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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 (standard-dose 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.
Although outcomes after liver transplantation are usually excellent, with current 5- and 10-year patient survival rates exceeding 70% and 60%, late complications remain of concern. Renal dysfunction remains a major cause of both morbidity and mortality. Significant renal impairment, occurring in up to 27% of liver allograft recipients at 5 years, results in end-stage renal disease in as many as 10% of patients at 10 years posttransplant and late chronic renal dysfunction or renal failure is associated with the risk of premature death.
Late renal failure is associated with both pre- and postliver transplant factors, including higher concentrations of CNIs both early and late posttransplant and can be predicted by creatinine levels in the first posttransplant year. Strategies to minimize the adverse renal effects of CNIs in patients include reducing the CNI dose or complete withdrawal of the CNI, while adding other immunosuppressive agents such as mycophenolate mofetil (MMF) or sirolimus. Alternatively, a preemptive strategy may be adopted by attempting to avoid CNI-induced renal impairment. Antibody induction therapy (such as interleukin-2 [IL2] receptor antagonists) may allow reduction in dose or delayed introduction of CNIs.
We conducted the ReSpECT study, a prospective, randomized trial in de novo adult liver transplant patients with good renal function pretransplant, to assess the effect on renal function, acute rejection, and graft and patient survival of three regimens: standard-dose tacrolimus and corticosteroids; MMF with reduced-dose tacrolimus and corticosteroids; and induction with daclizumab, MMF and delayed introduction of reduced-dose tacrolimus and corticosteroids.
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