Delayed Introduction of Reduced-Dose Tacrolimus, and Renal Function in Liver Transplantation: The ‘ReSpECT’ Study

Abstract

We report a multicenter, prospective, randomized, open-label trial investigating the effect of lower levels and delayed introduction of tacrolimus on renal function in liver transplant recipients. Adult patients with good renal function undergoing primary liver transplant were randomized to either: group A (standarddose tacrolimus [target trough levels >10 ng/mL] and corticosteroids; n = 183); group B (mycophenolate mofetil [MMF] 2g/day, reduced-dose tacrolimus [target trough levels ≤8 ng/mL], and corticosteroids; n = 170); group C (daclizumab induction, MMF, reduced-dose tacrolimus delayed until the fifth day posttransplant and corticosteroids, n = 172). The primary endpoint was change from baseline in estimated glomerular filtration rate (eGFR) at 52 weeks. The eGFR decreased by 23.61, 21.22 and 13.63 mL/min in groups A, B and C, respectively (A vs C, p = 0.012; A vs B, p = 0.199). Renal dialysis was required less frequently in group C versus group A (4.2% vs. 9.9%; p = 0.037). Biopsy-proven acute rejection rates were 27.6%, 29.2% and 19.0%, respectively. Patient and graft survival was similar. In conclusion, daclizumab induction, MMF, corticosteroids and delayed reduced-dose tacrolimus was associated with less nephrotoxicity than therapy with standard-dose tacrolimus and corticosteroids without compromising efficacy or tolerability.

Hot-topic debate on kidney function: Renal-sparing approaches are beneficial

“…[16][17][18] The results of these studies are concordant and show that patients receiving reduced-dose CNI regimens have improved renal function 6 months to 1 year after transplantation in comparison with those receiving the standard-dose regimen (Table 1). Compensation for CNI minimization was generally achieved with the addition of mycophenolate mofetil (MMF).…”

“…In these studies, the target trough level of tacrolimus for the patients on the reduced-dose regimen was less than 8 ng/mL (10-15 ng/mL for the standard-dose group). 17 In one study, the best results in terms of renal function were observed in the group receiving induction with anti-IL-2R antibodies plus reduced-dose tacrolimus. 17 However, in another controlled study, reduced-dose tacrolimus without induction or the delayed introduction of CNIs was also associated with improved renal function in comparison with standard-dose tacrolimus.…”

“…17 In one study, the best results in terms of renal function were observed in the group receiving induction with anti-IL-2R antibodies plus reduced-dose tacrolimus. 17 However, in another controlled study, reduced-dose tacrolimus without induction or the delayed introduction of CNIs was also associated with improved renal function in comparison with standard-dose tacrolimus. 18 It must be noted that a reduction in the CNI dose with the addition of MMF did not result in higher rates of acute or chronic rejection.…”

Renal Dysfunction in Chronic Liver Disease

“…Th e study had a few limitations, however, namely the use of estimated GFR calculated with the Cockcroft-Gault formula, and the fact that a signifi cant number of patients were withdrawn from the high dose group. However, it importantly demonstrated that the tailoring of an immunosuppressive regimen can have a signifi cant impact on nephrotoxicity without detrimental eff ects on graft function or patient survival [54].…”

“…Th e ReSpECT study compared standard tacrolimus dosing and steroids; lowdose tacrolimus plus steroids; and delayed introduction and low-dose tacrolimus plus steroids plus mycophenolate moefi til. Th e authors demonstrated reduced nephrotoxicity in the delayed, low dose tacrolimus group [54]. Daclizumab, a monoclonal antibody, was used to provide immunosuppressive cover during the delayed period before the introduction of tacrolimus.…”