Immunosuppression in renal transplantation: some aspects for the modern era

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Transplantation Reviews 22 (2008) 241 – 251 www.elsevier.com/locate/trre

Immunosuppression in renal transplantation: some aspects for the modern era☆,☆☆ Steven Chadban a,⁎, Randall Morris b , Hans H. Hirsch c , Suphamai Bunnapradist d , Wolfgang Arns e , Klemens Budde f a

Royal Prince Alfred Hospital and University of Sydney, Camperdown, NSW 2050, Australia b Novartis Pharma AG, CH-5056 Basel, Switzerland c Institute for Medical Microbiology, University of Basel, CH-4031 Basel, Switzerland d David Geffen School of Medicine, Los Angeles, CA 90095, USA e Merheim Medical Center, Cologne General Hospital, 51109 Cologne, Germany f Charité Universitätsmedizin Berlin, Campus Charité Mitte, 10098 Berlin, Germany

Abstract New classes of agents have sequentially increased the specificity of post-transplant immunosuppression, leading to profound improvements in success rates after renal transplantation. The next era will focus on increased long-term survival rates through optimal use of existing agents and the rational development of drugs based on prior identification of specific immunologic targets. Conventionally, long-term outcomes after kidney transplantation have been assessed by surrogate markers, notably acute rejection, but graft-threatening complications such as development of new-onset diabetes mellitus and polyomavirus nephropathy must be addressed if long-term survival rates are to be improved. Mycophenolic acid therapy must be administered optimally to ensure that adequate exposure is achieved in the immediate posttransplant period and, subsequently, by avoiding underdosing due to gastrointestinal events. Chronic allograft nephropathy remains a major concern, and protocol-led, reliable monitoring strategies are essential to enable early intervention, for example, through introduction of proliferation signal inhibitor therapy with concomitant calcineurin inhibitor reduction or withdrawal. The range of immunosuppressive regimens now available and in development, together with improved assessment of patients' risk profiles for immunologic events and comorbid disease, offers the opportunity for further individualization of immunosuppression after renal transplantation. © 2008 Elsevier Inc. All rights reserved.

1. Introduction Advances in transplant medicine in recent years have helped to avoid or overcome many clinical challenges in renal transplant recipients, most notably reducing the previous high rates of graft loss to acute rejection, ameliorating the toxicity associated with early immunosuppression regimens, and lowering infection-related mortality.

☆ H.H.H., S.B., and K.B. have received research grants from Novartis; S.C., H.H.H., S.B., W.A., and K.B. have received honoraria from Novartis. R.M. is an employee of Novartis. ☆☆ The meeting from which this report is derived was supported by an unrestricted educational grant from Novartis Pharma AG, Basel, Switzerland. ⁎ Corresponding author. Tel.: +61 2 9515 7120; fax: +61 2 9515 6329. E-mail address: [email protected] (S. Chadban).

0955-470X/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.trre.2008.05.003

As these areas have been addressed, however, new concerns have become apparent in the quest for higher long-term graft survival rates and quality of life for patients. The clinician is faced with an increasingly diverse range of issues to consider when deciding on the optimal immunosuppressive strategy to adopt based on an individual's specific profile. The relative risk of complications such as diabetes mellitus, the emerging problem of polyomavirus-associated nephropathy, time-dependent adequate dosing of adjunctive therapy, avoidance of chronic nephropathy, and use of novel regimens to achieve balanced calcineurin inhibitor (CNI) exposure are all questions that now need to be taken into account as part of post-transplant management. Remaining up-to-date with the latest findings relating to such a variety of complex areas is a demanding task. Against this background, an international, multidisciplinary meeting was convened in Berlin in June 2007. The

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objective was to offer a forum in which transplant clinicians could update themselves on state-of-the-art thinking relating to a wide range of today's challenges in the renal transplant population. This review provides a summary of the data that were presented and discussed at the meeting and seeks to give an insight into how the current knowledge base may influence contemporary clinical practice.

2. Advances in transplantation medicine—past, present, and future Development of the surgical expertise to transplant solid organs preceded the immunologic advances necessary to control allograft rejection. Thus, instead of having effective immunosuppressive regimens available from the start of the transplant era, the challenge of organ rejection has stimulated immunologic discoveries that now are beginning to be applied to transplantation. Progress in immunosuppression has focused on the introduction of agents with greater efficacy combined with increasing selectivity for immune cells, to improve safety. The nonselective total-body X-irradiation that was used for the first 20 to 30 years of transplantation was superseded by azathioprine and steroids, which, however, are not entirely selective for the subset of immune cells that cause rejection. Cyclosporin (CsA) was the first immunosuppressant to target T-cells without inducing myelotoxicity, inflammation, or immune cell depletion, and the use of CsA led to a significant increase in graft and patient survival rates [1,2]. Tacrolimus then followed, using a similar mechanism of action via calcineurin inhibition. The next generation of low-molecularweight immunosuppressants comprised, firstly, the inosine monophosphate dehydrogenase inhibitor mycophenolic acid (MPA) in the form of mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) and, secondly, the proliferation signal inhibitors (PSIs) sirolimus and everolimus. The addition of adjunctive MPA therapy further increased graft survival [3], and while long-term data on PSIs are awaited, surrogate markers for graft survival have been shown to improve in specific patient populations [4]. In addition, monoclonal antibodies to the interleukin-2 receptor, which are highly selective for immune cells, received approval in the mid-1990s and are now widely prescribed [5]. Post-transplant immunosuppression is now entering an entirely new era. In the past, immunosuppressant agents have been adopted from other indications or discovered by serendipity, but the compounds now undergoing clinical trials were developed rationally based on prior identification of the immunologic target. Currently, Belatacept, which blocks costimulation, is in phase III trials; CP-690-550, which suppresses JAK3 signal 3 transduction, is in the completion of phase II trials; and AEB071, which blocks T-cell activation by inhibiting protein kinase C, is in phase II trials. Advances in our understanding of the biochemistry of

the cells responsible for the array of different types of rejection will continue to identify intracellular and cell membrane targets for which novel low-molecular-weight drugs and biologic immunosuppressants, respectively, will be designed. The next era of immunosuppression may focus on drug targets for molecular events in allograft cells that, if left unchecked, progress to cause graft injury and, finally, graft failure. Equally important will be the development of more sensitive and specific diagnostic and biomarker tests to allow individualization of therapeutic regimens. Such tests could assess immune cell function, monitor nephrotoxicity, and identify immune graft injury to allow early modification of the intensity or type of immunosuppression used. 3. Efficacy and glucose metabolism disorders: CNIs in renal transplantation In recent years, long-term graft survival rates after kidney transplantation have remained largely unchanged despite a concurrent reduction in the incidence of acute rejection [6,7]. Acute rejection is associated with several disadvantages: treatment with antibody preparations impacts negatively on long-term mortality [8]; steroid treatment increases the risk of complications; more intense maintenance immunosuppression is mandated; and additional health care costs are incurred. The effect of acute rejection on subsequent graft survival, however, varies according to the type of rejection episode. In contrast to late, recurrent, or vascular rejection, the risk of graft loss is unaffected by an early (b90 days) first rejection episode with subsequent recovery of renal function (Fig. 1) [7]. Thus, acute and reversible rejection may be a less important determinant of long-term outcomes than previously thought, and the influence of nonimmunologic events such as CNI-induced toxicity, viral infection (eg, cytomegalovirus and BK polyomavirus), or new-onset diabetes mellitus (NODM) should be taken into account. New-onset diabetes mellitus is an independent predictor of

Fig. 1. Graft survival to 5 years after renal transplantation according to response to first rejection episode (S. Chadban and S. McDonald, ANZDATA, unpublished data, September 2007).

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graft loss and death [9], and both NODM [10,11] and newonset hyperglycemia [12] significantly increase the risk of major cardiac events after transplantation. Indeed, it has been suggested that NODM may be as important a risk factor for graft loss as acute rejection [13]. Many factors that contribute to either acute rejection or onset of NODM cannot be altered, and choice of CNI represents one of the few modifiable risk factors for both events. Several analyses of registry databases have investigated graft outcomes with CsA and tacrolimus in renal transplant patients receiving MPA therapy [14-18] and have shown similar survival rates with either CNI. Kaplan et al [14] undertook a paired-donor analysis in which 2 kidneys from the same donor were allocated to a patient receiving CsA and a patient receiving tacrolimus, thus avoiding any selection bias in donor organs or year of transplant. In this cohort of 6140 patients, there was no difference in graft survival between the CsA- and tacrolimus-treated patients up to 5 years post-transplant (66.9% and 65.9%, respectively; P = .4663). Analyses of data from transplant registries have consistently indicated that NODM after kidney transplantation is more frequent in patients receiving tacrolimus than CsA [9,19]. Recently, the 6-month DIRECT study, which compared the relative efficacy and diabetogenic effect of CsA microemulsion (CsA-ME; Neoral Novartis Pharma AG, Basel, Switzerland) and tacrolimus, has been completed [20]. De novo renal transplant patients were randomized to CsA-ME using C2 monitoring or to tacrolimus using C0 monitoring. All patients received MPA, steroids, and basiliximab induction. The intent-to-treat population comprised 682 patients, of whom 567 were nondiabetic at baseline. Both treatment groups showed equivalent efficacy in regard to each parameter of the combined end point. The primary efficacy end point (biopsy-proven acute rejection, graft loss, or death at 6 months) occurred in 43 CsA-ME patients (12.8%) and 34 tacrolimus patients (9.8%; P = .211). The incidence of biopsy-proven acute rejection was numerically lower in the tacrolimus group (6.9% vs 10.1%; P = .132), consistent with findings from previous studies [21]. Interestingly, however, in the CsA-ME arm, 20 (59%) of 34 episodes of rejection were graded mild (grade IA or IB) and only 1 (3%) of 34 was graded severe (grade ≥2B) compared with 11 (46%) of 24 and 6 (25%) of 24, respectively, in the tacrolimus group. Severe rejection has a greater impact on renal function recovery and incurs greater management time and costs. Graft survival rate was similar with CsA or tacrolimus (97.6% and 97.1%, respectively), as was patient survival (99.7% and 99.1%, respectively). Mean glomerular filtration rate (GFR) (Cockcroft-Gault) was 63.6 ± 20.7 mL/min per 1.73 m2 in the CsA cohort and 65.9 ± 23.1 mL/min per 1.73 m2 in the tacrolimus group (P = .285); mean serum creatinine was 139 ± 58 and 133 ± 57 μmol/L, respectively (P = .005). The primary safety end point of DIRECT was the incidence of NODM or impaired fasting glucose at 6

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months. This end point occurred in significantly fewer CsAME patients (n = 73, 26.0%) than tacrolimus patients (n = 96, 33.6%; P = .046) (Fig. 2). Treated diabetes was also significantly lower in the CsA-ME group (25/281, 8.9%) than in the tacrolimus group (48/286, 16.8%; P = .005). For other safety parameters, triglycerides were higher with CsAME, but the ratio of total cholesterol to HDL was similar. There were no clinically relevant differences between CsAME and tacrolimus for other cardiovascular risk factors. In conclusion, acute rejection is not necessarily a sensitive predictor of subsequent graft loss. This is compatible with the finding that the small differences in rejection rates between CNIs do not seem to affect graft survival rates, which are similar with CsA or tacrolimus up to 5 years after kidney transplantation [14-18]. The incidence of glycemic abnormalities, including treated diabetes, is significantly lower with CsA-ME than tacrolimus, and because NODM increases the risk of cardiovascular disease and graft loss, this may contribute to improved long-term outcomes in kidney transplant recipients. 4. Polyomavirus infection, replication, and disease in renal transplant recipients Polyomavirus infection typically occurs during childhood, with seroprevalence rates of 65% to 90% by the age of 10 years, and is usually asymptomatic. Individuals with altered immunity, however, can experience high-level replication and may present with urine cytology (“decoy” cells). In renal transplant recipients, polyomavirus-associated nephropathy (PVAN) develops in 5% of patients and leads to graft loss in approximately 50% of cases. The pathogenesis of PVAN is characterized by persisting high-level polyoma BK virus (BKV) replication in renal tubular epithelial cells, inflammation, and progressive organ failure with tubular atrophy and fibrosis. Definitive diagnosis requires histopathological assessment, notably to exclude acute rejection. Between 20% and 40% of renal transplant patients exhibit BK viruria,

Fig. 2. Incidence of NODM or impaired fasting glucose (IFG) at 6 months after renal transplantation among patients who were not diabetic at the time of transplant, randomized to CsA-ME or tacrolimus. Data from Vincenti et al [20].

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with BK viremia being observed in approximately 12% of patients [22]. Retrospective [23] and prospective [24] studies have indicated that BK viremia greater than 10e4/mL is predictive of definitive PVAN, and these patients should be regarded as having “presumptive PVAN,” and reduced immunosuppression should be considered. A variety of factors related to the recipient, donor, transplant, or viruses have been proposed as risk factors for PVAN after renal transplantation, including the use of intense immunosuppression (often, but not exclusively, comprising triple therapy with tacrolimus-MMF-prednisolone). It seems likely that both the potency of immunosuppression and agentspecific influences may contribute to the risk of BK reactivation and PVAN. Although CsA or tacrolimus alone does not seem to exert an independent effect on risk of BK infection [25], the cumulative incidence of viruria has been reported to be significantly higher with tacrolimus-MMF than CsA-MMF (46% vs 13%, respectively; P = .005) [25], and it is possible that the combination of tacrolimus and MMF may create a permissive environment for BK reactivation to a greater extent than other immunosuppressive regimens. The relative incidence of BK viruria and viremia with CsA vs tacrolimus was assessed in a planned analysis within the recent DIRECT study. In this 6-month trial, de novo kidney transplant recipients were randomized to CsA-ME or tacrolimus, with MPA and steroids. An additional follow-up visit took place 6 months after the end of the study (month 12), at which time BK viruria was present in 20.3% of all patients screened and viremia was detected in 8.4% of patients. Fewer CsA-treated patients had BK viremia than tacrolimus-treated patients at month 6 (P = .064), a difference that reached significance by month 12 (P = .001) (Fig. 3). Moreover, the plasma BK load was approximately 10-fold higher in the tacrolimus arm at 12 months, with 2 × 10e5/mL in the tacrolimus cohort vs 2 × 10e4/mL in the CsA arm (P = .004) [26]. Screening for PVAN is based upon detection of decoy cells in urine, BKV DNA in urine or plasma, and BKV RNA in urine. If results are indicative of PVAN, plasma BKV DNA and urine BKV VP1 mRNA should be monitored to identify

Fig. 3. Incidence of BKV viremia to 12 months post-transplant in de novo renal transplant patients randomized to CsA-ME or tacrolimus in the DIRECT study.

“presumptive cases,” which then require confirmation by biopsy. After intervention in presumptive or definitive cases, plasma BKV DNA should be monitored regularly. After a reduction in immunosuppression, the immune system curtails BKV infection within 7 to 11 weeks. It has been suggested based on case reports that leflunomide may be of value because of an as yet poorly understood antiviral mechanism [27], but MMF had been discontinued in all patients, and the antiviral effect took approximately 12 weeks to achieve 1 log decline. The effect of the antiviral agent cidofovir seems moderate and is associated with a level of risk because of its potential nephrotoxic effect [28]. For both agents, randomized controlled trials are lacking to demonstrate superiority over timely reduction of immunosuppression. In summary, BKV is a major pathogenic driver after kidney transplantation. Inadequate antiviral control is a key permissive factor for BKV reactivation, and risk of PVAN seems higher with tacrolimus-MMF combinations. Results from the DIRECT study suggest that BK viremia is significantly less frequent, with a lower viral load, in CsAtreated patients compared with tacrolimus-treated patients. Early diagnosis is important, allowing a reduction in immunosuppression to help preserve graft function when renal damage is still limited.

5. Current issues in MPA therapy With MPA therapy now routine after renal transplantation, there is a growing need to optimize MPA dosing. One important concern relates to gastrointestinal (GI) symptoms and the consequent need for MMF dose changes or withdrawal, which can have a profound impact on graft outcomes. A series of retrospective analyses has shown a significant increase in the risk of acute rejection [29,30] or graft loss [31-34] in renal transplant patients receiving a reduction in or discontinuation of MMF, which in turn translates to impaired graft survival. In a population of 721 patients, 3-year death-censored graft survival was 88.3% in patients with no MMF dose change vs 76.3% in those requiring a dose change (P = .003) [31]. Several analyses of data from transplant registries have also observed that MMF dose changes are associated with an increased risk of graft loss [32-34]. One of the most frequent reasons for MMF dose changes is GI complications [29-32], which account for a fifth of all MMF dose changes [30,31]. Data from 6400 patients registered with the US Renal Data System (USRDS) have shown that onset of GI complications significantly increases the risk of MMF withdrawal: multivariate analysis showed GI events to be associated with a 19% increase in risk of MMF discontinuation (P b .01) [33]. In a separate analysis of USRDS data involving 3675 MMFtreated patients with a GI complication, only 46% of patients remained on full-dose MMF, with 34% discontinuing the drug and a further 12% required a dose reduction of 50% or more [32]. In the same population, intervals of MMF dose

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reduction of 50% or more were associated with a 64% increased risk of graft loss (P = .010), and MMF discontinuation was associated with more than a doubling of risk (P = .0002), compared with patients who remained on full-dose MMF (Fig. 4) [32]. Based on these findings, maintaining MPA exposure should be considered a priority when reviewing management options in MMF-treated patients who are experiencing GI complications. In this regard, the choice of MPA formulation may be important. An enteric-coated formulation (EC-MPS) that delays release of MPA by approximately 1.5 hours but has a similar MPA exposure (area under the curve [AUC]) to MMF [35], a key determinant of MPA efficacy [36], has been developed. Pivotal trials have shown that EC-MPS offers equivalent efficacy and safety to MMF in de novo renal transplant recipients [37,38]. Moreover, converting maintenance renal transplant recipients from MMF to EC-MPS does not compromise efficacy with regard to biopsy-proven acute rejection or graft loss [39,40]. Recently, the PROGIS study has used patient-reported outcomes instruments to evaluate the impact of converting 177 renal transplant patients with GI symptoms from MMF to EC-MPS and observed significant and clinically relevant reductions in the GI-related symptom burden and health-related quality of life at the end of the 4- to 6-week follow-up period [41]. In addition to implications for GI symptom burden, 3 concerns relating to the use of different MPA formulations were considered at the meeting: treatment of patients with diabetes, administration in tacrolimus-treated patients, and intensified dosing in the early post-transplant period. Patients with diabetes are of particular interest because of the high incidence of gastroparesis in this population [42]. Results of pooled and subpopulation analyses have confirmed the treatment of diabetic de novo renal transplant patients with EC-MPS to be as efficacious as MMF, with no significant differences in the incidence of drug-related adverse events, serious adverse events, or laboratory abnormalities between

Fig. 4. Hazard ratio for graft loss among 3675 recipients of a primary renal transplant based on a retrospective analysis of data from USRDS/Medicare. All patients had a diagnosis of a GI complication and were receiving MMF at the time of the first GI diagnosis. Reference group was patients who did not receive an MMF dose change after diagnosis of a GI complication. DR indicates dose reduction; DC, discontinuation. Data from Bunnapradist et al [32].

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Fig. 5. EC-MPS dosing regimens in the optimyze study. Data from Budde et al [50].

the 2 formulations, whereas conversion of diabetic maintenance patients from MMF to equimolar doses of EC-MPS showed no compromise in safety or efficacy [43]. Regarding MPA therapy with concomitant tacrolimus, a multicenter study has been undertaken in which 63 patients receiving MMF and tacrolimus were converted to equimolar doses of EC-MPS at a mean of 38 months post-transplant [44]. During the 6-month study, there was 1 episode of biopsy-proven rejection (1.6%, grade IA) after conversion to EC-MPS with no graft losses or deaths, and mean creatinine clearance was stable (70.6 mL/min at baseline, 68.6 mL/min at month 6). Pharmacokinetic and pharmacodynamic analyses in a subpopulation of 21 patients showed similar mean MPA exposure (39.3 mg h/L with MMF and 43.2 mg h/L with EC-MPS), with both formulations exerting an almost identical pharmacodynamic effect on inosine monophosphate dehydrogenase activity [44]. Lastly, the use of intensified early MPA dosing is being explored in the “optimyze” study. Several authors have confirmed that MPA exposure (AUC) correlates with risk of acute rejection in renal transplant recipients [45-49], and it has been proposed that an MPA AUC of greater than 30 mg h/ L is associated with effective rejection prophylaxis [47-49]. However, only 50% of patients reach this exposure level in the early post-transplant period when receiving standard doses of MPA (eg, 1440 mg EC-MPS) in combination with CsA. The optimyze study is being undertaken with the objective of determining whether an intensified early ECMPS dosing regimen leads to significantly higher MPA exposure early post-transplant. A total of 120 adult de novo kidney transplant recipients will be randomized (1:1) to either an intensified EC-MPS dosing regimen or to standard ECMPS dosing (Fig. 5) [50]. All patients receive CsA, corticosteroids, and basiliximab induction. Preliminary data from 62 patients taking part in a pilot phase have been reported, with full 12-hour pharmacokinetic profiles available in 46 patients [51]. Mean MPA exposure (AUC) was significantly higher in the intensified regimen group on day 3 post-transplant vs the standard regimen patients (44.4 ± 15.4 vs 32.5 ± 19.1 mg h/L, respectively; P = .012) (Fig. 6). Exposure to MPA remained constant over the first 3 weeks in

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Fig. 6. MPA AUC at day 3 post-transplant according to EC-MPS dosing regimen in the optimyze study. Values are shown as mean ± SD (bars) with upper and lower quartiles (lines).

both treatment arms. An independent data review committee concluded that the overall safety profile was comparable between the intensified and the standard dosing groups in this preliminary data set, with no differences in risk of infections, GI disorders, or hematological side effects [51]. The optimyze study is part of a 2-tiered approach, in which the results from this national feasibility study will be

analyzed with data from a multinational study (myID) that follows the same study design. In myID, 306 patients will be randomized, resulting in a total population of 426. The results of these trials will help to determine whether the fixed-dose MPA regimens that are currently used could be modified to decrease rejection rates further without affecting tolerability, particularly the incidence of GI side effects. In summary, GI adverse events are common in MMFtreated patients, frequently necessitating MMF dose reduction or discontinuation that leads to suboptimal MPA exposure and a significantly increased risk of acute rejection and graft loss. Management strategies that achieve adequate MPA exposure are a priority under these circumstances, and preliminary data suggest that early intensive MMF dosing in the first few weeks after kidney transplantation may offer an improved efficacy outcome early post-transplant.

6. Chronic allograft nephropathy: a clinical syndrome in renal transplantation Jeremy Chapman of the Centre for Transplant and Renal Research at the University of Sydney, Australia, discussed

Fig. 7. Treatment guidelines proposed by Pascual et al [79] for use of everolimus in (A) de novo kidney transplant patients receiving CsA or (B) maintenance patients receiving CNI therapy.

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Fig. 7 (continued).

strategies for early detection of chronic allograft nephropathy (CAN). Accounting for more than a third of graft losses, CAN is the most frequent cause of graft loss after renal transplantation other than patient death [52,53]. Using the Banff '97 schema, mild CAN (grade I) is observed in almost all grafts by the end of the first year post-transplant [54], with grade II or III CAN occurring in 25% of grafts at 1 year and 90% by 10 years post-transplant [54]. In the most recent Banff discussions, the histological focus has returned to the definition of interstitial fibrosis and tubular atrophy (IFTA), dispensing with the term CAN and placing the emphasis on differential diagnosis from conditions such as chronic cellular or humoral rejection, CNI nephrotoxicity, or transplant glomerulopathy. Nevertheless, CAN is a useful term for the “clinical syndrome” in which progressive decline in renal function is associated with multiple potential factors contributing to

pathological changes. Superimposed on chronic donor disease or acute donor disease, ischemia-reperfusion injury at time of transplant, acute rejection, CNI nephrotoxicity, and untreated or poorly managed subclinical rejection or chronic humoral rejection can contribute to histological damage to the graft. These insults result in interstitial fibrosis, arteriolar hyalinosis, and vascular remodelling, ultimately leading to progressive glomerulosclerosis. Clinical manifestations unfortunately appear relatively late and include hypertension, proteinuria, and falling GFR before an increase in serum creatinine levels is finally evident [55]. Identification of risk factors before the development of clinical signs of CAN is the best hope for early intervention and prevention of deteriorating graft function. Although a variety of immunologic and nonimmunologic risk factors for CAN have been identified, many cannot be modified, restricting the management options available. The most

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significant immunologic risk factors are acute rejection, ongoing subclinical rejection, HLA mismatch, and delayed graft function [53-55]. Nonimmunologic factors include CNI nephrotoxicity, extended criteria donor grafts, and recipient comorbidities, notably hypertension, hyperlipidemia, and diabetes [53,55-59]. Conventionally, measurement of serum creatinine has been considered an adequate measurement of renal function. Increasing serum creatinine, however, is a late occurrence and underestimates declining graft function [60]. It is a poor predictor of renal function, particularly at levels of GFR between 30 and 70 mL/min [55], and cannot be relied upon to identify patients with early CAN. Direct measurement of GFR by inulin or DTPA clearance is the gold standard, but although important as a research tool, it can be impractical in routine practice. Calculated GFR is an alternative, especially in the range of 30 to 70 mL/min [55]. Histological findings of IFTA are predicted by a creatinine clearance of less than 50 mL/min at 6 months post-transplant and an unstable slope of renal function after 6 months [61]. When there is clinical suspicion of CAN, for example, based on increasing serum creatinine accompanied by newonset proteinuria and rising blood pressure, there is little alternative to a biopsy to confirm the diagnosis of CAN before intervention for CAN is initiated. Early intervention centers on 2 issues: identification and management of subclinical allograft rejection to ameliorate IFTA; and the avoidance or reduction of CNI exposure. Subclinical rejection depends on the intensity of immunosuppression and responds successfully to treatment, with improvements in both histological damage and renal function [62]. Lowdose CNI therapy or CNI elimination has been studied in a variety of different protocols and seems more successful than completely CNI-free immunosuppression, which has frequently been associated with higher rates of acute rejection or infectious complications [63]. To conclude, CAN is a major cause of renal graft loss, developing early and progressing relentlessly in a high proportion of renal transplants. Key risk factors include CNI nephrotoxicity, acute and subclinical rejection, and extended criteria donor grafts. Increasing serum creatinine occurs late in the progression of CAN and is a poor marker for future deterioration of renal function; calculated GFR is a more robust marker and should be estimated routinely in all renal transplant patients. Early detection of CAN based on the level and trends in calculated GFR may allow for early warning, formal diagnosis, and intervention, for example, through elimination or reduction of CNI exposure.

7. The potential role of PSIs in de novo and early intervention in maintenance transplant patients One response to the growing demand for donor kidneys has been the introduction of “old-for-old” transplant programs, in which expanded criteria organs from elderly

donors are age-matched to recipients. Increasing donor age, however, is associated with deteriorating renal function, a higher prevalence of risk factors for CAN, and greater susceptibility to CNI nephrotoxicity, all of which contribute to the reduced long-term renal function observed with elderly donors [64]. In addition, older recipients are at increased risk of complications such as cardiovascular disease, which impact on quality of life and patient survival rates. Against this background, adequately reducing exposure to CNIs could be of particular benefit in old-for-old transplantation, with the objective of minimizing both CNI nephrotoxicity [56] and CNI-related risk factors for cardiovascular disease [65]. However, all attempts of reducing CNIs have to be weighted against the potential risk of increasing rejection episodes. Regimens that are CNI-free have been attempted in oldfor-old transplants, using a combination of MMF, corticosteroids, and induction therapy [66,67], but a recent meta-analysis has shown PSIs to provide a lower rate of acute rejection than antimetabolites [4], and an immunosuppression regimen in which PSI therapy is used in combination with reduced-exposure CNI is another promising option. At the Cologne Medical Center, a small series of de novo old-for-old renal transplant recipients at low immunologic risk has been managed using a regimen of everolimus with reduced-exposure CsA, corticosteroids, and basiliximab induction. Among the 9 patients to date, efficacy and safety have been excellent, with the exception of 1 case of graft nonfunction. Only 1 patient has experienced acute rejection during follow-up of up to 42 weeks post-transplant, and there has been only 1 case each of urinary tract infection, wound healing complications, and lymphocele (W. Arns, oral communication September 2007). These initial results suggest that de novo PSI therapy within a low-dose or CNI-free regimen is an effective option in preventing acute rejection in old-for-old recipients. In maintenance patients, the contribution of CNI treatment to the risk of CAN has led to considerable interest in minimization or, possibly, withdrawal of CNI with concomitant introduction of PSI-based therapy. Reducing CNI exposure in PSI-treated patients can frequently be an appropriate option, for example, in patients with early CAN, and may be adequate to stabilize the patient's condition without the need for complete CNI withdrawal. Where conversion from CNI- to PSI-based immunosuppression is undertaken, 2 types of protocol are generally used: either tapered withdrawal of CNI over approximately 1 week with concurrent introduction and dose increases of PSI, or abrupt CNI withdrawal and initiation of PSI [68]. In the ongoing CONVERT trial [69], renal transplant patients at least 6 months post-transplant were randomized to convert to sirolimus (C0 8–20 ng/mL) or remain on their current CNI. Corticosteroid therapy is continued; adjunctive therapy with MMF or azathioprine is optional. Among patients with baseline GFR greater than 40 mL/min (Nankivell formula [54]), GFR was significantly higher at all postconversion time

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points in the sirolimus-treated cohort vs the CNI group. Stepwise conversion from either CsA-based or tacrolimusbased immunosuppression to everolimus has also been assessed, with results showing an improvement in renal function after conversion with no rejection [70-72]. More recently, 2 small pilot studies have evaluated abrupt conversion from CsA to everolimus and reported no additional acute rejection after conversion [68,73]. Together, these data indicate that early conversion of maintenance renal transplant patients to PSI therapy as early intervention for CAN may not be associated with an increased risk of rejection and improves renal histology and function [74]. It is important to note, however, that late CNI withdrawal has achieved more variable results, possibly because the benefits of withdrawal were mitigated by previous extensive damage to the kidney [74]. In studies in which sirolimus has been introduced as rescue therapy to replace CNI in kidney transplant patients with established CNI-related nephrotoxicity or CAN, patients with the worst renal function frequently continued to show a decline in calculated GFR [75-77]. Reports of proteinuria progression after conversion to sirolimus have generally been observed in patients with preexisting proteinuria or advanced glomerular lesions [78], underscoring the limitations of late conversion from CNI therapy after long-term deterioration of kidney function. Suggested algorithms have been developed for the use of concentration-controlled everolimus, either in de novo renal transplant recipients under CsA therapy or in maintenance patients with deteriorating renal function (including CAN) (Fig. 7) [79]. The authors have no other conflicts of interest to declare. References [1] Kahan BD. Cyclosporine. N Engl J Med 1989;321:1725-38. [2] Calne R. Cyclosporine as a milestone in transplantation. Transplant Proc 2004;36(Suppl 2):13S-5S. [3] Ojo AO, Meier-Kriesche HU, Hanson JA, et al. Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection. Transplantation 2000;69:2405-9. [4] Webster AC, Lee VW, Chapman JR, et al. Target of rapamycin inhibitors (sirolimus and everolimus) for primary immunosuppression of kidney transplant recipients: a systematic review and meta-analysis of randomized trials. Transplantation 2006;81:1234-48. [5] Shapiro R, Young JB, Milford EL, et al. Immunosuppression: evolution in practice and trends, 1993–2003. Am J Transplant 2005; 5:874-86. [6] Meier-Kriesche HU, Schold JD, Srinivas TR, et al. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004;4: 378-83. [7] McDonald S, Russ G, Campbell S, et al, on behalf of ANZDATA. Kidney transplant rejection in Australia and New Zealand: relationships between rejection and graft outcome. Am J Transplant 2007;7: 1201-8. [8] Jamil B, Nicholls K, Becker GJ, et al. Impact of acute rejection therapy on infections and malignancies in renal transplant recipients. Transplantation 1999;68:1597-603.

249

[9] Kasiske B, Snyder JJ, Gilbertson D, et al. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003;3: 178-85. [10] Cosio FG, Pesavento TE, Kim S, et al. Patient survival after renal transplantation: IV. Impact of post-transplant diabetes. Kidney Int 2002;62:1440-6. [11] Hjelmesaeth J, Hartmann A, Leivestad T, et al. The impact of earlydiagnosed new-onset post-transplantation diabetes mellitus on survival and major cardiac events. Kidney Int 2006;69:588-95. [12] Cosio FG, Kudva Y, van der Velde M, et al. New onset hyperglycemia and diabetes are associated with increased cardiovascular risk after kidney transplantation. Kidney Int 2005;67:2415-21. [13] Cole EH, Johnston O, Rose C, et al. PTDM and acute rejection are associated with a similar risk for graft loss. Am J Transplant 2007;7 (Suppl 2) [Abstract 150]. [14] Kaplan B, Schold JD, Meier-Kreische HU. Long-term graft survival with Neoral and tacrolimus: a paired kidney analysis. J Am Soc Nephrol 2003;14:2980-4. [15] Bunnapradist S, Peng A, Fukami S, et al. Renal allograft outcomes according to initial immunosuppressive regimen: a five year follow-up of OPTN database. Am J Transplant 2005;5(Suppl 11):251. [16] Woodward RS, Kutinova A, Schnitzler MA, et al. Renal graft survival and calcineurin inhibitor. Transplantation 2005;80:629-33. [17] Habib AN, Smith L, Barenbaum LL, et al. The role of maintenance immunosuppressive regimen in long term kidney transplant outcome. Am J Transplant 2005;5(Suppl 11):465. [18] Irish W, Sherrill B, Brennan DC, et al. Three year posttransplant graft survival in renal-transplant patients with graft function at 6 months receiving tacrolimus or cyclosporine microemulsion within a triple drug regimen. Transplantation 2003;76:1686. [19] Woodward RS, Schnitzler MA, Baty J, et al. Incidence and cost of new onset diabetes mellitus among U.S. wait-listed and transplanted renal allograft recipients. Am J Transplant 2003;3:590-8. [20] Vincenti F, Friman S, Scheuermann E, et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant 2007;7: 1506-14. [21] Webster AC, Woodroffe RC, Taylor RS, et al. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data. BMJ 2005;331:810. [22] Hirsch HH, Knowles W, Dikenmann M, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 2002;347:488-96. [23] Hirsch HH, Brennan DC, Drachenberg CB, et al. Polyomavirusassociated nephropathy in renal transplantation: interdisciplinary analyses and recommendations. Transplantation 2005;79:1277-86. [24] Hirsch HH, Drachenberg C, Ramos E, et al. BK viremia level strongly correlates with the extent/pattern of viral nephropathy (BKPVN): implications for a diagnostic cut-off value. Transplantation 2006;82(1 Suppl 3 WTC Abstracts):460. [25] Brennan DC, Agha I, Bohl DL, et al. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplant 2005;5:582-94. [26] Hirsch HH, Friman S, Wiecek A, et al. Prospective study of polyomavirus BK viruria and viremia in de novo renal transplantation. Am J Transplant 2007;7(Suppl 2) [Abstract 14]. [27] Williams JW, Javaid B, Kadambi PV, et al. Leflunomide for polyomavirus type BV nephropathy. N Engl J Med 2005;352: 1157-8. [28] Rinaldo CH, Hirsch HH. Antivirals for the treatment of polyomavirus BK replication. Expert Rev Anti Infect Ther 2007;5:105-15. [29] Tierce JC, Porterfield-Baxa J, Petrilla AA, et al. Impact of mycophenolate mofetil (MMF)–related gastrointestinal complications and MMF dose alterations on transplant outcomes and healthcare costs in renal transplant recipients. Clin Transplant 2005; 19:779-84.

250

S. Chadban et al. / Transplantation Reviews 22 (2008) 241–251

[30] Knoll GA, MacDonald I, Khan A, et al. Mycophenolate mofetil dose reduction and the risk of acute rejection after renal transplantation. J Am Soc Nephrol 2003;14:2381-6. [31] Pelletier RP, Akin B, Henry ML, et al. The impact of mycophenolate mofetil dosing patterns on clinical outcome after renal transplantation. Clin Transplant 2003;17:200-5. [32] Bunnapradist S, Lentine KL, Burroughs TE, et al. Mycophenolate mofetil dose reductions and discontinuations after gastrointestinal complications are associated with renal transplant graft failure. Transplantation 2006;82:102-7. [33] Hardinger K, Brennan DC, Lowell J, et al. Long-term outcome of gastrointestinal complications in renal transplant patients treated with mycophenolate mofetil. Transpl Int 2004;17:609-16. [34] Legorreta AP, Robinson M, Gilmore AS, et al. Gastrointestinal event associated dose reduction and discontinuation of renal transplant patients receiving MMF. Transplantation 2006;82(Suppl 3 WTC Abstracts):485. [35] Arns W, Bruer S, Choudhury S, et al. Enteric-coated mycophenolate sodium delivers bioequivalent MPA exposure compared with mycophenolate mofetil. Clin Transplant 2005;19:199-206. [36] Kiberd BA, Lawen J, Fraser AD, et al. Early adequate mycophenolic acid exposure is associated with less rejection in kidney transplantation. Am J Transplant 2004;4:1079-83. [37] Salvadori M, Holzer H, de Mattos A, et al, on behalf of the ERLB301 Study Group. Enteric-coated mycophenolate sodium is therapeutically equivalent to mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2004;4:231-6. [38] Salvadori M, Holzer H, Civati G, et al, on behalf of the ERL B301 Study Group. Long-term administration of enteric-coated mycophenolate sodium (EC-MPS; myfortic) is safe in kidney transplant patients. Clinical Nephrol 2006;66:112-9. [39] Budde K, Curtis J, Knoll G, et al, on behalf of the ERL B302 Study Group. Enteric-coated mycophenolate sodium can be safely administered in maintenance renal transplant patients: results of a 1-year study. Am J Transplant 2004;4:237-43. [40] Budde K, Knoll G, Curtis J, on behalf of the ERL B302 Study Group. Long-term safety and efficacy after conversion of maintenance renal transplant recipients from mycophenolate mofetil (MMF) to entericcoated mycophenolate sodium (EC-MPA, Myfortic). Clin Nephrol 2006;66:103-11. [41] Revicki DA, Zodet MW, Joshua-Gotlib S, et al. Health-related quality of life improves with treatment-related GERD symptom resolution after adjusting for baseline severity. Health Qual Life Outcomes 2003; 1:73. [42] Gwilt PR, Nahhas RR, Tracewell WG. The effects of diabetes mellitus on pharmacokinetics and pharmacodynamics in humans. Clin Pharmacokinet 1991;20:477-90. [43] Pietruck F, Budde K, Salvadori M, et al. Efficacy and safety of entericcoated mycophenolate sodium in renal transplant patients with diabetes mellitus: post hoc analyses from three clinical trials. Clin Transplant 2007;21:117-25. [44] Budde K, Glander P, Krämer BK, et al. Conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in maintenance renal transplant recipients receiving tacrolimus: clinical, pharmacokinetic, and pharmacodynamic outcomes. Transplantation 2007;83: 417-24. [45] Takahashi K, Ochiai T, Uchida K, et al. Pilot study of mycophenolate mofetil (RS-61443) in the prevention of acute rejection following renal transplantation in Japanese patients. RS-61443 Investigation Committee-Japan. Transplant Proc 1995;27:1421-4. [46] Nicholls AJ. Opportunities for therapeutic monitoring of mycophenolate mofetil dose in renal transplantation suggested by pharmacokinetic/pharmacodynamic relationship for mycophenolic acid and suppression of rejection. Clin Biochem 1998;31:329-33. [47] Oellerich M, Shipkova M, Schütz E, et al. Pharmacokinetic and metabolic investigations of mycophenolic acid in pediatric patients after renal transplantation: implications for therapeutic drug monitor-

[48]

[49]

[50]

[51]

[52]

[53]

[54] [55] [56]

[57]

[58]

[59]

[60]

[61]

[62]

[63] [64] [65]

[66]

ing. German Study Group on Mycophenolate Mofetil Therapy in Pediatric Renal Transplant Recipients. Ther Drug Monit 2000;22: 20-6. van Gelder T, Hilbrands LB, Vanrenterghem Y, et al. A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation. Transplantation 1999;68: 261-6. Hale MD, Nicholls AJ, Bullingham RES, et al. The pharmacokineticpharmacodynamic relationship for mycophenolate mofetil in renal transplantation. Clin Pharmacol Ther 1998;64:672-83. Budde K, Arns W, Grandaliano G, et al. Rationale, design and statistical analysis of a prospective randomized trial comparing initially intensified vs standard dose regimens of enteric-coated mycophenolate sodium in de novo renal transplant patients. 13th Congress of the European Society for Organ Transplantation, 28 September – 3 October; 2007. [Abstract 637]. Budde K, Arns W, Glander P, et al. Intensified dosing regimen of ECMPS leads to higher MPA-AUC at day 3 post-transplant in de novo renal transplant patients. Preliminary results of the Pharmacokinetic and Safety of the optimyze trial. Am J Transplant 2007;7(Suppl 2) [Abstract 1723]. ANZDATA Registry Report 2004. Eds. Macdonald S, Excell L. Australia and New Zealand Dialysis and Transplantation Registry. Adelaide, Australia. Available at: www.anzdata.org. Accessed September 26, 2007. Pascual M, Theruvath T, Kawai T, et al. Strategies to improve longterm outcomes after renal transplantation. N Eng J Med 2002;346: 580-90. Nankivell BJ, Borrows RJ, Fung CLS, et al. The natural history of chronic allograft nephropathy. N Eng J Med 2003;349:2326-33. Chapman JR, O'Connell PJ, Nankivell BJ. Chronic renal allograft dysfunction. J Am Soc Nephrol 2005;16:3015-26. Nankivell BJ, Borrows RJ, Fung CLS, et al. Calcineurin inhibitor nephrotoxicity: longitudinal assessment by protocol histology. Transplantation 2004;78:557-65. Nankivell BJ, Borrows RJ, Fung CLS, et al. Evolution and pathophysiology of renal-transplant glomerulosclerosis. Transplantation 2004;78:461-8. Solez K, Vincenti F, Filo RS. Histopathologic findings from 2-year protocol biopsies from a U.S. multicenter kidney transplant trial comparing tacrolimus versus cyclosporine: a report of the FK506 Kidney Transplant Study Group. Transplantation 1998;66: 1736-40. Oppenheimer F, Aljama P, Asensio Peinado C, et al. The impact of donor age on the results of renal transplantation. Nephrol Dial Transplant 2004;19(Suppl 3):iii11-5. Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Inter Med 1999;130:461-70. Sijpkens YWJ, Zwinderman AH, Mallat MJK, et al. Intercept and slope analysis of risk factors in chronic renal allograft nephropathy. Graft 2002;5:108-13. Rush D, Nickerson P, Gough J, et al. Beneficial effects of treatment of early subclinical rejection: a randomized study. J Am Soc Nephrol 1998;9:2129-34. Bestard O, Cruzado JM, Grinyó JM. Calcineurin-inhibitor–sparing immunosuppressive protocols. Transplant Proc 2005;37:3729-32. Arns W, Citterio F, Campistol JM. “Old-for-old”—new strategies for renal transplantation. Nephrol Dial Transplant 2007;22:336-41. Jardine AG. Assessing the relative risk of cardiovascular disease among renal transplant patients receiving tacrolimus or cyclosporine. Transpl Int 2005;18:379-84. Arbogast H, Hückelheim H, Schneeberger H, et al. A calcineurin antagonist–free induction/maintenance strategy for immunosuppression in elderly recipients of renal allografts from elderly cadaver

S. Chadban et al. / Transplantation Reviews 22 (2008) 241–251

[67]

[68]

[69]

[70]

[71]

[72]

donors: long-term results from a prospective single centre trial. Clin Transplant 2005;19:309-15. Diekmann F, Campistol JM, Saval N, et al. Sequential quadruple immunosuppression including sirolimus in extended criteria and nonheartbeating donor kidney transplantation. Transplantation 2007; 84:429-32. Pohanka E. Conversion to everolimus in maintenance patients— current clinical strategies. Nephrol Dial Transplant 2006(21 Suppl 3): iii24-9. Racusen L. Renal allograft histopathology in protocol biopsies obtained before conversion from calcineurin inhibitor (CNI)– to sirolimus (SRL)-based immunosuppression: a report from the CONVERT study. Transplantation 2006;82(Suppl 3 WTC Abstracts):413. Arns WW, Glander P, Schuhmann R, et al. Conversion from tacrolimus to everolimus does not influence the pharmacokinetic but increases pharmacodynamic response of mycophenolate sodium in renal transplant patients. Transplantation 2006;82(Suppl 3 WTC Abstracts):488. Budde K, Glander P, Schuhmann R, et al. Conversion from cyclosporine to everolimus leads to better renal function and to profound changes in everolimus and mycophenolate metabolism. Transplantation 2006;82(Suppl 3 WTC Abstracts):999. Ruiz JC, Sanchez-Fructuoso A, Rodrigo E, et al. Conversion to everolimus in kidney transplant recipients: a safe and simple procedure. Transplant Proc 2006;38:2424-6.

251

[73] Holdaas H, Pfeffer P, Bentdal Ø, Midtvedt K. Conversion from cyclosporine to everolimus at week 7 after renal transplantation is safe and improves renal function. Am J Transplant 2007;7(Suppl 2) [Abstract 1709]. [74] Flechner SM, Kobashigawa J, Klintmalm G. Calcineurin inhibitor– sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity. Clin Transplant 2008;22:1-15. [75] Wali RK, Mohanlal V, Ramos E, et al. Early withdrawal of calcineurin inhibitors and rescue immunosuppression with sirolimus-based therapy in renal transplant recipients with moderate to severe renal dysfunction. Am J Transplant 2007;7:1572-83. [76] Weber T, Abendroth D, Schelzig H. Rapamycin rescue therapy in patients after kidney transplantation: first clinical experience. Transpl Int 2005;18:151-6. [77] Bumbea V, Kamar N, Ribes D, et al. Long-term results in renal transplant patients with allograft dysfunction after switching from calcineurin inhibitors to sirolimus. Nephrol Dial Transplant 2005;20: 2517-23. [78] Tomlanovich SJ, Vincenti F. Sirolimus: defining nephrotoxicity in the renal transplant recipient. Clin J Am Soc Nephrol 2007;2:198-9. [79] Pascual J, Boletis IN, Campistol JM. Everolimus (Certican) in renal transplantation: a review of clinical data, current usage, and future directions. Transplant Reviews 2006;20:1-18.