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The purpose of this study was to determine whether acute renal injury develops more frequently in women than in men after cardiac surgery and whether this complication is associated with operative mortality in women.
Prospectively collected data were evaluated from 9461 coronary artery bypass graft and/or cardiac valve surgery patients (3080 women) not on preoperative dialysis. Glomerular filtration rate (eGFR) was estimated by the Modification of Diet in Renal Disease equations using the last plasma creatinine before surgery (baseline) and the highest level of the first postoperative week. The primary renal injury outcome was the composite endpoint of renal injury according to RIFLE criteria (eGFR decrease > 50% from baseline) or failure.
Thirty-day operative mortality and renal injury were more common in women than in men (5.9% vs 2.8%, P=0.01; 5.1% vs 3.6%, P<0.001, respectively). Nonetheless, patient sex was not independently associated with risk for renal injury when baseline eGFR was included in multivariate modeling. Perioperative complications, ICU length of stay, and mortality were more frequent for patients with than without renal injury (women, 20.6% vs 3.2%, P<0.0001; men, 18.3% vs 2.2%, P<0.001). Renal injury was independently associated with 30-day mortality for women (OR, 3.96; 95% CI, 1.86–8.44, P<0.0001) and men (OR, 4.05; 95% CI, 2.19–7.48, P<0.0001).
Postoperative renal injury is independently associated with 30-day mortality regardless of patient sex. Higher rates of renal injury in women compared with men might be explained in part by a higher prevalence of low eGFR before surgery.
Renal injury is more common in women than in men after cardiac surgery. Regardless of patient sex, the development of this complication is independently associated with elevated 30-day mortality.
Women are at higher risk for mortality after cardiac surgery than are men, but an explanation for this higher risk is not completely clear.(1) Understanding the gender-specific causes of operative mortality is fundamental for developing preventative strategies. Acute renal failure develops in 5% to 30% of patients after cardiac surgery when cardiopulmonary bypass (CPB) is used, predisposing affected patients to in-hospital and long-term mortality.(2-6) Even small elevations in serum creatinine (0.5 mg/dL) after surgery are associated with high mortality, longer length of hospitalization, and higher hospital costs.(4, 6) Female gender has been identified as an independent risk factor for postoperative renal failure, although it has not been a consistent finding.(2, 5-7) Notably, investigators who have evaluated the role of postoperative renal dysfunction in patient outcomes have not separately considered the impact of female sex. (2-6) This omission is important because women represented a minority (<30%) of patients in these studies, and the small number might limit extrapolation of data derived predominately from men. Further, compared with men, women usually have less muscle mass and are typically older at the time of surgery; both of these factors could affect the levels of serum creatinine.(1, 8) Thus, the purpose of this study was to evaluate whether acute renal injury that develops after cardiac surgery is more common in women than men and whether it is associated with operative mortality in women.
All study procedures were approved by the IRB of Johns Hopkins Medical Institutions, and each patient gave written informed consent for data collection and analysis prior to surgery. Data were prospectively collected by trained abstractors from an electronic medical record system at The Johns Hopkins Hospital as part of data collection for the Society of Thoracic Surgery (STS) National Cardiac Surgery Database.(9) Data collected included inpatient medical records, review of outpatient records, letter mailings, and telephone interviews. Patients receiving preoperative dialysis were excluded from the study. We identified 9461 consecutive patients (≥30 years old) who had undergone coronary artery bypass graft (CABG) and/or cardiac valve surgery between January 1, 1995 and December 31, 2006. Patients’ serum creatinine levels were obtained from a system-wide electronic patient record database.
Serum creatinine was measured as part of clinical care before and after surgery. The testing was carried out at the Clinical Chemistry Laboratory of The Johns Hopkins Hospital with commercial kits (Roche Diagnostics, Indianapolis, IN) that had a sensitivity of 0.2 mg/dL (1995 to February 2003) or 0.1 mg/dL (February 2003 onward). The last measurement before the day of surgery was considered the baseline value when more than one preoperative serum creatinine result was available. In determining the change from baseline, we considered the maximum serum creatinine as the highest level obtained during the first seven days after surgery. Glomerular filtration rate (eGFR) was estimated by the Modification of Diet in Renal Disease (MDRD) equations: eGFR=175 × (Scr)−1.154 × (age)−0.203 in mL/min per 1.73 m2 of body surface area (the product was multiplied by 0.742 if the subject was female or by 1.212 if the subject was African American).(10, 11)
There is no universally accepted definition of renal injury after cardiac surgery. We based our definition of renal injury on the RIFLE criteria: 1) Risk when eGFR decreases >25% from baseline; 2) Injury when eGFR decreases >50% from baseline; and 3) Failure when plasma creatinine is ≥350 μmol/L or when there is an acute rise of ≥44 μmol/L from baseline.(12) We also included new dialysis as an indicator of renal failure. The primary renal outcome of this study was the composite endpoint of renal injury or failure.
Relevant clinical, demographic, and outcome variables from files in our STS databases were extracted and merged into a STATA 10.0 data set, which was used for all statistical analyses (StataCorp. College Station, TX 2007). In initial confirmatory analyses, we considered univariate tests of associations between operative mortality and renal injury on gender, clinical measures, and complications from surgery. These analyses consisted of the chi-square test for categorical variables and the Student’s t-test, or when appropriate the non-parametric Kruskal-Wallis test, for continuous measures. Demographic and operative outcome variables with a P-value < 0.1 in the univariate analyses or those that were deemed to be clinically significant were considered in the multivariable logistic regression model predicting renal injury and operative mortality. Here, operative mortality was defined as death from any cause that occurred during hospitalization or after discharge but within 30 days after surgery. We considered spline parameters to account for possible non-linear associations continuous variables on renal injury or operative mortality. Definitions for clinical variables were those used by the STS database found http://www.sts.org/sections/stsnationaldatabase/datamanagers/adultcardiacdb/datacollection/index.html.
Patient characteristics for the 9150 survivors and the 311 patients who suffered operative mortality are listed in Table 1 according to patient sex. Operative mortality was higher for women than for men (4.2% vs 3.0%, P = 0.001). Compared with survivors, women and men who died were older and were more likely than surviving patients of the same sex to have low eGFR before surgery. Other differences between survivors and non-survivors for each sex are noted in Table 1. Comparisons of the frequency of variables that differed between non-surviving women and men are listed in Table 1. For the most part, variables associated with mortality were similar between women and men with a few exceptions. Compared with non-surviving men, women who suffered operative mortality had a higher frequency of diabetes, left ventricular ejection fraction <50%, hypercholesterolemia, hypertension, prior myocardial infarction, and current smoking. Non-surviving women had a lower frequency of triple vessel coronary artery disease than did non-surviving men. Differences in the type of surgery between women and men non-survivors were noted.
Baseline eGFR, the frequency of different levels of reduced eGFR, and the distribution of RIFLE criteria for renal injury by patient sex are listed in Table 2. Women had a lower eGFR before surgery than did men, and higher frequencies of women had eGFR < 30 mL/min per 1.73 m2 of body surface area and eGFR = 30–60 mL/min per 1.73 m2 of body surface area. Forty-four women and 33 men were reported to have new dialysis after surgery but were not listed as having renal injury or failure by the RIFLE criteria (due to dialysis correction of serum creatinine levels); these patients were included in the renal injury outcome. The primary renal injury outcome occurred in 5.1% of women and 3.6% of men (P<0.001). The Chi-square value for each category is provided in Table 2 and shows that most of the weighting for the combined P-value was from the RIFLE categories of “risk” or “injury”, suggesting that these two categories drive the statistical association between gender and RIFLE criteria. Characteristics for surviving and non-surviving patients with and without renal injury for each sex are listed in Table 3. Although many univariate predictors of mortality for patients with renal injury were similar for women and men, differences were noted. As in Table 1, the frequency of variables that differed between survivors and non-survivors for each sex are listed, and comparisons between non-surviving women and men are provided for these variables. In contrast to non-surviving men, women with renal injury who suffered mortality had a higher frequency of left ventricular ejection fraction < 30%, hypercholesterolemia, hypertension, three vessel coronary artery disease, and significant left main coronary stenosis. Non-surviving women with renal injury had a lower frequency of left ventricular ejection fraction < 50% than did non-surviving men with renal injury.
Perioperative complications and operative mortality are listed in Table 4 based on the presence or absence of renal injury for both sexes. With the exception of perioperative myocardial infarction, reported complications were more common in patients with renal injury than in those without such injury, irrespective of sex. In addition, duration of mechanical lung ventilation and duration of intensive care unit hospitalization were longer in patients of both sexes with renal injury compared with those without this complication. Operative mortality was markedly higher in both women and men with renal injury than in patients who did not suffer renal injury.
Variables independently associated with renal injury are listed in Table 5. Factors independently associated with renal injury after correction for baseline eGFR are listed in Table 6. Whereas male sex was independently associated with a reduced risk of renal injury in the first model, after correction for baseline eGFR in the second model, patient sex was no longer significantly related to risk for renal injury. Because of the non-linear relationship between eGFR and risk for renal injury, these data were splined at a baseline eGFR of 100 mL/min per 1.73 m2 of body surface area. A “U-shaped” relationship between baseline eGFR and risk for renal injury was observed. That is, a reduced risk for renal injury was associated with baseline eGFR of 100 mL/min per 1.73 m2. The risk of renal injury was higher above and below a baseline eGFR of 100 mL/min per 1.73 m2.
Independent predictors of operative mortality based on multivariate logistic regression analysis in a model that included both women and men are listed in Table 7. Multi-organ failure was a strong predictor for operative mortality. Renal injury was associated with risk for operative mortality for women and men after adjustment for other variables associated with death.
The data presented here show that the frequency of renal injury is more common in women than in men after cardiac surgery. This risk, however, might be explained in part by women having a lower baseline eGFR than men. In our study, patients who developed renal injury generally had more predisposing risk factors for morbidity and were more likely to develop postoperative complications than were those who did not develop renal injury, regardless of sex. Renal injury was independently associated with operative mortality for women and men.
Women have consistently been shown to have higher operative mortality after cardiac surgery than men due in part to a higher prevalence of risk factors for poor outcomes, including advanced age.(1, 13-15) Nonetheless, in the large multicenter STS database, female sex was reported to be an independent predictor of operative mortality for all but the highest risk patients.(1) Our group has reported that a large portion of the excessive risk for operative mortality in women can be explained by a higher prevalence of perioperative stroke in women than in men.(13, 14) The results of the current study now show that renal injury is an additional important determinant for operative mortality in women after cardiac surgery.
Renal insufficiency and renal failure after cardiac surgery are known to be associated with risk for adverse operative outcomes, including in-hospital, short-term, and long-term mortality.(2-6) Prior studies have reported that women are at higher risk for renal injury after cardiac surgery, but these findings are inconsistent.(2, 7, 16) One explanation for why women may have increased susceptibility to postoperative renal injury is that they have a higher prevalence of predisposing risk factors compared with men, including advanced age, diabetes, and hypertension.(1, 2, 13, 15) Another explanation might be related to the modulating effects of sex hormones on renal physiology and responses to ischemia and reperfusion.(17) Studies in whole-animal models have demonstrated greater functional and histological injury from global renal ischemia in male than in female animals, a finding linked to male and female sex steroids.(17) Whether the absence of estrogens associated with the postmenopausal state modifies these responses is not entirely clear. Nonetheless, in our study we found that after correcting for baseline eGFR, patient sex was no longer significantly associated with renal injury after surgery. Since we found that women had lower eGFR before surgery than did men, our findings indicate that the higher risk of postoperative renal injury in women is related in part to their lower baseline eGFR that may, perhaps, contribute to less functional reserve to injury.
Previous investigations that have examined the importance of renal injury on patient outcomes after cardiac surgery have not separately examined whether this risk applies equally to women and men. Rather, most studies have combined data from both sexes, a design that may limit extrapolation of the data to women since they are a minority of cardiac surgical patients.(2-6) Another disadvantage of the previous studies that may limit comparisons is that they have used multiple definitions for renal injury based on changes in serum creatinine levels.(3) Serum creatinine levels are influenced by multiple factors in addition to glomerular filtration.(8) Thus, relative and/or absolute serum creatinine concentrations may poorly predict renal function in elderly women. In this study, we estimated eGFR with the MDRD equations that take into account age, sex, and race.(10, 11) Further, we used RIFLE criteria for defining grades of renal injury.(12) Regardless, the frequency of renal injury and the associated mortality in our study was similar to those of other studies.(2-6, 18-20)
Renal injury associated with cardiac surgery likely results from hypotension, embolism, or exposure to nephrotoxins, including radiocontrast dye used before surgery.(4, 21, 22) Patients with renal injury are more likely than others to have postoperative complications. The development of complications such as sepsis and other organ injury might predispose them to hemodynamic instability and renal ischemia as well as to exposure to nephrotoxic antibiotics. Non-surgical patients with renal injury have prothrombotic tendency, endothelial dysfunction, and other abnormalities that predispose them to cardiovascular disease.(23) Perhaps these variables contribute to the poorer outcomes seen in patients who develop renal injury after cardiac surgery. In our study, we observed an apparent “U-shaped” relationship between baseline eGFR and risk for renal injury after surgery. Below a baseline of 100 mL/min 1.73 m2 of body surface area, each unit increase in eGFR reduced the risk for renal injury. In contrast, for patients with baseline eGFR > 100 mL/min per 1.73 m2 of body surface area, each unit increase in eGFR increased the risk for renal injury. Reasons for the latter observation are not clear other than the potential for higher renal embolic load during surgery for patients with high baseline eGFR. Importantly, our observations suggest that optimizing eGFR before surgery in patients with a baseline eGFR up to 100 mL/min per 1.73 m2 of body surface area might provide a strategy for reducing the risk for renal injury, particularly in women. One potential strategy would be to allow recovery of renal function from radiocontrast dye exposure before subjecting patients to the added risk of renal injury for surgical perturbations.
Many of the variables that we identified to be independently associated with mortality are widely recognized.(1) Women are likely to be older than men at the time of surgery and are more likely to have hypertension, fewer coronary artery stenoses, and preserved left ventricular function.(1) Thus, differences in preoperative co-morbidities between patient sexes might confound our examination of the importance of renal injury for operative mortality. Nonetheless, most of these risk factors for mortality were similar between patient sexes based on univariate analysis, although several variables did differ between survivors and non-survivors in analysis within each gender. However, our use of multivariate logistic regression analysis to adjust for other potential confounding factors between the patient sexes suggests that a higher co-morbidity rate in women with renal injury is an unlikely explanation for the link between this outcome and operative mortality. We observed that hypercholesterolemia was associated with lower mortality risk in men. This finding might represent an epiphenomenon that identifies patients receiving statin drugs, which have been shown to be associated with a lowered risk for mortality after cardiac surgery.(24) However, whether preoperative statin therapy lowers the risk of postoperative acute kidney injury is not conclusive.(24, 25)
In addition to the retrospective nature of this analysis, several limitations are associated with this study. Our analysis included a heterogeneous population of patients undergoing CABG surgery and/or valvular surgery. Serum creatinine levels, which were used in the definition of renal injury, may have been influenced by non-renal factors, including body weight, ethnicity, sex, and nutrition.(1, 8) Cystatin C is an endogenous marker of renal function that is more sensitive than creatinine for identifying mild and moderate decrements in eGFR.(26) Although use of the latter marker might have provided a more accurate detection of mild renal injury, it was not widely available or routinely measured during the period of this study. Likewise, aprotinin use, a variable found in retrospective studies to be associated with renal injury, was not recorded in our database.(27) Antifibrinolytic drugs consisted of aminocaproic acid; aprotinin was mostly restricted to re-operative surgery. Whether inclusion of aprotonin in our multivariate models of operative mortality would have modified our findings that renal injury is independently associated with operative mortality in women and men is not known but unlikely because only a minority of patients received the drug.
In summary, we have shown that the occurrence of renal injury after cardiac surgery is independently associated with an increased risk of postoperative mortality. Furthermore, the incidence of renal injury after cardiac surgery appears to be higher in women than in men. However, this discrepancy could be caused in part by women having a lower baseline eGFR than men. Optimizing eGFR before surgery in patients with a baseline eGFR below 100 mL/min per 1.73 m2 of body surface area and allowing patients time to recover renal function after exposure to renal toxins such as radiocontrast dye might provide strategies for reducing the risk of renal injury after cardiac surgery.
Source of Funding: Supported in part by grant 64600 from the National Institutes of Health, Bethesda, MD (C.W.H)
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