Insights from the use in clinical practice of eculizumab in adult patients with atypical hemolytic uremic syndrome affecting the native kidneys: an analysis of 19 cases.

Atypical hemolytic uremic syndrome (aHUS) is a devastating form of renal thrombotic microangiopathy. Despite plasma exchange, the standard treatment of aHUS for decades, the renal prognosis for patients with aHUS has remained poor. We assessed the off-trial use of eculizumab in adult patients with aHUS affecting the native kidneys. A retrospective study was conducted. aHUS was defined as the presence of 3 or more of the following: acute kidney injury (serum creatinine >1.4 mg/dL [120 μmol/L]), mechanical hemolytic anemia, thrombocytopenia, and the presence of thrombotic microangiopathy features in a kidney biopsy specimen. Patients who had received 4 or more weekly 900-mg infusions of eculizumab were included. 19 patients were identified through a query sent to all French nephrology centers. Evolution of kidney function, hemolysis, and thrombocytopenia after the initiation of eculizumab therapy. All patients had acute kidney injury (serum creatinine range, 2.2-17.0 mg/dL) and 12 required hemodialysis. Thirteen patients carried a mutation in 1 complement gene and 1 had anti-factor H antibodies. For first-line therapy, 16 patients underwent plasma exchange and 3 patients received eculizumab. Median time between aHUS onset and eculizumab therapy initiation was 6 (range, 1-60) days and median time to platelet count normalization after eculizumab therapy initiation was 6 (range, 2-42) days. At the 3-month follow-up, 4 patients still required dialysis, 8 had non-dialysis-dependent chronic kidney disease, and 7 had normalized kidney function. At last follow-up (range, 4-22 months), 3 patients remained dialysis dependent, 7 had non-dialysis-dependent chronic kidney disease (estimated glomerular filtration rate, 17-55 mL/min/1.73 m(2)), and 9 had normal kidney function. Risks of reaching end-stage renal disease within 3 months and 1 year of aHUS onset were reduced by half in eculizumab-treated patients compared with recent historical controls. Retrospective study and use of historical controls. Our data indicate that eculizumab improves kidney disease outcome in patients with aHUS.

Fakhouri F ，Delmas Y ，Provot F ，Barbet C ，Karras A ，Makdassi R ，Courivaud C ，Rifard K ，Servais A ，Allard C ，Besson V ，Cousin M ，Châtelet V ，Goujon JM ，Coindre JP ，Laurent G ，Loirat C ，Frémeaux-Bacchi V ... -  《-》

Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome.

Legendre CM ，Licht C ，Muus P ，Greenbaum LA ，Babu S ，Bedrosian C ，Bingham C ，Cohen DJ ，Delmas Y ，Douglas K ，Eitner F ，Feldkamp T ，Fouque D ，Furman RR ，Gaber O ，Herthelius M ，Hourmant M ，Karpman D ，Lebranchu Y ，Mariat C ，Menne J ，Moulin B ，Nürnberger J ，Ogawa M ，Remuzzi G ，Richard T ，Sberro-Soussan R ，Severino B ，Sheerin NS ，Trivelli A ，Zimmerhackl LB ，Goodship T ，Loirat C ... -  《-》

Eculizumab in anti-factor h antibodies associated with atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a life-threatening multisystemic condition often leading to end-stage renal failure. It results from an increased activation of the alternative pathway of the complement system due to mutations of genes coding for inhibitors of this pathway or from autoantibodies directed against them. Eculizumab is a monoclonal antibody directed against complement component C5 and inhibiting the activation of the effector limb of the complement system. Its efficacy has already been demonstrated in aHUS. The present article reports for the first time the use of eculizumab in a patient presenting with aHUS associated with circulating anti-complement Factor H autoantibodies and complicated by cardiac and neurologic symptoms. Our observation highlights the efficacy of eculizumab in this form of aHUS not only on renal symptoms but also on the extrarenal symptoms. It also suggests that eculizumab should be used very promptly after aHUS presentation to prevent life-threatening complications and to reduce the risk of chronic disabilities. To obtain a complete inhibition of the effector limb activation, the advised dosage must be respected. After this initial therapy in the autoimmune aHUS form, a long-term immunosuppressive treatment should be considered, to prevent relapses by reducing anti-complement Factor H autoantibody plasma levels.

Diamante Chiodini B ，Davin JC ，Corazza F ，Khaldi K ，Dahan K ，Ismaili K ，Adams B ... -  《-》

Terminal Complement Inhibitor Eculizumab in Adult Patients With Atypical Hemolytic Uremic Syndrome: A Single-Arm, Open-Label Trial.

Atypical hemolytic uremic syndrome (aHUS) is a rare genetic life-threatening disease of chronic uncontrolled complement activation leading to thrombotic microangiopathy (TMA) and severe end-organ damage. Eculizumab, a terminal complement inhibitor approved for aHUS treatment, was reported to improve hematologic and renal parameters in 2 prior prospective phase 2 studies. This is the largest prospective study of eculizumab in aHUS to date, conducted in an adult population. Open-label single-arm phase 2 trial. Patients 18 years or older with aHUS (platelet count <150 × 10(3)/μL, hemoglobin ≤ lower limit of normal, lactate dehydrogenase ≥1.5 × upper limit of normal [ULN], and serum creatinine ≥ ULN) were included in this multicenter multinational study. Intravenous eculizumab (900mg/wk for 4 weeks, 1,200mg at week 5 and then every 2 weeks) for 26 weeks. Primary end point was complete TMA response within 26 weeks, defined as hematologic normalization (platelet count ≥150 × 10(3)/μL, LDH ≤ ULN), and preservation of kidney function (<25% serum creatinine increase from baseline), confirmed by 2 or more consecutive measurements obtained 4 or more weeks apart. 41 patients were treated; 38 (93%) completed 26 weeks of treatment. 30 (73%) were included during their first TMA manifestation. 30 (73%) had complete TMA response. Platelet counts and estimated glomerular filtration rates increased from baseline (P<0.001). All 35 patients on baseline plasma exchange/plasma infusion discontinued by week 26. Of 24 patients requiring baseline dialysis, 5 recovered kidney function before eculizumab initiation and 15 of the remaining 19 (79%) discontinued dialysis during eculizumab treatment. No patients lost existing transplants. Quality-of-life measures were significantly improved. Two patients developed meningococcal infections; both recovered, and 1 remained on eculizumab treatment. Single-arm open-label design. Results highlight the benefits of eculizumab in adult patients with aHUS: improvement in hematologic, renal, and quality-of-life parameters; dialysis discontinuation; and transplant protection.

Fakhouri F ，Hourmant M ，Campistol JM ，Cataland SR ，Espinosa M ，Gaber AO ，Menne J ，Minetti EE ，Provôt F ，Rondeau E ，Ruggenenti P ，Weekers LE ，Ogawa M ，Bedrosian CL ，Legendre CM ... -  《-》

Atypical hemolytic uremic syndrome: from the rediscovery of complement to targeted therapy.

Atypical hemolytic uremic syndrome (aHUS) is a devastating form of renal thrombotic microangiopathy. In the last five years, we have finally witnessed a dramatic improvement in the management of aHUS patients, and three breakthroughs in our understanding of aHUS have led to such an improvement. The first breakthrough was the emergence of a new clinical picture of aHUS (frequency of adult cases, and overall poor renal prognosis despite plasma therapy). The second breakthrough was the identification of complement alternative pathway dysregulation as a major risk factor for aHUS. The third breakthrough was the availability in clinical practice of the first complement inhibitor, the anti-C5 monoclonal antibody, eculizumab. Available data from case series and prospective studies indicate that eculizumab use has dramatically improved the renal prognosis of aHUS. These breakthroughs have prompted the French working group on aHUS to propose a new algorithm for the management of aHUS in children and in adults. This algorithm will evolve as we gain new insights in the pathogenesis and evolution of aHUS in the eculizumab era.

Fakhouri F ，Frémeaux-Bacchi V ，Loirat C 《-》