- Email: [email protected]
HLA-Identical Sibling Renal Transplantation: Influence of Donor and Recipient Gender Mismatch on Long-term Outcomes
HLA-Identical Sibling Renal Transplantation: Influence of Donor and Recipient Gender Mismatch on Long-term Outcomes Mediha Borana,*, Mertay Boranb, and Ertay Boranc a Department of Nephrology, Hemodialysis and Transplantation, Turkiye Higher Education Hospital, Ankara; bDepartment of Thoracic Surgery and cDepartment of Anesthesiology and Reanimation, Duzce University School of Medicine, Duzce, Turkey
ABSTRACT Background. Long-term function of living-related kidney allograft depends on multiple variables. The aim of the present study was to assess the influence of donor and recipient gender mismatch on the short and long-term outcomes in human leukocyte antigen (HLA)-identical sibling renal transplants (SRTs) receiving induction therapy and different immunosuppressive regimens. Material and Methods. Twenty-nine recipients who were grafted from their HLAidentical siblings between 1994 and 2008 were divided into 2 groups (same and mismatched) according to gender of donor and recipient. The analyzed variables were age, gender, cholesterol, triglyceride, proteinuria, estimated glomerular filtration rate, weight, body mass index, and serum creatinine at 6, 12, 24, 36, 48, and 60 months, and median follow-up. Univariate and multivariate logistic regression models (when appropriate) were used to evaluate the effects of variables on allograft survival. Results. The number of male donors (P ¼ .001) and recipient age (P ¼ .019) was significantly higher in the same gender group than in mismatched gender group; there were no relationships between remainder analyzed parameters. Multivariate regression analysis revealed that after median follow-up period of 84 months (range, 60e232) the most important potential factors to significantly influence long-term outcomes were male donor (P ¼ .002), recipient age (P < .001), and donor age (P ¼ .021). Conclusion. Our study demonstrated that male donor, and donor and recipient age affected long-term survival of HLA-identical SRTs, supported with antibody induction therapy and lifetime immunosuppression.
T
HE USE of calcineurin inhibitors in kidney transplantation has resulted in improvement of graft survival [1]. Instead, lifetime immunosuppressive drugs remain necessary even in human leukocyte antigen (HLA)-identical renal transplants [2]. Moreover, it is well-known that graft survival in HLA-identical kidney transplants have a much lower incidence of acute rejection episodes than HLAnonidentical recipients [3,4]. These outcomes are the result of HLA-identical recipients being less immunogenic than HLA-nonidentical recipients, because all major HLA molecules are identical, and only mismatches in minor histocompatibility antigens (mHAgs) may exist. H-Y mHAgs have been associated with acute rejection episodes in smaller gender mismatched investigations of bone marrow [5] and corneal and kidney transplants [6,7]. Our
retrospective analysis compared the influence of donor and recipient gender mismatch in HLA-identical sibling renal transplants (SRTs) receiving induction therapy and maintenance immunosuppression in the long term. MATERIALS AND METHODS The present study included 29 HLA-identical SRTs who were transplanted between February 1994 and June 2008 in a single center. The transplant was classed as HLA identical if a sibling was reported to have identical HLA-A-B-C-DR. The sibling pairs were not identical twins. It was a first transplantation for all of the
*Address correspondence to Mediha Boran, Çetin Emeç Blv 101/ 41 Balgat, Ankara, Turkey. E-mail: [email protected]
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.06.076
Transplantation Proceedings, 46, 3423e3425 (2014)
3423
3424
BORAN, BORAN, AND BORAN Table 1. Patient Demographics and Laboratory Data by Gender Groups Gender Groups
Same Group
Mismatched Group
P
Recipient age (y) Recipient sex, male (n, %) Donor age (y) Donor sex, male (n, %) Cholesterol (mg/dL) Triglycerides (mg/dL) Proteinuria (mg/d) eGFR (mL/min/1.73 m2) Median follow-up (mo) Creatinine (mg/dL) 6 months 12 months 24 months 36 months 48 months 60 months Final Weight/BMI Preoperatively 6 months 12 months 24 months 36 months 48 months 60 months Final
39.3 10.2 16 (84.2) 37.6 10.2 16 (84.2) 187.8 44.8 154.1 65.2 75.9 45.2 87.3 19.2 91 (60e232)
31.3 6.9 8 (80) 34.1 8.1 2 (20) 196.2 24.6 184.2 64.3 76.6 30.4 88.6 14.2 78 (60e231)
.019 .7 .5 .001 .5 .2 .6 .8 .4
1.09 1.11 1.118 1.16 1.13 1.07 1.09
0.24 0.24 0.33 0.38 0.35 0.32 0.25
1.08 1.15 1.10 1.04 1.07 1.01 1.00
66.0 12/23.7 3.2 70.6 10.8/23.8 3.3 72.9 11.1/25.6 2.7 75.2 10.2/27.1 2.8 75.2 10.3/27.2 2.9 75.1 10.8/27.2 2.9 76.1 11.6/27.5 3.3 76.9 10.3/27.9 2.9
0.22 0.33 0.24 0.18 0.19 0.17 0.17
60.1 8.5/22.6 3.0 66.2 11.7/25.7 4.2 70.1 12.2/26.4 4.4 70.5 11.6/26.5 4 71.8 12.9/26.9 4.4 72.1 13.1/27.1 4.5 707 12.1/26.5 4.2 70.2 11.1/26.4 3.9
.9 .9 .7 .6 .8 .8 .4 .1/.3 .5/.9 .6/.8 .4/.7 .5/.8 .3/.8 .3/.6 .4/.5
Numerical values are expressed as means standard deviation. Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; SD, standard deviation.
recipients. All sibling pairs were determined to have negative crossmatches before transplantation. The recipients were divided into 2 groups according to gender of donor and recipient: Same gender and mismatched gender groups. There were 16 male recipients of male kidney and 3 female recipient of female kidney in the same gender group (n ¼ 19; 65.5%), and 8 male recipients of female kidneys and 2 female recipients of male kidneys in the mismatched group (n ¼ 10; 34.5%). For induction therapy, we used an interleukin 2-receptor-antagonist (basiliximab) 20 mg intraoperatively and on posttransplant day (PTD) 4. Methylprednisolone was administered during surgery (500 mg) and progressively tapered to 10 mg by PTD 8 and 5 mg through PTD 30. Antifungal, antibacterial, and cytomegalovirus prophylaxis were similar between the groups. After PTD 180, 12 patients with stable allograft function, who received a calcineurin inhibitor, were converted to sirolimus. All patients received mycophenolate mofetil 1000 mg/d. Allograft function of transplants was stable during the follow-up period and renal allograft biopsy was not performed. The analyzed variables were age, gender, cholesterol, triglyceride, proteinuria, estimated glomerular filtration rate, and weight, body mass index, and serum creatinine at 6, 12, 24, 36, 48, and 60 months and thereafter, and median follow-up.
Statistical Analysis Statistical analyses were carried out by SPSS for Windows Version 15.0 (SPSS Inc., Chicago, IL). Only descriptive summary statistics, including frequency, mean, median, standard deviations, and/or ranges, were computed for each data. The c2 test was used to compare frequencies. Mean and/or median values of the study variables between groups were compared by KruskaleWallis and
ManneWhitney U tests. Variables (age, gender, cholesterol, triglyceride, proteinuria, estimated glomerular filtration rate, weight, body mass index, and serum creatinine at 6, 12, 24, 36, 48, and 60 months and thereafter) affecting the long-term outcome were studied by univariate analyses than variables which have significant effect on graft survival were studied by stepwise multiple linear regression models (when appropriate). P < .05 were considered significant.
RESULTS
The median follow-up time of patients was 84 months (range, 60e232). The recipient and donor demographics and laboratory data by gender groups are listed in Table 1. The immunosuppressive treatment (cyclosporine, tacrolimus, or sirolimus) was similar (P ¼ .4) across the same gender group (6 [31.6%], 6 [31.6%], and 7 [36.8%], respectively) and the mismatched gender group (1 [10%], 4 [40%], and 5 [50%], respectively). The male donor number and recipient age was significantly higher in the same gender group (P ¼ .001) than in mismatched gender group (P ¼ .019). There were no differences in serum creatinine at 6, 12, 24, 36, 48, or 60 months and thereafter between the groups. Additionally, there was no difference in proteinuria among the groups, which was evaluated with 24-hour urine collections. No difference was shown in total cholesterol, triglyceride, estimated glomerular filtration rate, weight, body mass index, or median follow-up between gender groups. Multivariate linear regression analyses revealed that male donor (b ¼ 0.622; 95% CI, 0.345e0.874;
HLA-IDENTICAL SIBLING RENAL TRANSPLANTS
odds ratio [OR], 1.65; P < .001), donor age (b ¼ 0.555; 95% CI, 0.005e0.052; OR, 1.14; P ¼ .021), and recipient age (b ¼ 0.751; 95% CI, 0.06 to 0.14; OR, 0.793; P ¼ .002) significantly influenced long-term graft survival.
DISCUSSION
HLA-identical SRTs represent a small group of kidney recipients with the best long-term graft survival [4]. Nevertheless, Opelz [8] described an association between the presence of panel- reactive antibodies in kidney transplant from HLA-identical sibling donors and long-term graft loss. After HLA-identical kidney transplantation, mHAgs including H-Y antigens, along with other non-HLA antigens, might be responsible for the induction of acute or chronic rejection of the transplants [8,9]. However, in 67% of HLA-identical kidney transplants donor-reactive T-cell responses are directed to mHAgs or other non-HLA antigens that are detectable even 1 year after transplantation [10]. Therefore, in HLA-identical renal transplants with long-term allograft outcome and lifetime immunosuppressive treatment, discontinuation of immunosuppression may disturb the immunologic balance and lead to rejection [11,12]. Our data showed that induction therapy with basiliximab and maintenance immunosuppression with a calcineurin inhibitor combined with mycophenolate mofetil, or therapy with sirolimus combined with mycophenolate mofetil, provides an effective and safe regimen with stable renal graft function in HLA-identical SRTs. However, overweight and obesity are highly prevalent in the renal transplant population [13]. Consequently, in present study all patients were counseled with attention to nutrition and appropriate diet and weight loss programs with physical activities and immunosuppressive drug doses were lowered in the long term. Many studies have reported inferior longterm allograft survival in male recipients with female organs [14,15]. In contrast, in 195,516 recipients of allograft from deceased female donors had high risk of failure, irrespectively of the sex of recipients [16]. Nevertheless, the investigators found that, compared with all other donore recipient gender groups, the male donorefemale recipient group demonstrated significantly higher H-Y mHAgs (54% vs 8%) [17]. However, it is not known whether the H-Y effect is a short- or long-term effect. In the present study, multivariate analysis revealed that after median follow-up period of 84 months (range, 60e232), the most important potential factors were male donor (P ¼ .002), recipient age (P < .001), and donor age (P ¼ .021), which significantly influenced long-term outcomes. The limitations of our study are its retrospective nature and a small number of patients (organ transplantation between identical twins is very rare and the number of HLA-
3425
identical siblings recipients is also small). Future multicenter, controlled studies are needed to confirm our results. In conclusion, male donor gender, and donor and recipient age were the factors that affected long-term survival of immunologically privileged HLA-identical SRTs, supported with antibody induction therapy and lifetime immunosuppressive regimen. REFERENCES [1] Hariharan S, Johnson CP, Bresnahan BA, et al. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000;342:605e12. [2] Seigler HF, Gunnells Jr JC, Robinson RR, et al. Renal transplantation between HL-A identical donor-recipient pairs. Functional and morphological evaluation. J Clin Invest 1972;51:3200e15. [3] Keitel E, Santos AF, Alves MA, et al. Immunosuppression protocols for HLA identical renal transplant recipients. Transplant Proc 2003;35:1074e5. [4] Shimmura H, Tanabe K, Ishida H, et al. Long-term results of living kidney transplantation from HLA-identical sibling donors under calcineurin inhibitor immunosuppression. Int J Urol 2006;13: 502e8. [5] Voogt PJ, Goulmy E, Fibbe WE, et al. Minor histocompatibility antigen H-Y is expressed on human hematopoietic progenitor cells. J Clin Invest 1988;82:906e12. [6] Böhringer D, Spierings E, Enczmann J, et al. Matching of the minor histocompatibility antigen HLA-A1/H-Y may improve prognosis in corneal transplantation. Transplantation 2006;82:1037e41. [7] Pfeffer PF, Thorsby E. HLA-restricted cytotoxicity against male-specific (H-Y) antigen after acute rejection of an HLAidentical sibling kidney: clonal distribution of the cytotoxic cells. Transplantation 1982;33:52e6. [8] Opelz G. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet 2005;365:1570e6. [9] Joosten SA, van Kooten C. Non-HLA humoral immunity and chronic kidney-graft loss. Lancet 2005;365:1522e3. [10] Gerrits JH, van de Wetering J, Drabbels JJ, et al. Non-HLA T-cell reactivity during the first year after HLA-identical livingrelated kidney transplantation. Clin Transplant 2009;23:740e7. [11] Peddi VR, Weiskittel P, Alexander JW, et al. HLA-identical renal transplant recipients: immunosuppression, long-term complications, and survival. Transplant Proc 2001;33:3411e3. [12] Goulmy E, Schipper R, Pool J, et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med 1996;334:281e5. [13] Meier-Kriesche HU, Arndorfer JA, Kaplan B. The impact of body mass index on renal transplant outcomes: a significant independent risk factor for graft failure and patient death. Transplantation 2002;73:70e4. [14] Kwon OJ, Kwak JY. The impact of sex and age matching for long-term graft survival in living donor renal transplantation. Transplant Proc 2004;36:2040e2. [15] Zeier M, Döhler B, Opelz G, et al. The effect of donor gender on graft survival. J Am Soc Nephrol 2002;13:2570e6. [16] Gratwohl A, Döhler B, Stern M, et al. H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study. Lancet 2008;372:49e53. [17] 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;86:75e81.
ABSTRACT Background. Long-term function of living-related kidney allograft depends on multiple variables. The aim of the present study was to assess the influence of donor and recipient gender mismatch on the short and long-term outcomes in human leukocyte antigen (HLA)-identical sibling renal transplants (SRTs) receiving induction therapy and different immunosuppressive regimens. Material and Methods. Twenty-nine recipients who were grafted from their HLAidentical siblings between 1994 and 2008 were divided into 2 groups (same and mismatched) according to gender of donor and recipient. The analyzed variables were age, gender, cholesterol, triglyceride, proteinuria, estimated glomerular filtration rate, weight, body mass index, and serum creatinine at 6, 12, 24, 36, 48, and 60 months, and median follow-up. Univariate and multivariate logistic regression models (when appropriate) were used to evaluate the effects of variables on allograft survival. Results. The number of male donors (P ¼ .001) and recipient age (P ¼ .019) was significantly higher in the same gender group than in mismatched gender group; there were no relationships between remainder analyzed parameters. Multivariate regression analysis revealed that after median follow-up period of 84 months (range, 60e232) the most important potential factors to significantly influence long-term outcomes were male donor (P ¼ .002), recipient age (P < .001), and donor age (P ¼ .021). Conclusion. Our study demonstrated that male donor, and donor and recipient age affected long-term survival of HLA-identical SRTs, supported with antibody induction therapy and lifetime immunosuppression.
T
HE USE of calcineurin inhibitors in kidney transplantation has resulted in improvement of graft survival [1]. Instead, lifetime immunosuppressive drugs remain necessary even in human leukocyte antigen (HLA)-identical renal transplants [2]. Moreover, it is well-known that graft survival in HLA-identical kidney transplants have a much lower incidence of acute rejection episodes than HLAnonidentical recipients [3,4]. These outcomes are the result of HLA-identical recipients being less immunogenic than HLA-nonidentical recipients, because all major HLA molecules are identical, and only mismatches in minor histocompatibility antigens (mHAgs) may exist. H-Y mHAgs have been associated with acute rejection episodes in smaller gender mismatched investigations of bone marrow [5] and corneal and kidney transplants [6,7]. Our
retrospective analysis compared the influence of donor and recipient gender mismatch in HLA-identical sibling renal transplants (SRTs) receiving induction therapy and maintenance immunosuppression in the long term. MATERIALS AND METHODS The present study included 29 HLA-identical SRTs who were transplanted between February 1994 and June 2008 in a single center. The transplant was classed as HLA identical if a sibling was reported to have identical HLA-A-B-C-DR. The sibling pairs were not identical twins. It was a first transplantation for all of the
*Address correspondence to Mediha Boran, Çetin Emeç Blv 101/ 41 Balgat, Ankara, Turkey. E-mail: [email protected]
ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/14 http://dx.doi.org/10.1016/j.transproceed.2014.06.076
Transplantation Proceedings, 46, 3423e3425 (2014)
3423
3424
BORAN, BORAN, AND BORAN Table 1. Patient Demographics and Laboratory Data by Gender Groups Gender Groups
Same Group
Mismatched Group
P
Recipient age (y) Recipient sex, male (n, %) Donor age (y) Donor sex, male (n, %) Cholesterol (mg/dL) Triglycerides (mg/dL) Proteinuria (mg/d) eGFR (mL/min/1.73 m2) Median follow-up (mo) Creatinine (mg/dL) 6 months 12 months 24 months 36 months 48 months 60 months Final Weight/BMI Preoperatively 6 months 12 months 24 months 36 months 48 months 60 months Final
39.3 10.2 16 (84.2) 37.6 10.2 16 (84.2) 187.8 44.8 154.1 65.2 75.9 45.2 87.3 19.2 91 (60e232)
31.3 6.9 8 (80) 34.1 8.1 2 (20) 196.2 24.6 184.2 64.3 76.6 30.4 88.6 14.2 78 (60e231)
.019 .7 .5 .001 .5 .2 .6 .8 .4
1.09 1.11 1.118 1.16 1.13 1.07 1.09
0.24 0.24 0.33 0.38 0.35 0.32 0.25
1.08 1.15 1.10 1.04 1.07 1.01 1.00
66.0 12/23.7 3.2 70.6 10.8/23.8 3.3 72.9 11.1/25.6 2.7 75.2 10.2/27.1 2.8 75.2 10.3/27.2 2.9 75.1 10.8/27.2 2.9 76.1 11.6/27.5 3.3 76.9 10.3/27.9 2.9
0.22 0.33 0.24 0.18 0.19 0.17 0.17
60.1 8.5/22.6 3.0 66.2 11.7/25.7 4.2 70.1 12.2/26.4 4.4 70.5 11.6/26.5 4 71.8 12.9/26.9 4.4 72.1 13.1/27.1 4.5 707 12.1/26.5 4.2 70.2 11.1/26.4 3.9
.9 .9 .7 .6 .8 .8 .4 .1/.3 .5/.9 .6/.8 .4/.7 .5/.8 .3/.8 .3/.6 .4/.5
Numerical values are expressed as means standard deviation. Abbreviations: BMI, body mass index; eGFR, estimated glomerular filtration rate; SD, standard deviation.
recipients. All sibling pairs were determined to have negative crossmatches before transplantation. The recipients were divided into 2 groups according to gender of donor and recipient: Same gender and mismatched gender groups. There were 16 male recipients of male kidney and 3 female recipient of female kidney in the same gender group (n ¼ 19; 65.5%), and 8 male recipients of female kidneys and 2 female recipients of male kidneys in the mismatched group (n ¼ 10; 34.5%). For induction therapy, we used an interleukin 2-receptor-antagonist (basiliximab) 20 mg intraoperatively and on posttransplant day (PTD) 4. Methylprednisolone was administered during surgery (500 mg) and progressively tapered to 10 mg by PTD 8 and 5 mg through PTD 30. Antifungal, antibacterial, and cytomegalovirus prophylaxis were similar between the groups. After PTD 180, 12 patients with stable allograft function, who received a calcineurin inhibitor, were converted to sirolimus. All patients received mycophenolate mofetil 1000 mg/d. Allograft function of transplants was stable during the follow-up period and renal allograft biopsy was not performed. The analyzed variables were age, gender, cholesterol, triglyceride, proteinuria, estimated glomerular filtration rate, and weight, body mass index, and serum creatinine at 6, 12, 24, 36, 48, and 60 months and thereafter, and median follow-up.
Statistical Analysis Statistical analyses were carried out by SPSS for Windows Version 15.0 (SPSS Inc., Chicago, IL). Only descriptive summary statistics, including frequency, mean, median, standard deviations, and/or ranges, were computed for each data. The c2 test was used to compare frequencies. Mean and/or median values of the study variables between groups were compared by KruskaleWallis and
ManneWhitney U tests. Variables (age, gender, cholesterol, triglyceride, proteinuria, estimated glomerular filtration rate, weight, body mass index, and serum creatinine at 6, 12, 24, 36, 48, and 60 months and thereafter) affecting the long-term outcome were studied by univariate analyses than variables which have significant effect on graft survival were studied by stepwise multiple linear regression models (when appropriate). P < .05 were considered significant.
RESULTS
The median follow-up time of patients was 84 months (range, 60e232). The recipient and donor demographics and laboratory data by gender groups are listed in Table 1. The immunosuppressive treatment (cyclosporine, tacrolimus, or sirolimus) was similar (P ¼ .4) across the same gender group (6 [31.6%], 6 [31.6%], and 7 [36.8%], respectively) and the mismatched gender group (1 [10%], 4 [40%], and 5 [50%], respectively). The male donor number and recipient age was significantly higher in the same gender group (P ¼ .001) than in mismatched gender group (P ¼ .019). There were no differences in serum creatinine at 6, 12, 24, 36, 48, or 60 months and thereafter between the groups. Additionally, there was no difference in proteinuria among the groups, which was evaluated with 24-hour urine collections. No difference was shown in total cholesterol, triglyceride, estimated glomerular filtration rate, weight, body mass index, or median follow-up between gender groups. Multivariate linear regression analyses revealed that male donor (b ¼ 0.622; 95% CI, 0.345e0.874;
HLA-IDENTICAL SIBLING RENAL TRANSPLANTS
odds ratio [OR], 1.65; P < .001), donor age (b ¼ 0.555; 95% CI, 0.005e0.052; OR, 1.14; P ¼ .021), and recipient age (b ¼ 0.751; 95% CI, 0.06 to 0.14; OR, 0.793; P ¼ .002) significantly influenced long-term graft survival.
DISCUSSION
HLA-identical SRTs represent a small group of kidney recipients with the best long-term graft survival [4]. Nevertheless, Opelz [8] described an association between the presence of panel- reactive antibodies in kidney transplant from HLA-identical sibling donors and long-term graft loss. After HLA-identical kidney transplantation, mHAgs including H-Y antigens, along with other non-HLA antigens, might be responsible for the induction of acute or chronic rejection of the transplants [8,9]. However, in 67% of HLA-identical kidney transplants donor-reactive T-cell responses are directed to mHAgs or other non-HLA antigens that are detectable even 1 year after transplantation [10]. Therefore, in HLA-identical renal transplants with long-term allograft outcome and lifetime immunosuppressive treatment, discontinuation of immunosuppression may disturb the immunologic balance and lead to rejection [11,12]. Our data showed that induction therapy with basiliximab and maintenance immunosuppression with a calcineurin inhibitor combined with mycophenolate mofetil, or therapy with sirolimus combined with mycophenolate mofetil, provides an effective and safe regimen with stable renal graft function in HLA-identical SRTs. However, overweight and obesity are highly prevalent in the renal transplant population [13]. Consequently, in present study all patients were counseled with attention to nutrition and appropriate diet and weight loss programs with physical activities and immunosuppressive drug doses were lowered in the long term. Many studies have reported inferior longterm allograft survival in male recipients with female organs [14,15]. In contrast, in 195,516 recipients of allograft from deceased female donors had high risk of failure, irrespectively of the sex of recipients [16]. Nevertheless, the investigators found that, compared with all other donore recipient gender groups, the male donorefemale recipient group demonstrated significantly higher H-Y mHAgs (54% vs 8%) [17]. However, it is not known whether the H-Y effect is a short- or long-term effect. In the present study, multivariate analysis revealed that after median follow-up period of 84 months (range, 60e232), the most important potential factors were male donor (P ¼ .002), recipient age (P < .001), and donor age (P ¼ .021), which significantly influenced long-term outcomes. The limitations of our study are its retrospective nature and a small number of patients (organ transplantation between identical twins is very rare and the number of HLA-
3425
identical siblings recipients is also small). Future multicenter, controlled studies are needed to confirm our results. In conclusion, male donor gender, and donor and recipient age were the factors that affected long-term survival of immunologically privileged HLA-identical SRTs, supported with antibody induction therapy and lifetime immunosuppressive regimen. REFERENCES [1] Hariharan S, Johnson CP, Bresnahan BA, et al. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 2000;342:605e12. [2] Seigler HF, Gunnells Jr JC, Robinson RR, et al. Renal transplantation between HL-A identical donor-recipient pairs. Functional and morphological evaluation. J Clin Invest 1972;51:3200e15. [3] Keitel E, Santos AF, Alves MA, et al. Immunosuppression protocols for HLA identical renal transplant recipients. Transplant Proc 2003;35:1074e5. [4] Shimmura H, Tanabe K, Ishida H, et al. Long-term results of living kidney transplantation from HLA-identical sibling donors under calcineurin inhibitor immunosuppression. Int J Urol 2006;13: 502e8. [5] Voogt PJ, Goulmy E, Fibbe WE, et al. Minor histocompatibility antigen H-Y is expressed on human hematopoietic progenitor cells. J Clin Invest 1988;82:906e12. [6] Böhringer D, Spierings E, Enczmann J, et al. Matching of the minor histocompatibility antigen HLA-A1/H-Y may improve prognosis in corneal transplantation. Transplantation 2006;82:1037e41. [7] Pfeffer PF, Thorsby E. HLA-restricted cytotoxicity against male-specific (H-Y) antigen after acute rejection of an HLAidentical sibling kidney: clonal distribution of the cytotoxic cells. Transplantation 1982;33:52e6. [8] Opelz G. Non-HLA transplantation immunity revealed by lymphocytotoxic antibodies. Lancet 2005;365:1570e6. [9] Joosten SA, van Kooten C. Non-HLA humoral immunity and chronic kidney-graft loss. Lancet 2005;365:1522e3. [10] Gerrits JH, van de Wetering J, Drabbels JJ, et al. Non-HLA T-cell reactivity during the first year after HLA-identical livingrelated kidney transplantation. Clin Transplant 2009;23:740e7. [11] Peddi VR, Weiskittel P, Alexander JW, et al. HLA-identical renal transplant recipients: immunosuppression, long-term complications, and survival. Transplant Proc 2001;33:3411e3. [12] Goulmy E, Schipper R, Pool J, et al. Mismatches of minor histocompatibility antigens between HLA-identical donors and recipients and the development of graft-versus-host disease after bone marrow transplantation. N Engl J Med 1996;334:281e5. [13] Meier-Kriesche HU, Arndorfer JA, Kaplan B. The impact of body mass index on renal transplant outcomes: a significant independent risk factor for graft failure and patient death. Transplantation 2002;73:70e4. [14] Kwon OJ, Kwak JY. The impact of sex and age matching for long-term graft survival in living donor renal transplantation. Transplant Proc 2004;36:2040e2. [15] Zeier M, Döhler B, Opelz G, et al. The effect of donor gender on graft survival. J Am Soc Nephrol 2002;13:2570e6. [16] Gratwohl A, Döhler B, Stern M, et al. H-Y as a minor histocompatibility antigen in kidney transplantation: a retrospective cohort study. Lancet 2008;372:49e53. [17] 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;86:75e81.