Prevention of Acute Kidney Injury Using Vasoactive or Antiplatelet Treatment
Authors: Wolfgang C. Winkelmayer, Kevin W. Finkel
Journal: JAMA (2014)

Acute kidney injury (AKI) is a serious complication of surgery and other severe health events (eg, sepsis). Its most severe form, AKI requiring dialysis, occurred during almost 164 000 hospitalizations in the United States in 2009 and was associated with almost 39 000 deaths.1 The incidence of AKI has been increasing substantially over the past decade, by 7% per year even after adjustment for changes in case mix.1 The in-hospital mortality rate associated with AKI requiring dialysis was approximately 25% for all cases, and even higher (35%) in patients undergoing cardiac surgery.1,2 In cardiac surgery, the population-attributable fraction (ie, the excess event rate or risk fraction for the outcome estimated to be potentially “attributable” to the exposure) of in-hospital mortality was almost 50% for all AKI, and 14% for AKI requiring dialysis.2 The costs associated with AKI are substantial and impose a significant burden on the health care system.3 As a consequence, numerous research efforts are under way to facilitate earlier detection and more effective prevention or treatment of AKI. However, it appears that little progress has been made because few interventions have been proven beneficial in the prevention of AKI.4 The recent Kidney Disease Improving Global Outcomes (KDIGO) AKI guidelines included numerous suggestions and recommendations for what interventions not to use, clearly indicating that “experience-based” medicine has flourished in the absence of conclusive and high-quality evidence.5 JAMA is publishing reports from 2 large clinical trials that tested a total of 3 pharmaceutical interventions for the primary or secondary prevention of AKI in patients undergoing surgery. In one report, Garg et al6 present the results from a substudy of the large Perioperative Ischemia Evaluation-2 (POISE-2) trial, which randomized 10 010 patients undergoing noncardiac surgery in a 2 × 2 factorial design to clonidine vs placebo and aspirin vs placebo. While the main trial focused on the prevention of short-term mortality and cardiovascular (myocardial infarction) risk over the first 30days following noncardiac surgery, there was substantial laboratory and preliminary clinical evidence supporting the hypotheses that either agent may also be efficacious in reducing the risk of AKI in the context of the index surgery. However, neither aspirin nor clonidine reduced the risk of AKI (13.4% for aspirin vs 12.3% for placebo; 13.0% for clonidine vs 12.7% for placebo). Moreover, aspirin use was associated with an increased risk of major bleeding, whereas clonidine was associated with an increased risk of clinically important hypotension. In another report, Bove et al7 present findings fromamulticenter, randomized,double-blind,placebo-controlled trial of fenoldopamas secondaryprevention in 667patientswhohad developedearly-stageAKI immediately following cardiac surgery. The study, which was stopped early for futility, demonstratednosignificantdifference in theprimaryoutcomeofuse of dialysis for advanced-stage AKI (69/338 [20%] patients in the fenoldopam group vs 60/329 [18%] patients in the placebo group), or in mortality at 30 days (78/338 [23%] with fenoldopamvs74/329 [22%]withplacebo). Inaddition, the rate of hypotensionwas higher with fenoldopam (26%) thanwith placebo (15%). The findings from these 2 trials demonstrated that none of the 3 interventions proved efficacious, but that all 3 exposures yielded signals towardpotential harm.These results are sobering and constitute a setback to finding effective interventions to prevent AKI and the burden of its consequences. The rationale for the use of these 3 agents (vasodilators, antiplatelet agents, anti-inflammatorydrugs)wasbasedon the presumed mediators of renal injury in the postoperative period: renal vasoconstrictionwithmedullary ischemia, inflammation, and microthrombosis. Despite the positive results shown in both animal models and small studies in humans, these large, randomizedclinical trials failed todemonstrateany benefit for the use of aspirin, clonidine, or fenoldopam. Such results raise theconcern that cliniciansand researchers arenot targeting the actual or relevantmechanisms of AKI. This lack of benefit could also be explained by the timing of the administration of studydrug, the intensity of the inflammatory cascade, or the untoward adverse effects of the specific agents. Increased rates of hypotension (clonidine, fenoldopam) and gastrointestinal bleeding (aspirin), all known precipitants of AKI, were found in patients randomized to treatment in both trials. Amongpatients experiencing these adverse effects,AKI was significantlymore common. Thus, the new evidence not only fails to demonstrate any benefit, but rather indicates net harm for each intervention tested. These outcomes are reminiscent of the experience with low-dose (“renal dose”) dopamine for thepreventionor treatment of AKI.Whereas small clinical trials suggested a benefit from infusion of low-dose dopamine, and the drug was used Related articles pages 2244 and 2254 Opinion