|Year : 2019 | Volume
| Issue : 3 | Page : 640-647
|A study of the main determinants of kidney allograft long-term survival in the era of new immunosuppressive drugs
Reza Hekmat1, Mark Sturdevant2
1 Department of Nephrology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Nephrology, Starzel Institute of Transplantation, Pittsburg University, Pittsburgh, PA, USA
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|Date of Submission||03-Feb-2018|
|Date of Acceptance||07-Mar-2018|
|Date of Web Publication||26-Jun-2019|
| Abstract|| |
The outcome of long-term kidney allograft is extremely important. The present study aimed to discern the factors affecting long-term kidney allograft survival, including the type of donation and the use of extended criteria donors. Seven hundred and thirty-seven kidney transplant alone patients entered this retrospective cross-sectional study. The impact of different factors on death-censored long-term kidney allograft survival was evaluated. The Cox proportional survival model was employed to identify these factors. A value of P < 0.05 was considered statistically significant. The data were analyzed using IBM Statistical Package for the Social Sciences version 19.0. The study was conducted at the Mashhad University of Medical Sciences, Mashhad, Iran. In comparison with living kidney donations, both nontraumatic and traumatic brain death cadaveric kidney donations showed statistically significant inferior graft survival. Furthermore, the Kaplan–Meier survival analysis showed better durability of living kidney donations in comparison with traumatic and nontraumatic deceased donors (Log-rank test value = 0.001). Patients with delayed graft function (DGF) had a significantly shorter long-term death censured long-term graft survival in comparison with those without this complication. The Cox proportional models showed that DGF occurrence and the type of donation play a statistically significant role in long-term kidney graft survival. In addition, regarding graft survival, there was no difference between standard criteria and extended criteria donors. The occurrence of DGF and living or deceased types of donations have a significant effect on long-term kidney allograft survival.
|How to cite this article:|
Hekmat R, Sturdevant M. A study of the main determinants of kidney allograft long-term survival in the era of new immunosuppressive drugs. Saudi J Kidney Dis Transpl 2019;30:640-7
|How to cite this URL:|
Hekmat R, Sturdevant M. A study of the main determinants of kidney allograft long-term survival in the era of new immunosuppressive drugs. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2019 Jul 23];30:640-7. Available from: http://www.sjkdt.org/text.asp?2019/30/3/640/261338
| Introduction|| |
In recent years, the cadaveric kidney donor pool was extended to include donors who might have been considered unsuitable in earlier times, thus evolving to the concepts of “marginal” and “expanded criteria donors” (ECDs). Although eligible for organ donation, such organs, may expose the allograft to the higher risk for reduced posttransplant function, because of extreme old age and some other clinical characteristics. Thus, reducing the difference between the graft outcome ofpatients grafted with “marginal” and “optimal” donors is a new challenge.
Recent developments in organ allocation and transplantation immunosuppression therapy has also led to improved kidney graft survival, but long-term graft survival may be impacted by the increasing usage of kidneys from ECD. There are many presumed or proven factors either affecting kidney allograft function and longevity or not: kidney donor profile index (KDPI), machine perfusion techniques,, acute kidney injuries in deceased donors, obesity with diabetes mellitus (DM), history of smoking, parameters of machine perfusion such as flow rate and the resistance index, prekidney transplantation (KT), parathyroidectomy, obesity as a risk factor independent of DM, super obesity, and hypothermic machine perfusion techniques. Some studies have reported that KT from even high risk and unconventional donors and brain-dead donors, offer acceptable long-term kidney graft survival. A new surge in delayed graft function (DGF) occurrence, in the coming years is expected because of the increasing use of kidneys from ECD, and from donations after cardiac death (DCD) donors, both of which have shown more DGF than that of standard criteria donors (SCDs). The occurrence of DGF has grave consequences for kidney allograft., In the last decade, the incidence of DGF in adult recipients of deceased kidney donor transplants has been reported to be within the 15%–30% range., Besides, due to the lack of acute rejection control in most studies, the impact of DGF on patient and graft outcome is controversial. Some studies have found shorter allograft survival time when the duration of DGF is more than six days, whereas other research has documented no effect. We tried to find out which factors affect long-term kidney graft survival, including acute rejection, the occurrence of DGF, and the type of donor or the interaction of multiple factors.
| Patients and Methods|| |
Seven hundred and thirty-seven kidney transplant alone patients, 272 woman and 465 men with a mean age of 51 ± 14.28 years, during the period of the study from January 2003 to January 2013, entered this retrospective cross-sectional study. Patients younger than 18 years or older than 65 years, whose with advanced heart or hepatic failure, active infection, malignancy were excluded from the study, all other patients entered the study. All patients were on a triple immune suppression therapy of calcineurin inhibitor (Astellas Pharma USA, Inc.,), mycophenolate mofetil (Roche Company, USA), and prednisolone (Teva Pharmaceuticals, USA). The current study evaluated the impact of different factors on death-censored long-term kidney allograft survival, including the occurrence of DGF which was defined as the requirement of dialysis in the 1st week after transplantation. Also evaluated for this impact were the effect of cause of donor death (categorized as traumatic and nontraumatic; nontraumatic including cerebrovascular accidents and other brain insults like anoxia), in addition to age, type of donation deceased or living, numbers of HLA mismatches, primary nonfunction, acute rejection occurrence within six and 12 months after engraftment, cold ischemia time (minutes). With α (two-tailed) = 0.001, β = 0.2, q1 (proportion of patients with living kidney donors) = 0.339, q2 (proportion of patients with deceased kidney donors) = 0.661 and relative hazard = 0.44, a total of 114 events were calculated as necessary for comparing the survival analysis between patients with living kidney donors and those with deceased, kidney donors. In the same manner, the sample size calculated for all other statistical tests was smaller that of the 737 of patients who entered this study. The Cox proportional survival model was used for identifying factors affecting kidney allograft survival. For comparing the survival of the kidney allograft among living, traumatic and nontraumatic deceased donors, Kaplan–Meier survival analysis, and plots were employed. Fisher’s exact test or Chi-square test was used to compare nominal variables. A value of P of <0.05 was considered statistically significant. The data were analyzed using IBM Statistical Package for the Social Sciences version 19.0, (IBM Corp., Armonk, NY, USA).
In the search for factors, most significantly affecting kidney allograft durability in the long-term, categorical and scalar factors, DGF occurrence, type of donation, and age, were entered in both the univariate general linear model and the cox proportional survival model. ECD was defined as any brain-dead donor aged >60 years or a donor aged >50 years with two of the following conditions: history of hypertension, terminal serum creatinine level >1.5 mg/dL, or death resulting from a cerebro-vascular accident. A written consent to report the cases was obtained from all patients. Due to the retrospective nature of this study, registration and approval by the Ethics Committee were not required. The study was conducted at the Mashhad University of Medical Sciences, Mashhad, Iran. The data were provided by the second author from Pittsburg University, Starzel Institute of Transplantation, Pittsburgh, PA, USA.
| Results|| |
The difference in graft survival was statistically significant when comparing living versus traumatic and nontraumatic brain death cadaveric kidney donation [Table 1]. Furthermore, the Kaplan–Meier survival analysis indicated greater durability of livening kidney donations in comparison with that of traumatic and nontraumatic deceased donors (Log-rank test value <0.001, [Figure 1]). The DGF incidence in the current study was about 10%. The Fisher’s exact test showed no correlation between DGF and acute cellular rejection in the first six or 12 months after engraftment (P = 0.56). Although there was a significant negative correlation between the age and death-censored graft survival (r = -0.08, P = 0.038), there was no statistically significant correlation between either cold ischemia time or operation time with death-censored graft survival (P-values = 0.27 and 0.07, respectively). Almost all warm ischemia times were under 60 min. Patients with DGF had a significantly shorter long-term death-censured long-term graft survival in comparison with those without this complication [Table 1]. In cases of more than three HLA mismatches between donors and recipients, graft durability was statistically comparable with those with <3 HLA mismatches [Table 1]. The factors of age, DGF occurrence, and the type of donation were statistically shown to significantly impact kidney graft survival. Both DGF occurrence and type of donation, in univariate general linear model and the Cox proportional survival models, showed a statistically significant role in long-term kidney graft survival, while age as covariate in the Cox proportional survival model had also a significant effect on graft durability [Table 2] and [Table 3]. There was no difference between the standard criteria and extended criteria donors in terms of graft survival [Table 1], but a significant correlation between the type of donation and DGF occurrence was found (Chi square P < 0.001).
|Table 1: Effect of different types of kidney donation, the occurrence of delayed graft function and the number of HLA mismatches between donors and recipients, on graft survival (days).|
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|Figure 1: Kaplan–Meier survival plot for living donors, nontraumatic deceased donors and traumatic deceased donors, showing more longevity for kidney allograft engraftment from living donors.|
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|Table 2: Effect of the delayed graft function, type of donation, and age on the dependent variable death censured graft survival as obtained by the univariate general linear model.|
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|Table 3: Effect of the delayed graft function, type of donation, and age on the dependent variable death censured graft survival as obtained by Cox’s proportional hazards model for survival time.|
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| Discussion|| |
The usage of potent immunosuppressive regimens, including mycophenolate mofetil and monoclonal antibodies, in addition to less recipient HLA sensitization due to a decrement in pretransplant blood transfusions, have produced a better graft outcome., Furthermore, improved kidney allocation strategies, has resulted in shortened cold ischemia time which is a major risk factor for ischemia-reperfusion injury.,, This amelioration of the long-term graft outcome has occurred in spite of the increase in risk factors, such as extended criteria and DCD donors, recipient diabetes, high body mass index, and cardiovascular diseases, that have a detrimental effect on long-term graft outcome., Among brain-dead donors, the cause of donor death, can potentially affect the survival of transplant recipient and the function of the transplanted kidney. The rather small size of the studied population may explain the lack of effect of extended criteria donations on graft survival, as emerged by this study, only a minority of deceased donors (11.9%) were nonSCD [Table 4]. Although there are indications that some SCD kidneys may actually have lower estimated quality, with a higher Kidney Donor Risk Index, than some ECDs, the current study’s results are in concordance with these indications. The incidence of DGF in ECD recipients has been shown to significantly decrease over time, from 35.2% in 2003 to 29.6% in 2011 (P = 0.007). However, our study showed more DGF in kidney allograft from extended criteria as opposed to SCD. A recent study in Japan has also found no difference in long-term outcomes of KT from expanded-criteria donation after circulatory death (DCD) in comparison with standard criteria deceased donor (SCD) kidneys one, five and 10 years after transplantation. Other research on KT from deceased donors with acute kidney injury (AKI) has indicated a significantly deteriorating effect by six months after kidney engraftment in deceased donors with AKI in comparison with the nonAKI group; however, the differences disappeared one year from KT and long-term allograft survival did not differ among those with and without AKI. Others have claimed that data from deceased donor transplantations should be analyzed in depth in regard to factors such as donor category (heart death), age, mean urine output, history of hypertension and donor creatinine level immediately before donor nephrectomy, total ischemic time, warm ischemic time, the presence of cerebrovascular disease, and especially, KDPI, that may influence renal function after transplantation., The improved long-term KT from expanded criteria donors can probably be explained by a better understanding of the donor risk profile and increased use of hypothermic machine perfusion and pretransplant biopsy for optimal allograft selection., Among the brain-dead donors, the cause of donor death can potentially affect the survival of the transplant recipient and the function of the transplanted kidney. It seems that the traumatic group of brain dead donors is better donors than non-traumatic ones, although this superiority has not reached the threshold of statistical significance in our study [Table 4]. Proposed explanations include the younger age, masculine gender, having less comorbidities, and a lower body mass index of the traumatic group of brain-dead donors., There is remarkable variation in the definition and diagnosis of the DGF. For discerning the main cause of DGF the analysis of factors derived from both the donor (ischemic injury, inflammatory signaling) and the recipient (reperfusion injury, innate immune response, and adaptive immune response, are required. Because no definition of DGF is superior, we used the most widely, and most reproducible and easily calculated definition for defining DGF: need and use of dialysis in the 1st week after the transplant operation. Risk factors for DGF are very similar but different from those for acute rejection and the certain effect of those risk factors is controversial because of not controlling for acute rejection in most studies. DGF incidence has consistently fallen over the past few decades because of the decrement in its major causal mechanisms, ischemia-reperfusion injury, and early acute rejection episodes. The study shows that the occurrence of DGF, perhaps through nonimmunological causes such as ischemia-reperfusion injury (IRI) and nontraumatic deceased donation still have a major impact on long-term kidney graft. In concordance with the current paper’s results, others studies have indicated that DGF consequences are important, including worse graft function and survival, as well as impact on recipient morbidity and mortality. However, poor graft survival attributed to DGF in this and other studies, might be due to unrecognized rejection,, and/or poorly characterized lower intrinsic kidney quality. DGF a consequence of postischemic acute tubular necrosis caused by IRI., While a detrimental association between DGF and graft survival has been found by some researchers, others have proposed that DGF may only have an effect on graft survival, or even according to one study, DGF per se has no effect on patient and graft outcome. In respect to the effect of DGF occurrence, independent of acute rejection, on the long-term graft function in cadaveric renal transplant recipients, some studies have found that DGF in the absence of rejection has no long-term impact, while deleterious effects of DGF, independent of acute rejection, on graft survival was detected by others. There was no correlation found between early acute rejection and DGF in the present study. Some other studies have described DGF, as a consequence of IRI related ischemic graft insult that impacts both the short and long-term outcome of the kidney graft., Whereas ischemia-reperfusion injury has been described as a short-lived process, limited to the 1st week after transplantation in some studies, acute rejection and later on, chronic rejection by immunologic processes, are said to impact the long-term graft survival. There are some limitations in our study. First, this is a single center kidney transplant survival analysis and there is center variation in KT outcome. Second, we were not able to evaluate the impact of the KDPI on the graft outcome in our study. KDPI may deeply influence renal function after transplantation.,
|Table 4: The number and percentage of the type of donation, HLA mismatches, primary nonfunction, delayed graft function, acute rejection within 6 and 12 months, cold ischemia time, and death censured graft survival.|
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| Conclusion|| |
Shorter long-term survival in DGF-inflicted patients was observed, in comparison with those not suffering from this complication. DGF occurrence and the type of donation significantly affect long-term kidney allograft survival. Kidney allografts from traumatic and nontraumatic brain death kidney donors have a statistically nonsignificant survival difference.
| Acknowledgment|| |
The present study was funded by the Vice Chancellor of Research and Technology of Mashhad University of Medical Sciences, Mashhad, Iran.
Conflict of interest: None declared.
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Department of Nephrology, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad
[Table 1], [Table 2], [Table 3], [Table 4]
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