Anna Richards Raine Award Winner 2005
1. Title and place of work and what doing now 
I am now an Honorary Consultant and Senior Lecturer in Nephrology, based in Edinburgh. I started a four year Wellcome Intermediate Clinical Training fellowship in July 2009 after completing higher renal training and then doing a nine month locum consultant post at the Royal Infirmary in Edinburgh and the Borders General Hospital in Melrose. I currently spend 80% of my time in research, based at the Queens Medical Research Centre, where I am working hard to develop my own research group. My remaining time is spent in clinical work with contribution to the ward-based services and renal transplantation clinic. The locum was a real transitional period for me, with both highs and lows. I think it was a formative time which gave me the clinical confidence and experience needed to practice as a Consultant even though only 20% of my time is on clinical service.
I feel very fortunate to work in a department where the differing contributions made by academic and NHS nephrologists are respected and encouraged. There is a great spirit of cooperation with individual strengths used to provide the best possible clinical service. I have also really valued having the mentorship of other academic colleagues to guide me.
2. What was the work which led to you receiving the Raine Award?
Working with the research group of Professors Tim and Judith Goodship in Newcastle, I reported some of the earliest descriptions of mutations in families and individuals with atypical Haemolytic Uraemic Syndrome (aHUS). These mutations were in the complement regulatory proteins factor H, membrane cofactor protein (CD46) and factor I. A collaboration with John Atkinson’s group in Washington University, St Louis, U.S.A. published in PNAS, allowed us to show that the mutations in CD46 were functionally significant and suggested mechanisms underlying the pathogenesis of aHUS. CD46 was discovered by John and his coworkers in 1986 so this progression of science and medicine was very exciting. The work on CD46 was awarded the prize for best oral presentation at the Renal Association in 2003.
3. Who or what inspired you to become involved in this work?
My career in renal medicine is definitely related to my contacts with renal patients and their doctors during my initial student placements. I vividly remember ‘clerking in’ a patient with polycystic kidney disease for a renal transplant, taking bloods and marveling at the rapid improvement in health (and reciprocal creatinine plot!) over the following days. I knew then that I would become a nephrologist. Bed-side teaching given by Professor Bob Wilkinson at Freeman Hospital, led me to approach him to do a renal BMedSci as I wanted to understand the science underlying what I was being taught. Tim Goodship was my thesis examiner and as a House Officer, gave me excellent teaching using his library of renal slides. The enthusiasm and enjoyment of their specialty shown by all the nephrologists in the centres I have worked was also very motivating. I would particularly acknowledge the help from Andrew Paterson from Middlesborough who prepared me for my first research presentation at the Scottish Renal Association. I still follow his advice now! With respect to my choice of PhD topic, the clinical experience of looking after a local family with aHUS, the enthusiasm of Paul Warwicker and Rosie Donne who had undertaken research in this area with the Goodships’ group and the chance to learn more about genetics were all important factors.
4. What did winning the Raine Award mean to you?
I am very proud to have received the AEG Raine Award. Above all, it meant recognition for the sustained efforts of the Goodship research group; the clinicians and the patients and families from all over the world who had supported the work in Newcastle investigating atypical HUS. From a personal perspective it was recognition of my own contribution to renal science by a community which I respected. I also felt conscious of belonging to an organisation which valued the importance of honouring a colleague who had tragically died.
5. How has your career developed since you won the Raine Award?
I did the research which led to the Raine Award between 1999 and 2002, relatively early in my career. I then trained in general medicine and nephrology in Newcastle and Middlesborough. I was given a USA/UK Fulbright Distinguished Scholar Award in 2005 and went to John Atkinson’s laboratory in St Louis with my husband David Kavanagh, who is also a nephrologist working on aHUS. I moved back to Edinburgh from the U.S.A. and with valuable insights from John Savill and Jeremy Hughes successfully identified the key research questions which formed the basis of my successful Intermediate fellowship application. My time in St Louis reinforced my wish to work as an Academic Nephrologist and gave me the confidence to follow this career path.
6. What are the implications for clinical practice of your research?
An important observation was our identification of a family with aHUS caused by a CD46 mutation (membrane regulator) in whom there was no recurrence of HUS after kidney transplantation. his was in striking contrast to the very high risk of recurrence reported in those with plasma factor H and factor I mutations. In the former case, the renal allograft is usually protected by the transplant donor’s CD46. This has led to the understanding of the critical importance of performing genotyping prior to transplantation for patients with atypical HUS.
Secondly, the acceptance of the importance for the alternative complement pathway in aHUS has led to the first trial of the complement inhibitor Eculizumab (a humanised monoclonal antibody against C5), led by Tim Goodship, in this condition. Results from this trial are awaited but anecdotal published case report data seems encouraging.
7. What is your proudest accomplishment?
Academically, I think I am most proud of some of the work I did in St Louis where I had the opportunity to investigate a collection of families with a rare condition, now called RVCL (Retinal Vasculopathy with Cerebral Leukodystrophy). As part of a large collaboration of investigators, I was able to build on my experience of linkage analysis from my PhD to help successfully identify the causative gene, TREX1, from amongst 150 possible candidates. We published this finding in Nature Genetics, which having ‘Nature’ in the title meant that I could convince all of my non-medical family my time away overseas had been worthwhile.
8. What is the focus of your current research?
My major research focus is to try and understand why, of all the large endothelial cell beds in the body, there is such a susceptibility to irrecoverable renal failure in the atypical forms of haemolytic uraemic syndrome and other renal thrombotic microangiopathies.
We know from the work performed in Newcastle, and from the many excellent research groups working in this field, that mutations, polymorphic haplotypes or autoantibodies to the complement proteins of the alternative pathway are key predisposing factors for excessive complement activation and subsequent tissue injury. However, as the penetrance of mutations is only 50%, there are a large number of diverse and seemingly unrelated triggers, for example pregnancy, infection, drugs, which lead to a common end point.
I have now moved to look at effects of complement injury and protection at the level of the endothelium. I am helped very much here by having access to the immortalised renal glomerular endothelial cells and podocytes developed by Simon Satchell and Moin Saleem in Bristol. I now consider myself an endothelial cell biologist and ‘complementologist’ as well as a nephrologist. My research interests include developing complement therapies for renal as well as eye diseases like age-related macular degeneration and I am hopeful complement therapies will be an area of future growth not only for aHUS and dense deposit disease but also renal transplantation.
9. What do you think is the most pressing problem in nephrology today?
One concern for me is the negative effect of the radical changes which have overtaken junior doctor training in recent years. These have fractured the old established ‘firm’ organisation with an identifiable leader, and the apprenticeship model of training that went with it. Despite junior doctors working fewer hours we have somehow lost a culture which provides time to think and we have diminished opportunities for young doctors to be inspired by their leaders since contact is so fragmentary. Continuity of care is much harder to achieve and this is concerning because of the implications for patient care.
10. What advice do you have for juniors?
Advice I would have given me
Ask for advice earlier, I think I learnt quite late on in my research career that not asking for help is not a strength but a missed opportunity. The people I have met through meetings such as the Renal Association, my time in the States and increasingly through new scientific collaborations have always enriched my experience and productivity.
Advice I try to give
Trust your instincts – they generally guide you in right direction even if you only realise this later. Enjoy what you do; if getting up in the morning everyday is hard, then change something. Value senior advice and support your own juniors, it is amazing what they may later remember about you. I always remind myself that to practice medicine and care for patients is an enormous privilege. Respect the roles and knowledge of all members of the wider team, the individual expertise a dialysis nurse, dietician or palliative care consultant can bring to a situation always reminds me what we can achieve when teams work well. For my juniors specifically, I am much more effective after a skinny latte!
11. What are your plans for the future?
My goal is to continue as an academic nephrologist in a post which enables me to commit about 50% of my time to research and 50% to clinical practice. I love research but that love came from my experiences in clinical nephrology and so I will always strive to contribute to both.