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
) 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
) 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
) Prior studies have reported that women are at higher risk for renal injury after cardiac surgery, but these findings are inconsistent.(2
) 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
) 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
) 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
) 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
Renal injury associated with cardiac surgery likely results from hypotension, embolism, or exposure to nephrotoxins, including radiocontrast dye used before surgery.(4
) 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
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
) 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.