Journal Logo

Reviews

Equally Interchangeable? How Sex and Gender Affect Transplantation

Melk, Anette MD, PhD1; Babitsch, Birgit PhD, MPH2; Borchert-Mörlins, Bianca MD1; Claas, Frans PhD3; Dipchand, Anne I. MD4; Eifert, Sandra MD5; Eiz-Vesper, Britta PhD6; Epping, Jelena PhD7; Falk, Christine S. PhD8; Foster, Bethany MD9,10; Geyer, Siegfried PhD7; Gjertson, David PhD11; Greer, Mark MD12; Haubitz, Marion MD13; Lau, Ashley MD14; Maecker-Kolhoff, Britta MD15; Memaran, Nima MD1; Messner, Hans A. MD, PhD16,†; Ostendorf, Karen1; Samuel, Undine MD17; Schmidt, Bernhard M.W. MD18; Tullius, Stefan G. MD19; West, Lori MD, PhD20; Wong, Germaine PhD21,22; Zimmermann, Tanja PhD23; Berenguer, Marina MD24

Author Information
doi: 10.1097/TP.0000000000002655
  • Free

Abstract

INTRODUCTION

In this review, we highlight sex- and gender-specific issues in transplantation as relevant but potentially underrecognized factors influencing patient and transplant outcomes. The review is based on an interactive workshop held in March 2018 in Hannover, Germany. As potential differences between women and men may occur at different levels, including (1) access to a transplantation waiting list; (2) access to transplantation once waitlisted; and (3) outcome after transplantation, we provide the epidemiological findings on access and outcome in solid organ and hematopoietic stem cell transplantation (HSCT) and evaluate the evidence with regard to underlying and causative factors for potential disparities. In addition, we discuss how to implement sex/gender in basic and clinical research proposals and how to translate generated evidence into guidelines and policies.

There is an important difference between sex and gender. Sex is the biological attribute that includes anatomical, endocrine, or genetic traits, whereas gender encompasses social, cultural, and psychological identities and behaviors. Every cell has a sex; individuals generally have one gender (except for gender-diverse persons). Throughout this review, we take a sex- and gender-based perspective, being aware that many times, we may discuss sex rather than gender due to very limited data on gender. This comprehensive overview of the current evidence also intends to dispel existing myths on sex- and gender-specific questions in transplantation. Finally, we will identify areas where more basic and/or clinical research is needed.

ORGAN DONATION

Women are more likely to be living donors than men.1-4 This disparity was seen in parental as well as marital relationships and might be explained by a higher level of empathy in women3 or because of economic factors, the father or husband being the family’s provider.2 Although more deceased donors are male than female,5 women show more willingness to become deceased donors.6,7 The predominance of young male deceased donors likely reflects the higher rates of traumatic death among young males.6,8 Female deceased donors tend to be older, and the most common cause of death are cerebrovascular accidents. The sex imbalances among donors and recipients result in women giving more often than receiving, as will be further discussed below.

SEX DISPARITIES IN ACCESS TO TRANSPLANTATION AND OUTCOME OF TRANSPLANTATION

Access to transplantation can be broken down into (1) access to living donation, (2) access to the deceased donor waiting list, and (3) access to receiving a transplant.

The absolute numbers of patients on the waiting lists for kidney (KT), liver (LiT), heart (HT), and lung (LuT) transplantation show sex imbalances (Figure 1A and B). In the United Network for Organ Sharing (UNOS) and the Eurotransplant (ET) database, there are fewer women than men on the waiting list for KT (39% women in UNOS and ET) and LiT (39% in UNOS, 38% for ET). The waiting list for HT shows an even stronger male preponderance (only 26% of waiting patients are females in UNOS and only 18% in ET). The opposite is true in LuT, where more women than men are waiting for an LuT (60% in UNOS and 58% in ET). As will be elaborated in the following sections, a major reason for these imbalances is most likely the different prevalence of underlying diseases leading to terminal organ failure, but other factors may also contribute. Figure 2 summarizes sex- and gender-dependent factors that may influence patients’ likelihood of waitlisting, transplantation, and eventually transplant outcome.

FIGURE 1.
FIGURE 1.:
Sex distribution of kidney, liver, heart, andlung patients in percentages, with the total number of patients given below the respective chart. A, Sex distribution at transplantation. B, Sex distribution on the waiting list. Data is derived from United Network for Organ Sharing (UNOS), Eurotransplant and the respective registries for the indicated time periods. aModified from data from a Kaplan-Meier survival analysis of European Liver Transplant Registry (ELTR) data, personal communication (M.B.). bData from the International Society of Heart and Lung Transplantation (ISHLT) registry.184 Organ sketches were hand-drawn and generously provided by N.M.
FIGURE 2.
FIGURE 2.:
Sex- and gender-dependent factors that influence patients’ likelihood of waitlisting, transplantation, and eventually transplant outcome. MELD, Model for End-Stage Liver Disease.

KIDNEY TRANSPLANTATION

KT is the most common transplantation. From 1988 to 2017, 426 842 patients received a kidney allocated by UNOS, and from 2008 to 2017, 34 100 kidneys were transplanted within the ET system (Figure 1A). Sixty percent of transplanted patients in UNOS and 62% of transplanted patients in ET were males. At present, 103 156 patients are waitlisted in UNOS and 11 105 in ET (61% males in each system; Figure 1B).

Sex- and gender-based disparities were already reported in the late 1980s, showing women to have lower access to KT.9,10 While some studies showed disparities in waitlisting as well as in transplantation rates,11 more recent studies reported disparities mainly in waitlisting after adjustment for confounders, including the panel-reactive antibody (PRA) status, comorbidities, and underlying disease. Several available studies highlight a preponderance of males entering the waiting list for KT.12-16 However, a male preponderance on the waitlist does not necessarily imply a disparity. No high-quality studies have compared waitlist access between transplant-eligible men and women with end-stage renal disease (ESRD). Sex differences in transplant eligibility may exist due to differences in primary disease or comorbidities. There are also more men than women with ESRD. Studies are needed to assess whether men and women have equal access to deceased donor KT. Most prior studies on this topic were performed in the context of the US healthcare system, leading the authors to conclude that socioeconomic factors may have explained the observed differences.17,18 This economic explanation of sex differences was challenged by European studies with more universal coverage, for example from France, where sex differences were also reported for waitlisting.16 More recent studies from the United Kingdom were not uniform19-21 with two studies reporting a lack of sex disparities in waitlisting. A potential reason might be that both studies had either only included a minority of patients ≥65 years of age or completely excluded them. It is important to note though that sex disparities do occur in children22 as well, and it has been shown that girls have poorer access to pre-emptive transplantation when compared with boys.22

Potential reasons for reduced or delayed access to transplantation for women versus men have been described for all steps of the transplantation process,23 including a lower probability of discussing transplantation as a treatment option with women,24 fewer women completing the clinical workup needed for transplantation,25 and sex discrimination in waitlisting.11 Physicians may assess a woman’s health differently.26 Furthermore, women more often have health-related and psychosocial concerns about transplantation27 and have more personal concerns in asking for potential living-related donation.27 Finally, medical reasons such as the presence of PRA or active autoimmune diseases, which are more prevalent in women, may also impede transplantation for women.28,29 This has been recently demonstrated in a single-center US study showing that despite equal referral of women and men for living-donor transplantation, men were more likely to receive a living-donor transplant than women.30 This was due primarily to a high prevalence of pregnancy-related sensitization of women making them incompatible with spouse or child potential living donors. Factors that have been shown to modify the effect of sex on access to transplantation are age, comorbidities, race, and body mass index. In data from the US Renal Data System (USRDS) and UNOS, access to KT was similar in men and women <45 years but lower in older women than men, particularly in those >65 years.31 Interestingly, the presence of the same comorbidities was associated with lesser access to KT in women than in men.31 In another analysis using USRDS data, a body mass index >25 kg/m2 was associated with a reduced access to KT in women, whereas a body mass index between 25 and 35 kg/m2 in men facilitated access.32

Race is also strongly associated with access to KT, as shown in several studies from the United States33-35 and Australia.36 There are few data on how race influences sex disparity. In a study using data from the Canadian Organ Replacement Register, the negative impact of female sex was weaker among Caucasians and persons of Eastern-Asian origin and stronger among African Canadians, persons of Asian Indian origin, and Inuits.17 In a small, single-center study, the completion of the pretransplant workup was faster in men than in women in White and Hispanic patients, but not in African Americans.25 An analysis of Scientific Registry of Transplant Recipients (SRTR) data focusing on living-donor KT showed that recipients of living donors are more likely to be male. Different access to a living-donor KT depended also on the recipient’s race/ethnicity. White patients had the highest probability, followed by Hispanics, Asians, and Blacks. The race disparities in access to living-donor KT increased from 1995–1999 to 2010–2014.4 When interpreting these data, it has to be kept in mind that race is difficult to define and definitions are not uniform. In addition, race (which refers to biological traits, such as skin and hair color) is sometimes confused with ethnicity (which refers to nonbiological factors such as culture, language, country of residence, or parental origin) and is even harder to define.

Most studies showed poorer KT outcomes in women than men,37-39 although similar outcomes have also been reported.40,41 In particular, pediatric studies show poorer graft survival in girls than in boys.42 In addition, girls showed smaller improvements in graft survival than in boys between 1987 and 2012.43 It is important to look at the source of these discrepancies. One recent study elucidated, at least in part, the complex relationship between sex and KT survival by examining interactions between recipient sex, donor sex, and recipient age.44 In survival models adjusted for race, primary cause of ESRD, duration of pretransplant dialysis, donor age, donor weight, recipient weight, and PRA, the authors showed that in the setting of a male donor, female recipients of all ages have significantly higher rates of graft failure than males. The largest differences were observed in children and the smallest differences among adults >45 years. When the donor was female, only adolescent girls and young adult women (15–24 y) had higher rates of graft failure than boys and young men of the same age. In fact, in the setting of a female donor, female recipients >45 years had lower graft failure rates than men of the same age (Table 1).44 This unique and detailed analysis might explain the discrepancies between earlier studies that had not taken into account the effect of age. The authors hypothesized that several factors may have contributed to these observations, including an immune reaction of female recipients to the HY antigen (present on all male tissues), an immune-stimulating effect of estrogen and an immune-suppressing effect of testosterone. They also suggested that better medication adherence in women than men45-47 may also play a role in the observed differences. Table 2 summarizes all available studies investigating the importance of sex on KT outcome.

TABLE 1.
TABLE 1.:
Comparison of graft outcome by recipient sex in kidney transplantation, stratified on donor sex (44)
TABLE 2.
TABLE 2.:
Effect of donor and/or recipient sex on outcome

LIVER TRANSPLANTATION

The liver is the second most common type of transplanted organ. A total of 156 587 (63% male recipients) procedures were performed in the UNOS system between 1988 and 2017, and 16 568 (66% male recipients) transplantations in ET (Figure 1A). Most recent data show that 14 198 patients (61% male) are waitlisted for LiT at UNOS and 1714 patients (62% male) at ET (Figure 1B).

Poorer access to LiT for women than men might be explained by different analytical approaches or different national contexts and has two facets, biological and sociocultural.48,49 Because the demand for organs has always exceeded the supply, the transplant community has long recognized the need to ensure that the organ allocation system is equitable. To establish an equitable LiT allocation process, the Model for End-Stage Liver Disease (MELD) score was adopted in 2002. The MELD score is based on 3 objectives and readily available variables (bilirubin, international normalized ratio, and creatinine) and accurately predicts short-term mortality in the cirrhotic population on the LiT waiting list.50 Compared with the Child-Pugh score and time spent on the waiting list, which were the main criteria for liver allocation in the past, the MELD score was conceived in an effort to improve transparency, objectivity, and equity.

Since the introduction of MELD, reductions in the number of patients listed for transplantation, deaths on the waiting list and median waiting time have been reported. Unfortunately, not all disparities in access to LiT were solved with the prioritization of patients with the highest MELD score. While racial disparities appear to have been resolved post-MELD, sex disparities persist; women are less likely to receive a transplant than men.48,49,51,52 Of all the LiT done in the United States, only 30% of the recipients were women.48

The smaller proportion of women than men on the LiT waiting list is mostly explained by the lower prevalence of chronic liver disease in women, particularly viral-related cirrhosis and hepatocellular carcinoma, the two most common indications for LiT in most transplant centers.49,53 Importantly, with the introduction of highly efficacious direct-acting antiviral agents against both hepatitis B virus and hepatitis C virus (HCV) and with the substantial increase in nonalcoholic liver disease as an indication for LiT, it is expected that a greater proportion of individuals with liver failure will be women in the near future. Indeed, a recent study based on the SRTR database from 2003 to 2015 showed a 32% decrease in the proportion of patients on the LiT waiting list for decompensated cirrhosis secondary to HCV in the era of direct-acting antiviral therapy as compared with the interferon era. The rate of decompensated cirrhosis secondary to HCV is now equal to that of nonalcoholic steatohepatitis.54 In addition, a meta-analysis of studies evaluating LiT for nonalcoholic steatohepatitis-related cirrhosis demonstrated that candidates were more frequently women.55 Interestingly, one study showed that in the MELD era, women had greater access to the waiting list compared with men.56 Whether a delay in referring men to transplant centers or termination of the evaluation process due to medical, surgical, or psychosocial reasons could account for a proportion of the observed differences could not be evaluated in that study. However, few well-designed studies compared access to the LiT waiting list by sex.

Most prior studies compared access to LiT among patients on the waiting list. Women appear to be disadvantaged at each step following registration on the LiT waitlist. Women have a higher likelihood of death on the waiting list and of being removed from the list due to an illness precluding LiT and a lower likelihood of receiving a liver graft than men.48,49,51,52 An SRTR study of 78 998 adult candidates listed before (August 1997 to February 2002) or after (February 2002 to February 2007) implementation of MELD-based liver allocation compared transplant rates between men and women. After adjusting for several patient-level factors and stratifying by the MELD score, women had lower transplant rates than men in both eras, with a 9% deficit in the pre-MELD era and a 14% deficit in the MELD era.51 In the MELD era, the disparity in transplant rate for women increased as waiting list mortality risk increased, particularly for MELD scores ≥15. In another large study, women experienced approximately 30% higher odds of death or becoming too sick for LiT compared with men after the introduction of the MELD allocation system.52 Finally, in a third study, delisting was more frequent in women (11% versus 9%; P < 0.001).57 A competing risk analysis demonstrated that female sex was independently associated with a 10% (95% confidence interval [CI], 2%-18%) higher risk of delisting when accounting for rates of death and transplantation and adjusting for confounders.

Several hypotheses have been proposed to explain sex differences in access to LiT, including limitations in MELD calculation and donor-recipient size mismatch. Many studies have clearly shown that women are systematically disadvantaged by the MELD score, because it includes creatinine rather than the glomerular filtration rate resulting in an underestimation of renal dysfunction in women.58-61 Creatinine concentration is influenced by factors unrelated to renal function—most importantly total muscle mass. As a result, individuals with the same renal function but of different age, race, or sex may have different creatinine levels. Thus, women have lower MELD scores than men despite the same degree of renal dysfunction.58-60 Unfortunately, including glomerular filtration rate in the MELD score rather than creatinine did not improve prediction of mortality in the entire study population.60 In 1 study, the utilization of a “corrected” MELD score was proposed to account for the discrepancy in renal function assessment. Correction of the MELD score resulted in a 2–3 MELD point increase in 65% of female LiT candidates.58 Of note, 75% of female LiT candidates with MELD >19 had a 3-point difference between uncorrected and “corrected” MELD. In addition, women typically have a smaller stature compared with men, resulting in a more limited donor pool. Women may have to wait longer for an appropriately sized donor and may have higher rates of offer refusal due to size discrepancy.62-64 In a recent large study (n = 90 720 from the Organ Procurement and Transplantation Network [OPTN] registry), women had higher mortality than men (4 y after listing: 22% versus 18%; P < 0.0001) and lower likelihood of LiT (49% versus 58%; P < 0.0001). Overall, women were 20% less likely to be transplanted, with differences in height and MELD exception scores accounting for most of the LiT deficit in women. Women received between 1 and 2.4 fewer creatinine-derived MELD points than men with similar renal dysfunction. Unfortunately, MELD-Na worsened the sex disparity. Addition of 1 or 2 MELD points to women significantly impacted LiT access.65 Interestingly, one study suggested that even after accounting for the contributions of lower MELD scores and estimated liver volume and liver weight to sex differences in LiT rates, at least half of the sex disparity still remained unexplained.63

Most studies have shown similar outcomes post-LiT for men and women. However, similar to KT, interactions between donor sex, recipient sex, and recipient age may influence outcome. Male recipients of female grafts were shown to have shorter graft survival than male recipients of male grafts in several studies.66-71 With living donation, similar findings were reported, with female to male LiT having the lowest graft and patient survival and female to female LiT the highest.72 A recent study of male recipients of living-donor LiT showed higher 5-year post-LiT failure rates when female grafts with donor age ≤36 years were used, but not if donor age was >36 years (hazard ratio [HR], 3.57; 95% CI, 1.81-6.99; P < 0.001). After adjusting for anastomosis-related factors, the effect persisted (HR 2.30; 95% CI, 1.14-4.67; P = 0.021). Moreover, the effect was observed in pediatric recipients as well (HR 4.05; 95% CI, 1.09-14.96; P = 0.036), again suggesting that it is not a size- but sex-related phenomenon.71 However, other studies did not reach the same conclusions when correcting for parameters of donor and recipient quality,73,74 suggesting this effect to be the summative effect of female donor organs having inferior outcomes, and female recipients superior outcomes. Interestingly, a study from the Collaborative Transplant Study database found poorer graft survival in male recipients of female donors in North American centers only, but not in Europe.75 All available studies on outcome are listed in Table 2.

In children, the few available studies on the influence of sex on the outcome show conflicting results, reporting either a negative impact of female donor sex71,76 or no difference.77 Regarding complications and comorbidities, in an analysis of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) liver transplant database, girls were more likely to develop surgical site infections (odds ratio 7.77; P = 0.038)78 and have higher cognitive function scores in a detailed functional outcome analysis from Studies in Pediatric Liver Transplantation (SPLIT) (odds ratio 0.45; P = 0.0031)79; boys were more likely to develop ESRD in a large SRTR-USRDS database linkage analysis (HR 1.44; P = 0.022).80

LUNG TRANSPLANTATION

LuT is recognized as a treatment option for a variety of end-stage lung diseases, with approximately 4000 adult procedures being performed worldwide annually. A total of 36 000 patients (55% male) underwent LuT in the UNOS system from 1988 to 2017; 6279 patients (53% male) in ET from 2008 to 2017 (Figure 1A). In terms of organ allocation, similar patterns of increase have been seen in men and women over the past 25 years. At present, 1416 patients (40% male) are waitlisted at UNOS, 817 patients (42% male) at ET (Figure 1B). Traditionally, tobacco-associated chronic obstructive pulmonary disease (COPD) was the leading indication for LuT in both sexes (38%) in adults. Due to improved preoperative management, demographics have changed with a disproportionate rise in transplantation rates for patients with interstitial lung disease which has recently superseded COPD as the leading indication.

In terms of graft survival, data from both the International Society of Heart Lung Transplantation (ISHLT) and ET suggest that women perform better than men, both in Europe (median 7.6 versus 6.1 y; P < 0.0001) and internationally (median 6.2 versus 5.6 y; P < 0.0001).81 Reasons for these differences are likely multifactorial but still limited by a lack of good-quality follow-up data. Acute cellular rejection rates, however, are similar in both sexes.81 Multicenter data for the leading cause of death, referred to as chronic lung allograft dysfunction, are lacking.

Moreover, the ISHLT Registry does not provide robust data regarding the cause of death in their survival analyses. Although no systematic evaluation is available, it appears conceivable that the differences in survival may be influenced by the extrapulmonary comorbidity associated with the specific end-stage lung diseases. COPD is a well-accepted risk factor for all forms of cardiovascular disease and certain forms of cancer. The higher proportion of older COPD male LuT recipients appears to have confounded current survival analyses.

Few studies have considered the impact of donor-recipient sex matching on outcomes in LuT (refer also to Table 2 for a complete list). Female donor sex was associated with poorer long-term survival than male donor sex (adjusted HR [aHR] 1.45; P = 0.02); male recipients of female LuT donors experienced the worst survival of all sex combinations in a French multicenter study.82 Similarly, the overall mortality was higher in female to male LuT recipients than male to male (aHR 1.11; 95% CI, 1.01-1.22), and lower for female-to-female than male-to-male LuT (aHR 0.93; 95% CI, 0.87-0.98), but no difference for male-to-female LuT in an analysis of ISHLT registry data.83 Interestingly, 5-year mortality conditional on 1-year survival was found to be higher in male to female LuT than male to male (relative risk 1.15; 95% CI, 1.01-1.30; P = 0.031) in a later annual ISHLT report.84 A single-center study did not find any sex-matching related effect on 30-day mortality, primary graft dysfunction, freedom from bronchiolitis obliterans syndrome, or overall survival, possibly due to smaller patient numbers.85

In a pediatric cohort, a single-center report (n = 58) found male versus female recipient sex (HR 0.37; 95% CI, 0.15-0.91; P = 0.031) and sex matching versus mismatching (HR 0.29; 95% CI, 0.11-0.74; P = 0.010) to be associated with better patient survival.86 This is in contrast to the adult data and to an older single-center report (n = 47) that did not find any effect of donor or recipient sex on mortality.87

There is no evidence of sex disparity in the allocation of LuT. Graft survival has traditionally been reported to be better among females, but the quality of data is weak. Institutional experience suggests that extrapulmonary manifestations of the underlying disease and older recipient age at the time of transplant may play a key role in explaining differences. Sex matching of donors and recipients occurs in the majority of LuT procedures, due mainly to anatomical considerations. Among sex-mismatched patients, no disadvantages with regard to chronic lung allograft dysfunction or graft survival were evident at Hannover Medical School (M. Greer, personal communication).

HEART TRANSPLANTATION

Of the 69 198 HT recipients in the UNOS system between 1988 and 2017, 75% were male (Figure 1A). This is comparable to the numbers in ET, where of the 5955 patients transplanted from 2008 to 2017, 73% were male (Figure 1A). Of the 67 855 HT registered by ISHLT between 1980 and 2009 worldwide, 20.4% (13 863) were female.8 In the United States between 2004 and 2015, 25% of patients active on the waiting list for HT were women.88 Approximately 25% of patients who died on the list were also female. However, adjustment for a variety of risk factors showed that women with UNOS status 1A and 1B (ie, the most urgent) had a higher risk for death on the waiting list than men, while women with UNOS status 2 had superior survival.88 At present, of the 4035 patients listed at UNOS, 26% are female. The percentage of female patients on the waitlist is even smaller in ET, where of the 1141 patients only 18% were female (Figure 1B).

Data from ET suggested a shorter waiting time for women (95 versus 144 days).89 This was explained by a more frequent diagnosis of New York Heart Association (NYHA) class III° and IV° in women who were therefore classified as more urgent. Regitz-Zagrosek et al89 pointed out that men were referred to the transplant center more frequently than women and were often supported by their spouse while talking to their physician. Furthermore, male physicians seem to treat women suffering from chronic heart failure less comprehensively than men, possibly leading to later listing of women; this may be an explanation for the worse outcome in sicker female patients.

Cardiac conditions and cardiovascular comorbidities are different between the sexes. Dilated cardiomyopathy was the most common underlying disease in females (61.7%) followed by ischemic heart disease (24.0%), and vice versa for men (41.1% and 48.5%, respectively).8,88 Men were more likely than women to suffer from hypertension, diabetes, and kidney disease before90 and after HT.91 Female recipients were significantly younger than males (51 versus 54 y; P < 0.0001), while female donors were significantly older than male donors (37 versus 28 y; P < 0.0001) possibly due to different causes of donor death.8 According to an analysis of the ISLHT database, 30.1% of all donors were female, while just 20.4% of the recipients were female.8

In the ISHLT registry, female HT recipients showed better long-term patient survival compared with their male counterparts (P < 0.0001).81 In contrast, an analysis of UNOS data found lower 5-year patient survival for female than male HT recipients.92 Sex matching was found to be advantageous for patient survival75,81,92 or death-censored graft survival.90 A single-center study focusing on the interaction of donor and recipient age as well as sex found inferior survival of male recipients with a graft from a female donor >45 years. Moreover, all male recipients >45 years with a graft from a female donor of any age also had inferior survival compared with male recipients of male graft. Female recipient survival was not influenced by donor age or sex.93 Microvasculopathy after HT occurred equally in men and women. However, men diagnosed with microvasculopathy developed major cardiac events more often.91 When considering sex matching, a single-center study (n = 166, 87% male) found higher rates of rejection, myocardial infarction, cardiac allograft vasculopathy, and ESRD in male recipients of a female donor, compared to male to male HT.94 In contrast, Al-Khaldi et al93 (n = 869) found no significant difference in rejection rate by donor sex. Female recipient sex was found to be a risk factor for death due to rejection in a registry study (n = 10 131) including children and adults.95

A few studies have addressed sex differences in the pediatric population. An OPTN study showed higher mortality for female than male recipients of a male donor (aHR 1.27; 95% CI, 1.12-1.44; P = 0.02; male to female versus male to male 1.38; 95% CI, 1.17-1.63; P < 0.001).96 Analysis of the Pediatric Heart Transplant Study (PHTS) database showed that among those with cardiomyopathy, females had a higher risk for graft loss during the first year post-HT than males, but no sex differences were seen among those with congenital heart disease.97 An analysis of HT recipients with up to 20 years of follow-up recorded in the SRTR showed that female recipients of a male donor had a higher risk of death or retransplant (aHR 1.18; 95% CI, 1.00-1.38) compared with male recipients of a male donor, and the poorest 20-year survival of all donor-recipient sex combinations.98

Sex-related differences in outcome have been noted in the annual ISHLT pediatric HT reports in the past predominantly related to donor/recipient sex combination with male to female consistently faring worse than male to male for many years.99-101 In accordance with the findings in the adult population, male to female HT was described as a risk factor for 5- and 10-year mortality (HR 1.35; P < 0.01 and HR 1.23; P < 0.01, respectively) when compared with male to male HT, but not for 1-year mortality.102 Previous ISHLT analyses have also found modest differences in survival with females doing worse in the 1–5-year age group at 1 year posttransplant, and females having lower survival at 10 and 15 years posttransplant.100 In 2016, the difference in survival (better for males) reached a modest statistical significance (P = 0.05) for the first time,101 though this was not born out in the most recent ISHLT report.102 Two large analyses further explored the question of all four donor-recipient sex combinations on long-term survival in pediatric heart transplant recipients96,98 with both reporting sex-matched males having the best survival and sex-mismatched females having the worst survival. Taken together, the pediatric studies had fairly consistent findings, with female recipient sex associated with a higher risk of overall mortality or graft loss; this risk appears to be exacerbated by a male donor. Table 2 lists all available studies on HT and outcome.

HEMATOPOIETIC STEM CELL TRANSPLANTATION

Several studies have evaluated the impact of recipient and donor sex on the outcome of HSCT.103-107 The initial studies of patients with chronic myeloid leukemia and multiple myeloma103,104 showed a lower relapse rate, but higher transplant-related mortality for male recipients of female allografts compared with other recipient-donor sex combinations, mainly due to an excess risk of chronic graft versus host disease (GvHD).108 Based on these observations, female donor sex was included in the European Group for Blood and Marrow Transplantation (EBMT) risk score109 and transplant physicians developed a preference for male donors.105 This is reflected in the choice of male donors from unrelated donor registries and preferred recruitment of male donors. More recently, the observation of lower relapse rates when using female donors for male recipients was re-evaluated107 for patients with acute myeloid leukemia. This combination was particularly effective in reducing the relapse rate for younger patients transplanted in the first complete remission. Hematopoietic progenitor cells110 and mesenchymal stem cells express sex hormone receptors and show increased proliferative activities when exposed to these in culture. A female environment may thus favor a higher proliferative rate of transplanted progenitor cells, although faster engraftment has so far been reported.

BIOLOGICAL FACTORS FOR DIFFERENCES IN GRAFT OUTCOMES BY DONOR SEX

The biological mechanisms that have been invoked to explain differences in transplantation outcomes by donor sex include differences in organ size,111 differences in regenerative capacity or susceptibility to ischemia/reperfusion injury112-114 and the presence of male-specific minor histocompatibility (HY) antigens.41,115,116 In KT, the number and size of nephrons are greater in male than female donors, which may also influence outcome.117,118 While some have reported higher rates of acute rejection associated with female donors,40,75 these findings require confirmation. SRTR data have limitations capturing acute rejection rates,75 and the other available study could only show the effect in KT, but not HT or LiT.40

Male and female cells show different responses to stress. Female cells tend to be more resistant to injury because they are more likely to initiate a lesser inflammatory response compared with male cells. Female cells respond to injury predominantly by activating apoptosis through caspases 9 and 3. Male cells initiate apoptosis more likely through release of apoptosis-inducing factor (AIF)- poly–adenosine diphosphate ribose peroxynitrite (PARP) ions independent of caspases.119 Sex-specific vulnerability was demonstrated in a well-defined murine KT model, revealing a higher tolerance for ischemia-reperfusion injury in female recipients, which could not be observed in estrogen receptor-deficient female mice.112

In HSCT, potential immunization during pregnancy of donors was shown to influence the risk for chronic GvHD. Grafts from parous but not nulliparous female sibling donors increased the risk of chronic GvHD in both male and female HSCT recipients.108

BIOLOGICAL FACTORS FOR DIFFERENCES IN GRAFT OUTCOMES BY RECIPIENT SEX

Pregnancy-associated sensitization has long been recognized as a risk factor for poor graft outcomes.120 Sex differences in the immune response have also been appreciated in other disease contexts,29 suggesting that sex differences in the alloimmune response may also contribute to sex differences in graft outcomes.

The molecular basis of sex differences can be categorized into genetic and hormonal aspects. Approximately 50 genes on the X chromosome have immunological functions121,122 and may be relatively overexpressed in females because of X chromosomal inactivation, the resulting mosaicism, skewing, and incomplete dosage compensation.123-125 Multiple immune cell types express hormone receptors and are likely affected by the divergent hormonal environments in males and females via effects on signaling cascades and direct transcriptional consequences.

In general, females produce more vigorous cellular and humoral immune reactions than males, driven in part by enhancing the effects of estrogens and suppressive effects of androgens.29,126-129 Females appear to have stronger innate immune responses that stem in part from differences in toll-like receptor expression and dendritic cell function. Higher toll-like receptor 7 levels result from biallelic expression,130 while estrogen signaling may promote expression of other toll-like receptors.131-133 Estrogen promotes maturation of dendritic cells,134 whereas progesterone has opposing effects and may be dominant when both hormones are present.135,136 In the context of transplantation, these differences could promote a more robust antigen presentation in female donor grafts, initiating stronger recipient T-cell responses that result in higher rates of graft rejection.

Sex hormones can also affect the differentiation of CD4+ T cells, with progesterone and testosterone promoting Th2 phenotypes.136-138 At lower levels, estrogen appears to promote a Th1 phenotype,139 whereas higher levels closer to pregnancy conditions may promote a Th2 phenotype.140 Regulatory T-(Treg) cell development is also influenced by hormonal signaling, with estrogen and progesterone both increasing CD4+CD25+Foxp3+ Treg levels.141,142 Antibody production and B-cell survival also appear to be promoted by estrogen signaling.143-145 Females show greater antibody responses than males, with higher basal immunoglobulin (Ig)M and IgG levels and greater vaccine response,128 suggesting a potential role for female sex hormones in stimulating and male sex hormones in inhibiting B cells.127 In vitro, estrogen stimulates polyclonal B-cell activation, and testosterone inhibits IgM and IgG production. Estrogens also inhibit apoptosis of immature B cells, promoting antibody class-switch, whereas testosterone enhances apoptosis, inhibiting antibody class-switch.146 Testosterone also suppresses B-cell lymphopoiesis, stimulates Treg expansion (resulting in immune suppression), promotes thymic involution, and may reduce thymic output of T cells.129 These differences in cellular and humoral aspects of alloimmunity linked to changes in hormonal signaling in female recipients likely promote the protolerogenic environment in pregnancy and may add to the improved graft survival outcomes observed in older postmenopausal female recipients in combination with the effects of age-associated immunosenescence.44,147

Alloimmunization is a major factor negatively affecting the graft. Pregnancy is a common and potent alloimmunizing event and naturally only concerns women.148 This leads to higher prevalence of PRA in women and was shown to be a potent contributor to sex disparity in living-donor KT, leading to more deceased donor KT and thus longer waiting time in women.30 This problem has to be addressed with special means such as paired donation,30 or ET’s Acceptable Mismatch (AM) program. The AM program prioritizes highly sensitized individuals in the allocation algorithm. To date, 408 men and 601 women have received a kidney graft through the AM program (F. Claas, personal communication), counteracting the disadvantage for women.

Pharmacokinetics and -dynamics may also be affected by recipient’s sex.149 Calcineurin inhibitors are substrates of P-glycoprotein (P-Gp) and cytochrome p450 (CYP) 3A.150 As the activity of P-Gp and CYP3A is dependent on sex, various studies have shown a more rapid clearance of cyclosporine in females.151 However, more recent studies examining patients in a steady-state situation rather than performing single-dose kinetics showed the opposite, that is, a slower clearance of cyclosporine in females152 and also found a lower gene expression of the ABCB1 gene in peripheral blood mononuclear cells, associated with lower activity of P-Gp in female KT recipients. This is likely to cause higher intracellular drug exposure.152 Accordingly, it could be shown that female sex especially in the context of certain ABCB1 gene haplotypes is associated with an increased risk of adverse events due to calcineurin inhibitors in KT recipients.153 In LuT and HT recipients also a reduced clearance of cyclosporine could be demonstrated in females.154 The discrepancies between the older and the newer studies are likely due to different settings of the pharmacokinetic examinations (single-dose kinetics versus steady-state pharmacokinetics) difficult to reconcile. The mammalian target of rapamycin inhibitors sirolimus and everolimus are also substrates of P-Gp and CYP3A. For sirolimus, a higher clearance in females has been shown,155 whereas for everolimus, there was no effect of sex.156,157

Further work remains to delineate how sex-specific immune responses influence transplantation outcomes. The role of sex chromosomes remains to be characterized in more detail, which will benefit from technological advances in sequencing and genome editing. The role of sex hormones needs further clarification, in particular regarding how hormone receptor modulators may alter immune functions. Future studies will provide insights into immunological contributions toward sex-based differences in transplantation and will likely optimize posttransplantation management for improved clinical outcomes.

SOCIAL FACTORS

Social determinants of health are key factors of health inequities in chronic disease. Nearly all diseases occur more frequently in individuals with low income, low education, and in the lower occupational ranks (eg, myocardial infarction, type 2 diabetes, stroke, lung cancer). Socioeconomic factors are of interest within the focus of this review because women still have a greater likelihood to have a lower social economic status (SES) than men in terms of occupational position and income.158 However, the negative effect of lower SES on a variety of health measures was less pronounced in women than in men across the whole SES spectrum. In other words, female health is less affected by SES than male health but varies between different cultures and countries.159,160 Data on SES and measures of transplantation outcome are limited, even more so for studies including the effect of sex and gender.

A recent meta-analysis reported strong associations between chronic kidney disease and SES.161 For chronic kidney disease, it was shown that lower SES affected the quality of therapy after renal failure, poorer access to the waiting list and to KT. In a US-based study, disparities by education were examined. The chance of patients on dialysis to be listed was about 1.8 times higher and for being transplanted twice as high in patients with higher education than in those with the lowest educational level.162 A recent Swedish study was based on the national Swedish Renal Register covering the years 2005–2013.163,164 Classifying patients by income and education revealed higher chances for waitlisting and access to transplantation for patients with higher income and education. The authors explained their findings by higher communicative competences of individuals with higher education and closer relationships between patients and physicians. Attitudes toward medical care and preferences for certain types of treatment may also play a role. Interestingly, in the multivariable models assessing the effect of education, male sex emerged as a favorable factor, whereas it was not a significant factor in the models assessing the effect of income. This points toward an interaction between sex and SES highlights that each SES component may interact differently with sex. Nonetheless, the interaction between SES and sex or gender is evident and is very likely to influence transplantation outcome but is considered in very few studies.

The effects of personal relationships on health are very complex. Marriage generally has a positive effect on most, but not all health endpoints.165 This is due to a variety of marital aspects, such as an increased likelihood for women for obtaining health insurance coverage (according to US data) or a reduction in risky behaviors on the one hand, or a more sedentary lifestyle with a tendency toward weight gain and physical inactivity on the other.165 The beneficial effect of marriage is reported to be larger for men than for women.166 Gender or sexual orientation, however, are usually not considered in studies investigating marriage or cohabitation (ie, a union between two persons involving coresidence, an intimate sexual relationship, and economic consolidation). A study using the US National Health Interview Study (n = 460 459) analyzed the role of gender, SES, sexual orientation, and relationship status on self-rated health. They found that correcting for SES abrogated advantages for same-sex cohabitors and disadvantages for different-sex cohabitors for self-reported health, resulting in comparable increased odds for self-reported poor health when compared with their married counterparts.167 Doing justice to the complexity of these intricate interrelationships, however, is beyond the scope of this review.

Medication adherence also appears to differ by gender—although this relationship is modified by age. Adherence does not appear to differ by gender in children, likely because parents take responsibility.45,168-170 However, for those >17 years, women consistently show better objectively measured adherence than men.45,168-171 Comparing self-reported adherence by gender is complicated because reporting behavior likely also differs by gender.

Studies addressing the different components of SES and their interactions with sex, gender, sexual orientation, cultures, and countries are lacking, especially with regard to transplantation. Further studies are therefore needed to allow for informed decisions in health policy and clinical practice.

LIMITATIONS OF AVAILABLE RESEARCH AND HOW TO OVERCOME THEM

As described above, sex differences in graft and patient survival have only begun to be characterized in solid organ transplantation. Prior studies examining sex differences (summarized in Table 2) were inconsistent and difficult to interpret mainly because the vast majority of studies failed to consider the potential modifying effects of recipient age and/or donor age.44 Sex differences in the immune response are expected to vary with age. Because sex hormone levels change with age, any effect of sex hormones on immune reactivity will be most evident between puberty and menopause. Not considering potential modifying effects of age on the association between graft survival and each of the recipient and donor sex may be a key reason for the conflicting findings of prior studies. The age distributions of patients included in prior studies likely influenced results, with no sex differences seen in studies of older patient cohorts, and significant sex differences in studies with younger patient cohorts.37,38,40,41,71,115

Another important reason for inconsistent findings and thereby difficult interpretations is that the primary outcome differed greatly between studies, with some studies considering death-censored graft failure, some graft failure, or death (including death with graft function), and others all-cause mortality, or even a composite of all-cause mortality and graft failure. Some of these outcomes fail to recognize that death may occur with a functioning graft and that graft failure does not inevitably lead to death. Patients may return to a bridging modality (dialysis for KT, or assist devices for HT) or undergo retransplantation. In addition, death with graft function is very common (approximately 75% of deaths in adult KT,172 similar in LiT173-175). The mechanisms underlying the association between sex and graft failure may differ from those underlying the association between sex and death with graft function; indeed, these associations may be in opposite directions. For example, women may be at higher risk of graft failure due to rejection than men but at lower risk of death with graft function. Worldwide, females in the general population have lower mortality rates than males of the same age.176 Therefore, it may be expected to find lower mortality rates among female than male transplant recipients. In fact, equal survival rates for men and women would mean a disproportionate disadvantage for women. It is not known, however, whether the excess mortality risk (ie, the risk above that of the sex- and age-matched general population) among transplant recipients differs by sex. Studies of death with a functioning graft showed higher rates for male KT recipients in an adult cohort,172 but higher rates for female recipients in a pediatric group,177 again highlighting the importance of recipient age. Sex differences in the risk of death with a functioning graft will contribute to sex differences in the overall mortality risk, particularly at older ages, when the rate of death with graft function is highest. To fully elucidate the influence of recipient and donor sex on transplant outcomes, graft survival and patient survival should be analyzed separately.178

Future research distinguishing sex differences in graft failure rates from sex differences in the excess risk of all-cause mortality and the excess risk of death with a functioning graft may help clarify conflicting findings of prior studies. Assessments of sex differences in both graft failure rates and excess mortality rates that account for the potentially modifying effects of recipient age may lead to sex-specific diagnostic and therapeutic strategies in the field of solid organ transplantation.

Furthermore, as discussed above, nonbiological gender-specific issues (including, but not limited to SES, sexual orientation, relationship status, culture, ethnicity, or nationality) are essential pillars of an individual’s life and are known to influence health. However, they are rarely considered in the context of transplantation. Their impact on outcome remains to be elucidated. In this context, it also has to be mentioned that most studies investigating transplantation outcome are based on North American data. This is in part due to many studies using registry data and the fact that many registries are (predominantly, if not entirely) North American, but it may also reflect a publication bias. As we pointed out above, factors influencing health in men and women vary in scale and significance depending on culture and country.160 We therefore strongly encourage researchers to focus on non-North American cohorts as well.

RESEARCH POLICY CONCERNING SEX AND GENDER

The vast majority of published studies are “sex and gender blind,” ignoring potentially important sex- and gender-based differences in physiology and behavior. The need for and benefits of studying the influence of both donor and recipient sex on graft outcomes have been outlined above. Changes at every step of the research process are needed to steer toward meaningful systematic incorporation of sex and gender into research.

The North American national research funding agencies have long been aware that clear guidelines on the inclusion of sex and gender considerations in research are needed. The US National Institutes of Health require all applicants to report their plans for the balance of male and female cells and animals in preclinical studies, and of male and female participants in human studies.179 Similarly, the Canadian Institutes of Health Research requires applicants to report their plans on how sex and gender considerations will be included in their design for animal and human research projects. Furthermore, as a part of the Canadian Institutes of Health Research, the Institute of Gender and Health’s mission is to foster research on the influence of sex and gender on health, but also “…to ensure that knowledge generated by our community is translated into improved policies, products, services and systems that support better health for everybody” (http://www.cihr-irsc.gc.ca/e/8673.html). Editors, reviewers, and authors also have important roles to play in ensuring appropriate consideration of sex and gender in research publications. The Sex and Gender Equity in Research guidelines were published in 2016 to provide guidance on how best to include considerations of sex and gender in manuscripts.180

International medical societies have always been instrumental in challenging the status quo and advancing worthwhile goals in their field. In the context of this review, two bodies should be mentioned: The Transplantation Society’s initiative Women in Transplantation added the goal of championing issues of sex and gender in transplantation to its mandate in 2017 (http://www.tts-wit.org). The International Liver Transplantation Society’s committee Women in Transplantation has the aim to promote the engagement of women involved in liver transplantation in all society activities, and to advocate on their behalf both within the society and in the wider transplant community (https://ilts.org/about/committees/women-in-transplantation).

CONCLUSIONS

Future studies aimed at clarifying sex differences in access to transplant, graft outcomes, and patient survival should keep in mind 3 key points: (1) The magnitude of sex differences may vary by age. The potentially modifying effect of recipient age must be considered. (2) The outcome measure must be selected wisely. Combined endpoints like “graft failure or death with functioning graft” may be misleading because the association between sex and of each component may be in opposite directions. (3) The expected sex differences in mortality rates must be taken into account. The goal of transplantation is to restore health and life expectancy to what would have been expected had the organ not failed. Given the known higher mortality rates in males than females in the general population, even equal mortality rates for male and female transplant recipients would represent poorer than expected survival in females. Finally, clinical studies of transplant outcomes using large databases are helpful in identifying disparities and should be done in different populations. However, these studies must be followed up with fundamental research addressing the mechanisms by which biological differences between males and females influence solid organ transplant outcomes.

Patients in the need of transplantation should have an equal chance to be listed for transplantation. We have discussed the evidence that currently this is not the case. Due to limited availability, transplantation cannot be provided to every patient; therefore, patients have to be prioritized based on medical need and waiting time. We recognize that a situation could arise, whereby males or females may have higher medical priority. We do not advocate for a “sex-blind” allocation procedure where donor sex is not disclosed. As highlighted, donor sex may influence graft outcome; therefore, treating physicians should be able to take this into account in their acceptance decisions. However, it must not happen that the method used to establish medical priority systematically disadvantages one sex over the other. The MELD score is a good example for a tool that systematically disadvantages women. We have shown a significant burden of disparities that are not explained by medical needs. The reasons are manifold and often difficult to depict. Some of them might be systematic, like MELD, but may also reflect a general attitude of the society. Awareness of these disparities is a critical first step, but consequent measures have to be taken to overcome them. It is therefore mandatory that not only transplant centers implement processes to rectify sex disparities but also the whole transplantation community has to support further research on underlying causes and mechanisms, to develop policies ensuring equitable access to transplantation and to disseminate available information on inequities and ways to combat them.

ACKNOWLEDGMENTS

We dedicate this work to Dr. Hans August Messner, who worked on the manuscript just weeks before his passing. We are grateful for his guidance and help, which he provided for many years, and will dearly miss his advice, friendship, and humanity, which he so generously shared.

REFERENCES

1. Puoti F, Ricci A, Nanni-Costa A, et al. Organ transplantation and gender differences: a paradigmatic example of intertwining between biological and sociocultural determinants. Biol Sex Differ. 2016;7:35.
2. Zimmerman D, Donnelly S, Miller J, et al. Gender disparity in living renal transplant donation. Am J Kidney Dis. 2000;36:534540.
3. Biller-Andorno N. Gender imbalance in living organ donation. Med Health Care Philos. 2002;5:199204.
4. Purnell TS, Luo X, Cooper LA, et al. Association of race and ethnicity with live donor kidney transplantation in the United States from 1995 to 2014. JAMA. 2018;319:4961.
5. Eurotransplant Statistics Report Library. Available at http://statistics.eurotransplant.org/index.php?search_organ=all+organs&search_characteristic=sex. 2017. Accessed August 28, 2018.
6. Ge F, Huang T, Yuan S, et al. Gender issues in solid organ donation and transplantation. Ann Transplant. 2013;18:508514.
7. Steinman JL. Gender disparity in organ donation. Gend Med. 2006;3:246252.
8. Kaczmarek I, Meiser B, Beiras-Fernandez A, et al. Gender does matter: gender-specific outcome analysis of 67,855 heart transplants. Thorac Cardiovasc Surg. 2013;61:2936.
9. Held PJ, Pauly MV, Bovbjerg RR, et al. Access to kidney transplantation. Has the United States eliminated income and racial differences? Arch Intern Med. 1988;148:25942600.
10. Kjellstrand CM. Age, sex, and race inequality in renal transplantation. Arch Intern Med. 1988;148:13051309.
11. Bloembergen WE, Mauger EA, Wolfe RA, et al. Association of gender and access to cadaveric renal transplantation. Am J Kidney Dis. 1997;30:733738.
12. Nguyen S, Martz K, Stablein D, et al. Wait list status of pediatric dialysis patients in North America. Pediatr Transplant. 2011;15:376383.
13. Schold JD, Gregg JA, Harman JS, et al. Barriers to evaluation and wait listing for kidney transplantation. Clin J Am Soc Nephrol. 2011;6:17601767.
14. Wolfe RA, Ashby VB, Milford EL, et al. Differences in access to cadaveric renal transplantation in the United States. Am J Kidney Dis. 2000;36:10251033.
15. Patzer RE, Amaral S, Wasse H, et al. Neighborhood poverty and racial disparities in kidney transplant waitlisting. J Am Soc Nephrol. 2009;20:13331340.
16. Couchoud C, Bayat S, Villar E, et al.; REIN registryA new approach for measuring gender disparity in access to renal transplantation waiting lists. Transplantation. 2012;94:513519.
17. Schaubel DE, Stewart DE, Morrison HI, et al. Sex inequality in kidney transplantation rates. Arch Intern Med. 2000;160:23492354.
18. McCauley J, Irish W, Thompson L, et al. Factors determining the rate of referral, transplantation, and survival on dialysis in women with ESRD. Am J Kidney Dis. 1997;30:739748.
19. Ravanan R, Udayaraj U, Ansell D, et al. Variation between centres in access to renal transplantation in UK: longitudinal cohort study. BMJ. 2010;341:c3451.
20. Dudley CR, Johnson RJ, Thomas HL, et al. Factors that influence access to the national renal transplant waiting list. Transplantation. 2009;88:96102.
21. Oniscu GC, Schalkwijk AA, Johnson RJ, et al. Equity of access to renal transplant waiting list and renal transplantation in Scotland: cohort study. BMJ. 2003;327:1261.
22. Hogan J, Couchoud C, Bonthuis M, et al.; ESPN/ERA-EDTA RegistryGender disparities in access to pediatric renal transplantation in europe: data from the ESPN/ERA-EDTA registry. Am J Transplant. 2016;16:20972105.
23. Alexander GC, Sehgal AR. Barriers to cadaveric renal transplantation among blacks, women, and the poor. JAMA. 1998;280:11481152.
24. Salter ML, McAdams-Demarco MA, Law A, et al. Age and sex disparities in discussions about kidney transplantation in adults undergoing dialysis. J Am Geriatr Soc. 2014;62:843849.
25. Monson RS, Kemerley P, Walczak D, et al. Disparities in completion rates of the medical prerenal transplant evaluation by race or ethnicity and gender. Transplantation. 2015;99:236242.
26. Salter ML, Gupta N, Massie AB, et al. Perceived frailty and measured frailty among adults undergoing hemodialysis: a cross-sectional analysis. BMC Geriatr. 2015;15:52.
27. Salter ML, Gupta N, King E, et al. Health-related and psychosocial concerns about transplantation among patients initiating dialysis. Clin J Am Soc Nephrol. 2014;9:19401948.
28. Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front Neuroendocrinol. 2014;35:347369.
29. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16:626638.
30. Bromberger B, Spragan D, Hashmi S, et al. Pregnancy-induced sensitization promotes sex disparity in living donor kidney transplantation. J Am Soc Nephrol. 2017;28:30253033.
31. Segev DL, Kucirka LM, Oberai PC, et al. Age and comorbidities are effect modifiers of gender disparities in renal transplantation. J Am Soc Nephrol. 2009;20:621628.
32. Gill JS, Hendren E, Dong J, et al. Differential association of body mass index with access to kidney transplantation in men and women. Clin J Am Soc Nephrol. 2014;9:951959.
33. Ayanian JZ, Cleary PD, Weissman JS, et al. The effect of patients’ preferences on racial differences in access to renal transplantation. N Engl J Med. 1999;341:16611669.
34. Saunders MR, Lee H, Alexander GC, et al. Racial disparities in reaching the renal transplant waitlist: is geography as important as race? Clin Transplant. 2015;29:531538.
35. Joshi S, Gaynor JJ, Bayers S, et al. Disparities among blacks, hispanics, and whites in time from starting dialysis to kidney transplant waitlisting. Transplantation. 2013;95:309318.
36. Cass A, Cunningham J, Snelling P, et al. Renal transplantation for indigenous Australians: identifying the barriers to equitable access. Ethn Health. 2003;8:111119.
37. Foster BJ, Dahhou M, Zhang X, et al. Association between age and graft failure rates in young kidney transplant recipients. Transplantation. 2011;92:12371243.
38. Keith DS, Cantarovich M, Paraskevas S, et al. Recipient age and risk of chronic allograft nephropathy in primary deceased donor kidney transplant. Transpl Int. 2006;19:649656.
39. Kaboré R, Couchoud C, Macher MA, et al. Age-dependent risk of graft failure in young kidney transplant recipients. Transplantation. 2017;101:13271335.
40. Meier-Kriesche HU, Ojo AO, Leavey SF, et al. Gender differences in the risk for chronic renal allograft failure. Transplantation. 2001;71:429432.
41. Kim SJ, Gill JS. H-Y incompatibility predicts short-term outcomes for kidney transplant recipients. J Am Soc Nephrol. 2009;20:20252033.
42. Bobanga ID, Vogt BA, Woodside KJ, et al. Outcome differences between young children and adolescents undergoing kidney transplantation. J Pediatr Surg. 2015;50:996999.
43. Van Arendonk KJ, Boyarsky BJ, Orandi BJ, et al. National trends over 25 years in pediatric kidney transplant outcomes. Pediatrics. 2014;133:594601.
44. Lepeytre F, Dahhou M, Zhang X, et al. Association of sex with risk of kidney graft failure differs by age. J Am Soc Nephrol. 2017;28:30143023.
45. Boucquemont J, Pai AL, Dharnidharka VR, et al. Gender differences in medication adherence among adolescent and young adult kidney transplant recipients. Transplantation. [Epub ahead of print. Jul 9, 2018]. doi: 10.1097/TP.0000000000002359.
46. Chisholm-Burns MA, Spivey CA, Tolley EA, et al. Medication therapy management and adherence among US renal transplant recipients. Patient Prefer Adherence. 2016;10:703709.
47. Spivey CA, Chisholm-Burns MA, Damadzadeh B, et al. Determining the effect of immunosuppressant adherence on graft failure risk among renal transplant recipients. Clin Transplant. 2014;28:96104.
48. Gordon EJ, Ladner DP. Gender inequities pervade organ transplantation access. Transplantation. 2012;94:447448.
49. Sarkar M, Watt KD, Terrault N, et al. Outcomes in liver transplantation: does sex matter? J Hepatol. 2015;62:946955.
50. Wiesner R, Edwards E, Freeman R, et al.; United Network for Organ Sharing Liver Disease Severity Score CommitteeModel for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124:9196.
51. Mathur AK, Schaubel DE, Gong Q, et al. Sex-based disparities in liver transplant rates in the united states. Am J Transplant. 2011;11:14351443.
52. Moylan CA, Brady CW, Johnson JL, et al. Disparities in liver transplantation before and after introduction of the MELD score. JAMA. 2008;300:23712378.
53. Oloruntoba OO, Moylan CA. Gender-based disparities in access to and outcomes of liver transplantation. World J Hepatol. 2015;7:460467.
54. Flemming JA, Kim WR, Brosgart CL, et al. Reduction in liver transplant wait-listing in the era of direct-acting antiviral therapy. Hepatology. 2017;65:804812.
55. Wang X, Li J, Riaz DR, et al. Outcomes of liver transplantation for nonalcoholic steatohepatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2014;12:394402.e1.
56. Mathur AK, Ashby VB, Fuller DS, et al. Variation in access to the liver transplant waiting list in the United States. Transplantation. 2014;98:9499.
57. Cullaro G, Sarkar M, Lai JC. Sex-based disparities in delisting for being “too sick” for liver transplantation. Am J Transplant. 2018;18:12141219.
58. Cholongitas E, Marelli L, Kerry A, et al. Female liver transplant recipients with the same GFR as male recipients have lower MELD scores–a systematic bias. Am J Transplant. 2007;7:685692.
59. Mindikoglu AL, Regev A, Seliger SL, et al. Gender disparity in liver transplant waiting-list mortality: the importance of kidney function. Liver Transpl. 2010;16:11471157.
60. Myers RP, Shaheen AA, Aspinall AI, et al. Gender, renal function, and outcomes on the liver transplant waiting list: assessment of revised MELD including estimated glomerular filtration rate. J Hepatol. 2011;54:462470.
61. Huo SC, Huo TI, Lin HC, et al. Is the corrected-creatinine model for end-stage liver disease a feasible strategy to adjust gender difference in organ allocation for liver transplantation? Transplantation. 2007;84:14061412.
62. Lai JC, Terrault NA, Vittinghoff E, et al. Height contributes to the gender difference in wait-list mortality under the MELD-based liver allocation system. Am J Transplant. 2010;10:26582664.
63. Mindikoglu AL, Emre SH, Magder LS. Impact of estimated liver volume and liver weight on gender disparity in liver transplantation. Liver Transpl. 2013;19:8995.
64. Nephew LD, Goldberg DS, Lewis JD, et al. Exception points and body size contribute to gender disparity in liver transplantation. Clin Gastroenterol Hepatol. 2017;15:12861293.e2.
65. Allen AM, Heimbach JK, Larson JJ, et al. Reduced access to liver transplantation in women: role of height, MELD exception scores, and renal function underestimation. Transplantation. 2018;102:17101716.
66. Kahn D, Gavaler JS, Makowka L, et al. Gender of donor influences outcome after orthotopic liver transplantation in adults. Dig Dis Sci. 1993;38:14851488.
67. Marino IR, Doyle HR, Aldrighetti L, et al. Effect of donor age and sex on the outcome of liver transplantation. Hepatology. 1995;22:17541762.
68. Brooks BK, Levy MF, Jennings LW, et al. Influence of donor and recipient gender on the outcome of liver transplantation. Transplantation. 1996;62:17841787.
69. Rustgi VK, Marino G, Halpern MT, et al. Role of gender and race mismatch and graft failure in patients undergoing liver transplantation. Liver Transpl. 2002;8:514518.
70. Croome KP, Segal D, Hernandez-Alejandro R, et al. Female donor to male recipient gender discordance results in inferior graft survival: a prospective study of 1,042 liver transplants. J Hepatobiliary Pancreat Sci. 2014;21:269274.
71. Lee KW, Han S, Lee S, et al. Higher risk of posttransplant liver graft failure in male recipients of female donor grafts might not be due to anastomotic size disparity. Transplantation. 2018;102:11151123.
72. Yoshizumi T, Shirabe K, Taketomi A, et al. Risk factors that increase mortality after living donor liver transplantation. Transplantation. 2012;93:9398.
73. Feng S, Goodrich NP, Bragg-Gresham JL, et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant. 2006;6:783790.
74. Lai JC, Feng S, Roberts JP, et al. Gender differences in liver donor quality are predictive of graft loss. Am J Transplant. 2011;11:296302.
75. Zeier M, Döhler B, Opelz G, et al. The effect of donor gender on graft survival. J Am Soc Nephrol. 2002;13:25702576.
76. Francavilla R, Hadzic N, Heaton ND, et al. Gender matching and outcome after pediatric liver transplantation. Transplantation. 1998;66:602605.
77. Pillay P, Van Thiel DH, Gavaler JS, et al. Donor gender does not affect liver transplantation outcome in children. Dig Dis Sci. 1990;35:686689.
78. Hollenbeak CS, Alfrey EJ, Sheridan K, et al. Surgical site infections following pediatric liver transplantation: risks and costs. Transpl Infect Dis. 2003;5:7278.
79. Alonso EM, Martz K, Wang D, et al.; Studies of Pediatric Liver Transplantation (SPLIT) Functional Outcomes Group (FOG)Factors predicting health-related quality of life in pediatric liver transplant recipients in the functional outcomes group. Pediatr Transplant. 2013;17:605611.
80. Ruebner RL, Reese PP, Denburg MR, et al. Risk factors for end-stage kidney disease after pediatric liver transplantation. Am J Transplant. 2012;12:33983405.
81. Chambers DC, Yusen RD, Cherikh WS, et al.; International Society for Heart and Lung TransplantationThe registry of the international society for heart and lung transplantation: thirty-fourth adult lung and heart-lung transplantation report-2017; focus theme: allograft ischemic time. J Heart Lung Transplant. 2017;36:10471059.
82. Thabut G, Mal H, Cerrina J, et al. Influence of donor characteristics on outcome after lung transplantation: a multicenter study. J Heart Lung Transplant. 2005;24:13471353.
83. Sato M, Gutierrez C, Kaneda H, et al. The effect of gender combinations on outcome in human lung transplantation: the International Society of Heart and Lung Transplantation Registry experience. J Heart Lung Transplant. 2006;25:634637.
84. Christie JD, Edwards LB, Kucheryavaya AY, et al. The registry of the international society for heart and lung transplantation: twenty-eighth adult lung and heart-lung transplant report–2011. J Heart Lung Transplant. 2011;30:11041122.
85. Alvarez A, Moreno P, Illana J, et al. Influence of donor-recipient gender mismatch on graft function and survival following lung transplantation. Interact Cardiovasc Thorac Surg. 2013;16:426435.
86. Mangiameli G, Arame A, Boussaud V, et al. Lung transplantation in childhood and adolescence: unicentric 14-year experience with sex matching as the main prognosticator. Eur J Cardiothorac Surg. 2016;49:810817.
87. Görler H, Strüber M, Ballmann M, et al. Lung and heart-lung transplantation in children and adolescents: a long-term single-center experience. J Heart Lung Transplant. 2009;28:243248.
88. Hsich EM, Blackstone EH, Thuita L, et al. Sex differences in mortality based on united network for organ sharing status while awaiting heart transplantation. Circ Heart Fail. 2017;10:e003635.
89. Regitz-Zagrosek V, Petrov G, Lehmkuhl E, et al. Heart transplantation in women with dilated cardiomyopathy. Transplantation. 2010;89:236244.
90. Khush KK, Kubo JT, Desai M. Influence of donor and recipient sex mismatch on heart transplant outcomes: analysis of the international society for heart and lung transplantation registry. J Heart Lung Transplant. 2012;31:459466.
91. Hiemann NE, Knosalla C, Wellnhofer E, et al. Beneficial effect of female gender on long-term survival after heart transplantation. Transplantation. 2008;86:348356.
92. Weiss ES, Allen JG, Patel ND, et al. The impact of donor-recipient sex matching on survival after orthotopic heart transplantation: analysis of 18 000 transplants in the modern era. Circ Heart Fail. 2009;2:401408.
93. Al-Khaldi A, Oyer PE, Robbins RC. Outcome analysis of donor gender in heart transplantation. J Heart Lung Transplant. 2006;25:461468.
94. Peled Y, Lavee J, Arad M, et al. The impact of gender mismatching on early and late outcomes following heart transplantation. ESC Heart Fail. 2017;4:3139.
95. George JF, Taylor DO, Blume ED, et al. Minimizing infection and rejection death: clues acquired from 19 years of multi-institutional cardiac transplantation data. J Heart Lung Transplant. 2011;30:151157.
96. Tosi L, Federman M, Markovic D, et al. The effect of gender and gender match on mortality in pediatric heart transplantation. Am J Transplant. 2013;13:29963002.
97. Schumacher KR, Almond C, Singh TP, et al.; PHTS Study Group InvestigatorsPredicting graft loss by 1 year in pediatric heart transplantation candidates: an analysis of the pediatric heart transplant study database. Circulation. 2015;131:890898.
98. Kemna M, Albers E, Bradford MC, et al. Impact of donor-recipient sex match on long-term survival after heart transplantation in children: an analysis of 5797 pediatric heart transplants. Pediatr Transplant. 2016;20:249255.
99. Kirk R, Edwards LB, Kucheryavaya AY, et al. The registry of the international society for heart and lung transplantation: fourteenth pediatric heart transplantation report–2011. J Heart Lung Transplant. 2011;30:10951103.
100. Dipchand AI, Kirk R, Edwards LB, et al.; International Society for Heart and Lung TransplantationThe registry of the international society for heart and lung transplantation: sixteenth official pediatric heart transplantation report–2013; focus theme: age. J Heart Lung Transplant. 2013;32:979988.
101. Rossano JW, Dipchand AI, Edwards LB, et al.; International Society for Heart and Lung TransplantationThe registry of the international society for heart and lung transplantation: nineteenth pediatric heart transplantation report-2016; focus theme: primary diagnostic indications for transplant. J Heart Lung Transplant. 2016;35:11851195.
102. Rossano JW, Cherikh WS, Chambers DC, et al.; International Society for Heart and Lung TransplantationThe registry of the international society for heart and lung transplantation: twentieth pediatric heart transplantation report-2017; focus theme: allograft ischemic time. J Heart Lung Transplant. 2017;36:10601069.
103. Gratwohl A, Hermans J, Niederwieser D, et al.; Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation EBMTFemale donors influence transplant-related mortality and relapse incidence in male recipients of sibling blood and marrow transplants. Hematol J. 2001;2:363370.
104. Gahrton G, Iacobelli S, Apperley J, et al. The impact of donor gender on outcome of allogeneic hematopoietic stem cell transplantation for multiple myeloma: reduced relapse risk in female to male transplants. Bone Marrow Transplant. 2005;35:609617.
105. Stern M, Brand R, de Witte T, et al. Female-versus-male alloreactivity as a model for minor histocompatibility antigens in hematopoietic stem cell transplantation. Am J Transplant. 2008;8:21492157.
106. Kim HT, Zhang MJ, Woolfrey AE, et al. Donor and recipient sex in allogeneic stem cell transplantation: what really matters. Haematologica. 2016;101:12601266.
107. Kongtim P, Di Stasi A, Rondon G, et al. Can a female donor for a male recipient decrease the relapse rate for patients with acute myeloid leukemia treated with allogeneic hematopoietic stem cell transplantation? Biol Blood Marrow Transplant. 2015;21:713719.
108. Loren AW, Bunin GR, Boudreau C, et al. Impact of donor and recipient sex and parity on outcomes of HLA-identical sibling allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2006;12:758769.
109. Gratwohl A, Stern M, Brand R, et al.; European Group for Blood and Marrow Transplantation and the European Leukemia NetRisk score for outcome after allogeneic hematopoietic stem cell transplantation: a retrospective analysis. Cancer. 2009;115:47154726.
110. Abdelbaset-Ismail A, Suszynska M, Borkowska S, et al. Human haematopoietic stem/progenitor cells express several functional sex hormone receptors. J Cell Mol Med. 2016;20:134146.
111. Brenner BM, Milford EL. Nephron underdosing: a programmed cause of chronic renal allograft failure. Am J Kidney Dis. 1993;21(5 Suppl 2):6672.
112. Aufhauser DD Jr, Wang Z, Murken DR, et al. Improved renal ischemia tolerance in females influences kidney transplantation outcomes. J Clin Invest. 2016;126:19681977.
113. Harada H, Pavlick KP, Hines IN, et al. Selected contribution: effects of gender on reduced-size liver ischemia and reperfusion injury. J Appl Physiol (1985). 2001;91:28162822.
114. Gabel SA, Walker VR, London RE, et al. Estrogen receptor beta mediates gender differences in ischemia/reperfusion injury. J Mol Cell Cardiol. 2005;38:289297.
115. Gratwohl A, Döhler B, Stern M, et al. H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study. Lancet. 2008;372:4953.
116. Tan JC, Wadia PP, Coram M, et al. H-Y antibody development associates with acute rejection in female patients with male kidney transplants. Transplantation. 2008;86:7581.
117. Hughson M, Farris AB 3rd, Douglas-Denton R, et al. Glomerular number and size in autopsy kidneys: the relationship to birth weight. Kidney Int. 2003;63:21132122.
118. Tan JC, Kim JP, Chertow GM, et al. Donor-recipient sex mismatch in kidney transplantation. Gend Med. 2012;9:335347.e2.
119. Lang JT, McCullough LD. Pathways to ischemic neuronal cell death: are sex differences relevant? J Transl Med. 2008;6:33.
120. Bouma GJ, van Caubergh P, van Bree SP, et al. Pregnancy can induce priming of cytotoxic T lymphocytes specific for paternal HLA antigens that is associated with antibody formation. Transplantation. 1996;62:672678.
121. Fish EN. The X-files in immunity: sex-based differences predispose immune responses. Nat Rev Immunol. 2008;8:737744.
122. Libert C, Dejager L, Pinheiro I. The X chromosome in immune functions: when a chromosome makes the difference. Nat Rev Immunol. 2010;10:594604.
123. Carrel L, Willard HF. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature. 2005;434:400404.
124. Tukiainen T, Villani AC, Yen A, et al.; GTEx Consortium; Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group; Statistical Methods groups—Analysis Working Group; Enhancing GTEx (eGTEx) groups; NIH Common Fund; NIH/NCI; NIH/NHGRI; NIH/NIMH; NIH/NIDA; Biospecimen Collection Source Site—NDRI; Biospecimen Collection Source Site—RPCI; Biospecimen Core Resource—VARI; Brain Bank Repository—University of Miami Brain Endowment Bank; Leidos Biomedical—Project Management; ELSI Study; Genome Browser Data Integration &Visualization—EBI; Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa CruzLandscape of X chromosome inactivation across human tissues. Nature. 2017;550:244248.
125. Wang J, Syrett CM, Kramer MC, et al. Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X. Proc Natl Acad Sci U S A. 2016;113:E2029E2038.
126. Klein SL. Immune cells have sex and so should journal articles. Endocrinology. 2012;153:25442550.
127. Bouman A, Heineman MJ, Faas MM. Sex hormones and the immune response in humans. Hum Reprod Update. 2005;11:411423.
128. Klein SL, Marriott I, Fish EN. Sex-based differences in immune function and responses to vaccination. Trans R Soc Trop Med Hyg. 2015;109:915.
129. Trigunaite A, Dimo J, Jørgensen TN. Suppressive effects of androgens on the immune system. Cell Immunol. 2015;294:8794.
130. Souyris M, Cenac C, Azar P, et al. TLR7 escapes X chromosome inactivation in immune cells. Sci Immunol. 2018;3:eaap8855.
131. Rettew JA, Huet YM, Marriott I. Estrogens augment cell surface TLR4 expression on murine macrophages and regulate sepsis susceptibility in vivo. Endocrinology. 2009;150:38773884.
132. Scotland RS, Stables MJ, Madalli S, et al. Sex differences in resident immune cell phenotype underlie more efficient acute inflammatory responses in female mice. Blood. 2011;118:59185927.
133. Calippe B, Douin-Echinard V, Delpy L, et al. 17beta-estradiol promotes TLR4-triggered proinflammatory mediator production through direct estrogen receptor alpha signaling in macrophages in vivo. J Immunol. 2010;185:11691176.
134. Paharkova-Vatchkova V, Maldonado R, Kovats S. Estrogen preferentially promotes the differentiation of CD11C+ CD11B(intermediate) dendritic cells from bone marrow precursors. J Immunol. 2004;172:14261436.
135. Xiu F, Anipindi VC, Nguyen PV, et al. High physiological concentrations of progesterone reverse estradiol-mediated changes in differentiation and functions of bone marrow derived dendritic cells. PLoS One. 2016;11:e0153304.
136. Xu Y, He H, Li C, et al. Immunosuppressive effect of progesterone on dendritic cells in mice. J Reprod Immunol. 2011;91:1723.
137. Kissick HT, Sanda MG, Dunn LK, et al. Androgens alter T-cell immunity by inhibiting T-helper 1 differentiation. Proc Natl Acad Sci U S A. 2014;111:98879892.
138. Palaszynski KM, Smith DL, Kamrava S, et al. A yin-yang effect between sex chromosome complement and sex hormones on the immune response. Endocrinology. 2005;146:32803285.
139. Maret A, Coudert JD, Garidou L, et al. Estradiol enhances primary antigen-specific CD4 T cell responses and th1 development in vivo. Essential role of estrogen receptor alpha expression in hematopoietic cells. Eur J Immunol. 2003;33:512521.
140. Lambert KC, Curran EM, Judy BM, et al. Estrogen receptor alpha (eralpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through eralpha to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation. J Immunol. 2005;175:57165723.
141. Polanczyk MJ, Carson BD, Subramanian S, et al. Cutting edge: estrogen drives expansion of the CD4+CD25+ regulatory T cell compartment. J Immunol. 2004;173:22272230.
142. Mao G, Wang J, Kang Y, et al. Progesterone increases systemic and local uterine proportions of CD4+CD25+ treg cells during midterm pregnancy in mice. Endocrinology. 2010;151:54775488.
143. Butterworth M, McClellan B, Allansmith M. Influence of sex in immunoglobulin levels. Nature. 1967;214:12241225.
144. Medina KL, Strasser A, Kincade PW. Estrogen influences the differentiation, proliferation, and survival of early B-lineage precursors. Blood. 2000;95:20592067.
145. Grimaldi CM, Cleary J, Dagtas AS, et al. Estrogen alters thresholds for B cell apoptosis and activation. J Clin Invest. 2002;109:16251633.
146. Giefing-Kröll C, Berger P, Lepperdinger G, et al. How sex and age affect immune responses, susceptibility to infections, and response to vaccination. Aging Cell. 2015;14:309321.
147. Tullius SG, Tran H, Guleria I, et al. The combination of donor and recipient age is critical in determining host immunoresponsiveness and renal transplant outcome. Ann Surg. 2010;252:662674.
148. Porrett PM. Biologic mechanisms and clinical consequences of pregnancy alloimmunization. Am J Transplant. 2018;18:10591067.
149. Franconi F, Brunelleschi S, Steardo L, et al. Gender differences in drug responses. Pharmacol Res. 2007;55:8195.
150. Momper JD, Misel ML, McKay DB. Sex differences in transplantation. Transplant Rev (Orlando). 2017;31:145150.
151. Kahan BD, Kramer WG, Wideman C, et al. Demographic factors affecting the pharmacokinetics of cyclosporine estimated by radioimmunoassay. Transplantation. 1986;41:459464.
152. Tornatore KM, Brazeau D, Dole K, et al. Sex differences in cyclosporine pharmacokinetics and ABCB1 gene expression in mononuclear blood cells in african american and caucasian renal transplant recipients. J Clin Pharmacol. 2013;53:10391047.
153. Venuto RC, Meaney CJ, Chang S, et al. Association of extrarenal adverse effects of posttransplant immunosuppression with sex and ABCB1 haplotypes. Medicine (Baltimore). 2015;94:e1315.
154. Fruit D, Rousseau A, Amrein C, et al. Ciclosporin population pharmacokinetics and bayesian estimation in thoracic transplant recipients. Clin Pharmacokinet. 2013;52:277288.
155. Zimmerman JJ. Exposure-response relationships and drug interactions of sirolimus. Aaps J. 2004;6:e28.
156. Kovarik JM, Hsu CH, McMahon L, et al. Population pharmacokinetics of everolimus in de novo renal transplant patients: impact of ethnicity and comedications. Clin Pharmacol Ther. 2001;70:247254.
157. Moes DJ, Press RR, den Hartigh J, et al. Population pharmacokinetics and pharmacogenetics of everolimus in renal transplant patients. Clin Pharmacokinet. 2012;51:467480.
158. OECD. OECD Employment Outlook 2018. 2018:Paris, France: OECD Publishing; Chap 6.
159. Mustard CA, Etches J. Gender differences in socioeconomic inequality in mortality. J Epidemiol Community Health. 2003;57:974980.
160. Phillips SP, Hamberg K. Women’s relative immunity to the socio-economic health gradient: artifact or real? Glob Health Action. 2015;8:27259.
161. Vart P, Gansevoort RT, Joosten MM, et al. Socioeconomic disparities in chronic kidney disease: a systematic review and meta-analysis. Am J Prev Med. 2015;48:580592.
162. Schaeffner ES, Mehta J, Winkelmayer WC. Educational level as a determinant of access to and outcomes after kidney transplantation in the United States. Am J Kidney Dis. 2008;51:811818.
163. Zhang Y, Jarl J, Gerdtham UG. Are There Inequities in Treatment of End-Stage Renal Disease in Sweden? A Longitudinal Register-Based Study on Socioeconomic Status-Related Access to Kidney Transplantation. Int J Environ Res Public Health. 2017;14:119.
164. Zhang Y, Gerdtham UG, Rydell H, et al. Socioeconomic inequalities in the kidney transplantation process: a registry-based study in Sweden. Transplant Direct. 2018;4:e346.
165. Wood RE, Goesling B, Avellar S. The Effects of Marriage on Health: A Synthesis of Recent Research Evidence. 2018:Washington, DC: U.S. Department of Health and Human Services; Chap 5.
166. Rendall MS, Weden MM, Favreault MM, et al. The protective effect of marriage for survival: a review and update. Demography. 2011;48:481506.
167. Denney JT, Gorman BK, Barrera CB. Families, resources, and adult health: where do sexual minorities fit? J Health Soc Behav. 2013;54:4663.
168. Chisholm-Burns MA, Spivey CA, Rehfeld R, et al. Immunosuppressant therapy adherence and graft failure among pediatric renal transplant recipients. Am J Transplant. 2009;9:24972504.
169. Dew MA, Dabbs AD, Myaskovsky L, et al. Meta-analysis of medical regimen adherence outcomes in pediatric solid organ transplantation. Transplantation. 2009;88:736746.
170. Dobbels F, Ruppar T, De Geest S, et al. Adherence to the immunosuppressive regimen in pediatric kidney transplant recipients: a systematic review. Pediatr Transplant. 2010;14:603613.
    171. Feinstein S, Keich R, Becker-Cohen R, et al. Is noncompliance among adolescent renal transplant recipients inevitable? Pediatrics. 2005;115:969973.
    172. Tapiawala SN, Tinckam KJ, Cardella CJ, et al. Delayed graft function and the risk for death with a functioning graft. J Am Soc Nephrol. 2010;21:153161.
    173. Rubín A, Sánchez-Montes C, Aguilera V, et al. Long-term outcome of ‘long-term liver transplant survivors’. Transpl Int. 2013;26:740750.
    174. Åberg F, Gissler M, Karlsen TH, et al. Differences in long-term survival among liver transplant recipients and the general population: a population-based nordic study. Hepatology. 2015;61:668677.
      175. Watt KD, Pedersen RA, Kremers WK, et al. Evolution of causes and risk factors for mortality post-liver transplant: results of the NIDDK long-term follow-up study. Am J Transplant. 2010;10:14201427.
        176. Owens IP. Ecology and evolution. Sex differences in mortality rate. Science. 2002;297:20082009.
          177. Laskin BL, Mitsnefes MM, Dahhou M, et al. The mortality risk with graft function has decreased among children receiving a first kidney transplant in the United States. Kidney Int. 2015;87:575583.
          178. Sapir-Pichhadze R, Pintilie M, Tinckam KJ, et al. Survival analysis in the presence of competing risks: the example of waitlisted kidney transplant candidates. Am J Transplant. 2016;16:19581966.
          179. Clayton JA, Collins FS. Policy: NIH to balance sex in cell and animal studies. Nature. 2014;509:282283.
          180. Heidari S, Babor TF, De Castro P, et al. Sex and gender equity in research: rationale for the SAGER guidelines and recommended use. Res Integr Peer Rev. 2016;1:2.
          181. Foster BJ, Dahhou M, Zhang X, et al. Change in mortality risk over time in young kidney transplant recipients. Am J Transplant. 2011;11:24322442.
          182. Schoening WN, Helbig M, Buescher N, et al. Gender matches in liver transplant allocation: matched and mismatched male-female donor-recipient combinations; long-term follow-up of more than 2000 patients at a single center. Exp Clin Transplant. 2016;14:184190.
            183. Eifert S, Kofler S, Nickel T, et al. Gender-based analysis of outcome after heart transplantation. Exp Clin Transplant. 2012;10:368374.
              184. The International Society for Heart and Lung Transplanatation. The International Society for Heart and Lung Transplanatation Quarterly Reports. 2019. Available at: https://ishltregistries.org/registries/quarterlydatareport.asp. Accessed August 29, 2018.
                Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.