Short term and long term survival rate and risk factors of graft rejection after deceased donor kidney transplantation: a systematic review and meta-analysis


 The purpose of the current meta-analysis is to determine the short-term and long-term graft and patient survival after deceased donor (DD) transplantation, as well as to determine prognostic factors. Method : Articles published until March 2019 in PubMed, Scopus, and Google Scholar databases, reporting short-term and/or long term graft and patient survival were searched. In addition to this, we included articles that analyzed the hazard ratio (HR) of graft rejection and/or patient death caused by DD related risk factors. The summary measures of this study included the survival rate, the HR of graft rejection, and patient death in response to DD related risk factors. This study, which is the first comprehensive meta-analysis of graft and patient survival rates after transplantation from the deceased donor, showed that overall short and long-term survival of graft and patient is desirable. In addition to this, it confirms that ECD and DCD recipients have a lower graft survival rate than standard donors.

immunological and hormonal changes compared to living donors (25,26), other studies have reported desirable results from the function of the DD renal transplantation (27,28). Even though various studies have been carried out in order to determine the effect of cadaveric donors on renal transplantation rejection, these estimations vary from one study to another, and some cases have rejected the results of other studies. The current meta-analysis was performed to determine the short and long-term survival rate of kidney transplantation from the deceased donor, as well as to determine the factors influencing it, using all of the observational and registry-based studies.

Method
In this systematic review and meta-analysis, all prospective, retrospective, and registry-based studies that examined the survival rate of kidney transplantation from DDs all around the world were included without any restriction.

Inclusion criteria for studies
All of the stages of this study were performed under PRISMA guidelines. The criteria for including studies were: study design (prospective, retrospective or registry-based studies), report of patient or graft survival rate, or report of hazard ratio (HR) for determination of the effect of DD related factors on graft rejection. Articles that did meet at least two of these inclusion criteria were included. The outcome measures included the one-year, five-year or ten-year patient or kidney transplantation survival rates from DD and risk factors of rejection related to characteristics of DD such as age, sex, weight, history of chronic disease, and type of DD which includes donation after brain death (DBD), donation after circulatory death (DCD), expanded-criteria donors (ECDs) or standard-criteria donors (SCDs).

Search strategy
In this study, using the search strategy shown in Table 1, we searched PubMed and Scopus databases to obtain relevant studies until March 2019. In order to obtain more articles and to ensure proper search of databases, references of selected articles were reviewed. and studied 923 full-text articles. According to our objectives and quality assessment of selected articles, 845 papers were withdrawn, and finally, 75 articles were included in the final analysis (Fig 1). Table 2 represents article information including author, country, research design, donor sex, male donor (%), donor mean age (year) ± SE, type of the deceased donor (DBD or DCD), criteria (ECD or SCD), donor BMI, sample size, patient survival rate, and graft survival rate.   Table 3 shows the most important causes of deaths in the deceased donor reported by twenty-six articles. Trauma and cerebrovascular were the most common causes of death. Graft and patient survival rate The one-year graft survival rate was 90% (95% CI: 89% to 92%). Two, three, five and ten-year graft survival rates were 80% (95% CI: 90% -70%), 82% (95% CI: 75% -88%), 76% (95% CI: 73% -79%) and 52% (48% -60%), respectively (Fig 2). One-year patient survival rate was 95% (95% CI: 94% -96%).

Hazard Ratio
Although most of the studies have found that the HR of graft rejection and patient death risk factors are attributed to the recipient, few studies have been performed to determine the HR of risk factors associated with the deceased donor. Therefore, only three factors, including the age of the donor, ECD kidney and male sex, were included for analysis. HR of age of deceased donor was 1.01 (95% CI: 0.99 to 1.04) for graft rejection and patient death (Fig 11). ECD kidney was a risk factor for graft rejection (HR: 1.14, 95% CI: 1.00, 1.27) (Fig 12). Male sex was a significant protective factor in patient survival rate. According to the results shown in graph 13, the risk of death in men had an HR of 0.86 (95% CI: 75,97). However, the male sex does not affect the survival of the kidney transplant (HR=0.95, 95% CI: 0.83, 1.06) (Fig 13).

Discussion
In this systematic review and meta-analysis, we estimated the graft and patient survival after kidney transplantation form DD for the first time. Currently, the demand for kidney transplantation is much higher than the number of kidney donors. While in response to this need, kidney donation from DDs has been developed around the world, concerns and inconsistencies about the graft and patient survival after transplantation from these donors have also increased. Our findings showed that one- year kidney transplant and patient survival rates were respectively 90% and 95%. According to Fig Cellcept was added to the treatment protocol. This immunosuppressive drug not only increased longterm kidney transplant survival rate from 15-20% but also reduced the rate of acute transplant rejection (108). Therefore, included articles from the 1980s and 1990s will increase the variability of short-and long-term graft survival and patient survival. cerebrovascular accident as a cause of brain death, and (3) final pre-procurement serum creatinine (SCr) level > 1.5 mg/dL. Also, a kidney that has a relative risk of rejection higher than 1.7 compared to the age group of 10 to 39 without hypertension and high creatine is considered an ECD kidney. One of our inclusion criteria was the HR report for ECD compared to SCD. As shown in graph 12, only four studies, using Cox regression, measured the HR of graft loss for ECD. Our findings showed that HR of graft rejection for ECD donors was 14% higher than the standard group. OPTN/SRTR 2017 Annual Data Report (110) showed a dramatic increase in the number of deceased donation, and this increase in the age group of 18 to 34 years is more than other groups. Their report shows that despite a deceased donor increase, 18% have been discarded due to older age and diabetes. In summary, although ECD is associated with an increased risk of graft rejection in comparison with SCDs, the five-  (112,113). Even though the development of DCD transplantation policy and the importance of awareness of the outcomes of DCD recipients, one of the limitations of some of the articles in our study was that they did not report graft and patient survival according to the type of deceased donor and cause of death. We showed that one-year graft survival in DCD recipients was 5% lower than DBD recipients, whereas no differences were observed in one- year patient survival. Prolonged warm ischemia time, higher risk of ischemia-reperfusion injury, (114,115), inferior quality of vessels, and/or endothelial activation (102) have been presented as the most important causes of lower graft survival in DCD recipients.
In one of the most extensive cohort studies in the UK, after adjusting the age of recipient and donor as well as cold ischemic time, the HLA mismatch level, number of HLA mismatches, HLA-DR mismatches, machine perfusion, and warm ischemic time showed no influence on graft rejection from DCD. According to the findings of this cohort, the age of the recipient and donor were the only factors affecting DCD graft rejection (116).
Although the incidence of DFG after DCD has been reported 27-73% in different studies (116)(117)(118), the practical factors such as donor and recipient age, cold ischemic time, and HLA-matching, make the result of kidney transplants from DCD acceptable compared to dialysis.

Conclusion
The findings of our study, which is the first comprehensive meta-analysis of graft and patient survival of the deceased donor, using all single-center, multicenter, and registry-based studies, show that overall, short-term and long-term graft and patient survival is desirable after kidney transplantation from DD. Our findings confirm that ECD recipients have lower graft survival rates than SCDs, and despite the shorter one-year survival rate in DCDs, the short-term patient survival rate is similar to DBDs. We also concluded that men had better survival than women but did not differ in graft survival. The flow of information through the different phases of the systematic review Hazard ratio of graft rejection and patient death by age of donors Figure 12 Hazard ratio of graft rejection and patient death by male sex of donors Figure 13 Hazard ratio of graft rejection and patient death by ECD