Statin therapy did not prevent acute kidney injury after cardiac surgery

Billings FT, Hendricks PA, Schildcrout JS, et al.
JAMA 2016;published online ahead of print

Background

Approximately 30% of patients undergoing cardiac surgery are complicated with acute kidney injury (AKI), and postoperative dialysis rates are increasing [1,2]. AKI is related to higher rates of postoperative arrhythmias, respiratory failure, systemic infection, and myocardial infarction, and has been independently associated with a 5-fold increase of in-hospital death [3-5].
Statins affect several mechanisms underlying AKI, and short-term statin treatment has been shown to limit vascular superoxide generation [6,7], reduce endothelial dysfunction by restoring endothelial-derived nitric oxide synthase activity during hypoxia [8], attenuate lymphocyte activation [9]. These effects decrease inflammation, endothelial dysfunction, and oxidant stress, mechanisms implicated in AKI development [10].
However, observational studies testing whether statin therapy may reduce AKI after cardiac surgery have yielded conflicting results [11,12]. This study tested the hypothesis that short-term administration of high-dose perioperative atorvastatin reduces AKI (defined as:  increase of 0.3mg/dL in serum creatinine concentration within 48 hours of surgery, according to Acute Kidney Injury Network criteria) [13] after cardiac surgery.
The group of statin-naïve patients was stopped prematurely due to increased AKI rates in patients with chronic kidney disease (CKD) who were randomised to atorvastatin. Later, the study was stopped completely for futility.

Main results

• Overall, AKI occurred in 20.8% in the atorvastatin group vs 19.5% in the placebo group (RR: 1.06; 95%CI: 0.78-1.46; P = 0.75)
• Median serum creatinine concentrations increased by 0.07 mg/dL (10th-90th percentile: −0.13 to 0.51 mg/dL) within the first 48 postoperative hours among participants on atorvastatin compared with 0.07 mg/dL (10th-90th percentile: −0.12 to 0.52 mg/dL) in the placebo group (mean difference: −0.01 mg/dL; 95% CI: −0.06 to 0.04 mg/dL; P = 0.89)
• In patients already on statin therapy AKI occurred in 20.4% in the atorvastatin group vs 22.4% in the placebo group (RR: 0.91; 95%CI: 0.63-1.32; P = 0.63).

• In statin-naive patients, AKI occurred in 21.6% in the atorvastatin group vs 13.4% in the placebo group (RR: 1.61; 0.86-3.01; P = 0.15).
• In statin-naïve patients, serum creatinine concentration increased more in the atorvastatin group (median: 0.11mg/dL, 10th-90th percentile: −0.11 to 0.56mg/dL) than in the placebo group (median: 0.05mg/dL (10th-90th percentile: −0.12 to 0.33mg/dL) (mean difference: 0.08 mg/dL; 95%CI: 0.01-0.15mg/dL; P = 0.007).
• In patients with CKD at baseline, the incidence of AKI was 35.7% in the atorvastatin group and 32.6% in the placebo group (RR: 1.09; 95%CI: 0.73-1.65; P = 0.76).
• In the patients with CKD and naive to statin treatment, AKI occurred in 52.9% in the atorvastatin group vs. 15.8% in the placebo group (RR: 3.35; 95% CI: 1.12-10.05; P = 0.03).

Conclusion

In patients undergoing cardiac surgery, high-dose perioperative atorvastatin treatment compared with placebo did not reduce the risk or severity of AKI following surgery. In patients naive to statins, there was some evidence that statin therapy may increase the risk of AKI in those with preexisting CKD. In patients already on statins, perioperative statin continuation or withdrawal did not affect postoperative AKI. These results do not support the initiation of high-dose statin therapy to prevent AKI following cardiac surgery.

Find this article online at JAMA

References

1. Rosner MH, OkusaMD. Acute kidney injury associated with cardiac surgery. Clin J AmSoc Nephrol.2006;1(1):19-32
2. Siddiqui NF, Coca SG, Devereaux PJ, et al. Secular trends in acute dialysis after elective major surgery—1995 to 2009. CMAJ. 2012;184(11):1237-1245
3. Birnie K, Verheyden V, Pagano D, et al. UK AKI in Cardiac Surgery Collaborators. Predictive models for kidney disease: improving global outcomes (KDIGO) defined acute kidney injury in UK cardiac surgery. Crit Care. 2014;18(6):606
4. Ryckwaert F, Boccara G, Frappier JM, et al. Incidence, risk factors, and prognosis of a moderate increase in plasma creatinine early after cardiac surgery. Crit Care Med. 2002;30(7):1495-1498
5. Thakar CV, Yared J-P, Worley S, et al. Renal dysfunction and serious infections after open-heart surgery. Kidney Int.2003;64(1):239-246
6. Wassmann S, Laufs U, Baumer AT, et al. HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension. 2001;37(6):1450-1457
7. Wagner AH, Kohler T, Ruckschloss U, et al. Improvement of nitric oxide-dependent vasodilatation by HMG-CoA reductase inhibitors through attenuation of endothelial superoxide anion formation. Arterioscler Thromb Vasc Biol.2000;20(1):61-69
8. Laufs U, Fata VL, Liao JK. Inhibition of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase blocks hypoxia-mediated down-regulation of endothelial nitric oxide synthase. J Biol Chem. 1997;272(50):31725-31729
9. Kwak B, Mulhaupt F, Myit S, et al. Statins as a newly recognized type of immunomodulator. Nat Med. 2000;6(12):1399-1402
10. Billings FT IV, PretoriusM, Schildcrout JS, et al. Obesity and oxidative stress predict AKI after cardiac surgery. J AmSoc Nephrol. 2012;23(7):1221-1228
11. Layton JB, Kshirsagar AV, Simpson RJ Jr, et al. Effect of statin use on acute kidney injury risk following coronary artery bypass grafting. Am JCardiol. 2013;111(6):823-828
12. Argalious M, Xu M, Sun Z, et al. Preoperative statin therapy is not associated with a reduced incidence of postoperative acute kidney injury after cardiac surgery. Anesth Analg. 2010;111(2):324-330
13. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31