Key words : Cardiovascular disease, Infections, Kidney transplant

Introduction

Death with graft function (DWGF) is a major cause of graft and patient loss after kidney transplant. In large cohort studies of kidney transplant recipients, DWGF accounted for 38% and 42.5% of deaths and graft losses, respectively,¹ with fatalities in almost one-fourth of patients within the first posttransplant decade.² Various pretransplant and posttransplant risk factors have been linked to DWGF, but cardiovascular disease (CVD) remains the leading cause of death.^3,4

Kidney transplant in developing countries faces many challenges.⁵ Therefore, every attempt should be made to improve its outcome. Death with graft function, an important yet a potentially modifiable cause of graft loss, has been poorly investigated among Egyptian kidney transplant populations. Two decades after our previous report,⁶ we here report on DWGF among our living donor kidney transplant patients throughout a period of more than 4 decades.

Materials and Methods

This retrospective study was carried out in accordance with the code of ethics of the 2013 World Medical Association (Declaration of Helsinki) for studies involving humans. Data on transplant recipients are stored in internal servers and system (patient information system). Data were retrieved from our patient information system at our urology and nephrology center after agreement from the head of the department and director of the center. No patient names, initials, or hospital numbers were used. This study was approved by the ethical and research committee of the Urology and Nephrology Center, Mansoura University (Mansoura, Egypt).

This study included 2953 recipients who had kidney transplant procedures between March 1976 and December 2018 at our Urology and Nephrology Center at Mansoura University. During this period, 3018 kidney transplant procedures were performed. There were 65 recipients who were not followed up at our center (referred to other centers) after transplant and thus were excluded from the study. All patients received their grafts from living blood-related donors.

Patients included in the study were divided into 4 groups according to the condition at last follow-up: DWGF group, alive with graft function (AWGF) group, alive with graft loss (AWGL) group, and death with graft loss (DWGL) group. In our study, DWGF was defined as death of a kidney transplant recipient without the need for dialysis or retransplant. Patient data were retrospectively analyzed. The DWGF group was compared with each of the other 3 groups with regard to pretransplant and posttransplant data. Primary immunosuppression protocols showed successive modifications following global evolutions in the immunosuppression armamentarium.

Our study period was divided into 4 eras: era 1 (era of conventional immunosuppressive regimen: steroid plus azathioprine) was from 1976 to 1985, era 2 (era of cyclosporine) was from 1986 to 1995, and era 3 and era 4 were from 1996 to 2005 and from 2006 to 2018, respectively, when tacrolimus and mycophenolate mofetil were utilized. After 2007, a steroid-free regimen has been utilized for patients with low immunologic risk. Induction therapy with basiliximab has been routinely used for all patients since 2010 with the exception of high immunologic risk candidates for whom antithymocyte globulin induction was implemented. Since 1993, rejection has been defined according to the consecutively published Banff schemas.

Causes of death among kidney transplant recipients in the DWGF group were analyzed and compared with causes of death in the DWGL group. In addition, both groups were compared with regard to causes of death during the different transplant eras. Further analyses of fatal infections (causative organisms and organs affected) and of fatal malignancies (site and type) among both groups were also conducted.⁴

Statistical analyses
Qualitative data are displayed in cross tabulation, whereas quantitative data are shown as arithmetic mean and standard deviation. Data of the DWGF group were compared with each of the other 3 groups using chi-square and Fisher exact tests for qualitative variables and unpaired t tests for quantitative variables. P < .05 was considered significant. Multi-variate analysis was performed using hazard Cox regression model. Kaplan-Meier survival curves were used to evaluate patient and graft survival rates. Analysis was carried out using the computer package SPPS for Windows version 10.

Results

Among our kidney transplant recipients, 1654 (56%) were male patients and 1299 (44%) were female patients. The mean follow-up for the total patient group was 8.37 ± 5.76 years (median of 7.65 years; range, 0-33.54 years). Death was reported in 499 patients (16.9%): DWGF in 291 patients (58.3%) and DWGL in 208 patients (41.7%). In terms of graft function, 2061 patients (69.8%) had a functioning graft at last follow-up: 1770 (85.9%) in the AWGF group and 291 (14.1%) in the DWGF group. Graft loss was reported in 1183 patients (40.06%) at last follow-up: 24.6% in the DWGF, 17.6% in the DWGL, and 57.8% in the AWGL group. Among the combined patient groups, 9.9% had DWGF and 59.9% had AWGF at last follow-up (Figure 1). The proportion of DWGF among total graft losses in different eras of immunosuppression is shown in Figure 2.

Pretransplant and posttransplant features of the death with graft function group
We compared the DWGF group with the AWGF, AWGL, and DWGL groups with regard to different pretransplant (Table 1) and posttransplant (Table 2) characteristics. Among the whole group of patients, 2059 patients (69.7%) had unidentified original kidney disease, 2793 (94.6%) underwent pretransplant dialysis, 1250 (42.3%) received pretransplant blood transfusion, 1600 (54.2%) had pretransplant hypertension, and 170 (5.8%) had pretransplant diabetes mellitus. According to the policy of our transplant program, recipients and donors must share at least 1 DR locus. All primary immunosup-pressive protocols included steroids at variable doses except for the tacrolimus-based regimen, which included both steroid-free and steroid-containing regimens. Posttransplant hypertension and new-onset diabetes mellitus were reported in 1336 patients (45.2%) and 628 patients (21.3%), respectively.

Among pre- and posttransplant characteristics that showed a statistically significant difference between DWGF and AWGF groups, only pretrans-plant diabetes mellitus, total dose of steroid within the first 3 months, and posttransplant infections had persistently significant differences between the 2 groups on multivariate analysis (Table 3).

Causes of death among the death with graft function group
Figure 3 illustrates the different causes of death among the DWGF group compared with the DWGL group. Apart from death attributed to chronic renal failure in the DWGL group (35.1%), cardiovascular accidents were the most common cause of death (30.9% in the DWGF group and 27.4% in the DWGL group), followed by infection (29.2% in the DWGF group and 21.2% in the DWGL group). Malignancy was the third-leading cause of death in the DWGF group (13.4%), followed by liver cell failure in the DWGL group (6.2% and 8.6% respectively).

The relative frequency of different causes of mortality in the DWGF group varied according to posttransplant time (Figure 4). Infection was the leading cause of death within the first year after transplant (39.6%) and second cause of death thereafter. On the other hand, CVD was the second-leading cause of death during the first year (24.5%) but became the leading cause and showed a progressive increase thereafter (27.8% of deaths at >10 years posttransplant). Malignancy was an uncommon cause of death early after transplant but gradually increased thereafter to become the third-leading cause of death at 5 to 10 years and >10 years posttransplant (22.2%). For each of the 3 causes, the highest number of DWGF occurred more than 10 years after transplant.

Sites and causes of infections and types of malignancies that led to death (DWGF and DWGL) were further analyzed (Table 4). The respiratory system was the most common site, and bacterial infection was the most common cause of fatal infections in both groups. Despite higher prevalence of genitourinary infections in the DWGF group, this difference did not rank to a statistical significance. The etiology was unknown in 3.1% of all infection-related deaths. Posttransplant lymphopro-liferative disorder, the most common fatal malignancy in the DWGF group, was not among malignancies that led to DWGL.

Discussion

The prevalence of DWGF remains relatively constant in our current and previous reports (9.9% vs 9.4%, respectively). This could be explained by the longer follow-up period, which may have mitigated possible modifications of risk factors of DWGF after our previous report.⁶ We found that DWGF was responsible for a quarter of graft losses among our patients. This concurred with the proportion (19.3%) reported by a similar single-center study conducted by Yu and associates,⁴ which had a comparable number of patients and follow-up duration. In addition, the proportion of DWGF/total graft losses among our patients decreased over time similar to what was observed by Yu and colleagues. This observation could be due to the shorter follow-up period of the more recent transplants. It could also be (at least partially) explained by improved patient survival due to greater attention paid to comor-bidities and the adoption of less toxic immunosup-pressive regimens.

Almost half of our patients received pretransplant blood transfusion, and only a small percentage had preemptive transplant procedures. This might reflect the late referral of patients with chronic kidney disease, the limited resources available for treatment of their anemia, and the shortage of transplant services in our country.⁵ In a study that analyzed United Network for Organ Sharing data of more than 47 000 living donor kidney transplants,⁷ preemptive transplant (31% compared with almost 5% in our study) was associated with better graft and patient survival. Hemodialysis is the principal modality of dialysis among our patients due to a shortage of peritoneal dialysis facilities in our country. Hemodialysis may be associated with an altered immune system, higher cardiovascular risk, and DWGF.⁸

The significantly higher prevalence of pretransplant blood transfusions in the DWGF group is a reflection of pretransplant anemia, which may have an impact on patient survival. In addition, it may lead to allosensitization⁹ with a subsequent impact on the posttransplant immunosuppression regimen and patient survival. On the other hand, higher HLA mismatch was noted in our DWGF group. This could also be explained by the need to adopt more aggressive immunosuppression protocols with subsequent higher infection and cardiovascular events.¹⁰

Antithymocyte globulin induction and cyclosporine-based protocols were more common and tacrolimus and mechanistic target of rapamycin (mTOR)-based regimens were less frequently reported among the DWGF group versus the AWGF group. Antithymocyte globulin induction carries the risk of infection and malignancy with subsequent lower patient survival.^6,11 In addition, the steroid-free protocol is one of the tacrolimus-based regimens used by patients in our study and, therefore, is less commonly used in the DWGF group with a possible negative impact on patient survival. Furthermore, the use of mTOR-based protocols after transplant is associated with lower prevalence of malignancy¹² and may favorably affect patient survival. The cumulative steroid dose after transplant was higher in the DWGF than in the AWGF group, agreeing with our earlier report⁶ and with the Collaborative Transplant Study (CTS) data, which showed an association between steroid dose and DWGF from CVD or infection.³

The highest prevalence of pretransplant diabetes and new-onset diabetes mellitus after transplant was noted among our DWGF patients and was highly significantly different compared with the prevalence observed in the AWGF and AWGL groups. Our findings agree with the known negative impact of pretransplant diabetes on posttransplant patient survival¹³ and the association of new-onset diabetes mellitus after transplant with unfavorable cardiovascular risk and reduced survival of kidney transplant recipients.^6,14 Pretransplant hypertension and nephrosclerosis as well as posttransplant hyper-tension were also more common among DWGF patients compared with the AWGF group, which concurred with previous data that showed that pre- and posttransplant hypertension is associated with poor posttransplant patient survival.¹⁵

Causes of death and their order of frequency among our DWGF group were similar to those reported by the CTS.^3,10 Cardiovascular disease was the most common cause of death among our DWGF patients, accounting for about one-third of mortalities. There was a preponderance of male patients among our DWGF group, which is similar to that reported by Yu and colleagues.⁴ Infection was the leading cause of DWGF throughout the whole follow-up period in our earlier report.⁶ In the present study, infection was the leading cause of death among our DWGF group during the first year posttransplant and the second-leading cause of death over the whole follow-up period. The introduction of a steroid-free regimen and routine antiviral prophylaxis in our program during the past 10 years¹⁶ may explain this difference. However, fatal infections (especially those due to viruses) have increased during the most recent era of our study. Similar results were reported by Yu and colleagues.⁴ This could be attributed to improvements in diagnostic techniques, especially those for viral infections.¹⁷ In both studies, respiratory pneumonia and bacterial infection were the most common site and cause of infection, respectively. The proportion of malignancy as a cause of death among our DWGF group increased over time after transplant. Posttransplant lymphoproliferative disease was the most common cause of fatal malignancy, agreeing with a previous report.⁴ Posttransplant malignancy is related to intensity of immunosuppression and infection. Kaposi sarcoma, which was previously the most common malignancy among our transplant patients, has not been reported for the last 10 years, possibly due to the use of less aggressive immuno-suppression and chemoprophylaxis.¹⁶ Overall, the highest prevalence of mortality among our DWGF patients occurred 10 years after transplant, a period after which CVD, infection, and malignancy are expected to increase.

In our earlier report, Cox multivariate analyses revealed that posttransplant infection was the only risk factor of DWGF.⁶ In our present study, pretransplant diabetes and cumulative dose of steroids within the first 3 months posttransplant were further risk factors in addition to posttransplant infection. We attributed this to the introduction of a steroid-free regimen and the acceptance of patients with diabetes for transplant in our program over the past 2 decades.

Conclusions

Death with graft function remains an important contributor to graft loss among kidney transplant recipients. Cardiovascular disease, infections, and malignancy are the most common causes of DWGF among our patients. Attention to modifiable risk factors of CVD, strict vaccination policies, timed surveillance for malignancy, and less aggressive immunosuppressive protocols, such as a steroid-free regimen, are therefore, crucial to prevention of DWGF.

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