The optimism generated by these findings has recently been seriously dampened. The ONTARGET trial did not demonstrate any cardiovascular benefit for dual RAAS blockade (with the ACE-I ramipril and the ARB telmisartan), in a population at high risk of CVD, but did suggest an increased risk of major renal outcomes with dual RAAS blockade.281 This finding has been questioned for a range of reasons, and it has been suggested that the result may have been different if the population included a greater number of patients with CKD.425 The ALTITUDE trial randomized type 2 diabetic partici- pants to receive either aliskiren or matching placebo on top of an ACE-I or ARB113 and included a large number of diabetic individuals with CKD.426 Although the results have not been published at the time of writing this Guideline, the trial was recently stopped early due to a low likelihood of ever demonstrating benefit and a suggestion of an increased risk of some adverse outcomes, including non-fatal stroke, renal complications, hyperkalemia and hypotension,427 resulting in the US FDA counselling against this practice.114 As a result, any benefits of combined blockade of the RAAS for clinically important renal outcomes currently remain unproven, and the safety issues should be taken into account prior to using this therapeutic approach. 8.5: SHOULD ACE-IS AND ARBS BE DISCONTINUED IN CKD 5 BECAUSE THEY COMPROMISE RESIDUAL KIDNEY FUNCTION? It has long been recognized that commencing ACE-Is and ARBs can lead to an acute reduction in GFR that may be reversed if the dose is reduced or if the drug is discontinued. This phenomenon has been observed in the context of RCTs such as the RENAAL trial. 