Tacrolimus rescue in liver transplant patients with refractory rejection or intolerance or malabsorption of cyclosporine

Abstract

Tacrolimus is an effective immunosuppressant in the rescue of liver allograft patients in whom conventional immunosuppression failed. Efficacy and safety were examined in a multicenter trial of liver transplant recipients converted to tacrolimus because of rejection despite cyclosporine (CyA) therapy or intolerance to CyA. Six hundred seventy-seven patients were enrolled onto the study; 475 patients for rejection, 197 patients for intolerance, and 5 patients treated compassionately. The mean daily dose of tacrolimus was less in the intolerance (Int) patients throughout the study: 0.22 versus 0.17 mg/kg at 1 week and 0.14 versus 0.11 mg/kg at 24 months in rejection (Rej) and Int patients, respectively. Mean blood levels paralleled dosing in both groups, but were greater in the Rej patients (10.7 v 8.3 ng/mL at 18 months). Kaplan-Meier estimates of patient and graft survival were similar in the two groups. Patient survival rates were 80.1% and 81.5%, and graft survival rates were 72.7% and 73.9% at 24 months in the Rej and Int patients, respectively. Most adverse events occurred with a similar incidence in the two groups. Those with a 4% or greater incidence were fever, viral hepatitis, and pneumonia. The incidence of sepsis, gastrointestinal hemorrhage, kidney failure, and convulsion was greater in the Int group. The incidence of abnormal liver function test results, hyperglycemia, headache, and abnormal kidney function was greater in the Rej group. Mean liver function test results decreased with time postrescue in both groups. Mean serum creatinine level increased from baseline to 18 months postrescue in both groups (1.44 to 1.51 mg/dL for Int patients, 1.14 to 1.48 mg/dL for Rej patients). We conclude tacrolimus is safe and effective rescue in liver transplant recipients with rejection or CyA intolerance.

Stimulation of osteogenic activity in mesenchymal stem cells by FK506

“…20 FK506 has numerous nonimmune effects, such as the stimulation of hair growth, liver cell regeneration, and nerve protection. 21 It is generally considered that the systemic application of immunosuppressants causes bone loss, especially when a high dose is given over a long period.…”

Conversion from Cyclosporin to Tacrolimus in Paediatric Liver Transplant Recipients

“…Other single centre experiences with conversion from cyclosporin to tacrolimus have been reported by Moreno et al, [22] Reggiani et al, [23] and Cao et al [4] The US Multicenter FK506 study group [20] also included a cohort of children receiving tacrolimus as rescue therapy. 132 children were converted to tacrolimus; the indications for conversion were rejection (n = 92) and intolerance or malabsorption of cyclosporin (n = 40).…”

“…[46] As expected, rates of EBV infection or PTLD in children after secondary conversion to tacrolimus from cyclosporin are higher, ranging from 4.5 to 21.7%. [4,[16][17][18][19][20][21] This is related to the higher overall immunosuppression used in these patients and argues for earlier conversion. [16,21] In patients who have been heavily immunosuppressed prior to conversion, monitoring for EBV infection during treatment for chronic rejection is essential.…”

“…IV administration of tacrolimus (0.05 to 0.1 mg/kg/day) may be required when oral absorption is poor or unpredictable, although this is rare. [20,37] In refractory acute rejection a tapered regimen of methylprednisolone is also used (see table II). Monoclonal antibody therapy is used in conjunction with tacrolimus conversion only if there is biopsy evidence of residual cellular rejection after a cycle of methylprednisolone therapy.…”

The immunoreactive patient: Rejection and autoimmune disease

“…During the historical evolution of immunosuppression, new agents made an early impact by rescuing patients with SRR. In the 1990s, a multicenter experience of 475 patients who suffered rejection while they were receiving cyclosporine‐based immunosuppression yielded a 2‐year graft survival rate of 74% after their conversion to tacrolimus 3. In the same era, approximately two‐thirds of patients with SRR on cyclosporine‐based immunosuppression regimens were rescued with either the addition or substitution of mycophenolate mofetil 4.…”