Prophylaxis against and treatment of graft rejection are at the heart of the success of kidney transplantation. Since the 1960s, the protocols for renal transplantation have undergone remarkable evolution.
All the protocols for immunosuppression aim at disruption of the lymphocyte cell cycle. Azathioprine and steroids, with or without antilymphocyte preparations, were the mainstay of clinical immunosuppression in the 1960s and 1970s. Since the introduction of cyclosporine early the number of capable of suppressing the immune system increased ily.
These agents, by virtue of their specific mode of action, have succeeded in preventing most patients from having early and irreversible graft rejections without severe toxic effects. The mechanism of action of some of the most commonly used immunosuppressants is illustrated in text. The addition of cyclosporine to protocols in the early 1980s favorably affected graft survival, with a 20% increase in cadaveric kidney survival in the first year. The newer microemulsion preparations of cyclosporine result in more predictable levels and less dependence on bile for absorption. The hepatic cytochrome oxidase P-450 system is essential for cyclosporine metabolism, and several drugs can induce or inhibit this system and thus may cause significant changes in cyclosporine levels. Cyclosporine exerts its specific immunosuppressive activity by inhibition of immunocompetent lymphocytes most important side effects of cyclosporine are listed in Table , and most respond to an appropriate reduction in the dose. The most significant of these effects is which is usually secondary to decreased glomerular blood flow and, again, responds to does reduction. Tacrolimus has a mechanism of action and side effect profile similar to those of but with additional problems of hyperglycemia and an increased tendency toward neurotoxicity. Mycophenolate mofetil(CellCept) specifically inhibits T- and B-lymphocyte proliferation by interfering with purine synthesis and thus DNA synthesis.
Mycophenolate mofetil has been associated with a 60% to 70% reduction in acute transplant rejection when compared with conventional therapies and thus promotes long-term graft survival. Mycophenolate mofetil is replacing azathioprine either as initial immunosuppressive therapy in combination with steroids and cyclosporine or after an acute episode of rejection.
The major toxicity, occurring in 30% of patients, is gastric distress or diarrhea.