Outcomes with Tacrolimus-Based Immunosuppression After Kidney Transplantation from Standard- and Extended-Criteria Donors - A Post Hoc Analysis of the Prospective OSAKA Study

Abstract

BACKGROUND This post hoc analysis of data from the prospective OSAKA study evaluated the efficacy and safety of prolonged- and immediate-release tacrolimus in patients who received kidneys from extended-criteria (ECD) and standard-criteria (SCD) donors. MATERIAL AND METHODS Within the ECD and SCD groups, patients were randomized to one of 4 tacrolimus-based regimens (initial dose): Arm 1, immediate-release tacrolimus (0.2 mg/kg/day); Arm 2, prolonged-release tacrolimus (0.2 mg/kg/day); Arm 3, prolonged-release tacrolimus (0.3 mg/kg/day); Arm 4, prolonged-release tacrolimus (0.2 mg/kg/day) plus basiliximab. All patients received mycophenolate mofetil and bolus corticosteroids; Arms 1-3 also received tapered corticosteroids. ECDs met the definition: living/deceased donors aged ≥60 years, or 50-60 years with ≥1 other risk factor, and donation after circulatory death. Primary composite endpoint: graft loss, biopsy-confirmed acute rejection or renal dysfunction by Day 168. Outcomes were compared across treatment arms with the chi-squared or Fisher's exact test. RESULTS A total of 1198 patients were included in the analysis (ECD: n=620 [51.8%], SCD: n=578 [48.2%]). Patients with kidneys from ECDs were older versus SCDs (mean age, 55.7 vs. 44.5 years, p<0.0001). A higher proportion of patients with kidneys from ECDs versus SCDs met the primary composite endpoint (56.8% vs. 32.4%, p<0.0001). However, no statistically significant differences in clinical outcomes or the incidence of treatment-emergent adverse events were seen between treatment arms within each donor group. CONCLUSIONS Worse outcomes were experienced in patients who received kidneys from ECDs versus SCDs. Prolonged-release tacrolimus provided similar graft survival to the immediate-release formulation, with a manageable tolerability profile.

Figure 1

Flow of patients throughout the study, stratified by ECDs and SCDs (FAS). A total of 1198 patients were randomized and received ≥1 dose of tacrolimus; FAS according to treatment group and donor criteria is shown. ECD – extended-criteria donor; FAS – full-analysis set; SCD – standard-criteria donor.

Figure 2

Incidence of composite endpoint by Day 168 in patients who received kidneys from ECDs and SCDs (FAS). The composite endpoint of efficacy failure was defined as graft loss (retransplantation, nephrectomy, death or dialysis ongoing at study end or at time of premature study discontinuation), BCAR diagnosed locally, or renal dysfunction (eGFR [MDRD4] <40 mL/min/1.73 m²) by Day 168. P values shown are those across all treatment arms for ECDs and SCDs, calculated using the chi-squared test. BCAR – biopsy-confirmed acute rejection; ECD – extended-criteria donor; eGFR – estimated glomerular filtration rate; FAS – full-analysis set; MDRD4 – Modification of Diet in Renal Disease-4; SCD – standard-criteria donor.

Figure 3

Incidence of renal dysfunction by Day 2 and after Day 2 (Day 3 to Day 168) in patients receiving kidneys from ECDs and SCDs (FAS). Renal dysfunction was defined as eGFR (MDRD4) <40 mL/min/1.73 m². P values shown are those across all treatment arms for ECDs and SCDs, calculated using the chi-squared test. ECD – extended-criteria donor; eGFR – estimated glomerular filtration rate; FAS – full-analysis set; MDRD4 – Modification of Diet in Renal Disease-4; SCD – standard-criteria donor.