Compared with the long-term dialysis treatment, the successful renal transplantation increases the opportunities of patients to survive from the end-stage renal disease (ESRD) and enables them to enjoy a better life since recovery (1,2). Within 25 years, (September 1, 1987, through December 31, 2012), the kidney transplant has saved 1,372,969 life-years (3). The number of candidates on the waiting list has nearly doubled from over 50,000 in 2002 to more than 96,000 by 2013 (4). The median waiting time for the renal transplantation of adults has grew from 3 years in 2003 to more than 4.5 years in 2009, while the donation rates have not increased (4). The prolonged waiting time for the kidney transplantation and the dialysis shares a close relationship with the significant morbidity and mortality (5). Due to the demand of donor organs over supply, the kidneys are being transplanted from donors according to the increasingly expanded criteria.
Grafts from small deceased pediatric donors are the potentially underused resources, including the single kidney or en bloc kidney (6). Previous researches have shown that it was technically challenging to transplant the kidneys of the small pediatric deceased donors to adults, which was associated with the vascular and urinary complications, acute rejection, delayed graft function, and the development of the hyperfiltration injury (7,8). Several studies have indicated that the en bloc kidney transplantation, first reported by Meakins et al. in 1972 (9), could avoid the size of the small anastomotic vessel and potentially limit the thrombotic complications, achieving excellent long-term graft outcomes (10-13). Consequently, the dual en bloc allografts from small pediatric donors have become primarily acceptable in the kidney transplantation.
In recent years, there has been growing interest in the single renal transplantation from small pediatric donors as it allows each graft to be transplanted into different recipients that increases the organ utilization (14,15). Although the single kidney transplantation enables more recipients to survive, it remains controversial on the clinical survival that some studies suggested that the superior survival outcomes (16) had been reported by others to be the inferior outcomes with an increased risk of graft failure. In addition, a few researches have directly compared the outcomes between the recipients of en bloc and the single kidney transplantation from the small pediatric donors (17-20). Therefore, the aim of this meta-analysis with trial sequential analysis (TSA) was to precisely evaluate the clinical significance of patients receiving en bloc versus single allograft from small pediatric donors, for the first time.
A comprehensive online search for the relevant studies (updated on Nov 1st, 2016) was performed in the PubMed, Embase, and web of science by two independent researchers (JY Zhang and HC Zhang). The MeSH search items included the keywords, including “pediatric donor”, “survival”, “en bloc”, and “single” combined with the “kidney transplantation”. In addition, the reference lists of all the identified articles, and the abstracts of the Annual Meeting of the American Society of Nephrology and the American Society of Urology were reviewed respectively. The most recent study with comprehensive data was selected while there was more than one publication focusing on the same study cohort.
Inclusion and exclusion criteria
This meta-analysis was strictly performed by the guidelines of the statement of the preferred reporting items of systematic reviews and meta-analyses (PRISMA) (21). Studies were considered eligible if they met the below criteria: (I) allografts were transplanted from ‘small pediatric’ donors (children younger than 10 years) to recipients; (II) both en bloc and single grafts were utilized for the kidney transplant; (III) the graft survival between en bloc and the single kidney transplantation was compared, along with a corresponding survival outcome, like the hazard ratio (HR) or Kaplan-Meier (KM) curve.
The key points of the quality assessment included the following definitions: (I) the study population and country of origin; (II) the number of donors and recipients; (III) the age and weight of donors; (IV) the age and weight of recipients; (V) the assessment for outcome, and (VI) a sufficient follow-up period. Studies were considered of low-quality when they did not satisfy the above criteria to maintain the quality of the meta-analysis. In addition, the sensitivity analysis was performed to avoid bias among studies due to the certain low-quality studies.
Information was carefully extracted from eligible studies independently by HC Zhang and CJ Suo, per the inclusion criteria as listed above. The extracted data were reassessed by a third reviewer (M Gu). The following elements were collected from each literature: (I) the first author and the publication year; (II) patients’ nationality; (III) the length of follow-up; (IV) the study size; (V) the mean age ± SD, and the mean weight ± SD of donors and recipients; (VI) the source of HRs. If HRs were not directly reported, the key data were extracted from KM plots by Engauge Digitizer V.5.1 (license type: GPL; developed by: Mark Mitchell; category: C:\Science/CAD) (22), and HRs with 95% confidence intervals (95% CIs) were then calculated by the practical methods (23). Besides, if the univariate and multivariate results were reported, only the latter ones were selected as they were adjusted for the confounding factors.
HRs and the corresponding 95% CIs of included studies were combined to compare the prognostic value of en bloc versus the single kidney transplantation from small pediatric donors. Besides, a cumulative meta-analysis was carried out on the basis of publication year. Heterogeneity among studies was identified by the Cochran Q test and was quantified by the Higgins I2 statistic. The quantification of heterogeneity was assigned of low, moderate, and high to I2 values of 25%, 50%, and 75%, respectively (24). The Galbraith plot and sensitivity analysis for individual studies were also implemented to identify the source of heterogeneity. In addition, the publication bias was estimated with the usage of Begg’s test with the funnel plot. All the P values were two-sided, and a P value of less than 0.05 was considered as statistically significant. All the above-mentioned statistical analyses were performed by the Stata V.12.0 (StataCorp LP, College Station, Texas, USA), and Microsoft Excel (V.2010, Microsoft Corporation, Redmond, Washington, USA).
Trial sequential analysis
TSA was conducted for the final studies included in the meta-analysis. TSA, which was performed per the monitoring boundaries, can combine a prior sample size to evaluate the accumulating evidence (25). Our assumptions included two-sided testing with the type I error of 5%, and the type II error of 20% (power of 80%). The main results of TSA were presented in the cumulative Z-curve graph, and the monitoring boundary of required information size in the graph was determined according to the O’Brien-Fleming spending function (26). Also, the futility boundary was set on the basis of the O’Brien-Fleming -spending function. A sufficient level of evidence is reached and no further trial is needed if the cumulative Z-curve crosses the monitoring boundaries except the futility lines, otherwise the insufficient evidence is considered as a conclusion. TSA was carried out by the statistical software, and TSA version 0.9 beta (User Manual for TSA, Copenhagen Trial Unit 2011, http://www.ctu.dk/tsa).
A total of 49 articles were identified through the comprehensive online search. After six duplicates were removed, 43 records were screened by the title and abstract. Thirty-five studies were excluded by the preliminary review on full-text, and one study focusing on both pediatric and adult donors (age of <18 and 18–50 years) were eliminated by further detailed evaluation (27). Finally, seven studies were considered eligible for meta-analysis (16-20,28,29). A flow diagram of the study selection process was presented in Figure 1. The main characteristics and data of the enrolled studies are summarized in Table 1. All the eligible studies were retrospectively designed, and a total of 4,284 cases from the United States were investigated. The mean age of small pediatric donors for both en bloc kidney transplantation and single kidney transplantation was younger than 4 years. And the length of follow-up for en bloc and single kidney transplantation ranged from 1.0 year to 10.0 years. The HR values were directly reported in two studies (17,18), and the HRs of the other studies were respectively extracted from the survival data or the KM curves available (16,19,20,28,29).
Quantitative synthesis results
By pooling the outcomes of seven eligible studies on a random effect model, it could be found that compared with the single kidney transplantation from small pediatric donors, the en bloc kidney transplantation was significantly associated with a superior graft survival (HR=0.62; 95% CI: 0.47–0.81, P<0.001) (Figure 2). Nonetheless, a relative moderate level of heterogeneity among studies has been observed (I2=33.5%, P=0.172). To identify the source of heterogeneity, Galbraith plot and sensitivity analysis for the enrolled studies were performed (Figure 3,4). The value of I2 for the secondary meta-analysis has significantly reduced to 2.6% after one study of a potential risk of heterogeneity was excluded (29). Therefore, HRs of six studies were finally pooled for the quantitative analysis, indicating a better graft prognosis for the recipients of en bloc kidney transplant with a HR value of 0.57 (95% CI: 0.49–0.67, P<0.001) (Figure 5). Per the cumulative meta-analysis based on the publication year of the six included studies, the graft survival of en bloc kidney transplantation was superior to that of the single kidney transplantation (HR=0.56; 95% CI: 0.47–0.67) (Figure 6).
TSA of the six included studies was performed by a random effect model (Figure 7). The heterogeneity-adjusted information size to demonstrate 43.57% of relative risk reduction (low-bias risk trial estimate) of en bloc kidney transplantation (with an value of 5%, and a of 20%) was 5,493 patients. The cumulative Z-curve crossed the conventional boundary as well as the required information size (α-spending), yet not crossed the futility boundary, indicating that the clinical evidence was sufficient and no further trials were required although the number of the cases and controls has not achieved the required information size.
Begg’s test with the funnel plot was conducted to evaluate the publication bias (Figure 8). As expected, the funnel plot was symmetrical and the P value of Begg’s test was 0.707. Therefore, no evidence of publication bias was noted in the meta-analysis.
Kidney transplantation can provide ESRD patients with the improved survival and growth potential, as well as elevated quality of life while compared to dialysis. Nevertheless, under the current system, the number of candidates on the waiting list will continue to increase, as each year more candidates are added than those are removed (4). Therefore, a great deal of strategies has been employed to increase the organ supply and to maximize the utilization of donor grafts. Recently, increasing evidences have reported the effectiveness of recovering and transplanting kidneys from the deceased small pediatric donors (17,18,30), indicating a potential approach to expand the donor criteria. Single kidney transplantation and en bloc kidney transplant are utilized from small pediatric donors into recipients although there are several unique challenges and complications, such as post-transplant vasospasm which is caused by small renal vessels, and graft failure due to the vascular thrombosis (8). Single kidney transplantation increases the utilization rate of donor organs; however, en bloc kidney transplant has been considered to provide a better outcome for the recipients (27).
Meta-analysis, a very effective tool in clinical and medical areas, has a stronger power than a single research as it allows a further generalization of the results obtained from the individual studies (31). There existed several advanced results for the meta-analysis. First of all, the combined sample size is larger than any single population, allowing more precision for the results in the effect estimation. Secondly, the pooled outcome has been carried out with a minimum level of heterogeneity (I2=2.6%, P=0.400) and the Begg’s test showed no publication bias (P=0.707) after the exclusion of one low-quality study. Thirdly, our results with sufficient evidence were proved by TSA to reach a conclusion.
In the present meta-analysis, the results demonstrated that patients who received en bloc kidney transplantation from the small pediatric donors (mean age <4 years) were more likely to have better graft survival while compared with those who received the single renal transplant (HR=0.57; 95% CI: 0.49–0.67, P<0.001). In the TSA, the pooled sample size of the cases and controls was 4,251, which did not achieve the required information size of 5,493; nonetheless, the cumulative Z-curve has already crossed the conventional boundary and the -spending monitoring boundary, suggesting that no further trial was needed and our meta-analysis was considered to have sufficient evidence.
However, several limitations need to be further refined. First of all, the whole population included in the meta-analysis were from the United States, which might cause a risk of selection bias; thus, more populations from other countries and regions will be required in the future investigation. Secondly, a random effect model was utilized when the I2 value for heterogeneity quantification was 2.6% among the included studies. Empirically, the random-effect model was applied if the statistically significant heterogeneity was identified (P<0.10 or I2>50%), otherwise the fix-effect model was utilized (32). Nonetheless, a portion of recipients were found in the research by Pelletier et al. (17), including those who were younger than 17 years (age ranging from <2 to 17 years, 4.3% in en bloc kidney transplant and 9.3% in single kidney transplant), and other studies did not enroll pediatric recipients. Therefore, a random effect model was applied to minimize the residual influences caused by heterogeneity. Thirdly, the adjusted estimates could not be performed in our analysis by other covariates due to the lack of case information in certain studies. For instance, the characteristics of donors and recipients in several studies were not respectively listed according to en bloc or single kidney transplant, such as the average age, weight, and ethnicity (17-19). Fourthly, the follow-up period for en bloc and single kidney transplantation differed in various studies included, which might result in the risk of potential inaccuracy.
Our results indicated that compared with single renal transplant, en bloc kidney transplantation from small pediatric donors was significantly associated with a superior graft survival. Besides, TSA has been conducted for the first time to assess the prognosis of en bloc versus single kidney transplantation for recipients, and more studies by standardized unbiased methods are required to offer more detailed data of high quality.
The authors of this manuscript would like to thank the researchers of the primary studies.
Conflicts of Interest: The authors have no conflicts of interest to declare.
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Cite this article as: Zhang JY, Zhang HC, Suo CJ, Gu M. Graft survival of en bloc versus single kidney transplantation from small pediatric donors: a meta-analysis with trial sequential analysis. AME Med J 2017;2:126.