Eculizumab discontinuation in atypical haemolytic uraemic syndrome: TMA recurrence risk and renal outcomes

Abstract

Background: Eculizumab modifies the course of disease in patients with atypical haemolytic uraemic syndrome (aHUS), but data evaluating whether eculizumab discontinuation is safe are limited.

Methods: Patients enrolled in the Global aHUS Registry who received ≥1 month of eculizumab before discontinuing, demonstrated haematologic or renal response prior to discontinuation and had ≥6 months of follow-up were analysed. The primary endpoint was the proportion of patients suffering from thrombotic microangiopathy (TMA) recurrence after eculizumab discontinuation. Additional endpoints included: estimated glomerular filtration rate changes following eculizumab discontinuation to last available follow-up; number of TMA recurrences; time to TMA recurrence; proportion of patients restarting eculizumab; and changes in renal function.

Results: We analysed 151 patients with clinically diagnosed aHUS who had evidence of haematologic or renal response to eculizumab, before discontinuing. Thirty-three (22%) experienced a TMA recurrence. Univariate analysis revealed that patients with an increased risk of TMA recurrence after discontinuing eculizumab were those with a history of extrarenal manifestations prior to initiating eculizumab, pathogenic variants or a family history of aHUS. Multivariate analysis showed an increased risk of TMA recurrence in patients with pathogenic variants and a family history of aHUS. Twelve (8%) patients progressed to end-stage renal disease after eculizumab discontinuation; seven (5%) patients eventually received a kidney transplant. Forty (27%) patients experienced an extrarenal manifestation of aHUS after eculizumab discontinuation.

Conclusions: Eculizumab discontinuation in patients with aHUS is not without risk, potentially leading to TMA recurrence and renal failure. A thorough assessment of risk factors prior to the decision to discontinue eculizumab is essential.

Keywords: GFR; anaemia; haemoglobin; thrombosis; thrombotic microangiopathy.

Graphical abstract

FIGURE 1:

Patient disposition. A total of 1794 patients were enrolled in the Global aHUS Registry, of whom 151 patients were subsequently included in this analysis. These patients had been treated with eculizumab with clinical evidence of a response to therapy, and had received at least 1 month of therapy, AND had at least 6 months of follow-up after discontinuation OR had suffered a TMA recurrence within 6 months of follow-up. Additionally, patients fulfilling these criteria must also not have met any of the exclusion criteria.

FIGURE 2:

(A) Univariate logistic regression analysis and (B) multivariate logistic regression analysis to determine risk of TMA recurrence after eculizumab discontinuation. Data are shown as unadjusted (A) and adjusted (B) ORs with 95% CI error bars.