|Year : 2014 | Volume
| Issue : 5 | Page : 960-966
|The effect of cold ischemia time on delayed graft function and acute rejection in kidney transplantation
Ismail Sert1, Hulya Colak2, Cem Tugmen3, Sait Murat Dogan3, Cezmi Karaca3
1 Department of General Surgery, Van Training and Research Hospital, Van, Turkey
2 Department of Nephrology, Tepecik Training and Research Hospital, Izmir, Turkey
3 Department of Transplantation, Tepecik Training and Research Hospital, Izmir, Turkey
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|Date of Web Publication||2-Sep-2014|
| Abstract|| |
The objective of this study is to evaluate the impact of cold ischemia time (CIT) on delayed graft function (DGF) and acute rejection (AR) among deceased donor kidney transplant recipients. The medical records of 111 patients who underwent kidney transplantation from deceased donors between November 1994 and July 2009 were retrospectively analyzed. DGF was observed in 54% of the patients and the prevalence of AR in the first year after transplantation was 9.9%. The incidence of DGF was higher among patients with longer CIT. There was no correlation between CIT and AR episodes. Higher body weight of recipients and donors, history of prior blood transfusion and advanced donor age were related with DGF. Patients with DGF had higher serum creatinine levels at the first, third and fifth years. There was a negative correlation between recipient body weight and creatinine clearance at the first year. CIT has an important role in the development of DGF as a modifiable risk factor. Moreover, donors with advanced age and higher body weight as well as recipients with higher body weight and history of blood transfusions are at risk for the development of DGF. Prevention of DGF may help to improve graft function at the first, third and fifth years and shorten the hospital stay.
|How to cite this article:|
Sert I, Colak H, Tugmen C, Dogan SM, Karaca C. The effect of cold ischemia time on delayed graft function and acute rejection in kidney transplantation. Saudi J Kidney Dis Transpl 2014;25:960-6
|How to cite this URL:|
Sert I, Colak H, Tugmen C, Dogan SM, Karaca C. The effect of cold ischemia time on delayed graft function and acute rejection in kidney transplantation. Saudi J Kidney Dis Transpl [serial online] 2014 [cited 2019 Feb 19];25:960-6. Available from: http://www.sjkdt.org/text.asp?2014/25/5/960/139865
| Introduction|| |
Cold ischemia time (CIT) has a crucial role in the success of kidney transplantation from deceased donors.  Acute rejection (AR) and delayed graft function (DGF) are two important factors to be avoided in the early post-transplantation period.  DGF has been defined as the need for dialysis within the first week after transplantation. The reported prevalence of DGF varies between 10% and 40%, and is affected by both immu-nological and non-immunological factors.  Lower graft survival rates and poorer graft function are observed in recipients with DGF. 
AR is defined as an immune attack against the graft after transplantation. Although the prevalence of AR has decreased from 50% to 10-15% with the use of new immunosuppres-sive agents during the past decade, it is still an important problem for graft function in early and late periods. 
The relation between CIT and DGF has previously been shown, but the relationship between CIT and AR is still controversial. The aim of this study was to evaluate the effect of CIT on DGF and AR after deceased donor kidney transplantation. Beside this, we evaluated the effect of CIT, AR and DGF on graft function at one, three, and five years after transplantation, which makes this study especially important.
| Materials and Methods|| |
From October 1994 to June 2009, 188 patients underwent deceased donor kidney transplantation at the Izmir Tepecik Research Hospital, Turkey. Multi-organ transplantations (n = 5), subsequent transplants (n = 6), transplantation from non-heart beating donors (n = 2), patients with conversion from calcineurin inhibitors (CNIs) to m-tor inhibitors (n = 24) and those with insufficient data (n = 40) were excluded from the study. With the help of these exclusion criteria, we could focus on a homogeneous cohort. A total of 111 recipients and their donor charts were reviewed retrosectively. This study was approved by the local ethics committee of the Tepecik Research Hospital and performed according to the Helsinki Declaration.
Organ retrieval and immunosuppression
Selection of donors was performed by the National Co-ordination System of Tissue and Organ Transplantation. All kidneys were retrieved from conventional heart-beating, deceased donors with the diagnosis of brain-stem death. A standard surgical technique was used for organ procurement and only cold storage was used as the method of preservation. The University of Wisconsin (UW) solution was the only preservation fluid used during the entire period of the study.
Although not an accepted protocol, anti-thymocyte globulin (ATG) was generally used for patients with >3 HLA mismatches, donor age >60 years and CIT >24 h. Other patients received IL-2 receptor blockers (basiliximab or daclizumab) for induction therapy. Thus, ATG was used in 29% of the subjects, IL-2 receptor blockers in 44.9% and combination of ATG and IL-2 receptor blockers was used as induction treatment in 26.1% of the subjects. On the first day of transplantation, high-dose steroids (two doses of 250 mg) were administered to all recipients. The dose of prednisolone was tapered down gradually to 5 mg daily, and most of the patients discontinued prednisolone at the end of the first year. Anti-metabolites [azathioprine or mycofenolate mofetil (MMF)] and calcineurin inhibitor agents (CNIs) (cyclos-porine and tacrolimus) were used for maintenance therapy. The target blood levels of cyclosporine and tacrolimus were 250-350 ng/mL and 10-15 ng/mL, respectively during the first six months after transplantation and 100-175 ng/mL and 6-10 ng/mL, respectively thereafter.
Recipient and donor data
Recipient age, gender, weight, body mass index (BMI), number of HLA mismatches, duration on dialysis, DGF, AR, pre-operative hemoglobin levels and serum creatinine levels at the first, third and fifth years and creatinine clearance at the first and fifth years were analyzed. Donor age, gender, weight, HLA mismatch and CIT were all recorded.
It was defined as the duration between the beginning of cold storage and reperfusion of the graft. CIT was grouped as 0-10 h, 10-20 h, 20-30 h and over 30 h for analysis.
DGF was defined as the need for dialysis within the first week after transplantation.
Allograft biopsy was performed to evaluate the rejection episodes. Only biopsy-proven cases were included in this study. In our clinic, protocol biopsies are routinely performed in the sixth month after transplantation (it was started in 2004). In addition, diagnostic biopsy was performed for the suspected rejection cases. The first option for treatment of AR was three boluses of 500 mg methylprednisolone. ATG (1-1.5 mg/kg doses for 3-7 days) was used for treatment of steroid-resistant rejections.
Creatinine clearances at the first and fifth years
Creatinine clearances were calculated by using recipient age, gender, weight and serum creatinine level according to the Cockroft-Gault formula. 
| Statistical analysis|| |
Statistical analysis was performed by using SPSS (v. 13 for windows) software program. The chi-square test and Student's t test were used for quantitative variables and for continuous variables, respectively. The Mann-Whitney U-test (two samples) or the Kruskal-Wallis test (more than two samples) was used for analysis of abnormally distributed variables. The following covariates were considered in logistic regression analyses: Recipient and donor age, CIT, number of HLA mismatches, DGF (absent vs. present) and AR (absent vs. present). Quantitative variables are expressed as mean ± standard deviation. Level of significance is accepted at P <0.05.
| Results|| |
Mean recipient and donor age were 35.2 ± 12 and 34 ± 18.7 years, respectively. 65.7% of the recipients and 69.3% of the donors were male. Demographic data and transplantation-related variables of donors and recipients are summarized in [Table 1].
The mean CIT was 14.6 ± 5.6 h (min 4.5 h; max 33 h). Distribution of patients according to CIT was: <10 h (n = 23), 10-20 h (n = 65), 20-30 h (n = 14) and >30 h (n = 2). The number of donors with CIT less than 20 h was 88 (84.6%). The number of donors with CIT of 10-20 h was 65 (62.5%).
Shorter CIT was related to lower incidence of DGF (P = 0.018). When CIT was divided into groups, the prevalence of DGF was 47.8%, 51.6%, 73.3% and 100% in the 10 h, 10-20 h, 20-30 h and over 30 h-groups, respectively. Although the incidence of DGF was higher in the 20-30 h and over 30-h CIT groups, these figures were not statistically significant (P = 0.215).
Although the serum creatinine levels were higher and creatinine clearance was lower in recipients in the 20-30 h and over 30-h CIT group, they were not statistically significant (P = 0.344, P = 0.187, P = 0.295, P = 0.731 and P = 0.606) [Table 2].
|Table 2: The impact of cold ischemia time on delayed graft function and acute rejection episodes.|
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The relationship of hospital stay with CIT showed that longer hospital stay was observed in patients with longer CIT (P = 0.012). Hospital stay was especially longer in patients with CIT over 20 h (P = 0.014).
DGF was seen in 54.8% of the recipients (n = 57), with a mean duration of 7.8 days. The mean CIT was 15.9 ± 6.2 h and 13.3 ± 4.6 h in patients with and without DGF, respectively. The correlation between CIT and DGF was statistically significant (P = 0.018).
When comparing DGF with AR, the incidence of AR in the DGF-positive group was 8.6%, whereas it was 4.2% in the DGF-negative group (P = 0.358). Higher recipient BMI, recipient and donor weight and history of blood transfusions were related to development of DGF (P = 0.168, P = 0.01, P = 0.009 and P = 0.036). The incidence of DGF was higher in the donor and recipient pairs with advanced age (P = 0.002 and P = 0.415). There was no correlation with the number of HLA mismatches and pre-operative creatinine clearance of the recipient (P = 0.172 and P = 0.234). The hospital stay was 19 ± 6 days and 13 ± 6 days in patients with and without history of DGF, respectively (P = 0.001).
The serum creatinine values at the first, third and fifth years post-transplant were lower in patients without DGF (P = 0.001, P = 0.001 and P = 0.014). Also, higher levels of crea-tinine clearance at the first and fifth years post-transplant were seen in recipients without DGF (P = 0.132, P = 0.290).
Eleven recipients (9.9%) had AR episodes within the first year after transplantation. Only one graft loss due to AR episodes was seen. Others responded to treatment of AR. CIT, history of blood transfusion of recipient, number of HLA mismatches, selection of induction treatment, recipient and donor age, recipient and donor weight, recipient BMI (assessed for 52 cases' data) and also co-morbid diseases (hypertension: 12, diabetes mellitus: 5, cardiovascular disease: 1, chronic obstructive pulmonary disease: 1, hepatitis B: 2) had no influence on the occurrence of AR. Also, AR was not related to creatinine clearance at one and five years as well as serum creatinine levels at one, three and five years. The prevalence of AR episodes was higher in patients with DGF, but these data were not statistically significant (P = 0.358). There was no demonstrable difference in the prevalence of AR among recipients treated with IL-2Ra or ATG as induction treatment (P >0.05).
Factors effecting serum creatinine and crea-tinine clearance
The mean creatinine clearance at the first and fifth years were 69 ± 21 mL/min/1.76 m 2 (min 19, max 133) and 66 ± 21 mL/min/1.76 m 2 (min 22, max 138), respectively. The serum creatinine levels at the first, third and fifth years post-transplant were found to be significantly influenced by DGF (P = 0.001, P = 0.001 and P = 0.014) [Figure 1]. Advanced donor age was associated with lower creatinine clearance at the first and fifth years post-transplant (P = 0.012 and P = 0.015). There was a negative correlation between recipient weight and creatinine clearance at the first year post-transplant (P = 0.042). The AR, CIT and DGF, recipient BMI and age, donor weight and anemia had no effect on creatinine clearances at the first and fifth years post-transplant (P = 0.852, P = 0.346, P = 0.828, P = 0.287, P = 0.132, P = 0.290, P = 0.172, P = 0.522, P = 0.423, P = 0.759, P = 0.854 and P = 0.156, respectively). Although the serum creatinine values were higher in patients with CIT of 20-30 h and over 30 h, these correlations were not statistically significant (P = 0.344, P = 0.187, P = 0.295, P = 0.767, P = 0.740 and P = 0.568) [Figure 2].
|Figure 1: The effect of acute rejection and delayed graft function on graft function.|
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| Discussion|| |
Prolonged CIT is a risk factor for DGF, AR and graft loss. , In our study, the mean CIT was 14.6 ± 5.5 h. For kidneys with CIT longer than 37 h, a negative effect on graft function has been demonstrated.  The Collaborative Transplant Study claims that CIT shorter than 25 h has minimum effect on graft survival. However, they could not show any analysis to verify this data.  According to the United Network for Organ Sharing Registry (UNOS) data, the effect of CIT continues for years, beyond an average level of about 20 h.  As a reflection of our national status, Haberal et al reported the effect of CIT in 133 cadaveric kidney transplantations. It was as follows: 28% at 0-23 h, 17.4% at 24-35 h, 15.6% at 36-47 h and 39% when CIT was longer than 48 h.  In our study, 84.7% of the kidneys were exposed to CIT shorter than 20 h, while it was 49% according to the UNOS data. 
The incidence of DGF varies between 10% and 50%. ,,,,, Kidneys with CIT longer than 24 h were associated with a higher risk of DGF, with a prevalence of 60%.  The prevalence of DGF in our study was 55%.
The risk factors associated with DGF have been analyzed in multicenter studies, and the factors identified included the following: Donor-related (age, hypertension, serum creatinine level, non-heart beating donor); recipient-related (HLA mismatch, male gender, diabetes mellitus, serious hemodynamic problems, previous transplantation) and CIT. ,, Recent studies have shown that CIT was the most important risk factor for the occurrence of DGF. , The factors related to the development of DGF were higher recipient and donor weight and advanced donor age in our analysis, as also reported by Moreira et al.  Additionally, we defined the history of blood transfusion as a risk factor for the development of DGF. As van der Vliet et al reported earlier, a detrimental effect of DGF on kidney graft function was seen in the present study.  Patients with DGF had higher serum creatinine levels at the first, third and fifth years post-transplant. Patients with DGF had a longer period of stay in the hospital.
In our analysis, there was a positive correlation between longer CIT and higher incidence of DGF; these effects were especially clearly observed for kidneys with CIT 20-30 hours and longer than 30 h. Quroga et al claimed that there was a specific threshold for CIT to which the development DGF was linked and the risk increased with each additional hour of CIT.  Slahudeen et al reported that CIT was the most important risk factor for graft survival compared with donor and recipient ages, HLA mismatch, PRA (Panel Reactive Antibody) level and AR episodes in the first six months after transplantation. 
The relationship between AR and DGF is still controversial. Some studies have claimed that there is an important relationship, , while some others have claimed the opposite. , During DGF, an episode of AR may be masked and renal function may not be a good indicator.  Failure to diagnose and treat occult AR episodes rather than DGF may cause deterioration in long-term results.  In our study, although the prevalence of AR was higher in the DGF-positive group, it was not statistically significant, and a negative effect of AR episodes on graft function was not shown in this present study.
In the last decade, the prevalence of AR has decreased from 50% to 10-15% with the use of newer immunosuppressive drugs like MMF, IL-2 receptor blockers and CNIs.  In the present study, the overall prevalence of AR was 9.9%. Use of IL-2 receptor blockers or ATG as induction treatment showed no difference in the incidence of AR. These results were similar to the findings of a meta-analysis published by Webster et al. 
| Conclusion|| |
CIT has an important role in the development of DGF as a modifiable risk factor. Moreover, donors with advanced age, higher body weight and recipients with higher body weight and history of blood transfusions are the factors that may increase the risk for development of DGF. Prevention of DGF may help to improve the graft function at the first, third and fifth years post-transplant as well as shorten the hospital stay.
Conflict of Interest
All the authors declare that there is no conflict of interest. The study has been conducted without any grant or financial support.
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Dr. Ismail Sert
Department of General Surgery, Van Training and Research Hospital, Van
[Figure 1], [Figure 2]
[Table 1], [Table 2]
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