CTS Collaborative Transplant Study
Dear Colleagues
The Collaborative Transplant Study (CTS) was initiated in 1982 with the collection of data on kidney transplants. In 1988, the CTS database was expanded to liver transplants and currently contains, thanks to your continued support, more than half a million kidney and more than one hundred thousand liver transplants with follow-up. In the past, only a few of the CTS publications focused on analyses of liver transplants. This was mainly due to the inhomogeneity of liver data resulting from country-specific allocation rules, a wide range of original diseases with strongly varying impact on outcome, and changes over time in therapy as well as patient demographics.
In collaboration with the “Department of General, Visceral and Transplantation Surgery” of University Hospital Heidelberg, two CTS papers were published in the last quarter on the influence of donor age and cold ischemia time in liver organ recipients with different original diseases (Houben P, Döhler B, Weiß K, Mieth M, Mehrabi A, Süsal C. Differential influence of donor age depending on the indication for liver transplantation. Transplantation 104:779–787. doi: 10.1097/TP.0000000000002970; Lozanovski VJ, Döhler B, Weiss KH, Mehrabi A, Süsal C. The differential influence of cold ischemia time on outcome after liver transplantation for different indications – who is at risk? Front Immunol 11:892. doi: 10.3389/fimmu.2020.00892).
In this newsletter, we would like to supplement the results of these two papers with a side-by-side comparison of the impact of donor age and cold ischemia time on survival of liver transplants.
46,858 liver transplants performed in adults from 1998 to 2018 were analyzed (Figure 1). Only recipients of first full-sized grafts from ≥18-year-old deceased donors were included. Recipients of combined transplants and patients with missing data for the original disease or cold ischemia time were excluded. The original disease which led to liver transplantation was categorized according to the following indications: acute hepatic failure, hepatitis C (HepC), hepatocellular carcinoma (HCC), alcoholic cirrhosis (ALC), primary sclerosing cholangitis (PSC), autoimmune or cryptogenic cirrhosis, hepatitis B, primary biliary cholangitis (PBC), metabolic, congenital, and miscellaneous.
The demographic characteristics of liver transplant recipients changed significantly in the analyzed period 1998–2018:
Due to the complexity and strong inhomogeneity of data, no univariate Kaplan-Meier curves but only the results of multivariable Cox regression analyses are shown. The following confounding factors were included: geographical region (country or region), year of transplantation, recipient age and race, cause of end-stage liver disease, general evaluation of the patient, cold ischemia time, donor age, cause of donor death, recipient and donor gender combinations, immunosuppressive regimen, induction therapy, and urgency.
As illustrated in Figure 1, the cold ischemia time has a significant impact on outcome only during the first post-transplant year, whereas the influence of donor age becomes even more pronounced after year one. Both confounders are an integral part of the donor risk index (DRI) generated by Feng et al in 2006 (doi: 10.1111/j.1600-6143.2006.01242.x). In the DRI, a linear influence was modeled for cold ischemia time, whereas a different approach with <40-, 40–49-, 50–59-, 60–69-, ≥70-year categories was chosen for the influence of donor age. The results of the recent CTS papers and Figure 1 indicate that the inclusion of the donor age category ≥80 years is now appropriate and that a categorical rather than linear consideration reflects the impact of cold ischemia time on outcome more precisely.
Another important finding is that the influence of donor age and cold ischemia time strongly depends on the underlying liver disease that led to transplantation. There have been major changes in indications for liver transplantation in recent years, especially after the introduction of the direct-acting antiviral agents (DAAs) in 2013. The proportion of liver transplantations in patients with hepatitis C decreased from 35.8% in 1998 to 10.9% in 2018. Consequently, the proportion of patients with other indications increased; from 14.8% to 25.3% in the case of alcoholic cirrhosis and from 7.9% to 14.3% in the case of HCC (Figure 2).
For a better comparison of the influence of donor age and cold ischemia time in patients with different underlying diseases, both variables were considered as linear confounders in the Cox regression analysis using the six categories shown in Figure 1. The calculated hazard ratios roughly correspond to the risk per 10-year increase in donor age or 2-hour increase in cold ischemia time. Figure 3 illustrates the results for the three main original disease categories, namely hepatocellular carcinoma (HCC), hepatitis C, and alcoholic cirrhosis, and the other less frequent indications excluding acute hepatic failures (Other).
Because of the major changes over time, only the last 10 transplant years were considered. Other than in the publication of Lozanovski et al, the 5- instead of 1-year outcome was analyzed also for cold ischemia time. Furthermore, there were differences in the selection of study population, the statistical methodology (e.g. modeling of confounders in Cox regression), and the data status of CTS. While the results presented in Figure 3 are therefore not directly comparable with those of the above mentioned articles, their core findings could still be confirmed for the more recent period 2009–2018:
Figure 3 may suggest that donor age has a greater influence on outcome than cold ischemia time. However, this is due to the fact that 5-year organ survival was analyzed while the cold ischemia time only affects the first follow-up year.
The next shipping date of Serum and DNA is
November 16/17, 2020.
With sincere thanks for your support of the CTS.
Caner Süsal