Preconditioning donor with a combination of tacrolimus and rapamacyn to decrease ischaemia–reperfusion injury in a rat syngenic kidney transplantation model

Abstract

SummaryReperfusion injury remains one of the major problems in transplantation. Repair from ischaemic acute renal failure (ARF) involves stimulation of tubular epithelial cell proliferation. The aim of this exploratory study was to evaluate the effects of preconditioning donor animals with rapamycin and tacrolimus to prevent ischaemia-reperfusion (I/R) injury. Twelve hours before nephrectomy, the donor animals received immunosuppressive drugs. The animals were divided into four groups, as follows: group 1 control: no treatment; group 2: rapamycin (2 mg/kg); group 3 FK506 (0, 3 mg/kg); and group 4: FK506 (0, 3 mg/kg) plus rapamycin (2 mg/kg). The left kidney was removed and after 3 h of cold ischaemia, the graft was transplanted. Twentyfour hours after transplant, the kidney was recovered for histological analysis and cytokine expression. Preconditioning treatment with rapamycin or tacrolimus significantly reduced blood urea nitrogen and creatinine compared with control [blood urea nitrogen (BUN): P < 0·001 versus control and creatinine: P < 0·001 versus control]. A further decrease was observed when rapamycin was combined with tacrolimus. Acute tubular necrosis was decreased significantly in donors treated with immunosuppressants compared with the control group (P < 0·001 versus control). Moreover, the number of apoptotic nuclei in the control group was higher compared with the treated groups (P < 0·001 versus control). Surprisingly, only rapamycin preconditioning treatment increased anti-apoptotic Bcl2 levels (P < 0·001). Finally, inflammatory cytokines, such as tumour necrosis factor (TNF)-a and interleukin (IL)-6, showed lower levels in the graft of those animals that had been pretreated with rapamycin or tacrolimus. This exploratory study demonstrates that preconditioning donor animals with rapamycin or tacrolimus improves clinical outcomes and reduce necrosis and apoptosis in kidney I/R injury.

Autophagy and the Kidney: Implications for Ischemia-Reperfusion Injury and Therapy

“…79,80 These immunosuppressants mostly have protective properties on IRI through anti-apoptotic or anti-inflammatory mechanisms. 72,[81][82][83] In addition, tacrolimus also stimulates autophagy in vivo in the brain of mice, 51 while MMF is a potent inducer of chaperonemediated autophagy, a special form of autophagy specific for degradation of oxidized/misfolded proteins mediated by heat shock proteins.…”

Role of mechanistic target of rapamycin (mTOR) in renal function and ischaemia–reperfusion induced kidney injury

“…The role of mTOR in IR‐induced renal injury was evaluated in another set of animals treated with mTOR inhibitor rapamycin, in the presence or absence of clenbuterol, an mTOR activator. The doses of rapamycin and clenbuterol used in the current study were previously reported in the literature to inhibit or activate mTOR, respectively. Rats were randomly divided into five groups as follows (n=5‐7 per group):…”

Donor pre‐treatment in clinical kidney transplantation: a critical appraisal

“…Pre‐conditioning of rat donors with calcineurin inhibitors cyclosporine A or tacrolimus decreased structural damage and resulted in improved graft function after kidney transplantation . Moreover, pre‐treatment with tacrolimus combined with rapamycin even improved outcome synergistically . Not all studies could confirm these results, potentially explained by gross differences in experimental set‐up and dosing of immunosuppressives between studies .…”