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ARTICLE
Nonimmunologic Factors Affecting Long-Term Outcomes of Deceased-Donor Kidney Transplant

Objectives: We investigated the impact of nonimmuno-logic factors on patient and graft survival after deceased-donor kidney transplant.

Materials and Methods: All deceased-donor kidney transplants performed between January 2004 and December 2015 were included in our analyses. We used the independent t test to calculate significant differences between means above and below medians of various parameters.

Results: All study patients (N = 205; 58.7% males) received antithymocyte globulin as induction therapy and standard maintenance therapy. Patients were free from infection, malignancy, and cardiac, liver, and pulmonary system abnormalities. Most patients (89.2%) were recipients of a first graft. Median patient age, weight, and cold ischemia time were 38 years, 65 kg, and 15 hours, respectively. Delayed graft function, diabetes mellitus, and hypertension occurred in 19.1%, 43.4%, and 77.9% of patients, respectively. The 1- and 5-year graft survival rates were 95% and 73.8%. Graft survival was not affected by donor or recipient sex or recipient diabetes or hypertension. However, graft survival was longer in patients who received no graft biopsy (8.2 vs 6.9 y; P = .027) and in those who had diagnosis of calcineurin inhibitor nephrotoxicity versus antibody-mediated rejection after biopsy (8.19 vs 3.66 y; P = .0047). Longer survival was shown with donors who had traumatic death versus cerebro-vascular accident (5.9 vs 5.3 y; P = .029) and donors below the 50th percentile in age (8.23 and 7.14 y; P = .0026) but less with donors who had terminal acute kidney injury (6.97 vs 8.16 y; P = .0062). We found a negative correlation between graft survival and donor age (P = .01) and 1-year serum creatinine (P = .01).

Conclusions: Donor age, cause of brain death, and acute kidney injury affected graft survival in our study cohort but not donor or recipient sex or posttransplant or donor blood pressure.


Key words : Graft survival, Patient survival, Renal transplant

Introduction

The Saudi Center for Organ Transplantation was established in 1984 to control and organize the activities of transplantation and donation.1 In Saudi Arabia, 22% of all dialysis patients are on the wait list for renal transplants, with an additional 20% of patients under investigation for their suitability for transplant.2

Kidney transplant from ideal and marginal donors provides, on average, 13 and 5 years of increased life expectancy for recipients, respectively, compared with patients who remain on wait lists.3 Furthermore, data from the United States show that the wait time for receiving a kidney is more than 3 years; when combined with the high annual mortality rates of patients on wait lists, the use of suboptimal grafts is strongly needed.4-6

Categorizing kidneys is an essential tool for determining prognostic risk factors for kidney transplant to appropriately allocate the donated kidney, counsel the recipients, and assess kidney graft survival, expected kidney function, and incidence of rejection and delayed graft function (DGF).7 There are 2 widely recognized criteria for donated kidneys based on donor characteristics: (1) standard criteria donors (SCD) are under 50 years old and have cause of death of traumatic injury or stroke; (2) expanded criteria donors (ECD) include donors who are more than 60 years old, donors between 50 and 59 years old with history of hypertension and with serum creatinine level > 132.6 μmol/L (> 1.5 mg/mL), and donors with death due to cardiovascular incident.6 Cardiovascular events represent 33% of causes of deaths among brain-dead donors, with 18.1% being over 50 years old.8,9 There has been a steady increase in the use of ECDs due to shortages of donated kidneys coupled with an ever-increasing number of patients on wait lists for kidney transplant. In Saudi Arabia, about 25% of retrieved kidneys are ECD kidneys, which is similar to rates reported elsewhere.9 However, acquiring kidneys from ECDs has a risk of graft loss of more than 1.7 times compared with use of kidneys from SCDs.7

Although categorizing donors as either ECDs or SCDs is easy, it does not reveal the whole spectrum of associated risks nor does it consider risk factors of the recipients.7 Risk factors that predict poor outcomes include increased body weight, history of hypertension, longer hospital stay, and adrenaline use.7 Short- and long-term graft survival rates have also been shown to be affected by cause of death, immunosuppressive regimen, infection, acute rejection, cold ischemic time (CIT), which is the period between cold perfusion of the procured kidney and time the kidney is rewarmed for reimplantation, DGF (P < .0005), which is determined as need for dialysis after transplant, donor age, and serum creatinine level.10-12 With regard to 1-year allograft survival, recipient creatinine level, age, CIT, and DGF have been shown to be significant determining factors (P < .05).12,13 Infections also play an important role in graft survival. For example, hepatitis C virus and cytomegalovirus infections have been shown to be significant factors causing relapse or death of recipients.14-16 The recurrence of glomerulonephritis after transplant is another factor that is associated with DGF.17

With regard to long-term outcomes, recipient factors include degree of human leukocyte antigen (HLA) matching, presence of HLA antibodies, and preexisting cardiovascular comorbidities.15 Other factors associated with graft and recipient survival include presence of diabetes mellitus in the donor and lower levels of HLA-DR matching.18,19 Contrary to other findings, neither smoking nor ethnicity has been shown to be associated with transplant outcomes. In addition, in the United Kingdom, cardiovascular disease, diabetes, and terminal creatinine did not significantly affect outcomes.10

Conflicting results regarding factors affecting outcomes necessitate the exploration of risk factors in Saudi Arabia. Here, we present the first study that attempts to determine factors associated with graft survival in Saudi Arabia. The aim of our research is to inform readers of the results of deceased-donor kidney donor transplant at a single kidney transplant center.

Materials and Methods

This retrospective cohort study was conducted at the kidney transplant center of King Abdulaziz Medical City (KAMC) in Riyadh, Saudi Arabia. The KAMC is a governmental tertiary care center that performs living-donor and deceased-donor renal transplant procedures, provides emergency renal services to 5 to 7 patients per day, and provides consultation to 120 patients every month. The study participants were all adult patients who received a deceased-donor kidney transplant at KAMC between January 2004 and December 2015. The data collection period was between July 2017 and March 2018 and was performed by the consecutive sampling approach.

Patient details
All patients were over 18 years of age (N = 205). Transplant recipients received antithymocyte globulin as induction therapy (1 mg/kg intravenously × 4 doses). As maintenance immunosuppressive therapy, all recipients received prednisolone (30 mg daily), with tapering gradually to 5 mg daily at 6 months, mycophenolate mofetil (1 g), and tacrolimus target of 10 to 12 ng/mL at months 0 to 3, 8 to 10 ng/mL at months 4 to 6, 6 to 8 ng/mL at months 7 to 12, and 5 to 7 ng/mL afterward. Before transplant, patients were confirmed to be free from active infection, malignancy, and significant cardiac, liver, or pulmonary system abnormalities. All patients received dental evaluations, and those over 50 years of age had colonoscopies.

All data and variables regarding donors were obtained from the Saudi Center for Organ Trans-plantation registry by the coinvestigators. Donor variables included demographic characteristics (age, sex, weight, and blood group), cause of brain death, history of hypertension and diabetes mellitus, date of organ recovery, blood pressure before organ retrieval, serum creatinine on admission and at time of organ retrieval, CIT, and whether the left or right kidney was used.

All data and variables regarding recipients were obtained from the patient medical records via the Bestcare electronic system and physical paper files by the coinvestigators. Recipient variables included demographic characteristics (age, sex, weight, and blood group), incidence of DGF, posttransplant history of hypertension and diabetes mellitus, and incidence of cytomegalovirus, BK virus, or tuberculosis infection. The coinvestigators also documented the recipient’s date of transplant, serum creatinine level at 1 year and on the last available follow-up, death if it occurred and when, graft loss if it occurred and when, and result of graft biopsy if done and when. We also reviewed whether graft loss was due to antibody-mediated rejection (AMR), calcineurin inhibitor (CNI) nephrotoxicity, rejection, BK virus infection, acute tubular necrosis, or other causes. This research was approved by our Institutional Review Board (12/07/2017).

Statistical analyses
Statistical analyses of donor and recipient data were performed with SPSS software (SPSS: An IBM Company, version 24.0, IBM Corporation, Armonk, NY, USA). Data are presented as means and standard deviation for continuous variables and as percentages and proportions for categorical variables. The chi-square test was used to compare percentages and proportions. The 2-tailed independent t test was used for analysis of continuous data. We used the Kaplan-Meier method to calculate graft and patient survival. We used the Pearson t test to analyze correlations between recipient age and serum creatinine levels at 1 year and graft survival.

Multivariate analyses were performed to deter-mine the independence of factors that influenced graft outcomes. We used the Kruskal-Wallis test to assess the effects of donor terminal renal function on the final status of the recipient. P values of .05 or less were considered to be statistically significant.

Results

Our analyses included data of donors and recipients of 205 deceased-donor kidney transplant procedures carried out between 2004 and 2015 at the KAMC.

The mean duration of follow-up, median graft survival, and mean patient survival were 8.3 ± 3.1, 7.5 ± 3.4, and 7.95 ± 3.2 years, respectively. Mean weight of donors was 67.9 ± 11.9 kg, and mean donor age was 37.1 ± 11.8 years. Donor terminal systolic blood pressure was 127.9 ± 35.7 mm Hg, terminal diastolic blood pressure was 73.0 ± 21 mm Hg, and terminal median blood pressure was 91.3 ± 24.7 mm Hg. Donor serum creatinine levels were 101.1 ± 48.8 μmol/L at admission and 100.8 ± 65 μmol/L at time of organ retrieval (P = .9). Donor sodium levels were 142.6 ± 10.3 mmol/L at admission and 141.6 ± 13.3 mmol/L at time of organ retrieval (P = .6).

Mean age of recipients was 37.7 ± 17.4 years, with male patients accounting for 58.7%, and mean recipient weight was 62.9 ± 22.6 kg. Mean CIT was 13.8 ± 6.6 hours. The mean serum creatinine level was 156.3 ± 194.8 μmol/L at 1 year and 204.3 ± 263 μmol/L at last follow-up (P = .034). No recipients were hepatitis B or hepatitis C virus positive. Prevalence of diabetes mellitus and hypertension among recipients was 43.4% and 77.9%, respectively. The prevalence of DGF, graft loss, and death was 19.1%, 24.5%, and 11.8%, respectively. Recipient characteristics are shown in Table 1. In our recipient cohort, 89.2% had a first kidney transplant, whereas 10.8% had received 1 previous transplant.

There were 90.2% male donors and 9.8% female donors. The left donor kidney was utilized in 69.9% of cases and the right in 30.1%. Brain death in donors was mostly due trauma (44.6%) followed by cere-brovascular accident (37.4%) (Table 2).

Impact of donor characteristics on patient and graft survival
We observed no statistically significant impact of donor sex on graft survival (P = .56). Furthermore, donor sex had no significant effect on DGF (rate of 19% vs 15% in male vs female donors; P = .6), CIT (13.7 vs 13.5 h in male vs female donors; P = .8), or 1-year serum creatinine level in recipients (156.6 vs 148.8 µmol/L in recipients of male vs female donors; P = .86). Donor sex also did not affect patient survival (log-rank = 0.0117; P = .9139) (Figure 1).

We found a negative correlation between graft survival and donor age (r = 0.17; P = .01) and graft survival and serum creatinine level at 1-year posttransplant (r = 0.17; P = .01). We observed a statistically significant correlation between donor age and overall patient survival (log-rank = 9.0384; P = .0026) (Table 3).

Impact of recipient characteristics on graft survival
We observed no significant differences in graft survival between men (58.7%) and women (41.3%) (P = .9). Diabetes mellitus and hypertension status also did not significantly affect graft survival (P = .2). There was no significant adverse effect of DGF on graft survival (7.7 ± 3.2 vs 6.4 ± 3.7 y; P = .5). However, graft survival was longer in patients who did not require a biopsy versus those who did (8.2 vs 6.9 y; P = .27). Graft survival was also longer in patients with biopsy-proven CNI toxicity versus those with biopsy-proven AMR (8.19 vs 3.66 y; P = .0047) (Figure 2). Patients who received a second graft had longer graft survival than those who only had one transplant (Figure 3). When we compared the median graft survival in recipients of grafts from donors who developed AKI during their ICU stay to those who did not, we found a significant difference (6.97 vs 8.16 y, respectively; P = .0062).

Assessing the prevalence of delayed graft function, rejection, and infection among transplanted patients
During our follow-up period, 24.5% of grafts were lost and mortality rate was 11.8%. The prevalence of DGF was 19.1%. The incidences of infections in recipients were 7.4% for tuberculosis and 3.9% for BK virus (Table 1). Renal biopsies were performed in 41.2% of our study recipients. The following pathologic findings were shown: AMR in 5.3%, CNI toxicity in 14.7%, cellular rejection in 28%, BK nephropathy in 2.7%, acute tubular necrosis in 28%, and other findings in 21.3% (Table 3).

Discussion

Analysis of recipient and donor characteristics is important for finding ways to improve long-term transplant outcomes. In our retrospective/prospective cohort study involving 205 recipients of kidney transplant with a median follow-up of 11 years, we found that donor age had a significant effect on graft survival and overall patient survival. As reported by Ma and associates, donor age significantly affected both graft and patient survival.20 This is due to the well-recognized age-related decline in kidney function. It is estimated that glomerular filtration rate, on average, drops by 33% from the 3rd to 7th decade of life.21

We have also found that recipient sex did not affect graft survival and patient survival outcomes. However, Mun woo and Ostrowska and associates demonstrated that the risk of kidney allograft loss was associated with male sex.16,22 A previous report from Saudi Arabia also showed no impact of sex on graft and patient survival.6

In our study cohort, DGF did not affect graft survival (P = .5). This is consistent with the report by Noppakun and associates, which showed no dif-ferences between patients with DGF and those with immediate graft function in terms of patient or graft survival.23 In contrast, several studies have shown that kidney transplant recipients who developed DGF showed worse graft survival.21,24 This difference may be explained by the fact that, in our study, the mean ages of our donors and recipients were quite low; patients of lower ages can perhaps withstand and offset the long-term negative hemodynamic effects resulting from DGF. Moreover, Boom and associates showed that, although DGF negatively affected graft function, it did not affect graft survival.25

We showed that graft survival was longer in patients who did not require a biopsy compared with those who did (P = .03). This is not surprising since the biopsy must have been necessitated by some abnormality in kidney function. Graft survival was also longer in patients with biopsy-proven CNI toxicity than in those with biopsy-proven AMR (P = .02), as would be expected.

Our report also demonstrated that patients with a second transplant had longer graft survival than those who had just only 1 transplant. These results are in contrast with the report from Zeraati and associates, which showed that second transplant recipients had a poorer long-term prognosis than first transplant recipients. However, their results were based on recipients from a large multicenter cohort.26

Recommendations and limitations
Our study has both strengths and possible limita-tions. Our study specifically compiled a large number of demographic and laboratory factors that can affect graft survival. It also recorded comor-bidities associated with donors and recipients, thus providing a better analysis of factors affecting deceased-donor kidney transplants in one of Saudi Arabia’s largest transplant centers (KAMC). Further comparisons between other transplant centers may help to identify population-specific risk factors and geographic discrepancies. A limitation of our study is its retrospective nature, which reduces control of confounding factors.

Conclusions

Despite high mortality rates due to road traffic accidents in Saudi Arabia, there is a low rate of organ procurement. The lack of donors has decreased the organ pool. Therefore, we suggest implementing strategies to increase the rate of organ procurement from patients with brain death due to road traffic accidents.


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DOI : 10.6002/ect.2018.0396


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From the 1-5College of Medicine, King Saud Bin Abdulaziz University for Health Sciences; and 6King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Shahad Farhan Alenazi, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 14611, Saudi Arabia
Phone: +960 0118011111
E-mail: shahadf.alenazi@gmail.com