The Differential Influence of Cold Ischemia Time on Outcome After Liver Transplantation for Different Indications—Who Is at Risk? A Collaborative Transplant Study Report

Abstract

Introduction: Despite increasing awareness of the negative impact of cold ischemia time (CIT) in liver transplantation, its precise influence in different subgroups of liver transplant recipients has not been analyzed in detail. This study aimed to identify liver transplant recipients with an unfavorable outcome due to prolonged cold ischemia. Methods: 40,288 adult liver transplantations, performed between 1998 and 2017 and reported to the Collaborative Transplant Study were analyzed. Results: Prolonged CIT significantly reduced graft and patient survival only during the first post-transplant year. On average, each hour added to the cold ischemia was associated with a 3.4% increase in the risk of graft loss (hazard ratio (HR) 1.034, P < 0.001). The impact of CIT was strongest in patients with hepatitis C-related (HCV) cirrhosis with a 24% higher risk of graft loss already at 8-9 h (HR 1.24, 95% CI 1.05-1.47, P = 0.011) and 64% higher risk at ≥14 h (HR 1.64, 95% CI 1.30-2.09, P < 0.001). In contrast, patients with hepatocellular cancer (HCC) and alcoholic cirrhosis tolerated longer ischemia times up to <10 and <12 h, respectively, without significant impact on graft survival (P = 0.47 and 0.42). In HCC patients with model of end-stage liver disease scores (MELD) <20, graft survival was not significantly impaired in the cases of CIT up to 13 h. Conclusion: The negative influence of CIT on liver transplant outcome depends on the underlying disease, patients with HCV-related cirrhosis being at the highest risk of graft loss due to prolonged cold ischemia. Grafts with longer cold preservation times should preferentially be allocated to recipients with alcoholic cirrhosis and HCC patients with MELD <20, in whom the effect of cold ischemia is less pronounced.

Considering extended right lobe grafts as major extended donor criteria in liver transplantation is justified

“…ERLT in patients with low lab-MELD scores may achieve similar outcomes to WLT, but ERLT becomes less tolerable with increasing MELD scores [6]. This finding is supported by the results of our previous studies, in which the negative influence of maEDC diminished as the labMELD score decreased, especially in recipients with hepatocellular carcinoma who are generally in a better condition [10][11][12]. However, we could not verify this hypothesis in the case of ERLT because we were not able to analyze the underlying disease, the clinical condition and the MELD score of the recipients, and whether ERL grafts should be preferably allocated to recipients with lower labMELD scores needs to be considered with caution.…”

“…Indeed, similar to WLT, the risk of retransplantation after ERLT is higher in older donors and younger recipients and in recipients of ERL grafts with prolonged cold ischemia times [6,12,52]. Cold ischemia time influences graft and patient survival only during the first year after WLT indicating that once the liver has recovered from the ischemia-reperfusion injurythe duration of the cold storage becomes irrelevant [10]. Although the role of cold ischemia has been fueling intense debate for decades, it has not been addressed properly in ERLT so far.…”

“…In Eurotransplant, up to 30% of patients drop out from the waiting list because of death or disease progression [9]. The shortage of donor organs, especially in Eurotransplant, has encouraged the use of major extended donor criteria (maEDC: macrovesicular steatosis >40%, donor age >65 years, and cold ischemia time >14 h) organs, despite reports that these organs produce non-optimal results and affect graft and patient survival after transplantation [10][11][12]. Split-liver transplantation is an established procedure and an attractive way of expanding the limited organ pool for pediatric and adult graft recipients that may offer solution to the problem of chronic organ shortage.…”

Prognostic role of the Donor Risk Index, the Eurotransplant Donor Risk Index, and the Balance of Risk score on graft loss after liver transplantation

“…DRI and ET-DRI calculations include cold ischemia time, but Feng et al and Braat et al did not consider indication for transplantation as confounder and assumed constant linear influence of cold ischemia time with a fixed coefficient (0.010) [8,9]. By doing so, the categorical effect of cold ischemia could not be observed, especially when opposite, nonlinear influence is evident [73]. In our recent study, we found that the influence of cold ischemia is nonlinear and important only during the first year after liver transplantation and that it also depends on the indication for liver transplantation [73].…”

“…By doing so, the categorical effect of cold ischemia could not be observed, especially when opposite, nonlinear influence is evident [73]. In our recent study, we found that the influence of cold ischemia is nonlinear and important only during the first year after liver transplantation and that it also depends on the indication for liver transplantation [73]. This effect was especially strong in patients with hepatocellular carcinoma and alcoholic liver cirrhosis [73].…”