Title: Exercise Training and Progression of Chronic Kidney Disease: A Randomised Controlled Feasibility Study. The GFR-Exercise Feasibility Study.
Funder: Health Education England

Abstract: Background: Treatments that can potentially slow the decline of kidney function and delay end stage kidney failure, and associated costly, and life altering treatment options such as three times per week haemodialysis, are urgently needed. Although there is much excitement with the emergence of novel pharmacological interventions, which could potentially slow kidney progression in those patients with diabetic nephropathy, there is a growing need for an intervention such as exercise training that could potentially slow progression of chronic kidney disease (CKD) in those non-diabetic patients with progressive CKD, and also those patients who would seek a non-pharmacological intervention.There remains a gap in the evidence surrounding our understanding of the effects of exercise training on progression of CKD. Physical activity and muscle mass have been identified as strong predictors of disease progression in patients across the spectrum of CKD. A previous exploratory study of 20 patients led by Dr Greenwood, has shown that 12 months of combined aerobic and resistance exercise training could potentially slow the decline of kidney function in patients with stages 3 and 4 CKD. It also showed potential to reverse the stiffening of blood vessels, and improve the exercise capacity of patients with CKD. As the exploratory study utilised estimated glomerular filtration rate (eGFR) as the primary outcome, rather than the gold-standard measured iohexol clearance GFR measurement, a further feasibility study is required to fully elucidate the feasibility of using measured GFR in a 12-month exercise intervention study, and explore the relationship between exercise training, weight change and progression of CKD.Aims: The study will investigate whether measurement of GFR, with iohexol clearance, is a feasible method to explore progression of CKD with structured exercise training. This study will focus on demonstrating capacity for recruitment and retention of patients with stages 3-4 progressive CKD, patient experience, and describing the relationship between exercise, kidney function and weight change to inform the development of a multi-centre randomised controlled trial (RCT). Plan of investigation: 50 stages 3-4 CKD patients (GFR >15-60 mL/min) from local lab CKD-EPI determined eGFR, minimum decline = 5mL/min/year over previous 12- 24 months, as measured by linear regression analysis (minimum of 3 measurements of eGFR over 12 months) will be identified by an electronic renal database, and recruited and consented during nephrology clinic and randomised to exercise training or usual care (UC). Intervention: Combination of aerobic and strength training in a hospital gym (4x1hour sessions per week) for 12 months. UC group will receive standard care which doesn't involve referral for exercise-based rehabilitation. Outcomes and assessments: (0, 6 and 12 months): Kidney function, Pulse Wave Velocity, VO2peak, endothelial function, body composition, qualitative analysis. Feasibility analyses: Rates of recruitment, retention and completion of data collection and intervention sessions will be described. The mean rate of change in kidney function (measured GFR) values for exercising and non-exercising participants will be described and the effect size calculated to inform the future definitive study. One of the major outputs of the training award will be to generate grant income to fund the multi-centre RCT once feasibility has been established. Potential benefits to patients and the NHS: Potentially, patients with progressive CKD will benefit within 5 years from optimal placement of exercise training interventions early in the CKD management pathway to prevent progression to CKD if an association between exercise training and progression of CKD is identified. We are optimally placed to extend this research to identify the patient benefit as we have an established clinical research renal team in place and I lead the exercise and lifestyle clinical study group for the UK Kidney Research Consortium.

Lay abstract: Chronic kidney disease (CKD) affects 1 in 17 adults in the United Kingdom and describes progressive loss of function of the kidneys over a period of months or years, regardless of the original kidney disease. End stage kidney failure is where the kidneys no longer function well enough to meet the needs of daily life and patients need to have three times per week haemodialysis, or have a kidney transplant. Haemodialysis treatment is where the blood is removed from the body and filtered through a man-made membrane called a dialyser, or artificial kidney, and then the filtered blood is returned to the body. The cost of dialysis treatment is about 35,000/year. Non-drug related treatments that can slow down the decline of kidney function and delay end stage kidney failure are urgently needed. This was highlighted in a recent patient survey by Kidney Research UK as a top priority. Patients with CKD are prescribed a lot of different medications to help with associated complications from their kidney disease. New diabetic medications that may slow down progression of kidney disease are causing great excitement, and will potentially be useful early on in diabetic kidney disease. However, there is a very real need for non-drug related interventions, such as exercise training, to be evaluated for use in patients whose kidney disease is worsening. A previous study of 20 patients led by Dr Greenwood, has shown that 12 months of combined aerobic exercise (which increases stamina) and resistance exercise (which makes muscles stronger) could slow the decline of kidney function in patients with stages 3 and 4 CKD (patients with 15-60% kidney function). The study also showed potential to reverse the stiffening of blood vessels, and improve exercise capacity. We used an estimated measurement of kidney function in that small study. We would now like to do a feasibility study, which is an analysis of how well a project can be completed, with 50 patients using a measurement of kidney function called iohexol clearance. This is where a trained nurse measures how quickly an amount of special dye (iohexol) is cleared through the kidneys into the bloodstream. This measurement takes four hours and involves having a small amount of the iohexol dye injected into the body and then having four blood samples collected over four hours. This type of kidney function measurement is considered to be the gold standard measurement of kidney function, meaning it is the most accurate test possible to measure kidney function (how well the kidneys are working). As we haven't explored whether patients will be willing to take part, and remain, in a study that uses this kidney function measurement method, we need to investigate this before we do a larger study with lots of centres. Patients will be allocated by chance to a usual care plus exercise training group, or a usual care group. This is called a randomised controlled trial and is considered the best way to obtain impartial evidence about the value of a treatment. Exercise training will be supervised in small groups by a trained physiotherapy assistant for three one-hour sessions per week in a hospital gym-setting, and be encouraged to do a further one unsupervised session per week. As well as having their kidney function measured, patients will perform an exercise test called VO2peak, which involves a maximal cycling test, to accurately prescribe the dose of exercise training. Patients will also do tests to look at the health of their vessels and their body composition (using a machine to see how much fat, muscle and water make up the body). These will be completed at the beginning of the study, at 6 months and at 12 months. We would like to see if patients are willing to take part and remain in the study, and also what patients consider to be useful or unhelpful with the study design. We would also like to explore the effect of the exercise training, and any weight change, on the kidney function measurements. All of this information will be used to help plan a bigger study that we would like to do if this feasibility study is positive. Experts from the UK Kidney Research Consortium have worked together with patients to help design a study that is scientifically sound, and patient friendly. Patients will remain involved in all aspects of the research process, and have expressed a keen desire for a non-drug related therapy, which has the potential to slow the progression of kidney disease, to be urgently explored.

Research activity codes: 6.7 PHYSICAL
Health categories: RENAL AND UROGENITAL