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| Year : 2009 | Volume
: 20
| Issue : 2 | Page : 192-197 |
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| Transplantation: New protocols and new worries |
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Josep M Grinyo
Hospital Universitari de Bellvitge, University of Barcelona, Spain
Click here for correspondence address and email
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How to cite this article:
Grinyo JM. Transplantation: New protocols and new worries. Saudi J Kidney Dis Transpl 2009;20:192-7 |
In the era of the so-called conventional immunosuppression based on the use of azathioprine and steroids, short-term results of renal transplantation differed among centers with similar prophylactic regimens. The introduction of cyclosporine (CsA) globally reduced the incidence of acute rejection, the need for steroids, the prevalence of bacterial infections as well as improved one-year graft outcomes. However, the estimated graft half-lives only improved modestly, because of the permanent graft attrition in the long-term due to chronic allograft nephropathy, which may include distinct etiopathogenic entities. In the literature published over the last few years, there have been some discrepancies about the best methodology to be used in the evaluation of transplant results, which have raised concerns about the real assessment of the transplant programs. Data on estimated half-lives seem to provide too optimistic data about the impact of current practices on graft performance. The use of real halflives shows only a discrete increase in graft survival. Nevertheless, the current characteristics of donors and recipients should be taken into account, wherein there is increased use of extended criteria donors, especially in deceaseddonor based transplant programs in developed countries. Besides graft failure, transplant recipients also suffer from complications derived for pre-transplant clinical condition and de novo morbidity aggravated or induced by the use of immunosuppression. Major cardiovascular events, metabolic abnormalities and neoplasia are among the main causes of cumulative disabilities in transplant patients. Because of these limitations, the current immunosuppressive regimens are considered not to meet the ultimate needs of transplant population beyond low rates of acute rejection and shortterm graft survival.
These unmet needs have prompted the transplant community to address the so-called low toxicity regimens to attenuate recipient's comorbidity derived from adverse effects mainly related to steroids and calcineurin inhibitors (CNI). Steroids and CNI-sparing strategies have extensively been explored in the last decade. The major challenge of these approaches is how to properly balance the risk-benefit ratio, and how to evaluate it. These regimens might entail an increased risk and severity of acute rejection, subclinical rejection, as well as development of chronic rejection and ultimately graft loss, besides acquiring new toxicities of the drug combinations used.
The main questions that arise in steroid-sparing protocols are patient selection, the timing after transplantation and the concomitant immunosuppression. [1],[2] The risk factors for steroid withdrawal had been clearly identified in the first epoch of CNI. Younger age, renal function, race, sensitization and previous acute rejection episodes were the major determinants for successful withdrawal. Short-term evaluation of these protocols revealed to be insufficient considering that late graft failure occurred in the long-term after an apparently satisfactory initial transplant fate. [3] Because of these concerns, steroid withdrawal was not widely practiced. The introduction of mycophenolate mofetil (MMF) emphasized that in addition to the classical risk factors, the other immunosuppressants used played an important role in successful steroid withdrawal. [4] Initial conservative attempts explored the feasibility of late steroid discontinuation after three months following transplantation in patients treated with CNI and MMF in a multicenter European study. This manoeuvre was followed by a modest increase in rejection with an improvement of metabolic profile and with preserved renal function in the short-term. Induction was identified as a protective concomitant treatment. [5] A similar study in the USA had to be interrupted because of a high rate of failures due to the occurrence of rejection, although it was mainly observed in African-American patients. [6] In this population, steroid withdrawal using a potent sirolimus-tacrolimus drug combination also failed, which maintains the concerns on steroid withdrawal in black patients despite the use of potent new immunosuppressive regimens. [7] In contrast, some European investigators have reported more favorable outcomes with steroid withdrawal using m-TOR inhibitors and CNI. [8] In patients with a stable graft for more than six months after transplantation treated with MMF and CsA, we showed that steroids could be discontinued and that previous acute rejection and sensitization were the main risk factors for late graft loss, suggesting that steroid with drawal could be attempted in a relatively high proportion of patients treated with this drug combination. [9] Distinct analyses on steroid withdrawal have drawn some apparently discrepant conclusions. Some have shown an increased risk for acute rejection and no impact on patient and graft survival [10] whereas in another analysis from the Collaborative Transplant Study the authors concluded that steroid withdrawal was not followed by an increased risk for acute rejection and was associated with improved patient and graft survival. [11] The time after transplantation of discontinuation as well as the duration of follow-up may account for these discrepancies. Recent single center studies on late steroid discontinuation seem to indicate that this might be a beneficial strategy in stable patients. These positive results of steroid withdrawal in stable recipients have encouraged the transplant community to try early rapid steroid discontinuation with the help of biological agents. Due to the obvious benefits of steroid dose reduction in pediatric patients, these strategies were first explored in this transplant population. Induction therapies with polyclonal or monoclonal anti-IL2R antibodies seem to be necessary for an early and transient use or avoidance of steroids in renal transplantation. Polyclonal antibodies in conjunction with CNI, MMF or mTOR inhibitors may allow rapid steroid discontinuation in the first week after surgery, with an excellent graft and patient survival in the long-term. Rapid steroid elimination seems also feasible with anti-IL2R monoclonal antibodies, with acceptable rates of acute rejection and stable renal function at one-year after transplantation. [1] Very recently, the so-called Freedom Study [12] has been published comparing steroid avoidance, short use, or conventional use of steroids in patients receiving CsA, MMF and basiliximab induction. This study has shown an increased incidence of acute rejection in the two steroid sparing patient-groups. However, renal function, which was the primary end-point of this randomized study, did not significantly differ among the three therapeutic groups. In the majority of published trials, randomized and non-randomized, steroid sparing was associated with the expected reduction of metabolic complications and improvement of the cardiovascular risk profile. The ever-present question on an increased risk for more subclinical rejection and faster progression to chronic rejection in these kind of regimens remain open, especially in African American recipients. [13],[14] Despite these concerns, these regimens are being more accepted than in the last decade because of the expected benefits of steroids sparing strategies, [15] although many clinicians think that very low doses of maintenance steroids do not induce the well known complications of these drugs and may attenuate the risk of graft loss. The answer to these doubts will only be properly addressed after analyzing the extended follow-up data of the reported studies.
Renal allograft performance and transplant outcomes obtained with CNI-based immunosuppression have probably reached a plateau. New refinements in the last few years have apparently optimized renal function, attenuated CNI-related adverse effects and consolidated regimens widely used with slight variations among different centers. Triple therapies based on CNI, mycophenolic acid drugs, and steroids are the current standards in a vast majority of institutions. Despite the knowledge that CNI nephrotoxicity is almost inexorable in the longterm, attempts to minimize CNI are usually cautiously addressed, and they are more popular than CNI withdrawal or CNI avoidance. The balance between preventing immunologic allograft losses and the management of CNIrelated toxicities is still an issue in renal transplantation. CNI reduction or elimination may increase the risk of acute and chronic rejection. Because of these concerns, in most instances CNIs have been used at conventional doses in induction and maintenance therapy. However, historical reports from the early times of the CsA era showed that conversion from CsA to AZA at one-year after renal transplantation resulted in improvement in both blood pressure control and renal allograft function without significant adverse effects on long-term patient or graft survival, despite an increased incidence of acute rejection within the first few months after conversion. The introduction of MMF further enhanced CsA dose reduction and thus maintains renal function in stable patients. In patients with progressive deterioration of renal function, CNI minimization in conjunction with MMF is perceived as a safe regimen in maintenance immunosuppression, able in many instances to stabilize renal function without an increased risk of rejection. In induction therapy, the Symphony trial [16] has recently shown that the use of reduced doses of CNI may provide low rates of acute rejection and good graft function at one year, especially in patients treated with tacrolimus in comparison with those treated with CsA, although these functional differences might vanish in the long-term. In contrast, MMFbased CNI withdrawal therapies do not appear safe enough because of rejection occurrence of more than 10% in the majority of trials published. The same is true for complete avoidance of CNI in MMF-based regimens. In fact, the Symphony study resulted from successive failures in two consecutive trials trying to avoid or eliminate CsA in association with MMF and daclizumab induction. [17]
On the other hand, CNI withdrawal or avoidance seems more feasible with the use of mTOR inhibitors, which are generally considered more potent immunosuppressants than MMF. Meta-analysis on CNI withdrawal in CNI-treated recipients show a modest increase in the risk of rejection (less than 10%), a modest but significant improvement of renal function without an additional risk for graft loss. [18] Moreover, histological studies revealed that the elimination of CsA in SRL-treated recipients does not increase the risk of chronic rejection. Despite these data, CNI withdrawal is not routinely practiced in Europe. Interestingly, the EMEA authorized only a transient use of sirolimus and CsA, because this drug combination was considered overtly nephrotoxic. Conversion from CNI to mTOR inhibitors has been followed by variable success. [19] Conversion in cases with a significantly deteriorated renal function does not help to stabilize it. The levels of proteinuria and allograft histology have been also identified as good predictors for a successful conversion. [20] Thus, selection of appropriate candidates is crucial to get the benefits of CNI withdrawal with mTOR inhibitors. The increase of proteinuria noted following the conversion raises an intriguing question about the role of mTOR inhibitors on the development of this worrisome clinical sign. In distinct experimental models of proteinuria, sirolimus has shown opposite effects, protective in some instances and deleterious in others. On one hand, sirolimus might alter the glomerular capillary wall permeability and in this way increase proteinuria in some models, and on the other hand might have a protective effect in proteinuric models with or without associated renal inflammation.
CNI avoidance on patients receiving mTOR inhibitors has been used usually accompanied by MMF and induction therapy. In this regard, numerous single center experiences with antiIL2R monoclonal antibodies or polyclonals have shown better preservation of renal function. [21] A recent study from Egypt, [22] mainly in living donor transplantation, displayed that this approach may be feasible. In contrast, previous controlled multi-center studies were interrupted for safety reasons. A French multi-center trial [8] on the use of sirolimus and MMF even attempted CNI avoidance and steroid withdrawal, which was successfully achieved in more than 80% of the patients, but with higher proteinuria and higher percentage of discontinuations in MMF-sirolimus patients. In favour of this drug combination was the observed low incidence of cytomegalovirus infection.
All these recent data taken together suggest the relevance of defining the right target levels for mTOR inhibitors, and an adequate management of the overlapped toxicities of their use with antimetabolites. Low doses of tacrolimus and sirolimus for the first three months after transplantation may efficiently prevent the development of acute rejection and the subsequent elimination of the anticalcineurin macrolide, which is followed by improvement of allograft function. [23] This strategy might deserve further investigation. There is general consensus on the delayed use of mTOR inhibitors after transplantation to avoid woundhealing problems and to enhance the recovery of renal function in patients with delayed graft function. The Spare-the-Nephron trial [24] has explored the utility of a temporary use of CNI in association with MMF and a delayed conversion from CNI to sirolimus, in comparison with a permanent use of CNI-MMF. Data from this study appear highly promising at one-year after transplantation. The rates of acute rejection in both therapeutic arms were lower than 10%, with improved allograft function in the MMF-sirolimus group, which was tolerated in almost 80% of the patients.
Finally, co-stimulation blockade with second generation CTLA4Ig fusion proteins (LEA29Y), with a high avidity for CD86 and CD80 molecules, may help in the development of safe CNI-free regimens. In a phase II multi-center trial, [25] therapy with CsA, MMF, steroids plus basiliximab was compared to LEA29Y in conjunction with MMF, steroids and basiliximab. Both treatment arms had a similar low incidence of acute rejection (18% and 19%) at six months, lower incidence of chronic allograft nephropathy and a more favourable cardiovascular risk profile in the co-stimulation blockade arm without CsA. Whether this beneficial effect in the prevention of graft damage is due to the mere avoidance of CNI or to the immunomodulatory effects of co-stimulatory blockade needs further investigation. The novelty of using biological agents as maintenance immunosuppressants may raise concerns about the safety profile of these regimens in the long-term, which will need close followup. New phase III pivotal trials are in progress using a similar therapeutic schedule. Co-stimulatory blockade and ablative therapies might also allow exploring the feasibility of CNI and steroid-free therapies as a single regimen.
In summary, new immunosuppressive protocols have stimulated the transplant community to get the potential benefits of the increasing drug association possibilities to address the unmet needs in renal transplantation. At the same time, these new regimens are raising new worries that should be tackled with a gradual learning of their benefit-risk ratio and a better knowledge of the mechanistic properties of the new immunosuppressants.
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Correspondence Address:
Josep M Grinyo
University of Barcelona, Chief of Nephrology, Hospital Universitari de Bellvitge, Feixa Llarga, s/n.08907 Hospitalet de Ll. Barcelona
Spain
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PMID: 19237802 
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