The Impact of the donor-recipient gender matching on the graft survival from live donors

doi:10.21203/rs.2.12091/v2

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The Impact of the donor-recipient gender matching on the graft survival from live donors

https://doi.org/10.21203/rs.2.12091/v2

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Background: Several factors like age of recipient, BMI, serum cratinnine , and positive history of dialysis are important in predicting graft survival in kidney transplant recipients. One factor that can affect transplant outcomes and is usually ignored is the gender of donor and recipients. Methods: A total of 1113 kidney transplant recipients were studied in a retrospective cohort study. Several factors were taken into account for graft survival and outcomes like gender and age of donor and recipients in addition to common recipient factors like cratinnine , eGFR, BMI, and positive history of dialysis. Results: The most successful transplant based on donor-recipient gender was seen in male donor to male recipient and then male donor to female recipient. In female transplant recipients, level of serum cratinnine , and eGFR, positive dialysis history before transplant, and low donor hemoglobin level can be good prognostic factors recommended to be considered for kidney transplant survival. Conclusions: Our results suggested that gender matching for kidney transplant. Only on some exceptional occasions, male donor to female recipient kidney transplant may be successful and female donors to male recipients are not suggested, especially in aged patients with history of dialysis.

Urology & Nephrology

kidney transplant

Gender match

Survival

Dialysis

Renal transplantation is ideal treatment strategy. Kidney transplantation has become a more cost-effective alternative to dialysis as a result of several improvements in early graft survival and long-term graft function. The first kidney transplantation was about half a century ago in which transplant was conducted from a live donor to his identical twin. After that, the concept of living and non-living unrelated donor led to an increasing in the number of organ donation in ESRD and the number of kidney transplantations have escalated over the last ten years. More than two thousands kidney transplants in Iran have been reported from among which 50% are deceased (brain death) cases.

Several factors might affect patients and/or graft survival and transplant outcomes. Donor factors such as age, female gender, brain death due to cerebrovascular cause and prolonged criteria donor status had a noteworthy effect on renal graft function (1-3). Gender of both recipients and donors is one of the candidate elements that can be determining in better graft outcomes and gender matching is suggested. Similar graft survival rates for males and females have been reported and a systematic review on gender differences in kidney transplantation led to detecting 14 studies with contradicting results (4, 5). However, more recently, a study from Collaborative Transplant Study confirmed that female recipients of male donor kidneys had the worst graft survival after the first year and up to ten years post-transplant (6).

In this study, we aimed at checking the impact of gender matching on kidney donors and recipients. Moreover, we would like to evaluate predictive markers of graft survival.

In this retrospective cohort study, among 2000 graft recipient patients registered in the transplant center of Shariati Hospital transplant data bank from 2002-2018, 1113 renal graft recipients were chosen for our research. All selected patients were the same in receiving kidneys from living donor but they were different in having the same donor gender and relative or non-relative donors. Patients younger than 18 years old with positive cross-match, incompatible blood group, multiple organ transplantation history, positive chronic viral B, C hepatitis, HIV, pregnancy and diabetes were excluded from the study. In addition, patients with a history of liver disease like (cirrhosis, autoimmune hepatitis including Gamma globulin serum & FANA), primary biliary cirrhosis, biliary obstruction, hemochromatosis, alpha-1- antitrypsin deficiency, Wilson’s disease (including serum ceruloplasmin, transferrin saturation percentage), chronic disabling diseases (severe cardiac dysfunction, chronic obstructive pulmonary disease, malignancy) and known cancers were excluded from study.

Delayed graft function (DGF) is usually defined as need for dialysis during the first week post-transplant that may lead to increased allograft immunogenicity and a higher risk of acute rejection episodes, as well as decreased long-term recipient survival. Delayed graft function was defined by decrease in urine volume (≤400 ml in 24 hours), or needing dialysis one week after receiving the graft. The biopsy was done on patients at risk of rejection with more than 30% increase in basic levels of creatinine. Anti-rejection medication was done by Methylprednisolone and in case of resistance, anti-thymocyte globulin (ATG) is prescribed. Transplant rejection was defined by needing dialysis more than 30 days, death, or graft excision. Patients entering the study were categorized into the following four distinct sub-groups: group 1 (male donor; male recipient), group 2 (male donor; female recipient), group 3 (female donor; male recipient) and group 4 (female donor; female recipient). Clinical data like duration of dialysis before kidney transplantation, serum creatinine, and eGFR (Estimated Glomerular Filtration Rate) for transplant recipients were considered. In addition, some demographic information like age, BMI in both donors and recipients and hemoglobin of donors were also considered. The graft survival, and back to dialysis in addition to death were checked for several factors by multiple logistic regression models.

Statistical Analysis

Actuarial survival was assessed by Kaplan-Meier test and the log derivation of the survival percentage was employed for half-life prediction of grafts and/or patients. Differences in survival were done through log-rank test and p-value< 0.05 was considered as the significant. For determining factors with an independent impact on graft survival, a Cox proportional hazard analysis was utilized. P-value was obtained by Chi 2 test.

The average creatinine levels (mean and standard deviation (SD)) were 1.65 ± 1.46 mg/dl, 1.63 ±1.29 mg/dl, 1.37±0.69 mg/dl and 1.37±0.66 mg/dl one week, one month six months and one year post-transplant, respectively. The mean eGFR was 58.2±22.2 cm³/min in the first month, 62.0±21.4 cm³/min after six months and 62.15 ± 21.1 cm³/min one years after transplant. These decreasing trends in the amount of serum creatinine and the increasing trend in serum eGFR was meaningful (p-value = 0.039). Table 1 is the characteristics of both graft donors - recipients and table 2 the numbers of patients in each gender match groups. Additional data on serum creatinine and eGFR levels of transplant recipients and hemoglobin of donors are shown in table 3 over several times of sampling before and after transplantation.

Table 1: Characteristics considered for both graft donors and recipients.

	Kidney transplant Donor	Kidney transplant Recipient
Mean age (year)	28.20 ± 5.34	35.02 ± 15.63
Female (percent)	202 (18.2%)	438 (39.4%)
BMI	24.02 ± 4.40	23.29 ± 5.41
Dialysis Before Graft	-	852 (76.6 %)
Arterial anastomosis	-	972 (87.4%)
Venous anastomosis	-	1101 (99.2%)
DGF	-	103 (9.3%)

Table 2: The numbers of patients in each gender match groups.

Donor-Recipient Gender	Number	Percent
Male to Male	1123	53/1%
Male to Female	557	26.9%
Female to Female	179	8.8%
Female to Male	213	9.5%
Total	2072	100%

Table 3: Fluctuation of recipients’ serum creatinine and eGFR vs. donors’ hemoglobin

	Time	Male to Male (Means ± SD)	Male to Female (Means ± SD)	Female to Female (Means ± SD)	Female to Male (Means ± SD)	Total	p-value
Serum Creatinine in Graft Recipients	One week after transplant	1.72 ±1.48	1.60 ± 1.46	1.59 ± 1.66	1.65 ± 1.56	1.67 ±1.66	0.474
	One month after transplant	1.72 ± 1.41	1.51 ± 1.23	1.53 ± 1.40	1.56 ± 0.89	1.63 ± 1.32	0.009*
	Six months after transplant	1.42 ± 0.65	1.24 ± 0.69	1.21 ± 0.45	1.61 ± 0.93	1.37 ± 0.69	0.000*
	One year after transplant	1.42 ± 0.58	1.22 ± 0.56	1.32 ± 0.91	1.57 ± 0.92	1.37 ± 0.66	0.000*
eGFR in Graft Recipients	One month after transplant	61.64 ± 21.76	53.16 ± 21.58	52.69 ± 22.04	58.78 ± 21.73	58.31 ±22.08	0.000*
	Six months after transplant	66.35 ± 21.28	57.10 ±19.68	55.23 ± 19.35	57.69 ± 23.07	62.04 ± 21.39	0.000*
	One year after transplant	66.12 ± 19.99	57.59 ±20.39	55.44 ± 22.65	58.85 ± 22.60	62.18 ± 21.05	0.000*
Hemoglobin of Graft Donors	Before surgery	15.10 ± 1.28	15.05 ± 1.30	12.89 ± 1.24	12.83 ± 1.17	14.66 ± 1.54	0.000*
	After surgery	14.00 ± 1.33	13.92 ± 1.42	12.10 ± 1.30	12.03 ± 1.26	13.61 ± 1.54	0.000*
	Two days after surgery	13.86 ± 1.49	13.82 ± 1.34	11.83 ± 1.32	11.71 ± 1.21	13.45 ± 1.63	0.000*

*p-value<0.05 is considered as significant. P-value is estimated by Anova.

Side effects and complications after surgery were just seen in 4.6% of the patients. Graft rejection was reported in about 51 cases (4.6%) of graft recipients, and 130 (11.7%) of the patients were made to have dialysis after transplantation. There were 41 (3.7%) post-transplant death cases. Consequences of surgery, side effects, graft rejection, dialysis return, and death in transplant in recipients are presented in table 4 based on donor-recipient gender.

Table 4: Consequences of surgery like side effects, graft rejection, dialysis return, and death in transplant recipients

Consequence	Frequency	p-value
Side Effects
Male to Male	2.3 %	0.068
Male to Female	4.0 %
Female to Male	3.8 %
Female to Female	4.5 %
Graft Rejection
Male to Male	4.0 %	0.087
Male to Female	6.4 %
Female to Male	3.8 %
Female to Female	4.0 %
Dialysis Return
Male to Male	10.5 %	0.009*
Male to Female	15.0 %
Female to Male	8.4 %
Female to Female	12.1 %
Death
Male to Male	3.4 %	0.517
Male to Female	4.3 %
Female to Male	3.6 %
Female to Female	3.2 %

*p-value<0.05 is considered as significant. Chi 2 test is used for earning p-value.

Based the results of Kaplan-Meier test, the survival percentage was 97.3%, 95.7%, 95.1%, 94.8%, 94.4% and 93.7% one year, two, three, four, five , and 10 years post-transplant, respectively (figure 1). The distribution of patients in our four defined groups based on donor-recipient gender was 606 (54.4%) in group 1, 304 (27.4%) in group 2, 105 (99.4%) in group 3, and 98 (8.8%) in group 4.

Predictive factors for mortality, graft rejection, and back to dialysis in both genders of donor and recipient were age (esp. in transplant recipients), serum creatinin, eGFR, level of donor hemoglobuline, history and duration of dialysis before kidney transplant. The result of multiple logistic regression analysis of graft rejection, dialysis return, and death recipients are presented in table 5. The multiple logistic regression model for graft rejection indicated female recipient (p-value: 0.035), delayed graft function (DGF) (p-value: 0.001), age of recipients (p-value: 0.050), primary serum level of creatinine and eGFR (p-value: 0.001), and donor hemoglobin levels (p value: 0.043) are critical elements of graft rejection.

Table 5: Multiple logistic regression models for several factors and graft rejection requiring dialysis return and death.

	Candidate Variable	Beta coefficient	p-value	Probability Ratio
Graft Rejection	Recipient’s Gender	-0.437	0.040	0.646
	Age of Recipient	0.019	0.010*	1.019
	Creatinine/eGFR	-0.341	0.001*	0.711
	Donor’s hemoglobin level	0.019	0.001*	1.019

Dialysis Return	Recipient’s Gender	-0.602	0.002*	0.548
	Age of Recipient	0.038	0.001*	1.039
	Creatinine/eGFR	-0.275	0.001*	0.760
	Donor’s hemoglobin level	0.148	0.016*	1.159
	Arterial Anastomosis	0.171	0.650	1.187
	DGF	0.564	0.146	1.758
	Donor’s Age	-0.022	0.177	0.978

Death	History of Dialysis	0.417	0.453	1.518
	Age of recipient	-0.042	0.010*	1.959
	Creatinine/eGFR	-0.305	0.001*	0.749
	BMI of Recipient	0.009	0.009*	0.959
	Creatinine/eGFR	-0.067	0.642	0.935

The multiple regression models showed that kidney transplant recipients with history of dialysis, older age, higher Creatinine/eGFR and higher hemoglobin levels in their donors are more susceptible to return of dialysis after transplantation. In addition, higher Creatinine/eGFR, BMI and older age of recipients (≥35 years) can decrease the risk of transplant survival and increase the risk of death in graft recipients. Figure 2 represent the frequency of death, back to dialysis, graft rejection and other complications based on gender math.

Our observational study pointed to gender matching between kidney donors and recipients as an important graft survival determinant. Transplant survival depends on younger age of recipients and positive history of dialysis before transplant more than sex matching. Several factors suggested by some studies can change long-term survival in renal transplant recipients with graft function (7). For example, the incidence of post-transplant hyperglycemia due to pre-transplant cardiovascular disease and, particularly, glycemia during the first month post-transplant identified patients at risk of post-transplant diabetes . Our result showed that the age of recipient < 35 is more critical than the age of donor. For cardiac and hepatic grafts, no significant effect of donor gender on the proportion of patients treated for rejection episodes was seen and adverse effects of female donor gender for different organs is much less uniform (8). Donor’s age can be the potential confounder because a gender effect on graft survival was also observed for cardiac allograft. The age of donors> 60 years or other algorithms to simplify identification of organs with elevated risk of transplant failure (9). Our findings showed that the age of recipients<35 is more critical than the age of donors. Age matching can possibly increase the positive results of transplantation, particularly when kidneys from older donors are used (10). Consideration of age and gender as principles for the optimal donor/recipient selection may be considered in organ allocation (11, 12). Some structural and functional changes happening in kidney with age increase can change the efficacy of transplantation .

Peter Stenvinkel et al suggested that as inflamed females patients have a better outcome than inflamed males because sex hormones may have important cardioprotective effects that limit the effect of inflammation on vascular injury in female end-stage renal disease (ESRD) patients . This can be the logic that female recipients, even from male donors, showed higher transplant outcomes in comparison to male recipients (from female donors). Additional studies must conclude whether sex- and age-specific immunosuppressant is warranted for kidney graft recipients (13-15). Despite the conflicting data regarding the influence of gender on chronic kidney disease, it was shown by Idan Goldberg and Ilan Krause that the prevalence of chronic kidney disease tends to be higher in women, whereas the disease in men is more severe (16). In the pre-lung allocation score era, female gender was not connected with better survival. Female recipients showed considerably improved survival over five years compared to males (17). However, there are some suggestions that the impressive long-term graft survival benefit of male donor-female recipient versus female donor-male recipient and of male donor-female recipient versus matched groups (male-male, female-female) in transplant can be the result of some donor quality and recipient characteristics as the confounding elements (18-20). Time of being in waiting list of transplantation and duration of dialysis can be confounders like the age of donors and recipients. Our data suggested that in addition to age of recipients and gender matching as well as positive history of dialysis can be a prognostic element of transplant survival. Several previous studies pointed out the natural history of permanent renal dysfunction and severe liver failure in liver transplant recipients that can be helpful in the progress of non-nephrotoxic immunosuppressive regimens for high-risk liver transplant recipients (21, 22).

A paired donor kidney analysis indicated that waiting time on dialysis can be the strongest modifiable risk factor for renal transplant outcomes (23). The advantage of living-donor versus cadaveric-donor transplantation can be the logic of waiting time. Cadaveric renal transplant recipient with an end-stage renal disease time ≤6 months has the equivalent graft survival of living donor transplant recipients compared to those waiting on dialysis waiting list for ≥2 years (24). In fact, increased time on dialysis before kidney transplantation is linked to decreased survival of transplant recipients.

By far, the most successful transplants, based on donor-recipient gender, were seen in male donors to male recipients and then male donors to female recipients. Contradictory, the most unsuccessful transplant was seen when the donor was female and the recipient was male. In female transplant recipients, the level of serum creatinine, and eGFR, positive dialysis history before transplant, and low donor hemoglobin levels can be good prognostic factors in kidney transplant survival.

Ethics approval and consent to participate: An informed consent was taken before surgery based on the ethical code of Tehran University of Medical Sciences ethics committee.

Consent for publication: The information is published without the name of patients (both kidney donors and kidney recipients)

Availability of data and material: Information, data, and photos will be provided upon request.

Competing interests: All authors claim that there is not any potential competing or conflict of interest

Funding: Urology Research Center of Tehran University of Medical Sciences.

Authors' contributions: SMK.A. principal investigator. GH. N. supervising surgeon; F.KH., SR. Y. manuscript preparation. A.A. projectexecutor.

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Editorial decision: Major revision
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The Impact of the donor-recipient gender matching on the graft survival from live donors

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