Chronic kidney disease is a significant and growing contributor to the global burden of disease. Worldwide, there are an estimated two million people receiving kidney replacement therapy (dialysis or a kidney transplant), and in low- and some middle-income countries many die due to unavailability of these expensive treatments. More effective medications are needed to slow progression of chronic kidney disease and improve outcomes for people on kidney replacement therapy. Early stages of chronic kidney disease are also important to study, as even mildly decreased kidney function is associated with higher risk of developing a number of diseases, and particularly cardiovascular diseases like heart failure.
The Renal Studies Group has an interest in understanding the causes and treatment of chronic kidney disease. To date our main contributions to the field have been two large placebo-controlled randomised trials.
The Study of Heart and Kidney Protection with Empagliflozin (EMPA-KIDNEY). This trial was conducted in 241 centres in eight countries and reported results in 2022. EMPA-KIDNEY found that sodium glucose co-transporter-2 (SGLT-2) inhibition reduced risk of kidney disease progression or death from cardiovascular causes by 28% in a broad range of patients with chronic kidney disease at risk of progression. EMPA-KIDNEY provides a key component of the evidence base which is establishing SGLT-2 inhibitors as the standard of care for patients with chronic kidney disease, irrespective of their underlying cause of kidney disease or level of kidney function.
Study of Heart and Renal Protection (SHARP). This randomised trial was the largest randomised trial yet undertaken in patients with chronic kidney disease when reported in 2011. It recruited 9270 patients from 380 hospitals in 18 countries. The trial robustly demonstrated that lowering blood LDL cholesterol in patients with chronic kidney disease reduced their risk of heart attacks and strokes. SHARP has resulted in the widespread use of statin-based treatment in such patients worldwide.
In the area of kidney transplantation, we also coordinated the Campath, Calcineurin inhibitor reduction and Chronic allograft nephropathy (3C) trial, which recruited 850 patients at the time of their kidney transplant, and was run by a UK-based collaboration of transplant units. Campath-1H (alemtuzumab) is a humanised monoclonal antibody against CD52 which was shown to safely reduce risk of acute transplant rejection. 3C also compared two forms of other tablets used long-term to reduce risk of kidney transplant rejection. Of these two tablets, tacrolimus was shown to have a better safety profile than sirolimus. Long-term efficacy data following ten years of follow-up for 3C trial participants will soon be available.
We also designed and conducted three UK-HARP trials in patients with chronic kidney disease. The UK-HARP trials I and II piloted different LDL lowering regimens in patients with chronic kidney disease for the SHARP trial. UK-HARP-III trial assessed the effects of sacubitril/valsartan - an angiotensin receptor-neprilysin inhibitor - on progression of kidney disease measured by isotopic glomerular filtration rate as compared to irbesartan (i.e. standard treatment at the time). The primary outcome did not differ between the two groups. The number of adverse events was similar between the two groups, showing that the safety and tolerability of sacubitril/valsartan is similar to that of irbesartan. This is important as other large trials have established sacubitril/valsartan as an effective treatment for heart failure, and UK-HARP-III therefore provides important evidence of safe use in patients with chronic kidney disease.