Eculizumab in atypical hemolytic uremic syndrome: strategies toward restrictive use

Abstract

With the introduction of the complement C5-inhibitor eculizumab, a new era was entered for patients with atypical hemolytic uremic syndrome (aHUS). Eculizumab therapy very effectively reversed thrombotic microangiopathy and reduced mortality and morbidity. Initial guidelines suggested lifelong treatment and recommended prophylactic use of eculizumab in aHUS patients receiving a kidney transplant. However, there is little evidence to support lifelong therapy or prophylactic treatment in kidney transplant recipients. Worldwide, there is an ongoing debate regarding the optimal dose and duration of treatment, particularly in view of the high costs and potential side effects of eculizumab. An increasing but still limited number of case reports and small cohort studies suggest that a restrictive treatment regimen is feasible. We review the current literature and focus on the safety and efficacy of restrictive use of eculizumab. Our current treatment protocol is based on restrictive use of eculizumab. Prospective monitoring will provide more definite proof of the feasibility of such restrictive treatment.Electronic supplementary materialThe online version of this article (10.1007/s00467-018-4091-3) contains supplementary material, which is available to authorized users.

Das Komplementsystem: von den Grundlagen zur klinischen Bedeutung

“…Diese Aspekte sowie die Beobachtung, dass sich bei manchen, mit Eculizumab behandelten Patienten trotz Beachtung der empfohlenen Therapievorgaben ein unzureichender Behandlungserfolg aufgrund von Unterdosierung feststellen lässt [158], haben zu einem gesteigerten Interesse an einem komplementbasierten Therapiemonitoring für Eculizumab geführt. Als labordiagnostisches Korrelat für suffiziente Eculizumab-Wirkspiegel in vivo dient eine Reduktion der hämolytischen Aktivität des klassischen (CH50) und alternativen Wegs (AH50) der Komplementaktivierung auf ≤ 10 % der normalen Aktivität in vitro [159,160]. So konnte gezeigt werden, dass eine solche Reduktion der CH50-Aktivität mit einer Verbesserung der Hämolyseparameter bei PNH-Patienten assoziiert ist [158].…”

Gemcitabine-associated thrombotic microangiopathy – a role for eculizumab?

“…The duration of treatment has also been a matter of debate 27 . Since genetic studies were normal and the offending drug had been suspended, we decided to stop eculizumab after 4 initial induction doses plus another 2 for maintenance therapy, with no further occurrences.…”

Optimal duration of treatment with eculizumab in atypical hemolytic uremic syndrome (aHUS)—a question to be addressed in a scientific way

“…A new strong statement in favor of a restrictive approach for eculizumab treatment in aHUS, based on the studies discussed above and our own experience [52][53][54][55][56], has been advocated recently [57]. Expert research on C′ and a skilled Dutch clinical group has published a restrictive therapeutic aHUS protocol based on patient age, C′ gene variant profile, and coordination by a national referent center, to provide distinct eculizumab treatment patterns in terms of duration, full or reduced dose, and complete or partial C´activity blockade [57]. Unfortunately, the outcome of that approach is still unknown as a prospective observational national monitoring project (CUREiHUS, NTR5988) to guide eculizumab therapy in aHUS is ongoing.…”

“…Finally, the proposed restrictive approach in aHUS in adult transplant patients or in adult candidates for KTx [57] is highly questionable due to controversial results, limited recovery after eculizumab resumption, and lack of alignment with expert recommendations [22][23][24]33]. New information from the Global aHUS Registry analyzing the outcome of 188 KTx patients with at least 1 year of followup after their most recent transplant demonstrated significantly better 2-year eGFR (70.2 ml/min/1.73m 2 ) in the subgroup of patients receiving eculizumab beginning at the time of transplantation in comparison with the subgroup receiving eculizumab after KTx with a previous diagnosis of aHUS (44.8 ml/min/1.73m 2 ) or the subgroup diagnosed with aHUS and treated after KTx (24.2 ml/ min/1.73m 2 ) [58].…”