Chinese Medical Journal 2013;126(9):1738-1742
Factors potentially affecting the function of kidney grafts

Correspondence to:Dr. GUO Yu-wen, (Tel: . Fax:. E-mail:guoyuwen826@yahoo.com)
Keywords
kidney transplantation; gender; age; consanguinity
Abstract
Background  Donor and recipient risk factors on graft function have been well characterized. The contribution of demographic factors, such as age, gender, and other potential factors of donor and recipient at the time of transplantation on the function of a graft is much less well understood. In this study, we analyzed the effects of factors such as age, gender, etc., on the short-term and long-term graft function in kidney transplant recipients from living donor.
Methods  A total of 335 living donors and their recipients, who had kidney transplantation in our center from May 2004 to December 2009, were included. Serum creatinine level was used as the assessment criterion (serum creatinine level lower than 115 mmol/L is normal). Factors related to graft function such as age, gender, blood relation by consanguinity, human leukocyte antigen (HLA) mismatch, ABO type, etc., were analyzed separately.
Results  Donor age is the key factor affecting both the short-term and long-term function of a grafted kidney from a living donor. The group with donors younger than 48 years showed the best kidney function post transplantation. Match of gender and age is another important factor that influences the function of grafted kidney from a living donor. The older donor to younger recipient group had the worst outcome after kidney transplantation. After 36 months post transplantation, female donor to male recipient group had worse kidney function compared to other groups. We also found that calcinerin inhibitor used in the maintenance period may influence the function of a grafted kidney. No significant statistical differences were found in consanguinity, blood type, and mismatch of HLA.
Conclusions  Donor age is an important factor affecting the function of a grafted kidney from a living donor. We also recommend taking nephron, immunology factor, infection, and demographic information all into consideration when assessing the outcome of kidney transplantation.
Kidney transplantation is considered the best therapeutic option for end-stage renal disease (ESRD). The current imbalance between the demand and supply of kidney organs is growing universally. It has been proved that both short- and long-term graft function from living donors (LD) are better than that those from deceased donors (DD). In US, cases of LD first exceeded DD in 2005, and accounted for nearly 50% now, while they took 30% and 82% of kidney transplant cases, respectively, in Australia and Japan.1-4 Data from Chinese Scientific Registry of Kidney Transplantation reveals that cases of LD in China have increased from 2% in 2005 to 26% of all kidney transplant cases in 2011, and it continues increasing. However, while factors impacting grafts function from DD have been studied thoroughly, factors impacting grafts function from LD still remain unclear.
 
We studied age, gender, blood relation by consanguinity, blood type, and human leukocyte antigen (HLA) mismatch as factors potentially affecting the function of grafts from LD. Serum creatinine level was used as the assessment criterion of the grafts function.
 
METHODS
 
Clinical data
This retrospective study comprised of 353 living donor kidney transplantation cases, which were all the living donor kidney transplantation performed between May 2004 and December 2009 in our hospital.
 
Characteristics such as age, gender, primary cause of ESRD, duration of dialysis, and HLA mismatch were collected, respectively. Post transplantation follow-up included serum creatinine levels at 6, 12, 24, 36, 48, and 60 months after the operation. Serum creatinine level higher than 115 mmol/L is considered to be abnormal. The protocol and data collection sheet were approved by our ethics committee.
 
Management of data
Data of serum creatinine level were divided into different groups and analyzed according to donor age, gender of donor and recipient, consanguinity between donor and recipient, blood type of donor and recipient, type of calcinerin inhibitor (CNI) and antimetabolite medicine used in the maintenance period, HLA mismatch, and age difference between donor and recipient, respectively.
 
The data were divided into five groups according to donor age: (1) 18-27 years, (2) 28-37 years, (3) 38-47 years, (4) 48-57 years, and (5) >57 years.
 
The data were divided into three groups according to gender of donor and recipient: (1) same gender, (2) male-to-female, and (3) female-to-male.
 
The data were divided into three groups according to consanguinity between donor and recipient: (1) related relative, (2) husband/wife, and (3) unrelated.
 
The data were divided into two groups according to blood type of donor and recipient: (1) same type and (2) different type.
 
The data were divided into two groups according to the type of CNI used in maintenance period: (1) cyclosporin A (CsA) and (2) tacrolimus (Tac).
 
The data were divided into two groups according to the type of antimetabolite medicine used in maintenance period: (1) mycophenolate mofetil (MMF) and (2) others.
 
The data were divided into two groups according to HLA mismatch: (1) 0–3 and (2) ≥4.
 
The data were divided into three groups according to age difference between donor and recipient: (1) younger to older, (2) same generation, and (3) older to younger.
 
Treatment regimen after transplantation
During the induction treatment period, 206 cases were induced with antihuman thymocyte immunoglobulin, while 138 cases were induced with daclizumab. And we adopted the standard immunosuppression in all cases: i.e. (MP) 500-1000 mg at day 1 and day 2 post-transplantation; cyclosporine standard formulation from day 2 on post-transplantation (4-6 mg/kg) or tacrolimus (0.1 mg/kg, then the dosage was adjusted according to the blood concentration) combined with prednisolone (starting with 30 mg/d, rapidly tapered to 15-25 mg/d) and mycophenolate mofetil (1-2 g/d).
 
Statistical analysis
Donor, recipient, and transplant characteristics as well as outcome results were presented as mean ± standard deviation (SD) and/or frequency. One-way analysis of variance (ANOVA) was used to detect significant differences for quantitative data. The c2 test was used to compare categorical variables. P <0.05, in two-tailed testing, was considered statistically significant. Logistic regression was performed to identify the factors affecting grafts’ function at different times. Data were entered into Microsoft Excel for Windows (Microsoft Corporation, Redmond, USA). Statistical analysis was performed using SPSS 19.0 (SPSS Inc., USA).
 
RESULTS
 
The total sample (353 cases) had the mean follow-up time of 58.6 months with the range from 0 to 96 months. The mean age of recipients was (35.12±19.16) years (range 9–63 years) and of living donors (41.17±12.72) years (range 20–68 years). There were two graft losses during the study period and six patients died with functioning grafts.
 
Donor and recipient variables
When comparing post-transplantation outcomes of groups older than 48 years with other groups, there was significant statistical difference. It indicated that age younger than 48 years may be the optimum donor age (Tables 1 and 2).
 

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Table 1. Impact of donor age on graft function (serum creatinine) (mg/dl (n))
 

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Table 2. Impact of donor age on graft function between different age groups (P values)
 
When comparing data of groups of different gender of donor and recipient, female donor-to-male recipient group showed the worst kidney function at the time of 36 months post-transplantation (Tables 3 and 4).
 

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Table 3. Impact of donor gender on graft function (serum creatinine) (mmol/L (n))
 

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Table 4. Impact of donor gender on graft function (P values)
 
Significant differences were observed when we compared the study groups based on age difference between donor and recipient. We found that the best graft function appeared in the younger-to-older group, while the worst appeared in the older-to-younger group (Tables 5 and 6). No significant difference between groups of different consanguinity (P >0.05).
 

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Table 5. Impact of age difference between donor and recipient on graft function (serum creatinine) (mmol/L (n))
 

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Table 6. Impact of age difference between donor and recipient on graft function (P values)
 
Transplant-related variables
We found that after 12-24 months post-transplantation, graft function of patients using Tac was better than patients using CsA, but the benefit was no longer seen after 36 months. The characteristics of the study population grouped by different CNI used in the maintenance period are summarized in Table 7.
 

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Table 7. Impact of type of CNI used in maintenance period on graft function (serum creatinine) (mmol/L (n))
 
The characteristics of the study population grouped by blood type of donor and recipient, type of antimetabolite medicine used in the maintenance period and HLA mismatch were analyzed, respectively, but no difference was found between groups of different blood type (P >0.05).
 
Logistic regression analysis was also performed. We found that donor age was the factor that influences graft kidney throughout, while factors like gender of donor and recipient, recipient age, and CNI used in maintenance period showed different impact at different times after transplantation (Table 8).
 

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Table 8. Logistic regression analysis on the impact of donor age on graft function in different time
 
DISCUSSION
 
The best treatment for chronic renal failure is renal transplantation. However, there is a serious imbalance between the number of kidneys donated for transplantation and the number of persons wishing to receive a transplant. Data from CSRKT revealed that cases of LD in China had increased rapidly in recent years. Kidneys from different living donors may have very different outcome. For decesead donors, factors such as age, gender, HLA mismatch, ischemia time, etc., have been well studied, while only some attention has been paid to LD.5 In China, parents are usually the major source of living donors, which is very different from many other countries. Thus, in this study, we expected to identify the important factors influencing the function of graft in LD kidney transplantation at different time periods after transplantation based on the status quo in China.
 
It is commonly recognized that donor age is a great influence on the outcome of kidney transplantation, which may even be a predictor of the outcome. The proportion of pathological changes, such as glomerular sclerosis, tubulointerstitial fibrosis, and small arteries lesion, is positively correlated with donor age; donor age is an important factor affecting graft kidney quality. Kidney function is slipping as the age increases. Creatinine clearance reduces 0.167 ml/s every 10 years after 40 years of age.6
 
It is commonly accepted that when a donor is over 50 years of age, both function and survival rate of graft kidney decreases greatly, whether for LD or DD.7-9 According to the relevant laws and regulations in China, the lowest age of donor is 18 years. Therefore, we devided data into five groups with an interval of 10-years. The most significant difference was shown when comparing patients older than 48 years to younger ones, and the transplantation outcome in the younger group (<48 years) was much better than those in the older group (>48 years). Based on this study, we suggest that the best donor age is lower than 48 years. In order to improve the outcome of transplatation for donors older than 48 years, more comprehensive examination is advised. The limit for this result is that serum creatine, is used as the only assessment criterion in our study. Although it is the main index used in clinics to assess kidney function, it cannot reflect filtration function of glomerulus completely, and it can not predict damage of graft kidney in early stage either.
 
Donor and recipient gender may influence many aspects of kidney transplantation, but the nature of these interactions is still unclear. Male recipients of female kidneys may experience a greater risk of early graft loss compared with all other gender combinations.10-12 Causes in renal transplantation, donor age, and allograft size are all known to have important influence on the outcome of the graft reflecting functional renal mass.13 Women have smaller kidneys with 17% fewer nefrons than male kidneys.
 
But there are also some different findings from other groups. Zukowski et al14 reported that male-to-female had a higher garft loss rate than their male counterparts. There was no gender difference in graft survival, but female recipients of renal allografts had a higher mortality than their male counterparts.8 Some possible explanations for these findings are proposed. One possible reason is immunology elements, which were induced by gender difference. They can be the main cause of the higher mortality of male-to-female group. Immunology elements affecting survival rate of graft kidney includes the sensitization caused by pregnancy and predisposition to have serious bacterial infection.15,16 On the other hand, some researchers believe that body surface area ajustment for gender does not influence the weight.17
 
Our research showed that graft kidney function of female-to-male at 36 months post-transplantation was worse than other groups, but there was no difference after 36 months. The result supports the theory that graft kidney function of female-to-male is worse than that of male-to-female. Because of the low acute rejection rate and infection rate in our center, nephron theory plays a more important role.
 
According to the regulation of law of China, LD kidney transplantation can only be performed during (1) first-degree related relatives (like transplantation between brothers and sisters, parents and children), (2) husband/wife, and (3) second related relatives (like transplantation between nephew and uncle, cousins).
 
Spousal kidney transplantation is a special type. Theoretically, the closer genetic connection and the more similar genetic background they have, the weaker rejection responce and the higher survival rate they have.
 
It is shown that the graft outcomes of unsimilar HLA match of spousal kidney transplantations be next only to that of transplantations between identical twins. And no significance was found when compared with other groups. Statistics from the United Network for Organ Sharing (UNOS) revealed that 3-year survival rate of unrelated relative renal transplantation performed during 1994-1997 was 86%, which is equal to that of parent donors.
 
In our report, there was no difference found in the different groups split by consanguinity (P >0.05), which means spousal or second related relatives kidney transplantation is not inferior to first-degree related relatives kidney transplantation.
 
It is not reasonable to attribute the higher survival rate to better HLA match, espacilly with the development of great immunosuppressive agent. The ungenetics or unimmunology factors may play some more important roles. Facing the shortage of supply of graft kidney, spousal or second related relatives may become important donors.18 There is an increasing trend of spousal kidney transplantation in China. The similarity of outcome of spousal and related kidney transplantation may be attribute to the immune tolerance caused by the common conditions, dietary habits, and even the intimate sexual life.
 
LEE et al19 conducted a retrospecitive study for 100 LD cases with a 5-year follow-up. The cases were divided into two groups based on the age difference between donor and recipient (recipient age subtracted from donor age, donor-recipient <20 vs. ≥20). He found that although the cohort of a donor-young recipient age difference ≥20 years showed a greater risk of an acute rejection episode early post-transplantation, it did not affect the graft or patient survivals.
 
Our results suggest that younger-to-older have the best outcome, while older-to-younger have the worst outcome. So the match of age may affect the outcome of graft kidney, especially when the donor is very old.
 
According to the data from UNOS, HLA mismatch correlated with long-term survival of graft organ. Despite the great improvement in the latest immunosuppressive agents that can lower the AR rate, HLA mismatch is still the main factor affecting long-term survival of graft organ. Our result showed no significant difference in HLA match or mismatch group, which might be due to the good HLA match in our center.
 
Our study compared CsA group with Tac group. Tac had a better outcome at 12-24 months post-transplantation. But the advantages have disappeared from 36 months onwards. Therefore, we think that Tac is better than CsA for short-term graft kidney function. But long-term follow-up is needed in order to confirm this.
 
In conclusion, while male recipients and young recipients account for the great majority of the kidney graft,21 females especially older females are live kidney donors more often than males. When evaluating the potential graft function, it is very important to take nephron, immunology factor, infection, age, and gender of donor and recipient all into consideration.
 
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