Long Term Management of Liver Transplant Rejection in Children

Abstract

The current management of hepatic allograft rejection after liver transplantation in children requires effective baseline immunosuppression to prevent rejection and rapid diagnosis and treatment to manage acute rejection episodes. The subsequent impact on chronic rejection is dependent on the combination of adequate prevention and the treatment of acute rejection. Tacrolimus is a macrolide lactone that inhibits the signal transduction of interleukin-2 (IL-2) via calcineurin inhibition. Introduced in 1989, tacrolimus was first used in the salvage of refractory acute or chronic rejection under cyclosporin or to rescue patients with significant cyclosporin-related complications. The majority of paediatric transplant centres use a combination of steroids with tacrolimus as a basic immunosuppressant regimen following paediatric liver transplantation. This combination has allowed the acute cellular rejection-free rate to increase to between 30 and 60%, while lowering the rate of refractory rejection to less than 5%. Corticosteroid-resistant rejection is commonly treated with monoclonal (muromonab CD3) or polyclonal preparations. Although most episodes of acute cellular rejection occur during the first 6 weeks after liver transplant, the appearance of late acute liver allograft rejection must raise the question of noncompliance, especially in the adolescent population. Chronic rejection is becoming increasingly rare under tacrolimus-based immunosuppression. Tacrolimus is effective in reversing refractory acute cellular rejection or early chronic rejection in patients initially treated with cyclosporin-based regimens. Patients with a history of noncompliance as well as children with autoimmune liver disease are at risk of chronic rejection. Retransplantation therapy for chronic rejection has, fortunately, become more rare in the tacrolimus era with only 3% of retransplants being performed for this indication. Newer immunosuppressive agents are further modifying the long term management of liver allograft rejection. These include mycophenolate mofetil, rapamycin and IL-2 antibodies such as daclizumab. The development of these agents is allowing patient-specific immunosuppressive management to minimise rejection as well as the complications related to immunosuppression.

Muromonab-CD3 for the successful treatment of early chronic rejection after pediatric liver transplantation: Report of a case

“…On the other hand, Mazariegos et al reported fi nding that muromonab-CD3 was effective against ACR or early CR, especially in recipients initially treated with tacrolimus. 15 In our patient, the CD3 + T-cell counts decreased after muromonab-CD3 administration, descending further with subsequent doses of muromonab-CD3 and recovering to within the normal range after discontinuation. Several side effects can occur during the abatement and restitution of CD3 + T cells with muromonab-CD3 administration.…”

“…14 Early CR, including ACR, in recipients treated initially with tacrolimus responded well to muromonab-CD3. 15 We think that the induction phase of muromonab-CD3 was during ACR in our patient, which did not seem reasonable; however, this case fulfi lled some requirements for the induction of muromonab-CD3 for refractory ACR as specifi ed in previous reports. We decided on induction for this patient after careful consideration based on the severe lymphocyte infi ltration, comparatively early period after LT (PODs 24-31), coagulopathy, and proteinlosing ascites.…”

“…Most episodes of ACR occur during the fi rst 6 weeks after LT, and steroidresistant rejection is commonly treated with monoclonal or polyclonal preparations. 15 The antilymphocyte monoclonal antibody has been shown to be effective in the management of steroid-resistant and/or refractory ACR, 10,11 although the question of compliance for late ACR or early CR, especially in the adolescent population with severe bile duct loss, has been raised. On the other hand, Mazariegos et al reported fi nding that muromonab-CD3 was effective against ACR or early CR, especially in recipients initially treated with tacrolimus.…”

Antibody immunosuppressive therapy in solid-organ transplant

“…34,35 Since the late 1980s, OKT3 administration in liver transplantation was largely confined to steroid-resistant acute rejections, with a long-term graft survival rate of approximately 50%. [36][37][38] Its usage was specifically contraindicated in hepatitis C virus (HCV) infected patients because OKT3 treatment was associated with worse outcomes. [39][40][41] Finally, in comparative OKT3 studies in lung transplant patients, RATG produced fewer side-effects, a lower incidence of BOS, and superior 5-year survival outcomes (52% RATG versus 34% OKT3).…”

Conversion from Cyclosporin to Tacrolimus in Paediatric Liver Transplant Recipients

“…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.…”