Fig. 2.

Scenarios for the treatment of atypical hemolytic uremic syndrome (aHUS) patients with eculizumab. The current standard regime is reflected by scenario 6, lifelong therapy with standard-dose eculizumab at biweekly intervals. Scenarios 1–5 illustrate options of restrictive eculizumab therapy. According to scenario 1, eculizumab is given at standard dose, at biweekly intervals, with withdrawal after 3 months. According to scenario 2, eculizumab dose will be adapted to target trough levels of 50–100 μg ml⁻¹ with complete blockade of the complement system. After an observation period, eculizumab therapy will be withdrawn. In scenario 3, drug withdrawal is preceded by a period of eculizumab therapy at reduced dose and incomplete complement blockade (CH50 < 30%). For logistical reasons, dose reduction will be done by extending the dose interval. In scenarios 4 and 5, treatment with eculizumab will continue for an undefined period (“lifelong,” waiting for more data), either aiming at incomplete (scenario 4) or complete complement blockade (scenario 5). Of note, the observation periods are not strictly defined. The choice for a scenario as well as the length of the observation period will be dependent on patient characteristics, disease history, renal function, and patient or physician preferences. In patients with uncontrolled blood pressure, active (viral or bacterial) infection, reduced estimated glomerular filtration rate (eGFR) with evidence of continuous improvement (i.e., the nadir of serum creatinine has not been reached), or evidence of ongoing (extra-renal) thrombotic microangiopathy (TMA) activity, eculizumab treatment should be continued until stable remission is reached. Typical examples of the patient profiles which may best fit a proposed scenario are presented below. To aid the choice for a certain scenario a score can be calculated based on patient characteristics. The sum of the points will guide the selection of a scenario (online resource Table 6). Scenario 1: this is the proposed scenario used in adult patients with a first episode of aHUS in the native kidneys, who have adequately responded to treatment, with well-controlled blood pressure, stable renal function, and no signs of TMA. Scenario 2: this is the proposed scenario used in adults with a first relapse of aHUS in native kidneys, occurring more than 12 months after treatment withdrawal, who have adequately responded to treatment with recovery of eGFR, well-controlled blood pressure, and no signs of TMA. This scenario is also suitable for pediatric patients above 6 years of age and kidney transplant recipients with a relapse after transplantation with no pathogenic mutation. Scenario 3: this is the proposed scenario used in adults with first relapse of aHUS in native kidneys, occurring within 3–12 months after treatment withdrawal, who have adequately responded to treatment with recovery of eGFR, well-controlled blood pressure, and no signs of TMA. This scenario is also suitable for kidney transplant patients with a aHUS recurrence, successfully treated with eculizumab and pathogenic mutations in other genes than CFH. Scenario 4: this is the proposed scenario for patients with multiple relapses and kidney transplant recipients with a relapse (and CFH mutation) in which lifelong therapy is necessary. Scenario 5: this scenario is proposed for adult patients with relapse occurring during treatment with incomplete complement blockade, or with early (< 3 months) relapse after eculizumab withdrawal. This scenario is also used in pediatric patients below 6 years of age. They have an increased risk for frequent relapse since they are exposed to various infectious triggers during childhood. Therefore, withdrawal of eculizumab is not advised, but tapering of therapy to target serum trough levels could be beneficial to limit potential side effects and prevent overtreatment. Scenario 6: this scenario is proposed for patients with relapsing disease while receiving eculizumab therapy at doses targeted to levels of 50–100 μg ml⁻¹. This scenario may also apply to patients with ESRD due to aHUS, with a history of graft failure due to disease recurrence, CFH mutations, or other high-risk factors. In these patients, any risk of recurrence should be avoided. These scenarios illustrate the treatment with eculizumab, as induction therapy for new-onset aHUS, either as first episode in incident patients or as relapse in prevalent patients. Prophylactic therapy with eculizumab in kidney transplant patients is not illustrated. We do not advise prophylactic therapy with eculizumab in each patient with aHUS. Still, we do not exclude the use of prophylactic therapy, in particular in children, in adult patient with a severe disease history, previous graft loss due to recurrence aHUS, genetic mutations in CFH, comorbidity (prior vascular events, known macrovascular disease), or highly sensitized patients. When prophylaxis is considered, we suggest to start with the induction dose 7–10 days before the kidney transplantation with a second dose 0–3 days before transplantation as eculizumab through levels of 50–100 μg ml⁻¹ (and CH50 < 10%) may not yet be reached after the first dose. We would consider continued treatment with eculizumab after successful transplantation according to scenarios 4–6