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General Articles: Review Article

Renal Ischemia: Does Sex Matter?

Hutchens, Michael P. MD*; Dunlap, Jennifer MD; Hurn, Patricia D. PhD*; Jarnberg, Per O. MD, PhD*

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doi: 10.1213/ane.0b013e318178ca42
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Abstract

The knowledge that disease and age differentially affect women and men extends into antiquity, at least as far back as the writings of Aristotle.* Despite this, it is a recent realization that sex represents a phenotype that mediates response to disease. More important is the realization that understanding the underlying mechanisms of this phenotypic difference may lead to therapy. Significant research and clinical progress has resulted from recognizing gender differences in cerebrovascular and cardiac disease. Sexual dimorphism in renal injury has been a recognized clinical entity for at least 65 years,1 and sex steroid effects on renal tissue have been investigated for at least 30 years.2,3 Renal disease, including renal ischemia, is sexually dimorphic, and it appears likely that clinical benefit from this knowledge can be expected in the relatively near future. This review focuses on the sexual dimorphism of renal ischemia, with an emphasis on mechanisms and potential therapies.

DEFINITIONS

Renal ischemia, if sufficiently severe, results in acute renal failure (ARF). Historically, it has been difficult to achieve consensus on a repeatable, precise definition of ARF, with more than 35 definitions in the literature.4 Recently, an international workgroup, the Acute Dialysis Quality Initiative, developed a consensus definition (the RIFLE criteria: Risk, Injury Failure, Loss, End stage kidney disease) that is being rapidly adopted in the literature. RIFLE criteria assign labels to renal injury based on glomerular filtration rate and urine output. Strict borders are defined, and initiation of hemodialysis, which depends on clinician judgment, is not included in assessment. Under this schema, acute kidney injury (AKI) is the clinical result of renal ischemia. This standardization of terminology has not yet permeated the literature, however, which creates a dilemma. The RIFLE criteria are an important new standard, and it is inappropriate to use the term AKI to denote renal injury diagnosed by other than the RIFLE criteria. At the same time, it is imprecise to call AKI anything but AKI. Therefore, in the discussion that follows, “AKI” specifically denotes renal injury diagnosed by RIFLE criteria only, while “ARF” is used to refer to ARF based on historical definitions of renal failure such as elevation of blood urea nitrogen and creatinine, the need for dialysis, or anuria.

RELEVANCE

ARF is quite common in the perioperative period; depending on the definition used, the incidence is between 5% and 30% of patients undergoing cardiac and vascular surgery,5–9 with 1% to 5% of these patients requiring postoperative dialysis.6 In noncardiac surgery, the incidence of perioperative renal failure is still quite high at 0.8% to 1.2% of all surgical patients. Surgery is the second most frequent precedent of hospital-acquired renal injury.10,11 The incidence of hospital-acquired ARF is increasing,12 as hospitals treat an increasingly aged and higher acuity population.13 The attributable mortality of hospital-acquired and perioperative renal injury is high, with estimates of up to 70% depending on the presence of comorbidities such as sepsis or other critical illness.14–16 The processes and predispositions leading to AKI are therefore critically important to perioperative physicians.

Multiple large studies of mixed surgical and medical populations, one large study of perioperative patients, and several small studies of specific groups of perioperative patients strongly suggest that there is sexual dimorphism in perioperative renal failure. These data are summarized in Table 1.

T1-40
Table 1:
Summary of Clinical Evidence for Gender Dimorphism in Renal Ischemia

CLINICAL IMPLICATIONS OF BASIC SCIENCE METHODS

The basic science research regarding gender effects on renal ischemia is persuasive. However, generalizing results is problematic because of the limitations imposed by available models of renal ischemia.17 The complex interaction among many cell types in the functioning whole kidney renders results obtained from cell culture suspect when applied to global ischemia, but this model has clear value in evaluating single intracellular mechanisms. Most basic research in renal ischemia has been performed in the pedicle-clamp or renal artery clamp model.18 More clinically relevant models include suprarenal cross-clamping in rats,19,20 and in our laboratory, a model of cardiac arrest and cardiopulmonary resuscitation in which physiologically instrumented mice undergo 10 minutes of complete whole-body warm ischemia followed by reperfusion. All of these models, however, suffer serious limitations. Most human AKI is preceded by low flow,21 whereas all of the animal models entail a period of no flow. Models requiring laparotomy entail tissue hypothermia, if not whole organism hypothermia, both of which protect against ischemia.22,23 Pedicle clamping produces vascular congestion in addition to ischemia, altering the injury. Indeed neither pedicle clamping nor cardiac arrest and cardiopulmonary resuscitation produces injury identical to that of AKI.17,24 In short, all of the extant models of renal ischemia are in some way substantially unlike their clinical correlate. This must be considered when evaluating the clinical relevance of basic science data.

EVIDENCE FOR SEX DIFFERENCE IN RENAL ANATOMY, PHYSIOLOGY, AND PATHOPHYSIOLOGY

There is a wealth of experimental evidence of sexual dimorphism in baseline renal physiology important to renal ischemia reperfusion injury (IRI).25 Both androgen and estrogen receptors are present in human renal tissue.26,27 Baseline renal hemodynamics are dimorphic. Females have more glomeruli per gram of kidney weight compared to males, as well as higher renovascular resistance, lower absolute glomerular filtration rate and lower renal plasma flow. These effects are partially reversed after ovariectomy.28 Males and females have significant ultrastructural mitochondrial dimorphism, with males having larger mitochondria, more lysosomes, and more abundant ribosomes in proximal tubular cells than females. Orchidectomy ablates these differences.29 Furthermore, there are gender differences in many non-ischemic renal disease models, including age-related glomerular injury30 hypertension,31 polycystic kidney disease,32 and diabetic nephropathy.33

A significant sexual dimorphism in renal injury after ischemia has been found in both focal ischemia and global ischemia models. Females have significantly improved survival (75% vs 8%) when exposed to profound renal ischemia. Estradiol treatment of males improves survival, but ovariectomy or testosterone administration to females does not.34 Park et al.35 found that males had significantly greater functional and histologic renal injury from ischemia. In this cohort, there was significantly increased injury with increasing exposure to androgens and, to a lesser extent, a protective effect of estrogen.

In concordance with these results in focal ischemia models, we have found significantly greater functional and histologic renal injury after cardiac arrest in males versus females, with a protective effect exerted by estrogen.36,37 Based on these findings, we conclude that in our model of global renal ischemia, there is a sex difference that appears to be sex steroid-mediated. Findings from global and focal ischemia models have been divergent in both neurologic and cardiac models.38,39 Drawing clinical conclusions applied to global ischemia from a focal ischemia model may have unwanted results. The repetition of the finding of sex difference mediated by sex steroids in both focal and global ischemia models strongly suggests sexual dimorphism in renal IRI.

PATHOPHYSIOLOGY OF RENAL ISCHEMIA

Renal IRI is the consequence of complex molecular and structural alterations resulting in necrosis and apoptosis of renal tubular cells. Although our understanding of these mechanisms is incomplete, the vascular endothelium, the immune response, oxidative mediators, and cell death pathways all play important roles and are summarized in Figure 1. These major axes of renal IRI are known to be responsive to sex steroids or sexually dimorphic.25,40 Vascular paracrine mechanisms, inflammatory/immune mechanisms, ultrastructural changes, and cell death pathways all have gender dimorphic or sex steroid-responsive elements (Fig. 2). The evidence for this dimorphism is discussed below.

F1-40
Figure 1.:
Key molecular events during the initiation of renal ischemia-reperfusion injury. While tissue injury is sustained during the initial ischemic event, it is exacerbated by a robust inflammatory response during reperfusion. Inflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, INF-γ, and IL-2 are upregulated.24,128 Chemokines such as MCP-1 and IL-8, and complement are also released resulting in leukocyte recruitment and activation. Upregulated adhesion molecules, including ICAM-1 and E-selectin, enhance endothelial-immune cell interactions; interference with this axis improves outcome.129–131 Recruited leukocytes then enhance injury by generating reactive oxygen species and eicosanoids and by enhancing vascular tone.132 Reactive oxygen species directly injure many cytoskeletal and functional cellular components, causing, among other events, the redistribution of Na+-K+ ATPase133 This results in a loss of the normal sodium/potassium gradients, increased intracellular sodium, and subsequent cell swelling. Dysmorphic tubular cells with cytoskeletal aberrations detach and cause tubular luminal obstruction. Direct endothelial damage and abnormal vascular tone is a result of increased sensitivity to and release of vasoconstrictors such as endothelin-1.42,52,134 Endothelial expression of endothelial nitric oxide synthetase (eNOS) is inhibited, which worsens outcome.44 Conversely, increased nitric oxide (NO) is generated by inducible nitric oxide synthetase (iNOS),135 also exacerbating injury.45,47,136 Key regulators of apoptosis, such as mitogen-activated protein kinases (MAPK), are upregulated by these events, resulting in increased cell death.137,138
F2-40
Figure 2.:
Known gender and/or sex steroid effects on key molecular mediators of renal IRI. Not all mechanisms shown are gender dimorphic in the specific context of ischemia. Numbers refer to the references after the text. Heat shock protein (HSP)27 reduces renal injury and was augmented by orchidectomy and reduced by dihydrotestosterone administration.70 Ischemia induced superoxide dismutase (SOD) activity is attenuated and reactive oxygen species are reduced in intact males. This attenuation is not present in orchidctomized males and returns with dihydrotestosterone administration.35 Inducible nitric oxide synthetase (iNOS) is elevated in female relative to male renal tissue, reduced by oophorectomy, and increased by estradiol therapy in oophorectomized animals.48 Endothelial nitric oxide synthetase (eNOS) immunoreactive protein is increased in females relative to males, reduced by oophorectomy, and increased by estradiol treatment.48 Phosphorylated extracellular signal related kinase (phospho-ERK) activity is higher in ischemic females than males, but this effect is lost when testosterone is administered to females.35 Conversely, castration of males reduces phosphorylated c-jun N-terminal kinase (phospho-JNK) and testosterone administration to females increases it.35 Endothelin-1 expression is greater in ischemic males than females,52 and estradiol administration reduces endothelin-1 expression in response to ischemia.54

Vascular Paracrine Mediators

After IRI, direct endothelial damage and abnormal vascular tone occurs as a result of increased sensitivity to vasoconstrictors and decreased vasodilation in arterioles.41,42 Endothelial injury also causes cell swelling and narrowing of the vascular lumen, further reducing blood flow.43 Reperfusion paradoxically causes further impairment of flow.44 Increased solute delivery to the distal nephron, in part due to tubular epithelial injury, enhances vascoconstriction by activating tubuloglomerular feedback mechanisms. The resulting increase in basal tone and persistent vasoconstriction contributes to decreased glomerular filtration rate.

Endothelial damage also disrupts the normal arteriolar response to vasodilators, such as nitric oxide (NO). NO is produced by three forms of NO synthetase (NOS): inducible (iNOS), neuronal, and endothelial (eNOS), all of which are present in the kidney. The balance of eNOS and iNOS appears to alter injury.45–47

Strong evidence supports gender dimorphism of NO-related renal processes. Renal eNOS activity is increased in women relative to men.35,48 The effect of estradiol administration on renal eNOS is controversial, with some studies showing increased expression of renal eNOS49,50 and others showing no effect.51 Testosterone inhibits postischemic activation of renal eNOS.35 Other vasoconstrictors including adenosine, angiotensin II, and endothelin-1 are implicated in renal ischemia.41,52 The aldosterone-mediated response to angiotensin II is gender dimorphic,53 and endothelin-1 is dimorphic and sex steroid-responsive.34,54 These findings suggest a gender-dependent mechanism in the vasoconstrictor response to ischemia.

Innate Immunity and Inflammation

Although tissue injury is sustained during the initial ischemic event, it is further exacerbated by a robust inflammatory response during reperfusion. Endothelial injury causes upregulation of adhesion molecules which enhance leukocyte-endothelial interactions. After renal ischemia-reperfusion, inflammatory cytokines are upregulated, complement is activated, chemokines are released and leukocytes are recruited and activated.24,55

The robust immune and inflammatory response to ischemia is sex or sex steroid-mediated in several other organ systems, including liver,56 brain,57,58 and heart.59–62 Sex steroid-mediated innate immunity in non-renal IRI suggests that further research in sex steroid modulation of the immune response in renal IRI may yield similar findings.

Injury to the Cytoskeleton

Ischemia results in production of reactive oxygen species from altered peroxisomal function and mitochondrial electron transport chain failure. Reactive oxygen species directly injure many cytoskeletal and functional cellular components and activate cellular stress response pathways.63 Under normal conditions, tubular epithelial cells are polarized with the sodium-potassium adenosine triphosphatase (Na+-K+ ATPase) located on the basolateral membrane. Na+-K+ ATPase is redistributed during ischemia resulting in a loss of the normal sodium/potassium gradients, increased intracellular sodium and subsequent cell swelling. Cytoskeletal aberrations also cause detachment of renal tubular cells, and consequent luminal obstruction. These cytoskeletal aberrations are in part opposed by the actions of heat shock proteins (HSP).64 Similarly, the cytoskeleton is protected from oxidative injury by the expression of superoxide dismutase.65

These mechanisms are sexually dimorphic and responsive to sex steroids in renal IRI. In female mice exposed to focal ischemia, Na+-K+ ATPase translocation is reduced and its activity increased compared with males,66 suggesting a gender effect on the cytoskeletal degredation and subsequent Na+-K+ ATPase dysfunction that follows IRI. Renal mitochondrial superoxide dismutase activity is attenuated by testosterone, an effect associated with increased formation of reactive oxygen species in proximal tubular cells.35,67 Females enjoy more abundant quantities of the critical heat-shock protein HSP72 in cardiac and renal tissue at baseline, and the loss of estradiol ablates this disparity.68 HSP72 levels increase in both males and females within 2 hours of ischemia; but in females, the protective colocalization of HSP72 and Na+-K+ ATPase is preserved, whereas it is lost in males.69 Testosterone ablates the normal upregulatory HSP27 response to ischemia, an effect correlated with increased injury.70 The cytotoxic metalloproteinase meprin injures the renal tubular basement membrane during ischemia; it has recently been shown that meprin inhibition is renoprotective in males but not females.71 These findings suggest strongly that normal renal cellular responses to ischemia are sexually dimorphic.

Apoptosis and Cell Death Pathways

Microscopic examination of the postischemic kidney demonstrates prominent necrotic damage, which for some time fostered the belief that apoptosis did not play a role in renal IRI. However, several studies have shown that capases, proteases activated in apoptosis, are important mediators of injury in renal IRI.72–74 Mitogen-activated protein kinases, including c-jun N-terminal kinase (JNK), p38, and extracellular signal-related kinase (ERK), are serine/threonine kinases that control cell survival, necrosis, and apoptosis, and are upregulated in the kidney by ischemia.75–77 Inhibition of JNK and ERK appears to reduce ischemic injury.78,79 The phosphatidylinositol 3-kinase (PI3K) pathway has also been implicated in renal IRI. Activated PI3K phosphorylates and activates Akt, which has many anti-apoptotic effects. Renal IRI increases Akt phosphorylation.80 Many of these mechanisms are sex steroid-mediated in organ systems other than kidney, for example, heart,81 liver,82 isolated vascular tissue,83 and brain.84,85 This suggests the possibility that these systems are sex steroid-mediated in renal ischemia as well. Indeed, renal Akt and ERK phosphorylation after IRI are reduced in the presence of testosterone, whereas JNK phosphorylation is promoted.35 These data suggest a role for both androgens and estrogens in the death signaling pathways that mediate the response to renal ischemia.

GENDER AND PERIOPERATIVE ARF

In addition to strong basic science evidence for gender dimorphism in experimental renal IRI, a significant body of evidence suggests that gender dimorphism also exists, in both incidence and mortality of ARF, in perioperative patients as well (Table 1). Most of this evidence is focused on specific populations who are at high risk for perioperative ARF, particularly patients undergoing vascular and cardiac surgery. Until very recently, there were essentially no data regarding noncardiac, nonvascular surgery patients. Recently, however, University of Michigan investigators used a perioperative clinical information system to extract data and assess risk factors in 15,102 patients undergoing noncardiac surgery. Patients undergoing vascular surgery involving a suprarenal cross-clamp were also excluded. In this cohort, gender was not found to be a significant predictor of perioperative ARF. This seems to contradict both experimental and clinical evidence to the contrary, and the large number of patients assessed suggests significant power. However, the study authors defined ARF as a calculated creatinine clearance of <50 mL/min during the first 7 postoperative days and assigned all patients with higher clearance to the “normal” group. This resulted in an ARF incidence of 0.8%, somewhat low compared with previous figures,10 and only 121 patients in the cohort received the ARF diagnosis. Since this population included both pre- and postmenopausal women, an estrogenic effect cannot be excluded. This notion is supported by the relatively small margins by which male ARF exceeds that of females in very large population-based studies,12,86 although these studies include nonsurgical patients. Although it is not possible to state conclusively that gender has no effect on perioperative ARF, based on large population studies and smaller studies of high risk groups, it is possible that there is a gender effect but that it is diluted by the inclusion of pre- and postmenopausal women in the same group. No study has evaluated the effect of menopause on the incidence of perioperative ARF, but two high risk groups, cardiac and vascular surgery patients, contain large numbers of postmenopausal women.

GENDER AND RENAL FAILURE AFTER VASCULAR SURGERY

Perioperative ARF occurs in 16% to 22% of patients who have undergone major vascular surgery87 (defined here as aortic surgery, as no study has yet evaluated the prevalence of ARF specifically after carotid endarterectomy or extremity revascularization). Based on the experimental data, it is reasonable to postulate that women, and particularly premenopausal women, have a lower incidence of perioperative ARF in this setting. No study has specifically addressed this question, and the answer is confounded by significant gender disparity in the prevalence of vascular disease and its surgical treatment, i.e., women are less likely to present with surgical vascular disease,88 less likely to be operated on when they do present, and generally present at more advanced age than men.89 In a very large (more than 47,000 patients) population-based study by Katz et al., the incidence of ARF after aneurysm repair was significantly higher in women than men.89 In contrast, Safi et al. reported on 234 consecutive patients of the same surgeon. In this series, the occurrence of renal failure was primarily related to surgical factors, and no significant effect of gender was found. However, this group included only 85 women.90

Katz et al. note in their discussion that gender does not affect mortality from cardiac surgery after adjusting for coronary artery caliber, which is smaller in women. It is reasonable to speculate that smaller renal artery caliber similarly affects postoperative ARF. No study specifically addresses gender disparity in renal artery diameter; however, perirenal aortic diameter is smaller in women relative to men,91 and it is likely that women have smaller renal arteries as well. As we have seen, a large body of basic science research supports the notion that female sex or female sex steroids have effects that are salutary for the ischemic kidney. The incidence of aortic aneurysm in young women is so low as to preclude study, but it may be that menopause may affect the incidence of aortic disease in the same way it affects the incidence of stroke. Premenopausal women have substantially lower stroke risk than postmenopausal women,92 a phenomenon thought to be at least partially mediated by estrogen's vascular effects.93

Regardless of mechanism, the highest quality data suggest that women have increased risk of perioperative renal failure after abdominal aortic aneurysm repair. Given the already high risk of perioperative ARF in vascular surgery patients and the substantial increment in mortality that ARF confers, it is imperative to mitigate pre- and intraoperative factors that endanger renal function in female patients.

GENDER AFFECTS RENAL FAILURE AFTER CARDIAC SURGERY

In accordance with the data from vascular surgical patients, women have higher risk of ARF after coronary revascularization, cardiac valve repair or replacement, combined valve/revascularization, aortic root repair, and other non-transplant, noncongenital cardiac surgery involving cardiopulmonary bypass.94–98 In the largest study with this finding, Thakar et al.94 assessed 22,589 Cleveland Clinic patients and found an odds ratio of 1.6 for female perioperative ARF, which made female sex a better predictor of postoperative ARF than preoperative congestive heart failure (odds ratio 1.5) or left ventricular function <45% (odds ratio 1.2). Interestingly, women in this cohort were significantly older than men (64 ± 12.6 vs 62 ± 11.8), and on multivariate analysis, increased age was a greater risk factor for women than for men (odds ratio 1.3 vs 1.2). Two studies that included younger women (one of cardiac transplant patients, and one which excluded only patients less than 12-years-old) failed to show a significant gender effect on postoperative ARF.99,100 This may also suggest that menopause is a factor in the increased risk experienced by women in cardiac surgery.

GENDER AFFECTS OUTCOME OF RENAL TRANSPLANT

Gender dimorphic outcome in renal transplant has been widely observed, and ischemia at the time of transplant clearly plays a role in allograft survival. Kidneys come either from living donors (38%) or deceased donors (62%) for a total of 16,735 United States kidney transplantations in 2006. The unique situation of biphasic warm/cold ischemia makes renal transplant ischemia-reperfusion worthy of special discussion. Warm ischemia time starts when the donor vessels are clamped, and is interrupted when the kidney is perfused with cold preservation solution at the start of cold ischemia time. Warm ischemia resumes when the kidney is placed in the recipient and ends when the kidney is revascularized. Deceased donor kidneys have much longer cold ischemia time than planned living related donor kidneys. The unavoidable detrimental effects of events surrounding deceased donor kidney retrieval and preservation, particularly those resulting from cold storage ischemia, are demonstrated by a 6% higher 1-year graft survival rate in living unrelated donor kidney transplants compared with diseased donor kidney transplants.101 Prolonged cold ischemia is a significant predictor of long-term graft loss.102,103 In addition to cold ischemia, donor origin is a significant independent predictor of outcome favoring living donor transplants. This is possibly caused by factors inherent in living donors such as absence of brain death and cardiovascular instability before nephrectomy.104

Initial studies reported that kidney transplants have better outcomes in female than in male recipients.105,106 However, other studies have shown that male recipients of male donor kidneys have better graft survival than patients with other donor-recipient combinations.107 Female kidneys transplanted into male recipients have inferior short-term and long-term survival.108,109 This difference in survival is present in kidneys from both deceased donor kidneys and living related donor kidneys, and is thought to be caused by a mismatch between the number of donors’ glomeruli and the recipients’ demand. Female kidneys have fewer nephrons than male kidneys and may experience a compensatory hyperfiltration-mediated glomerular injury, with progressive loss of glomeruli and ultimately graft failure.110,111 However, a differing response to ischemia at the time of transplant cannot be excluded. Disputing this early ischemia hypothesis, a study that evaluated graft survival in 1,049 kidney transplants between 1979 and 1994, most of which were diseased donor kidneys, found no differences in graft survival between male and female donor kidneys transplanted into recipients of either gender before the advent of cyclosporine. After cyclosporine was incorporated in immunosuppressive protocols, overall graft survival improved markedly, but kidneys from female donors had worse graft survival compared with those from male donors, despite similar mean plasma cyclosporine levels in the recipients. This donor-gender effect appeared soon after transplantation, and increased with time to peak at 24 months post-transplantation. The reason for this is unknown.110 Recent studies of newer immunosuppression regimens without cyclosporine have shown improved graft survival but unfortunately have not assessed the effect of gender.112 Finally, recipient gender also appears to have an impact; graft and patient survival are better in female recipients compared with males. This appears to result from a 10% risk reduction in women for age-related chronic allograft failure. The risk of chronic allograft failure increases with age in both genders but is greater for men than for women.113 Taken together, these data suggest that donor and recipient gender influence the effects of perioperative ischemia on renal allograft outcome.

IMPLICATIONS FOR ANESTHESIOLOGY PRACTICE

The data on gender and renal ischemia are interesting, important, and complex. Regardless of gender, renal failure is a common perioperative complication and it is dangerous. Although it may be tempting to view elevated postoperative creatinine as a self-resolving minor complication, the data do not support this notion. Although it is common to assess a patient's risk factors for perioperative myocardial infarction or neurologic ischemia and adjust the anesthetic plan accordingly, such preparation should also be made with regard to the risk of ARF. Indeed, a mortality of up to 70% argues that the importance of renoprotection rivals that of cardioprotection and neuroprotection. Cardio- and neuroprotective strategies based on gender stratification specifically should consider the clinical evidence for gender dimorphism in ARF as well, i.e., a comprehensive, gender-cognizant approach to organoprotection.

Although clinical data indicate that women enjoy protection from ARF in general, the incidence of ARF is higher in women than in men when undergoing cardiac and vascular surgery. This bimodal risk distribution may be a phenomenon of the menopause and changing exposure to estrogen with age. This would be consistent with basic science data indicating a renoprotective effect of estrogen. Regardless of mechanism, the situation appears analogous to that of cardiovascular disease in women in the 1980s, when it became apparent that the ubiquitous teaching that men had higher risk of stroke, coronary artery disease, and hypertension throughout the life cycle was, in fact, wrong.114 Given the data that women are at higher risk for ARF after cardiac surgery and the suggestion that women have higher risk after vascular surgery, it is prudent to maintain a high level of vigilance for renal function in women in these settings. Since there are no proven pharmacologic interventions to treat or prevent AKI,115 the vigilant provider must prevent harm, mitigate harm that is inevitable, and monitor renal function assiduously. Renotoxins such as radiocontrast, aminoglycosides, nonsteroidal antiinflammatory drugs, dextran, and chemotherapeutic drugs should be avoided in the perioperative period if at all possible. Maintenance of renal perfusion pressure with volume resuscitation may be beneficial.116,117 However, one recent study suggests that use of vasopressors is an independent risk factor for postoperative ARF in patients with previously normal renal function,11 so administering vasopressors to preserve perfusion pressure may be counterproductive.

Although the evidence is far from sufficient to recommend prevention or treatment of ARF with sex steroids, their continuing use by patients who present for surgery raises the question of whether they should be continued in the perioperative period. Testosterone is approved by the United States Food and Drug Administration for treating hypogonadism118 and is sometimes used off-label in postmenopausal women for reduced sexual desire.119 There are few, if any, perioperative sequela of short-term discontinuation of this medication.120 Given the low risk of short-term discontinuation and the available pre-clinical data suggesting that testosterone is harmful in renal ischemia, it may be prudent to stop anabolic steroids during the perioperative period in individuals at increased risk for ARF.

Similarly, estrogen and progestin formulations are widely used for relief of perimenopausal vasomotor symptoms.118 Abrupt discontinuation of estradiol can certainly provoke increased vasomotor instability and discomfort in women. However, a vigorous debate currently rages regarding the ability of estradiol to increase or decrease cardiovascular events in humans.121 Formulations containing high levels of estradiol increase overall risk of thrombotic complications. However, the impact of estradiol on renal injury risk and outcome will require further study before it is possible to make evidence-driven recommendations for women in the perioperative period.

CONCLUSIONS

Renal ischemia is a common complication experienced by patients in the perioperative period. It has significant implications, not the least of which is a surprisingly high mortality. Like other forms of organ ischemia, the mechanisms of renal ischemia are not completely understood. Nonetheless, renal dysfunction arising from several etiologies is sexually dimorphic. A significant body of experimental evidence supports the notion that this dimorphism is mediated by sex steroids. Although there is much work to be done to characterize the biological mechanisms involved, the data are sufficient to support consideration of gender and the use of medications that impact steroid availability in the perioperative plan of care. Many patients will present to the preoperative area already receiving estradiol or testosterone. While it may be reasonable to discontinue testosterone for a short perioperative period, no recommendation can be made regarding estradiol since the data are inconsistent. Research into mechanisms of sex steroid action in renal ischemia is active and will likely lend more clarity to this discussion in the near future.

ACKNOWLEDGMENTS

The authors wish to thank Robin Feidelson and Kathy Gage for their assistance in preparing this manuscript.

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