Sequential Cohort Analysis After Liver Transplantation Shows de Novo Extended Release Tacrolimus Is Safe, Efficacious, and Minimizes Renal Dysfunction

Abstract

The use of once-daily extended-release tacrolimus (ERT) is associated with improved long-term graft and patient survival when compared with twice-daily tacrolimus (BDT), but the underlying reasons for differential survival are unclear. The aim of the study was to compare clinical outcomes known to impact on posttransplant survival for de novo BDT and ERT in liver transplantation (LT) recipients.

Methods: We conducted a single-center, prospective sequential cohort analysis of adult patients undergoing LT during a change in protocol from de novo BDT to ERT, with a 6-month post-LT follow-up.

Results: A total of 160 transplanted patients were evaluated; 82 were in the BDT group and 78 were in the ERT group. The cohorts were matched for standard variables and a similar proportion in each group received induction interleukin-2 receptor antibody (36% and 31%). There were no significant differences in the measured outcomes of patient and graft survival, biopsy-proven acute rejection episodes, post LT diabetes, and toxicity. A significantly lower number of patients developed chronic kidney disease Stage3-4 in the ERT cohort compared with BDT cohort. In patients with pre-LT renal dysfunction who received antibody induction, estimated glomerular filtration rate decreased significantly in the BDT but not the ERT group.

Conclusions: We show that once-daily ERT is as safe and efficacious as BDT in de novo LT but optimally conserves renal function post-LT.

FIGURE 1.

Median (IQR) DECs in patients receiving BDT and ERT. A, Comparison of DEC in cohort not treated with interleukin-2 receptor antagonist. B, Comparison of DEC in cohort that received interleukin-2 receptor antagonist. BDT, twice-daily tacrolimus; DEC, dose-equalized tacrolimus concentration; ERT, extended-release tacrolimus; IQR, interquartile range.

FIGURE 2.

Median (IQR) trough tacrolimus level in patients receiving BDT and ERT. A, Comparison of median tacrolimus levels in cohort not treated with interleukin-2 receptor antagonist. B, Comparison of median (IQR) trough tacrolimus level in cohort that received interleukin-2 receptor antagonist. BDT, twice-daily tacrolimus; ERT, extended-release tacrolimus; IQR, interquartile range.

FIGURE 3.

Rate of biopsy proven rejection episodes (at 6 months) in each group of patients receiving BDT, compared with once-daily ERT. Values were compared using Fisher exact test. BDT, twice-daily tacrolimus; ERT, extended-release tacrolimus.

FIGURE 4.

Evolution of mean eGFR post-LT between patients who received de novo BDT vs once-daily tacrolimus (ERT) in (A) cohort that was not treated with IL2RA and (B) cohort treated with interleukin-2 receptor antagonist. * eGFR decreased significantly in the BDT cohort from a pretransplant mean of 102.6 ± 5.9 mL/min to 80.6 ± 4.6 mL/min (P < 0.001), compared with 113.2 ± 6.4 mL/min to 80.6 ± 4.6 mL/min in the ERT cohort (P < 0.001). For the groups that received IL2RA, mean eGFR reduced significantly from a baseline of 79.6 ± 5.3 mL/min to 65.2 ± 4.3 mL/min (P = 0.006) in the BDT cohort, compared with 75.2 ± 5.7 mL/min to 68.5 ± 6.0 mL/min (P = 0.09) in the ERT cohort. BDT, twice-daily tacrolimus; eGFR, estimated glomerular filtration rate; ERT, extended-release tacrolimus; IL2RA, interleukin-2 receptor antibody; LT, liver transplantation.

FIGURE 5.

IPV in the tacrolimus concentration. The scatter plot shows the CoV, calculated as SD of all DEC after the first week, divided by mean DEC, in each group treated with de novo BDT and once-daily ERT. CoVs were compared using Mann-Whitney U test. There was no statistical difference between the 2 groups (P = 0.798). BDT, twice-daily tacrolimus; CoV, coefficient of variation; DEC, dose-equalized tacrolimus concentration; ERT, extended-release tacrolimus; IPV, intra-patient variability.