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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2007  |  Volume : 18  |  Issue : 1  |  Page : 1-23
Calcineurin Inhibitor-Free Protocols: Risks and Benefits

Lebanese Institute for Renal Diseases (LIRD), Beirut, Lebanon

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The nephrotoxic and extra-renal adverse effects associated with calcineurin inhibitor (CNI) therapies appear to have a negative impact on long-term graft survival. Several CNI minimization protocols have been recently studied. These protocols involve either early CNI avoidance or CNI withdrawal. CNI withdrawal strategies are associated with a significant improvement in renal function and graft survival on both a short and long-term basis. Delayed and progressive withdrawal appears to be safer. Maintaining a high mycophenolate mofetil (MMF) or sirolimus (SIR) exposure minimizes the risk of acute rejection. CNI avoidance regimens using maintenance mono-therapy or combination therapies without induction appear to be immunologically risky and unsafe. In contrast, the combination of SIR + MMF with induction therapy reduces markedly the incidence of acute rejection and chronic allograft nephropathy (CAN). Two year patient and graft survival levels were comparable. CAN as well as the incidence and the risk for cancer in addition to blood pressure profiles and uric acid levels were overall lower in the SIR-based treatment. In contrast, hyperlipidemia, delayed wound healing, lymphocele, arthralgias, thrombocytopenia and study protocol deviations were reported more frequently in the SIR-maintenance protocols. Longer­term follow-ups are definitely needed to determine whether these avoidance strategies will result in a significant improvement in long-term patient and graft survival. Outcome differences among various protocols within the same CNI elimination strategy are probably related to study design, patient selection criteria, immunosuppression monitoring methods, indications for graft biopsies, environmental, and both genetic and ethnic factors. All monitoring techniques are unreliable short of a graft biopsy. Preliminary results on drug lymphocyte binding may offer new guidelines for tailoring immunosuppression. Whether these protocols based on SIR or SIR + MMF can also be extended to high risk patients is currently unknown. These encouraging results allow speculation but with caution that the use of the combination of non-nephrotoxic immunosuppression such as SIR and MMF, might change dramatically the natural course of CAN and may influence long-term patient survival.

Keywords: Calcineurin inhibitor elimination, chronic allograft nephropathy, immunosuppressive drug lymphocyte level monitoring

How to cite this article:
Barbari A G, Stephan A G, Masri M A. Calcineurin Inhibitor-Free Protocols: Risks and Benefits. Saudi J Kidney Dis Transpl 2007;18:1-23

How to cite this URL:
Barbari A G, Stephan A G, Masri M A. Calcineurin Inhibitor-Free Protocols: Risks and Benefits. Saudi J Kidney Dis Transpl [serial online] 2007 [cited 2020 Oct 24];18:1-23. Available from: https://www.sjkdt.org/text.asp?2007/18/1/1/31840

   Introduction Top

Kidney transplantation has been a major breakthrough in the treatment of end-stage renal disease by improving quality of life and patient survival.[1] Despite these great achievements, long term graft function is far from satisfactory. Calcineurin inhibitors (CNI), mainly cyclosporine A (CsA) have become the cornerstone of immunosuppre­ssion therapy since the early 1980s followed by tacrolimus (TAC) a decade later. Despite their contribution to the unque-stionable and substantial improvement in the one year survival rates for renal allografts from approximately 60 percent to nearly 80 to 90 percent, the long-term graft outcome however, has remained nearly unchanged. [2],[3] Death with a functioning graft and chronic allograft nephropathy (CAN) represent the main leading causes of the late loss of renal allograft, resulting in an annual rate of 3­5%.[3],[4],[5] Recent data reveal that nearly half of the grafts are lost to recipient's death [6] with cardiovascular diseases and diabetes mellitus being the leading causes of mortality, followed by infections and malignancies.[4],[7] Furthermore, the natural history of CAN, the other major cause of graft loss, has been recently well elucidated [8] and appears to have two major components; an immunological component that is predominant in the early post-transplant period and nephrotoxic, CNI-induced component, which starts at early post-transplantation to reach a prevalence of 100% over a 10-year period. The hypertensive, atherosclerotic, thrombotic, diabetogenic, hyperlipidemic, hyperuricemic, infectious, carcinogenic, nephrotoxic and other adverse effects associated with CNI therapy appear to have a major negative impact on long term graft survival.[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16] These observations have recently prompted a justifiable and serious interest in the search for new immunosuppression tailoring strate­gies, mainly steroids and CNI, that could preserve the safety of immunosuppressive agents (ISA) while maintaining their efficacy.[17],[18] Several CNI minimization protocols have been rigorously tested at different intervals in the post-transplant period ranging from the pre-operative time to several months and even to more than one year after transplantation. These studies included patients with stable renal allograft function and/or patients with chronic allograft dysfunction.[19],[20],[21],[22]

In this review, we discuss the most important CNI minimization strategies in the early post-transplant period and up to six to 12 months post-transplantation. These protocols involve either:

  1. an early complete CNI avoidance from azathioprine (AZA), myco­phenolate mofetil (MMF) or a combination of either sirolimus (SIR) and MMF or SIR-AZA-based maintenance regimens without or with anti-IL2 receptor antibodies (IL2R-Ab), anti-lymphocyte globulin (ALG), and anti-thymocyte globulin (ATG) induction therapy or
  2. CNI tapering or withdrawal from either AZA, MMF or SIR maintenance therapies mainly without induction treatment.

We will focus in this analysis, on the risks and benefits of these strategies and the current hurdles preventing clinicians from obtaining optimal beneficial effects on both patient and graft survival with these regimens.

   Immunosuppression minimization: Objectives and methods Top

Immunosuppression (IS) minimization, consists of the lowering of any ISA dosage or its complete elimination in order to maximally reduce its extra-immune adverse effects, while preserving an optimal immunosuppressive activity that can provide the best conditions for survival for the patient and the graft. Tailoring IS therapy through minimization could be achieved either through complete drug avoidance from the time of engraftment or through progressive drug dosage tapering, starting at any interval in the post-transplantation period that results either in the maintenance of minimal drug dosage, complete drug with­drawal, or the conversion to another ISA, [Figure - 1].

   Current early CNI elimination strategies Top

Several clinical trials were conducted and others are still ongoing, to evaluate the safety and the potential benefits of early CNI­minimization regimens. Two major strategies are currently adopted:

  1. CNI-sparing, as defined by the initial use, after transplantation, of a standard or low dose of CNI with a subsequent immediate or gradual tapering of the dose until a complete withdrawal of the ISA is achieved.
  2. CNI-avoidance, which consists of the utilization of immunosuppressive regimens that completely exclude the use of CNI. While CNI are tapered from either AZA, or one of the anti­proliferative ISA (MMF or SIR)-based maintenance regimens in the first strategy, they are completely avoided in the second one from AZA or MMF alone or a combination of SIR-AZA or SIR-MMF therapies.

These reported CNI-minimization regimens differ in a number of ways that should be carefully considered in both the evaluation and comparison of these protocols. These differences include:

  1. Type of study (randomized, controlled, prospective, open label, single arm, multi or single center, one or multiple continents).
  2. Patient selection criteria (high or low immunological risk status, race, ethnic background, type of kidney donors, graft function or rejection episodes prior to study entry).
  3. Immunosuppression regimens and type of induction therapies used, the timing of CNI minimization post-transplantation and the duration of tapering or with­drawal process, the concomitant usage of other ISA either alone or in combination with different classes of immuno­suppressive drugs.
  4. Immunosuppression monitoring metho­dology (either drug dosage or plasma or whole-blood concentration measure­ments using different pharma-cokinetic parameters.)
  5. Graft function monitoring, mainly by graft biopsy, according to clinical indication and occasionally through protocol biopsies.
  6. Follow-up time period (varying from 6 months to fifteen years post­transplantation).
  7. Definition of primary and secondary endpoints (graft and patient survival, serum creatinine (Scr), measured or calculated creatinine clearance (CrCl) or glomerular filtration rate (GFR), incidence of biopsy-proven acute rejection (BPAR) or chronic rejection (BPCR), prevalence of CAN and the number of lost grafts).
  8. Adverse effects (blood pressure, lipid metabolism, post-transplant diabetes mellitus, uric acid level, de novo malignancies, infection rates and types, and other adverse effects such as delay in wound healing and the formation of lymphocele.)
  9. The rate of patient discontinuation or drop out of protocols.

   CNI Sparing Strategies Top

1-CNI withdrawal regimens:

a - Withdrawal from AZA or MMF:

A variety of CNI, mainly CsA dis­continuation protocols from an AZA or MMF-based maintenance therapy, have been recently tested through a total of eight single or multi-center randomized control clinical trials with different numbers of patients ranging from 64 to 536 patients per study, [Table - 1]. [23],[24],[25],[26],[27],[28],[29],[30] Induction therapy was avoided in all but two studies where ATG [24] or IL2R-Ab (Daclizumab)[30] was used. CsA was with­ drawn from an AZA[23],[24],[25] or from MMF-based maintenance regimens. [25],[26],[27],[28],[29],[30] The initiation time of CNI elimination varied from 3-12 months post-transplantation and lasted for a time period ranging from a minimum of four days to a maximum of three months. Most studies included transplant recipients of kidneys from both cadaver and living donors who had stable graft function at study entry with the majority being regular immunological risk patients. Immuno­suppressive therapy monitoring relied on trough levels (C0) for CsA using different target concentration ranges. MMF and AZA were maintained at a fixed dosage of 2 g and 2 mg/Kg per day, respectively. Graft biopsies were performed according to clinical indication. The follow-up time ranged from 6 to 24 months for most of the studies[25],[26],[27],[28],[30] and 5 to 15 years for the three remaining ones.[23],[24],[29] There were no significant differences in patient or graft survival in most of the trials except in the two most extended studies over15 years,[23],[24] where graft survival tended to be higher in the withdrawal groups (76% and 70% vs. 64% and 51% respectively). Moreover, patients who were converted to AZA in the Australian study experienced the lowest graft loss (33/165) as compared to the CsA­maintenance group (58/166). These differences became even more significant when death and graft loss within the first year post-transplantation was censored. In addition, the relative risk of CAN was significantly higher in patients maintained on CsA, and the incidence of CAN was lower in patients with AZA (28% vs. 62%). These findings suggest a role of long-term CsA nephrotoxicity in the development of CAN. In contrast, the CAEZAR study has shown higher graft loss in the CsA-withdrawal group within the first year after transplantation, when the risk for acute rejection is high. Renal graft function defined by Scr, CrCl and or GFR was either similar between groups in the study of Smak[27] or noticeably better in the CsA-elimination group in most trials,[23],[24],[25],[26],[28],[29] except in the CAEZAR study where kidney recipients withdrawn to MMF exhibited significantly lower GFR at 18 months than those who were maintained on a lower CsA dosage. This was paralleled by a higher rate of BPAR (40%) and graft loss (14/179) as compared to the low dose CsA group (29.4% and 6/183), respectively. Interestingly, an overall improvement in renal function was observed despite a strikingly higher rate of BPAR ranging from 11-40% in the CsA­withdrawal recipients. This has resulted in an obvious increase in the number of patients with BPCR 24, 27 and graft loss in particular, in the two most recent trials.[29],[30] The incidence of BPAR was even greater in patients withdrawn to AZA (36%) as compared to those who were withdrawn to MMF (12%).[25] There were no significant differences in infection or malignancy rates among study groups.[25],[27] Blood pressure and lipid profiles were better in the dis­continuation groups in some studies[26],[27] and similar between the groups in others. [28],[29]

In summary, the most evident benefit of CsA withdrawal from an AZA or from MMF-based maintenance regimens is a significant improvement in graft function related to the elimination of the short and long-term nephrotoxic adverse effect of CsA. This beneficial effect was blunted by an increased risk for BPAR, BPCR and graft loss, caused by the immunosuppression lowering effect that results from CNI disconti­nuation in the early post-transplant period, mainly in high immunological risk patients. This could explain the lack of translation of this amelioration in renal function into better graft survival in the short-term. Moreover, unlike the study from Bakker[23] and Gallagher[24] with the longest ever post­transplant follow-up (15 years), most of these trials did not exceed the two year time period. This may reconcile the observed differences between these two extended studies and the remaining ones in relation to greater graft survival in the CsA­withdrawal regimens. In the Australian study, the divergence in graft survival curves was most pronounced after eight years post­transplantation. Patients receiving long-term CsA therapies had higher Scr values and more episodes of deterioration in graft function and higher incidence of CAN, thereby reflecting the major negative effect of CsA-induced nephrotoxicity[8] on long­term graft survival. In the CAEZAR study,[30] CsA-free patients with low exposure to MMF determined by the measurement of the area under the curve (AUC) of Mycophenolic Acid (MPA) (< 30-40 h* µg/ml) were at an increased risk to develop BPAR.[31] In contrast, this risk for acute rejection was similar among groups of those patients with high AUC (>60-70 h* µg/ml). Furthermore, the incidence of BPAR was higher in the AZA withdrawal group as compared to the MMF one,[25] which is known to be a more potent ISA than AZA. All taken into consideration, this seems to suggest that CsA withdrawal could be safely achieved in low immuno­logical risk patients mainly from MMF, which is known to have, in addition to its immuno­suppressive potency and low adverse effects profile, a beneficial effect on CAN.[22] CsA elimination should be undertaken gradually, after the third month post-transplantation[23],[24] and preferably between six months and one year where the risk for acute rejection is low, and over a period of two to three months.[8] High exposure to MMF (MPA AUC > 60-70 h* µg/ml or 2g-MMF daily dosage) should be maintained in these patients in order to minimize the risk for acute rejection. Graft biopsy remains the gold standard for immunosuppression therapy monitoring.

b- Withdrawal from Sirolimus:

Five clinical trials were conducted to assess CNI elimination from SIR; [32],[33],[34],[35],[36] two major multi continental,[32],[33] two multi-center, one English[34] and another Spanish,[35] and one small Italian single-center study.[36] Six sub­ studies [37],[38],[39],[40],[41],[42] from the most important trial,[32] the Rapamune Maintenance Regimen Study Group (RMR), have been recently published, [Table - 2]. The number of patients enrolled in these studies varied from 40 to 525 patients per study. No induction therapy was used in any of these trials. CsA was withdrawn in 4 trials[32],[33],[34],[36] between the second and third month post-transplant either immediately[36] or during a time period from 4-8 weeks. TAC was discontinued at the third month and over an average period of 6 weeks.[35] Three studies included only recipients of deceased kidneys[33],[35],[36] with mixed HLA mismatches in one[33] and nearly 50% of graft dysfunction in the other.[36] The remaining two studies [32],[34] involved recipients of mixed deceased and living donors with stable renal function. Immunosuppressive protocols were quite comparable. A key difference in the English (CsA)[34] and the Spanish (TAC)[35] studies was a nearly 40% reduction in the target whole­blood C0 of SIR used for the maintenance phase after CNI elimination (8-16 ng/ml) instead of 15-25 ng/ml in the RMR study group.[32] Furthermore, a concentration­controlled SIR at 8-16 ng/ml was applied in both CsA and TAC minimization arms as opposed to a 2 mg fixed SIR dose in combination with moderately reduced CsA C0 levels, as in the other studies. Moreover, only patients who were free of acute rejection in the preceding three weeks prior to randomization were tapered off CsA in the Spanish[35] and the US-European CNI-sparing trials.[33] Immuno­suppression therapy monitoring relied on CsA, TAC and SIR whole-blood C0 measurements using different ranges of maintenance target levels varying from 50­250 ng/ml for CsA, 5-12 ng/ml for TAC and from 8-30 ng/ml for SIR therapy. Graft biopsies were performed according to clinical indications in all but one study[36] where in addition, grafted kidneys underwent baseline biopsies at engraftment and at 12 months post-transplantation. The follow-up time (6 to12 months) was rather short for all the studies except for the tri-continental trial[32] where the results of four and five year follow-ups have been recently reported.[40],[41],[42] Patient and graft survival were comparable within the first year post­transplant in all five studies. In the RMR trial, the divergence in graft outcome curves toward greater survival in the CsA­elimination regimen became evident at 24 months post- transplantation and statistic­cally significant after the third year.[38],40] Moreover, death censored graft loss after 4 years follow-up, was 3-fold higher in CsA­maintenance patient groups irrespective of the level of the calculated GFR.[41] It ranged from 21.2% to 7.7% in the first quartile (GFRD445 ml/min) and from 5.5% to 1.9% in the fourth quartile (>67 ml/min) in CNI-continuation as compared to the CNI-free group, respectively. The incidence of death decreased with increasing baseline GFR without reaching statistical significance between treatment groups. The incidence of BPAR varied between studies. It was comparable between the different therapy regimens (10% to 11%) in both the Spanish (after protocol amendment) and the Italian studies, [35],[36] and 3% after randomization in the English trial. [34] In the remaining two multi-continental trials, [32],[33] higher rates of first biopsy-proven acute rejection were reported in the CsA­withdrawal groups at one and five years in the former (13.5% vs 20% and 15.8% vs 20.5%, respectively) and at one year post­transplantation (18.6% vs 22%) in the latter. These differences did not reach statistical significance. The relatively higher percentage of BPAR observed in the US-European Sparing Trial[33] in comparison to the RMR study [32] despite design similarity, may be explained by the difference in recipient selection criteria. While recipients of a mixture of graft sources from both deceased and living donors were enrolled in the RMR trial; the US-European study involved exclusively recipients of deceased grafts with a high number of significant HLA­mismatches and 20% of black recipients. Interestingly, the lowest rate of acute rejection was reported in the study of Baloolal [34] with the lowest CsA and SIR­maintenance group blood C0 levels. Despite this modest but statistically insignificant increase in acute rejection in CsA elimination regimens that was reported in the two major trials, [32], [33] all trials demonstrated a marked early improvement in renal function starting at 6 months post-transplant, which was maintained up to the maximum follow­up period of 4 years [40], [41] as reported recently by the RMR study group. This was paralleled not only by a lower prevalence of CAN and a lesser severity of the histological lesions, [36],[39] but also by a significant amelioration at one year post­transplant in the baseline chronic lesions that existed at engraftments in the SIR treated group. This is probably responsible for the strikingly higher graft survival levels beyond the third post-transplant year. Recently published in-vitro and in-vivo data on SIR, regarding the pronounced inhibition of anti-smooth muscle cell (SMC) proliferation, [43] the significant suppressive effect on the platelet derived growth factor (PDGF) [44] and the marked prevention of luminal narrowing in both arterial allograft and balloon-injured carotid arteries of non human primates [45],[46],[47] seem to support these beneficial clinical findings. Furthermore, SIR therapy alone after early CsA withdrawal reduced significantly the risk for both cutaneous and non-cutaneous carcinomas after a follow-up period of 4 years and beyond, as compared to that including a combination of CsA and SIR, as was recently reported by Oberbauer, Campistol and their co-workers in the RMR study group. [41], [42] With regard to any skin malignancy, there were fewer lesions and lower annualized rates with CsA withdrawal. Moreover, the median time for any skin malignancies was significantly delayed in the SIR-only maintenance regimen. For non-skin malignancies the difference between treat­ment groups approached statistical significance in the on-therapy analysis (8.4 vs. 3.7%, P = 0.043) and it was significantly different in favor of the SIR­only therapy group for the intention to treat analysis (9.6% vs. 4%, P = 0.032). This could be explained by the recent experimental and clinical evidence that SIR can reduce or halt tumor growth and metastases that are accelerated by CNI, and also decreases the incidence of malignancy even in the presence of either CsA or TAC. [48],[49],[50],[51] Mammalian target of rapamycin (mTOR) inhibitors with or without CNI appear to reduce the relative risk for a de novo malignancy. Additional beneficial effects in the CsA-discontinuation regimens included lower means of BP measurements, lower percentage of hypertensive patients, less anti-hypertensive drug prescriptions in most studies and lower means of uric acid levels in the tri-continental trial. [32] Lipid profiles were overall comparable between therapeutic groups in most of the studies except the ones from the two Mediterranean countries, Spain and Italy, [35], [36] where the SIR-only treated patients showed increased hyper­lipidemia mainly after the fourth month post­transplant, when SIR dosages were increased after CsA withdrawal, with similar or higher percentage of patients utilizing lipid­lowering drugs. Other adverse events such as thrombocytopenia, arthralgias, edemas, delays in wound healing and lymphocele were more frequent in the SIR-only maintenance regimen. Protocol disconti­nuation was reported in the RMR study group to be significantly more frequent in the CsA­maintenance group at 2 (48% vs. 38%) and 4 years (60.9% vs. 44.2%) post-transplantation. [38],[40] In contrast, a similar rate of patient drop­out of study protocol at 1 year (41% vs. 18%) was reported in the CNI-free group in the Spanish trial. [35] The main reason for discontinuation in both studies was adverse events. Patients in the CNI-maintenance groups had significantly higher incidences of increased creatinine.

In summary, these findings suggest that early, gradual and complete withdrawal of CNI from SIR appears to be a safe, effective and beneficial immunosuppressive regimen regardless of baseline renal function. It slows significantly the deterioration in graft function, reduces the prevalence and the severity of the histological lesions associated with CAN and improves markedly graft survival beyond the third post­transplantation year despite a modest but statistically insignificant increase in the incidence of BPAR that occurs pre­dominantly within the first 6 months after engraftment. Moreover, it decreases noticeably the incidence of cancer, a major cause of graft loss in kidney transplant recipients with a functioning graft [4] and ameliorates BP profile. This therapeutic strategy could be applied preferably in low immunological risk patients with clinical and histological evidence of CNI-induced nephrotoxicity in the absence of acute or chronic rejection on graft biopsy and in the high cancer risk recipient. It should be avoided mainly in the high metabolic risk patient with either a strong personal or familial history of lipid metabolism disorders. CNI elimination may be initiated between 3 and 6 months post-transplantation after the adaptation period, when the risk for acute rejection is minimal, and continued gradually over a time period of 2 to 3 months. SIR target C0 level should be maintained between 8 to15 ng/ml. [34] Given the poor correlation between SIR blood levels and acute rejection, [52],[53] graft biopsy remains the gold standard in guiding the adjustment of immunosuppressive therapy. Longer term follow-up and additional studies are needed to confirm these promising results.

2-CNI avoidance regimens:

pA total of twelve trials were conducted to evaluate the efficacy and the safety of CNI avoidance in the immediate post-transplant eriod in kidney allograft recipients, [Table - 3]. [53],[54],[55],[56],[57],[58],[59],[60],[61],[62],[63],[64] Three studies were multi center [53],[54], [56] and nine were single center. [55], [57],[58],[59],[60],[61],[62],[63],[64] Eight trials were randomized controlled, [53], [54], [57], [58], [60],[62],[63],[64].four prospective open label non-randomized, two of which are single arm [55],[56] with the remaining two being double arm. [59],[61] Cyclosporine A was avoided in seven studies and TAC in three. CNI-free protocols used an AZA-based maintenance therapy in the French trial [64] with the longest follow-up time ever (12 years), a MMF-based maintenance protocol in 3 studies, [55], [56], [63] and a combination of either AZA-SIR [53] or MMF­SIR in the remaining studies. [54], [57],[58],[59],[60],[61],[62] The number of patients per study varied from 45­60. Induction therapy was used in all but 2 trials. [53], [54] It included ALG, [64] ATG, [58], [59],[61],[62] IL2 R-Ab-Daclizumab [55], [56], [63] and IL2 R-Ab­Basiliximab. [57],[60], [61] Six studies included mainly low risk recipients of only cadaveric renal allograft and six others, recipients of kidneys from both cadaver and living donors. Immunosuppressive protocols were quite different in the use or not of induction therapies and its type, in the class of ISA used for the maintenance therapy in the form of either mono or double therapy, in the way of monitoring immunosuppressive therapy that relied on either fixed or different dosages of the immunosuppressive drug or on whole-blood C0 level using a variety of target levels at different times post-transplant, and in the performance of graft biopsies according to pre-scheduled protocol biopsies starting at engraftment and repeated at specific intervals after transplantation, or to clinical indications. The follow-up time was rather short (6 to 24 months) in all but one study, the French trial [64] where the results were reported over 12 years. Overall, both patient and graft survival was comparable between the CNI­free and the CNI-maintenance regimens irrespective of the short or long-term follow-up period. As expected, survival rates were inversely related to the trial duration. In the study of Asberg, [63] one year graft survival was particularly lower than expected (89%) in the MMF group, due to the unacceptably high rate of BPAR (70%), the highest among all studies. This has led to a significant number of graft losses and hence the premature discontinuation of the trial. The rates of BPAR varied markedly from a low of 6 % to a high of 70%. The use of CNI-free mono therapy (AZA or MMF)­based maintenance regimens [55], [56], [63], [64] and the avoidance of induction therapies despite a SIR-based maintenance double therapy with either AZA [53] or MMF [54] were major determinants in this significant increase in the incidence of first BPAR ranging between 27% and 70%. The highest rates of acute rejection (38%, 53%, 56% and 70.3%) were reported in the four trials [53], [54], [62], [61] respectively, using mono therapy-based protocols in combination with induction therapy mainly with the IL2 R­Ab-Daclizumab as compared to the SIR­based combination regimens with either AZA (41%) or MMF (27.5%), but without induction treatments. The observed variations among studies in the rate of BPAR (38%, 53% and 70%) within the same MMF-based maintenance regimens may be related to differences in patient selection criteria, drug dosage, immunosuppression monitoring and approaches to graft biopsies. The lower incidence of acute rejection reported in the induction-free SIR-MMF (27.5%) protocol [54] as compared to that (41%) of the induction­free SIR-AZA [53] could be explained by the greater immunosuppressive potency of MMF in relation to AZA and the higher SIR dosages and blood trough levels that were used in the SIR-MMF combination group. This noticeable reduction in the rate of BPAR was negated by the marked increase in patients drop out (43%) due to adverse events. More recent CNI avoidance protocols involving a combination of SIR­MMF based maintenance regimen with induction therapy either with ATG or IL2 R­ Ab Basiliximab [57],[58],[59],[60],[61],[62] have been rigorously tested. In most of these studies, [57],[58],[59],[60],[61] the incidence of BPAR was strikingly low and similar, below the 10% range (6.4% to 8.8%) in the SIR-MMF groups irrespective of the type of induction used and the CNI avoided; whether it was CsA [57], [60] or TAC in a standard [58] or low dose. [59] Moreover, CNI-free therapy patients exhibited either comparable or lower rates of BPAR as compared to their counterparts in CNI-based maintenance regimens either with TAC [58], [59], [62] or CsA, [57], [60] respectively. This is due to the fact that TAC-MMF-based protocols are more immunologically potent and were associated with lower rates of BPAR when compared to the CsA-MMF combination. These differences, although noticeable, were statistically insignificant. Interestingly, the incidence of BPAR was above 10 % in the 2 studies where MMF was used in lower dosages than the 2g per day used in the remaining 4 studies [57],[58],[59],[60] of either 1g daily [61] adjusted in order to maintain MPA C0 levels between 1.8 - 4 µg/ml, or 1.5 g per day fixed dose adjusted in case of side effects. [62] These findings are in agreement with those of other investigators and our own observations, [54], [65],[66],[67],[68],[69],[70] namely that MPA C0 levels are an unreliable immuno­suppression efficacy monitoring tool of MMF therapy. It correlates poorly with acute rejection and decreasing daily dosage of MMF below 1.5 g may increase the risk for rejection. This was obvious in the study of Fleshner [61] in which a SIR-MMF (2g) arm was compared to a SIR-MMF (1g) arm. Patients treated with the 1g-MMF daily regimen experienced higher incidences of BPAR than those treated with 2g-MMF per day (13% vs. 8.8%, respectively). Both groups had comparable demographic and clinical characteristics, SIR dosages and C0 blood levels at several intervals post­transplantation. Mean MPA C0 levels were within therapeutic ranges in both groups although, slightly but insigni-ficantly higher in the 2g-MMF group. The main observed striking difference was in the mean MMF daily dosage that was persistently around 1 g per day in the 1g-MMF group and above 1.5 g per day in the 2g-MMF arm during the first 6 month follow-up period. These differences in MMF dosage among the 2 groups varied between a minimum of nearly 40% at 6 months to a maximum of 80-90% during the first month post-transplantation. Renal function was shown in most studies [53], [54], [57], [59], [60], [64] to be markedly superior in the CNI-free regimens than in those with CNI-based maintenance therapies, mainly CsA. This was reflected by either significantly lower Scr or higher GFR at different post-transplantation time intervals during a follow-up period of 2 years. In the French study [63] with the longest follow-up, there was a trend toward better renal function in the AZA-based CNI-avoidance regimen at 12 years post-transplantation. The difference became highly significant when Scr at 12 years were compared in rejection-free patients who were still receiving the initial treatment assigned at randomization (121±43 vs. 168.5±76 µmol/l, P = 0.006). In the two single arms of MMF-based trials from Tran and Vincenti, [55], [56] CNI were added after the first rejection episode or because of side effects. The one year mean Scr was lower among patients who were free of rejection and CNI use than among those who experienced rejection and / or were on CNI. These observations confirm the nephrotoxic adverse effect associated with the long term use of CsA. The 2-year mean level of renal function was similar among groups or greater in the CNI-avoidance regimens comparing SIR-MMF to either standard [58], [62] or low dose [59] TAC-MMF-based maintenance regimens, respectively, under the same induction treat-ment with ATG. These interesting obser-vations seem to suggest that standard dose TAC-MMF therapy offers greater renal protection than standard CsA-MMF treatments as compared to SIR-MMF-avoidance treatments, at least in the early post­transplant period. This could be explained by the fact that the combination TAC-MMF has been shown to reduce or eliminate sub­clinical rejections and decrease tubulointerstitial damage, a major early immunological component of CAN during the first post-transplantation year. [8],[71],[72] This is in contrast to CsA (less potent ISA) which increases chronic interstitial fibrosis. [8], [73], [74], [75] These findings are supported by the lower level of renal function reported in the reduced TAC dose [59] that was associated with a markedly higher incidence of CAN on 3 month protocol biopsies (53%) as compared to the SIR-MMF based avoidance regimen (15%). This is probably related to the reduced level of immunosuppression in the low TAC arm. Although sub-clinical acute rejection occurs less frequently in TAC-treated patients [71], [72] than in those on CsA; the total chronic score and the prevalence of CAN does not differ between groups (38.8% in CsA vs. 34.6% in TAC). [71] These findings are explained by micro vascular lesions and glomerular injuries induced by CNI therapies, which characterize the later phase of CAN. [8], [72] These vascular lesions (i.e. arterial hyalinosis, ischemic glomerulo­sclerosis) in addition to tubulointerstitial damage, represent the hallmark of CNI nephrotoxicity, and usually occur after one year and increase in frequency and severity thereafter. They appear to be implicated in late permanent injury and their prevalence reaches nearly 100% at 10 years. These observations are in agreement with the strikingly higher prevalence of CAN and chronic vascular lesions described on protocol biopsies in CNI-MMF treated patients by Lo, [59] Fleshner [60] and Larson [62] at 3 and 24 months (53% vs. 15% and 79.2% vs.34.4%) for the CAN and at 2 years for chronic vascular lesions (43% vs. 26%), respectively. This lower prevalence of CAN in avoidance regimens is related to the down regulation by SIR of pro-inflammatory and profibrotic genes responsible for the progression of CAN [60] as well as to its inhibitory effect on SMC proliferation, PDGF and its prevention of allograft arterial lumen narrowing. [42],[43],[44],[45],[46] The rate of malignancies at 12 years [64] was reported to be lower in the CNI- free AZA-based group (2.3% vs.17%). Patients on SIR therapy experienced more Herpes simplex viral infections and pneumonia in some, but not all studies. BP profile was either similar among groups or lower in CNI-free regimens. Overall, the percentage of de novo hyperlipidemic patients were either comparable between groups or greater in the SIR-maintenance group leading to a higher number of prescriptions of lipid lowering agents. Uric acid levels were mainly lower in the SIR-treated patients. Higher rates of protocol discontinuation ranging from 17% to 43% were reported mainly in the SIR regimens. These protocol drop-outs were related predominantly to adverse effects specific to SIR. The highest rate of study withdrawal was reported by Asberg[63] in the CNI-free, MMF-based regimen, because of a very high one year incidence of BPAR (70%) and poorer graft survival, leading to a premature disconti­nuation of the study.

In summary, these findings indicate that complete CNI avoidance using preferably a combination of two antiproliferative ISA, SIR and MMF, in association with anti­IL2R antibodies or ATG induction therapy seems to be a safe and effective therapeutic alternative to CNI-based regimens in renal transplantation. It appears to be the most immunosuppressive in comparison to other CNI-free protocols using a mono or double therapy with or without induction treatment. It provides a remarkable reduction in the incidence of BPAR by two to five fold when compared to the other avoidance protocols, and either similar or greater protection against acute rejection as compared to CNI-based regimens irrespective of the type of CNI and induction therapy used. Moreover, it decreases markedly the prevalence of CAN and slows the progression of its early tubulointerstitial and late microvascular components in the post-transplant course, by down regulating the pro-inflammatory and profibrotic genes, thereby reducing the risk for allograft vasculopathy. These renoprotective mechanisms explain the higher level of renal function. The short follow-up period in these trials may explain the lack of translation of these important beneficial effects into better graft survival in the CNI-free regimens. Additional benefits include lower long term cancer rates, better BP profiles and lower uric acid levels. Unfortunately, SIR-based therapies may be associated with several serious adverse events such as pneumonias, arthralgias, infections, severe hyperlipidemia mainly hypertriglyceridemia that counteract its beneficial effects, and hence may lead to the discontinuation of therapies in a sizeable percentage of recipients. Ethnic and genetic backgrounds play a major role in drugs metabolism, efficacy and toxicity and therefore, should be considered in all CNI minimization protocols. These negative side effects are probably genetically and ethnically related and could be potentiated by environmental factors such as food and drug interactions. [65], [76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86] Although target C0 levels differed among studies, it would be reasonable to maintain SIR C0 levels between 8-15 ng/ml and 5-10 ng/ml during and after the first six months post­transplantation, respectively, in combination with 2g MMF (if well tolerated). In order to maintain high drug exposure in the immediate post-transplantation period, a loading dose of SIR at day one followed by a mean maintenance dose of 3 mg per day to target HPLC levels of 8-16 ng/ml is recommended.[38],[87],[88] Given the poor correlation between SIR blood levels and clinical outcomes, [52], [53] graft biopsy and preferably protocol biopsies should remain the gold standard for immunosuppressive therapy monitoring. Longer term follow-up is needed to confirm these interesting observations and to assess whether these beneficial short-term findings will result in a significant improvement in long-term patient and graft survival.

   What are the hurdles? Top

The lack of a reliable immune response assay has been a major set back in guiding clinicians in the monitoring of the immune system. In fact, the clinical relevance of most of the monitoring techniques for CsA therapy and other ISA in solid organ transplantation remains an important controversy, despite the enormous amount of literature published over the last two decades. [89],[90],[91],[92],[93] Unfortunately, all of the currently used non-invasive therapeutic monitoring techniques (pharmacokinetics) are unreliable short of graft biopsies. [53],[65],[94],[95],[96] Monitoring immunosuppression therapy efficacy in most of CNI minimization trials depended mainly on target drug blood levels measurements, which differed among trials and among immunosuppressive protocols within each trial. Moreover, renal function surveillance relied mainly on graft biopsies performed according to clinical indication. In a few studies, fixed drug dosage and protocol graft biopsies were adopted as monitoring tools. The indication for graft biopsy as well as its interpretation varied among different transplant centers. In addition to the above mentioned diffi­culties in monitoring of both the immune status and graft function, the identification of the ideal low risk recipient represents one of the major obstacles for any immuno­uppression minimization, due to the lack of an immunological assay that can predict the immune response. The definition of low risk patients varied in between protocols. We and others have shown a weak correlation between drug blood levels, clinical outcome and immune response. [65],[66],[67], [91], [94],[95],[96],[97],[98],[99]

We have recently established that in contrast to blood levels, drug lymphocyte levels exhibit a strong association with therapeutic efficacy in relation to clinical outcome, mainly acute rejection and immune responsiveness [95], [96], [99] and hence may offer a new reliable alternative for CNI and other ISA minimization. [ 100] This discordance between bioavailability (drug blood level) and bioactivity ( lymphocyte drug content) is mainly related to the weak association between drug blood level and target cell content and tissue concentration, as we and others have demonstrated recently. [94],[95],[96],[97],[98],[99], [101] These variations are mainly related to genetic, ethnic and environmental parameters such as age, gender, body mass index, organ function, food, drugs interaction and availability of extra target cell binding sites. [78], [86], [102] Any redistribution of the drug between the different binding sites will ultimately affect its bioactivity without any change in its bioavailability. [95],[103],[104],[105],[106] It explains the intra and inter-individual varia­bility in therapeutic response and adverse reactions. It is currently estimated that genetic factors account for nearly half of the individual variations in the efficacy and toxicity of drugs. [76], [77], [82], [83] This could explain the differences despite similarities in study designs, in the reported incidences of BPAR in the CNI-sparing groups between the tri and the bi-continental trials, [32], [33] and the higher incidence of hyperlipidemia and the usage of lipid lowering agents in the SIR­maintenance groups that were observed mainly in the two studies that were conducted in two Mediterranean countries, Spain and Italy. [35], [36] These findings are in agreement with our own observations [52] on the relatively high rate of adverse events, mainly mixed hyperlipidemia, in our SIR­treated patients. Given the importance of these genetic parameters and their significant potential impact on outcome, it becomes essential to account for them in the design of future trials, using the newly emerging disciplines of pharmacogenetics and pharma­ cogenomics. [76], [77], [83] This should also warrant caution against any universal recommend­dations based on studies conducted in a specific geographic area or in a precise population with a particular ethnic background. Conducting similar studies in different areas of the world becomes therefore, an absolute necessity in the current era of applied clinical practice according to evidence-based medicine.

In conclusion, it is well established that CNI play an important role in preventing acute rejection and graft dysfunction. However, they are major contributors to the non-immunological, nephrotoxic late component of CAN that starts early in post­transplantation and to a variety of extra­renal adverse effects, which explains the very modest and insignificant improvement in long-term graft and patient outcome over the last two decades. This has prompted recently the emergence of several CNI elimination protocols that have been rigorously tested. They appear to gain an important support in the transplant community. CNI withdrawal strategies are associated with a significant improvement in renal function and graft survival on both a short and long-term basis, occurring beyond the third year and the eighth year for SIR and AZA maintenance therapies, respectively, despite the increased risk of acute rejection. The highest and lowest rates of BPAR were reported in the AZA-based and SIR-based regimens, respectively. Delayed and progressive withdrawal over two to three months time period between the third and sixth and preferably beyond the sixth month post-transplantation after the adap­tation phase appears to be safer. All CNI withdrawal trials from MMF-maintenance therapies were associated with a relatively greater incidence of acute rejection and high rate of chronic rejection and graft loss in some, in the first 2 years post-transplantation, as compared to SIR-based regimens. Main­taining an adequately high MMF or SIR exposure in CNI-free patients (MPA > 60­ 70 h* µg/ml and/or MMF daily dose > 1.5 g and SIR C0 level of 8-15 ng/ml and or daily SIR dose > 3mg) respectively, could minimize the risk for acute rejection. In the CNI-avoidance strategies, all but one trial [64] were short-term and did not exceed a two year follow-up period. Patient and graft survival were comparable between the CNI­free and CNI maintenance regimens in all of these trials except in the longest term (12 years) and the only avoidance study using [64] AZA-based maintenance with ATG-induction therapy. This French study reported superior renal function mainly in the non-rejecting patients as compared to those treated with long-term CsA-maintenance treatments with a trend toward better graft survival, despite a 56% incidence of acute rejection. This highlights the negative impact of chronic CsA nephrotoxicity on graft function. Avoidance regimens using maintenance monotherapy with induction treatment or combination therapy without induction are associated with an overall superior graft function but with an unacceptable increased rate, even in low risk recipients of BPAR and worse graft function in one study, [63] leading to its premature discontinuation. These avoidance regimens appear to be immunologically risky and unsafe and therefore should be completely abandoned in organ transplantation. In contrast, the use of a combination of anti-proliferative ISA (SIR and MMF) in association with any type of induction therapy seems to be promising. It provides a major positive impact on reducing markedly the incidence of acute rejection and CAN and hence, on the resulting significant improvement in renal function as compared to all CNI-maintenance regimens except those using the standard TAC maintenance dose where both renal function and rejection rates were similar.

The prevalence of CAN as well as the incidence and the risk for cancer when reported were always lower in SIR-based maintenance therapies irrespective of the CNI-elimination strategy, and the type and the dose of calcineurin antagonist used. Moreover, Blood pressure profiles and uric acid levels were overall lower in the CNI­free regimens. These beneficial effects highlight the potential beneficial role of SIR on both patient and graft survival. In contrast, hyperlipidemia, delayed wound healing, lymphocele, arthralgias, thrombocytopenia and study protocol deviations were reported more frequently in the SIR-maintenance protocols.

Outcome differences observed among various protocols within the same CNI elimination strategy are multifactorial and probably related to study design, patient selection criteria, immunosuppression monitoring methods, indications for graft biopsies, environmental and both genetic and ethnic factors. Given their potential impact on patient and graft outcome, these parameters should be accounted for in the design of future CNI elimination trials.

Preliminary results on lymphocyte drug binding may offer new guidelines for tailoring immunosuppression. These findings, however, require further validation with larger scale multi-center studies. Longer-term follow-ups are definitely needed to determine whether these avoidance strategies, mainly the combination SIR-MMF-based maintenance regimens with their established important short-term risks and benefits, will result in significant improvements in long-term patient and graft survival. Recent evidence suggests that TAC-based therapy in combination with either MMF or SIR is associated with significantly lower incidences of acute rejection compared with CsA, and that the combination TAC + MMF may result in better renal allograft function compared to TAC + SIR , CsA + SIR or CsA + MMF. [107],[108],[109],[110],[111] This may favorably affect long-term outcomes. Recent observations on TAC-free protocols either through withdrawal from a SIR-based therapy [ 35] or through TAC avoidance [58], [59], [62] using a SIR-MMF combination, demonstrated similar incidence of BPAR and graft survival to those reported in the TAC + MMF regimen in the early post­transplant period. These interesting findings should prompt the initiation of additional multi-center studies to determine whether SIR-based regimens alone or in combi­nation with MMF produces similar or better long-term results than those with TAC-based immunosuppression. Whether these protocols based on SIR or SIR + MMF can also be extended to high risk patients is currently unknown. These encouraging results allow speculation, but with caution, that the use of the combination of non-nephrotoxic ISA such as SIR and MMF, might change dramatically the natural course of CAN and may influence long-term patient survival. There is an urgent need to find new approaches to measure and predict the alloimmune response that could allow clinicians to optimize immuno-suppression minimization by establishing new immunotolerogenic regimens capable of providing complete immune tolerance [112] or graft acceptance with a minimal amount of immunosuppression.

   References Top

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A G Barbari
Lebanese Institute for Renal Diseases “LIRD” P.O. Box: 11-3288. Beirut
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