• Major vascular events (defined as non-fatal myocardial infarction [MI] or cardiac death, non-fatal or fatal stroke, or revascularisation) at end of study
  

• Major vascular events at end of study
  
• Major cardiac events (non-fatal MI or cardiac death) at end of study
  
• Stroke (fatal or non-fatal) at end of study
  
• Coronary or non-coronary revascularisation at end of study
  
• Mortality, both overall and within particular categories at end of study
  
• Hospital admission for angina at end of study
  
• End-stage renal disease (need for long-term dialysis or transplantation) at end of study
  
• End-stage renal disease or death from any cause at end of study
  

Among patients with pre-existing coronary heart disease, large-scale randomized trials have demonstrated that lowering LDL-cholesterol concentration by about 1 mmol/l for 4-5 years reduces the risk of coronary events and of strokes by about 25%. Patients with established chronic kidney disease (CKD) are at high risk of vascular disease, so the benefits of cholesterol-lowering therapy might be expected to be substantial in this population. But, patients with CKD have generally been excluded from previous trials, and there is currently no reliable randomized evidence that lowering LDL-cholesterol would be beneficial among them.

There are several reasons why the demonstrated benefits of lowering blood cholesterol in other populations might not translate to patients with CKD. First, observational studies among dialysis patients have reported a negative association between blood total cholesterol and mortality. Secondly, only about one quarter of cardiac mortality in such patients appears to be definitely attributable to acute myocardial infarction, and so potentially avoidable with cholesterol-lowering, while the other common causes (e.g. cardiac arrest, arrhythmia, and heart failure) may not be as dependent on cholesterol levels. Finally, the long-term safety of cholesterol reduction among patients with CKD remains unclear. Hence, there is an important need for reliable direct evidence on whether lowering cholesterol prevents a worthwhile proportion of vascular events, without unacceptable toxicity, among patients with chronic kidney disease.

Animal studies have suggested that glomerulosclerosis (a major mechanism leading to loss of renal function) shares many similarities with atherosclerosis, and may be promoted by certain blood lipid abnormalities. A meta-analysis of small-scale randomized trials among CKD patients has suggested that lowering LDL-cholesterol might reduce the rate of nephron loss among patients with progressive renal dysfunction. But, in order to confirm or refute this hypothesis properly, a large-scale trial of cholesterol-lowering therapy in such patients is now needed.

The Study of Heart and Renal Protection (SHARP) aims to assess the effects of cholesterol-lowering therapy with a combination of simvastatin and the cholesterol-absorption inhibitor ezetimibe among around 9,000 patients with CKD (around 6,000 of whom will be pre-dialysis and 3,000 on dialysis). Such large-scale recruitment will allow reliable assessment of the effects of lowering blood LDL-cholesterol on the risk of major vascular events and on the rate of loss of renal function in patients with various degrees of renal impairment. An international collaboration between nephrologists and clinical trialists, with an International Coordinating Centre and around 6 Regional Coordinating Centres, will conduct the trial in over 300 hospitals in about 20 countries. SHARP is “streamlined”; extra work for collaborating doctors and hospitals has been kept to a minimum, and essential data only will be collected electronically to help research staff record accurate information about participants.