David C Wheeler | Professor of Kidney Medicine, Centre for Clinical Kidney Disease, University College London, UK
Citation: EMJ Nephrol. 2024;. https://doi.org/10.33590/emjnephrol/XGSL6968. 
What inspired you to focus your career on chronic kidney disease (CKD) and its complications?
When I was a junior doctor, I was exposed to a number of different chronic diseases. However, kidney disease fascinated me the most because the kidneys were so complicated. They seemed to do so much: they controlled metabolism, removed waste products, modulated acid–base balance, and were involved in blood pressure control. I found the kidneys to be fascinating organs and got more and more interested in them. It was then, of course, that I realised the devastating consequences of kidneys becoming damaged and failing to work properly. But what got me interested in kidney disease was that we could support patients with treatments like dialysis and kidney transplantation and make people better again. We could take patients with this devastating disease who had gotten really sick and make them better.
Throughout your career, you have managed and led several large-scale randomised clinical trials assessing a variety of therapeutic interventions for CKD. What are the key qualities you believe are essential for effective leadership in clinical research?
Number one is being a clinician who asks questions and is not always happy that our current management strategies for diseases are correct. When I was a junior doctor, the eminent professors I worked for always seemed to know exactly what to do. As my career progressed and I was able to take on an academic position, I realised that I do not always know the right action because evidence upon which to base treatment was lacking. It was that inquisitiveness and desire to prove that treatments worked that led me to clinical research, particularly clinical trials. I wanted to know that if I was going to give a patient a drug, that drug had been proven to work in similar patients and had been proven not to cause unnecessary harm. This led to my desire to do my research in a clinical environment and involve patients in that research.
In your role managing the Clinical Research Team at The Royal Free Hospital and NIHR Clinical Research Network National Specialty Lead for Renal Disorders, what initiatives have you implemented to enhance patient participation in clinical research?
You should not design clinical trials without patient involvement. Patients participate in these trials, and if you talk to patients, you can understand what patients are willing to do and what they are not willing to do. With the trials I have developed, I have involved patient discussion panels and tried to get patient feedback. In one of the trials, I am involved with at present, I have actually got a patient on the steering committee. By putting patients in the centre of the research, I have noticed that sometimes patients are willing to do things that I thought they would not do and vice versa. Involving patients has often changed my views on clinical trial design. Patients give you a broader view, often changing your perspective and possibly even your approach.
Can you share some of the challenges you faced in the operationalisation of large-scale clinical trials, such as the DAPA-CKD and RESOLVE trials?
The DAPA-CKD study had a commercial sponsor, it was a study led by a pharmaceutical company. It was a global trial, and the challenge was to recruit patients from different countries around the world, dealing with lots of different investigators, different sites, and different patients. This required a considerable amount of coordination. However, the trial was a success in terms of our recruitment. In fact, we recruited faster than we predicted that we would.
The RESOLVE trial is an academic trial in which we are investigating different levels of sodium to use for haemodialysis. This is a different beast; it is an academic study; thus, driven by academia rather than by a pharmaceutical company, we have far fewer resources behind this trial. This trial runs largely on the goodwill of investigators in different countries, who support the trial by getting some local funding to recruit to the trial in their own country. Therefore, the big challenge in the RESOLVE trial is the lack of a central pot of money and the need for all investigators to find their own funding to allow their participation. Nevertheless, we are doing well, and we are going to be able to deliver the results of this trial in 3–4 years’ time.
Cardiovascular disease is a major complication for CKD patients. Can you explain the interplay between CKD and cardiovascular disease, and why this relationship is so critical?
The kidneys are a part of the cardiovascular system, and they get damaged when blood pressure is elevated. We look at the kidneys as a window to the cardiovascular system. It is not surprising that when patients develop cardiovascular disease, they develop kidney disease; and the other way around, when patients have a kidney problem, they often develop cardiovascular problems, often mediated by hypertension. We also have treatments that help in both cardiovascular disease and kidney disease. We mentioned the DAPA-CKD trial of dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor which acts on the kidney and reduces the risk of not only kidney failure but also of heart failure hospitalisation. Medications that reduce the risk of cardiovascular disease are important for people with kidney disease, many more die prematurely from cardiovascular problems than from the need for dialysis treatment.
Given the systemic nature of CKD and its complications, how important is a multidisciplinary approach in the management of these patients and interdisciplinary research in developing effective treatments for CKD?
Our patients do not just come with kidney disease; they come to us with hypertension, diabetes, heart failure, and other long-term conditions. Nephrologists find it difficult to manage these patients alone, so we involve others. Help comes from doctors in other specialities, for example, a diabetologist or a cardiologist. However, we increasingly manage these patients with multidisciplinary teams coordinated by our nursing colleagues, for example, kidney specialist nurses, heart failure nurses, diabetes nurses, etc. We are finding that nurses seem to work together far better than many doctors do. We find that we can coordinate the care of these patients far better by having this multidisciplinary team of nurses from different specialities communicating with each other and helping us to optimise treatments for patients. We also have input from other allied healthcare professionals including dieticians, psychologists, and physiotherapists. Management of complex patients is a team effort, and the more diseases there are, the more people you need to be involved in that team.
Do you believe there is a reason why nurse consultants and speciality nurses work better together in clinical research settings?
I think consultants can become too specialised and end up isolated in their particular area of expertise. Nurses have a much broader, more holistic approach to patient care and do not become so specialised. They are better at collaborating across specialities, and they are used to dealing with patients with multiple diseases across multiple teams. They seem to be able to link themselves together better than doctors do. I am generalising, but in our practice, the nurses can run the multidisciplinary team much better than the doctors can.
The results of the DAPA-CKD trial led to changes in the National Institute for Health and Care Excellence (NICE) guidance for the use of SGLT2 inhibitors. We recently spoke to Professor Peter Stenvinkel from the Karolinska Institutet who expressed excitement about the future of SGLT2 inhibitors. How do you see the role of such inhibitors evolving in the treatment of CKD and reducing cardiovascular burden in the future?
I’m also excited about the SGLT2 inhibitors. Although designed to treat diabetes, these drugs have also helped many patients with chronic kidney disease and heart failure. We are rolling out these drugs quite quickly now through many different specialities, such as cardiology, nephrology, and diabetology. We are trying to get as many patients as we can on these drugs. At present, we have only about 20% of patients who should be on these drugs are prescribed the medication. There is still this huge barrier to overcome to get all appropriate patients onto these therapies. One of the problems is that many of these patients are not in hospital clinics; they are in primary care, and our general practitioner colleagues are overburdened with other work to do and do not always have the time to identify these patients. We are working together with our primary care colleagues to identify these patients and get them on the right treatment.
With advancements in therapies for CKD, what are some emerging treatments or approaches that you are particularly excited about?
We are talking about drugs that protect kidney function. We have had ACE inhibitors and angiotensin receptor blockers for 20 years, we have had SGLT2 inhibitors now for several years, and we now realise that they are kidney protective. However, we have got other therapies coming along that are exciting. We have trials of mineralocorticoid receptor antagonists, the latest generation of spironolactone. These drugs are effective in diabetic kidney disease. We heard at the European Renal Association (ERA) meeting that a GLP-1 receptor agonist, semaglutide, slows the progression of kidney disease and reduces cardiovascular events and mortality in patients with type two diabetes and kidney disease. We have some early studies of other drugs, such as endothelin receptor antagonists and aldosterone synthase inhibitors. These drugs look promising. We are moving into an era where we will have many medications to protect residual kidney function in patients with kidney disease. One day, we might not need our dialysis machines, or at least we will not be using them so often because we will have prevented kidney failure with all these new drugs.
Looking back at your career, what achievements are you most proud of, and what do you hope to accomplish in the coming years?
The achievement I am most proud of, and of course, it was a team effort, was my role in delivering the DAPA-CKD trial. The DAPA-CKD trial demonstrated that SGLT2 inhibitors are effective at slowing the deterioration of kidney function in patients who are diabetic and non-diabetic, and also reduced mortality rates in patients with CKD. This was the first pharmacological therapy to reduce mortality rates and led to a change in NICE guidance. I led this trial with a colleague, Hiddo J L Heerspink, Professor of Clinical Trials and Personalized Medicine and Clinical Pharmacologist at the Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, the Netherlands.
In the coming years, I am looking forward to making trials easier to deliver by simplifying their design. We discussed the RESOLVE study, which is a pragmatic or simplified trial with very simple trial procedures. For example, we have an opt-out consensus system whereby patients tell us they do not want to be in the trial when they are told that their site is participating. There are many different ways of making trials more efficient and effective. We need many more simple studies that are integrated into our clinical practice. Entering patients into trials when we don’t know the best intervention to offer needs to become part of mainstream health care.
