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Ongoing improvements in immunosuppression and posttransplantation care have dramatically improved patient and graft outcomes after transplantation. The frequency of graft loss due to acute rejection has declined considerably as a result of the availability of a variety of more potent immunosuppressive agents and probably also because of refined clinical care and follow-up. Complications of long-term administration of corticosteroids (steroids) and calcineurin inhibitors, however, have become increasingly apparent as patients live longer with their transplant, and attention is shifting to long-term issues. Use of both steroids and calcineurin inhibitors is associated with metabolic toxicities such as hypertension, hyperlipidemia, diabetes, bone loss, and cataracts. These contribute to posttransplantation morbidity and may negatively affect patient and allograft survival. A variety of troublesome cosmetic side effects, such as hirsutism, gingival hyperplasia, alopecia, obesity, and cushingoid appearance, also are associated with these drugs. These effects can detract from patient self-esteem and compliance with the immunosuppressive regimen. In the past 2 decades, the introduction of second-generation immunosuppressive drugs, such as tacrolimus, mycophenolate mofetil, sirolimus, and anti-interleukin-2 receptor monoclonal antibodies, has provided some alternatives to classic immunosuppressant choices. Patients experiencing undesirable adverse events now can be converted to another immunosuppressive regimen that ultimately will improve graft and patient survival rates and improve quality of life after transplantation.
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PMID:Strategies to reduce toxicities and improve outcomes in renal transplant recipients. 1189 90

The anti-interleukin-2 receptor (anti-IL-2R) antibody therapy is an exciting approach to the prevention of acute rejection after renal allograft transplantation whereby immunosuppression is exerted by a selective and competitive inhibition of IL-2-induced T cell proliferation, a critical pathway of allorecognition. The anti-IL-2R antibodies specifically block the alpha-subunit of the IL-2R on activated T cells, and prevent T cell proliferation and activation of the effector arms of the immune system. The anti-IL-2R antibodies are used as induction therapy, immediately after renal transplantation, for prevention of acute cellular rejection in children and adults. During acute rejection, the IL-2Ralpha chain is no longer expressed on T cells; thus, the antibodies cannot be used to treat an existing acute rejection. Two anti-IL-2R monoclonal antibodies are currently in clinical use: daclizumab and basiliximab. In placebo-controlled phase III clinical trials in adults, daclizumab and basiliximab in combination with calcineurin inhibitor-based immunosuppression, significantly reduced the incidence of acute rejection and corticosteroid-resistant acute rejection without increasing the risk of infectious or malignant complications, and neither antibody was associated with the cytokine-release syndrome. Children who receive calcineurin inhibitors and corticosteroids for maintenance immunosuppression, as well as children who receive augmented immunosuppression to treat acute rejection, are at increased risk of growth impairment, hypertension, hyperlipidemia, lymphoproliferative disorders, diabetes mellitus, and cosmetic changes. In older children, the cosmetic adverse effects frequently reduce compliance with the treatment, and subsequently increase the risk of allograft loss. Being effective and well tolerated in children, the anti-IL-2R antibodies reduce the need for calcineurin inhibitors while maintaining the overall efficacy of the regimen; thus, the anti-IL-2R antibodies increase the safety margin (less toxicity, fewer adverse effects) of the baseline immunosuppression. Secondly, the anti-IL-2R antibodies decrease the need for corticosteroids and muromonab CD3 (OKT3) in children as a result of decreased incidence of acute rejection. The recommended pediatric dose of daclizumab is 1 mg/kg intravenously every 14 days for five doses, with the first dose administered within 24 hours pre-transplantation. This administration regimen maintains daclizumab levels necessary to completely saturate the IL-2Ralpha (5-10 microg/mL) in children for at least 12 weeks.The recommended pediatric dose of basiliximab for recipients <35 kg is 10 mg, and 20 mg for recipients > or =35 kg, intravenously on days 0 and 4 post-transplantation. This administration regimen maintains basiliximab levels necessary to completely saturate the IL-2Ralpha (>0.2 microg/mL) in children for at least 3 weeks.
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PMID:Anti-interleukin-2 receptor antibodies for the prevention of rejection in pediatric renal transplant patients: current status. 1451 Jun 27

Chronic allograft nephropathy and death with a functioning graft (mainly due to cardiovascular causes) are the most common causes of graft loss after the first year of renal transplantation. Immunosuppressants, and corticosteroids among them, contribute to an increase in cardiovascular risk because of their significant adverse effects, including hypertension, hyperlipidaemia and hyperglycaemia. Thus, corticosteroid discontinuation or avoidance has become a priority among the transplant community in order to enhance long-term graft and patient survival. Nevertheless, corticosteroid-sparing strategies may increase the risk of acute and chronic rejection and, thus, worsen the prognosis of transplant recipients. Initial attempts during the azathioprine epoch did not provide satisfactory results, as they were associated with high acute rejection rates, emphasising the risk of under-immunosuppression. The advent of new immunosuppressants, such as mycophenolate mofetil, mTOR inhibitors and anti-interleukin-2 receptor antibodies, have renewed the interest in corticosteroid-sparing protocols, and the results of new trials suggest that these corticosteroid-sparing strategies, even at an early stage after transplantation, are safe enough in view of the stable renal function and low rates of acute rejection reported. However, immunological risk factors, such as African American ethnicity, the presence of panel-reactive anti-HLA antibodies (even at low rates), and a history of previous acute rejection episodes should be taken into account and corticosteroid withdrawal strategies should be undertaken with caution. Long-term follow-up studies must be performed to confirm the encouraging short-term data.
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PMID:Corticosteroid-sparing strategies in renal transplantation: are we still balancing rejection risk with improved tolerability? 1659 59