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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2014  |  Volume : 25  |  Issue : 5  |  Page : 960-966
The effect of cold ischemia time on delayed graft function and acute rejection in kidney transplantation


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 Publication2-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 23];25:960-6. Available from: http://www.sjkdt.org/text.asp?2014/25/5/960/139865

   Introduction Top


Cold ischemia time (CIT) has a crucial role in the success of kidney transplantation from deceased donors. [1] Acute rejection (AR) and delayed graft function (DGF) are two impor­tant factors to be avoided in the early post-transplantation period. [2] 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. [3] Lo­wer graft survival rates and poorer graft func­tion are observed in recipients with DGF. [4]

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. [2]

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 Top


Patient selection

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.

CIT

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

DGF was defined as the need for dialysis within the first week after transplantation.

AR

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. [5]


   Statistical analysis Top


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 Top


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].
Table 1: Demographic data of the recipient and donor.

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CIT

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

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).

AR

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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Figure 2. The effect of cold ischemia time on graft function.

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   Discussion Top


Prolonged CIT is a risk factor for DGF, AR and graft loss. [1],[6] 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. [7] 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. [8] 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. [1] 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. [9] 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. [1]

The incidence of DGF varies between 10% and 50%. [10],[11],[12],[13],[14],[15] Kidneys with CIT longer than 24 h were associated with a higher risk of DGF, with a prevalence of 60%. [16] 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. [2],[11],[17] Recent studies have shown that CIT was the most important risk factor for the occurrence of DGF. [8],[18] 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. [19] 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. [20] 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. [8] 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. [1]

The relationship between AR and DGF is still controversial. Some studies have claimed that there is an important relationship, [8],[10] while some others have claimed the opposite. [21],[22] During DGF, an episode of AR may be masked and renal function may not be a good indicator. [22] Failure to diagnose and treat occult AR episodes rather than DGF may cause dete­rioration in long-term results. [8] 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. [2] 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. [23]


   Conclusion Top


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.

 
   References Top

1.Salahudeen AK, Haider N, May W. Cold ischemia and the reduced long-term survival of cadaveric renal allografts. Kidney Int 2004;65: 713-8.  Back to cited text no. 1
    
2.Mikhalski D, Wissing KM, Ghisdal L, et al. Cold ischemia is a major determinant of acute rejection and renal graft survival in the modern era of immunsuppresion. Transplantation 2008; 85(7 Suppl):S3-9.  Back to cited text no. 2
    
3.Patel SJ, Duhart BT Jr, Krauss AG, et al. Risk factors and consequences of delayed graft function in deceased donor renal transplant patients receiving antithymocyte globulin induction. Transplantation 2008;86:313-20.  Back to cited text no. 3
    
4.Figueiredo A, Moreira P, Parada B, et al. Risk factors for delayed renal graft function and their impact on renal transplantation outcome. Transplant Proc 2007;39:2473-5.  Back to cited text no. 4
    
5.Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.  Back to cited text no. 5
    
6.Ojo AO, Wolfe RA, Held PJ, Port FK, Schmouder RL. Delayed graft function: Risk factors and implications for renal allograft survival. Transplantation 1997;63:968-74.  Back to cited text no. 6
    
7.Su X, Zenios SA, Chakkera H, Milford EL, Chertow GM. Diminishing significance of HLA matching in kidney transplantation. Am J Transplant 2004;4:1501-8.  Back to cited text no. 7
    
8.Quiroga I, McShane P, Koo DD, Gray D, Friend PJ, Fuggle S. Major effects of delayed graft function and cold ischemia time on renal allograft survival. Nephrol Dial Transplant 2006;21:1689-96.  Back to cited text no. 8
    
9.Haberal M, Karakayali H, Moray G, et al. Cadaveric kidney transplantation: Effect of cold ischemia time and HLA mismatch. Transplant Proc 1999;31:3336-7.  Back to cited text no. 9
    
10.Tejani AH, Sullivan EK, Alexander SR, Fine RN, Harmon WE, Kohaut EC. Predictive factors for delayed graft function (DGF) and its impact on renal graft survival in children: A report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 1999;3:293-300.  Back to cited text no. 10
    
11.Jushinskis J, Trushkov S, Bicans J, et al. Risk factors for the development of delayed graft function in deceased donor in renal transplants. Transplant Proc 2009;41:746-8.  Back to cited text no. 11
    
12.Sanchez-Fructuoso A, Prats Sanchez D, Marques Vidas M, Lopez de Novales E, Barrientos Guzman A. Non-heart beating donors. Nephrol Dial Transplant 2004;19 Suppl 3:iii26-31.  Back to cited text no. 12
    
13.Johnston O, O'Kelly P, Spencer S, et al. Reduced graft function (with or without dialysis) vs. immediate graft function -com­parison of long-term renal allograft survival. Nephrol Dial Transplant 2006;21:2270-4.  Back to cited text no. 13
    
14.Brier ME, Ray PC, Klein JB. Prediction of delayed renal allograft function using an arti­ficial neural network. Nephrol Dial Trasplant 2003;18:2655-9.  Back to cited text no. 14
    
15.Azevedo LS, Castro MC, Monteiro de et al. Incidence of delayed graft functionin cadaveric kidney transplants in Brazil: A multicenter analysis. Transplant Proc 2005;37:2746-7.  Back to cited text no. 15
    
16.Bronzatto EJ, da Silva Quadros KR, Santos RL, Alves-Filho G, Mazzali M. Delayed graft function in renal transplant recipients: risk factors and impact on 1 year graft function: A single center analysis. Transplant Proc 2009; 41:849-51.  Back to cited text no. 16
    
17.Kayler LK, Srinivas TR, Schold TD. Influence of CIT-induced DGF on kidney transplant outcomes. Am J Transplant 2011;11:2657-64.  Back to cited text no. 17
    
18.Kyllönen LE, Salmela KT, Eklund BH, et al. Long term results of 1047 cadaveric kidney transplantations with special emphasis on ini­tial graft function and rejection. Transplant Int 2000;13:122-8.  Back to cited text no. 18
    
19.Moreira P, Sa H, Figueiredo A, Mota A. Delayed graft function: Risk factors and impact on the outcome of transplantation. Transplant Proc 2011;43:100-5.  Back to cited text no. 19
    
20.van der Vliet JA, Warle MC, Cheung CL, Teerenstra S, Hoitsma AJ. Influence of pro­longed cold ischemia time in renal transplan­tation. Clin Transplant 2011;25:E612-6.  Back to cited text no. 20
    
21.Cecka JM. The OPTN/UNOS renal transplant registry 2003. Clin Transpl 2003:1-12.  Back to cited text no. 21
[PUBMED]    
22.Troppmann C, Gillingham KJ, Benedetti E, et al. Delayed graft function, acute rejection and outcome after cadaver renal transplantation. The multivariate analysis. Transplantation 1995;59:962-8.  Back to cited text no. 22
    
23.Webster AC, Playford EG, Higgins G, Chapman JR, Craig JC. Interleukin 2 receptor antagonists for renal transplant recipeints: A meta-analysis of randomized trials. Transplantation 2004;77: 166-76.  Back to cited text no. 23
    

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Correspondence Address:
Dr. Ismail Sert
Department of General Surgery, Van Training and Research Hospital, Van
Turkey
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DOI: 10.4103/1319-2442.139865

PMID: 25193891

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