy and altered host cells and foreign intruders. By eliminating cellular debris and infectious microbes, orchestrating immune responses and sending 'danger' signals, complement contributes substantially to homeostasis, but it can also take action against healthy cells if not properly controlled. This review describes our updated view of the function, structure and dynamics of the complement network, highlights its interconnection with immunity at large and with other endogenous pathways, and illustrates its multiple roles in homeostasis and disease.

2,986 citations

Journal ArticleDOI
TL;DR: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome and was also associated with improvement in health-related quality of life.
Abstract: A b s t r ac t Background Atypical hemolytic–uremic syndrome is a genetic, life-threatening, chronic disease of complement-mediated thrombotic microangiopathy. Plasma exchange or infusion may transiently maintain normal levels of hematologic measures but does not treat the underlying systemic disease. Methods We conducted two prospective phase 2 trials in which patients with atypical hemo lytic–uremic syndrome who were 12 years of age or older received eculizumab for 26 weeks and during long-term extension phases. Patients with low platelet counts and renal damage (in trial 1) and those with renal damage but no decrease in the platelet count of more than 25% for at least 8 weeks during plasma exchange or infu sion (in trial 2) were recruited. The primary end points included a change in the platelet count (in trial 1) and thrombotic microangiopathy event–free status (no de crease in the platelet count of >25%, no plasma exchange or infusion, and no initia tion of dialysis) (in trial 2). Results A total of 37 patients (17 in trial 1 and 20 in trial 2) received eculizumab for a median of 64 and 62 weeks, respectively. Eculizumab resulted in increases in the platelet count; in trial 1, the mean increase in the count from baseline to week 26 was 73×10 9 per liter (P<0.001). In trial 2, 80% of the patients had thrombotic microangiopathy event–free status. Eculizumab was associated with significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR). In trial 1, dialysis was discontinued in 4 of 5 patients. Earlier intervention with eculiz umab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in healthrelated quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the exten

1,219 citations

Journal ArticleDOI
TL;DR: Current concepts about the pathobiology of atypical hemolytic–uremic syndrome are reviewed and its diagnosis and management are reviewed.
Abstract: The hemolytic–uremic syndrome, which is characterized by nonimmune hemolytic anemia, thrombocytopenia, and renal impairment, occurs most frequently in young children. Most cases are secondary to infection with Escherichia coli O157:H7 and other Shiga-toxin–producing strains. However, approximately 10% of cases are atypical and not associated with infection. This article reviews current concepts about the pathobiology of atypical hemolytic–uremic syndrome and its diagnosis and management.

1,108 citations

Journal ArticleDOI
TL;DR: Results underline the need of genetic screening for all susceptibility factors as part of clinical management of aHUS and for identification of patients who could safely benefit from kidney transplant.
Abstract: Background and objectives: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Most childhood cases are caused by Shiga toxin–producing bacteria. The other form, atypical HUS (aHUS), accounts for 10% of cases and has a poor prognosis. Genetic complement abnormalities have been found in aHUS. Design, setting, participants, and measurements: We screened 273 consecutive patients with aHUS for complement abnormalities and studied their role in predicting clinical phenotype and response to treatment. We compared mutation frequencies and localization and clinical outcome in familial (82) and sporadic (191) cases. Results: In >70% of sporadic and familial cases, gene mutations, disease-associated factor H ( CFH ) polymorphisms, or anti-CFH autoantibodies were found. Either mutations or CFH polymorphisms were also found in the majority of patients with secondary aHUS, suggesting a genetic predisposition. Familial cases showed a higher prevalence of mutations in SCR20 of CFH and more severe disease than sporadic cases. Patients with CFH or THBD (thrombomodulin) mutations had the earliest onset and highest mortality. Membrane-cofactor protein ( MCP ) mutations were associated with the best prognosis. Plasma therapy induced remission in 55 to 80% of episodes in patients with CFH , C3, or THBD mutations or autoantibodies, whereas patients with CFI (factor I) mutations were poor responders. aHUS recurred frequently after kidney transplantation except for patients with MCP mutations. Conclusions: Results underline the need of genetic screening for all susceptibility factors as part of clinical management of aHUS and for identification of patients who could safely benefit from kidney transplant.

845 citations


"Atypical Hemolytic Uremic Syndrome" refers background in this paper

  • ...The prognosis of aHUS with CFB mutations also is poor.(51,55,56) A proportion of patients will have combined mutations....

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  • ...Only 30% to 40% of individuals with CFI and C3 mutations will be alive with native kidney function at 3 to 5 years.(49,51) The prognosis of aHUS with CFB mutations also is poor....

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  • ...In patients with a CFH mutation the initial mortality rate was 30% in children and 4% in adults,(49) and evolution to ESRD at first episode in survivors was 19% to 33% in children and 48% in adults.(49,51) At 3 to 5 years of follow-up evaluation, up to 77% of patients with CFH mutations had developed ESRD or had died....

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  • ...Infectious events, mainly upper respiratory tract infections or diarrhea/gastroenteritis, trigger onset of aHUS in at least half of patients.(49,51) Likewise, in pregnancy-associated aHUS, Fakhouri et al(98) showed that 86% of patients for whom this was a trigger carried a complement gene mutation....

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  • ...diarrhea preceded aHUS in 23% of a French cohort(94) and in 28% of an Italian cohort.(51) Infectious events, mainly upper respiratory tract infections or diarrhea/gastroenteritis, trigger onset of aHUS in at least half of patients....

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Journal ArticleDOI
TL;DR: The recent approval of eculizumab as a first-in-class complement inhibitor for the treatment of PNH validates the concept of complement inhibition as an effective therapy and provides rationale for investigation of other indications in which complement plays a role.
Abstract: The complement system provides critical immunoprotective and immunoregulatory functions but uncontrolled complement activation can lead to severe pathology. In the rare hemolytic disease paroxysmal nocturnal hemoglobinuria (PNH), somatic mutations result in a deficiency of glycosylphosphatidylinositol-linked surface proteins, including the terminal complement inhibitor CD59, on hematopoietic stem cells. In a dysfunctional bone marrow background, these mutated progenitor blood cells expand and populate the periphery. Deficiency of CD59 on PNH red blood cells results in chronic complement-mediated intravascular hemolysis, a process central to the morbidity and mortality of PNH. A recently developed, humanized monoclonal antibody directed against complement component C5, eculizumab (Soliris; Alexion Pharmaceuticals Inc., Cheshire, CT, USA), blocks the proinflammatory and cytolytic effects of terminal complement activation. The recent approval of eculizumab as a first-in-class complement inhibitor for the treatment of PNH validates the concept of complement inhibition as an effective therapy and provides rationale for investigation of other indications in which complement plays a role.

685 citations


"Atypical Hemolytic Uremic Syndrome" refers background in this paper

  • ...Eculizumab, a recombinant humanized monoclonal antibody directed against C5, blocks the cleavage of C5 into its effector components C5a and C5b.(106) Since the initial use of this complement inhibitor in aHUS in 2009,(107) the effectiveness of eculizumab has been communicated in many case reports, meeting abstracts, and a recently published prospective trial....

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