Early Eculizumab Withdrawal in Patients With Atypical Hemolytic Uremic Syndrome in Native Kidneys Is Safe and Cost-Effective: Results of the CUREiHUS Study

Abstract

Introduction: The introduction of eculizumab has improved the outcome in patients with atypical hemolytic uremic syndrome (aHUS). The optimal treatment strategy is debated. Here, we report the results of the CUREiHUS study, a 4-year prospective, observational study monitoring unbiased eculizumab discontinuation in Dutch patients with aHUS after 3 months of therapy.

Methods: All pediatric and adult patients with aHUS in native kidneys and a first-time eculizumab treatment were evaluated. In addition, an extensive cost-consequence analysis was conducted.

Results: A total of 21 patients were included in the study from January 2016 to October 2020. In 17 patients (81%), a complement genetic variant or antibodies against factor H were identified. All patients showed full recovery of hematological thrombotic microangiopathy (TMA) parameters after the start of eculizumab. A renal response was noted in 18 patients. After a median treatment duration of 13.6 weeks (range 2.1-43.9), eculizumab was withdrawn in all patients. During follow-up (80.7 weeks [0.0-236.9]), relapses occurred in 4 patients. Median time to first relapse was 19.5 (14.3-53.6) weeks. Eculizumab was reinitiated within 24 hours in all relapsing patients. At last follow-up, there were no chronic sequelae, i.e., no clinically relevant increase in serum creatinine (sCr), proteinuria, and/or hypertension in relapsing patients. The low sample size and event rate did not allow to determine predictors of relapse. However, relapses only occurred in patients with a likely pathogenic variant. The cost-effectiveness analysis revealed that the total medical expenses of our population were only 30% of the fictive expenses that would have been made when patients received eculizumab every fortnight.

Conclusion: It is safe and cost-effective to discontinue eculizumab after 3 months of therapy in patients with aHUS in native kidneys. Larger data registries are needed to determine factors associated with suboptimal kidney function recovery during eculizumab treatment, factors to predict relapses, and long-term outcomes of eculizumab discontinuation.

Keywords: atypical hemolytic uremic syndrome; complement; complement inhibition; cost-effectiveness; eculizumab; thrombotic microangiopathy.

Graphical abstract

Figure 1

Flowchart of eculizumab therapy and outcomes in patients with suspected aHUS in native kidneys. In addition to the excluded patients, this figure shows our cohort, their treatment with dialysis and eculizumab, and outcomes (relapse vs no relapse). ¹These patients had a suspected aHUS recurrence after kidney transplantation. ²In these patients, kidney function did not recover. These patients did discontinue eculizumab and were not included in the analysis of relapse. Of note, in none of these patients eculizumab was restarted during follow-up on hemodialysis. aHUS, atypical hemolytic uremic syndrome; Ecu, eculizumab; ESKD, end-stage kidney disease (kidney failure); KRT, kidney replacement therapy; TMA, thrombotic microangiopathy.

Figure 2

Schematic overview of follow-up and eculizumab treatment in patients with aHUS in their native kidneys. This figure provides an overview of eculizumab treatment over time in all patients. aHUS, atypical hemolytic uremic syndrome; TMA, thrombotic microangiopathy.

Figure 3

Serum creatinine (μmol/l) concentrations over time in the 4 patients with relapsing aHUS. This figure shows the serum creatinine (μmol/l) concentrations over time of the 4 relapsing patients. The letters correspond to the following patient numbers: [A] 11, [B] 5, [C] 12, [D] 19. aHUS, atypical hemolytic uremic syndrome; B, biopsy; PT, plasma therapy; R, relapse.