Title: The renoprotective effects of Ursodeoxycholic acid in patients with type 1 diabetes and macroalbuminuria.
Funder: Department of Health and Social Care

Abstract: Background Patients with type 1 diabetes mellitus (T1DM) and macroalbuminuria remain at high risk of progression towards end stage renal disease (ESRD) with between a third and a half of all patients progressing to ESRD over 10-15 years despite improvements in clinical care/treatments[4]. Patients with macroalbuminuria are also at high risk of cardiovascular disease (CVD) the main cause of premature mortality in this patient group. Importantly treatments that lower macroalbuminuria can slow or prevent progression to ESRD and may lower CVD [1]. Aims: Our aim in this proof of concept study is to evaluate if Ursodeoxycholic acid reduces albuminuria in patients with T1DM and residual macroalbuminuria despite established standard care. The question we will answer is does Ursodeoxycholic acid, currently used for the treatment of gallstones and liver disease associated with cholestasis, be used as a novel treatment to reduce albuminuria. Laboratory work demonstrates that Ursodeoxycholic acid reduces albuminuria and improves the histological changes of diabetic renal disease by reducing cellular endoplasmic reticular (ER) stress and insulin resistance, novel pathways and emerging therapeutic targets to halt progression of renal disease in diabetes. Interestingly Ursodeoxycholic acid treatment improves endothelial function in patients with CVD [9,10]. Plan;We propose a single centre 24 week double blind placebo controlled cross over trial to evaluate if Ursodeoxycholic acid added to established standard care reduces albuminuria. We will specifically study patients with residual macroalbuminuria despite current best treatment, a group who are at very high risk of ESRD and CVD. All eligible patients will be seen as a minimum twice in the 2 week run in phase, at time of randomisation (baseline visit), 4 weeks after randomisation, 24 weeks, 28 weeks and 52 weeks. End point assessments will be at 24 weeks and 52 weeks (post 24 weeks treatment on Ursodeoxycholic acid or placebo) The primary endpoint will be change in albuminuria measured by the gold standard test of timed urine albumin excretion rate (AER) after 24 weeks treatment with Ursodeoxycholic acid as compared to placebo. Secondary endpoints will include blood pressure and estimated glomerular filtration rate (eGFR), and two other independent predictors and biomarkers of renal and CVD risk ;endothelium function measured by flow mediated vasodilation and arterial stiffness measured by aortic pulse wave velocity. Patients will be randomly allocated to receive either Ursodeoxycholic acid (500mg bid- maximum clinically recommended dose) for the first 24 weeks, 4 week wash out period followed by placebo for 24 weeks, or placebo for the first 24 weeks, 4 week wash out period followed by Ursodeoxycholic acid (500mg bid) for 24 weeks. Randomisation will be done by the Public Health Sciences department at King s College London. Monitoring of the trial will be performed by the King s Health Partners Clinical Trial Office (KHP CTO) and the Division of Health and Social Care at King s College London will provide statistical/data analysis support. KHP CTO will be the designated clinical trial monitor for this study. Potential benefits: ESRD is a feared complication of diabetes with significant morbidity and mortality to patients. Patients with ESRD have 5 year survival rate of 30% which is worse than certain advanced malignancies. In 2010/2011 estimated annual costs to the NHS of managing T1DM related renal disease was &pound;186.5 million a figure that is projected to increase to &pound;313 million by 2035/2036[11]. There is an urgent need for new treatments in this disease area, especially if the treatment is currently available for clinical use and may have added new benefits to patients. Ursodeoxycholic acid is such a treatment and our proof of concept study will test if this drug can prevent/delay ESRD in high risk patients.

Lay abstract: Kidney disease due to diabetes develops in 30-40% of all patients with diabetes and is the leading cause of end stage renal disease (ESRD). ESRD require dialysis or renal transplantation and has a significant impact on patients, their carers and wider society. A hallmark of kidney disease is the presence of raised amounts of the protein albumin in the urine which is termed albuminuria. Increased levels of albumin in the urine is termed macroalbuminuria and patients with macroalbuminuria are at high risk of ESRD. Drug treatments that are now routinely used and proven to prevent ESRD were first evaluated in patients with type 1 diabetes mellitus (T1DM) and macroalbuminuria. These drugs all demonstrated early reductions in macroalbuminuria which later translated to the prevention/delay of ESRD. However despite these drugs patients with T1DM and macroalbuminuria remain at high risk as current treatments cannot allways reduce macroalbuminuria sufficiently/fully with between a third and a half of all patients (32,000 T1DM patients in the UK) at very high risk of ESRD. Our research aims to address this issue by investigating if Ursodeoxycholic acid can reduce albuminuria in patients with T1DM and macroalbuminuria despite established standard care. Ursodeoxycholic acid is a bile acid secreted in humans that helps eliminate cholesterol and dissolve fats. It is currently approved for clinical use and treatment of gall stones and liver disease. In laboratory and animal studies Ursodeoxycholic acid reduces albuminuria and prevent progression of kidney damage. If our study indicates that 24 weeks treatment with Ursodeoxycholic acid can reduce albuminuria, this would be of importance as we are in urgent need for new treatments to improve the care of these high risk patients. This work would lead to a larger study with longer follow up to confirm the reduction in albuminuria with Ursodeoxycholic acid prevents/delays ESRD.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: METABOLIC AND ENDOCRINE;RENAL AND UROGENITAL