Challenges of calcineurin inhibitor withdrawal following combined pancreas and kidney transplantation: Results of a prospective, randomized clinical trial

Abstract

In a phase 2 multicenter open-label randomized trial sponsored by the National Institutes of Health, simultaneous pancreas-kidney (SPK) recipients were randomized to a calcineurin inhibitor (CNI)-based immunosuppressive regimen (tacrolimus) (n = 21), or an investigational arm using low-dose CNI plus costimulation blockade (belatacept) with intended CNI withdrawal (n = 22). Both arms included induction therapy with rabbit ATG, mycophenolate sodium, or mycophenolate mofetil and rapid withdrawal of steroids. Enrollment and CNI withdrawal were stopped after 43/60 planned subjects had been enrolled. At that time, the rate of biopsy-proven acute rejection (BPAR) of the pancreas was low in both groups until CNI was withdrawn, with four of the five pancreas rejections occurring during or after CNI withdrawal. The rate of BPAR of kidney allografts was low in both control (9.5%) and investigational (9.1%) arms. Pancreas graft survival at 52 weeks, defined by insulin independence, was 21 (100%) in the control group and 19 (86%) in the investigational arm. One subject in the investigational arm died with functioning pancreas and kidney grafts. Renal function at week 52 was similar in both arms. Costimulation blockade with belatacept did not provide sufficient immunosuppression to reliably prevent pancreas rejection in SPK transplants undergoing CNI withdrawal.

Keywords: clinical research/practice; costimulation; diabetes: type 1; immunosuppressant-calcineurin inhibitor: tacrolimus; immunosuppression/immune modulation; pancreas/simultaneous pancreas-kidney transplantation; rejection: acute; sensitization.

Conflict of interest statement

Disclosure

The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. Nulojix (belatacept) was donated by Bristol Myers Squib (Princeton, NJ).

© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.

Figures

Figure 1.

Study Design

Figure 2.

Tacrolimus trough levels (ng/mL) measured throughout the course of the first year post-transplant. Mean values (with standard deviation bars) are plotted over time for the control (blue) and investigational (red) arms. Individual trough measurements are plotted as circles within each group. Horizontal axis values range from day 5 (D05) to week 52 (W52).

Figure 3.

Renal function during the first year post-transplant as measured by estimated glomerular filtration rate (eGFR) using the CKD-EPI equation. Mean values (with standard deviation bars) are plotted over time for the control (blue) and investigational (red) arms. Individual eGFR values are plotted as circles within each group. A repeated measures liner mixed model yielded an estimated treatment group difference at week 52 of 2.1 mL/min/1.73m2 with a 95% CI of (−11.1, 15.2), p=0.75.

Figure 4.

Status of CNI Withdrawal in the Investigational Arm

Figure 5.

Freedom from biopsy-proven acute cellular rejection. Gray band depicts the timeframe in which withdrawal of calcineurin inhibitor was initiated. (A) Kidney biopsy proven ACR-free survival; (B) Pancreas biopsy proven ACR-free survival.

Figure 6.

Freedom from treated rejection. Gray band depicts the timeframe in which withdrawal of calcineurin inhibitor was initiated. (A) Kidney treated rejection-free survival; (B) Pancreas treated rejection-free survival.

Figure 7.

Elevations in serum amylase and lipase prompting pancreas biopsy confirming rejection.