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Spring 1994Volume 1, Number 1 |
Since the introduction of cyclosporine in the early 1980s, one-year survival of kidney grafts has increased dramatically; approximately 85% of cadaver kidney grafts in the United States survive for one year or more. The loss of kidney grafts due to rejection in the first year is an uncommon event for most transplant programs, mainly due to the effect of cyclosporine (cyclosporin A, Sandimmune®, Sandoz Pharmaceuticals) on acute rejection. However, chronic rejection causes a steady loss of transplants after the first year.
New insights into the pathogenesis of chronic rejection have led investigators to focus on nonimmunological factors as well as on a better definition of the immunology of chronic rejection. Previous theory held that antibody response (B cells) was more important than other mechanisms in the development of chronic rejection. Newer models, however, emphasize the role of the cellular immune system (T cells), particularly in the production of cytokines and adhesion molecules, in the development of chronic rejection. The major focus of research in chronic rejection is on the endothelium. Endothelial cell injury and the continued insults to the endothelium that occur following rejection represent the primary mechanisms underlying chronic rejection.
Current models suggest that even one episode of acute rejection is detrimental to long-term function. In a review of more than 650 primary cadaveric kidney transplants performed at Ohio State University, Ferguson et al found that the six-year graft survival in patients who received cadaveric transplants and who never suffered a rejection was 90%. In contrast, graft survival was 78% in patients with one rejection episode and only 50% in patients with multiple rejections. Other studies have demonstrated similar results. It appears that one rejection episode injures the endothelium and that the body's response to endothelial injury, coupled with an ongoing response to the foreign histocompatibility antigens, results in endothelial cell proliferation and obliteration of arterioles — the hallmarks of chronic rejection. There is no active treatment for chronic rejection. Therefore, the only way to prevent chronic rejection is to prevent acute rejection.
The 1990s have witnessed a proliferation of new immunosuppressive agents, some of which are already in clinical trials. Clinicians hope that these newer drugs will be useful in preventing acute rejection and therefore decreasing chronic rejection. Furthermore, their effect, if any, on endothelial proliferation, cytokine production, adhesion molecules, and B-cell function needs to be explored. If active in these areas, they may prove beneficial in the treatment of chronic rejection. One of the drugs closest to FDA approval is mycophenolate mofetil (see section on New Immunosuppressive Drugs ). This drug is an antimetabolite with particular specificity for lymphocytes. It is well-tolerated and has been used successfully for treatment of refractory rejection in kidney, liver, and heart transplantation. It is currently under study in an international placebo-controlled, double-blind, randomized trial for preventing rejection in primary cadaveric transplants. Results of this study should be available in the second quarter of 1994.
Various analogues of cyclosporin G are also under investigation. Cyclosporin G produces a similar degree of immunosuppression but demonstrates less nephrotoxicity than cyclosporin A. Clinical trials in kidney transplantation are in progress. FK506 acts by a mechanism similar to that of cyclosporin A, but appears to be more potent on a per weight basis. This drug has been used successfully in liver transplantation, and FDA approval for this indication is awaited (see next article). Preliminary studies in kidney transplantation show that FK506 appears effective in treating refractory rejection. Concerns remain over its nephrotoxicity and neurotoxicity. A multicenter prospective trial of FK506 in primary cadaveric kidney transplantation is scheduled to begin soon.
Rapamycin is another drug with a similar mechanism of action. Rapamycin, however, appears to be antagonistic to FK506 but synergistic with cyclosporin A. Rapamycin shows promise in animal studies, and human trials in kidney transplantation are planned. Brequinar is another antimetabolite with a mechanism of action similar to that of mycophenolate mofetil. To date, however, brequinar has been used only in animals.
The future is bright for kidney transplantation — all of these drugs and others under development will eventually be used either singly or in combination to increase graft survival by preventing acute rejection. Prevention of acute rejection should lead to lower rates of chronic rejection.
Thomas Gonwa, MD
Baylor University Medical Center
Dallas, Texas
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