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.

Eculizumab is the first drug approved for the treatment of complement-mediated diseases, and current dosage schedules result in large interindividual drug concentrations. This review provides insight into the pharmacokinetic and pharmacodynamic properties of eculizumab, both for reported on-label (paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia gravis) and off-label (hematopoietic stem cell transplantation-associated thrombotic microangiopathy) indications. Furthermore, we discuss the potential of therapeutic drug monitoring to individualize treatment and reduce costs.

Recent studies indicate that eculizumab is often given in excess to atypical hemolytic uremic syndrome (aHUS) patients. Individualization of treatment is thus highly requested; however, data on the pharmacokinetics and pharmacodynamics of eculizumab remain limited. We analyzed 11 patients during induction (weekly), maintenance (2-weekly), and tapering (every 3-8 weeks) phases of treatment. The trough eculizumab levels increased with each additional dose during the induction phase (depending on body weight). During maintenance, high eculizumab concentrations of up to 772 μg/mL were observed. The levels decreased with each following dose during tapering (3- and 4-week intervals); however, three patients maintained target eculizumab levels over long time periods (30-48 weeks). At intervals of 6-8 weeks, target eculizumab levels were no longer attained. Serum samples with eculizumab concentrations ≥50 μg/mL showed adequate complement blockade. Our data provide essential insight for optimization of eculizumab dosing schemes and lessening of therapy burden for the patients and cost of the treatment.

A restrictive eculizumab regimen in aHUS appears safe and effective. Prospective studies should further evaluate the most optimal treatment strategy.

BackgroundHemolytic uremic syndrome (HUS) is one of the most common causes of acute renal failure in children, with the majority of cases caused by an infection with Shiga toxin-producing Escherichia coli (STEC). Whereas O157 is still the predominant STEC serotype, non-O157 serotypes are increasingly associated with STEC-HUS. However, little is known about this emerging and highly diverse group of non-O157 serotypes. With supportive therapy, STEC-HUS is often self-limiting, with occurrence of chronic sequelae in just a small proportion of patients.Case diagnosis/treatmentIn this case report, we describe a 16-month-old boy with a highly severe and atypical presentation of STEC-HUS. Despite the presentation with multi-organ failure and extensive involvement of central nervous system due to extensive thrombotic microangiopathy (suggestive of atypical HUS), fecal diagnostics revealed an infection with the rare serotype: shiga toxin 2d-producing STEC O80:H2.ConclusionsThis report underlines the importance of STEC diagnostic tests in all children with HUS, including those with an atypical presentation, and emphasizes the importance of molecular and serotyping assays to estimate the virulence of an STEC strain.