|Year : 2019 | Volume
| Issue : 2 | Page : 365-375
|Impact of age and gender matching on long-term graft function and actual graft survival in live-related renal transplantation: Retrospective study from Sindh Institute of Urology and transplantation, Pakistan
Madhu Mati Shahani, Tanweer Iqbal, Muhammad Khalid Idrees
Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
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|Date of Submission||09-Dec-2017|
|Date of Decision||13-Feb-2018|
|Date of Acceptance||14-Feb-2018|
|Date of Web Publication||23-Apr-2019|
| Abstract|| |
In renal transplantation, donor and allograft age are known to have an important influence on the outcome of the graft, reflecting functional renal mass. We evaluated the impact of gender and age matching in living-donor renal transplantation on long-term graft survival and actual graft function over five years from the day of transplantation. We retrospectively analyzed 500 primary live-related donor renal transplants performed from August 2007 to December 2008 at Sindh Institute of Urology and Transplantation, Karachi, Pakistan. Donors and recipients were divided into two age groups [young (YD) and elderly (ER)] with 40 years as cutoff line. Four donor recipient groups according to age match and age mismatch: YD/YR – ED/ER – YD/ER – ED/YR and four groups according to donor-recipient gender combinations: male recipients of male donors (MR/MD)–female recipients of male donors (FR/MD)–female recipients of female donors (FR/FD)–male recipients of female donors MR/FD) were studied. Serum creatinine was used to assess graft function after transplantation. The Kaplan–Meier method with the log-rank test was used to assess actual graft survival at five years. Actual graft function of four study groups based on age difference had no statistically significant difference at five years (P = 0.094). Regarding the actual graft survival, the best results were seen in young donor to elderly recipient group as compared to all other age combination groups. At five-year post-transplant, MD/MR had significantly better graft function than MR/FD and FR/MD had significantly better graft function than FD/FR and FD/MR. The actual graft survival was best in male-to-male (86%) compared to the lowest in female-to-female transplants (75%). The graft function at five years was better in elderly recipients of young donor kidneys. The actual graft survival was influenced positively by young donor age and negatively influenced by pre-transplant hepatitis C positivity of recipients.
|How to cite this article:|
Shahani MM, Iqbal T, Idrees MK. Impact of age and gender matching on long-term graft function and actual graft survival in live-related renal transplantation: Retrospective study from Sindh Institute of Urology and transplantation, Pakistan. Saudi J Kidney Dis Transpl 2019;30:365-75
|How to cite this URL:|
Shahani MM, Iqbal T, Idrees MK. Impact of age and gender matching on long-term graft function and actual graft survival in live-related renal transplantation: Retrospective study from Sindh Institute of Urology and transplantation, Pakistan. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 May 24];30:365-75. Available from: http://www.sjkdt.org/text.asp?2019/30/2/365/256844
| Introduction|| |
Kidney transplant is till now the best available treatment of end-stage renal disease (ESRD), but it is available to only a small number of patients requiring renal replacement therapy. Pakistan, like many other developing countries, is facing an epidemic of chronic kidney disease with limited resources to manage this epidemic. Only 25% of ESRD patients get renal replacement therapy and only lucky ones get kidney transplant as live donors are the only source of organs in the absence of cadaveric transplantation in the country. Donor shortage is a universal problem. In developing countries, living donors (LDs) provide 85% to 100% of donations as compared to 1% to 25% in the developed world. The availability of live donors is limited by predominantly young people affected by renal failure, collapsing joint family system, multiple family members having renal or systemic diseases, social and religious beliefs, and lack of awareness. The gap between demand and supply of organs for transplantation is widening with each passing day. In an attempt to close the widening gap, transplant physicians nowadays accept organs from older donors who might have been considered inappropriate in the past. As a consequence, the question which has become of growing importance is to what extent donor age and recipient age influence long-term outcome after renal transplantation. Meanwhile, it is well established that graft survival of the kidneys from younger donors is significantly better as compared to that of the kidneys from older donors. Concerning recipient age, graft survival has been shown to be equal in old and young recipients. Unfortunately, the influences of donor age and recipient age on renal allograft survival were analyzed separately from each other and most of the studies included data from deceased donors (DDs). Few investigations, in which the combined influence of donor age and recipient age on renal allograft survival have been analyzed and had inconclusive results. It has been proved that both short-term and long-term graft function from LDs are better than those from DDs. However, factors impacting graft function from DD have been studied thoroughly; factors impacting graft function from LD still remain unclear. As there is ongoing discussion about the question of whether the influence of donor age and recipient age on long-term renal allograft survival is dependent on each other, we performed the following study on LD.
| Subjects and Methods|| |
This retrospective study comprised ABO compatible live-related kidney transplants performed at the Sindh Institute of Urology and Transplantation Karachi, Pakistan, from August 2007 to December 2008. Only blood-related donors (siblings/parents/maternal/paternal uncle/ aunt) or spouse, 18–60 years old were accepted as donors. Variables included in this study were age, gender, body mass index, primary kidney disease, duration on dialysis before transplantation, degree of the human leukocyte antigen (HLA) mismatch, donor creatinine clearance, and consanguinity. Serum creatinine was used to assess graft function after transplantation. Posttransplant follow-up included serum creatinine levels at 6, 12, 24, 36, 48, and 60 months after transplantation. Renal allograft survival was defined as the interval between transplantation and either resumption of dialysis or second transplantation. Both actual graft survival and functional graft survival were analyzed. Death with functioning graft was considered as allograft failure in the analysis of actual graft survival.
Treatment regimen after transplantation
All one haplotype match recipients received triple immunosuppression prednisolone/azathioprine/cyclosporine, whereas recipients with poor match received prednisolone/mycophenolate/ tacrolimus and induction with IL2RB (basili-ximab) or anti-thymocyte globulin. All pediatric age-group recipients (<14 years) received induction with basiliximab. After an episode of rejection, the immunosuppression medications were altered for patients receiving azathioprine and cyclosporine to mycophenolate (MMF) and tacrolimus in 1 haplotype match recipients for certain duration, and then if the creatinine remains static and there is no further episode of rejection, medications were switched back to initial ones. Cyclosporin was gradually tapered and stopped over three years in recipients with identical match (zero mismatch). Calcineurin inhibitors (CNIs) were switched to the mammalian target of rapamycin inhibitors (everolimus) in selected patients who showed CNI toxicity on renal biopsy. In our center, we try to switch patients back on azathioprine/ cyclosporin from MMF/ tacrolimus if no rejection episode occurs and graft function remains well. Because of these reasons, this variable was not considered in this study.
Management of data
Donors and recipients were divided into two groups according to age: young donor (YD) and young recipient (YR) (<40 years), elderly donor (ED), and elderly recipient (ER) (>40 years). Based on this, four groups were generated, representing four possible age match combination:
Group 1: YD/YR (n = 300), Group 2: ED/ER (n = 28), Group 3: YD/ER (n = 54), and Group 4: ED/YR (n = 118).
The cases were also divided into groups based on the age difference between donor and recipient.
The data were divided into four groups according to gender match and mismatch transplant between donor and recipient; Group A – male donor/male recipient (MD/MR), Group B – male donor/female recipient (MD/FR), Group C – female donor/female recipient (FD/FR), and Group D – female donor/male recipient (FD/MR).
| Statistical Analysis|| |
Donor, recipient, and transplant characterristics as well as outcome results were presented as mean ± standard deviation and/or frequency. One-way analysis of variance (ANOVA) was used to detect significant differences for quantitative data. The Chi-square test was used to compare categorical variables. P <0.05 in two-tailed testing was considered statistically significant. Renal allograft survival was analyzed according to the Kaplan–Meier plots with a log-rank test. In order to assess the unadjusted relationship of other relevant predictors for actual graft survival, a univariate regression analysis was performed. All variables that were predictive (P <0.20) in the univariate analysis were candidates for subsequent multivariate analysis. Controlling for these relevant predictors, actual graft survival according to age match between donor and recipient was analyzed using multivariate, stepwise Cox proportional hazards regression analysis. Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) software version 20.0 (SPSS, Chicago, IL, USA).
| Results|| |
The total sample of 500 cases had follow-up for five years. The mean age of recipients was 29.06 ± 11.08 years (range 7–62 years). The mean age of living donors was 34.67 ± 9.69 years (range 18–60 years).
In the early posttransplant period at six months, allograft function was better in both young and elderly recipients of young donor kidneys as compared to that of recipients whose donors were elderly and this difference persisted till 48 months. Subsequently, at five years, graft function was better in elderly recipients of young donor kidneys (YD/ER) [Table 1] and [Table 2]. The actual graft survival of kidneys from young donors (<40 years) was slightly better in elderly recipients as compared to that of young recipients (87% vs. 85%), but it was not statistically significant. Kidneys from elderly donors transplanted in elderly recipients had the lowest survival as compared to young recipients (80% vs. 75%), but it was not statistically significant (P = 0.12) [Figure 1].
|Table 1: Posttransplant serum creatinine level (mg/dL) (n) in different age match groups.|
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|Figure 1: The influence of age match on actual graft survival (Kaplan–Meier plot with a log-rank test). Survival of kidneys from elderly donors was lowest in elderly recipients as compared to young recipients (80% vs. 75%), but it was statically nonsignificant (P = 0.12).|
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Age difference was calculated by subtracting donor age from recipient age. The age difference between donors and recipients ranged from few months to 42 years (donor older than recipient) and few months up to 30 years (donor younger than recipient). Age difference ≤10 years between donor and recipient showed better graft survival at five years when donor was younger as compared to when the donor was older than the recipient (89% vs. 86%). When the age difference was >10 years, similar results were observed; better graft survival at five years when donor was younger than recipient (86% vs. 78%). However, the difference was not statistically significant (P = 0.38/0.07) [Table 3].
Results are shown in [Table 4] and [Table 5]. At six, 12, 24 months, Group B (MD/FR) had better renal function than all other groups whereas Group D (FD/MR) had worst renal function as compared to other groups. There was no significant difference between Group A (MD/MR) and C (FD/FR). At three to four years, recipients of male donor kidney (Group A and B) had statistically significant better renal function than recipients of female donor kidney (Group C and D). At five-year posttransplant, Group A (MD/MR) had better graft function than Group D (FD/MR) and Group B (MD/ FR) had better graft function than Group C (FD/FR) and Group D (FD/MR). This difference was statistically significant. The actual graft survival was best in male to male (86%) compared to lowest in female to female (75%) while male to female was 85% versus 82% in female to male, but the difference in graft survival among groups was not statistically significant (P = 0.34) [Figure 2].
|Table 4: Posttransplant serum creatinine (mg/dL) (n) in gender match groups.|
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|Figure 2: The influence of gender match on actual graft survival (Kaplan–Meier plot with a log-rank).|
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Donor and recipient variables
The relevant patient characteristics of the four patient groups are shown in [Table 6]. In ANOVA, there was significant difference in creatinine clearance among the groups. On applying the post-hoc test, it was found that creatinine clearance of YD/YR was significantly better than that of ED/YR. In order to evaluate the unadjusted relationship of each of these variables with regard to actual graft survival, a univariate regression analysis was performed, characteristics included and results are shown in [Table 7]. Hepatitis C antibody positive patients were transplanted when either disease was not active or it had been treated with antiviral regimen consisting of interferon and ribavarin (HCV RNA not detected in blood by polymerase chain reaction). Frequency of hepatitis C in our transplant patients was 16.6% (n = 83). Etiology of ESRD did not have any significant impact of graft survival except the patients who had ESRD secondary to DM. From this analysis, it turned out that donor age, DM and HCV positivity in recipients before transplant were predictive for renal allograft survival (P <0.05) while the remaining factors were not predictive (P >0.05). To further evaluate these relevant predictors, a multivariate stepwise Cox proportional hazards regression analysis was performed which showed that actual graft survival was significantly influenced by donor age [P = 0.03, (relative risk) RR - 1.58] and recipient HCV positivity (P = 0.004, RR - 2.013).
| Discussion|| |
The influence of donor age and recipient age on renal allograft survival is well described. However, the question whether their influence on renal allograft survival is dependent on each other, is still sufficiently not answered. The results of few studies in which this question is answered are controversial. There is a widely held belief that placing older donor kidneys in older recipients reduces the physiologic stress on the allograft and thereby prolongs allograft survival.
Donnelly et al, in 1990, reported that the detrimental effect of using organs from donors >50 years can be offset by ensuring the recipient is not more than five years younger than the donor. Waiser et al reported data from 1269 cadaveric renal allograft recipients that functional allograft survival (censored for patient death) was 22.5% when a kidney from an elderly donor (age limit is 55 years) was transplanted into a young recipient, but 68.7% when it was given to an older recipient. The results indicated that functional and even actual long-term graft survival of kidneys from old donors is significantly reduced in young recipients as compared to all other age combinations. They concluded that kidneys from older donors should be transplanted in older recipients. Similar results were reported by Cecka and Terasaki in 1995, that functional graft survival of kidneys from old donors (>60 years) was better in old recipients (>60 years) as compared to all other age groups. In 1994, investigating >30,000 cadaveric kidney transplantations, Alexander confirmed that the impact of both donor and recipient age on the risk of graft failure were independent of each other up to two years after transplantation. Lee et al analyzed 201 cases of the primary living donor kidney transplantation divided into two groups, age-matched (n = 123) versus age-discrepant (n = 78). Results showed disparities of graft survival (P = 0.008) and death-censored graft survival (P = 0.003) between the groups. Five years death-censored graft survival was 97% in the age-matched group and 88% in the age-discrepant group. They further concluded that donor-young recipient age difference of 20 years or more did not affect graft or patient survival. Kute et al from India also found that graft survival up to 10 years was not different when donor-recipient age difference was <20 years as compared with the age difference of >20 years. They concluded that it is reassuring to induct older donors in kidney paired donation program when donor pool is small.
Investigating 397 consecutive first cadaver renal transplants in adult patients, Newstead and Dyer found that one- and three-year graft survival of donor’s kidneys within five years of the recipient’s age was not different from those with age difference of >5 years. They proposed that age-matching need not be used as a recipient selection criterion. Pirsch et al described similar one- and three-year graft survival rates when donors were >30 years younger, 6–29 years younger, within five years of age, and >5 years older than recipients. Young et al from Ontario (Canada) noted that total graft loss was not significantly different between older (≥60 years) and younger living kidney recipients, and standard criteria deceased recipients up to four years after transplantation. Ferrari et al from Australia concluded that living donors up to 30 years older than their recipients provide kidneys of excellent quality and high donor-recipient age difference should not be a restriction in the paired kidney donation program. Thus, it is unclear from these studies whether giving older kidneys to older recipients improves graft survival. Our observational study showed it does not.
None of these studies reported the effects of specific donor and recipient age combinations (interactions) in multivariate analysis that independently adjusted for the intrinsic effects of recipient and donor age. Most of the studies conducted to address the issue of age matching between donor and recipient are referred to data from cadaveric donors. The study is an effort to address this issue.
In this study, the initial transplant period (6, 12, and 24 months) renal function was better in both young and elderly recipients whose donor was young (<40 years), but at five years only elderly recipients of young donors had better renal function and there was no statistically significant difference in serum creatinine among the other groups. In the actual graft survival concerning kidneys from young donors (<40 years), there was a statistically nonsignificant trend toward an improved actual graft survival in elderly recipients as compared to that of young recipients (87% vs. 85%). Survival of kidneys from elderly donors was lowest when transplanted in elderly recipients as compared to young recipients (80% vs. 75%), but the difference was statically nonsignificant (P = 0.12).
When the donor was younger than the recipient, whether age difference was <10 or >10 years, the graft survival at five years showed no statistical significance. Similarly, when the donor was elder than recipient with the age difference between them <10 or >10 years, no statistical significance at five -year graft survival was noted. Hence, we should not restrict live-related organ donation from older donors.
Our results concur with those of Kasiske and Snyder who analyzed 74,297 first cadaver kidney transplantations by using data from the United States Renal Data System. They reported that giving older kidneys to older recipients does not improve overall graft survival and there was no reciprocal adverse effect of giving older donor kidneys to younger recipients. Foley et al found that increased donor age was a significant risk factor for death and graft loss among all age-groups after DD kidney transplantation but not among livingdonor kidney recipients. Our results differ from those of Lin et al who conducted a study on 353 living donors and suggested that younger donor (<48 years) to older recipient has the best renal graft outcome, whereas older donor to young recipient has the worst outcome.
Concerning gender match, kidneys from male donors transplanted to male or female recipients showed better graft function than all other gender combinations, whereas in other groups, there was no statistically significant difference in graft function at five years. The actual graft survival was best in male to male (86%) compared to the lowest in female to female (75%). Difference in graft survival among groups was not statistically significant (P = 0.34). Lin et al observed the worst outcome with female donor to male recipient. Zukowski et al reported that female recipients of male kidneys had a higher graft loss rate than any other gender combinations. Another study showed that after five years of transplantation, male donor gender was the only additional risk factor for graft loss. Retrospective analysis of 766 renal transplant recipients by Chen et al identified that female recipients had significantly longer five-year graft survival than males, irrespective of donor gender. Male transplant recipients have been observed to have worse prognosis than females and this can be due to social and immunological factors. Females are more likely to be donors than recipients. However, females can be better “guardian” as organ recipient because females have better immunosuppressant compliance than males and they undergo follow-up visits, show concern with regard to protecting the graft function and more likely to change habits and adopt healthy lifestyle. The better survival of male donor kidney could be due to better nephron dosing as males have a higher number of nephrons than females. Shortage of organ donors has encouraged the acceptance of spouse as potential live donors. The study included 40 spousal transplants. There remains an issue as to which donor is more acceptable; parents (older age but better HLA matching) versus spouse (young age but poor HLA matching). We did not compare graft function among the two categories of parent versus spouse. Graft survival from spousal donation in the western world is comparable to donation from parent and better than cadaver donor grafts. However, strict criteria for acceptance of spouse as donor should be enforced in Asian countries because of exploitation of female spouse. Our institute has devised strict criteria of accepting spouse (especially wife) as donor only when none of the family members is suitable to donate kidney.
The limitations of our study include retrospective study design with highly varied number of patients in different groups and the use of serum creatinine values as a marker of transplanted kidney (graft) function instead of eGFR.
| Conclusion|| |
The graft function at five years after living donor kidney transplant was better in recipients of young donor kidneys and both male and female recipients of male donor kidneys while actual graft survival was influenced positively by young donor age and negatively influenced by pretransplant hepatitis C positivity of recipients. Keeping in mind, these factors may improve graft function and survival.
Conflict of interest: None declared.
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] [Full text]
Muhammad Khalid Idrees
Department of Nephrology, Sindh Institute of Urology and Transplantation, Karachi
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]
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