Organ transplantation and gender differences: a paradigmatic example of intertwining between biological and sociocultural determinants
© The Author(s). 2016
Received: 11 March 2016
Accepted: 19 July 2016
Published: 28 July 2016
Organ transplantation, e.g., of the heart, liver, or kidney, is nowadays a routine strategy to counteract several lethal human pathologies. From literature data and from data obtained in Italy, a striking scenario appears well evident: women are more often donors than recipients. On the other hand, recipients of organs are mainly males, probably reflecting a gender bias in the incidence of transplant-related pathologies. The impact of sex mismatch on transplant outcome remains debated, even though donor-recipient sex mismatch, due to biological matters, appears undesirable in female recipients. In our opinion, the analysis of how sex and gender can interact and affect grafting success could represent a mandatory task for the management of organ transplantation.
KeywordsTransplantation Sex differences Gender differences
Thanks to the improvement of surgical techniques and immunosuppressant treatments, organ transplantation is nowadays considered as a routine strategy for patients suffering a series of pathological states of a number of organs such as the heart, kidney, or liver. Transplant of these organs in patients with end-stage diseases has been demonstrated to significantly improve survival and/or quality of life. However, a refinement of therapeutic strategies, including immunosuppressant treatments, as well of the comprehension of the pathogenetic mechanisms leading to successful or ineffective transplantation outcome appears mandatory. Several lines of evidence suggested that successful organ transplantation could depend upon a plethora of factors. Among these are race, size, age, weight, and even sex/gender . Gender-related factors, i.e., sociocultural matters, or sex-related factors, i.e., biological determinants, appeared in fact as a pivotal matter in this scenario, being capable of influencing transplant outcome. In this Commentary, we would like to briefly underscore some of these critical points in order to stimulate a reappraisal of the gender/sex issue in transplantation studies and practice. We underline the strict intertwining between sociocultural and biological questions as pivotal issues in this field.
Impact of gender on organ transplantation
The gender of donors and recipients is involved in the entire process, including organ donation and transplant surgery. In general, women seem to have more self-sacrifice and sense of responsibility than men . As a consequence, it has been observed that women are more predisposed to donate their organs. In fact, in cost-free living donation, two thirds of all organs were donated by women . In contrast, women are less disposed than males to accept transplant surgery . Despite comprising 35 % of transplants, the number of female transplant recipients continued to decline. Several factors have been suggested to explain these differences . Nowadays, women and men present different social, economic, and cultural roles, and a disparity of knowledge may exist. In fact, women were considered to have less information about transplantation diagnosis and therapy. However, besides these psychosocial aspects, another important factor should be considered to explain the above reported gender bias: men have a higher incidence of end-stage diseases that necessitate a transplant and are more inclined to hypertension or ischemic heart disease, leading to their inappropriateness as donors.
Regarding graft outcome, male recipients have been observed to have a worse prognosis than females and this could be partially explained by the observation that women have better immunosuppressant compliance than men; they undergo follow-up visits and habit change and show more concern with regard to protecting graft function .
Impact of sex on organ transplantation
Several clinical studies have connected the use of female donor organs as a risk factor for death and rejection . In renal transplantation, female donor kidneys have a worse 5-year survival [6, 7] and this observation could be explained by the lower number of nephrons in the female kidney in comparison to men . In addition, animal experiments suggested that kidneys of females express more HLA antigens and are more antigenic . Moreover, male grafts are less susceptible to nephrotoxic effects of some immunosuppressants than female grafts . Long-term retrospective studies in renal transplants revealed that male recipients undergo a worse survival in comparison to females . It can be hypothesized that protection afforded by hormones in women could result in their better long-term prognosis. Estradiol can in fact improve graft function, preserve graft architecture, and diminish cellular infiltration, including mononuclear cell infiltration .
The impact of sex mismatch on transplant outcome still remains a matter of debate. Several studies reported that female donor to male recipient grafts seems to have a worst prognosis in particular for liver [11–13] and heart transplantation . In particular, in a recent single-center retrospective study, Schoening et al. , evaluating the effect of sex differences on long-term graft survival after liver transplant, found that female donor-male recipient combination showed the worst graft survival. They suggested that this event could be caused by the reduced female donor “quality” (female donors were significantly older, died significantly more frequently from cerebrovascular causes and less frequent by trauma) and by unfavorable characteristics of male recipients (higher incidence of hepatocellular carcinoma in the male recipient group). Interestingly, in studies carried out in animal models, livers from female rats have been demonstrated to present an increased acidosis during transplant-associated ischemia in comparison with livers from male rats; this sex difference in the liver’s metabolic response to ischemia appeared estrogen-mediated and could have a significant influence on the outcome of transplantation [16, 17]. Since a similar sex-dependent metabolic response has been found also in myocardial function , the possibility that this sexual disparity could influence cardiac transplants cannot be ruled out. In contrast with these studies, other studies on renal transplantation observed that male donor to female recipient combination is an independent risk factor for poor graft survival [19, 20] and the significantly higher percentage of H-Y antibody production in the male donor-female recipient population could play a role in this phenomenon . Regarding heart transplant patients, the observation that donor-recipient sex mismatch could result in a lower survival suggested that sex mismatch can be undesirable in female, as well as male, recipients .
Transplant activity in Italy 2002–2015
Living donor transplants
Cadaveric donor transplants
A multivariate analysis could represent in our mind, the unique and proper statistical approach capable of providing valuable information about possible gender disparity in organ transplantation allowing to understand the strict intertwining between biological and sociocultural determinants.
The impact of sex mismatch on transplant outcome still remains a matter of debate. Both gender- and sex-related aspects might affect the donation, the access, and the outcome of transplantation. In particular, how sex and gender interact and affect graft success should be taken into account in the management of organ-transplanted patients. In our opinion, this appears as a mandatory task to be promoted, developed, and regulated.
CNT, National Transplant Centre; F, female; M, male; SIT, Transplant Information System
Italian Ministry of Health.
Availability of data and materials
Reported data are available at the Italian SIT https://trapianti.sanita.it/statistiche/.
FP participated in the acquisition and data analysis. AR participated in the design of the study and performed the statistical analysis. ANC contributed to the conception and design of the study. WR coordinated the study and critically revised the manuscript. WM conceived the study and participated in its design and its writing. EO contributed to the design of the study and wrote the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Ethics approval and consent to participate
Research involves human subjects and has been performed in accordance with the Declaration of Helsinki.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Ge F, Huang T, Yuan S, Zhou Y, Gong W. Gender issues in solid organ donation and transplantation. Ann Transplant. 2013;18:508–14.View ArticlePubMedGoogle Scholar
- Legato MJ. Gender-specific issues in organ transplantation. In: Sanfey IH, Frcsi, Frcsi F, editors. Principles of gender-specific medicine. 1st ed. New York: Academic; 2004. p. 1116–27.Google Scholar
- Steinman JL. Gender disparity in organ donation. Gend Med. 2006;3:246–52.View ArticlePubMedGoogle Scholar
- Rosenberger J, Geckova AM, van Dijk JP, Nagyova I, Roland R, van den Heuvel WJ, et al. Prevalence and characteristics of noncompliant behaviour and its risk factors in kidney transplant recipients. Transpl Int. 2005;18:1072e8.View ArticleGoogle Scholar
- Zeier M, Döhler B, Opelz G, Ritz E. The effect of donor gender on graft survival. J Am Soc Nephrol. 2002;13:2570–6.View ArticlePubMedGoogle Scholar
- Głyda M, Czapiewski W, Karczewski M, Pięta R, Oko A. Influence of donor and recipient gender as well as selected factors on the five-year survival of kidney graft. Pol Przegl Chir. 2011;83:188–95.PubMedGoogle Scholar
- Shibue T, Kondo K, Iwaki Y, Terasaki PI. Effect of sex on kidney transplants. Clin Transplant. 1987;351–60.
- Kasiske BL, Umen JA. The influence of age, sex, race and body habitus on kidney weight in humans. Arch Pathol Lab Med. 1986;110:55–60.PubMedGoogle Scholar
- Chen PD, Tsai MK, Lee CY, Yang CY, Hu RH, Lee PH, Lai HS. Gender differences in renal transplant graft survival. J Formos Med Assoc. 2013;112:783–8.View ArticlePubMedGoogle Scholar
- Muller V, Szabo A, Viklicky O, Pörtl S, Philipp T, et al. Sex hormones and gender-related differences: their influence on chronic renal allograft rejection. Kidney Int. 1999;55:2011–20.View ArticlePubMedGoogle Scholar
- Yoshizumi T, Shirabe K, Taketomi A, Uchiyama H, Harada N, Ijichi H, et al. Risk factors that increase mortality after living donor liver transplantation. Transplantation. 2012;93:93–8.View ArticlePubMedGoogle Scholar
- Brooks BK, Levy MF, Jennings LW, Abbasoglu O, Vodapally M, Goldstein RM, et al. Influence of donor and recipient gender on the outcome of liver transplantation. Transplantation. 1996;62:1784–7.View ArticlePubMedGoogle Scholar
- Rustgi VK, Marino G, Halpern MT, et al. Role of gender and race mismatch and graft failure in patients undergoing liver transplantation. Liver Transplant. 2002;8:514–8.View ArticleGoogle Scholar
- Kaczmarek I, Meiser B, Beiras-Fernandez A, Guethoff S, Überfuhr P, Angele M, et al. Gender does matter: gender-specific outcome analysis of 67,855 heart transplants. Thorac Cardiovasc Surg. 2013;61:29–36.PubMedGoogle Scholar
- Schoening WN, Helbig M, Buescher N, Andreou A, Bahra M, Schmitz V, 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;14:184–90.PubMedGoogle Scholar
- Wittnich C, Belanger MP, Askin N, Boscarino C, Wallen WJ. Lower liver transplant success in females: gender differences in metabolic response to global ischemia. Transplant Proc. 2004;36:1485–8.View ArticlePubMedGoogle Scholar
- Soric S, Belanger MP, Askin N, Wittnich C. Impact of female sex hormones on liver tissue lactic acidosis during ischemia. Transplantation. 2007;84:763–70.View ArticlePubMedGoogle Scholar
- Wittnich C, Tan L, Wallen J, Belanger M. Sex differences in myocardial metabolism and cardiac function: an emerging concept. Pflugers Arch. 2013;465:719–29.View ArticlePubMedGoogle Scholar
- Zukowski M, Kotfis K, Biernawska J, Zegan-Barańska M, Kaczmarczyk M, Ciechanowicz A, et al. Donor-recipient gender mismatch affects early graft loss after kidney transplantation. Transplant Proc. 2011;43:2914–6.View ArticlePubMedGoogle Scholar
- McGee J, Magnus JH, Islam TM, Jaffe BM, Zhang R, Florman SS, et al. Donor-recipient gender and size mismatch affects graft success after kidney transplantation. J Am Coll Surg. 2010;210:718-725.e1, 725-6.
- Scott DM, Ehrmann IE, Ellis PS, Chandler PR, Simpson E. Why do some females reject males? The molecular basis for male-specific graft rejection. J Mol Med. 1997;75:103–14.View ArticlePubMedGoogle Scholar
- Kittleson MM, Shemin R, Patel JK, Ardehali A, Kawano M, Davis S, et al. Donor-recipient sex mismatch portends poor 10-year outcomes in a single-center experience. J Heart Lung Transplant. 2011;30:1018–22.View ArticlePubMedGoogle Scholar