Sex and Kidney Transplantation: Why Can’t a Woman Be More Like a Man?

So lamented Rex Harrison in the famous musical “My Fair Lady.” These amusing, but clearly tongue in cheek, albeit politically incorrect lyrics, may be relevant to sex-based differential outcomes after kidney transplantation, as pointed out by two provocative and timely articles in this month’s issue of the Journal of the American Society of Nephrology (JASN).^1,2

In the United States as well as worldwide, women are more often living kidney donors than men, whereas men are more often recipients of living donor kidneys.³ Women represented 63% of living kidney donors in the United States and only 37% of living donor kidney recipients, as per the US Scientific Registry of Transplant Recipients (SRTR) 2015 Annual Data Report.³ Undoubtedly, multiple factors contribute to this disparity, some social and some biologic, and in this issue of JASN, Bromberger et al.¹ provide a thoughtful analysis of the barriers to transplantation in women compared with men. In a cohort of 807 participants referred for living donor kidney transplantation (LDKT) to the University of Pennsylvania between 2007 and 2013, the authors compared the ability of men and women living donor kidney transplant candidates to navigate the pretransplant evaluation process, with particular attention to sensitizing events including pregnancy, blood transfusions, and prior transplants. Reassuringly, men and women progressed equally through the referral and evaluation processes but women ran into immune barriers when tested for preformed circulating antibodies directed at the potential donor’s T and B cells. Among the crossmatched candidates, 50% of men went on to receive a living donor kidney compared with only 35% of women (P=0.01).¹ This differential access to LDKT could be ascribed to a higher level of presensitization in women compared with men; 21% of women compared with 5% of men were incompatible with their crossmatched donors. The rates of sensitization due to prior transfusion or an earlier transplant were similar among men and women, and prior pregnancy was the primary contributor to the higher presensitization status among potential female recipients. Given that in both men and women, spouses are among the most commonly available donors, the authors correctly conclude that pregnancy induced sensitization is an important contributor to the decreased rates of LDKT among women. In this regard, it is worth remembering that women with multiple pregnancies were the primary source of HLA-typing sera because of their propensity to develop anti-HLA antibodies. It is also worth recognizing that in the modern era of transplantation, histocompatibility laboratories employ multiple platforms with different levels of sensitivity to screen and identify donor-specific antibodies (DSA), and some of the DSA detected by high sensitivity assays may not be clinically relevant, since they can be kept in check by the therapeutic arsenal available to the transplant clinician. Immune memory, a virtue when viewed through the lens of protection against infection, might be unforgiving in the context of kidney transplantation. For example, a female recipient sensitized by pregnancy and harboring memory B cells may be at a heightened risk for rejection when transplanted with her husband’s kidney.

The transplant community currently uses two distinct strategies to abrogate the adverse effect of preexisting DSA. One strategy includes immune preconditioning with a combination of apheresis, intravenous IgG, and immunosuppressive agents such as anti-CD20 mAb and/or proteasome inhibitors. Alternatively, the potential recipient and donor pair may participate in a paired exchange program: in its simplest version, the donor kidney that is incompatible with the original intended recipient is swapped for a compatible donor kidney that is incompatible for its intended recipient. Neither approach is a panacea, since immune preconditioning is associated with higher risk of kidney graft failure rates and paired exchanges impose considerable logistical challenges.

Pregnancy associated sensitization is not the only challenge females transplant candidates face. Lepeytre et al.,² also in this issue of JASN, report that kidney graft failure rates differ on the basis of kidney recipient’s age and sex, as well as donor’s sex. They studied a large cohort of 159,417 recipients of first deceased donor kidneys transplanted between 1995 and 2013 and recorded in the SRTR database. Using time-varying Cox models of the association between recipient sex- and death-censored graft failure, including a recipient sex by current age interaction term in their models, the authors report that when the kidney donor was a man, female recipients grouped 0–14, 15–24, 25–44, or >45 years have a higher adjusted hazard ratio of death-censored graft failure compared with similarly age-grouped male recipients.² In contrast, when the kidney donor was a woman, the adjusted hazard ratio was recipient age dependent; female and male recipients of 0–14 years or 25–44 years having similar rates of graft failure, and female recipients in the 15–24 group having a higher rate and female recipients >45 years having a lower rate of death-censored graft failure compared with male recipients of similar age groups.² Also, female recipients, except those >45 years old, had numerically higher death-censored graft failure rates compared with men irrespective of the sex of the kidney donor.²

Lepeytre et al.,² in addition to bringing to our attention the effect of age on graft survival rates in female recipients of kidneys from female donors, proffer sex hormones and H-Y antigens (in the case of women receiving a male kidney) as potential contributors to the increased risk of graft failure rates in female recipients of male kidneys compared with male recipients. Although we are in broad agreement with the author’s thoughtful interpretation of the data summarized in their article, we note that the higher numerical rate of graft failures was in female recipients of kidneys from either sex; and recipients aged >45 years, of either sex, have the numerically lowest risk of death-censored graft failure. Although less adherence to chronic immunosuppressive drug therapy leading to inadequate immunosuppression in the 15–24 year age group may be a contributory factor to inferior graft outcomes in this age group compared with other age groups, we also wonder whether we are over-immunosuppressing individuals aged >45 years old, since the increased rate of all-cause graft failure appears to rob them of the benefit seen with death-censored graft failure in this age group.² What is also particularly striking about their data are the impressive increase in graft failure risk in the 0–14 year age group who received male kidneys, when compared with men in a similar age group who received either a male or female kidney.² Young female recipients with a female donor had graft failure rates similar to men receiving a female kidney. Prior studies, including an earlier analysis of SRTR data addressing the effect of sex on allograft outcomes also reported inferior outcomes in younger female recipients (pediatric and adolescent) compared with males,⁴ however, the Lepeytre analysis goes further by stratifying the results on the basis of donor sex. Inferior outcomes of renal allografts in female children compared with males was also reported by the North American Pediatric Renal Trials and Collaborative Studies, without stratifying by donor sex.^5,6

Earlier studies of the effect of donor sex on allograft outcome include data from 124,911 transplant recipients recorded in the Collaborative Transplant Study (CTS) from 29 different countries.⁷ Although the results were not stratified by recipient age, inferior outcomes were observed when female kidneys compared with male kidneys were transplanted into male recipients, similar to the findings of Lepeytre et al.² The CTS study also reported worse allograft outcomes in female recipients of female compared with male kidneys. These results are broadly consistent with the Lepeytre study.

The basis for any real differences in outcomes attributable to donor or recipient sex are complex, and as these and other authors acknowledge, may be due to immunologic, hormonal, anatomic (e.g., size mismatch, nephron mass), and pharmacologic factors.⁶ Additional factors not addressed in this database such as recipient pregnancy or urinary tract infection, may also be relevant and may partially explain the increased rate of graft failure in women aged 15–24 years, regardless of donor sex.

The two studies published in this issue of JASN have shed new light on issues of significance to the transplantation field, and invite revisiting approaches to kidney transplantation including policy considerations. Regarding the dilemma brought to our attention by Bromberger et al.¹ that women are distinctly disadvantaged from receiving their husband’s kidney, our vote is to create a national pool of spousal recipient–donor pairs, including even compatible pairs, and enable a chain of transplants by leveraging the extraordinary diverse HLA polymorphisms and overcoming pregnancy induced adverse presensitization. The investigation of Lepeytre et al.² raises the intriguing question of whether female kidneys should be preferentially allocated to young female recipients aged 0–14 years. Also, better strategies for adherence in the 15–24 year age group, and personalizing immunosuppression, especially in the >45 year age group, may be beneficial. Obviously, our suggestions for creating a national spousal transplant pair pool and preferential allocation of female kidneys to females aged 0–14 years need to be statistically modeled for outcomes to mitigate unintended consequences.

Disclosures

None.