An international consensus approach to the management of atypical hemolytic uremic syndrome in children

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.

Orphan drug policies and use in pediatric nephrology

“…Atypical hemolytic uremic syndrome (aHUS) manifests as recurrent episodes of hemolytic anemia, thrombocytopenia, and acute renal failure, and is often associated with heterozygous mutations in one or more complement proteins, or autoantibodies to the soluble complement regulator factor H [23]. The result is a hyperactive alternative pathway of complement leading to damage to host cells.…”

“…Patients were previously exclusively treated with plasma exchange or infusions but the prognosis regarding renal function and mortality was poor until the introduction of eculizumab, which was shown to be highly effective in both adults and children with aHUS [24,25]. Current international consensus (2015) recommends the start of eculizumab treatment upon diagnosis of aHUS, although treatment can be discontinued in a small subset of patients, particularly those with autoantibodies [23]. For all other patients, continuous treatment is recommended as long as the patient has renal function (native or transplant).…”

Thrombotic microangiopathy caused by interferon β-1b for multiple sclerosis: a case report

“…After discriminating our case from TTP and STEC-HUS, we had made a differential diagnosis [3]. Abnormal complement activation by gene mutation, which usually presents in the family history or could present recurrent onset of TMA, or autoantibody against factor H is a main cause of aHUS.…”

“…In addition, eculizumab, an anti-C5 monoclonal antibody, could be effective in controlling TMA, but it is still unclear whether this monoclonal antibody would also be effective in drug-induced TMA until now [3]. Further information is required to elucidate the mechanism of TMA induced by interferon b-1b.…”

“…aHUS has been further classified as complementmediated TMA, drug-mediated TMA (immune reaction or toxic dose-related reaction), coagulation-mediated TMA and metabolism-mediated TMA [2]. A diagnostic algorithm for aHUS has been recently proposed [3]. During these steps, a decision is made to immediately initiate plasma exchange (PE) with fresh frozen plasma (FFP) combined with corticosteroid therapy when TTP or TMA that required PE is suspected [2,4,5].…”