Type of calcineurin inhibitor and long-term outcomes following liver transplantation in patients with primary biliary cholangitis - an ELTR study

Abstract

Background & aims: Tacrolimus has been associated with recurrence of primary biliary cholangitis (PBC) after liver transplantation (LT), which in turn may reduce survival. This study aimed to assess the association between the type of calcineurin inhibitor used and long-term outcomes following LT in patients with PBC.

Methods: Survival analyses were used to assess the association between immunosuppressive drugs and graft or patient survival among adult patients with PBC in the European Liver Transplant Registry. Patients who received a donation after brain death graft between 1990 and 2021 with at least 1 year of event-free follow-up were included.

Results: In total, 3,175 patients with PBC were followed for a median duration of 11.4 years (IQR 5.9-17.9) after LT. Tacrolimus (Tac) was registered in 2,056 (64.8%) and cyclosporin in 819 (25.8%) patients. Following adjustment for recipient age, recipient sex, donor age, and year of LT, Tac was not associated with higher risk of graft loss (adjusted hazard ratio [aHR] 1.07, 95% CI 0.92-1.25, p = 0.402) or death (aHR 1.06, 95% CI 0.90-1.24, p = 0.473) over cyclosporin. In this model, maintenance mycophenolate mofetil (MMF) was associated with a lower risk of graft loss (aHR 0.72, 95% CI 0.60-0.87, p <0.001) or death (aHR 0.72, 95% CI 0.59-0.87, p <0.001), while these risks were higher with use of steroids (aHR 1.31, 95% CI 1.13-1.52, p <0.001, and aHR 1.34, 95% CI 1.15-1.56, p <0.001, respectively).

Conclusions: In this large LT registry, type of calcineurin inhibitor was not associated with long-term graft or recipient survival, providing reassurance regarding the use of Tac post LT in the population with PBC. Patients using MMF had a lower risk of graft loss and death, indicating that the threshold for combination treatment with Tac and MMF should be low.

Impact and implications: This study investigated the association between immunosuppressive drugs and the long-term survival of patients with primary biliary cholangitis (PBC) following donation after brain death liver transplantation. While tacrolimus has previously been related to a higher risk of PBC recurrence, the type of calcineurin inhibitor was not related to graft or patient survival among patients transplanted for PBC in the European Liver Transplant Registry. Additionally, maintenance use of mycophenolate was linked to lower risks of graft loss and death, while these risks were higher with maintenance use of steroids. Our findings should provide reassurance for physicians regarding the continued use of Tac after liver transplantation in the population with PBC, and suggest potential benefit from combination therapy with mycophenolate.

Keywords: Calcineurin inhibitors; Graft survival; Liver Transplantation; Primary Biliary Cholangitis; Survival.

Graphical abstract

Fig. 1

Study flowchart. The flowchart starts with 5,306 adults transplanted for PBC with a graft following DBD LT. Patients without data on immunosuppressants post LT were excluded. Data on immunosuppressive regimen was available in 4,040 patients, of whom 3,175 had at least 365 days of event-free follow-up and could be included for the primary analyses. DBD, donation after brain death donor; LT, liver transplant(ation); PBC, primary biliary cholangitis.

Fig. 2

Maintenance calcineurin inhibitor by transplant year. Absolute numbers of patients in our primary analysis who either used Tac or CsA according to the year of LT. Type of CNI was primarily based on maintenance regimen, or if maintenance data was missing on the initial type of CNI. CNI, calcineurin inhibitor; CsA, cyclosporin; LT, liver transplant; Tac, tacrolimus.

Fig. 3

Graft and overall survival according to type of calcineurin inhibitor. Only patients with at least 1 year of follow-up were included in these Kaplan Meier survival curves for (A) graft survival (p = 0.396∗) and (B) patient survival (p = 0.150∗) according to CsA or Tac. ∗Survival was compared by log-rank test. CsA, cyclosporin; Tac, tacrolimus.