Chronic kidney disease is a significant and growing contributor to the global burden of disease. There are around 60,000 kidney transplants globally per year. There are more than half a million people worldwide with a transplant with many more people waiting for a transplant, so a priority for research is to better understand how treatment can extend the life of transplanted kidneys. People with kidney disease are also at a much higher risk of developing a number of diseases, particularly cardiovascular disease, and so more research is also needed on treatments to prevent these diseases in people with kidney disease.
CTSU has an interest in understanding the causes and treatment of chronic kidney disease, and has to date our main contribution to the field has been the Study of Heart and Renal Protection (SHARP). This randomized trial is the largest randomised trial yet undertaken in patients with chronic kidney disease, having recruited about 9400 patients in 400 hospitals in 18 countries. The trial showed that lowering blood cholesterol in patients with chronic kidney disease reduced their risk of heart attacks and strokes, and has resulted in the widespread use of statin-based treatment in such patients worldwide.
In the area of kidney transplantation, we are coordinating the Campath, Calcineurin inhibitor reduction and Chronic allograft nephropathy (3C) trial, which has recruited 850 patients at the time of their kidney transplant, and is being run by a UK-based collaboration of transplant units. Campath-1H (alemtuzumab) is a humanized monoclonal antibody against CD52, which is expressed on many immune cells, and two doses around the time of surgery rapidly deplete the body of lymphocytes (the main immune cell responsible for rejection). This powerful ‘induction’ therapy allows a significant reduction in the amount of maintenance immunosuppression required, and therefore limits the exposure to CNIs. Sirolimus can be used for maintenance immunosuppression, but is not a CNI and is not nephrotoxic. Many trials have shown that switching patients from a CNI-based regimen to sirolimus has a beneficial effect on the function of the graft, which could well translate into a prolonged lifespan. The 3C study is investigating both of these approaches to investigate whether using Campath-1H induction with or without a switch to sirolimus-based immunosuppression improves the function, and long-term survival, of kidney transplants.
Currently, we are also running a pilot study, the UK-HARP-III trial, to assess the effects of a new drug (LCZ-696) on the progression of kidney disease (as measured by isotopic glomerular filtration rate) as compared to standard treatment (irbesartan). Neprilysin (also known as neutral endopeptidase) degrades natriuretic and other vasodilatory peptides and therefore neprilysin inhibition increases concentrations of these peptides and can lower blood pressure (in combination with ACEi or ARB). LCZ696 is a first-in-class ARNI (angiotensin receptor-neprilysin inhibitor) which has been shown to reduce cardiovascular mortality in patients with heart failure. The anti-fibrotic and anti-inflammatory effects of LCZ696 may be beneficial both in terms of reducing renal progression and reducing vascular events. Recruitment of 414 patients into UK-HARP-III was completed in March 2016, and results are expected in early 2017.