Significantly Reduced Renal Allograft Histopathology after Single-Dose rATG Induction and Calcineurin-Inhibitor Withdrawal vs. Minimization: Final Report from a Prospective, Randomized Clinical Trial

Abstract

We conducted a randomized study of single- vs. divided-dose rATG induction with early steroid withdrawal, followed by CNI minimization vs. withdrawal. 180 patients received either single-dose rATG (one 6 mg/kg dose over 24 hours) or divided-dose rATG (4 doses of 1.5 mg/kg on alternate days), and maintenance immunosuppression with tacrolimus and sirolimus, until tacrolimus was replaced with MMF after 6 months in half the patients of each group. (Maximum follow-up = 7 years; minimum = 2 years.) Demographics were not different among the four groups. Single-dose rATG associated with fewer infectious complications (p = 0.01) and quicker recovery of lymphocyte counts (p = 0.03). Patients who received deceased donor (but not living donor) kidneys had better renal function both for the first 6 months (p = 0.02) and 3 years (p = 0.04). When analyzed by induction treatment, death-censored graft survival and rejection were not different among the 4 groups, but patient survival was inferior among divided-dose rATG recipients (p = 0.02). CNI withdrawal associated with sustained improved graft function and reduced histopathology, but did not impact rejection or graft survival. Average renal function (calculated GFR, aMDRD formula) was superior for 30 months after CNI withdrawal vs. minimization (p = 0.03) without increased graft fibrosis/tubular atrophy. In a blind comparison of 12-month protocol biopsies of all four regimens, the group with the least histopathology at 12 months received both single-dose rATG induction and CNI withdrawal, (tubular atrophy, p = 0.013; cumulative Banff chronic injury score, p = 0.07). When comparing just the effect of CNI minimization vs. withdrawal on these 12-month biopsy specimens, the CNI-withdrawal patients displayed significantly less Banff score cumulative histopathology (p = 0.016). We conclude that single-dose rATG induction followed by calcineurin-inhibitor withdrawal is associated with improved patient outcomes including graft function and reduced histopathology, and may be safely undertaken in a steroid-free context