Cyclosporine Avoidance
Authors: PHILIPPE GAUTHIER, J. HAROLD HELDERMAN
Journal: Journal of the American Society of Nephrology (2000)

The introduction of cyclosporine A (CsA) into clinical practice in the early 1980s ushered in a new era in organ transplantation. Hitherto, almost all renal transplant recipients had been treated with a similar regimen of corticosteroids and azathioprine. With the advent of cyclosporine, a triple therapy regimen including the newly discovered immunosuppressant resulted in a dramatic improvement in allograft survival (1). The use of such a triple therapy approach represents the beginning of the traditional “constructive,” or additive, philosophic approach to immunosuppression. This philosophy states that as each new medicine immunosuppressant is discovered, it is added to the already extant package or substituted for one element of the present package, a philosophy that resulted from the need to reduce acute rejection rates. This additive approach was relatively simplistic in a time in which there was a relative paucity of antirejection medication choices. With the advent of a wide range of immunosuppressive choices, such as mycophenolate mofetil (MMF), tacrolimus, sirolimus, and the new monoclonal IL-2 antibodies, all of which are effective at preventing acute rejection rates and improving short-term outcomes, such a simplistic approach has become untenable. This explosion of new agents has led many to begin examining a new philosophic approach, one that can be thought of as reductive, in which the least number of immunosuppressive drugs is employed with maximum efficacy and minimum toxicity. The article by Tran and his colleagues published in this issue examines this topic with particular reference to the historic backbone of modern immunosuppression, the use of CsA. The rationale for CsA minimization or avoidance flows from its considerable toxicity profile, especially to nephrotoxicity. This nephrotoxic potential of CsA was recognized by Sir Roy Calne after his first experience with human use (2). The toxic impact of cyclosporine can be divided into acute effects and those that are apparent after more chronic use. Acutely, the drug can cause afferent glomeruloarteriolar constriction with a hemodynamically mediated decrease in the GFR, solute transport alterations such as sodium and water retention and hyperkalemia, and an acute thrombotic microangiopathy related to direct endothelial injury. Chronic administration of CsA inhibits the renin-angiotensin-aldosterone axis; activates profibrotic genes such as that for transforming growth factor-β; and maintains relative intrarenal ischemia, which leads to cycles of injury and repair in the regions of the kidney that are most vulnerable to hypoxia. This process culminates in a distinct form of chronic organ dysfunction that is easily apparent in recipients of extrarenal transplants in which other mechanisms of renal injury are not present to cloud histologic interpretation. Histologically, the findings include a tubulointerstitial fibrosis in a stripped pattern along with degenerative hyaline changes in the walls of afferent arterioles, which, when present in its classical form, can be distinguished from chronic rejection (3). Other important clinical toxicities of chronic administration of cyclosporine include exacerbation or genesis of hypertension and hyperlipidemia, both relevant risk factors for ischemic cardiovascular disease that might limit long-term allograft outcomes (4). Complicating the use of the drug, cyclosporine has a narrow therapeutic window and can be conceived of as a critical-dose drug driving the need for careful and expensive laboratory monitoring of use. Before one decides whether to eliminate CsA from the immunosuppressant package for renal transplantation, it must be clear that such a treatment strategy offers more benefits than harm. The equation for continued long-term allograft survival under the umbrella of cyclosporine can be reduced to a consideration of the benefits that flow from the impact on graft integrity, from effective acute rejection prophylaxis against the detriment related to chronic nephropathy. To ascertain which element of this equation predominates, several large clinical studies of long-term CsA impact have been conducted. In one such large series of 1663 renal transplant patients, Burke and colleagues (5) found that the most common cause of graft failure in renal transplants was acute rejection. Few patients with chronic allograft dysfunction responded to a decrease in the dose of CsA with an improvement in renal function. Furthermore, too little CsA was associated with worse long-term outcomes. Thus, acute rejection episodes and chronic cyclosporine doses of less than 5 mg/kg were the best predictors of the development of chronic allograft nephropathy in this multicenter analysis (6). Others confirmed that cumulative cyclosporine dose was associated with the rate of chronic allograft nephropathy (7,8). Last, Hariharan et al. (1), examining the UNOS Database, clearly showed that not only have 1-yr renal transplant outcomes been spectacularly improved by the advent of the cyclosporine element in the immunosuppressive package, but also long-term results have progressively increased adjudged by graft half-life. One might conclude that on balance, the salutary effects of cyclosporine as a potent inhibitor of alloantigen-driven lymphocyte activation have far outweighed the detriment to outcomes imposed by nephrotoxicity in the renal transplantation model. As one analyzes factors that predict extended allograft survival, it becomes clear that premature death, often with a well-functioning transplant, has become a major cause of graft loss constituting half or more of all graft losses after the first year in many series (1). This inescapable fact drives a more in-depth analysis of the cost/benefit ratio for this immunosuppressive agent. Although the immunosuppressive benefits of CsA may outweigh fears of chronic nephrotoxic limitation to long-term graft success, the alterations of classical risk factors for ischemic cardiovascular disease, the leading cause of this excess death in the renal transplant recipient, attendant to cyclosporine use, must be added to the cost/benefit equation. The high prevalence of hypertension and of hypercholesterolemia that follows CsA use may play an important role in supporting the unconscionably high rates of ischemic heart disease in renal transplant recipients, which provides an additional argument for CsA minimization, withdrawal, or avoidance protocols. Throughout the history of renal transplantation, the superb outcomes experienced have required lifelong immunosuppression. The discussion has so far been reduced to the argument of the cost/benefit ratio for CsA use as one of the unique elements in a given immunosuppressive package. The establishment of classic transplant tolerance, host unresponsiveness to graft antigens without further immunosuppression and with normal responses to nongraft antigen, established by a perigraft conditioning immunologic regimen, has been one of the Holy Grails of the transplant community (9). The impact of CsA on the creation of acquired transplant tolerance provides another argument for CsA avoidance. Recently, the laboratories of Turka and Strom have shown that CsA abrogates several pathways of lymphocyte response to alloantigen in such a way as to forestall tolerance, thus relegating renal transplant recipients to lifelong, albeit highly effective, immunosuppression (10,11). These scientists discovered that lymphocyte response to alloantigen can lead to opposing signals culminating in lymphocyte activation on the one hand with its clonal expansion of effector cells and in apoptosis on the other hand, both signals of which are inhibited by the calcineurin inhibitor class of drugs. Tolerance was induced in rodents using strategies that delimit but do not abrogate IL-II receptor-linked signal transduction, coupled to alloantigen signal and cell cycle inhibition. Thus, on immunologic grounds, blockade of the potential for tolerance induction provides additional scientific rationale for immunosuppression using CsA avoidance regimens. Attempts to manipulate CsA from its standard use are not new and have been composed generally of one of three regimens: (1) dose reduction in which CsA is not discarded but rather given in doses that achieve lower than traditional target blood levels, (2) cyclosporine withdrawal in which CsA is halted at some time after successful engraftment, and (3) cyclosporine avoidance in which CsA is never administered. Several recent trials of cyclosporine minimization used the use of newly discovered immunosuppressants such as MMF in an effort to allow decreased CsA exposure. In one such study, 43 patients with chronic allograft nephropathy as defined by a 20% increase in creatinine in the absence of acute rejection on a renal transplant biopsy were started on MMF while the CsA dose was cut by half. After 15 mo, serum creatinine and the slope of the 1/creatinine relationship over time both had improved significantly (12). In a similar trial, Weir and colleagues (13) substituted MMF for CsA in a series of patients with biopsy-proven chronic allograft nephropathy believed to be related to cyclosporine nephrotoxicity with no acute rejection episodes and on important improvement in renal function. We expect a rush of additional studies that test the principle that newer agents such as sirolimus may be used either to reduce the CsA dose or to substitute for CsA in well-functioning grafts. Additional studies have examined the strategy of total CsA withdrawal with mixed results. An early study found withdrawal of CsA from patients with stable renal transplant function 12 mo posttransplantation to be associated with a high rate of acute rejection (14). Sanders et al. (15) compared a group of African American patients who were withdrawn from the CsA therapy for financial reasons with a similar group of individuals who continued to receive the medication through an indigent program. The withdrawal group had a significantly worse long-term graft survival. Another series examined 97 patients who were electively withdrawn from CsA 22 mo posttransplantation with this cohort exhibiting improved 6-yr graft outcomes compared with 287 patients who were maintained on a regimen in which CsA was maintained. Although outcomes seemed improved, the withdrawal group exhibited higher rates of acute rejection (16). This latter study points out some of the foibles of these trials in which the groups maintained on CsA were not immunologically similar to the withdrawn group. In that study, those selected for CsA withdrawal were at the lowest immunologic risk and those maintained were believed to be at higher risk for acute rejections. Kasiske et al. (17) performed a great service to the analysis of this field by using strict meta-analysis statistical technique to merge several small series that examined CsA withdrawal to enhance power and confidence in outcome. Kasiske found temporally related to CsA withdrawal a clear increase in acute rejection rates that did not impair short-term graft survival. He cautioned that long-term consequence of these acute rejection episodes had not been well understood. One can conclude from these and other withdrawal studies that acute rejection episodes may be causally linked to CsA withdrawal in a multidrug regimen using the so-called classical or traditional agents, that short-term allograft success has not been effected by these rejection episodes, but that caution must be voiced in the context of the strong link of acute rejection episodes to diminish long-term allograft success. One might expect that a hybrid approach of withdrawal of CsA followed by the addition of one of the newer agents to protect against early acute rejection episodes will be attempted. Already, small anecdotal studies using this strategy are surfacing. Ducloux et al. (18) converted six patients with biopsyproven cyclosporine toxicity from CsA to mycophenolate. After 12 mo, none of the patients had experienced acute rejection. Scharma et al. (19) converted 17 patients posttransplantation from CsA to mycophenolate. Not only were there no acute rejections in this cohort, but there was a significant decrease in both BP and low-density lipoprotein profiles. There have been few studies in which CsA or the companion calcineurin inhibitor immunosuppressant tacrolimus was completely avoided. The development of the array of new and powerful immunosuppressive medication has made such trials a possibility. CsA avoidance may be of greatest benefit to patients who were at risk for delayed graft function. In a recent trial, six patients who were deemed to be at high risk for delayed graft function were treated with anti-CD25 monoclonal antibody, sirolimus, and corticosteroids. CsA was withheld until the creatinine fell below 3 mg/dl, a period of time that ranged between 16 and 65 d. There were no acute rejection episodes in this study, and all patients had good graft function by 8 wk posttransplantation. Unfortunately, in terms of the test of the principle that CsA may be avoided completely, cyclosporine was started at this later time, although at doses lower than usually used at the center of the investigator (20). This pilot study can be taken as proof of principle that CsA may be at least avoided early. In this issue of the Journal of the American Society of Nephrology, Tran and colleagues attempt to bring the above trends to their logical conclusion: that of permanent and complete CsA avoidance (21). Their study, a prospective, nonrandomized, open-label trial, examined 45 consecutive transplant patients at Brigham and Women's Hospital in Boston who were treated with an immunosuppressive package that contained MMF at 3 g/d, corticosteroids, after induction by the anti-IL-2 monoclonal antibody daclizumab. No subjects received any CsA unless they were deemed to be a treatment failure either because they had an acute allograft rejection episode or because of intolerance to the mycophenolate component of the regimen. After 8 mo, 22 of the 45 patients remained free of CsA. In this group, 17 patients experienced acute rejection, none of which was judged to be severe by the authors; 12 responded to pulse corticosteroids and 5 required OKT3. An additional six individuals, who were intolerant to mycophenolate in the absence of acute cellular rejection, were also switched to CsA. There were no significant differences between the CsA-spared and the CsA- requiring groups with regards to demographics or immunologic variables. After 3 mo, the CsA-spared group had significantly lower serum creatinine than the rejection group, which was not found in the small cohort of CsA switch in the face of mycophenolate intolerance. The CsA-spared group also needed fewer antihypertensive medications than did the control group. Several cautionary notes must be made. First, half of the study group ultimately required CsA. Second, the acute rejection rate of 38% is substantially greater than that found for CsA/mycophenolate/prednisone triple therapy in all of the randomized, prospective pivotal trials using this regimen, the impact of which on long-term outcomes was not measured here. The authors suggestion that low-dose CsA may be used at the time of transplantation to prevent these early rejections obviates the uniqueness of this total CsA avoidance approach. The lack of difference in creatinine between the CsA avoidance group and the mycophenolate-intolerant group suggests that the higher creatinine in the Tran study might have been due to acute rejection rather than to a cyclosporine affect, further damaging the argument that CsA avoidance was salutary. Thus, three study defects delimit the actual lessons learned from the Tran study: the high rejection rate, the short follow-up, and the lack of statistical power of 45 cases. This high rate of rejection in total CsA avoidance was also found by Vincente (22) in a multicenter, open-label trial of 98 patients utilizing anti-CD25 induction, MMF, and prednisone in a protocol similar to that of Tran et al. (21). The possibility of CsA avoidance trials deserves the formation of larger, prospective, and randomized studies perhaps using one of the newer immunosuppressive drugs, such as sirolimus, to reduce the high early acute rejection rate. We expect that additional studies similar to the pioneering work of Tran and his co-workers will continue to test the hypothesis that CsA avoidance can be met with better long-term renal allograft outcomes than that currently experienced or lead to the induction of a state of allograft tolerance. Until this hypothesis can be proved, we also expect that the calcineurin inhibitor spine of immunosuppression for renal transplant patients will remain the standard of practice.