Poster Session II: Platelets disorders
Atypical haemolytic uraemic syndrome (aHUS) is a rare thrombotic microangiopathy with a predilection for the kidneys, and results from dysregulation of the alternative pathway of complement. The prognosis has historically been poor but the humanised monoclonal anti-C5 antibody eculizumab has revolutionised management in the last decade. Whilst haematological and renal efficacy has been demonstrated, the optimum treatment duration is unknown, and is of key clinical relevance given the high drug costs and potential adverse effects including bacterial meningitis.
- To review presenting features and responses to eculizumab therapy in cases of acute aHUS
- To assess outcomes of eculizumab withdrawal in cases of complete response
All cases of acute aHUS presenting to a single UK centre between 2012-2018 and managed with eculizumab were retrospectively reviewed, from diagnosis to last follow up in our institution. AHUS was diagnosed according to international consensus criteria. Withdrawal of eculizumab, with subsequent close monitoring, was offered to all patients achieving complete haematological response (platelets >150 x109/L and normal LDH) and complete renal recovery (eGFR back to baseline without significant proteinuria), with discussion of risks/benefits.
22 patients (68% female, median age 32 years (range 16-67), all with native kidneys and no known chronic kidney disease (CKD), were identified. 21/22 were de novo presentations. Median nadir platelet count was 23 x109/L (range 7-85), and median nadir eGFR was 11.5 ml/min/1.73m2 (range 3-57), with a high incidence of nephrotic range proteinuria (47%). 14/22 (64%) of patients required renal replacement therapy (RRT). GI (64%) and neurological (41%) symptoms were common. 77% had elevated cardiac troponin T (median 64.5 ng/L, range 17-397, NR 0-14), suggesting subclinical cardiac involvement. 41% had an associated complement genetic abnormality but mutation status did not affect severity of clinical presentation.
Eculizumab followed a median of 6 days (range 2-38) of plasma exchange (PEX). After a median duration of therapy of 11 weeks (range 1-227), haematological recovery was seen in 100%, while 81% achieved at least partial renal recovery (median increase in eGFR 49 ml/min/1.73m2 (range 22-80)). At median duration of follow up of 85 weeks (range 4-255), 54.5% had eGFR >60 ml/min/1.73m2, 27% had CKD, 14% were on RRT, and 4.5% had died.
Eculizumab was withdrawn in 13/22 (59%) following complete haematological and renal recovery, after a median 10 weeks (range 1-26). 10/13 remained in remission at median 66 weeks (range 14-238) since withdrawal. 3/13 (23%) subsequently relapsed, all within 1 year of withdrawal, with defined triggers in 2/3. All made a full recovery with rapid resumption of eculizumab without need for PEX or RRT. Those who relapsed were more likely to have a complement genetic abnormality, with a trend for a shorter duration of initial therapy (Table 1).
The cohort demonstrates the multisystem nature of aHUS, and reiterates that severe thrombocytopenia and mild renal impairment, although classically associated with TTP, can also be seen in aHUS. Haematological and renal outcomes in the cohort compare favourably with the existing prospective and retrospective literature, demonstrating a positive outlook for aHUS in the eculizumab era. Our withdrawal strategy led to no long term adverse effects, with undeniable benefits (including drug cost savings of over £11 million), and as such adds to the growing body of evidence in favour of such an approach.