Impact of Donor-Recipient Relationship on Long-Term Outcomes in Living-Related Donor Kidney Transplantation

Introduction

Kidney transplantation is the optimal treatment option for most patients with end-stage renal disease (ESRD). Since the Chinese government prohibited organ procurement from executed convicts in 2015 [1], organ donation after death has become the primary source for organ transplantation. However, due to the ongoing shortage of organs, living donor kidney transplantation remains an essential component of transplant programs. In recent years, the number of living donor kidney transplants has increased in mainland China, accounting for approximately 20% of all kidney transplants nationwide [2]. As China prohibits living-unrelated organ donation, only a recipient’s spouses, lineal relatives, and collateral blood relatives within 3 generations can legally donate a kidney. In clinical practice, the most common types of living donation are from parents to children, followed by siblings, spouses, collateral relatives, and children to parents. Many reports suggest that living-related kidney transplantation (LRKT) provides better early and late outcomes than cadaveric donor transplantation in terms of rejection, postoperative complications, and graft survival [3], although there are some opposing views [4,5]. Several studies have analyzed the impact of the relationship between donors and recipients on short- and long-term graft outcomes, with contradictory results. Choi et al [6] demonstrated that mother-to-child (M-to-C) donations have a notably lower graft survival rate than father-to-child (F-to-C) donations. On the contrary, it has been speculated that the presence of fetal-maternal microchimerism may play a role in inducing some level of immune tolerance towards transplants from M-to-C, potentially leading to enhanced graft survival rates [7,8]. Similar contradictory conclusions have also been reported regarding kidney transplants from offspring donors. Therefore, this study aimed to compare the long-term outcomes depending on donor-recipient pairings in LRKT, exploring the effect of the donor-recipient relationship on kidney graft survival.

Material and Methods

DATA SOURCE AND PATIENTS:

This retrospective study analyzed data on kidney transplant recipients from a single center between 2001 and 2021, using data from patients’ medical records. The study included patients over 18 years old who received a kidney donation from their relatives. All patients included in the study had negative donor-specific HLA antibodies (DSA) before transplantation. Patients who had undergone previous kidney transplantation, received multiple transplant organs, or received ABO-incompatible transplant organs were excluded from the study. Recipients were classified into 5 groups based on the donor identity: M-to-C group (donated by a mother), F-to-C group (donated by a father), sibling group (donated by a brother or sister), spouse group (donated by a wife or husband), and offspring group (donated by a child). Follow-up information was collected at postoperative 7 days and at 1, 3, 6, and 12 months, and every 6 months thereafter [9]. Therefore, individual opt-in patient consent was not required.

ETHICS DECLARATION:

This study was approved by the Chinese People’s Liberation Army General Hospital (No. 2022080200072) and was conducted in compliance with the international human rights guidelines of the Declaration of Helsinki and the Declaration of Istanbul. Data obtained from executed prisoner donations were not included in this study. The requirement for patient-informed consent was waived as this was a retrospective analysis that reviewed historical medical documents and follow-up data. No personal identifying information was used.

OUTCOMES AND VARIABLE DEFINITION:

The primary objective of this study was to determine the survival rate of the grafts. The secondary objectives were to evaluate kidney function at postoperative 1, 3, 5, 7, and 10 years, as measured by serum creatinine (Scr) levels. The outcomes also included the incidences of major postoperative complications within 1 year of transplantation, such as delayed graft function (DGF), rejection, graft loss, and death. For this study, all-cause graft loss was defined as patient death, nephrectomy, or graft failure (return to regular dialysis). The calculation of graft survival was based on the time from transplantation to the occurrence of all-cause graft loss or the last follow-up (May 10, 2022), whichever occurred first. The survival probabilities at 1, 3, 5, 7, and 10 years were compared among the kidneys classified by different donor-recipient relationships. Rejection was confirmed by the administration of anti-rejection medication, with or without biopsy confirmation. DGF was defined as the need for dialysis within 1 week after transplantation, excluding rejection and primary non-function of the graft. The measurement of Scr was taken from a recipient who had a functioning kidney. For some out-of-hospital patients who required remote follow-up in this study, we were concerned that the self-reported weight data may exhibit some degree of heterogeneity or inaccuracy, potentially affecting the calculated eGFR. Therefore, we used Scr levels as the index for evaluating kidney function, rather than relying on eGFR as calculated by the formula. The HLA mismatches were calculated by summing the total number of mismatches in the A, B, and DR alleles.

STATISTICAL ANALYSIS:

Statistical analyses were performed using the SPSS 20.0 statistical software (SPSS, Inc., Chicago, USA). Continuous variables were presented as mean and standard deviation for normally distributed data and as the median and interquartile range (IQR) for non-normally distributed data. Categorical variables were described as percentages. Group comparisons were made using one-way analysis of variance and Pearson’s chi-squared test. The Kaplan-Meier method was used to analyze graft survival probabilities, which were compared among groups using the log-rank test. Cox proportional hazards regression was used to analyze risk ratios for all-cause graft survival, with hazard ratios (HRs) and their 95% confidence intervals (CIs) calculated. Since our focus was on the effect of the donor-recipient relationship, we used siblings as the reference group. After conducting univariate analysis on the baseline data in Table 1, multivariate Cox proportional hazards regression was performed by adjusting recipient and donor age (>50 years or not) [10], sex of recipient and donor, year of transplantation (before 2010 or not), and history of diabetes (yes or no). A two-sided p-value of less than 0.05 was considered statistically significant.

Results

DEMOGRAPHIC CHARACTERISTICS AND POSTOPERATIVE COMPLICATIONS WITHIN 1 YEAR AFTER TRANSPLANTATION:

Table 1 presents the demographic data of 598 LRKTs, grouped based on the donor-recipient relationship. The M-to-C and F-to-C groups had the youngest recipients and oldest donors, while the offspring donor group had the oldest recipients and youngest donors. There was a slight age gradient between donors and recipients in the sibling and spouse donor groups, with the spouse donor group having the highest number of HLA mismatches. The offspring donor group had a higher incidence of preoperative comorbidities, such as diabetes and cardiovascular disease, compared to other groups. Table 2 demonstrates that within 1 year after transplantation, the incidence of delayed graft function (DGF), rejection, and death was similar across all groups. However, the offspring group showed a higher rate of graft loss compared to the other groups.

KIDNEY FUNCTION INDICATED BY SCR:

As presented in Table 3, the Scr levels at 1, 3, 5, 7, and 10 years after transplant were significantly higher in the M-to-C and F-to-C groups compared to the other groups. However, patients with functioning graft kidneys in the sibling, spouse, and offspring donor groups exhibited stable and similar postoperative Scr levels during the 10-year follow-up period.

GRAFT SURVIVAL AND HAZARD RATIO FOR GRAFT LOSS:

The graft survival rates of the 598 kidney transplants in our cohort were 96.0% at 1 year, 92.4% at 3 years, 86.4% at 5 years, 79.9% at 7 years, and 69.9% at 10 years (Table 4). Although the sibling group had slightly higher graft survival rates compared to the M-to-C and F-to-C groups, the differences were not significant. Comparable graft survival rates were also observed in transplants from spouses and offspring, which were inferior to those from sibling and parent donors (Figure 1). Additional analysis using the Cox proportional hazard test is shown in Table 5, with covariate-adjusted hazard ratios (HRs) presented for all-cause graft loss depending on donor-recipient pairs, and the sibling donor group serving as the reference. The results indicate that kidney donation from spouses and offspring increases the risk of graft loss, with HRs of 3.8 (95% CI, 1.7–8.4, P=0.001) and 3.3 (95% CI, 1.6–6.9, P=0.002), respectively. It should also be noted that M-to-C and F-to-C pairing increases the risk of graft loss, with HRs of 1.9 (95% CI, 1.2–3.4, P=0.004) and 1.8 (95% CI, 1.1–3.1, P =0.024), respectively.

Discussion

Although numerous Chinese studies on LRKT have been published, most of them have only focused on short-term or mid-term follow-up periods of less than 5 years. Additionally, limited research has investigated the association between donor-recipient relationships and long-term outcomes. Our study is the first to present 10-year survival data on different donor-recipient pairings, providing valuable insights into the association between donor-recipient relationships and graft survival in Chinese LRKT. We observed that parental donors were the primary source of kidneys due to China’s strict regulations on living organ donations between relatives. Furthermore, the proportion of spouse and offspring donors was comparatively lower in our study than in data reported in other research [11]. This disparity may be attributed to variances in economic, cultural, ideological, emotional, and other aspects between Eastern and Western countries.

This study found that the 1-, 5-, and 10-year graft survival rates in LRKT were equivalent to those reported by Matter et al [12]. We also observed that transplants from sibling donors had the highest graft survival rates, followed by M-to-C and F-to-C, although we did not find any significant differences between them. However, kidneys from spouses and offspring donors had significantly lower survival rates compared to siblings, M-to-C pairs, and F-to-C pairs. These results contradict previous studies reporting inferior graft survival in M-to-C pairings, in comparison to transplants from other first-degree relative donors [13], as well as similar patient and graft survival rates between spousal donor kidney transplantation and other types of LRKT [14,15]. Possible explanations for these findings include HLA mismatches, genetic susceptibilities to ESRD primary diseases, and age-related factors. Firstly, spousal recipients had higher HLA mismatches, which are believed to be linearly correlated with graft survival, particularly in LRKT [16,17]. Additionally, within our cohort, the spouse group had a higher proportion of male recipients receiving kidneys from female donors, which may have negatively impacted graft survival [18]. Secondly, compared to siblings, who only have a one-quarter chance of being homozygous for a susceptibility gene, parents and children have a higher genetic susceptibility to ESRD primary diseases, such as focal segmental glomerulosclerosis, polycystic kidney disease, and diabetes [19]. These diseases have been associated with primary disease recurrence or worse graft survival, which could explain the much lower graft survival rates of the offspring group compared to the sibling group, as well as the decreasing trend of graft survival in the M-to-C and F-to-C groups in this study. Lastly, age is an important predictor of kidney transplantation outcome. Consistent with reports that older recipients have lower graft survival and higher mortality [20], we observed higher incidences of pretransplant diabetes and cardiovascular disease in the offspring group, which may account for their inferior graft survival rates.

Some researchers propose that the presence of HLA antibodies obtained during pregnancy have a greater influence on sensitization compared to microchimerism, theoretically increasing the risk of rejection in the graft kidneys of M-to-C [13]. Previously, it was believed that kidney donation between parent and child was a risk factor for T-cell-mediated rejection [21]. However, our results showed that most complications within 1 year postoperatively, such as DGF, rejection, and death, were comparable in all groups, except for the incidence of graft loss, which was higher in the offspring group than in the sibling group. A study from China reported that parent-to-child transplant and older donor age (≥50 years) significantly increased the risk of elevated Scr levels at 6 months and 1 and 3 years after transplant compared to situations where neither factor was present [22]. Consistent with these findings, our results showed that Scr levels in the M-t-C and F-t-C groups were significantly higher than those in other groups at 1, 3, 5, 7, and 10 years after kidney transplantation, indicating that parent-to-child donation, along with older donor age, was associated with impaired graft function. Therefore, it is reasonable to assume that older donor age could lead to lower survival rates for parental donor grafts in the long term [19]. Our results confirm this idea, as both the M-to-C and F-to-C groups showed a trend towards inferior graft survival rates compared to the sibling group, and also increased the risk of graft loss, with hazard ratios of 1.9 and 1.8, respectively. However, we did not find significant differences in clinical outcomes between M-to-C and F-to-C donor-recipient pairings.

This study also revealed another important finding. Holscher et al found that, after adjusting for recipient and transplant-related characteristics, kidneys from offspring donors showed lower graft failure and comparable mortality compared to those from non-offspring donors, due to the younger donor age and excellent HLA matching [23]. However, Cohen et al [24] demonstrated that transplant kidneys from offspring donors resulted in significantly increased mortality, indicating that patient death is the main cause of reduced graft survival. This agrees with our findings, which could be partially explained by genetic susceptibility to some primary diseases, older recipient age, more medical comorbidity, and susceptibility to postoperative complications. Therefore, due to the risk of graft loss and ethical considerations for elderly recipients and young donors, the clinical application of child-to-parent transplantation has been limited in recent years in China. Our findings also suggest that, whenever feasible, offspring-living donors should be avoided for recipients who have multiple donor options.

The novelty of this study lies in its observation of the long-term outcomes of kidney transplantation based on different donor-recipient relationships. However, there are certain limitations. First, kidney transplants from offspring and spouses have become less common in most Chinese organ transplant centers in recent years, resulting in a small sample size for spouses and offspring donors in this retrospective, single-center analysis. This limitation affects the precision of our estimates. Secondly, similar to most long-term observational studies, we did not thoroughly analyze the details of immunosuppressive regimen adjustments and other medications, which may have caused some evaluation biases in graft survival or complication incidence. However, our long-term observation suggests that selecting the appropriate donor-recipient relationship can affect transplantation outcomes. Although there was an insignificant difference, kidneys from siblings tended to exhibit better graft survival than those from mothers and fathers. This observation needs to be confirmed by a larger sample size study. On the other hand, we observed significantly inferior graft survival in kidneys from spouses and offspring donors compared to those from siblings and parents. In other words, parent, spouse, and offspring donors increased the risk of graft loss compared to sibling donors.

Conclusions

Our study highlights that compared to sibling donors, donations from spouses and offspring significantly increased the risk of graft loss. This was followed by M-to-C and F-to-C pairings, which yielded higher postoperative Scr. Although short- and long-term graft survival after kidney transplantation depends on various elements that interact in a complex manner, our research highlights the importance of caution when examining the donor-recipient relationships during preoperative assessments and postoperative management, particularly when the donors are children or spouses.