ACE and ARBs reduced the progression of renal disease in trials such as COOPER ATE, RENAAL, IDNT and BENEDICT. Very recently there has been some draw back in producing successful clinical trials when moving from the endpoint “kidney death” to “cardiovascular death or all cause mortality”. Attempts to reduce the burden of cardiovascular disease by cholesterol lowering (4D, ALERT), by dialysis dose (HEMO, ADEMEX), by targeting haemoglobin or serum phosphate (DCOR) produced mixed results in respect to the primary endpoint of such studies.

The nephrology community is very puzzled by those results and we have been discussing a number of causes why these RCTs did not provide support to our hypotheses. We are currently asking our selves three major questions: (1) “did we test the wrong hypothesis with the wrong intervention using the wrong population?”; (2) “did we estimate/calculate the wrong effect size or sample size, given the multifactorial causes of comorbidity and damage to the cardiovascular apparatus” and (3) “did we design or perform the RCT incorrectly, e.g. by giving priority to feasibility versus staying with the scientific question with methodological purity?” We have learnt a lot during recent years with the support of epidemiologists and clinical trialists. They have shown us that in some cases the answer to one or more of these questions was ‘yes’, at least in part. Now, new study protocols and new treatment strategies are needed and, wherever possible, the high quality clinical trial is the only way to explore urgent questions. Definitely, we need to significantly in crease our efforts in this important area. The nephrology community should create an atmosphere where we (1) decide on the most important questions which will impact patient outcome, (2) design simple large studies (better low hanging fruits than failure!) and (3) enrol more patients into clinical trials studying meaningful outcomes (e.g. survival off dialysis, hospitalizations, survival, quality of life).