Statins do not prevent cardiac surgery-associated AKI: is ubiquinone the missing link?

Abstract

Statins have become one of the most commonly prescribed drugs worldwide in the prevention of cardiovascular disease. Most benefits are secondary to inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase) which lowers low-density lipoprotein cholesterol levels. However, statins also have cholesterolindependent, pleiotropic effects that occur within hours of initiation and include improved endothelial function, anti-apoptotic, anti-inflammatiory, antioxidant, antithrombotic, and immunomodulatory effects [1].Cardiac surgery-associated acute kidney injury (AKI) is the second most common cause of AKI in critically ill patients. It is associated with poor short-and long-term outcome [2]. Attempts at pharmacologic prevention have been disappointing. Its pathogenesis is complex, but inflammation, oxidative stress, and endothelial dysfunction are pathogenic factors [2] that could, potentially, be mitigated by the pleiotropic effects of statins. Animal models of ischemia-reperfusion indeed show a beneficial effect of statins on kidney function [3]. In patients receiving radiocontrast for coronary angiography and percutaneous coronary interventions, statins reduce the incidence of post-contrast AKI [4]. In the setting of cardiac surgery, observational trials found inconsistent results regarding the association between preoperative statin use and postoperative AKI [5,6]. A Cochrane meta-analysis of small randomized controlled trials (RCTs), mostly with high risk of bias, could, however, not find a beneficial effect of statins on AKI after cardiac surgery [7]. This meta-analysis concludes that large highquality trials are required.In an article published in Intensive Care Medicine, Park et al. report an investigator-initiated double-blind randomized placebo-controlled trial evaluating the perioperative short-term use of high-dose atorvastatin in 200 statin-naïve patients scheduled for elective valvular heart surgery [8]. The choice for valvular surgery is motivated by the high prevalence of statin use in coronary artery bypass graft (CABG) patients and the possible rebound inflammatory response due to statin withdrawal [9]. Baseline characteristics and surgical procedures were well balanced. The primary endpoint, the incidence of AKI within the first 48 h according to the Acute Kidney Injury Network (AKIN) criteria, was not affected (21 % in the statin group and 26 % in the control group; p = 0.404). Only 6 % in both groups had AKI stage 2 or 3. In addition, more sensitive markers of kidney injury (creatinine, NGAL) and inflammation (IL-18, CRP), the secondary endpoints, were comparable between groups. Intraoperative vasopressor requirement was lower in the statin group, but this did not reflect in clinical benefit. There was no evidence for toxicity in terms of creatinine kinase (CK > 5000 U) [8].Two other recent RCTs evaluated the renoprotective effect of statins in elective cardiac surgery [10,11]. The first RCT randomized 199 statin-naïve patients and 416 patients already taking statins before surgery to ...

Possible nephrotoxic effects of high dose statin therapy; current knowledge

“…Meanwhile, a Cochrane review could not find a benefit of statins on AKI after cardiac surgery (5). Additionally, some studies showed that statins are not renoprotective against AKI after contrast administration following cardiac surgery (6)(7)(8). Likewise, there is a 25-fold increased relative risk of AKI associated with high-dose statins over low-dose statins in patients with congestive heart failure (2).…”

Statins barely touch the heart but bite the kidneys after cardiac surgery. Coenzyme Q10 deficiency in the dock?

“…The observed statin-related adverse effect on renal function, however, was unexpected and not explained. This fueled a hypothesis, recently put forward by Schetz and Oudemans-van Straaten, linking the lack of renoprotection to a statin-induced depletion of coenzyme Q10 (CoQ10, aka ubiquinone) (8). CoQ10 is a naturally occurring, lipid-soluble electron carrier which is essential for mitochondrial oxidative phosphorylation and production of adenosine triphosphate (9).…”