Anesth Analg 2008; 107:232-238
© 2008 International Anesthesia Research Society
doi: 10.1213/ane.0b013e318163feaf
GENERAL ARTICLES
Gender Issues in Transplantation
Marie Csete, MD, PhD
From the Departments of Anesthesiology and Cell Biology, Emory University School of Medicine, Atlanta, Georgia.
Address correspondence and reprint requests to Marie Csete, MD, PhD, Emory Anesthesiology Labs, 1462 Clifton Rd. NE, Room 420, Atlanta, GA 30322. Address e-mail to marie.csete{at}emoryhealthcare.org.
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Abstract
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The effects of gender mismatch in clinical transplantation have been recognized for half a century. But gender issues in clinical transplantation affect outcomes at many levels beyond immunologic concerns. Many diseases leading to transplantation are predominantly expressed in one gender. Organ donation patterns have consistently been defined by a greater tendency of women to be live donors. Access to transplantation may be affected by subtleties in the interactions of transplant personnel with women versus men candidates. In the new field of stem-cell transplantation, functional differences in male versus female adult stem cells may shed light on gender differences in outcomes for solid organ transplantation. This review highlights gender issues related to transplantation with a goal of optimizing the care of all transplant patients.
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Introduction
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Fifty years ago, investigators noted that female mice reject skin grafts from male mice of the same inbred strain.1 Many years later, the minor histocompatibility H-Y antigen responsible for this phenomenon has re-emerged as an important factor in corneal graft survival, with poorer long-term outcomes in H-Y mismatched (male-to-female) grafts compared with those in H-Y matched grafts.2 In modern solid organ transplantation, donors in general cannot be matched by gender, because there are not sufficient donors available, but gender differences in graft and recipient outcomes are still important. This review will highlight gender differences in diseases that lead to transplantation, gender differences in patterns of living donation of solid organs, access to organ transplantation, as well as outcomes of transplantation in multiple organ systems. Data are best for kidney and liver transplantation, the most common solid organ transplants. Other gender issues, including pain management and pharmacokinetic differences, also have implications for transplant patients. These issues are discussed elsewhere in this issue of Anesthesia & Analgesia.
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PREGNANCY AND ALLOIMMUNITY
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The ultimate natural immunologic stress is pregnancy, and women may develop blood group antibodies as a consequence of the immunologic reaction to the paternal antigens in the fetus. Half of pregnancies result in development of anti-human leukocyte antigen (HLA) antibodies.3 The incidence of clinically significant alloantibodies is more frequent in women than in men, and the degree of sensitization to red cell antigens increases with increasing number of pregnancies.4 Some of these sensitizations may be difficult to detect, but can still result in increased alloreactivity to a kidney graft.5 For any transplant recipient who may require perioperative transfusion, alloantibodies developed during pregnancies can complicate cross-matching.
Pregnancy after solid organ transplantation should be managed by a specialty team. The tolerance of the fetus by the mother involves elaborate changes in the immune system6 that may negatively impact immune suppression directed at tolerance to a graft. In general, after both kidney and liver transplantation, deterioration in renal function is the most common complication of pregnancy, and prepregnancy renal function is the major determinant of renal function during the pregnancy,7 but chronic hypertension is also a significant problem.8 Immunosuppression regimens can be complicated by fetal metabolism of drugs and renal dysfunction during pregnancy, among other factors, and so drug levels must be carefully monitored.
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ORGAN DONATION
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The United Network of Organ Sharing lists 97,000 patients on waiting lists for solid organ transplantation in the United States. Overall, for the period 2001–2005, 58% of patients on waiting lists were male.9 These lists continue to grow and a major medical challenge to transplant centers is optimal donor organ use, balancing the needs of individual patients with the needs of the community of all waiting recipients. Living donation was an increasing source of donor organs until 2004, when the numbers of living donors started to decrease. (In 2005, 6895 living donors were recovered versus 7003 in 2004, according to the USTransplant.org.)9 For living kidney donors, despite these recent decreases in overall donor numbers, women have consistently given more of these organs than men. In 2005, 59.2% of living kidney donors in the United States were women. In contrast, 58.2% of all kidney recipients in the United States were men. A similar predominance of female kidney donors is also the pattern outside the United States, including Brazil.10 Globally, it is estimated that 65% of all living kidney donors are female and 65% of all kidney recipients are male. Reported gender disparity in spousal donations can be very striking. A study from Canada suggested that 36% of wives who were adequate donors for their husbands were willing to be donors whereas only 6.5% of suitable husband donors volunteered their kidneys.11 Another study from the University of Michigan showed that female spousal donors are 69% of these pairs, and that male-to-male living unrelated donation is significantly more common than male-to-female living unrelated kidney donation.12 In general, women are felt to offer kidneys more often than men because of a greater sense of duty to relieve suffering and an inability to resist subtle pressures,13 but these issues are difficult to quantify. Nonetheless, given the cultural pressures on women to donate (especially in parts of the world where the family elder exerts enormous influence), the role of the physician in enforcing truly voluntary donation is essential.14
Unfortunately, gender selection bias on the part of health care workers may contribute to the disparity in access to kidney transplantation. A large study from the Southeastern part of the United States suggested that women were less likely to be perceived as candidates for renal transplantation compared with male patients, independent of medical factors.15 It is important to be aware of these studies so that gender bias can be openly discussed, and becomes part of the education of transplant physicians and other personnel.
For living liver segment donors, recently women have also predominated in living donation: In 2005, 58.3% of liver donors in the United States were women and 58% of the recipients of living liver segments were male,9 similar to the higher rates of liver disease in men in the United States, and higher rates of men as recipients of livers from brain-dead donors.
The number of donor cells is an important factor in marrow (hematopoietic stem cell) transplantation. Brain-dead donors can contribute marrow as well as solid organs for transplant. A study from the University of Washington showed that fewer nucleated cells are recovered from donor vertebral bodies in female than in male donors.16 Cell number is important in islet transplantation as well, but gender has not proven to be a significant factor in the islet yield from brain-dead donors.17
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DONATION OF CARE
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The most skewed organ recipient population by gender is the cardiac transplant recipient. Of the more than 2000 heart transplants performed in the United States each year, most recipients are men. In 1996, 81.2% of recipients in the United States were men and this percentage has steadily decreased, but only to 76.8% of recipients in 2005.9 In the earlier decades of heart transplantation, considerable literature suggested that women had delayed diagnosis of cardiovascular disease, but as diagnostics have improved in women, the male predominance in heart transplant recipients has not changed in tandem. Young men are more likely to be affected by coronary artery disease than young women, and between age 55 and 64 years, men are twice as likely to have congestive heart failure than women. However, with age, the difference becomes smaller, and after age 65, men and women are similarly impacted by coronary artery disease.18 Of heart transplant recipients in 2005, 52.3% were age 50–64 years and 10.3% were 65 years or older. These numbers raise concerns that women are disproportionately prevented from access to heart transplantation. The issue is thorny because more women than men who are offered heart transplantation decide not to accept the offer,19 so this gender skewing can be attributed to complex choices made by women themselves, and not imposed on them. On the other hand, female gender is considered to be a risk factor for mortality after heart transplantation, and feminist thinkers have raised concerns that heart transplant surgeons, worried about outcome statistics, may be motivated to selectively approve men candidates. The concern raised is that the way treatment options are presented to women and men may be different, and that the presentation may discourage women from accepting the option of heart transplantation.20 The numbers suggest that the reasons for women receiving less heart transplantation deserve more study and are likely to be multifactorial, including insurance and financial considerations as well as other familial obligations and other psychosocial issues. Furthermore, health care providers should recognize that the majority of caretakers of heart transplant patients are women, and all caretakers assume a large, under-recognized burden.
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POST-TRANSPLANT BONE DISEASE
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Post-transplant osteoporosis is a major complication of all solid organ transplants and immunosuppression. The risk of osteoporosis after kidney transplantation is higher in women than in men, prompting investigators to recommend that prophylaxis against bone loss should be started as soon as possible after renal transplantation, even in patients with normal bone density before transplantation.21 For patients with cholestatic autoimmune disease such as primary biliary cirrhosis (PBC), bone loss can be a devastating and painful complication of the disease, and usually worsens in the first year after liver transplantation. For patients with PBC, physicians should have a low threshold for initiating therapy with calcium, vitamin D, and biphosphonates.22 Accelerated bone loss is also a major problem after cardiac transplantation (and most cardiac transplant patients are men). In heart transplant recipients, low testosterone levels are a risk factor for rapid bone loss, leading to recommendations that hypogonadal patients should receive testosterone or estrogen therapy as appropriate as part of their bone protection regimen.23 After bone marrow transplantation, the risk of avascular osteonecrosis with steroid treatment is higher in female than in male recipients, and female donors also predispose to this side effect.24
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KIDNEY TRANSPLANTATION
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Men in general are more likely to develop renal disease than women.25 Furthermore, a meta-analysis suggested that men have more rapidly progressive renal disease in general than women. The increased mortality of men on dialysis versus women has been documented in multiple studies, and may be related in part to the generally better creatinine clearance in elderly women at baseline compared with elderly men.26 Several groups have suggested that the biologic basis of this difference in outcome may be due to estradiol-mediated suppression of mesangial cell proliferation.27 Many complex, hormonal differences may contribute to more rapid progression of renal disease in men, as males may generally have higher intraglomerular pressures than females, increased reactivity to angiotensin, as well as effects of sex hormones on cytokine levels, growth factors, and oxidant status.25 Although several reports suggest that women with renal failure (predialysis) have less cardiovascular morbidity than do men,28 after transplantation, cardiovascular mortality in men and women is fairly similar.29
Several small studies suggested that male renal allografts may function better over time than grafts from female donors.30–32 A review and analysis of the large Collaborative Transplant Study (124,911 kidney transplants) showed that both patient and renal allograft survival are worse with a female donor. In primary kidney transplants, actuarial survival in female recipients of male donors was 48.4 ± 0.4 yr vs 46.9 ± 0.6 yr for female donors (P = 0.0020). In male recipients, actuarial survival was 46.5 ± 0.3 yr for male donors versus 42.1 ± 0.5 yr for female donors (P < 0.0001).33 Renal function was significantly improved in recipients of male donors in this large cohort at 1 and 10 years after transplantation, and recipients of male kidneys were less likely to require antirejection therapies beyond their baseline immunosuppression.33 Other reviews of the literature have suggested that female kidney recipients are more likely to have acute rejection episodes, perhaps related to sensitization after pregnancy, but are less likely to develop chronic graft rejection.7
Since male kidneys are assumed to have more nephrons than female kidneys, a reasonable assumption about the relative benefit of a male donor is simply that male kidneys have greater nephron number or mass, but clear experimental support for this explanation of "nephron under-dosing" with female donor grafts is lacking. Many other factors are likely to play a role in the difference between male and female donors. In addition to complex effects of androgens and estrogens on the function of many cell types, there is increasing evidence that immunologic differences between men and women may contribute to poorer renal graft outcome with female donors. That immunologic and hormonal differences between males and females are important in renal graft survival is suggested by analysis of transplants between HLA identical siblings, in which long-term graft survival is superior in male donors.33 But gender is not considered a significant enough issue to reconsider the way kidneys are allocated, because of the constraints of chronic shortage of donor organs and because of the more significant effects of other donor factors including age. The ultimate hormonal challenge to a graft, the hormone surge of pregnancy, was studied in a small group of kidney transplant recipients (22 pregnancies). In this study, there was no clinically significant difference in renal function of a male versus female allograft during pregnancy.34
Specific complications after kidney transplantation and immunosuppression have also been investigated for gender bias. Female kidney transplant patients are at greater risk of serious bacterial infection requiring hospitalization than males, and vascular access infections and urinary tract infections are the most common types.35 A review of records from 89,260 kidney transplant recipients confirmed an increased risk of lymphoma in these patients overall, but no affect of gender on its incidence.36
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LIVER TRANSPLANTATION
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Depending on how data are analyzed, liver disease is the 8th or 10th most common cause of death in the United States.37 In general, men have more liver disease than women. In 2005, for example, only 40.3% of the patients placed on liver transplant waiting lists were female. Because of long latency to disease manifestation the incidence of chronic liver diseases is difficult to define.37 About 2.7 million Americans have chronic hepatitis C virus (HCV) infections, making this disease the most common blood-borne infection in this country,38 and HCV affects men more than women (7:3 ratio). The reason why men are more commonly affected by liver disease than are women, then, is mostly due to the epidemiology of HCV infection.37 Consequently, more men than women undergo liver transplantation in the United States. Studies in Egypt,39 where HCV infection rates are extremely high, and in Japan40 suggest that women may spontaneously clear HCV after infection better than men. Patients who clear virus are anti-HCV positive but do not have detectable viral RNA by polymerase chain reaction studies.
Alcoholic liver disease and nonalcoholic fatty liver disease (NAFLD) are the next most common liver diseases in the United States.37 With alcohol-related liver disease, men have a significantly higher mortality rate than women.37 NAFLD can be mild or result in hepatitis (steatohepatitis) and can lead to fibrosis and end-stage liver disease requiring transplantation. Despite an initial impression that women had more NAFLD than men (an impression formed from the bariatric surgery population which has a female predominance), several studies from around the world suggest that men have more NAFLD than women.41
Biliary atresia is more common in girls than in boys,42 and is by far the most common indication for liver transplantation in children.
Less common liver diseases show striking gender skewing. PBC is at least six times more common in women than in men, whereas another cholestatic autoimmune disease, primary sclerosing cholangitis, is more common in men than in women. The reason for gender preponderance in these autoimmune liver diseases is not known. The particular treatment issues related to these diseases, then, are not gender-specific so much as disease-specific. Pruritis can be a devastating, truly painful symptom of cholestatic diseases and is often poorly treated. Major reviews of the disease cite antihistamines, bile salt sequestration agents (cholestyramine, colestipol, rifampin, marinol,43 and plasmapheresis44) as possible ways to alleviate itching. Some success has been reported with opiate antagonist therapy,45 and very low doses of mixed agonist-antagonist opioids can be very useful in these patients as well.46
Primary sclerosing cholangitis is often associated with ulcerative colitis, and patients with the two diseases are probably at higher risk of colorectal carcinoma than patients with ulcerative colitis alone.47 Among the even more unusual liver diseases, men with hereditary hemochromatosis are more likely to progress to cirrhosis than are women.48
Autoimmune hepatitis is more common in women than in men, and unlike PBC, specific diagnostic markers have not been identified. Furthermore, retrospective observations of HLA matching in liver transplantation suggest that HLA matching correlates with graft survival in autoimmune hepatitis patients (although it is not as important in other forms of cirrhosis).49 Although liver transplant teams do not generally use HLA to match donors to recipients, these data suggest that some matching may benefit women liver transplant recipients with an underlying diagnosis of autoimmune hepatitis.
Graft versus host disease is relatively rare in liver transplant recipients, but a recent review of the literature combined with the University of Washington experience suggests that recipients with autoimmune hepatitis are at most risk of this complication.50 Since autoimmune hepatitis is a diagnosis predominantly of women, graft versus host disease is more likely to appear in women after transplantation, and further analysis of other donor factors that contribute to this complication seem warranted.
Analysis of the Collaborative Transplant Study database did not demonstrate any effect of donor gender on hepatic graft survival overall. However, when the North American data were separated from the Western European data, recipients of female donor livers in North America had significantly lower actuarial survival than recipients of male livers.33 Older large-scale analyses (about 1000 patients) also suggested a graft survival advantage for male donors, and better graft survival in gender-matched transplants in general.51
Gender mismatch in liver transplantation also increases the likelihood of graft failure, with female donor-male recipients at greatest risk52; but it is important to note that gender alone is not considered a major risk for graft failure, which always has complicated underpinnings. Donor gender and mismatch are not contributing factors in chronic rejection in pediatric liver transplant recipients.53
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CARDIAC AND LUNG TRANSPLANTATION
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Gender mismatching of organs appears to negatively affect heart transplant outcome as well as liver transplant outcome. The Collaborative Transplant Study database analysis included 25,432 cardiac transplants. In this large cohort, male recipients had lower actuarial survival if they received female donations. There was not a donor gender effect in female cardiac transplant recipients.33 Women are more often listed for lung transplant than are men, with 59.7% of lung transplants in 2005 performed on women.
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MARROW (HEMATOPOIETIC STEM CELL) TRANSPLANTATION
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Access to stem cell transplantation for females has not been plagued by the access issues for females associated with solid organ transplantation, and there is no significant bias towards males in stem cell transplant allocation.54 Male gender of the marrow donor has a positive impact on long-term survival after bone marrow transplantation.55,56 The specific diagnosis leading to marrow transplantation is also important in evaluating outcomes based on gender. For example, multiple myeloma patients who receive female donor cells generally have better outcome than patients who received male cells, and the pairing of female donor and female recipient has the best outcome for this diagnosis.57 Females appear to be at greater risk of thrombotic thrombocytopenic purpura after bone marrow transplantation compared with male recipients,58 in addition to the severe complication of thrombotic microangiopathy.59
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STEM CELL TRANSPLANTATION
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Stem cells transplants are the subject of intense studies in animal models and in clinical trials. Study of homogeneous stem cell populations may help identify gender differences in cell types that are difficult to dissect in whole organ transplant studies, where the whole organ contains many cell types that can elicit distinct immunologic responses. One of the first clinical trials of nonmarrow stem cells to correct an inherited disease was the use of myoblasts (skeletal muscle progenitor cells) to treat Duchenne muscular dystrophy, a disease that affects mostly boys. The trials used pooled myoblasts from several donors injected into multiple sites of diseased muscle. The transplanted myoblasts did not significantly improve muscle function, in part, because the immunogenicity of the cells was under-estimated.60 Recent work in mouse models suggest that female muscle stem cell donors may be better at regenerating new muscle than male stem cells in the mouse model of muscular dystrophy.61 In this work, using a muscle-derived stem cell population distinct from myoblasts, the increased regenerative capacity of female stem cells was not related simply to estradiol stimulation, and was accompanied by increased resistance to oxidative stress.
Mesenchymal stem cell transplants are being studied clinically for a variety of diseases, including myocardial infarction. Some animal work is emerging to suggest that male and female mesenchymal stem cells may be very different. Female murine mesenchymal stem cells, like muscle-derived stem cells, survive hypoxia better than do male cells. In response to lipopolysaccharide, the female mesenchymal stem cells express less of the proinflammatory cytokine, tumor necrosis factor-
, but more vascular endothelial growth factor.62 For the stem cell transplant recipient, this secretory pattern of the female mesenchymal stem cells appears advantageous compared with the male pattern. In human studies, endothelial progenitor cells from females are apparently more potent than male cells, using colony forming capacity and migration as end-points.63
The immunogenicity of various stem cells is a subject of much concern, as stem cell transplants are contemplated for treating a variety of disease processes. A recent review reminds researchers that stem cell populations derived from parous women may be chimeric, containing remnant cells from previous fetuses carried by the donor.64 This chimerism may be one reason why female donors have generally been less favorable than male donors when all organ transplants are considered, but the possible chimerism has not been acknowledged in clinical outcome studies.64
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SUMMARY
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Gender affects transplantation at multiple levels. The interplay of psychosocial and cultural pressures on women and subtle differences in perception of women as transplant candidates by transplant teams appear to limit the full use of transplant treatment options for women. Similar issues contribute to the over-representation of women among living donors. Many immunologic differences between men and women contribute to poorer outcome in mixed-gender transplants, and sensitization of women during pregnancy can complicate blood cross-matching. Many diseases leading to transplantation display gender skewing, and thus complications related to these diseases are also gender-biased. This review is a reminder that attention to disease detail, including gender distribution, is a critical factor in designing therapies and reviewing outcomes after transplantation.
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Footnotes
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Accepted for publication November 19, 2007.
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Abstract
Introduction
