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therapy update Immnosssiv is

1961Am J Health-Syst PharmVol 69 Nov 15, 2012

t h e r a p y u p d a t e

Current trends in immunosuppressive therapiesfor renal transplant recipients

Ruth-Ann LeeAnd StevenGAbARdi

Ruth-Ann Lee, PhARm.D., CPP, is Solid Organ Transplant ClinicalSpecialist, Department o Pharmacy, and Clinical Assistant Proes-sor, Department o Pharmacy Practice and Experiential Education,Eshelman School o Pharmacy, University o North Carolina, ChapelHill. Steven GAbARDi, PhARm.D., BCPS, is Abdominal Organ Trans-plant Clinical Specialist, Renal Division, Departments o TransplantSurgery and Pharmacy Service, Brigham and Womens Hospital,Boston, MA, and Instructor in Medicine, Department o Medicine,Harvard Medical School, Boston.

Address correspondence to Dr. Lee at the Eshelman School oPharmacy, University o North Carolina, 301 Pharmacy Lane,CB# 7574, Bearch Hall 202 A, Chapel Hill, NC 27599-7574([email protected]).

The authors have declared no potential conicts o interest.

Copyright 2012, American Society o Health-System Pharma-cists, Inc. All rights reserved. 1079-2082/12/1102-1961$06.00.

DOI 10.2146/ajhp110624

Purpose. Current trends in immunosup-

pressive therapies or renal transplant

recipients are reviewed.

Summary. The common premise or

immunosuppressive therapies in renal

transplantation is to use multiple agents

to work on dierent immunologic targets.

The use o a multidrug regimen allows or

pharmacologic activity at several key steps

in the T-cell replication process and lower

dosages o each individual agent, thereby

producing ewer drug-related toxicities. In

general, there are three stages o clinical

immunosuppression: induction therapy,

maintenance therapy, and treatment o

an established acute rejection episode.

Only immunosuppressive therapies used

or maintenance therapy are discussed in

detail in this review. The most common

maintenance immunosuppressive agents

can be divided into ve classes: (1) the

calcineurin inhibitors (CNIs) (cyclosporine

and tacrolimus), (2) costimulation blockers

(belatacept), (3) mammalian target o ra-

pamycin inhibitors (sirolimus and everolim-

us), (4) antiprolieratives (azathioprine and

mycophenolic acid derivatives), and (5) cor-

ticosteroids. Immunosuppressive regimens

vary among transplantation centers but

most oten include a CNI and an adjuvant

agent, with or without corticosteroids. Se-

lection o appropriate immunosuppressive

regimens should be patient specic, taking

into account the medications pharmaco-

logic properties, adverse-event prole, and

potential drugdrug interactions, as well

as the patients preexisting diseases, risk o

rejection, and medication regimen.

Conclusion. Advancements in transplant

immunosuppression have resulted in a sig-

nicant reduction in acute cellular rejection

and a modest increase in long-term patient

and grat survival. Because the optimal

immunosuppression regimen is still un-

known, immunosuppressant use should be

infuenced by institutional preerence and

tailored to the immunologic risk o the pa-

tient and adverse-eect prole o the drug.

Am J Health-Syst Pharm. 2012; 69:1961-

75

The common premise or im-munosuppressive therapies inkidney transplantation is to use

multiple agents to work on dier-ent immunologic targets. The useo a multidrug regimen allows orpharmacologic activity at severalkey steps in the T-cell replicationprocess and lower dosages o eachindividual agent, thereby produc-ing ewer drug-related toxicities.In general, there are three stages oclinical immunosuppression: induc-tion therapy, maintenance therapy,and treatment o an established

acute rejection episode. Only im-munosuppressive therapies used ormaintenance therapy are discussedin detail in this review.

It is important to understand thethree-signal model o T-cell activa-tion and cell prolieration, becausemultidrug regimens act on several keytargets. Briey, signal 1 is an antigen-specifc signal that is provided bythe triggering o T-cell receptorsby antigen-presenting cells (APCs)and is transduced through the CD3complex.1 Signal 2 is activated by thebinding o costimulatory moleculesand their ligands. These two signals

activate the intracellular pathwaysthat lead to the expression o inter-

leukin 2 (IL-2) and other growthactors. Signal 3 triggers cell proli-eration via stimulation o the IL-2receptor.1,2

Maintenance immunosuppres-sion is generally achieved by com-

bining two or more medicationsrom dierent drug classes. Thismaximizes the regimens eective-ness by targeting unique components


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1962 Am J Health-Syst PharmVol 69 Nov 15, 2012

o the immune response. The goalso maintenance immunosuppres-sion are to prevent acute rejectionepisodes and optimize long-termpatient and grat survival. Careul se-

lection o antirejection medicationsand vigilant dosage adjustment arerequired to balance the risk o rejec-tion with the risk o toxicities. Someo the most notorious adverse post-transplantation events (e.g., inec-tion, malignancy) are associated withthe net state o immunosuppression;thereore, it is essential that the de-gree o immunosuppression can begradually reduced in the absence orejection episodes.

Between the 1960s and 1980s,azathioprine and corticosteroidswere the cornerstones o mainte-nance suppression therapy or renaltransplantation. The development ocyclosporine in the early 1980s revo-lutionized renal transplantation bydramatically reducing rejection ratesand improving one-year grat sur-vival rates. The evolution o main-tenance immunosuppressants in the1990s resulted in several new drugoptions to urther prevent rejectionand improve outcomes. These agentshave made it possible to attain acuterejection rates o10% and increaseone-year grat survival rates to over90%.

The most common maintenanceimmunosuppressive agents can bedivided into ive classes: (1) thecalcineurin inhibitors (CNIs) (cy-closporine and tacrolimus), (2)costimulation blockers (belatacept),(3) mammalian target o rapamycin

(mTOR) inhibitors (sirolimus andeverolimus), (4) antiprolieratives(azathioprine and mycophenolic acidderivatives), and (5) corticosteroids.

Immunosuppressive regimensvary among transplantation centersbut most oten include a CNI andan adjuvant agent, with or withoutcorticosteroids. Selection o appro-priate immunosuppressive regimensshould be patient speciic, takinginto account the medications phar-

macologic properties, adverse-eventproile, and potential drugdruginteractions, as well as the patientspreexisting diseases, risk o rejection,and medication regimen.

CNIs

Pharmacology. The CNIs cyclo-sporine and tacrolimus elicit theirimmune response by orming a com-plex with cytoplasmic proteins (cy-closporine with cyclophilin, and ta-crolimus with FK binding protein-12[FKBP-12]).1,2 These drugproteincomplexes bind to and inhibit cal-cineurin phosphatase, which pre-vents the dephosphorylation and

translocation o the nuclear actoro activated T cells. Inhibition othe passage o these cells throughthe nuclear membrane hampers theexpression o several key cytokinegenes that promote T-cell activationand expansion. The end result ocalcineurin inhibition is a reduc-tion in cytokine synthesis and asubsequent decline in lymphocyteprolieration.1-3

Drugs and dosages. Cyclosporineis available in oral and injectableormulations with markedly variablebioavailability.1-3 The original, oil-based ormulation, frst available in1983, had bile-dependent absorptionresulting in erratic bioavailability.Thereore, a modifed microemul-sion became available in 1994, allow-ing an improved pharmacokineticproile and more consistent drugexposure. Cyclosporine (modifed)is the preerred ormulation ormost transplantation centers that

continue to use cyclosporine-basedmaintenance therapy.3 It is importantto note that the two ormulationsare not interchangeable; however,conversion rom the unmodifed tothe modifed ormulation is sae withproper therapeutic drug monitoring(TDM). The labeled initial oral dos-age o cyclosporine or adults aterrenal transplantation is dependenton the ormulation, ranging rom 6to 18 mg/kg daily; however, the high-

er dosage is rarely used.1-4 The biliarypathway is the primary eliminationroute or more than 25 identifedmetabolites o cyclosporine; how-ever, the parent compound provides

almost all o the immunosuppressiveeects.1 Although the unmodiiedormulation is rarely prescribed inpractice, it is not recommended to al-ter the ormulation or patients whoare stable on this agent.

Tacrolimus was approved by theFood and Drug Administration(FDA) in 1994 to prevent grat rejec-tion in transplant recipients and iscommercially available in oral andinjectable ormulations.1,2,5 The rec-

ommended oral dosage o tacrolimusor adults ater renal transplantationis 0.2 mg/kg daily (range, 0.10.3 mg/kg daily) given in two divided doses.In rare instances, tacrolimus may begiven sublingually i gut absorptionis questionable.6,7 More than 95%o tacrolimus metabolites are elimi-nated via the biliary route; thereore,biliary obstruction increases theconcentration o tacrolimus metabo-lites in the blood.1 Two once-daily,extended-release tacrolimus ormu-lations (LCP-Tacro, Veloxis Phar-maceuticals, and Advagra, AstellasPharma Europe Ltd.) are currentlyunder review in the United States.2,8

The i.v. ormulation o tacrolimushas the potential to cause anaphy-laxis, most likely attributable tothe polyoxyethylated hydrogenatedcastor oil delivery vehicle, and to in-crease the risk o nephrotoxicity andneurotoxicity because o overexpo-sure to the vehicle; thus, the i.v. or-

mulation is generally used only i theoral route is unavailable.9 I.V. CNIsare commonly administered as a con-tinuous inusion; alternatively, thetotal daily dose can be divided intotwo doses and inused over 4 hours.Conversion rom oral to i.v. adminis-tration o cyclosporine or tacrolimusrequires a reduction to one third orone fth o the total daily oral dose,respectively, with close TDM. Whenconverting rom the i.v. to oral


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route, the frst oral dose should beadministered within 812 hours aterdiscontinuation o i.v. therapy. Poly-vinyl chloride containers and tubingmay compromise drug stability and

should thus be avoided.4,5,9

CNIs should be initiated as soonas possible. There is no evidence thatdelaying CNI initiation will beneftrenal unction, improve delayed gratunction, or prevent acute rejection.10The earlier that a CNI reaches tar-get serum levels, the more eectivethe CNI will be in preventing acuterejection. Generic ormulations ocyclosporine (unmodifed and modi-fed) and tacrolimus are considered,

by FDA standards, to be bioequiva-lent to their innovator products.The initial dosage must take intoaccount the patients immunologicrisk profle, preexisting disease states,history o common transplantationcomplications, and use o adjuvantimmunosuppressive agents.1,2,10

TDM. Constant monitoring oserum cyclosporine and tacrolimuslevels is imperative, especially in theperiod immediately ollowing trans-plantation, given the great variationin interpatient and intrapatientabsorption and metabolism o theseagents.11-13 Although not the ocuso this review, it is important to notethat contributing actors inuenc-ing this variation may be due tothe method used to measure bloodconcentrations o these agents, in-cluding radioimmunoassay, high-perormance liquid chromatography(HPLC), and enzyme-multiplied im-munoassay technique.1 Identiying

the institutions preerred methodis essential, because HPLC mea-sures only the parent compound,while other methods will detect allmetabolites.1

Trough serum levels have been thestandard monitoring parameter orthe management o patients takingboth cyclosporine and tacrolimus.11,12However, or cyclosporine, troughconcentrations may not provide op-timal correlation with either efcacy

or toxicity.12,13 The medical literaturesuggests that total exposure to cyclo-sporine as determined by the areaunder the serum concentrationtimecurve (AUC) is best predicted by a

two-hour-postdose concentration(C2) level and that a desirable C

2

range is 8001500 ng/mL.12-14 Thelong-term benefts oC

2monitoring

are unclear; however, initial improve-ments in renal unction and reduc-tions in the requency and severity ocyclosporine-induced hypertensionhave been observed when such moni-toring is employed.12-14 Manuacturerrecommendations or cyclosporineand tacrolimus trough concentra-

tions range rom 100 to 400 ng/mLand rom 5 to 20 ng/mL, respec-tively,4,5 depending on several actors,including the patients immunologicrisk profle, the time elapsed sincetransplantation, adverse events, andinstitution-specifc protocols.1,2,10-14Trough concentrations toward theupper limit o the target range aregenerally avoided due to drug-relatedtoxicities, and several studies haveound excellent efcacy and toler-ability with tacrolimus trough con-centrations o12 ng/mL.12

Adverse events. One o the majordrawbacks o CNIs is their extensiveadverse-eect profle (Appendix A),with most toxicities being dose de-pendent. One o the most challengingeects o CNIs is their ability to causeacute and chronic nephrotoxicity, aswell as neurotoxicity, hypertension,hyperlipidemia, and posttransplan-tation diabetes.1,2,21 However, slightdierences between cyclosporine and

tacrolimus may inuence the use oone agent over another.

Comparative efficacy. The useo cyclosporine has signiicantlydecreased since the advent o tacro-limus in 1994. However, it remainsunclear which CNI should be pre-erentially used in renal transplantrecipients.22-25 Early trials demon-strated lower one-year requencyo biopsy-proven acute rejection(BPAR) and lower serum creatinine

levels with tacrolimus comparedwith both cyclosporine ormulations;however, long-term ollow-up re-vealed minimal dierences in patientand grat survival and unction.

Gonwa et al.25

evaluated 30 ran-domized controlled trials includingover 4000 patients in an attempt todierentiate the relative efcacy andsaety o cyclosporine and tacrolimusin renal transplantation. The meta-analysis revealed that tacrolimuswas associated with a signifcantlyreduced rate o grat loss, indepen-dent o the type o cyclosporineormulation used, at 6 months atertransplantation (relative risk [RR],

0.56; 95% confdence interval [CI],0.360.86). This beneit persistedthree years ater transplantation butwas diminished in patients in whomhigher tacrolimus concentrationswere targeted. Tacrolimus was oundto have a 12-month beneft on therequency o rejection (RR, 0.69; 95%CI, 0.600.79) and corticosteroid-resistant rejection (RR, 0.49; 95%CI, 0.370.64). A comparison o thedrugs saety profles revealed that ta-crolimus was associated with a higherrisk o posttransplantation diabetesand neurologic and gastrointestinaleects compared with cyclosporine.Cyclosporine-treated patients com-plained o more cosmetic-relatedadverse events and had higher rateso hyperlipidemia.

Recent consensus guidelines havesuggested a beneft in using tacroli-mus over cyclosporine in preventingearly acute rejection; however, nodierences in patient survival, grat

unction, inection, malignancy, orblood pressure have been ound.10

CNI minimization strategies.CNIs have undeniably improvedshort-term outcomes in renal trans-plantation.10 Attention has recentlyshited toward preventing CNI-related toxicities while improvingoverall grat unction and survival.Several comprehensive reviews oCNI-sparing regimens have beenpublished.26-30 The larger trials ex-


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ploring these strategies are reviewedbelow.

Vincenti et al.27 explored de novoCNI avoidance in 98 renal transplantrecipients with low immunologic

risk.

Immunosuppression consistedo daclizumab induction, myco-phenolate moetil, and prednisone.The rates o one-year patient andgrat survival were excellent (97%and 96%, respectively); however,the requency o acute rejection at6 months was 48%. This high rateo acute rejection prompted theCAESAR trial,28 designed to inves-tigate the efcacy and saety o denovo CNI reduction versus cyclo-

sporine withdrawal.

This prospective,multicenter trial randomized 536renal transplant recipients into threegroups: (1) standard-dose cyclo-sporine, (2) daclizumab inductionwith low-dose cyclosporine (targetcyclosporine trough, 50100 ng/mL),and (3) daclizumab induction withlow-dose cyclosporine, which waswithdrawn at 6 months. All patientsreceived mycophenolate moetil andprednisone. The primary endpointwas renal unction; secondary end-points included rates o BPAR andgrat survival. The 12-month meanglomerular fltration rate (GFR) didnot signifcantly dier among thegroups; however, the requency oBPAR at 12 months was signifcantlyhigher in the low-dose cyclosporinewithdrawal group (38%) versus thelow-dose (25.4%) and standard-dose (27.5%) groups (p < 0.05).The investigators concluded that(1) cyclosporine withdrawal was as-

sociated with a higher requency oBPAR, potentially contributing tourther organ damage, and (2) low-dose cyclosporine was not inerior tostandard-dose cyclosporine in termso BPAR and showed no impact onreducing adverse eects.

The same group o investiga-tors urther explored the use olow-dose CNI in the largest ran-domized controlled trial involvingpatients who underwent de novo

renal transplantation to date.29 TheELITE-SYMPHONY trial random-ized 1645 renal transplant recipientsto one o our treatment groups: (1)standard-dose cyclosporine (target

cyclosporine trough, 150300 ng/mLor 3 months, ollowed by 100200ng/mL), (2) daclizumab inductionwith low-dose tacrolimus (targettacrolimus trough, 37 ng/mL), (3)daclizumab induction with low-dosesirolimus (target sirolimus trough,48 ng/mL), or (4) daclizumab in-duction with low-dose cyclosporine(target cyclosporine trough, 50100ng/mL). All patients received myco-phenolate moetil and prednisone.

The primary endpoint o this studywas renal unction, and the sec-ondary endpoints were requencyo BPAR and grat survival at 12months. The mean calculated GFR at12 months was higher in the tacroli-mus group (65.4 mL/min) comparedwith the other three groups (range,56.759.4 mL/min), and the requen-cy o BPAR was lower in the tacroli-mus group (12.3%) than in the otherthree groups (range, 2437.2%). Therate o grat survival was signii-cantly higher in the tacrolimus group(94.2%) compared with the otherthree groups (range, 89.393.1%;p = 0.02). Serious adverse eventswere most commonly reported inthe sirolimus group (53.2%) com-pared with the other groups (range,43.444.3%). Three-year observa-tional ollow-up continued to showsuperior GFR and grat survivalin the tacrolimus group comparedwith the other groups.30 Based on

this trial, the Ekberg et al. concludedthat low-dose tacrolimus providedeective immunosuppression whilepotentially avoiding negative eectson renal unction.

A meta-analysis o 19 trials in-cluding 3321 patients was con-ducted to evaluate a CNI-sparingregimen with mycophenolate moetilonly with a median ollow-up timeo 12 months.31 Five subgroupswere analyzed and compared with

standard-dose or higher-dose CNItherapy: (1) de novo CNI minimi-zation, (2) elective CNI minimiza-tion, (3) elective CNI elimination (2months ater transplantation), (4)

CNI minimization in renal dysunc-tion, and (5) CNI elimination inrenal dysunction. Overall, the risk oacute rejection did not signifcantlydier among groups; however, ahigher GFR was apparent among allCNI-sparing trials versus controls,potentially aecting long-term gratsurvival. Signiicant heterogeneitybetween subgroups was evident, asthere was an increased risk o acuterejection between subgroups, par-

ticularly with elective CNI elimina-tion regimens in patients with nor-mal renal unction compared withpatients in any CNI minimizationor elimination subgroup with renaldysunction. De novo CNI minimi-zation and early withdrawal may bea sae alternative or patients withdeclining renal unction; however,late CNI withdrawal to stabilize orimprove renal unction may resultin irreversible kidney damage beoreCNI discontinuation. The authorsconcluded that CNI withdrawalshould be done careully to minimizethe risk o acute rejection.

Overall, de novo CNI minimiza-tion, rather than CNI avoidance, maybe the best regimen or sparing renalunction and maintaining acceptableacute rejection rates. Furthermore,identiying a population with a lowimmunologic risk that may beneftrom this regimen is essential. Long-term data are needed to confrm that

the short-term benefts will persist.

Costimulation blockade

Pharmacology. Belatacept is anewly approved biological indi-cated or long-term maintenanceimmunosuppressive therapy in renaltransplant recipients.32,33 This agentworks by binding to CD80 and CD86receptors on APCs and blocking theCD28-mediated costimulation o Tcells. Costimulation is a critical com-


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ponent o the three-signal transplantmodel o T-cell activation.

Belatacept dosage. Belataceptrepresents a major paradigm shit inimmunosuppression or transplant

recipients, being the irst FDA-approved i.v. maintenance immu-nosuppressant. This medication isadministered in two distinct phases:the initial phase and the mainte-nance phase.15,33 In the initial phase,belatacept is administered at 10 mg/kg i.v. on postoperative days 0 and 4,ollowed by postoperative weeks 2,4, 8, and 12. The maintenance phasebegins at the end o postoperativeweek 16, with a belatacept dose o 5

mg/kg, which is administered every 4weeks (within three days) thereater.The manuacturer recommends thatdoses should be calculated using thepatients actual body weight at thetime o transplantation and shouldnot be modifed during the courseo therapy, unless there is a change inbody weight o greater than 10%.15

The manuacturer also recommendsthat the fnal dose be evenly divisibleby 12.5 mg in order or the dose tobe prepared accurately. Each doseshould be inused over 30 minutes.

TDM. One o the beneits obelatacept is that TDM is not re-quired. In clinical trials, belatacepttrough concentrations remainedconstant 336 months ater renaltransplantation.15,33 Moreover, be-latacept clearance is not aectedby patient age, sex, or race; renal orhepatic unction; or the presence orabsence o diabetes.

Adverse events. The adverse-

event profle o belatacept is simi-lar to or better than that o CNItherapy.34-36 However, belataceptslabeling carries a black-box warningregarding the risk o posttransplan-tation lymphoprolierative disorder,predominantly involving the centralnervous system.15,33 Because therisk o this disorder is particularlyhigh in potential transplant recipi-ents who have not been exposed tothe Epstein-Barr virus (EBV), the

manuacturer recommends usingbelatacept only in patients testingseropositive or the virus.15 The mostcommon adverse events associatedwith belatacept are listed in Appen-

dix A. Although inusion-relatedreactions have occurred inrequently,belatacept inusions have been gen-erally well tolerated; thereore, pre-medication is not required beore theinusion.34,35,37 Two cases o progres-sive multiocal leukoencephalopathyhave been reported15; however, inboth cases, the patients were receiv-ing doses much higher than thosecurrently approved.34,35,37

Comparative efficacy. A Phase

III, randomized, active-controlled,partially blind, parallel-group studyo belatacept-based immunosup-pression regimens versus cyclospo-rine in renal transplant recipients(BENEFIT) was conducted over three

years in 100 centers worldwide.34 Twobelatacept-based regimens (a more-intensive regimen [10 mg/kg duringmonths 06, ollowed by 5 mg/kgduring months 712] and a less-intensive regimen [10 mg/kg duringmonths 03, ollowed by 5 mg/kgduring months 312] were comparedwith a cyclosporine-based regimen.Three primary outcomes were evalu-ated: (1) a composite o patient andgrat survival, (2) composite renalimpairment, and (3) the requency oacute rejection at 12 months. All pa-tients received basiliximab induction,maintenance therapy with myco-phenolate moetil (2 g orally daily),and corticosteroids in addition tothe study drug. Both belatacept regi-

mens met the nonineriority margino 10% as well as a more rigorousthreshold o 5% or patient and gratsurvival compared with the cyclo-sporine regimen. Renal unction wassuperior in patients who receivedbelatacept versus cyclosporine. Therequency o acute rejection at 12months was 22% in patients receiv-ing the more-intensive belataceptregimen, 17% in those receiving theless-intensive belatacept regimen,

and 7% in the cyclosporine-treatedgroup. The less-intensive belataceptregimen was deemed noninerior orpreventing acute rejection comparedwith cyclosporine by satisying a

20% margin or comparison. Themean measured GFR was 1315mL/min higher in the belataceptgroupsdespite a higher requency oBPAR. Cardiovascular and metabolicoutcomes were considerably betterin both belatacept groups versus thecyclosporine group. Blood pressurewas lower in both belatacept groupsversus the cyclosporine group (p 0.0273), and cyclosporine-treatedpatients required more antihyper-

tensive therapies. Concentrationso non-high-density lipoproteinsincreased in all treatment groups,and triglyceride levels decreased inboth belatacept groups compared toincreases that were observed in thecyclosporine group. The requencyo new-onset diabetes mellitus wasnot statistically dierent among thetreatment groups. No signifcant di-erences were noted in the requen-cies o the most common adverseevents (anemia, urinary tract inec-tion, hypertension, constipation,diarrhea, and nausea) among treat-ment groups. Frequencies o bacte-rial, viral, and ungal inections weresimilar in all groups.

A one-year, randomized, open-label, Phase II, multicenter trialwas conducted to evaluate the ef-cacy and saety o tacrolimus-basedimmunosuppression versus twobelatacept-based regimens withwhich corticosteroid and CNI avoid-

ance was attempted.36 Eighty-nineEBV-seropositive adults who re-ceived a renal transplant rom aprimary living donor or standard-criteria deceased donor were ran-domized in a 1:1:1 ashion to one othree treatment groups: belataceptand mycophenolate moetil (n = 33),belatacept and sirolimus (n = 26),or tacrolimus plus mycophenolatemoetil (n = 30). All patients receivedrabbit-antithymocyte globulin induc-


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tion and underwent corticosteroidwithdrawal. The belatacept mainte-nance dose was 10 mg/kg i.v. or thefrst six months ater transplanta-tion and then reduced to 5 mg/kg

thereater. The primary endpoint wasrequency o acute rejection at sixmonths, which occurred at a rate o12%, 4%, and 3% in the belataceptplus mycophenolate, belatacept plussirolimus, and tacrolimus plus myco-phenolate groups, respectively. Mostrejection episodes occurred withinthe frst three months ater trans-plantation; however, one episode inthe belatacept plus mycophenolategroup occurred ater month 6. The

composite endpoint o patient andgrat survival was similar amongtreatment groups (91%, 92%, and100% in the belatacept plus myco-phenolate, belatacept plus sirolimus,and tacrolimus plus mycophenolategroups, respectively). One patient inthe belatacept plus mycophenolategroup died during the study period.The calculated GFR or each groupwas 64 27 mL/min, 62 31 mL/min, and 54 15 mL/min or thebelatacept plus mycophenolate,belatacept plus sirolimus, and tacro-limus plus mycophenolate groups,respectively. CNI and corticosteroidavoidance was successul in 73% othe belatacept plus mycophenolate-treated patients and 77% o thebelatacept plus sirolimus-treated pa-tients; corticosteroid avoidance alonewas achieved in 93% o patients re-ceiving tacrolimus plus mycopheno-late. Frequencies o serious inectionwere similar in each treatment group:

21%, 15%, and 17% in the belataceptplus mycophenolate, belatacept plussirolimus, and tacrolimus plus myco-phenolate groups, respectively.

Several studies have demonstratedthat belatacept is as efcacious asCNIs in preventing acute rejectionand is associated with improvedoutcomes in GFR or renal trans-plant recipients.34-38 Substitution obelatacept or a CNI may spare renaltransplant patients rom the adverse

nephrotoxic and cardiovascular e-ects o CNIs. A Phase II, random-ized, open-label study was conduct-ed to evaluate conversion rom aCNI-based regimen to belatacept in

renal transplant recipients.39

A totalo 171 patients who had undergonerenal transplantation 636 monthsprior, were receiving CNI-based im-munosuppression, and had stablerenal unction were randomized toreceive one o two treatments: con-version to belatacept 5 mg/kg withCNI discontinuation (n = 83) orcontinued CNI therapy (n = 88). Allpatients remained on their mainte-nance immunosuppressive agents,

including mycophenolate, sirolimus,azathioprine, and corticosteroids. Atmonth 12, the primary outcome omean S.D. change in GFR (as cal-culated with the Modifcation o Dietin Renal Disease ormula) rom base-line increased by 7.0 11.99 mL/minin the belatacept group and by 2.1 10.34 mL/min in the CNI group.Six patients (7%) who underwentbelatacept conversion experiencedan acute rejection episode withinthe frst 6 months versus none in theCNI group. The requency o patientand grat survival was 100% in thebelatacept group and 99% in the CNIgroups. The overall saety profle wassimilar in each treatment group.

mTOR inhibitors

Pharmacology. The mTOR in-hibitors sirolimus and everolimusare macrolide antibiotics that inhibitlymphocyte activation and proliera-tion.2,16,40 Intracellularly, both agents

orm a complex with FKBP-12, sub-sequently binding to and modulatingthe activity o mTOR, a key regula-tory kinase in cytokine-dependentT-cell prolieration. Inhibition omTOR results in the arrest o thecell-division cycle in the G

1-to-S

phase. Both mTOR inhibitors alsoaect hematopoietic and nonhema-topoietic cells.

Drugs and dosages. Sirolimus isavailable only in an oral ormula-

tion.16 When initiating sirolimus inde novo renal transplant recipientswith a low-to-moderate immuno-logic risk, a sirolimus loading doseo 6 mg be given, ollowed by a

maintenance dosage o 2 mg daily.16,40

Although maintenance dosages o5 mg/day, ater a 15-mg loadingdose, have been studied or thisindication, no eicacy advantageover the 2-mg/day dosage has beenestablished. For renal transplantrecipients with a high immunologicrisk, a sirolimus loading dose o 15mg is recommended, ollowed by amaintenance dosage o 5 mg daily.16Despite the manuacturers dosing

recommendations, loading doses arerarely used in clinical practice, andloading and maintenance doses areoten lower than those that appearin the drugs FDA-approved labeling.Everolimus was recently approvedby FDA or the prevention o rejec-tion in low-to-moderate-risk renaltransplant recipients when given inconjunction with basiliximab induc-tion, reduced-dosage cyclosporine,and corticosteroids.17,41 The recom-mended starting dosage o everoli-mus is 0.75 mg twice daily, withoutthe need or a loading dose.17

TDM. An excellent correlationexists between whole-blood troughconcentrations and the AUC or siro-limus.42 The target sirolimus troughranges rom 5 to 24 ng/mL; however,in clinical practice, this target is high-ly dependent on institution-specifcprotocols.16,42 In low-to-moderateimmunologic risk patients, cyclo-sporine withdrawal is recommended,

and the target sirolimus trough rangeis 1624 ng/mL within the frst yearposttransplantation.16 Thereater,target trough sirolimus concentra-tions should be 1220 ng/mL. In pa-tients with a high immunologic risk,sirolimus doses should be adjustedto obtain troughs o 1015 ng/mL incombination with cyclosporine andcorticosteroids. Additional thera-peutic ranges or various immuno-suppression strategies can be ound


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in the package insert.16 Due to thedose-dependent adverse eects otenassociated with sirolimus, highertherapeutic ranges o sirolimus arenot encouraged. Sirolimus has a

hal-lie o approximately 62 hours,so patients receiving maintenancesirolimus who require a dosageadjustment will not achieve a newsteady-state level or several days.Thus, trough serum levels

should be

monitored fve to seven days aterthe dosage adjustment. The admin-istration o a loading dose generallyhelps achieve a steady-state trough

within 24 hours or de novo renaltransplant recipients; however, it is

not recommended to use sirolimusimmediately ater renal transplan-tation. Despite the approved TDMrecommendations, sirolimus is o-ten used with target trough concen-trations below those recommendedby the manuacturer, and its use isoten dictated by center-speciicprotocols, adjuvant immunosup-pression, and patient-specifc im-munologic risk. For everolimus,the recommended target troughis 38 ng/mL.17,41 With a signii-cantly shorter hal-lie, steady-stateeverolimus levels can be reached in90150 hours.17

Adverse events.Some o the mostrequently reported adverse eventsassociated with mTOR inhibitorsare listed in Appendix A. Early post-transplantation complications osirolimus, particularly the potentialto prolong or increase the occurrenceo delayed grat unction, as well aspoor wound healing, lymphocele

ormation, pneumonitis, and muco-sitis, have limited the de novo use othis agent.39,40 Everolimus is indicatedor de novo use despite the potentialto have a toxicity profle similar tothat o sirolimus. Proteinuria andglomerulonephropathy have beenreported with mTOR inhibitors,especially ater conversion rom aCNI.43-48 Other important, yet rare,adverse events with these agents in-clude hemolytic uremic syndrome,

thrombotic microangiopathy, andliver dysunction.16,17,40

Clinical efcacy. The efcacy osirolimus or primary maintenanceimmunosuppression ater renal

transplantation is well documented.Early studies ocused on its use as anadjunct agent in combination withcyclosporine and ound higher rateso impaired renal unction. Newerstudies have ocused on its use asa primary immunosuppressant toreplace CNIs. The clinical use o si-rolimus has been investigated in denovo transplant recipients with CNIavoidance regimens and CNI conver-sion protocols.

De novo utilization strategies. Ina single-center, prospective trial,Flechner and colleagues49 random-ized 61 renal transplant recipientsto receive either concentration-controlled sirolimus (target trougho 1012 ng/mL or the irst sixmonths, then 510 ng/mL therea-ter) or cyclosporine (target trougho 200250 ng/mL) in addition tobasiliximab induction, mycophe-nolate, and prednisone. There wassignifcantly improved renal unctionat one, two, and fve years in the siro-limus group versus the cyclosporinegroup (66.7 mL/min versus 50.7 mL/min at fve years,p = 0.0075).49-51 Incontrast, several retrospective analy-ses have ound sirolimus-containingregimens to be associated withsignifcantly worse long-term out-comes.52,53 The largest o these stud-ies was a retrospective analysis o theScientifc Registry o Renal Trans-plant Recipients that included over

2000 patients receiving immunosup-pression with sirolimus and myco-phenolate.52 Compared with severalregimens involving the combinationo CNI with either mycophenolateor sirolimus, the combination osirolimus and mycophenolate wasassociated with higher six-monthacute rejection rates compared withother regimens (16% versus 11.2%,

p < 0.01) and lower fve-year gratsurvival (64% versus 78%,p = 0.001).

For deceased-donor renal transplantrecipients, delayed grat unction washighest in the sirolimus and myco-phenolate group (47% versus 27%,

p < 0.001). Inconsistent outcomes

may be attributable to several actors,including population size and trialdesign. However, several investiga-tors have alluded to the importanceo maintaining higher trough siro-limus levels or the frst six months.In the SYMPHONY trial, low-dosesirolimus (target trough o 48 ng/mL) resulted in the highest rates oacute rejection compared with theother treatment groups.29,30

Most recently, the ORION study

demonstrated that there was no ben-eft associated with sirolimus-basedimmunosuppression in regimensthat either withdraw or completelyavoid CNIs.53 The ORION study wasan open-label multicenter trial thatrandomized 469 renal transplantrecipients to receive sirolimus andtacrolimus with a subsequent tacro-limus withdrawal at postoperativeweek 13 (group 1), sirolimus and my-cophenolate (group 2), or tacrolimusand mycophenolate (group 3). Allpatients received IL-2 receptor antag-onist induction and corticosteroids.Overall, there was no dierencebetween patient or grat survival orrenal unction at one and two years.The requency o acute rejection washighest in group 2, most o which oc-curred during the frst six months otreatment and led to the terminationo the study in that group. The rate oadverse eects that necessitated drugdiscontinuation was higher in the

sirolimus-treated groups. Overall,these data, along with the potentialor early posttransplantation compli-cations with sirolimus, have limitedthe use o this agent in de novo renaltransplant recipients at some cen-ters. Several Phase II and III studieshave demonstrated the efcacy andsaety o everolimus when used witha cyclosporine-sparing regimen in denovo renal transplant recipients.41,54These studies also demonstrated that


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use o everolimus with reduced-dosecyclosporine preserves renal unctionwithout the loss o efcacy comparedwith ull-dose cyclosporine regimens.

Conversion strategies. Due to in-

conclusive results and an increasedrequency o delayed grat unctionwith de novo sirolimus regimens,recent studies evaluated newer regi-mens that entailed early (three to sixmonths posttransplantation) and late(more than six months posttrans-plantation) CNI withdrawal andconversion to sirolimus. The Spare-the-Nephron trial was a two-year,open-label, multicenter trial evaluat-ing preservation o renal unction in

a CNI-ree regimen.

55

Two hundredninety-nine patients were random-ized to remain on standard immuno-suppression, mycophenolate moetiland a CNI (n = 151), or convert tomycophenolate and sirolimus, witha target sirolimus trough o 510ng/mL (n = 148) between 30180days posttransplantation. At one

year ater the conversion, the meanchange in the GFR was signifcantlyhigher in the sirolimus group (24.4%versus 5.2%, p = 0.012); however,the change was indistinguishable bytwo years. There was no dierencein acute rejection rates. O note, 41patients were switched back rommycophenolate plus sirolimus tomycophenolate plus a CNI, whichmay be a reason why the change inthe GFR did not persist at two years.

Several randomized trials haveevaluated late conversion to siro-limus in the setting o CNI toxic-ity or development o chronic grat

nephropathy. The CONVERT trialwas similar in design except conver-sion took place between 6 and 120months posttransplantation.56 In-vestigators identifed that convertedpatients with a GFR o >40 mL/minand a urine protein:creatinine ratioo


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tions may be necessary in patientswith severely impaired renal unc-tion, since 6-MP and its metabolitesare eliminated by the kidneys.

Mycophenolate moetil was ap-

proved by FDA in 1995, and enteric-coated mycophenolate sodium wasapproved in 2004. Mycophenolatemoetil is available in oral and in-

jectable ormulations.19 The recom-mended dosage o mycophenolatemoetil in renal transplant recipientsis 2000 mg daily in two divided doses.The bioavailability o the oral dos-age orms o mycophenolate moetilexceeds 90%; thereore, conversionbetween oral and i.v. mycophenolate

moetil is 1:1. I.V. mycophenolatemoetil must be reconstituted and di-luted to a concentration o 6 mg/mLusing 5% dextrose injection only. Ad-ministration must be by slow i.v. in-usion over no ewer than two hours,and rapid or bolus administrationshould be avoided.The recommend-ed starting dose o enteric-coatedmycophenolate sodium is 720 mg (omycophenolic acid) given twice daily,as this dosage provides the equivalentequimolar mycophenolic acid con-centrations seen with mycophenolatemoetil 1000 mg twice daily.19,57

Enteric-coated mycophenolatesodium was developed in an at-tempt to decrease the occurrence oadverse upper-gastrointestinal-tractevents associated with mycophen-olate moetil.58 Both medicationshave been studied head-to-head inde novo and stable renal transplantrecipients.59-62 In both analyses, e-fcacy and tolerability outcomes were

comparable between the ormula-tions. Most notably, there were nosignifcant dierences in adverse gas-trointestinal eects between the twoormulations. An open-label studyound distinct benefts in the relie ogastrointestinal symptoms with en-teric-coated mycophenolate sodium;however, this study was not random-ized and its data can only be regardedas indicative.63 Patients complainingo signifcant gastrointestinal dis-

tress associated with mycopheno-late moetil were converted to anequimolar dose o enteric-coatedmycophenolate sodium, resulting insignifcantly lower rates o gastroin-

testinal symptoms and an improvedquality o lie.Adverse events. The most com-

mon adverse events associated withthese agents are listed in AppendixA. Myelosuppression (mainly leu-kopenia and thrombocytopenia)is a requent, dose-dependent, anddose-limiting complication (>50%o patients) that oten necessitatesdosage reductions.18,19 Importantly,pancreatitis and veno-occlusive dis-

ease o the liver occur in ewer than1% o patients ater chronic azathio-prine therapy.18 The mycophenolicacid derivatives are considered tohave excellent tolerability comparedwith azathioprine.

TDM. Mycophenolic acid has avery complex pharmacokinetic profle;thereore, interpretation o concentra-tions is difcult.64 Results regardingactual improvement in efcacy andsaety outcomes when using TDMor patients receiving mycopheno-lic acid are conicting. Three largerandomized prospective trials haveattempted to address the role oTDM or mycophenolic acid.65-67 TheAPOMYGRE study was a 12-monthstudy that included 11 French cen-ters and randomized 137 patientsto either ixed-dose (2 g/day) orconcentration-controlled (target my-cophenolic acid AUC of 40 mg hr/L)oral mycophenolate moetil in a qua-druple immunosuppression regimen

consisting o basiliximab, cyclospo-rine modifed, and corticosteroids.65The primary endpoint was the re-quency o treatment ailure, defnedby a composite score o death, gratloss, acute rejection, and discon-tinuation o mycophenolate moetiltherapy. Mean S.D. mycophenolatemoetil doses in the concentration-controlled group were 2969 780mg, 2279 878 mg, and 1827 654mg at months 1, 3, and 12, respec-

tively. The requency o treatmentailure was signiicantly lower inthe concentration-controlled groupcompared with the fxed-dose group(29.2% versus 47.7%, p = 0.03). In-

terestingly, 7 o 10 rejection episodesoccurring in the frst 3 months o theconcentration-controlled group wereassociated with a mycophenolic acidAUC value of 45 mg hr/L. Rates of reportingat least one adverse eect were simi-lar or patients reporting at least oneadverse event in both groups (90% in

the controlled-concentration groupversus 97% in the fxed-dose group),and there were no dierences in re-quency or severity o inectious com-plications between the two groups.

In contrast, the Fixed Dose ver-sus Concentration Control (FDCC)study compared ixed-dose oralmycophenolate moetil (2 g daily)with a concentration-controlledregimen (target mycophenolic acidAUC of 3060 mg hr/L) with eithercyclosporine or tacrolimus in 901patients.66 The primary endpoint wassimilar to that in the APOMYGREtrial. During the study, 54% o pa-tients received cyclosporine, 46%received tacrolimus, and 46% o allpatients received induction therapy.There was no signifcant dierence ingrat or patient survival, BPAR, treat-ment ailure composite endpoint,rates o adverse eects, inection,or malignancy between the groups.This was expected due to the lack

o dierence in mycophenolic acidexposure between the groups. None-theless, the risk o developing BPARin the frst year ater transplantationwas 18.8% in patients with a day3 mycophenolic acid AUC o


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the concentration-controlled group.As expected, mycophenolic acidexposure was lower in the cyclospo-rine subgroup, with only 51.2% othe cyclosporine subgroup reaching

a mycophenolic acid AUC o >30mg hr/L, compared with 76.2% inthe tacrolimus group. Throughout alltime points o the study, the cyclo-sporine subgroup had a lower meanmycophenolic acid AUC comparedwith the tacrolimus group, despitethe higher mean daily doses o my-cophenolate used. Disparities inoutcomes between the two large tri-als may have been inuenced by di-erent methods used to calculate the

AUC as well as ailure to reach targetAUC levels in the FDCC trial.The Opticept trial evaluated the

saety and efcacy o mycopheno-lic acid TDM in patients receivingeither cyclosporine or tacrolimusin whom mycophenolic acid levelswere measured 12 hours beore theadministration o mycophenolatemoetil.67 In this two-year, open-label, prospective trial, 720 renaltransplant recipients were random-ized to receive one o the ollowingregimens: concentration-controlledoral mycophenolate moetil and re-duced CNI (group A), concentration-controlled mycophenolate moetiland standard CNI (group B), orixed-dose mycophenolate moetil(1 g twice daily) and standard-doseCNI (group C). In groups A and B,mycophenolate moetil dosages wereadjusted to achieve mycophenolicacid trough concentrations o 1.3mg/mL i receiving cyclosporine and

1.9 mg/mL i receiving tacrolimus.The primary endpoint was treatmentailure, a composite defned similarlyto that in the previous trials. Therewas no dierence between groupswhen standard-dose CNI was used;however, group A had ewer treat-ment ailures than did the two othergroups (22.6% versus 2829%, p =0.18). O note, mycophenolic acid12-hour predose concentrations o1.6 mg/mL were associated with

longer times to the frst BPAR.Theresults o this trial suggest thatTDM or mycophenolic acid maybe suitable in CNI-minimizationregimens. However, it is difcult to

decipher whether the low-dose CNIor concentration-controlled my-cophenolate moetil inuenced thepositive outcome o this trial.

Many o the studies evaluatingthe mycophenolic acid AUC havecalculated the AUC using limited-sampling strategies (two to oursamples at dierent times ater doseadministration).68 It is important tonote that given the dierences in ab-sorption characteristics between my-

cophenolate moetil and mycophen-olate sodium, the limited-samplingequations have not been validated incalculating AUCs resulting rom theuse o mycophenolate sodium.

Recently updated guidelines romthe 2008 Transplantation Societyconsensus meeting provided recom-mendations on the specifc patientpopulations or whom TDM isappropriate.69 Recommendationsor the target mycophenolic acidAUC remain 3060 mg hr/L forreduced risk o acute rejection.68,69Furthermore, the consensus state-ment recommends a trough myco-phenolic acid concentration o 1.3mg/L when cyclosporine is used and1.9 mg/L when tacrolimus is used;these recommendations were basedon the assumption that achievingthese trough concentration wouldensure that at least 80% o patientsreached a mycophenolic acid AUCof >30 mg hr/L. Close estimates of

the AUC can be obtained by usinglimited-sampling strategies over twoto three hours. Van Gelder and col-leagues68 outlined possible acceptablealgorithms. The use o mycophenolicacid and azathioprine TDM in renaltransplant recipients is not routinelyrecommended; however, or patientstaking regimens involving CNI mini-mization or high-risk patient popu-lations, higher mycophenolic acidexposure may be necessary.68,69

Comparative efficacy. The my-cophenolic acid derivatives havelargely replaced azathioprine as theantiprolierative agent o choicein most renal transplant centers.

Most o the initial studies compar-ing mycophenolate moetil withazathioprine ound superior acuterejection rates with mycophenolatein combination with the originalcyclosporine ormulation.70 A pooledefcacy analysis o early trials usingthe original cyclosporine ormula-tion revealed a signifcant reductionin the requency o acute rejectionand an improvement in short-termrenal unction, though no beneft in

patient or grat survival was observedwhen compared with azathioprine.71Despite earlier trials that have ledto the replacement o azathioprinewith mycophenolate, several trialshave yielded conicting data.72-76 Inthe MYSS trial, Remuzzi and col-leagues72 compared mycophenolatemoetil with azathioprine in con-

junction with cyclosporine (modi-fed) and corticosteroids in 336 renaltransplant patients. The requencyo acute rejection and grat loss wassimilar between the two groups inboth phases. Renal unction andadverse events were also compa-rable between mycophenolate- andazathioprine-treated patients at alltime points. A fve-year ollow-upstudy o these patients was con-ducted and ound a comparable rateo patient survival, grat loss, and laterejection.73 In addition, renal unc-tion and the rate o adverse eventswere similar with both agents. The

authors concluded that the previoustrials demonstrated greater efcacywith mycophenolate in conjunctionwith the original cyclosporine or-mulation.72,73 Due to the lower ac-quisition cost o azathioprine versusmycophenolate moetil, the authorssuggested the consideration o usingazathioprine over mycophenolate ormaintenance immunosuppression.

Shah et al.74 perormed a paired-kidney analysis in the United Kingdom


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in which 238 deceased donors rom1999 to 2002 donated one kidney toa patient treated with mycopheno-late moetil and the other kidney toa patient treated with azathioprine.

All patients received cyclosporine(modifed). Mycophenolate-treatedpatients exhibited increased acuterejection rates (44% versus 31%, p

immuno supre sive

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