Clinicians have to think outside the box to identify rare cases of atypical haemolytic uraemic syndrome (aHUS) in a timely manner – but it’s key to getting patients onto early effective treatment and improving outcomes.
In an Alexion-sponsored Satellite Symposium at the XXVII Congress of the International Society on Thrombosis and Haemostasis (ISTH), Professor Marie Scully described two cases of suspected thrombotic microangiopathies (TMA) with acute kidney injury to emphasise how complex the diagnosis of exclusion could be.
Apart from HUS, thrombotic thrombocytopenic purpura (TTP) and disseminated intravascular coagulation (DIC), other differential diagnoses included drugs, cancer, vasculitis, pregnancy, infection and malignant hypertension.
She told delegates attending the atypical HUS – Finding a Needle in Haystack symposium that investigations which yielded valuable insights included coagulation screens, further biochemistry including LDH, CRP and albumin, ADAMTS13 activity, microbiology and autoimmune screens.
Professor Scully, clinical lead for haematopathology and blood transfusion at the University College London Hospital, said plasma exchange and supportive care including renal replacement, blood pressure control and fluids should be instigated as soon as possible.
And the complement-directed monoclonal antibody eculizumab (Soliris) should be introduced as soon as the diagnosis of atypical haemolytic uraemic syndrome (aHUS) was confirmed.
“The quicker you start eculizumab the better,” she said.
One of her cases was eventually determined to be leptospirosis causing an infective vasculitis; the other was an E.coli triggered, complement-mediated HUS (or aHUS).
The kidney is particularly vulnerable
Associate Professor Nicole Isbel, a nephrologist from the Princess Alexandra Hospital in Brisbane, told the symposium that aHUS affected both children and adults and time to treatment was critical.
Given plasma exchange does not “save the kidney”, there was some urgency to introduce eculizumab (Soliris) she said.
“In some circumstances, for example in children, because of the risk profile of doing plasma exchange – that they have to have a line and they have smaller plasma volumes and there is a lot of comorbidity in that – if you exclude Shiga toxin-associated HUS due to infection with Escherichia coli (STEC-HUS) then they often move to eculizumab much more quickly [than adults].”
Similarly in adults, eculizumab has been used as a first-line therapy in patients presenting with a personal or family history of the disorder and where everything else has been excluded.1
“And even if they have had a triggering infection and we know they are most likely to have the complement-mediated HUS, we have initiated those patients directly onto eculizumab.”
“Getting the diagnosis right is really the critical thing.”
She said there was an urgent clinical need for a test to “rule in” aHUS; the equivalent of the ADAMTS13 for TTP.
Managing patients on eculizumab therapy
Professor Scully told the symposium that patients with aHUS typically need to be on eculizumab for at least six months.2
“We’ve got a slightly different population but what we’ve proven is you’ve got to keep them on it for six months because otherwise the chances of relapse increase. It’s telling you something about the underlying disease; it needs to settle down.”
And the reality is that some patients shouldn’t stop therapy.
“Not everyone should be stopping; you need to have specific criteria with regards to stopping and that has to be normal kidneys and normal haematology.”
Associate Professor Isbel agreed some patients could end up on long-term maintenance eculizumab.
“It is a drug that has made a very big difference to the subset of patients with very severe complement disorders and people who would have been on dialysis or unable to be transplanted are now off dialysis or able to be transplanted. So I think that has made a huge difference for that subset,” Associate Professor Isbel told the audience.
She added there was evidence that eculizumab improved graft survival in people with aHUS who had received a kidney transplant.3
“Their outcomes are equivalent to the rest of the transplant population whereas before they had up to 80-90% of recurrence, and if they got recurrence, 50% of those grafts were lost within one year. Graft survival was very poor so for those patients eculizumab (Soliris) has been again a life-changing advance in therapy.”
- Consult with the local aHUS expert early.
“In some cases it’s the haematologists who are the people with expertise in the condition; in other cases it’s the nephrologist. It depends on the local area and where your expertise lies,” Associate Professor Isbel said.
While aHUS was a rare condition, Associate Professor Isbel said awareness and the pick-up rate had increased enormously over the last 5-10 years.
- Malignant hypertension is a major differential diagnosis for aHUS.
Associate Professor Isbel said to look to the role of complement if the disease was not settling after aggressive treatment of hypertension, preferably with angiotensin receptor blockade. There was a subset of people with malignant hypertension who would also have an underlying complement mutation.
- Genetic testing is useful
Associate Professor Isbel said genetic testing for complement mutations was very useful and served as a guide to management. In patients with no mutation, it was a clue to stopping eculizumab. Where a severe mutation was identified, it would inform genetic counseling with the patient and family.
- There is no role for steroids in aHUS
Steroids do not help, patients already have renal injury, which could be exacerbated, and there was the risk of infection or underlying precipitating infection.
- Women with HELLP syndrome can experience TMA after delivery
Professor Scully said HELLP was a very difficult condition. Patients should be given 48 hours to turn around as long as they were not deteriorating rapidly. However if there was progression [of the TMA] in patients with a normal ADMATS13, plasma exchange or eculizumab should be started quickly as hypertension and obstetric TMAs were a precipitant for aHUS post-delivery.
- Fox L, et al. Consensus opinion on diagnosis and management of thromboticmicroangiopathy in Australia and New Zealand. Internal Medicine Journal. 2018;48:624–636.
- Neave L, et al. Atypical haemolytic uraemic syndrome in the eculizumab era: presentation, response to treatment and evaluation of an eculizumab withdrawal strategy. British Journal of Haematology. 2019; 186(1):113-24.
- Siedlecki AM, et al. Eculizumab Use for Kidney Transplantation in Patients With a Diagnosis of Atypical Hemolytic Uremic Syndrome. Kidney Int Rep. 2019;4:434–46.