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.

Keywords: CIT; CTS; EDC; cold ischemia time; collaborative transplant study; extended donor criteria; liver transplantation; outcome.

Figure 1

Development of (A) original underlying disease, (B) cold ischemia time (h), (C) recipient age (years), and (D) donor age (years) for first deceased donor liver transplants of adult recipients (P < 0.001 for all parameters).

Figure 2

Distribution of cold ischemia time in deceased donor liver transplantations that were performed during 1998–2017 in adult patients.

Figure 3

Influence of cold ischemia time on overall graft survival (A,B) and patient survival (C,D) during first post-transplant year (A,C) and after first post-transplant year (B,D). P-values of log rank test with linear trend are shown.

Figure 4

Kaplan-Meier curves demonstrating the impact of cold ischemia time on 1-year graft survival for the main underlying disease categories (A) hepatocellular carcinoma (HCC), (B) hepatitis C, (C) alcoholic cirrhosis, and (D) the other less frequent original diseases (autoimmune disorders, cryptogenic cirrhosis, congenital diseases, hepatitis B, metabolic disorders, primary biliary cirrhosis, and primary sclerosing cholangitis). All log rank P-values with trend <0.001.

Figure 5

Kaplan-Meier curves demonstrating the impact on (A) 5-year graft survival and (B) 5-year patient survival of the main original disease categories hepatocellular carcinoma (HCC), hepatitis C (HepC), alcoholic cirrhosis (Alc), and the other less frequent original diseases (autoimmune disorders, cryptogenic cirrhosis, congenital diseases, hepatitis B, metabolic disorders, primary biliary cirrhosis, and primary sclerosing cholangitis) (Oth).

Figure 6

Influence of cold ischemia time on 1-year graft survival in subpopulations of patients transplanted because of hepatocellular carcinoma with (A) low and (B) high Model of End Stage Liver Disease (MELD) score. Log rank P-values with trend are shown.