Renal Function in De Novo Liver Transplant Recipients Receiving Different Prolonged-Release Tacrolimus Regimens—The DIAMOND Study

Abstract

DIAMOND: multicenter, 24‐week, randomized trial investigating the effect of different once‐daily, prolonged‐release tacrolimus dosing regimens on renal function after de novo liver transplantation. Arm 1: prolonged‐release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged‐release tacrolimus (0.15–0.175mg/kg/day) plus basiliximab; Arm 3: prolonged‐release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids). Primary endpoint: eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p = 0.001, p = 0.047). Kaplan–Meier estimates of composite efficacy failure‐free survival were 72.0%, 77.6%, 73.9% in Arms 1–3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p = 0.016, p = 0.039). AEs were comparable. Prolonged‐release tacrolimus (0.15–0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged‐release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher‐dose prolonged‐release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable.

Advancing Transplantation

“…The study design was similar to that of the ReSpECT study, with 857 liver transplant recipients receiving MMF and a single bolus of intraoperative corticosteroids, in combination with one of the following: standard-dose, prolonged-release tacrolimus (target trough level, 5-15 ng/mL until day 42 then 5-12 ng/mL); lower-dose, prolongedrelease tacrolimus (4-12 ng/mL until day 42 then reduced by 20-25%) and basiliximab; or standard-dose, prolongedrelease tacrolimus (5-15 ng/mL until day 42) delayed until day 5 and basiliximab. 171 Results from this study indicated that lower-dose, prolonged-release tacrolimus administered immediately posttransplant (and a subsequent lower tacrolimus exposure over the first month), together with MMF and basiliximab, was associated with a significant renal function benefit and a significantly lower incidence of biopsy-confirmed acute rejection (BCAR) versus the standard-dose, prolongedrelease tacrolimus-based regimen (Figure 11). 171 Delayed initiation of standard-dose, prolonged-release tacrolimus significantly reduced renal function impairment; however, the BCAR incidence advantage was not seen with delayed initiation (Figure 11).…”

“…171 Results from this study indicated that lower-dose, prolonged-release tacrolimus administered immediately posttransplant (and a subsequent lower tacrolimus exposure over the first month), together with MMF and basiliximab, was associated with a significant renal function benefit and a significantly lower incidence of biopsy-confirmed acute rejection (BCAR) versus the standard-dose, prolongedrelease tacrolimus-based regimen (Figure 11). 171 Delayed initiation of standard-dose, prolonged-release tacrolimus significantly reduced renal function impairment; however, the BCAR incidence advantage was not seen with delayed initiation (Figure 11). 171 Results from this study indicate that early tacrolimus exposure in the immediate posttransplant period may be critical in maintaining renal function over the long term.…”

“…171 Delayed initiation of standard-dose, prolonged-release tacrolimus significantly reduced renal function impairment; however, the BCAR incidence advantage was not seen with delayed initiation (Figure 11). 171 Results from this study indicate that early tacrolimus exposure in the immediate posttransplant period may be critical in maintaining renal function over the long term.…”

Practical Recommendations for Long-term Management of Modifiable Risks in Kidney and Liver Transplant Recipients

“…Results from a 24-week study of 857 liver transplant recipients (Figure 8) indicated that lower-dose prolonged-release tacrolimus capsules (0.15-0.175 mg/kg per day subsequently reduced by 20-25%, target trough level, 4-12 ng/mL) a , administered with MMF and basiliximab immediately posttransplant, was associated with a significant renal function benefit and a significantly lower incidence of biopsy-confirmed acute rejection, compared with a higher-dose (5-15 ng/mL until day 42 then 5-12 ng/mL) prolonged-release tacrolimus-based regimen. 178 The Impact of Underimmunosuppression…”

“…251 The randomized controlled DIAMOND study (Figure 8) showed that an initial lower dose prolongedrelease tacrolimus capsules regimen, or the delayed initiation (Day 5) of the higher dose prolonged-release tacrolimus capsules regimen (together with MMF and basiliximab), was associated with significant improvement in renal function at 6 months, compared to the prolonged-release tacrolimusbased regimen administered at a higher initial dose immediately after transplantation. 178 A recent nonrandomized study showed that conversion from immediate-release to prolongedrelease tacrolimus >1 month postliver transplantation limits the increase in serum creatinine concentrations. 114 It is generally accepted that methods based on serum creatinine for the detection of kidney dysfunction underestimate the extent of renal impairment in transplant recipients.…”