Calcineurin inhibitor minimization in pediatric liver allograft recipients

Abstract

The use of CNI in pediatric LTx has dramatically improved the outcome for children with end-stage liver disease by significantly reducing the rate of acute and chronic rejection. Long-term concerns about CNI-induced nephrotoxicity and other adverse effects remain an issue, particularly as the emphasis moves from short-term survival to long-term quality of life. This review summarizes lessons learnt from pediatric and adult solid organ transplantation in minimizing CNI use in immunosuppression protocols in children following LTx. There are three models for CNI minimization: dose reduction, withdrawal or avoidance, supplemented by the use of IL-2 receptor blocking antibodies in the peri-transplant period, and early transition to alternate drugs such as MMF or SRL. Prospective studies evaluating reduction or withdrawal protocols in adult and pediatric LTx indicate that rejection rates are comparable with traditional CNI-based immunosuppression and that two and five yr patient and graft survival are similar, with recovery in renal function. There are few studies evaluating complete avoidance of CNI, apart from that in renal transplantation, although the benefits of long-term reduction in cardiovascular, metabolic, and possibly neoplastic side effects may justify this approach. It is not clear yet how CNI minimization will affect the development of tolerance but experimental and preliminary clinical studies indicate that CNI and steroid avoidance or minimization in the peri-operative period may favor the development of long-term graft tolerance. In summary, CNI minimization may be safe and effective in the short term but large-scale pediatric randomized studies are required to evaluate the long-term efficacy of these regimes in the development of chronic rejection, PTLD, and graft tolerance.

CD25 Appears Non Essential for Human Peripheral Treg Maintenance In Vivo

“…However, these in vitro results may not accurately reflect Treg responsiveness in vivo, as previously reported for Treg proliferative capacity [28]. No autoimmune disorders have so far been observed in our series of pediatric transplant recipients, and none have been reported in other series of pediatric transplant recipients who received basiliximab during induction therapy [29], [30]. Accumulating evidence points to a role of Tregs in immune tolerance of allergens [31].…”

Glomerular Filtration Rate Following Pediatric Liver Transplantation—The SPLIT Experience

“…Similarly, since SPLIT Posttransplant Kidney Function mGFRs were included from patients at variable times post-LT, it is possible that immunosuppression was altered in response to earlier GFR measurements leading to subsequent improvement in kidney function. The use of decreased calcineurin inhibitor dosing in combination with mycophenolate mofetil is one of several effective kidneysparing strategies commonly used in clinical practice but not captured in this data set (47)(48)(49)(50). These potential differences among center populations and practices leave the opportunity for comparative effectiveness studies to identify best clinical strategies for specific subgroups of patients.…”

Long-term outcomes of children after solid organ transplantation

“…For patients on MMF, drug monitoring is important to ensure adequately high therapeutic dosages, which may explain the increase in rejection in other studies (76,77). Among patients on the mTOR inhibitors sirolimus and everolimus who exhibit improved renal function, there is a high incidence of side effects, including aphthous ulcers, dyslipidemia, myeloid suppression and proteinuria, necessitating the conversion to alternative medications (78) and counterfoing the benefit of CNI minimization (73,74,79). A new immunosuppressive agent that was recently approved by the FDA is the co-stimulatory inhibitor belatacept.…”