Abstracts

INTRODUCTION

Kidney transplants are considered to be the best therapeutic alternatives for persons suffering from advanced chronic kidney disease.¹³13 .Howard K, Salked G, White S, MacDonald S, Chadban S, Craig JC, et al. The cost efectiveness of increasing kidney transplantation and home-based dialysis. Nephrology(Carlton). 2009;14(1):123-32. DOI:10.1111/j.1440-1797.2008.01073.x^,1818 .Kontodimopoulos N, Niakas D. An estimate of lifelong costs and QALYs in renal replacement therapy based on patients’ life expectancy. Health Policy. 2008;86(1):85-96. DOI:10.1016/j.healthpol.2007.10.002^,3232 .Perovic S, Jankovic S. Renal transplantation vs hemodialysis: cost-effectiveness analysis. Vojnosanit Pregl.2009;66(8):639-44. DOI:10.2298/VSP0908639P Gender differences regarding kidney transplants have been reported in the literature and observed in the clinical practice over the last decades. They affect transplant results, such as in acute and chronic rejections and graft and patient survival rates. Women have less access to transplants. They have increased risk of acute rejection and decreased risk of chronic rejection – those risks increase with age.⁹9 .Gallieni M, Mezzina N, Pinerolo C, Granata A. Sex and gender differences in nephrology. In: Oertelt-Prigione S, Regitz-Zagrosek V, editors. Sex and gender aspects in clinical medicine. New York꞉ Springer Science & Business Media; 2011. p.83-100.^,2222 .Meier-Kriesche HU, Ojo AO, Leavy SF, Hanson JA, Leichtman AB, Magee JC, et al. Gender differences in the risk for chronic renal allograft failure.Transplantation. 2001;71(3):429-32. DOI:10.1097/00007890-200102150-00016 In turn, women are observed to account for around 65.0% of living kidney donors.⁷7 .Csete M. Gender issues in transplantation. Anesth Analg. 2008;107(1):232-8. DOI:10.1213/ane.0b013e318163feaf^,3737 .Segev DL, Kucirka LM, Oberai PC, Parekh RS, Boulware LE, Powe NR, et al. Age and comorbidities are effect modifiers of gender disparities in renal transplantation. J Am Soc Nephrol. 2009;20(3):621-8. DOI:10.1681/ASN.2008060591 The etiology of those differences is still unknown, but it probably reflects hormone, immunological, and aging differences, as well as prejudice.⁷7 .Csete M. Gender issues in transplantation. Anesth Analg. 2008;107(1):232-8. DOI:10.1213/ane.0b013e318163feaf^,2222 .Meier-Kriesche HU, Ojo AO, Leavy SF, Hanson JA, Leichtman AB, Magee JC, et al. Gender differences in the risk for chronic renal allograft failure.Transplantation. 2001;71(3):429-32. DOI:10.1097/00007890-200102150-00016^,2828 .Oertelt-Prigione S. Sex and gender in medical literature. In: Oertelt-Prigione S, Regitz-Zagrosek V, editors. Sex and gender aspects in clinical medicine. London Springer; 2012. p.9-15.

Survival rates are higher among women following kidney transplants,⁹9 .Gallieni M, Mezzina N, Pinerolo C, Granata A. Sex and gender differences in nephrology. In: Oertelt-Prigione S, Regitz-Zagrosek V, editors. Sex and gender aspects in clinical medicine. New York꞉ Springer Science & Business Media; 2011. p.83-100.^,1111 .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(4):188-95. DOI:10.2478/v10035-011-0029-1 but the data are not confirmed by the literature. In a South African study, worse survival rates have been observed among women, but no significant differences were found between genders in graft survival.²³23 .Moosa MR. Impact of age, gender and race on patient and graft survival following renal transplantation: developing country experience.S Afr Med J. 2003;93(9):689-95. In another study, no differences were observed between genders in patient and graft survival rates.²⁷27 .Nyberg G, Blohmé I, Nordén G. Gender differences in a kidney transplant population. Nephrol Dial Transplant.1997;12(3):559-63. DOI:10.1093/ndt/12.3.559

Knowing differences across genders is necessary to identify possible barriers in the achievement of ideal results and in the development of interventions that overcome those barriers. This review, by focusing on those gender-related differences in the clinical effectiveness of immunosuppressive therapies for kidney transplant maintenance, may promote better understanding, provide more efficient health care, contribute to the creation of clinical protocols, and promote better long-term results for patients.

The objective of this review was to analyze whether genders influence patient and graft survival rates in kidney transplants.

METHODS

This review was conducted according to the recommendations from the Cochrane Collaboration Handbook.^aa Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions: version 5.1.0. London: The Cochrane Collaboration; 2011 [cited 2014 Feb 6]. Available from: http://www.cochrane-handbook.org The article was prepared according to Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA).²¹21 .Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med.2009;151(4):W-65-94. DOI:10.7326/0003-4819-151-4-200908180-00136

Observational cohort studies were selected. The selection included studies with patients who received kidney transplants from living or deceased donors for the first time or more than once, mentioning gender differences concerning pre-transplant characteristics, and finding survival results for grafts, patients, or for both. Studies that did not involve immunosuppressants for maintenance of kidney transplants, pharmacokinetic studies, economic evaluation studies, review studies, and studies conducted on animals were excluded, as per the exclusion criteria.

An electronic search was performed for articles published until December 2013, on Medline (PubMed), Latin-American and Caribbean Center on Health Sciences Information (LILACS), Cochrane Controlled Trials Databases (CENTRAL), Embase databases. Manual searches were also conducted in the reference lists of all studies selected from the published systematic review.⁴⁴44 .Zhou JY, Cheng J, Huang HF, Shen Y, Jiang Y, Chen JH. The effect of donor recipient gender mismatch on short- and- long term graft survival in kidney transplantation: a systematic review and meta analysis. Clin Transplant. 2013;27(5):764-71. DOI:10.1111/ctr.12191Studies from the grey literature were also sought after: in the thesis and essay database from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior(CAPES – Coordination for the Improvement of Undergraduate Personnel), inBiblioteca Digital Brasileira de Teses e Dissertações(Brazilian Digital Library of Thesis and Dissertations), and in Universidade de São Paulo’s Digital Library of Theses and Dissertations. There were no restrictions regarding dates and languages of publications. Table 1 describes the search strategy used in each surveyed database.

After duplicate studies were excluded, two independent reviewers selected the references in three phases: analysis of titles, abstracts, and full texts. The disagreements were settled by a third reviewer. The data – including methodological quality, subject information, treatment length, and patient and graft survival rates – were extracted and collected in duplicate in a Microsoft Excel 2010 spreadsheet.

Methodological quality evaluations were independently conducted by the reviewers, and related disagreements were settled through the consensus among reviewers. Newcastle-Ottawa scale^bb Wells GA, Shea B, O’Connelll D, Peterson J, Welch V, Losos M, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Ottawa: Ottawa Hospital Research Institute; 2014 [cited 2014 Feb 6]. Available from: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp for observational studies was used. In this scale, each study is evaluated in three dimensions: selection of study groups; the comparability among groups; and the ascertainment of either the exposure or outcome of interest. Total score was up to nine stars – above six, studies are considered to be high quality.

In order to be analyzed, the studies were grouped according to the comparison of results among:

a)Donor genders – male donors (MD) and female donors (FD);

b)Recipient genders – male recipients (MR) and female recipients (FR);

c)Donor-recipient genders – male donor-male recipient transplants (MD-MR), male donor-female recipient transplants (MD-FR), female donor-female recipient transplants (FD-FR), female donor-male recipient transplants (FD-MR).

The study data were combined using randomized effects model in Metaview module of Review Manager software, version 5.3. The results were presented as relative risk for dichotomous variables, with a confidence interval of 95%. Analyses with I²2 .Avula S, Sharma RK, Singh AK, Gupta A, Kumar A, Agrawal S, et al. Age and gender discrepancies in living related renal transplant donors and recipients. Transplant Proc. 1998;30(7):3674. DOI:10.1016/S0041-1345(98)01189-0 > 40.0% and p-value of Chi-squared test < 0.10 were considered to be significant heterogeneity. A sensitivity analysis was conducted to investigate heterogeneity causes, with the exclusion of one study at a time, with changes being verified in the values of I²2 .Avula S, Sharma RK, Singh AK, Gupta A, Kumar A, Agrawal S, et al. Age and gender discrepancies in living related renal transplant donors and recipients. Transplant Proc. 1998;30(7):3674. DOI:10.1016/S0041-1345(98)01189-0 and p.

The outcomes that were evaluated in the meta-analysis were graft survival and patient survival per follow-up period (one, two, three, five, eight, 10 years or more).

RESULTS

A total of 5,993 publications were initially identified in the electronic databases, and seven through manual searches, all adding up to 6,000 publications. Of these, 500 publications were excluded because of the participant type, 5,251 due to study type and 177 due to the intervention. The main causes for excluded studies were: studies that did not analyze the outcome of interest (patient and graft survival rates), ones that did not include kidney transplants, review, pharmacokinetic, pharmacoeconomic studies, among others. After duplicate publications were eliminated and the reviewers conducted their analyses, 29 cohort studies were included, which involved 765.753 patients. Among those, six studies compared the measurements from results involving donor genders (MD and FD); eight studies, involving recipient genders (MR and FR), and for 20 others, results involving donor-recipient genders (MD-MR, MD-FR, FD-FR, FD-MR) (Figure). One study was included in donor, recipient, and donor-recipient gender comparisons;⁵5 .Busson M, Benoit G. Is matching for sex and age beneficial to kidney graft survival? Societé Française de Transplantation and Association France Transplant. Clin Transplant.1997;11(1):15-8. another one¹⁴14 .Inoue S, Yamada Y, Kuzuhara K, Ubara Y, Hara S, Ootubo O. Are women privileged organ recipients? Transplant Proc.2002;34(7):2775-6. DOI:10.1016/S0041-1345(02)03408-5 was included in the comparison between recipient and donor-recipient genders; and two studies, in the comparison between donor and donor-recipient genders.³3 .Ben Hamida F, Ben Abdallah T, Abdelmoula M, Mejri H, Goucha R, Abderrahim E, et al. Impact of donor/recipient gender, age, and HLA matching on graft survival following living-related renal transplantation.Transplant Proc. 1999;31(8):3338-9. DOI:10.1016/S0041-1345(99)00817-9^,2525 .Neugarten J, Srinivas T, Tellis V, Silbiger S, Greenstein S. The effect of donor gender on renal allograft survival. J Am Soc Nephrol. 1996;7(2):318-24.

Out of the 29 observational studies included, 28 were retrospective and one was prospective.³⁸38 .Shaheen FAM, Al Sulaiman M, Mousa D, El Din ABS, Hawas F, Fallatah A, et al. Impact of donor/recipient gender, age, HLA matching, and weight on short-term graft survival following living related renal transplantation.Transplant Proc. 1998;30(7):3655-8. DOI:10.1016/S0041-1345(98)01179-8 Most studies have not reported average follow-up periods, and the data from the cohorts were collected from 1978 to 2009. In the comparison between donor genders, 9,673 subjects were evaluated in the six studies. In the comparison between recipient genders, 84,070 subjects were evaluated in the eight studies included. In the comparison between donor-recipient genders, 672,010 subjects were evaluated in the 20 studies included. In regards to types of donors, 12 studies evaluated deceased donors, eight evaluated living donors, and nine evaluated both kinds (living and deceased) (Table 2).

The majority of subjects (donor, recipient, and donor-recipient) were males, for all gender comparisons. All studies included evaluated graft survival rates, but only eight of them evaluated patient survival rates.¹1 .Abou-Jaoude MM, Abou-Jaoude WJ, Almawi WY. Sex matching plays a role in outcome of kidney transplant. Exp Clin Transplant. 2012;10(5):466-70. DOI:10.6002/ect.2011.0205^,1414 .Inoue S, Yamada Y, Kuzuhara K, Ubara Y, Hara S, Ootubo O. Are women privileged organ recipients? Transplant Proc.2002;34(7):2775-6. DOI:10.1016/S0041-1345(02)03408-5^,2020 .Lankarani MM, Assari S, Nourbala MH. Improvement of renal transplantation outcome through matching donors and recipients. Ann Transplant. 2009;14(4):20-5.^,2222 .Meier-Kriesche HU, Ojo AO, Leavy SF, Hanson JA, Leichtman AB, Magee JC, et al. Gender differences in the risk for chronic renal allograft failure.Transplantation. 2001;71(3):429-32. DOI:10.1097/00007890-200102150-00016^,2323 .Moosa MR. Impact of age, gender and race on patient and graft survival following renal transplantation: developing country experience.S Afr Med J. 2003;93(9):689-95.^,2727 .Nyberg G, Blohmé I, Nordén G. Gender differences in a kidney transplant population. Nephrol Dial Transplant.1997;12(3):559-63. DOI:10.1093/ndt/12.3.559^,3939 .Shaheen MF, Shaheen FAM, Attar B, Elamin K, Al Hayyan H, Al Sayyari A. Impact of recipient and donor nonimmunologic factors on the outcome of deceased donor kidney transplantation. Transplant Proc.2010;42(1):273-6. DOI:10.1016/j.transproceed.2009.12.052^,4343 .Zeier M, Dohler B, Opelz G, Ritz E. The effect of donor gender on graft survival. J Am Soc Nephrol. 2002;13(10):2570-6. DOI:10.1097/01.ASN.0000030078.74889.69

Out of the 29 studies included, two of them were observed to have scores of six as per New-Castle Ottawa scale;²2 .Avula S, Sharma RK, Singh AK, Gupta A, Kumar A, Agrawal S, et al. Age and gender discrepancies in living related renal transplant donors and recipients. Transplant Proc. 1998;30(7):3674. DOI:10.1016/S0041-1345(98)01189-0^,44 .Buchler M, Al Najjar A, Duvallon C, Lanson Y, Bagros P, Nivet H, et al. Role of donor characteristics on long-term renal allograft survival.Transplant Proc. 1997;29(5):2345. DOI:10.1016/S0041-1345(97)00394-1 14 (48,3%) of them had score seven; and 13, eight (Table 2).

Out of the six studies included in the systematic review for donor gender comparison, five of them were included in the meta-analysis for graft survival outcome.³3 .Ben Hamida F, Ben Abdallah T, Abdelmoula M, Mejri H, Goucha R, Abderrahim E, et al. Impact of donor/recipient gender, age, and HLA matching on graft survival following living-related renal transplantation.Transplant Proc. 1999;31(8):3338-9. DOI:10.1016/S0041-1345(99)00817-9

4 .Buchler M, Al Najjar A, Duvallon C, Lanson Y, Bagros P, Nivet H, et al. Role of donor characteristics on long-term renal allograft survival.Transplant Proc. 1997;29(5):2345. DOI:10.1016/S0041-1345(97)00394-1^-55 .Busson M, Benoit G. Is matching for sex and age beneficial to kidney graft survival? Societé Française de Transplantation and Association France Transplant. Clin Transplant.1997;11(1):15-8.^,2929 .Oien CM, Reisaeter AV, Leivestad T, Dekker FW, Line PD, OS I. Living donor kidney transplantation: the effects of donor age and gender on short-and long-term outcomes. Transplantation. 2007;83(5):600-6. DOI:10.1097/01.tp.0000255583.34329.dd^,4141 .Valdes F, Pita S, Alonso A, Rivera CF, Cao M, Fontan MP, et al. The effect of donor gender on renal allograft survival and influence of donor age on posttransplant graft outcome and patient survival. Transplant Proc. 1997;29(8):3371-2. DOI:10.1016/S0041-1345(97)01026-9 The study by Neugarten et al²⁵25 .Neugarten J, Srinivas T, Tellis V, Silbiger S, Greenstein S. The effect of donor gender on renal allograft survival. J Am Soc Nephrol. 1996;7(2):318-24. was not found to have enough numerical data for the quantitative analysis. The studies included in the donor gender comparison did not evaluate patient survival.

Regarding graft survival, the relative risks (RR), as grouped chronologically according to follow-up periods of one, two, three, five, and ten years were, respectively, 1.02 (95%CI 0.97;1.07; p = 0.43; I² = 70.0%), 1.03 (95%CI 1.00;1.07; p = 0.07; I² = 27.0%), 1.02 (95%CI 0.94;1.12; p = 58; I² = 67.0%), 0.89 (95%CI 0.79;1.00; p = 0.06; I² = 0%), 0.86 (95%CI 0.73;1.02; p = 0.09; I² = 11.0%;), and 0.82 (95%CI 0.68;0.98; p = 0.03; I² = 0%). Only at the 10-year follow-up period was the difference significant for graft survival, favoring male donors. Heterogeneity was high and significant for follow-up periods of one and three years (Table 3).

Out of the eight studies included in the systematic review for recipient gender comparison, six were included in the meta-analysis for graft survival outcome.²2 .Avula S, Sharma RK, Singh AK, Gupta A, Kumar A, Agrawal S, et al. Age and gender discrepancies in living related renal transplant donors and recipients. Transplant Proc. 1998;30(7):3674. DOI:10.1016/S0041-1345(98)01189-0^,55 .Busson M, Benoit G. Is matching for sex and age beneficial to kidney graft survival? Societé Française de Transplantation and Association France Transplant. Clin Transplant.1997;11(1):15-8.^,66 .Chen PD, Tsai MK, Lee CY, Yang CY, Hu RH, Lee PH, et al. Gender differences in renal transplant graft survival. J Formos Med Assoc. 2013;112(12):783-8. DOI:10.1016/j.jfma.2013.10.011^,1414 .Inoue S, Yamada Y, Kuzuhara K, Ubara Y, Hara S, Ootubo O. Are women privileged organ recipients? Transplant Proc.2002;34(7):2775-6. DOI:10.1016/S0041-1345(02)03408-5^,2323 .Moosa MR. Impact of age, gender and race on patient and graft survival following renal transplantation: developing country experience.S Afr Med J. 2003;93(9):689-95.^,3535 .Sánchez Garcia F, Torres A, Magariño M, Wichmann I, Nuñez Roldán A. Influence of cyclosporine on sex-related differences observed in the outcome of cadaveric human-kidney allografts. Inmunologia.1989;8(3):107-9. The studies by Nyberg et al²⁷27 .Nyberg G, Blohmé I, Nordén G. Gender differences in a kidney transplant population. Nephrol Dial Transplant.1997;12(3):559-63. DOI:10.1093/ndt/12.3.559 and Meier-Kriesche et al²²22 .Meier-Kriesche HU, Ojo AO, Leavy SF, Hanson JA, Leichtman AB, Magee JC, et al. Gender differences in the risk for chronic renal allograft failure.Transplantation. 2001;71(3):429-32. DOI:10.1097/00007890-200102150-00016 were not found to have numerical data in order to be included in the quantitative analysis. Thus, meta-analyses were conducted for monitored periods of one, five, and 10 years or more.

In the meta-analysis regarding graft survival for one year, four comparisons of three studies were included. In the study by Sánchez Garcia et al,³⁵35 .Sánchez Garcia F, Torres A, Magariño M, Wichmann I, Nuñez Roldán A. Influence of cyclosporine on sex-related differences observed in the outcome of cadaveric human-kidney allografts. Inmunologia.1989;8(3):107-9. (1989) the influence from immunosuppressive therapy was compared to genders in two groups: Sánchez Garcia et al³⁵35 .Sánchez Garcia F, Torres A, Magariño M, Wichmann I, Nuñez Roldán A. Influence of cyclosporine on sex-related differences observed in the outcome of cadaveric human-kidney allografts. Inmunologia.1989;8(3):107-9. (1989a), ciclosporin-treated; and Sánchez Garcia et al³⁵35 .Sánchez Garcia F, Torres A, Magariño M, Wichmann I, Nuñez Roldán A. Influence of cyclosporine on sex-related differences observed in the outcome of cadaveric human-kidney allografts. Inmunologia.1989;8(3):107-9. (1989b), ciclosporin-untreated.

Regarding graft survival, the relative risks (RR), as grouped chronologically according to follow-up periods of one, five, and 10 years or more were, respectively, 1.01 (95%CI 0.99;1.03; p = 0.30; I² = 0%), 0.99 (95%CI 0.88;1.12; p = 0.88; I² = 75.0%), 1.23 (95%CI 0.68;2.24; p = 0.50; I² = 95.0%). No significant differences were found for any of the follow-up periods, and no recipient genders were highlighted among the groups. Heterogeneity was high and significant for follow-up periods of five and 10 years or more (Table 3).

Regarding patient survival, two studies were included in the related meta-analysis.¹⁴14 .Inoue S, Yamada Y, Kuzuhara K, Ubara Y, Hara S, Ootubo O. Are women privileged organ recipients? Transplant Proc.2002;34(7):2775-6. DOI:10.1016/S0041-1345(02)03408-5^,2424 .Muller V, Szabó A, Viklicky O, Gaul I, Portl S, Philipp T, et al. Sex hormones and gender related-differences: their influence on chronic renal allograft rejection. Kid Intern. 1999;55(5):2011-20. The meta-analysis was conducted for the follow-up period of 10 years or more, heterogeneity was high and the difference was not significant (RR = 0.96; 95%CI 0.67;1.37; p = 0.81; I² = 95.0%) (Table 3).

In order to evaluate donor-recipient genders, six comparisons were analyzed: MD-MRversus FD-MR, MD-MR versus FD-FR, MD-MRversus MD-FR, MD-FR versus FD-FR, MD-FRversus FD-MR, FD-FR versus FD-MR. Regarding graft survival outcome, 13 studies were included¹1 .Abou-Jaoude MM, Abou-Jaoude WJ, Almawi WY. Sex matching plays a role in outcome of kidney transplant. Exp Clin Transplant. 2012;10(5):466-70. DOI:10.6002/ect.2011.0205^,55 .Busson M, Benoit G. Is matching for sex and age beneficial to kidney graft survival? Societé Française de Transplantation and Association France Transplant. Clin Transplant.1997;11(1):15-8.^,88 .Ellison MD, Norman DJ, Breen TJ, Edwards EB, Davies DB, Daily OP. No effect of H-Y minor histocompatibility antigen in zero-mismatched living-donor renal transplants. Transplantation.1994;58(4):518-20. DOI:10.1097/00007890-199408270-00020^,1111 .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(4):188-95. DOI:10.2478/v10035-011-0029-1^,1515 .Jacobs SC, Nogueira JM, Phelan MW, Bartlett ST, Cooper M. Transplant recipient renal function is donor renal mass- and recipient gender-dependent. Transpl Int. 2008;21(4):340-5. DOI:10.1111/j.1432-2277.2007.00617.x

16 .Kayler LK, Rasmussen CS, Dykstra DM, Ojo AO, Port FK, Wolfe RA, et al. Gender imbalance and outcomes in living donor renal transplantation in the United States. Am J Transplant. 2003;3(4):452-8. DOI:10.1034/j.1600-6143.2003.00086.x^-1717 .Kim SJ, Gill JS. H-Y incompatibility predicts short-term outcomes for kidney transplant recipients. J Am Soc Nephrol.2009;20(9):2025-33. DOI:10.1681/ASN.2008101110^,1919 .Kwon OJ, Kwak JY. The impact of sex and age matching for long-term graft survival in living donor renal transplantation. Transplant Proc. 2004;36(7):2040-2. DOI:10.1016/j.transproceed.2004.07.046^,2020 .Lankarani MM, Assari S, Nourbala MH. Improvement of renal transplantation outcome through matching donors and recipients. Ann Transplant. 2009;14(4):20-5.^,3838 .Shaheen FAM, Al Sulaiman M, Mousa D, El Din ABS, Hawas F, Fallatah A, et al. Impact of donor/recipient gender, age, HLA matching, and weight on short-term graft survival following living related renal transplantation.Transplant Proc. 1998;30(7):3655-8. DOI:10.1016/S0041-1345(98)01179-8

39 .Shaheen MF, Shaheen FAM, Attar B, Elamin K, Al Hayyan H, Al Sayyari A. Impact of recipient and donor nonimmunologic factors on the outcome of deceased donor kidney transplantation. Transplant Proc.2010;42(1):273-6. DOI:10.1016/j.transproceed.2009.12.052^-4040 .Tan JC, Kim JP, Chertow GM, Grumet FC, Desai M. Donor-recipient sex mismatch in kidney transplantation. Gend Med. 2012;9(5):335-47. DOI:10.1016/j.genm.2012.07.004^,4343 .Zeier M, Dohler B, Opelz G, Ritz E. The effect of donor gender on graft survival. J Am Soc Nephrol. 2002;13(10):2570-6. DOI:10.1097/01.ASN.0000030078.74889.69 in the meta-analyses (Table 4).

The remaining studies were not found to have enough data for the quantitative analysis.³3 .Ben Hamida F, Ben Abdallah T, Abdelmoula M, Mejri H, Goucha R, Abderrahim E, et al. Impact of donor/recipient gender, age, and HLA matching on graft survival following living-related renal transplantation.Transplant Proc. 1999;31(8):3338-9. DOI:10.1016/S0041-1345(99)00817-9^,1010 .Giral M, Nguyen JM, Karam G, Kessler M, Ligny BH, Buchler M, et al. Impact of graft mass on the clinical outcome of kidney transplants. J Am Soc Nephrol. 2005;16(1):261-8. DOI:10.1681/ASN.2004030209^,1212 .GratwohL A, Döhler B, Stern M, Opelz G. H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study. Lancet. 2008;372(9632):49-53. DOI:10.1016/S0140-6736(08)60992-7^,1414 .Inoue S, Yamada Y, Kuzuhara K, Ubara Y, Hara S, Ootubo O. Are women privileged organ recipients? Transplant Proc.2002;34(7):2775-6. DOI:10.1016/S0041-1345(02)03408-5^,2525 .Neugarten J, Srinivas T, Tellis V, Silbiger S, Greenstein S. The effect of donor gender on renal allograft survival. J Am Soc Nephrol. 1996;7(2):318-24.^,4242 .Vereerstraeten P, Wissing M, De Pauw L, Abramowicz D, Kinnaert P. Male recipients of kidneys from female donors are at increased risk of graft loss from both rejection and technical failure. Clin Transplant. 1999;13(2):181-6. DOI:10.1034/j.1399-0012.1999.130205.x^,4545 .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(8):2914-6. DOI:10.1016/j.transproceed.2011.08.068 For the patient survival outcome, two studies were included in the meta-analysis.¹1 .Abou-Jaoude MM, Abou-Jaoude WJ, Almawi WY. Sex matching plays a role in outcome of kidney transplant. Exp Clin Transplant. 2012;10(5):466-70. DOI:10.6002/ect.2011.0205^,2020 .Lankarani MM, Assari S, Nourbala MH. Improvement of renal transplantation outcome through matching donors and recipients. Ann Transplant. 2009;14(4):20-5.

The studies by Ellison et al⁸8 .Ellison MD, Norman DJ, Breen TJ, Edwards EB, Davies DB, Daily OP. No effect of H-Y minor histocompatibility antigen in zero-mismatched living-donor renal transplants. Transplantation.1994;58(4):518-20. DOI:10.1097/00007890-199408270-00020 and Tan et al⁴⁰40 .Tan JC, Kim JP, Chertow GM, Grumet FC, Desai M. Donor-recipient sex mismatch in kidney transplantation. Gend Med. 2012;9(5):335-47. DOI:10.1016/j.genm.2012.07.004 separately evaluated transplants from living and deceased donors, and the total numbers of events and subjects in each study were included in the meta-analysis, considering living and deceased donors. In the study by Abou-Jaoude et al,¹1 .Abou-Jaoude MM, Abou-Jaoude WJ, Almawi WY. Sex matching plays a role in outcome of kidney transplant. Exp Clin Transplant. 2012;10(5):466-70. DOI:10.6002/ect.2011.0205 rates regarding general graft survival and graft survival as interrupted by death with functioning graft were calculated. The uninterrupted graft survival rate was the one used in the meta-analysis.

In the MD-MR versus FD-MR comparison, the RRs as grouped for graft survival in a chronological order of follow-up periods of one, two, three, five, and 10 years were, respectively, 1,03 (95%CI 1.01;1.05; p = 0.0002; I² = 92.0%), 1.05 (95%CI 1.03;1.08; p < 0.0001; I² = 25.0%), 1.06 (95%CI 1.02;1.09; p = 0.0008; I² = 72.0%), 1.15 (95%CI 1.00;1.33; p = 0.05; I² = 100%), and 1.08 (95%CI 1.05;1.11; p < 0.00001; I²= 91.0%). The graft survival rate was significantly higher in all follow-up periods evaluated, and it favored MD-MR pair. Heterogeneity was high and significant for all periods, except for the two-year follow-up period. The patient survival analysis was only conducted for the one-year follow-up period, and no pairs were observed to be favored (RR = 0.99; 95%CI 0.96;1.02; p = 0.52; I² = 0.0%).

In the MD-MR versus FD-FR comparison, the RRs as grouped for graft survival in a chronological order of follow-up periods of one, two, three, five, and 10 years were, respectively, 1.02 (95%CI 1.01;1.04; p = 0.0008; I² = 83.0%), 1.02 (95%CI 1.00;1.04; p < 0.10; I² = 9.0%), 1.05 (95%CI 1.01;1.09; p = 0.02; I² = 73.0%), 1.02 (95%CI 1.01;1.03; p = 0.0004; I² = 50.0%), and 1.02 (95%CI 0.97;1.07; p = 0.43; I² = 97.0%). The graft survival rate was significantly higher in follow-up periods of one, three, and five years, and it favored MD-MR pair. Heterogeneity only was not significant for the two-year follow-up period. The patient survival meta-analysis was observed to favor none of the pairs (RR = 0.98; 95%CI 0.95;1.01; p = 0.21; I² = 0%).

In the MD-MR versus MD-FR comparison, the RRs as grouped for graft survival in a chronological order of follow-up periods of one, two, three, five, and 10 years were, respectively, 1.01 (95%CI 1.01;1.02; p = 0.0009; I² = 67.0%), 1.01 (95%CI 0.99;1.03; p = 0.32; I² = 0%), 1.03 (95%CI 1.00;1.06; p = 0.07; I² = 76.0%), 1.00 (95%CI 0.97;1.03; p = 0.98; I² = 91.0%), and 0.96 (95%CI 0.86;1.06; p = 0.38; I² = 99.0%). The graft survival rate was only significantly higher for the one-year follow-up period, favoring the MD-MR pair. Heterogeneity only was not significant for the two-year follow-up period. The patient survival meta-analysis was observed to favor none of the pairs (RR = 1.00; 95%CI 0.98;1.03; p = 0.86; I² = 0%).

In the MD-FR versus FD-FR comparison, the RRs as grouped for graft survival in a chronological order of follow-up periods of one, two, three, five, and 10 years were, respectively, 1.01 (95%CI 0.99;1.02; p = 0.30; I² = 77.0%), 1.01 (95%CI 0.98;1.03; p = 0.61; I² = 0%), 1.01 (95%CI 1.00;1.02; p = 0.0007; I² = 0%), 1.01 (95%CI 1.00;1.03; p = 0.11; I² = 66.0%), and 1.04 (95%CI 1.02;1.06; p = 0.0003; I² = 80.0%). The graft survival rate was significantly higher in follow-up periods of three and ten years, and it favored MD-FR pair. Heterogeneity only was not significant for the two and three-year follow-up periods. The patient survival meta-analysis was observed to favor none of the pairs (RR = 0.98; 95%CI 0.94;1.01; p = 0.19; I² = 0%).

In the MD-FR versus FD-FR comparison, the RRs as grouped for graft survival in a chronological order of follow-up periods of one, two, three, five, and 10 years were, respectively, 1.01 (95%CI 1.00;1.03; p = 0.15; I² = 90.0%), 1.05 (95%CI 1.01;1.10; p = 0.01; I² = 36.0%), 1.03 (95%CI 1.00;1.05; p = 0.04; I² = 44.0%), 1.18 (95%CI 1.03;1.35; p = 0.02; I² = 100%), and 1.10 (95%CI 1.01;1.21; p = 0.03; I² = 99.0%). The graft survival rate was significantly higher for all follow-up periods, except for the one-year one, favoring MD-FR pair. Heterogeneity was high and significant for all periods, except for the two-year follow-up period. The patient survival meta-analysis was observed to favor none of the pairs (RR = 0.99; 95%CI 0.95;1.02; p = 0.44; I² = 0%).

In the FD-FR versus FD-MR comparison, the RRs as grouped for graft survival in a chronological order of follow-up periods of one, two, three, five, and 10 years were, respectively, 1.01 (95%CI 0.99;1.02; p = 0.45; I² = 80.0%), 1.03 (95%CI 0.99;1.07; p = 0.18; I² = 51.0%), 1.01 (95%CI 0.98;1.04; p = 0.53; I² = 44.0%), 1.14 (95%CI 0.99;1.31; p = 0.07; I² = 100%), and 1.06 (95%CI 0.98;1.14; p = 0.14; I² = 98.0%). There were no significant differences regarding graft survival considering all follow-up periods. Heterogeneity was high and significant for all periods, except for the three-year follow-up period. The patient survival meta-analysis was observed to favor none of the pairs (RR = 1.01; 95%CI 0.97;1.06; p = 0.54; I² = 0%).

DISCUSSION

This meta-analysis evaluated the influences of donor genders, recipient genders, and the donor-recipient combination in regards to kidney transplant patient and graft survival rates.

In the comparison between donor genders, 9,022 subjects were evaluated in the meta-analysis. Donor genders were not found to favor gender rates in the evaluation of one, two, three, five, and eight-year follow-up periods (p < 0.05). Ten-year follow-up period was the only observed to differ significantly, favoring male donors (p = 0.03). The study by Muller²⁴24 .Muller V, Szabó A, Viklicky O, Gaul I, Portl S, Philipp T, et al. Sex hormones and gender related-differences: their influence on chronic renal allograft rejection. Kid Intern. 1999;55(5):2011-20.concluded that kidney grafts from male patients work better than the ones from female donors in the long run. Several studies suggest that, in those cases, the grafts from female donors are more antigenic, which may explain the lower survival rates.²²22 .Meier-Kriesche HU, Ojo AO, Leavy SF, Hanson JA, Leichtman AB, Magee JC, et al. Gender differences in the risk for chronic renal allograft failure.Transplantation. 2001;71(3):429-32. DOI:10.1097/00007890-200102150-00016^,3030 .Paavonen T. Hormonal regulation of immune responses. Ann Med. 1994;26(4):255-8. DOI:10.3109/07853899409147900^,3131 .Panajotopoulos N, Ianhez LE, Neumann J, Sabbaga E, Kalil J. Immunological tolerance in human transplantation. The possible existence of a maternal effect. Transplantation. 1990;50(3):443-5. DOI:10.1097/00007890-199009000-00016^,3636 .Sanfey H. Gender-specific issues in liver and kidney failure and transplantation: a review. J Womens Health. 2005;14(7):617-26. DOI:10.1089/jwh.2005.14.617

In the comparison between recipient genders in all follow-up periods, 9,593 subjects were evaluated in the meta-analysis, and no significant differences were observed regarding graft survival. Patient survival analysis considered 747 patients. No significant differences were found among the studies. The study by Busson and Benoit⁵5 .Busson M, Benoit G. Is matching for sex and age beneficial to kidney graft survival? Societé Française de Transplantation and Association France Transplant. Clin Transplant.1997;11(1):15-8. evaluated the influence from recipient and donor genders and the donor-recipient combination. Recipient genders were the only ones for which significant differences were not found.

The comparison between donor-recipient genders included 471,252 patients. MD-MR pair should be highlighted for having been observed to have the best results in all comparisons (MD-MR versus FD-MR, MD-MR versusFD-FR, MD-MR versus MD-FR); that is, kidney transplants from male donors to male recipients were found to have the best graft survival rates. Nonetheless, FD-MR pair was found to have the worst results (FD-MRversus MD-MR, FD-MR versus MD-FR), except for the FD-MR versus FD-FR comparison. Those results are comparable with other reviews.⁷7 .Csete M. Gender issues in transplantation. Anesth Analg. 2008;107(1):232-8. DOI:10.1213/ane.0b013e318163feaf^,4444 .Zhou JY, Cheng J, Huang HF, Shen Y, Jiang Y, Chen JH. The effect of donor recipient gender mismatch on short- and- long term graft survival in kidney transplantation: a systematic review and meta analysis. Clin Transplant. 2013;27(5):764-71. DOI:10.1111/ctr.12191

The assessment of differences between genders is important to improve transplant results. Men and women have different biological factors, different body conditions, hormone circumstances, and immune responses, as well as different metabolic and functional demands, which can influence kidney transplant results.⁴⁴44 .Zhou JY, Cheng J, Huang HF, Shen Y, Jiang Y, Chen JH. The effect of donor recipient gender mismatch on short- and- long term graft survival in kidney transplantation: a systematic review and meta analysis. Clin Transplant. 2013;27(5):764-71. DOI:10.1111/ctr.12191 Gender incompatibilities in FD-MR pair are argued to negatively influence graft survival due to kidney sizes and their numbers of nephrons. The ratio between graft and recipient weights is an important one.²⁶26 .Nicholson ML, Windmill DC, Horsburgh T, Harris KP. Influence of allograft size to recipient body-weight ratio on the long-term outcome of renal transplantation. Br J Surg. 2000;87(3):314-9. DOI:10.1046/j.1365-2168.2000.01390.x^,3333 .Poggio ED, Hila S, Stephany B, Fatica R, Krishnamurthi V, Del Bosque C, et al. Donor kidney volume and outcomes following live donor kidney transplantation. Am J Transplant. 2006;6(3):616-24. DOI:10.1111/j.1600-6143.2005.01225.x

Giral et al¹⁰10 .Giral M, Nguyen JM, Karam G, Kessler M, Ligny BH, Buchler M, et al. Impact of graft mass on the clinical outcome of kidney transplants. J Am Soc Nephrol. 2005;16(1):261-8. DOI:10.1681/ASN.2004030209 analyzed the consequences from kidney mass reduction following kidney transplants, and they concluded kidney graft mass to impact glomerular filtration and proteinuria rates. The authors suggest that great kidney-to-recipient weight ratios be avoided, once that might significantly influence long-term kidney function.

That meta-analysis only included cohort studies. One of the limitations from systematic reviews with meta-analyses of observational studies regards to the selection bias that is intrinsic to this study design and to uncontrolled confounding factors. Observational cohort studies are the ones conducted in the real world, under conditions uncontrolled for. In regards to that, differences were observed in the subject numbers among the groups, types of donors (living, deceased, or both), numbers of transplants, monitored periods, among others. Despite that, observational studies are observed to have the advantages of gathering a large number of patients and best representing the real world.

Another limitation in the interpretation of results was the statistical heterogeneity among studies, which was found in the meta-analyses. The small number of studies included in the comparisons, and the lack of complete, accurate information in the studies made it difficult to account for heterogeneity sources. Most studies were not observed to include immunosuppressive therapies, ages (donors and recipients), or monitored periods. The sensitivity analysis, in which studies were included and excluded for each comparison, in general, has not altered the directions of outcomes, having changes of small relevance in heterogeneity values. It has not provided information on the possible causes for heterogeneity either.

However, the results from this review can be considered for decision-making by medical teams responsible for transplants in the clinical practice, once it represents the best level of evidence regarding the topic.

Gender incompatibilities must be avoided whenever possible. Genders must be considered as criteria in the choices regarding allocation of organs from donors and to recipients. Gender combinations may make a difference in survival rates. Nonetheless, that reality is utopic in the clinical practice, due to the scarcity of donors and the increase in the number of patients on waiting lists for transplants. A change in that scenario is required in order to improve the allocation of organs.

In conclusion, recipient and donor genders, when evaluated isolatedly, do not influence patient or graft survival rates. However, combinations between donor-recipient genders may be a determining factor for graft survival, favoring MD-MR pair.

REFERENCES

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