Key literature on aHUS, from seminal reviews and practice guidelines to the latest clinical trials

Uncontrolled complement activation can cause or contribute to glomerular injury in multiple kidney diseases. Although complement activation plays a causal role in atypical hemolytic uremic syndrome and C3 glomerulopathy, over the past decade, a rapidly accumulating body of evidence has shown a role for complement activation in multiple other kidney diseases, including diabetic nephropathy and several glomerulonephritides. The number of available complement inhibitor therapies has also increased during the same period. In 2022, Kidney Diseases: Improving Global Outcomes (KDIGO) convened a Controversies Conference, "The Role of Complement in Kidney Disease," to address the expanding role of complement dysregulation in the pathophysiology, diagnosis, and management of various glomerular diseases, diabetic nephropathy, and other forms of hemolytic uremic syndrome. Conference participants reviewed the evidence for complement playing a primary causal or secondary role in progression for several disease states and considered how evidence of complement involvement might inform management. Participating patients with various complement-mediated diseases and caregivers described concerns related to life planning, implications surrounding genetic testing, and the need for inclusive implementation of effective novel therapies into clinical practice. The value of biomarkers in monitoring disease course and the role of the glomerular microenvironment in complement response were examined, and key gaps in knowledge and research priorities were identified.

Purpose of review: Thrombotic microangiopathy (TMA) is suspected in patients presenting with thrombocytopenia and evidence of a microangiopathic hemolytic anemia. Patients with TMA can be critically ill, so rapid and accurate identification of the underlying etiology is essential. Due to better insights into pathophysiology and causes of TMA, we can now categorize TMAs as thrombotic thrombocytopenic purpura, postinfectious (mainly Shiga toxin-producing Escherichia coli-induced) hemolytic uremic syndrome (HUS), TMA associated with a coexisting condition, or atypical HUS (aHUS). We recognized an unmet need in the medical community to guide the timely and accurate identification of TMA, the selection of tests to clarify its etiology, and the sequence of steps to initiate treatment.

Sources of information: Key published studies relevant to the identification, classification, and treatment of TMAs in children or adults. These studies were obtained through literature searches conducted with PubMed or based on the prior knowledge of the authors.

Methods: This review is the result of a consultation process that reflects the consensus of experts from Canada, the United States, and the United Arab Emirates. The members represent individuals who are clinicians, researchers, and teachers in pediatric and adult medicine from the fields of hematology, nephrology, and laboratory medicine. Authors, through an iterative review process identified and synthesized information from relevant published studies.

Key findings: Thrombotic thrombocytopenic purpura occurs in the setting of insufficient activity of the von Willebrand factor protease known as ADAMTS13. Shiga toxin-producing Escherichia coli-induced hemolytic uremic syndrome, also known as "typical" HUS, is caused by gastrointestinal infections with bacteria that produce Shiga toxin (initially called verocytotoxin). A variety of clinical conditions or drug exposures can trigger TMA. Finally, aHUS occurs in the setting of inherited or acquired abnormalities in the alternative complement pathway leading to dysregulated complement activation, often following a triggering event such as an infection. It is possible to break the process of etiological diagnosis of TMA into 2 distinct steps. The first covers the initial presentation and diagnostic workup, including the processes of identifying the presence of TMA, appropriate initial tests and referrals, and empiric treatments when appropriate. The second step involves confirming the etiological diagnosis and moving to definitive treatment. For many forms of TMA, the ultimate response to therapies and the outcome of the patient depends on the rapid and accurate identification of the presence of TMA and then a standardized approach to seeking the etiological diagnosis. We present a structured approach to identifying the presence of TMA and steps to identifying the etiology including standardized lab panels. We emphasize the importance of early consultation with appropriate specialists in hematology and nephrology, as well as identification of whether the patient requires plasma exchange. Clinicians should consider appropriate empiric therapies while following the steps we have recommended toward definitive etiologic diagnosis and management of the TMA.

Limitations: The evidence base for our recommendations consists of small clinical studies, case reports, and case series. They are generally not controlled or randomized and do not lend themselves to a stricter guideline-based methodology or a Grading of Recommendations Assessment, Development and Evaluation (GRADE)-based approach.

Evidence-based recommendations on ravulizumab (Ultomiris) for treating atypical haemolytic uraemic syndrome in people weighing 10 kg or more.

This review article covers the diverse pathophysiological pathways that can lead to microangiopathic hemolytic anemia and a procoagulant state with or without damage to the kidneys and other organs.

Background: Despite significant advances in therapeutic management of atypical hemolytic uremic syndrome (aHUS), guidelines are not timely updated and achieving a consensus on management recommendations remains a topic of ongoing discussion.

Methods: A Scientific Committee with five experts was set up. A literature review was conducted and publications addressing the classification of aHUS, patient profiles and therapeutic approach were selected. Recommendations were proposed at an initial meeting, evaluated through an online questionnaire and validated during a second meeting.

Results: Patients with confirmed or clear suspicion of aHUS should be treated with C5 inhibitors within 24 h of the diagnosis or suspicion of aHUS. Treatment monitoring and the decision to interrupt treatment should be individualised according to the risk of relapse and each patient's evolution. aHUS with a genetic variant or associated with pregnancy should be treated for at least 6-12 months; de novo aHUS associated with kidney transplant until renal function is recovered and genetic variants are ruled out; aHUS associated with malignant hypertension until genetic variants are ruled out; aHUS associated with non-kidney transplant, autoimmune diseases, infection-or drug-induced until the thrombotic microangiopathy is resolved. Patients with a high risk of relapse should be treated for longer than 6-12 months.

Conclusion: These recommendations provides physicians who are not familiar with the disease with recommendations for the management of aHUS in adults. The experts who participated advocate early treatment, maintenance for at least 6-12 months and treatment interruption guided by genetic background, trigger factors, risk of relapse and evolution.

A typical Hemolytic Uremic Syndrome (aHUS) is a severe, systemic, rare disease (RD) that can occur in people of all ages, and is associated with high rates of morbidity and mortality. Because the management of patients with aHUS can be difficult, more effective strategies should be implemented. Faculty members from several Italian Scientific Societies, Patient Associations and Regional Institutional Experts on RDs met to discuss aHUS management within a multidisciplinary team (MDT), using a Delphi process to develop consensus recommendations. Consensus (≥70% agreement by faculty members) was reached on 51 statements with the aim of improving patient management and outcomes. These statements provide a unified framework for the differential diagnosis of aHUS, prompt recognition of the pathology, referral to RD reference centers, selecting between treatment relapse prevention measures options, patient management by a MDT and improving the overall awareness of aHUS. Despite the broad scope of the consensus statements, several unmet needs in the management of patients with aHUS were identified, including diagnostic suspicion, rapid genetic investigations, regular review of the centers of expertise (considering the number of treated patients), permanent clinical referral in treatment centers and widespread expertise among adult and pediatric specialists. We hope that this standardized framework will form the basis of the "digital ecosystem" concept and development of possible information technology solutions to assist the MDT involved in the management of patients with aHUS.

Atypical hemolytic uremic syndrome (aHUS) is a rare cause of thrombotic microangiopathy (TMA) caused by the dysregulation of the alternative complement pathway. The diagnosis of TMA is made clinically by the triad: microangiopathic hemolytic anemia, thrombocytopenia, and organ damage (mainly acute kidney injury). The heterogeneity of clinical manifestation and the lack of a gold standard diagnostic test makes the precise diagnosis of aHUS a challenging process that may impact patient management. Until one decade ago, there was no specific treatment for aHUS and patients were submitted to plasma therapy (plasma exchange and/or plasma infusion) and/or liver transplantation, procedures that are not free of serious complications and that do not address the underlying pathophysiology of the disease. Since 2011, an anti-C5 complement monoclonal antibody has been approved by the Food and Drug Administration (FDA) for aHUS patients beginning a new era in treatment. Clinical trials on new complement inhibitors may also add to the treatment portfolio in the future. The Brazilian population is a mixed race with a unique genetic and clinical profile. This consensus aims to offer recommendations for the diagnosis and treatment of patients with aHUS in this population based on expert experience, data from the aHUS Brazilian Registry and literature review. The GRADE system was used to classify the quality of the evidence.

The term atypical hemolytic uremic syndrome has been in use since the mid-1970s. It was initially used to describe the familial or sporadic form of hemolytic uremic syndrome as opposed to the epidemic, typical form of the disease. Over time, the atypical hemolytic uremic syndrome term has evolved into being used to refer to anything that is not Shiga toxin-associated hemolytic uremic syndrome. The term describes a heterogeneous group of diseases of disparate causes, a circumstance that makes defining disease-specific natural history and/or targeted treatment approaches challenging. A working group of specialty-specific experts in the thrombotic microangiopathies was convened to review the validity of this broad term in an era of swiftly advancing science and targeted therapeutics. A Delphi approach was used to define and interrogate some of the key issues related to the atypical hemolytic uremic syndrome nomenclature.

Thrombotic microangiopathy (TMA), a pathological lesion observed in a wide spectrum of diseases, is triggered by endothelial injury and/or dysfunction. Although TMA lesions are often accompanied by clinical features of microangiopathic hemolytic anemia, thrombocytopenia, and ischemic end-organ injury, renal-limited forms of TMA are not infrequently encountered in clinical practice. The presence of renal-limited manifestations can be diagnostically challenging, often delaying the initiation of targeted therapy. Prompt investigation and empirical treatment of TMA is warranted to reduce associated morbidity and mortality. Major advances have been made with respect to the pathophysiology of primary TMA entities, with the subsequent development of novel diagnostic tools and lifesaving therapies for diseases like thrombotic thrombocytopenic purpura and complement-mediated TMA. This article will review the clinical presentation and pathologic hallmarks of TMA involving the kidney, and the disease-specific mechanisms that contribute to the endothelial injury that characterizes TMA lesions. Diagnostic approach and both empirical and disease-specific treatment strategies will be discussed, along with the potential role for emerging targeted disease-specific therapies.

Our understanding and management of atypical hemolytic uremic syndrome (aHUS) have dramatically improved in the last decade. aHUS has been established as a prototypic disease resulting from a dysregulation of the complement alternative C3 convertase. Subsequently, prospective nonrandomized studies and retrospective series have shown the efficacy of C5 blockade in the treatment of this devastating disease. C5 blockade has become the cornerstone of the treatment of aHUS. This therapeutic breakthrough has been dulled by persistent difficulties in the positive diagnosis of aHUS, and the latter remains, to date, a diagnosis by exclusion. Furthermore, the precise spectrum of complement-mediated renal thrombotic microangiopathy is still a matter of debate. Nevertheless, long-term management of aHUS is increasingly individualized and lifelong C5 blockade is no longer a paradigm that applies to all patients with this disease. The potential benefit of complement blockade in other forms of HUS, notably secondary HUS, remains uncertain.

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.

Atypical hemolytic-uremic syndrome (aHUS) is associated with genetic complement abnormalities/anti-complement factor H antibodies, which paved the way to treatment with eculizumab. We studied 44 aHUS patients and their relatives to (1) test new assays of complement activation, (2) verify whether such abnormality occurs also in unaffected mutation carriers, and (3) search for a tool for eculizumab titration. An abnormal circulating complement profile (low C3, high C5a, or SC5b-9) was found in 47% to 64% of patients, irrespective of disease phase. Acute aHUS serum, but not serum from remission, caused wider C3 and C5b-9 deposits than control serum on unstimulated human microvascular endothelial cells (HMEC-1). In adenosine 5'-diphosphate-activated HMEC-1, also sera from 84% and 100% of patients in remission, and from all unaffected mutation carriers, induced excessive C3 and C5b-9 deposits. At variance, in most patients with C3 glomerulopathies/immune complex-associated membranoproliferative glomerulonephritis, serum-induced endothelial C5b-9 deposits were normal. In 8 eculizumab-treated aHUS patients, C3/SC5b-9 circulating levels did not change posteculizumab, whereas serum-induced endothelial C5b-9 deposits normalized after treatment, paralleled or even preceded remission, and guided drug dosing and timing. These results point to efficient complement inhibition on endothelium for aHUS treatment. C5b-9 endothelial deposits might help monitor eculizumab effectiveness, avoid drug overexposure, and save money considering the extremely high cost of the drug.

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.

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.

The diagnostic terms hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP) are based on historical and overlapping clinical descriptions. Advances in understanding some of the causes of the syndrome now permit many patients to be classified according to etiology. The increased precision of a diagnosis based on causation is important for considering logical approaches to treatment and prognosis. It is also essential for research. We propose a classification that accommodates both a current understanding of causation (level 1) and clinical association in cases for whom cause of disease is unclear (level 2). We tested the classification in a pediatric disease registry of HUS. The revised classification is a stimulus to comprehensive investigation of all cases of HUS and TTP and is expected to increase the proportion of cases in whom a level 1 etiological diagnosis is confirmed.

Ravulizumab, a long-acting complement C5 inhibitor engineered from eculizumab, allows extending maintenance dosing from every 2-3 weeks to every 4-8 weeks depending on bodyweight. Here, we evaluated the efficacy and safety of ravulizumab in complement inhibitor-naïve children (under 18 years) with atypical hemolytic uremic syndrome. In this phase III, single-arm trial, ravulizumab was administered every eight weeks in patients 20 kg and over, and four weeks in patients under 20 kg. The primary endpoint was a complete thrombotic microangiopathy response (normalization of platelet count and lactate dehydrogenase, and a 25% or more improvement in serum creatinine) through 26 weeks. Secondary endpoints included change in hematologic parameters and kidney function. 18 patients with a median age of 5.2 years were evaluated. At baseline, symptoms of atypical hemolytic uremic syndrome outside the kidney were present in 72.2% of patients and 38.9% had been in intensive care. Baseline estimated glomerular filtration rate was 22 mL/min/1.73 m2. By week 26, 77.8% of patients achieved a complete thrombotic microangiopathy response; 94.4%, 88.9% and 83.3% of patients achieved platelet normalization, lactate dehydrogenase normalization and a 25% or more improvement in serum creatinine, respectively. By week 50, 94.4% patients had achieved a complete thrombotic microangiopathy response. Median improvement in platelet count was 246 and 213 x109/L through week 26 and week 50, respectively. The median increase above baseline in estimated glomerular filtration rate was 80 and 94 mL/min/1.73m2 through week 26 and week 50, respectively. No unexpected adverse events, deaths, or meningococcal infections occurred. Thus, ravulizumab rapidly improved hematologic and kidney parameters with no unexpected safety concerns in complement inhibitor-naïve children with atypical hemolytic uremic syndrome.

The optimal duration of eculizumab treatment in patients with atypical hemolytic uremic syndrome (aHUS) remains poorly defined. We conducted a prospective national multicenter open-label study to assess eculizumab discontinuation in children and adults with aHUS. Fifty-five patients (including 19 children) discontinued eculizumab (mean treatment duration, 16.5 months). Twenty-eight patients (51%) had rare variants in complement genes, mostly in MCP (n = 12; 22%), CFH (n = 6; 11%), and CFI (n = 6; 10%). At eculizumab discontinuation, 17 (30%) and 4 patients (7%) had stage 3 and 4 chronic kidney disease, respectively. During follow-up, 13 patients (23%; 6 children and 7 adults) experienced aHUS relapse. In multivariable analysis, female sex and presence of a rare variant in a complement gene were associated with an increased risk of aHUS relapse, whereas requirement for dialysis during a previous episode of acute aHUS was not. In addition, increased sC5b-9 plasma level at eculizumab discontinuation was associated with a higher risk of aHUS relapse in all patients and in the subset of carriers with a complement gene rare variant, both by log-rank test and in multivariable analysis. Of the 13 relapsing patients, all of whom restarted eculizumab, 11 regained their baseline renal function and 2 had a worsening of their preexisting chronic kidney disease, including 1 patient who progressed to end-stage renal disease. A strategy of eculizumab discontinuation in aHUS patients based on complement genetics is reasonable and safe. It improves the management and quality of life of a sizeable proportion of aHUS patients while reducing the cost of treatment. This trial was registered at www.clinicaltrials.gov as #NCT02574403.

Pregnancy and postpartum are high-risk periods for different forms of thrombotic microangiopathy (TMA). However, the management of pregnancy-associated TMA remains ill defined. This report, by an international multidisciplinary working group of obstetricians, nephrologists, hematologists, intensivists, neonatologists, and complement biologists, summarizes the current knowledge of these potentially severe disorders and proposes a practical clinical approach to diagnose and manage an episode of pregnancy-associated TMA. This approach takes into account the timing of TMA in pregnancy or postpartum, coexisting symptoms, first-line laboratory workup, and probability-based assessment of possible causes of pregnancy-associated TMA. Its aims are: to rule thrombotic thrombocytopenic purpura (TTP) in or out, with urgency, using ADAMTS13 activity testing; to consider alternative disorders with features of TMA (preeclampsia/eclampsia; hemolysis elevated liver enzymes low platelets syndrome; antiphospholipid syndrome); or, ultimately, to diagnose complement-mediated atypical hemolytic uremic syndrome (aHUS; a diagnosis of exclusion). Although they are rare, diagnosing TTP and aHUS associated with pregnancy, and postpartum, is paramount as both require urgent specific treatment.

Ravulizumab is a long-acting C5 inhibitor engineered from eculizumab with increased elimination half-life, allowing an extended dosing interval from two to eight weeks. Here we evaluate the efficacy and safety of ravulizumab in adults with atypical hemolytic uremic syndrome presenting with thrombotic microangiopathy. In this global, phase 3, single arm study in complement inhibitor-naïve adults (18 years and older) who fulfilled diagnostic criteria for atypical hemolytic uremic syndrome, enrolled patients received ravulizumab through a 26-week initial evaluation period. The primary endpoint was complete thrombotic microangiopathy response defined as normalization of platelet count and lactate dehydrogenase and 25% or more improvement in serum creatinine. Secondary endpoints included changes in hematologic variables and renal function. Safety was also evaluated. Ravulizumab treatment resulted in an immediate, complete, and sustained C5 inhibition in all patients. Complete thrombotic microangiopathy response was achieved in 53.6% of patients. Normalization of platelet count, lactate dehydrogenase and 25% or more improvement in serum creatinine was achieved in 83.9%, 76.8% and 58.9% of patients, respectively. Improvement in estimated glomerular filtration rate by one or more stage was achieved in 68.1% of patients by day 183. No unexpected adverse events were reported across a safety analysis set of 58 patients. Four deaths occurred (three within one month of study initiation, including one in a patient excluded based on eligibility criteria after the first dose) with none considered treatment-related by the study investigator. Thus, treatment with ravulizumab once every eight weeks resulted in rapidly improved hematologic and renal endpoints with no unexpected adverse events in adults with atypical hemolytic uremic syndrome.

Background: 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.

Study design: Open-label single-arm phase 2 trial.

Setting & participants: 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.

Intervention: Intravenous eculizumab (900mg/wk for 4 weeks, 1,200mg at week 5 and then every 2 weeks) for 26 weeks.

Outcomes & measurements: 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.

Results: 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.

Limitations: Single-arm open-label design.

Conclusions: 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.

Atypical hemolytic uremic syndrome (aHUS) is a rare, possibly life-threatening disease characterized by platelet activation, hemolysis and thrombotic microangiopathy (TMA) leading to renal and other end-organ damage. We originally conducted two phase 2 studies (26 weeks and 1 year) evaluating eculizumab, a terminal complement inhibitor, in patients with progressing TMA (trial 1) and those with long duration of aHUS and chronic kidney disease (trial 2). The current analysis assessed outcomes after 2 years (median eculizumab exposure 100 and 114 weeks, respectively). At all scheduled time points, eculizumab inhibited terminal complement activity. In trial 1 with 17 patients, the platelet count was significantly improved from baseline, and hematologic normalization was achieved in 13 patients at week 26, and in 15 patients at both 1 and 2 years. The estimated glomerular filtration rate (eGFR) was significantly improved compared with baseline and year 1. In trial 2 with 20 patients, TMA event-free status was achieved by 16 patients at week 26, 17 patients at year 1, and 19 patients at year 2. Criteria for hematologic normalization were met by 18 patients at each time point. Improvement of 15 ml/min per 1.73 m(2) or more in eGFR was achieved by 1 patient at week 26, 3 patients at 1 year, and 8 patients at 2 years. The mean change in eGFR was not significant compared with baseline, week 26, or year 1. Eculizumab was well tolerated, with no new safety concerns or meningococcal infections. Thus, a 2-year analysis found that the earlier clinical benefits achieved by eculizumab treatment of aHUS were maintained at 2 years of follow-up.

Objective: To determine the efficacy and safety of eculizumab for patients with atypical haemolytic uraemic syndrome (aHUS), compared with current treatment options.

Design: A systematic review was performed according to the general principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. All study designs were included, except case histories.

Participants: All patients diagnosed with aHUS were included; no age restrictions were used.

Interventions: Eculizumab compared with current treatment options.

Identification of studies: 12 databases were searched. Additional searches were performed through the Food and Drug Administration (FDA) and the Electronic Medicines Compendium websites, Google internet searches and contacting clinical experts. Reference lists of relevant articles were checked for additional studies.

Results: 2 small, uncontrolled prospective multinational, multicentre studies and one small uncontrolled multinational, multicentre retrospective study were included. No meta-analyses were performed. Compared with baseline measures, thrombotic microangiopathy event-free status was achieved in 84% of patients in the prospective studies. Adverse events, as documented by enrolling investigators were frequent, with upper-respiratory tract infection affecting a third of patients. No deaths or episodes of meningitis or meningococcal septicaemia occurred in the prospective studies. Results of the study extension phases up to 114 weeks indicate that the benefits of the treatment are sustained.

Conclusions: Eculizumab is clinically effective for the treatment of aHUS. Further research is needed to evaluate eculizumab, ideally using patient-related clinical outcomes. If randomised studies are not feasible, study investigators should ensure that the threat of bias is minimised in future studies of eculizumab with respect to the reporting of patient recruitment and selection.

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 hemolytic-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 infusion (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 decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation 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 eculizumab was associated with significantly greater improvement in the estimated GFR. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, were observed through the extension period.

Conclusions: Eculizumab inhibited complement-mediated thrombotic microangiopathy and was associated with significant time-dependent improvement in renal function in patients with atypical hemolytic-uremic syndrome. (Funded by Alexion Pharmaceuticals; C08-002 ClinicalTrials.gov numbers, NCT00844545 [adults] and NCT00844844 [adolescents]; C08-003 ClinicalTrials.gov numbers, NCT00838513 [adults] and NCT00844428 [adolescents]).

Background: Atypical hemolytic uremic syndrome (HUS) is associated with high recurrence rates after kidney transplant, with devastating outcomes. In late 2011, experts in France recommended the use of highly individualized complement blockade-based prophylaxis with eculizumab to prevent post-transplant atypical HUS recurrence throughout the country.

Methods: To evaluate this strategy's effect on kidney transplant prognosis, we conducted a retrospective multicenter study from a large French nationwide registry, enrolling all adult patients with atypical HUS who had undergone complement analysis and a kidney transplant since January 1, 2007. To assess how atypical HUS epidemiology in France in the eculizumab era evolved, we undertook a population-based cohort study that included all adult patients with atypical HUS (n=397) between 2007 and 2016.

Results: The first study included 126 kidney transplants performed in 116 patients, 58.7% and 34.1% of which were considered to be at a high and moderate risk of atypical HUS recurrence, respectively. Eculizumab prophylaxis was used in 52 kidney transplants, including 39 at high risk of recurrence. Atypical HUS recurred after 43 (34.1%) of the transplants; in four cases, patients had received eculizumab prophylaxis and in 39 cases they did not. Use of prophylactic eculizumab was independently associated with a significantly reduced risk of recurrence and with significantly longer graft survival. In the second, population-based cohort study, the proportion of transplant recipients among patients with ESKD and atypical HUS sharply increased between 2012 and 2016, from 46.2% to 72.3%, and showed a close correlation with increasing eculizumab use among the transplant recipients.

Conclusions: Results from this observational study are consistent with benefit from eculizumab prophylaxis based on pretransplant risk stratification and support the need for a rigorous randomized trial.