Last year Global Action brought attention to a research article ( Closing the CaHUS knowledge gap ) which stood out as one of the best contributions to aHUS knowledge we had seen in a long time.
It confirmed and revealed much about aHUS, its treatment and genetics. Possible because the research involved a larger group of aHUS patients for a study than by typical rare disease standards.
Ever wonder how such research gets done?
Global Action asked the lead author of the study report, Dr Vicky Brocklebank ( see right) from the University of Newcastle upon Tyne Hospitals, UK and the National aHUS Centre there, about how it was done and what is important about what the study had found.
GLOBAL ACTION: Vicky can you start by briefly summarising what your study is about?
VICKY: In this study we wanted to look at the ‘real world’ impact of Eculizumab in aHUS. It was an ambitious project – we wanted to look at how patients respond to the drug, the long term outcomes, the safety of the drug, the safety of stopping the drug, as well as detailed genetic analysis. In England all patients with suspected aHUS are referred to a national specialised centre, the National Renal Complement Therapeutics Centre in Newcastle, which was commissioned by NHS England when Eculizumab was approved by the National Institute for Health and Care Excellence (NICE). This ensures that every patient has access to expert diagnosis and care. It also means that we can undertake research on a large scale for a national cohort – and a research programme was one of the conditions stipulated by NICE when the use of Eculizumab in aHUS was recommended by NICE.
What motivated and inspired you to carry out this research?
I was very fortunate to start my renal medicine training in Newcastle and I was inspired by Professors Tim Goodship and David Kavanagh and what they and their team had accomplished through hard work and dedication. In my first week on the renal unit I met patients with aHUS who had spent years on dialysis and thought they would never be able to receive a kidney transplant, and then Eculizumab was approved and they did and their lives were transformed! There is a phrase in research, ‘bench to bedside’, and the aHUS research story is inspirational – seeing how the complement and genetic laboratory science translates to improving clinical practice and changing lives. This motivated me to pursue aHUS research, and the research team at the NRCTC have mentored and supported me. I am grateful to the Northern Counties Kidney Research Fund who funded my first project and gave me an opportunity, and to the Medical Research Council and Kidney Research UK who awarded me a research fellowship and enabled me to undertake this study.
Why did you tackle the study the way you did, it has such a wide scope and several co-author contributions?
A study on this scale would not have been possible without a close collaboration between patients, clinicians, researchers, charities and NHS England. Clinicians across the country were enthusiastic to collaborate on this study because they are invested in improving outcomes for the patients they look after. And underpinning this research is the strong engagement from patients with aHUS and their relatives – the genetic analysis encompassed a detailed genetic profile of blood samples donated over three decades.
Has there been published work that is close to yours? In what ways is your work different?
The clinical trials of Eculizumab in aHUS that were published in 2013 in the New England Journal of Medicine was the first suggestion that patients responded and this revolutionised the management of aHUS. However, the trials were small, short-term, and there was no control cohort. Additionally, we now know that there are Eculizumab non-responsive causes of disease as well as self-limiting causes of aHUS that were not taken into account at the time. These were gaps in knowledge that we wanted to address – particularly about the long term impacts of Eculizumab.
Why did you use the research methodologies you have? Was there anything you did you not gain from them?
The most robust research methodology is a randomised controlled trial. This is not feasible in rare diseases because of the large numbers of patients that such trials need to recruit, which is why the original trials of Eculizumab were single-arm, meaning that there was not a group who did not receive Eculizumab with which to compare outcomes.
Our methodology was an observational study that was genotype matched. This was critically important as we show that the genetics of aHUS determines disease outcome and unless you match for this, you risk comparing apples and oranges. By matching patients by mutation type we can ensure as best we can the treated and untreated groups were comparable. This enabled us to include a large number of patients.
What do you think are the strongest / weakest parts of your study.
This is the largest study of its kind and the first to show how Eculizumab has impacted patient survival. I think this, as well as the comprehensiveness of the data we analysed, are the main strengths. A key limitation is that the treated cohort presented from 2013 onwards, but individuals in the control cohort were referred in the 1990s through to 2012. The impact of this selection bias is difficult to determine, but differences in clinical practice over time and the quality of supportive care may have influenced prognosis independently of the introduction of Eculizumab.
Your findings are based on UK aHUS patients, to what extent can your contributions to aHUS knowledge generalise?
This is a good point to make. One of the limitations of a national study is that there will always be uncertainty about how transferable it is to other populations, and when applying our findings to patients or populations outside the UK the fact that this is a national cohort study should be taken into account. The granularity and the size of the dataset make this a valuable resource for the aHUS community.
Who do you think will be most interested in your study?
The international community of clinicians who look after people with aHUS as well as researchers are interested – I was invited to present the data at the International Complement Workshop, and at an ISN (International Society of Nephrology) aHUS forum. We have presented this work at our aHUS patient roadshows and our patients and their relatives were very interested and were keen to be involved in more research (https://www.atypicalhus.co.uk/roadshows-and-webinars/) . I think that this study helps to address some of the questions on the aHUS Global Patients’ Research Agenda, and looks at ‘real world’ outcomes that patients can relate to, such as coming off or not needing dialysis.
In what ways will your work help guide aHUS clinical practitioners?
I think it provides important information to help clinicians deliver personalised management of aHUS – care that is individualised and targeted to achieve best outcomes.
Which do you think are the most important contributions to aHUS knowledge from your study?
I think our study contributes a comprehensive evaluation of aHUS in the UK: patient characteristics, clinical presentation, laboratory findings, genetic analysis, response to Eculizumab, non-response to Eculizumab, relapse rates when Eculizumab is stopped – in addition to the primary outcome which was long-term outcome of aHUS. Additionally we define a new class of aHUS associated with RNA pathway genes, which opens up a whole new area of research.
How long term are these contributions?
There will be further advances but I think this study will provide a point of reference for aHUS in the pre-Eculizumab and Eculizumab eras. New complement inhibiting drugs are continually being developed. We have now defined the outcomes with which newer drugs will be compared in clinical trials.
What advice would you give to other researchers thinking of studying this aspect of aHUS.
Many unanswered questions remain. For example, our study showed that Eculizumab has had a huge impact on outcomes, but ~20% of people with aHUS and access to Eculizumab still develop end stage kidney disease. More research needs to be done to explore why, and how this can be addressed. And the discovery of non-complement genes that cause aHUS which does not respond to Eculizumab is a growing field. The field of complement therapeutics is exciting: the development of drugs with better efficacy, improved safety and importantly drugs that are less expensive so that the global inequalities in access to treatment can be addressed. Despite the tremendous advances in the field of aHUS research over the last three decades there is still much work to be done!
There is so much in your article and we could ask many more questions but here are a couple of questions about some patient characteristics.
In our study of global patients the number reporting a family history of aHUS was 9% . Not far different to your 10%. That surprised us as older patients advocates tended to see aHUS as a familial inherited disease. So your control total of nearly 40% was more like what we thought. Is this just statistical or are there just more novel genetic incidences being found than there used to be?
I think this is because in the early days of aHUS research, it was the patients who had a family history that stood out to clinicians, and so these patients and their relatives were referred to researchers which meant that the cohorts were enriched for familial cases. As you know the discovery* of the central role of complement mutations was only possible because of linkage analysis of large families. But as our understanding of the spectrum of aHUS has expanded and thorough diagnostic algorithms developed, it is being increasingly recognised that many individuals have aHUS without a complement mutation, but even the majority of those who do have a complement mutation do not have a family history. This is very interesting – it means that penetrance is not as high as was once thought, and therefore the interplay between genetics (complement gene mutations, as well as common variations in the genome – the variation in complement genes has been termed the ‘complotype’) and the environment (triggers – the infectious and pregnancy triggers that are recognised and documented, and the possibility of other triggers that are not recognised as such) is not yet fully understood.
In several of our Global Polls and our Diagnosis Process research we have similar results to you on the gender mix. We could not be entirely sure whether it was because more women joined in our social media than men so our participant sample could be distorted! In the Diagnosis Process cohort in the 55 years or over group there were 20 female participants out of 22 participants. Did you notice this in your database? Is this another possible hormonal change effect you mention?
We looked specifically at childhood (up to 14), years of child bearing potential (age 15-44) and later adulthood (55-84). We found that in childhood and later adulthood there were equal proportions of males and females, but in the years of child bearing potential there was a much higher proportion of females (1.7x more than males). We didn’t find a difference in the 55 and over group though so maybe this was as you say due to a sampling/participation bias.
Thank you Vicky for spending time to tell us about this study. We really appreciate the work you have done for aHUS patients everywhere. Our aHUS futures will be all the better with researchers like you continuing to close the aHUS knowledge gap.
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The early days of aHUS Research (Before aHUS Endeavours Fade)
Global Action is privileged to present a second article in the series BEFORE aHUS ENDEAVOURS FADE. Celebrating the work of people whose research made a significant difference for aHUS patients.…
Article No. 648
