What is the most effective treatment for atypical haemolytic uraemic syndrome?

What is the issue?

Haemolytic uraemic syndrome (HUS) is a condition involving blockages in small blood vessels leading to destruction of blood cells and dysfunction of several organs, most notably the kidneys. It is commonly caused by infections, often E.Coli, and can be associated with diarrhoea. A rare form of HUS known as atypical HUS (aHUS) is a more aggressive form of the disease caused by inherited or acquired abnormalities of proteins involved in controlling an aspect of our immune system known as “complement”. Almost half of cases involve patients aged less than 18 years. In the past a diagnosis of aHUS was associated with a poor prognosis with patients often progressing to kidney failure and death. More recently, an improved understanding of the condition has led to better treatments. This review aims to evaluate the usefulness of these treatments by systematically examining the available evidence in order to find out the most effective treatments available for aHUS.

What did we do?

We searched the literature extensively and found five studies which tested therapies for aHUS. In four studies the treatment used was eculizumab and in one study the treatment was ravulizumab. Both of these recently developed drugs act in a similar way and have shown promise in other medical conditions.

What did we find?

The included studies demonstrated that the majority of patients treated with either eculizumab or ravulizumab showed improvements in kidney function with a large proportion improving enough to stop dialysis treatment. Markers of disease activity in the blood also improved significantly. Over the course of 26 weeks of treatment, no patients given eculizumab died, although two patients did contract meningococcal infections, a likely consequence of the treatment. Although four patients treated with ravulizumab died, none of these deaths were thought to be caused by the drug. The quality of life of patients treated with both drugs was improved significantly.


aHUS is an extremely rare condition and without treatment is often fatal. For this reason, we found no studies which were able to compare one treatment with another, or one treatment with no treatment. Instead, the included studies gave all participants either eculizumab or ravulizumab, with results only comparable with historical data obtained before these drugs were available. This introduces substantial bias into the review, and therefore limits the confidence of any recommendations which stem from it. Nevertheless, the best available evidence suggests that treatment with either eculizumab or ravulizumab is effective in patients with aHUS and appears superior to previous therapies.

Authors' conclusions: 

When compared with historical data, terminal complement inhibition appears to offer favourable outcomes in patients with aHUS, based upon very low-quality evidence drawn from five single-arm studies. It is unlikely that an RCT will be conducted in aHUS and therefore careful consideration of future single-arm data as well as longer term follow-up data will be required to better understand treatment duration, adverse outcomes and risk of disease recurrence associated with terminal complement inhibition.

Read the full abstract...

Atypical haemolytic uraemic syndrome (aHUS) is a rare disorder characterised by thrombocytopenia, microangiopathic haemolytic anaemia, and acute kidney injury. The condition is primarily caused by inherited or acquired dysregulation of complement regulatory proteins with ~40% of those affected aged < 18 years. Historically, kidney failure and death were common outcomes, however, improved understanding of the condition has led to discovery of novel therapies.


To evaluate the benefits and harms of interventions for aHUS.

Search strategy: 

We searched the Cochrane Kidney and Transplant Register of Studies for randomised controlled studies (RCTs) up to 3 September 2020 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. MEDLINE(OVID) 1946 to 27 July 2020 and EMBASE (OVID) 1974 to 27 July 2020 were searched for non-RCTs.

Selection criteria: 

All randomised and non-randomised clinical trials comparing an intervention with placebo, an intervention with supportive therapy, or two or more interventions for aHUS were included. Given the rare nature of the condition in question, prospective single-arm studies of any intervention for aHUS were also included.

Data collection and analysis: 

Two authors independently extracted pre-specified data from eligible studies and evaluated risk of bias using a newly developed tool based on existing Cochrane criteria. As statistical meta-analysis was not appropriate, qualitative analysis of data was then performed.

Main results: 

We included five single-arm studies, all of which evaluated terminal complement inhibition for the treatment of aHUS. Four studies evaluated the short-acting C5 inhibitor eculizumab and one study evaluated the longer-acting C5 inhibitor ravulizumab. All included studies within the review were of non-randomised, single-arm design. Thus, risk of bias is high, and it is challenging to draw firm conclusions from this low-quality evidence. One hundred patients were included within three primary studies evaluating eculizumab, with further data reported from 37 patients in a secondary study. Fifty-eight patients were included in the ravulizumab study. After 26 weeks of eculizumab therapy there were no deaths and a 70% reduction in the number of patients requiring dialysis. Complete thrombotic microangiopathic (TMA) response was observed in 60% of patients at 26 weeks and 65% at two years. After 26 weeks of ravulizumab therapy four patients had died (7%) and complete TMA response was observed in 54% of patients. Substantial improvements were seen in estimated glomerular filtration rate and health-related quality of life in both eculizumab and ravulizumab studies. Serious adverse events occurred in 42% of patients, and meningococcal infection occurred in two patients, both treated with eculizumab.