Division of Nephrology and Dialysis, IRCCS Ospedale Maggiore di Milano, Milan, Italy
Introduction
Drugs which inhibit the calcineurin enzymatic complex may be responsible for renal toxicity, which is occasionally progressive and irreversible. Thus, in spite of improving results obtained with the use of calcineurin inhibitors in the field of renal transplantation, many physicians are concerned about the long-term use of these agents and try to replace them sooner or later with non-nephrotoxic immunosuppressive agents such as azathioprine, mycophenolate mofetil, and/or rapamycin. Before this policy is generally adopted, however, one should consider the results that can be achieved today with the correct use of calcineurin inhibitors.
The main aims of modern immunosuppression are: (i) to minimize risk and outcome of acute rejection; (ii) to reduce the risk of comorbidity caused by immunosuppressive agents, particularly corticosteroids; and (iii) to reduce late graft failure caused by chronic rejection. All these goals may be achieved through administration of the calcineurin inhibitors, cyclosporin (CsA) or tacrolimus (FK) respectively, especially when these drugs are given in combination with newer immunosuppressive agents.
Acute rejection
Controlled trials comparing CsA with azathioprine (Aza) showed a lower incidence of acute rejections in CsA-treated renal transplant recipients [13]. Randomized studies reported that the risk of acute rejection can be further reduced by using Neoral, i.e. the new microemulsion of CsA [4,5]. Two controlled trials compared FK with the old formulation of CsA and reported an incidence of rejection of 2428% with FK vs 4344% with CsA [6,7]. The combination of CsA with mycophenolate mofetil (MMF) yielded a reduction of the risk of acute rejection by more than 50% compared to CsA steroids/Aza or CsA steroids/placebo in three large multinational trials [8]. The prophylactic administration of anti-CD25 antibodies, basiliximab or daclizumab, in CsA-treated patients also reduced the number of acute rejections by about 30% in randomized studies [912]. Finally, the association CsArapamycin reduced the incidence of acute rejection to 7.5% in a series of 40 living mismatched kidney transplants [13]. We reviewed our own data of cadaveric renal transplants performed between January 1995 and December 1998. Only five of 248 cadaveric renal transplant recipients lost their allograft because of acute rejection. Three deaths and two non-viable kidneys accounted for other failures in the first year. This yielded an actual cadaveric kidney allograft survival of 96% at one year. All patients were treated with Neoral or Tacrolimus as basic immunosuppressive agent, often associated with MMF, anti-CD25 monoclonal antibodies or rapamycin.
It is our impression, therefore, that the frequency of acute rejection is decreasing progressively. Today it has become exceptional that it is the direct cause of graft failure. This success can be attributed in large part to the use of calcineurin inhibitors, although the combination with newer immunosuppressive drugs has certainly also played an important role.
Steroid-free immunosuppression
Today, the doses of steroids have been considerably reduced in comparison with the past. Yet corticosteroids are still mainly responsible for severe and life-threatening side effects in the short and long-term [14]. Several trials examined the safety of withdrawing steroids 612 months after renal transplantation. Steroid-related side effects, however, such as cardiovascular events, cataract, osteopenia, skin and Cushingoid changes often develop within the first year [15]. We think, therefore, that steroids should be stopped as early as possible in order to minimize their toxicity.
Calcineurin-inhibitors offer an unique opportunity to avoid steroids in a good proportion of patients at standard risk. In an Italian multicentre controlled trial, 354 cadaveric renal transplant recipients were randomly assigned to receive CsA alone, CsA plus steroids, or CsA plus steroids plus Aza. In spite of a higher number of acute rejections in patients without steroids, the 6-year graft survival rate, according to the intention-to-treat analysis, was 78% in monotherapy, vs 75% for triple therapy and 71% for double therapy [16]. Osteoskeletal complications, ocular complications, the frequency of hypercholesterolemia and cardiovascular complications were significantly lower in patients randomized to receive monotherapy with CsA [17]. In other studies, most patients treated with tacrolimus, either alone [18] or in combination with anti-thymocyte globulins and MMF [19], could stop steroids within a few weeks. The results were excellent. The association CsA-rapamycin allowed to stop corticosteroids in 25 of 32 recipients of a mismatched living kidney [13]. Finally, the data of the Collaborative Transplant Study showed that patients initially assigned to receive triple therapy who stopped corticosteroids at the end of the first post-transplantation year had the best 5-year kidney transplant survival when compared with patients who continued with post-transplantation steroids [20].
Thus, the use of calcineurin-inhibitors allows to withdraw corticosteroids in a large number of renal transplant recipients. This strategy offers the chance to reduce comorbidity with its adverse consequences on survival and the quality of life. It is reasonable to assume that the association of calcineurin inhibitors with newer immunosuppressive drugs allows the use of steroids to be avoided in a large proportion of patients.
Late graft failures
A number of factors influence long-term graft survival. Non-immunological factors such as advanced donor age and the poor donor kidney function have a deleterious effect on graft survival [21]. Nevertheless, compared to the past, improved management has improved results even for such borderline grafts [22]. Undoubtedly, however, the most important variable influencing the results in kidney transplantation is immunosuppressive therapy.
For many years, the UNOS registry reported that the cadaveric graft half-life did not change when comparing the periods before and after CsA [23]. This was interpreted to indicate progressive nephrotoxicity of CsA [24] or inability of CsA to prevent an ongoing subclinical immunological attack leading to irreversible chronic rejection. Recently, however, the UNOS kidney registry reported an improvement in cadaveric graft half-life, from 7.4 years of the Aza era [23] to 10.4 years for transplants performed between 19951996 [21], in spite of the more frequent use of marginal donors in the more recent period. Moreover, single-centre studies reported a graft half-life of 20 years or more in CsA-treated patients [25,26]. On the other hand, the role of chronic toxicity and chronic rejection as causes of late graft failure is probably lower than generally estimated. Although the mortality rate in renal transplant recipients is decreasing, death accounted for 48% of failure at 5 years in the UNOS registry [27]. Recurrence of primary renal disease is another important cause of late graft failure [28]. This aspect is often neglected by the large registries. Another 10% of late failures are accounted for by late ureteral stenosis or arterial stenosis. So, no more than one third of failures occurring beyond the first year after transplantation can be actually attributed to chronic rejection or chronicity toxicity. Which is the role of nephrotoxicity caused by CsA or FK in these late failures? Mihatsch et al. [29] reviewed the histology of 130 transplant nephrectomies in CsA-treated patients and found that only one graft loss could be attributed to CsA toxicity. The excellent graft half-life, 20 years or more, obtained by some groups [25,26] and the demonstration that creatinine clearance may remain stable over 1012 years in CsA-treated renal transplant patients [30,31] also show that the use of CsA does not inexorably lead to graft dysfunction. The Collaborative Transplant Study evaluated the 8-year graft survival in 31 915 first cadaveric kidney transplant recipients treated with CsA [32]. The worst results were observed in patients who received a mean CsA dose lower than 3 mg/kg/day or higher than 6 mg/kg/day. These data suggest that an insufficient administration of CsA exposes to chronic rejection and an excessive dosage may lead to progressive nephrotoxicity. It is reasonable to assume that the risk can be minimized by careful monitoring with appropriate dose adjustments. In this regard, we underline the importance of renal biopsy and measurement of blood levels of CsA. There is now evidence that CsA-arteriolopathy may be reversible if the dose of CsA is promptly reduced [33]. On the other hand, patients with large variations of the area-under-the curve of CsA are at high risk of chronic rejection [34]. The critical role of careful monitoring is also outlined by the extreme differences of results between centres [35].
Whether the association of calcineurin inhibitors with newer immunosuppressive drugs may allow to further improve the results of renal transplantation in the long-term is still unknown. Follow-up of the recent studies is still too short. Nevertheless, the reduction of the rate of acute rejection, yielded by combination of calcineurin inhibitors with newer drugs, could also permit to achieve lower rates of chronic rejection, although this remains conjectural. Moreover, the possibility of avoiding corticosteroids should permit reduction of iatrogenic morbidity and mortality from cardiovascular events and infections. Finally, the possibility of using calcineurin-inhibitors at lower doses should make it easier to handle CsA and FK, thus further reducing the risk of progressive nephrotoxicity.
Notes
Correspondence and offprint requests to: Claudio Ponticelli, MD, Divisione di Nefrologia e Dialisi, IRCCS Ospedale Maggiore di Milano, Via Commenda 15, I-20122 Milano, Italy.
References