Benefits of a loading dose of tacrolimus on graft survival of kidney transplants in nonhuman primates

Abstract

We examined the benefit of a loading dose of tacrolimus on the production of donor-specific antibodies (DSA), occurrence of acute rejection (AR) episodes, graft survival, and histological evidence of antibody-mediated rejection (ABMR) after kidney transplantation in nonhuman primates. Eight cynomolgus monkeys were assigned to two groups (n = 4 each): a maintenance dose-group, orally administered 1 mg/kg/day tacrolimus from the day of transplantation; and a loading-dose group, orally administered 2 mg/kg/day tacrolimus for 21 days after transplantation followed by 1 mg/kg/day. The monkeys were observed for up to 178 days after transplantation. Plasma creatinine was monitored over time. Recipients with increased plasma creatinine levels of >2 mg/dL received anti-acute rejection therapy. In the maintenance dose-group, DSA production, frequent AR episodes, and histological evidence of ABMR were observed in all recipients. Three of four recipients did not survive until the end of the observation period. In the loading-dose group, two recipients showed DSA production, frequent AR episodes and histological evidence of ABMR, while the remaining two had no DSA, AR episodes, or ABMR. Our findings indicate that a loading dose of tacrolimus may prevent DSA production, occurrence of AR events and ABMR, and prolong graft survival following kidney transplantation in monkeys.

Introduction

While the use of calcineurin inhibitors (CNIs) for the prevention of acute rejection (AR) has markedly improved kidney transplantation since the 1980s [1,2], both CNI toxicity [[3], [4], [5]] and chronic rejection (CR) remain important medical problems. Exploratory studies have attempted to identify replacement regimens to abrogate CNI-induced toxicity [[6], [7], [8], [9], [10]], but no agents to date have proven sufficiently efficacious to replace CNIs. Recently, patients have been prescribed low doses of CNIs to avoid their adverse effects [11]. While CR is the leading cause of late graft loss, details of its mechanism remain unclear. Recent reports have demonstrated that an increase in plasma creatinine (pCr) level within the first year of transplantation is an important predictive factor of CR [12,13].

Antibody-mediated rejection (ABMR), which is induced by the production of donor-specific antibodies (DSAs) [[14], [15], [16], [17], [18]], has drawn considerable attention in the past decade as a potential mechanism underlying late renal graft failure. Almost half of failed grafts are reportedly due to ABMR [19]. Given that expression of DSA adversely affects graft survival [20], antibody removal strategies such as plasmapheresis, intravenous immunoglobulin, and B cell depletion with rituximab have been employed as potential therapeutic interventions. However, such interventions have not reduced graft loss [21,22]. These findings suggest that DSA production itself in the early post-kidney transplantation period might be a critical event for ABMR. Further, recent reports indicate that DSA mediates and promotes both AR and CR [23]. Therefore, it might be prudent to focus on preventing DSA production to improve long-term outcomes.

Tacrolimus, a calcineurin inhibitor (CNI), prevents DSA production by strongly inhibiting T cell activation [24], suggesting that treatment with an optimal dose of tacrolimus could prevent CR. However, it may be difficult to reconcile the inhibition of DSA production and avoidance of CNI toxicities such as nephrotoxicity [25]. Therefore, it may be particularly valuable to devise a dosing regimen to augment the therapeutic benefits of tacrolimus.

We studied the effect of two dosage regimens, a tacrolimus maintenance-dose regimen and a tacrolimus loading-dose regimen, on DSA production, the incidence of AR episodes, graft survival and ABMR following kidney transplantation in cynomolgus monkeys.