In this large, contemporary, multi-center, prospective study of patients undergoing cardiac surgery who were selected for high AKI risk, the incidence of AKI was high, particularly among patients with greater comorbidity and impaired baseline kidney function. Although there are several well-known risk factors for AKI,6–9
associations between natriuretic peptides and AKI remain unclear. We found that pre-operative BNP, a biomarker of hemodynamic stress, is a strong and independent predictor of at least mild and severe AKI. The addition of BNP to known clinical parameters provided modest improvements in risk discrimination, as demonstrated by absolute increases in the AUCs of 0.02–0.03. Similarly risk classification was only modestly improved as demonstrated by continuous NRIs of 0.23–0.38. These findings inform the role of BNP when considering how to best stratify the risk of AKI in the cardiac surgery setting.
The prognostic importance of natriuretic peptides has been well described in both the non-cardiac and cardiac surgery settings. The results from sixteen unique studies were reported in two separate systematic reviews that identified strong associations of elevated BNP and NT-proBNP levels with cardiac events and mortality.21,22
Although various cut-points were used to define elevated BNP levels, the average number of patients with elevated BNP levels was 1 in 4.22
Despite some differences in study inclusion criteria, outcome definitions and analytic methods, both reviews estimated that elevated pre-operative BNP levels were associated with higher risk of cardiovascular outcomes (including cardiac death) to a similar extent. Further, this association appeared independent of conventional risk factors,22
although moderate heterogeneity in past study results limits inferences in this regard. Despite differences in analytic methods that may preclude direct comparisons with non-cardiac surgery studies, similar findings were observed among studies of patients undergoing cardiac surgery. The majority of these studies evaluated associations between BNP and mortality10–12,14–20
and cardiovascular complications,10,11,14,17–20
while some also examined length-of-stay.10,11,15–18
Most past studies were limited to fewer than 200 patients with only one large study that included over 1,000 patients.16
In the present study, we found that higher levels of pre-operative BNP were associated with higher incidence of post-operative mortality and longer lengths of stay in both the intensive care unit and hospital.
Few studies have examined the association between natriuretic peptides and risk of AKI following cardiac surgery. Although post-operative renal impairment is described as a study outcome in two recent studies,10,12
the findings are limited by small study sizes (both <500 patients) and limited information regarding the observed incidence or associations with BNP levels. However, in one small study (n=135),11
pre-operative NTproBNP levels were significantly higher among those who developed post-operative renal failure (defined as a 50% increase in serum creatinine or greater; median 1728 vs 194 ng/L, p<0.001). When AUCs were examined for predicting renal failure, pre-operative NTproBNP (AUC 0.86, 95% CI 0.78 to 0.94) was more predictive than either the euroSCORE34
or ejection fraction. Similarly, we found that pre-operative BNP levels were significantly higher among those who developed postoperative AKI. Quintiles of BNP were linearly associated with risk of at least mild AKI, whereas a risk threshold was observed above intermediate BNP levels when evaluating severe AKI. Because patients in our cohort were selected for high AKI risk, they represent a relatively homogenous high-risk population. It is possible that BNP may provide greater risk discrimination in more heterogeneous populations, such as in past studies which enrolled individuals at low- and medium-risk of AKI.11,34
Although many studies evaluating BNP in cardiac surgery have examined both pre-operative and post-operative levels,12,14,15,18–20
the relative advantages of each remain unclear. Consequently, we also assessed associations with post-operative BNP levels and found that pre-operative levels were more informative in predicting AKI.
The prognostic value of natriuretic peptide levels in the pre-operative setting is most likely related to their ability to measure small changes in right or left ventricular function among those with systolic or diastolic abnormalities, whether or not they are symptomatic. Ventricular myocardial wall stress stimulates natriuretic peptide secretion in the setting of volume expansion or pressure overload. Consequently, natriuretic peptides have prognostic abilities across a variety of conditions involving hemodynamic stress in addition to heart failure, including stable and acute coronary artery disease, sudden cardiac death, cardiac arrhythmias, pulmonary embolism, stroke, and septic shock.13
Our findings add to these prior observations by demonstrating that pre-operative BNP levels also independently predict post-cardiac surgery AKI. Further, this relationship is supported by early physiologic studies as well as recent clinical observations. In classic physiologic experiments, increased venous pressure reduced renal blood flow and urine flow.35
The magnitude of this effect proved even greater than equivalent decreases in arterial pressure.35
More recently, venous congestion has been demonstrated to be strongly associated with AKI among patients with heart failure,36–38
as well as those with atherosclerotic cardiovascular disease.39
Because of greater recognition of the importance of venous congestion, the clinical trial focus is shifting from addressing impaired cardiac output and inadequate arterial filling to renal-sparing treatment strategies that reduce venous congestion.40,41
Within the peri-operative setting, reducing the risk of AKI following cardiac surgery has been a focus of growing importance. The primary emphasis has been on optimization of hemodynamic status throughout the peri-operative course because a variety of studies have suggested that such measures decrease the risk of AKI.42
Despite the perceived importance of intra-operative hypo-perfusion as the dominant mechanism behind AKI following cardiac surgery, tight control of mean arterial pressure has not been consistently shown to reduce the risk of AKI. As observed in physiologic studies outside of the surgical setting, increased venous pressure may confer greater risk of post-operative AKI than decreased arterial pressure. Thus, reductions in elevated venous congestion prior to or during cardiac surgery may provide a novel approach to reducing the risk of AKI after cardiac surgery. Outpatient natriuretic-guided therapies have been effective in reducing heart failure deaths and re-hospitalizations.43
Similarly, serum BNP may provide a non-invasive indicator to evaluate the efficacy of peri-operative reductions in hemodynamic stress related to either volume expansion or pressure overload conditions.
This study is the largest, multi-center study to date to assess the association between BNP and post-operative AKI risk. Although the focus of our evaluation was on the relationship between pre-operative BNP and AKI, the risks associated with post-operative BNP and corresponding changes from pre-operative levels were also assessed. The diverse settings of the six institutions also ensured a broad inclusion of high-risk cardiac surgery patients. However, this study does have important limitations. Many studies evaluating natriuretic peptides have used NT-proBNP instead of BNP, which may be more influenced by factors such as body mass index. However, because BNP is less influenced by kidney function, it is the more reliable natriuretic peptide in this setting.44
We were also able to account for the factors that strongly affect BNP levels such as age, gender, and kidney disease. However, other factors could not be accounted for, including pulmonary disease, severity of cardiac disease (e.g., severity of pre-operative myocardial infarction, hypotension or atrial fibrillation), and body mass index. Limited cases of AKI requiring dialysis, as well as a lack of data on pulmonary disease and limited data on heart failure classification precluded application of our study data to existing risk models.7,8
In addition, our patients were mostly white limiting the generalizability of these findings to other populations. Nonetheless, all studies using natriuretic peptides suffer from limitations related to the biologic variability and intra-individual variation.13,43
Although our study had a very large number of at least mild AKI cases, we had few patients with severe AKI, including dialysis-requiring AKI (n=17, 1.5%). Therefore, the ability of BNP to predict risk for these outcomes could not be reliably assessed in our study. Finally, some predictors of AKI (pre-operative cardiogenic shock, intra-abdominal pressure) were not available, limiting our ability to determine whether BNP levels remain independent of these factors. In order to develop the best AKI risk model, future efforts should simultaneously evaluate markers of kidney filtration (eg, serum creatinine, cystatin C, UACR), injury (e.g., urine neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interkeukin-18, etc.), and hemodynamics (e.g., BNP). This multi-marker approach will then establish whether BNP is associated with AKI after simultaneously accounting for changes in other biomarkers that reflect different aspects of the AKI process. Our current results suggest that BNP will certainly need to be included in that development process.
In conclusion, we found that elevated pre-operative BNP levels were strongly associated with greater AKI risk. BNP was linearly associated with risk of at least mild AKI, whereas for evaluating severe AKI, a risk threshold was observed above intermediate levels of BNP. If confirmed in other populations not selected for high AKI risk, BNP may be a valuable component of future efforts to improve pre-operative risk stratification and discrimination among surgical candidates. These findings raise the possibility that pre-operative therapies to reduce hemodynamic stress indicated by elevated BNP levels may be effective in mitigating the high risk of AKI among select patients.