Early surgical treatment has been suggested to improve the outcome of patients with infective endocarditis (IE) 1 . Acute kidney injury (AKI) is a common complication following cardiac surgery, occurring in 5 to 20% of the patients 2 3 4 5 . It has been associated with increased mortality 3 6 7 . Furthermore, AKI has been reported to be associated with poor prognosis in patients with acute IE 8 9 10 . There is therefore a need to prevent episodes of post-operative AKI, which may improve the outcome.

Patients with IE are typically at risk of kidney injury and their renal function might further be compromised because of cumulative injuries occurring before, during and after surgery. However, there are limited data on the prognosis of AKI in patients with IE undergoing cardiac surgery, and particularly, the risk factors favoring post-operative worsening of renal function in this context are not well-described. The aim of the present study was to describe the incidence of AKI patients undergoing operation for an acute episode of endocarditis, and to identify the risk factors for post-operative AKI or worsening of renal function in these patients.

The present study aimed to investigate the incidence, risk factors and prognosis associated with the post-operative AKI during the seven days following cardiac surgery for IE. We identified multiple surgery, pre-operative anemia, transfusion requirement during surgery and the use of nephrotoxic agents within 48 hours before surgery, to be significant risk factors.

In this study we restricted our analysis to patients with IE requiring cardiac surgery, for several reasons. First, the role of surgery in the treatment of IE has been emphasized with recent studies, suggesting that early surgical management could decrease the risk of stroke and death 1 19 . Second, most patients treated medically have contraindications to surgery, such as severe comorbid conditions or poor performance status. In the latter patients, prior conditions may per se strongly increase the risk of mortality or morbidities 20 . Third, although risk factors for AKI following cardiac surgery have been previously studied, patients with IE are likely to differ because of the ongoing inflammatory and infectious processes. Even though surgery aims to control the infectious process, we hypothesized that the accumulation of injuries, such as infection, systemic inflammation related to the cardiopulmonary bypass or the use of nephrotoxic agents, further increase the risk of renal failure after surgery in such patients. We finally confirmed that patients with IE have a high risk of post-operative AKI following cardiac surgery 2 3 4 .

We identified pre-operative anemia as a risk factor for post-operative AKI. Our findings are in line with the study from Karkouti et al. who observed a relationship between pre-operative hemoglobin and AKI after cardiopulmonary bypass 21 22 . The reasons for such an association are likely multifactorial. Several experimental studies have stressed the susceptibility of the kidney to anemia, and the occurrence of renal hypoxia after decrease of hemoglobin level due to maintenance of high oxygen consumption and intrarenal oxygen shunting 23 . In a rat model where renal oxygen tension was altered by hemodilution despite normal arterial blood pressure 24 , a specific contribution of anemia to kidney damage through oxidative stress has been proposed 25 . Moreover, we found that red blood cell (RBC) transfusion per se was also a risk factor. Several authors have previously identified the negative impact of RBC transfusion on renal function after cardiac surgery. One of the reasons could be the inability of RBC transfusion to restore adequate microcirculatory oxygenation because of the multiple morphological and functional changes (less deformability, depletion of 2,3-diphosphoglycerate, inflammation, decrease of bioavailability of nitric oxide with liberation of free hemoglobin) occurring during blood storage.

Peri-operative administration of nephrotoxic agents, such as vancomycin, aminoglycosides or contrast iodine, was also found to be a risk factor. Furthermore, the interaction between vancomycin and aminoglycosides was also found to be a significant risk factor. This would suggest that these two drugs, when administrated together, might have potentialized nephrotoxicity. Vancomycin-induced nephrotoxicity has been much debated. Vancomycin has been described as nephrotoxic in patients with IE, in critically ill patients, especially after prolonged administration. High values for serum trough concentrations of vancomycin have been associated with an increased risk of AKI 26 27 . However maintenance of higher trough concentration is often required in serious methicillin-resistant Staphylococcus aureus infections because of the high minimum inhibitory concentration. Alternative strategies using less nephrotoxic antibiotics, such as daptomycin, certainly merits further evaluation in patients undergoing operation for IE 28 29 . Although aminoglycosides are well-known nephrotoxic agents, they have been scarcely studied in patients with IE and their indication remains debated 30 . Buchholtz et al. have specifically explored the nephrotoxic effects of aminoglycosides in patients with IE and observed that worsening of renal function correlated with the duration of gentamicin treatment 31 . Pooling together the results of four randomized controlled trials that included patients with IE, the relative risk of nephrotoxicity was 2.22 (95% CI 1.11, 4.35) in patients treated with aminoglycosides 32 . Consistently, in a recent randomized controlled trial, Fowler et al. reported fewer episodes of renal failure in patients treated with daptomycin compared with patients receiving aminoglycosides for IE (11 versus 26% respectively) 28 . Moreover, regarding risk associated with iodine contrast in our series, the benefit of contrast-enhanced computer tomography or angiography pre-operatively should be balanced with the risk to renal function. Finally, we identified multiple surgery as another risk factor for post-operative worsening of renal function. Multiple surgery exposes the kidney to repeated factors of aggression, including hemodynamic instability, renal venous congestion when tamponnade occurs, inflammatory response to cardiopulmonary bypass, anemia and RBC transfusions. We found that receiving several nephrotoxic agents in the 48 hours before surgery was an important risk factor for post-operative AKI. We realize that these agents are sometimes needed, but we highlight that this period is of high risk for the kidney and these agents should be avoided as much as possible during this period.

In contrast with previous studies 33 , we found no association between the causative pathogen and the risk of worsening in renal function in our cohort. Several studies have linked Staphylococcus species infections to poor outcome in patients with IE. Several reasons can be proposed to explain such a difference. First, our results might suggest that the causal relationship between Staphylococcus-related IE and kidney injury needs to be questioned. Indeed, the association between Staphylococcus species and AKI may be attributable - at least in part - to the fact that patient with Staphylococcus-related IE was more likely to be treated with vancomycin and aminoglycosides. Second, only patients undergoing surgery were included in our study, therefore, excluding patients with the most advanced comorbidities, older age or poor performance status, who were considered too ill or too old to benefit from surgery. Unexpectedly, age over 65 y was found to be associated with less impairment in renal function in the post-operative period. The fact that age was found to be protective in our cohort further supports a selection of patients prior to surgery. Indeed, while the majority of the young patients were considered suitable for surgery, only the healthiest elderly were selected to undergo surgical treatment. Such a protective effect of aging could also be explained by the presence of young patients in the cohort, in whom the prevalence of post-operative degradation in renal function was very high. This interpretation was supported by the fact that when comparing middle-aged patients (40 to 75 y) to the elderly (>75 y), the effect of age was no longer significant (OR 0.80, 95% CI 0.55, 1.18, P = 0.26).

Although AKI has been associated with a higher risk of mortality in patients with IE, the timing and different contributing factors of AKI have not been clearly explored so far. In a Spanish multicenter observational study of 705 patients with left-sided IE, using multivariate analysis, Gálvez-Acebal et al. reported AKI to be associated with mortality 34 . In our series, we found that post-operative AKI was clearly associated with in-hospital mortality, whereas the association between pre-operative AKI (excluding patients receiving pre-operative RRT) and mortality was not significant. This suggests the importance of developing and evaluating perioperative strategies to prevent the occurrence of post-operative AKI. Interestingly, we observed a sharp difference in mortality between patients reaching stage 3 AKI and patients with stage 1 or 2, suggesting that all forms of AKI should not be considered equal in their severity in this setting. Although we only observed a statistical association between AKI progression and mortality, we cannot exclude a lack of power in our cohort to show such an association with pre-operative AKI.

The statistical analysis used some innovative tools such as SuperLearner 35 for prediction and TMLE 16 17 for estimation. The idea behind super learning is to optimize the prediction performances, accepting the fact that we do not know anything about the true shape of the underlying data distribution, so that every kind of parametric regression model would be biased. SuperLearner allows us to use a large library of candidate regression algorithms, parametric of data-adaptive, to honestly evaluate their prediction performance, and to build a new, tailored algorithm that is a combination of the best candidates. As expected from theory, we found that SuperLearner outperformed each candidate algorithm included in its library. From such results, we expect SuperLearner to do the best possible job to estimate the overall probability distribution of the outcome in our dataset. However, when looking at risk factors, we do not really care about the whole probability distribution of the outcome. In fact, we do care about a far less dimensional object, which is the distribution of the outcome given the level of a given potential risk factor. Our efforts should then focus on optimizing the bias/variance tradeoff for this object rather than for the whole outcome probability distribution. The TMLE aims at targeting our estimation in a way that the optimal bias/variance tradeoff is achieved for the parameter of interest.

Our study has several limitations. First, it was performed in a tertiary center with wide experience in medical and surgical treatment of patients with IE, potentially limiting the external validity. Second, our definition of AKI was based on serum creatinine level and did not include urine output. Third, we only have limited information on transfusion requirements. We were only able to evaluate the risk associated with peri-operative transfusion, but not the amount of blood transfused, nor the risk associated with pre- or post-operative transfusion. Fourth, the results apply to a selected population of patients suitable for surgery. Finally, despite the SuperLearner procedure, which is intended to optimize the prediction, our predictive performance was in fact limited, with an AUROC of 0.760 (95% CI 0.694, 0.826) for the SuperLearner weighted algorithm. Improved predictive performance might first be achieved by expanding the library of candidate algorithms, as the SuperLearner is at least as good as the best of its library. Hence, it remains to be investigated if a more aggressive library will result in further improvements. If not, one should consider expanding the set of predictive variables considered, including, potentially, specific kidney biomarkers.

This study adds evidence to the current literature suggesting that post-operative AKI following cardiac surgery with cardiopulmonary bypass results from additive hits to the kidney. It also identified several modifiable risk factors of post-operative AKI such as treatment with vancomycin or aminoglycosides or pre-operative anemia. Development of post-operative AKI was associated with in-hospital mortality. Prevention or correction of these risk factors may improve outcome in patients with IE undergoing cardiac surgery.

•>50% patients undergoing cardiac surgery for IE develop post-operative AKI

•We identified six risk factors for post-operative AKI, most being treatment-related, including vancomycine and aminoglycoside administration, and contrast agent.

•Pre-operative anemia was associated with an increased risk of post-operative AKI

•Post-operative AKI was associated with an increased risk of death.

AIC: Akaike information criterion; AKI: Acute kidney injury; AKIN: Acute kidney injury network; AUROC: Area under the receiver operating curve; CPB: Cardiopulmonary bypass; COPD: Chronic obstructive pulmonary disease; GFR: Glomerular filtration rate; IE: Infective endocarditis; LVEF: Left ventricular ejection fraction; MDRD: Modification of diet in renal disease; NYHA: New York Heart Association; OR: Odds ratio; RBC: Red blood cell; RR: Relative risk; RRT: Renal replacement therapy; TMLE: Targeted maximum likelihood estimation.

JLM declares having received research grants from Novartis, Aventis, MSD; speaker fees from Pfizer, Novartis, Aventis, AstraZeneca, GSK; travel grants from Pfizer, Novartis, Janssen, Aventis, Wyeth, Astellas and is scientific adviser for Aventis and AstraZeneca.

Other authors declare that they have no competing interests.

ML designed the study, contributed to acquisition, analysis and interpretation of data; drafted the manuscript and has given final approval of this version; RP contributed to analysis and interpretation of data; drafted the manuscript and has given final approval of this version; AR contributed to acquisition, analysis and interpretation of data and has given final approval of this version; MLP revised the manuscript critically for important intellectual content and has given final approval of this version; MVL revised the manuscript critically for important intellectual content and has given final approval of this version; JNF revised the manuscript critically for important intellectual content and has given final approval of this version; MPFG revised the manuscript critically for important intellectual content and has given final approval of this version; IP revised the manuscript critically for important intellectual content; DS revised the manuscript critically for important intellectual content and has given final approval of this version; BC revised the manuscript critically for important intellectual content and has given final approval of this version; JLM designed the study, contributed to acquisition, analysis and interpretation of data; drafted the manuscript and has given final approval of this version. All authors read and approved the final manuscript.