Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Mache, Christoph J.; Acham-Roschitz, Birgit; Frémeaux‐Bacchi, Véronique; Kirschfink, Michael; Zipfel, Peter F.; Roedl, Siegfried; Vester, Udo; Ring, E

doi:10.2215/cjn.01090209

Cited by 143 publications

(109 citation statements)

References 29 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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“…Eculizumab was approved initially in the management of paroxysmal nocturnal hemoglobinuria (53) and has been recently approved by the Food and Drug Administration and European regulatory organizations for the treatment of aHUS. Several case reports have underlined its efficiency in the treatment of aHUS affecting the native kidneys or the renal graft and even in the management of severe typical HUS cases (28,(54)(55)(56)(57)(58)(59). At least three open-label prospective industry-sponsored studies assessing the use of eculizumab in adult patients with aHUS have been conducted, and their results have been published in part in abstracts.…”

Section: Tma In Pregnancy: the Great Paradigm Shiftmentioning

confidence: 99%

Obstetric Nephrology

Fakhouri

Vercel

Frémeaux‐Bacchi

2012

Clinical Journal of the American Society of Nephrology

141

121

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Summary AKI in pregnancy remains a cause of significant fetomaternal mortality and morbidity, particularly in developing countries. Hypertensive complications of pregnancy (preeclampsia/eclampsia or hemolysis, elevated liver enzymes, and low platelets count syndrome) are the leading cause of AKI in pregnancy worldwide. Thrombotic microangiopathy is another peculiar and devastating cause of AKI in pregnancy. During the last decade, our understanding, and in some cases, our management, of these causes of AKI in pregnancy has dramatically improved. For instance, convincing data have linked pre-eclampsia/eclampsia to an increase in circulating antiangiogenic factors soluble Flt 1 and endoglin, which induce endothelial cell dysfunction, hypertension, and proteinuria. Several distinct pathogenic mechanisms underlying thrombotic microangiopathy, including thrombotic microangiopathy occurring during pregnancy, have been established. Thrombotic microangiopathy, which can present as hemolytic uremic syndrome or thrombotic thrombocytopenic purpura, can be reclassified in four potentially overlapping subtypes: disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 deficiency-related thrombotic microangiopathy, complement alternative pathway dysregulation-related thrombotic microangiopathy, secondary thrombotic microangiopathy (verotoxin and antiangiogenic drugs), and thrombotic microangiopathy of undetermined mechanism. In most cases, pregnancy is only a precipitating factor for thrombotic microangiopathy. Treatment of thrombotic microangiopathy occurring during pregnancy should be tailored to the underlying pathogenic mechanism: (1) restoration of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 serum activity in the setting of thrombotic thrombocytopenic purpura through plasma exchanges and in some cases, B cell-depleting therapy and (2) inhibition of complement alternative pathway activation in atypical hemolytic uremic syndrome using antiC5 blocking antibody (eculizumab).

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“…Eculizumab inhibits activation of the terminal complement pathway (C5), and its effectiveness in treating aHUS was demonstrated in many studies. [94][95][96][97] Legendre et al 96 studied the outcome of 37 aHUS patients after 26 weeks of eculizumab therapy in two clinical trials. In total, 80% of patients treated with eculizumab had improvements in anemia, thrombocytopenia, and renal function, resulting in eventual cessation of dialysis.…”

Section: Role Of Tbi In the Development Of Post-bmt Tmamentioning

confidence: 99%

“…94 Future studies will be required to assess its efficacy more thoroughly in this patient population.…”

Section: Role Of Tbi In the Development Of Post-bmt Tmamentioning

confidence: 99%

Post-bone marrow transplant thrombotic microangiopathy

Obut

Kasinath

Abdi

2016

Bone Marrow Transplant

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Thrombotic microangiopathy (TMA) is a systemic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ failure. Post-bone marrow transplant TMA (post-BMT TMA) is a life-threatening condition that has been reported to afflict between 0.5 and 63.6% of BMT patients. The incidence of post-BMT TMA is affected by evolving therapies such as conditioning regimens. The etiology of post-BMT TMA is thought to be multifactorial, including the effects of immunosuppressive agents, viral infections, TBI and GvHD. A growing body of evidence highlights the importance of complement system activation and endothelial damage in post-BMT TMA. Although plasmapheresis has commonly been used, its therapeutic rationale for the majority of post-BMT TMA cases is unclear in the absence of circulatory inhibitors. It has become possible to target complement activation with eculizumab, a drug that blocks the terminal complement pathway. Early studies have highlighted the importance of anticomplement therapies in treating post-BMT TMA. Moreover, finding complement gene mutations may identify patients at risk, but whether such patients benefit from prophylactic anti-complement therapies before BMT remains to be studied. This review focuses on diagnostic criteria, pathophysiology, treatment and renal outcomes of post-BMT TMA.

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Complement Inhibitor Eculizumab in Atypical Hemolytic Uremic Syndrome

Cited by 143 publications

References 29 publications

Atypical Hemolytic Uremic Syndrome

Atypical Hemolytic Uremic Syndrome

Obstetric Nephrology

Post-bone marrow transplant thrombotic microangiopathy

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