Steroid Free Immunosuppression

Many liver recipients can be weaned from maintenance corticosteroids in the first or second post-transplant year with little risk of inducing rejection. But for other organs, acute rejection follows in 15 percent of recipients weaned from prednisone (24). Are the recipients who are refractory to weaning dependent on prednisone? Or do they simply need increased doses of the other drugs in the regimen to make the transition from steroids successfully? Perhaps high doses of maintenance steroids in the first post transplant months/years inhibit an active facilita-tive response that would otherwise permit homeostasis without maintenance steroids.

Rather than weaning from maintenance steroids, it may be simpler and more effective to start with a potent regimen that combines antibody and drugs but either restricts post transplant corticosteroids to a few days or avoids them altogether. In 2000, 2001 and 2002 more than ten centers for kidney, kidney/pancreas and islet transplantation reported excellent outcomes with up to five-year follow-up with regimens that excluded steroids completely or discontinued them within the first post-transplant week (17-22,25-33). Most of the regimens combine drugs with an antibody. Incidence of acute rejection episodes during the first year was 10-15 percent or less. Graft function up to four years was equal to or better than steroid regimens. An earlier 1997 report that compared three cyclosporine-based regimens in kidney recipients showed increased vertebral bone density during the first 18 post-transplant months for cyclosporine alone but decreased vertebral density for cyclosporine plus steroids or cyclosporine plus both steroids and aza-thioprine (34). The recently reported steroid free regimens probably will also increase bone density and spare recipients from many of the crippling side effects of osteoporosis.

The Edmonton steroid free regimen for pancreatic islets is a breakthrough. Steroids are especially toxic to islets. Investigators at the University of Alberta combined antibody (an IL-2 receptor antagonist or modified OKT3) with tacrolimus and sirolimus. Recipients usually underwent two islet infusions in the course of a year. Twenty-four recipients who have had both infusions have one year insulin independence of 87.5 percent and two year independence of 70 percent (25,26).

We have avoided maintenance steroids at Northwestern Memorial Hospital in more than 500 kidney transplant recipients with two different antibody induction regimens since mid 1998. All recipients were treated with tacrolimus and either MMF or sirolimus. Each also received intravenous methylprednisolone daily for three days only (500 mg, 250 mg, 125 mg, stop). From mid 1998 until September 2001 the induction antibody basiliximab was given in the operating room and on the third post-transplant day. After September 2001, intraoperative antibody treatment consisted of a single 30 mg I.V. infusion of alemtuzumab. First year patient and graft survival in both groups are 99% and 97% respectively. Acute rejection episodes occurred in 9 percent of recipients in both groups. The main difference between the two induction antibodies in these prednisone free protocols is that the onset of first rejection episode was earlier with basiliximab (7.5 days) than with alemtuzumab (107 days). In general, post transplant management is simpler and cost is less if first rejection episodes can be delayed until 30 days or more after transplantation. Avoidance of maintenance prednisone imposed no penalty upon graft or patient survival, level of renal function or freedom from rejection episodes (20,21).

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