Levosimendan and the Risk of Acute Kidney Injury After Cardiac Surgery

Acute kidney injury (AKI) carries a high risk of morbidity and mortality after cardiac surgery. AKI is more common in patients with a high burden of cardiovascular disease such as elderly and diabetic patients, who are more likely to need cardiac surgery.

Several agents failed to provide benefit in preventing AKI in humans after cardiac surgery.  Levosimendan, a novel calcium sensitizer, has two potential renoprotective effects. First it has an inotropic effect on the heart resulting in an increase in cardiac output and improved renal blood flow.  Second, it is a potent vasodilator, which further enhances renal blood flow and helps to maintain glomerular filtration rate in the setting of low cardiac output. Despite several studies and strong mechanistic rationale in preventing AKI after cardiac surgery, the data remains inconclusive as most of the performed studies were small and different dosing regimen were used.

In a recently study published in AJKD, Zhou et al performed a systematic meta-analysis to assess the clinical benefits of levosimendan given perioperatively in reducing the rate of AKI, need for renal replacement therapy (RRT), and mortality after cardiac surgery. A total of thirteen carefully selected studies based on their clinical qualities with a total of 1345 patients were included in the analysis.  The primary endpoint of their analysis was the occurrence of AKI defined as an increase of >50% or an absolute increase of >0.3 mg/dL in serum creatinine from baseline, or serum creatinine level >1.5 mg/dL within seven days after surgery. Secondary endpoints included inhospital need for RRT, all-cause mortality in hospital or within 30 days, ICU stay, and need for mechanical ventilation. The random effect model was used to analyze the extracted data due to studies heterogeneity.

The meta-analysis showed that levosimendan resulted in a statistically significant reduction in the risk of AKI (OR 0.51; 95% CI, 0.34 to 0.76; P= 0.001) when compared to control. Patients who received levosimendan as compared to control required less postoperative RRT (OR= 0.43; p= 0.002), had lower mortality rate (OR 0.41; P=0.001), had shorter course of mechanical ventilation, and shorter ICU stay.

These findings are compelling and make a strong case for a prospective, sufficiently powered, placebo controlled, randomized study. While confirming clinical benefit, such a study will also analyze the risk-benefit ratio, and should define the optimal dosing of levosimendan to maximize the benefit without increasing the risk of severe hypotension that could have a detrimental effect on the kidney function.

The authors acknowledged the limitations of their study, including no access to patient-level data, variable AKI definitions between the different studies, small sample size in the included studies, the exclusion of the non-English trials from there analysis, and reporting bias). Lack of effect of long-term mortality is another limitation of this study due to failure of reporting by primary studies.

In conclusion, this meta-analysis suggests potential benefit from levosimendan for AKI in the setting of post cardiac surgery, and provides a rationale for a prospective, randomized clinical trial. Further studies are needed to understand the risk-benefit ratio for personalized medicine.

Jean Francis, MD
AJKD Blog Contributor

To view the article abstract or full-text (subscription required), please visit AJKD.org.

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