Introduction to Introduction to TransplantationTransplantation

ImmunosuppressionImmunosuppression

HistoryHistory

19091909 - The first kidney transplant experiments were - The first kidney transplant experiments were performed in humans in France using animal kidneys performed in humans in France using animal kidneys (rabbit).(rabbit).

19331933 - The first human-to-human kidney transplant was - The first human-to-human kidney transplant was performed.performed.

19541954 - The first successful human-to-human transplant - The first successful human-to-human transplant from one twin to another by Dr. Joseph E. Murray and from one twin to another by Dr. Joseph E. Murray and his colleagues at Peter Bent Brigham Hospital in his colleagues at Peter Bent Brigham Hospital in Boston.Boston.

19621962 – The first cadaveric donor kidney transplant at – The first cadaveric donor kidney transplant at Peter Bent Brigham Hospital (now Brigham & Women's Peter Bent Brigham Hospital (now Brigham & Women's Hospital) in Boston. Hospital) in Boston.

General Principle of General Principle of ImmunosuppressionImmunosuppression

Primary immune responses are more easily repressed Primary immune responses are more easily repressed than secondary (memory)than secondary (memory)

Suppression is more likely to be achieved if therapy is Suppression is more likely to be achieved if therapy is begun before exposure to the immunogenbegun before exposure to the immunogen

Different immunosuppressants have different effects Different immunosuppressants have different effects on different immune reactions and mediatorson different immune reactions and mediators

IntroductionIntroduction

Advances in transplant immunosuppression have Advances in transplant immunosuppression have contributed to thecontributed to the decrease in the frequency of acute rejection decrease in the frequency of acute rejection increase in graft survival increase in graft survival longevity for renal allograft recipientslongevity for renal allograft recipients

Proliferation of agents meansProliferation of agents means more optionsmore options different mechanisms of actiondifferent mechanisms of action more complicated management schemesmore complicated management schemes increase potential for drug-drug interactions and increase potential for drug-drug interactions and

complex side effect profilescomplex side effect profiles

Categories of AgentsCategories of Agents

Induction agentsInduction agents

Monoclonal or polyclonal antibodies Monoclonal or polyclonal antibodies Administered intravenously immediately following Administered intravenously immediately following

surgerysurgery

Maintenance agentsMaintenance agents

PrednisonePrednisone CNIs form the cornerstone of immunosuppressive CNIs form the cornerstone of immunosuppressive

therapytherapy Antiproliferative agents: Cellcept, Imuran, RapamuneAntiproliferative agents: Cellcept, Imuran, Rapamune Triple agents / withdrawal / avoidance / conversionTriple agents / withdrawal / avoidance / conversion

Immunologic HistoryImmunologic History

SensitizationSensitization

First or re-transplantFirst or re-transplant

RejectionRejection

InfectionInfection

HLA-matchingHLA-matching

Induction AgentsInduction Agents

Muromonab (OKT3)Muromonab (OKT3)

Equine polyclonal ATG (ATGAM)Equine polyclonal ATG (ATGAM)

Rabbit polyclonal ATG (Thymoglobulin)Rabbit polyclonal ATG (Thymoglobulin)

Basiliximab (Simulect)Basiliximab (Simulect)

Daclizumab (Zenapax)Daclizumab (Zenapax)

Alemtuzumab (Campath-1H)Alemtuzumab (Campath-1H)

FTY 720FTY 720

InductionInduction

ThymoglobulinThymoglobulin

11STST dose given in OR dose given in OR Dose: 1.5 mg/kgDose: 1.5 mg/kg Total dose: usually 6 mg/kgTotal dose: usually 6 mg/kg

Adverse effects: cytokine release syndrome (fever, Adverse effects: cytokine release syndrome (fever, chills, arthralgia), leucopenia, thrombocytopeniachills, arthralgia), leucopenia, thrombocytopenia

Premedication: Tylenaol, Benadryl, HydrocortisonePremedication: Tylenaol, Benadryl, Hydrocortisone

Also effective in treating rejectionAlso effective in treating rejection

InductionInduction

Anti-IL-2 Receptor AntibodiesAnti-IL-2 Receptor Antibodies

Basiliximab (Simulect)Basiliximab (Simulect) Daclizumab (Zenapax)Daclizumab (Zenapax)

Anti-IL-2 Receptor AntibodiesAnti-IL-2 Receptor Antibodies

Basiliximab (Simulect)Basiliximab (Simulect) Chimeric antibody (75% human, 25% mouse)Chimeric antibody (75% human, 25% mouse) Dosing: 20 mg i.v. pre-op and POD# 4Dosing: 20 mg i.v. pre-op and POD# 4

Daclizumab (Zenapax)Daclizumab (Zenapax) Humanized (95% human, 5% mouse)Humanized (95% human, 5% mouse) Dosing: 1 mg/kg pre-op and q 2 w for total 6 dosesDosing: 1 mg/kg pre-op and q 2 w for total 6 doses

Not effective for treating rejectionNot effective for treating rejection

Calcineurin InhibitorsCalcineurin Inhibitors

CyclosporineCyclosporine

Different preparation are not equivalentDifferent preparation are not equivalent Sandimmune (cyclosporine, USP)Sandimmune (cyclosporine, USP) Gengraf (cyclosporine, USP – Modified)Gengraf (cyclosporine, USP – Modified) Neoral (cyclosporine, USP – Microemulsion)Neoral (cyclosporine, USP – Microemulsion)

Tacrolimus (FK 506, Prograf)Tacrolimus (FK 506, Prograf)

Advantages of CsA Microemulsion Advantages of CsA Microemulsion formulationformulation

Twice the bioavailability Twice the bioavailability

Less intraindividual and interindividual variabilityLess intraindividual and interindividual variability Reduced time (more than 30 percent) to maximal Reduced time (more than 30 percent) to maximal

concentration (Tmax) concentration (Tmax)

Absorption and drug levels are less susceptible to the Absorption and drug levels are less susceptible to the effects of food (particularly fatty foods), effects of food (particularly fatty foods),

Not dependent upon bile salts for absorption. Not dependent upon bile salts for absorption.

CNI: DosingCNI: Dosing

Cyclosprine (Neoral, Gengraf, Sandimmune)Cyclosprine (Neoral, Gengraf, Sandimmune)

Initial dosing: 8-10 mg/kg/dayInitial dosing: 8-10 mg/kg/day Maintenance: 2-6 mg/kg/dayMaintenance: 2-6 mg/kg/day

Tacrolimus (Prograf)Tacrolimus (Prograf)

Initial dosing: 0.15 mg/kg/dayInitial dosing: 0.15 mg/kg/day Maintenance:0.05-0.15 mg/kg/dayMaintenance:0.05-0.15 mg/kg/day

Cyclosporin: MonitoringCyclosporin: Monitoring

Low riskLow risk Mod RiskMod Risk High riskHigh risk

0-6 m0-6 m 150-250 150-250 ng/mlng/ml 175-325 175-325 ng/mlng/ml 200-350 200-350 ng/mlng/ml

6-12 m6-12 m 100-200 100-200 ng/mlng/ml 125-225 125-225 ng/mlng/ml 150-250 150-250 ng/mlng/ml

> 12 m> 12 m 50-150 50-150 ng/mlng/ml 75-175 75-175 ng/mlng/ml 100-200 100-200 ng/mlng/ml

S Hariharan. Am J Kidney Dis. 2006. 47(S2):S22-S36.

Trough or C0 level

MonitoringMonitoring

Cyclosporin: MonitoringCyclosporin: Monitoring

Cyclosporin: C2 LevelCyclosporin: C2 Level

< 6 months: 1000-1500 ng/ml< 6 months: 1000-1500 ng/ml > 6 months: 800-900 ng/ml> 6 months: 800-900 ng/ml

Little evidence from prospective studies to support the Little evidence from prospective studies to support the theoretical benefits of C2 monitoring. Potential dose theoretical benefits of C2 monitoring. Potential dose reductions in stable patients may reduce costs, but no reductions in stable patients may reduce costs, but no short-term clinical benefit is seen.* short-term clinical benefit is seen.*

*Knight, S R. et al. Transplantation 2007 Jun; 83(12):1525-1535

Tacrolimus (Prograf): MonitoringTacrolimus (Prograf): Monitoring

Low riskLow risk Mod RiskMod Risk High riskHigh risk

0-6 m0-6 m 6-12 6-12 ng/mlng/ml 8-12 8-12 ng/mlng/ml 8-15 8-15 ng/mlng/ml

6-12 m6-12 m 5-8 5-8 ng/mlng/ml 5-10 5-10 ng/mlng/ml 6-12 6-12 ng/mlng/ml

> 12 m> 12 m 4-8 4-8 ng/mlng/ml 5-10 5-10 ng/mlng/ml 6-12 6-12 ng/mlng/ml

S Hariharan. Am J Kidney Dis. 2006. 47(S2):S22-S36.

CNI Side EffectsCNI Side Effects

EventEvent CommentsCommentsHepatotoxicityHepatotoxicity Liver function should be Liver function should be

monitored at regular intervalsmonitored at regular intervals

Cardiovascular Cardiovascular HypertensionHypertension HypercholesteroleHypercholesterole

miamia

Fewer tacrolimus-treated patients Fewer tacrolimus-treated patients require antihypertensive require antihypertensive medicationsmedications

Tacrolimus’ impact on lipid levels Tacrolimus’ impact on lipid levels is less than that seen with is less than that seen with cyclosporinecyclosporine

Glucose intoleranceGlucose intolerance Recent studies indicate little Recent studies indicate little differences between tacrolimus differences between tacrolimus and cyclosporineand cyclosporine

NeurotoxicityNeurotoxicity TremorTremor HeadacheHeadache InsomniaInsomnia ParesthesiaParesthesia

Seen more often with tacrolimus Seen more often with tacrolimus and generally improve with dose and generally improve with dose reductionreduction

CNI Side EffectsCNI Side Effects

EventEvent CommentsCommentsCosmetic side effectsCosmetic side effects Gingival Gingival

hypertrophyhypertrophy HirsutismHirsutism AlopeciaAlopecia

Use of steroids may exaggerate Use of steroids may exaggerate development development

Gingival hypertrophy and Gingival hypertrophy and hirsutism are associated with hirsutism are associated with cyclosporine cyclosporine

Calcium channel blockers can Calcium channel blockers can exacerbate gingival hypertrophyexacerbate gingival hypertrophy

Alopecia can occur with Alopecia can occur with tacrolimustacrolimus

MalignancyMalignancy Skin cancersSkin cancers Cervical cancerCervical cancer LymphoproliferativLymphoproliferativ

e disorderse disorders

Incidence appears to be a Incidence appears to be a function of overall amount and function of overall amount and duration of immunosuppression duration of immunosuppression rather than any specific agentrather than any specific agent

CNI Side EffectsCNI Side Effects

Nephrotoxicity (Striped fibrosis)Nephrotoxicity (Striped fibrosis)

TMATMA

Type IV RTAType IV RTA

CNICNI

More with TacrolimusMore with Tacrolimus More with CyclosprinMore with Cyclosprin

Neurologic SENeurologic SE HypertensionHypertension

GI side effectsGI side effects HyperlipidemiaHyperlipidemia

PTDMPTDM

AlopeciaAlopecia HirsutismHirsutism

Hypertrophic Hypertrophic cardimyopathycardimyopathy

in childrenin children

Gingival hyperplasiaGingival hyperplasia

Metabolic Interactions That Metabolic Interactions That Increase CNI LevelsIncrease CNI Levels

Calcium channel blockersCalcium channel blockers VerapamilVerapamil DiltiazemDiltiazem AmlodipineAmlodipine Nicardipine Nicardipine

Antifungal agentsAntifungal agents KetoconazoleKetoconazole FluconazoleFluconazole ItraconazoleItraconazole ClotrimazoleClotrimazole Metronidazole Metronidazole

ImmunosuppressantsImmunosuppressants SirolimusSirolimus

GlucocorticoidsGlucocorticoids MethylprednisoloneMethylprednisolone

AntibioticsAntibiotics ErythromycinErythromycin ClarithromycinClarithromycin JosamycinJosamycin PonsinomycinPonsinomycin Azithromycin Azithromycin

Protease InhibitorsProtease Inhibitors SaquinavirSaquinavir IndinavirIndinavir NelfinavirNelfinavir Ritonavir Ritonavir

FoodsFoods GrapefruitGrapefruit Grapefruit juiceGrapefruit juice

Metabolic Interactions That Metabolic Interactions That Decrease CNI LevelsDecrease CNI Levels

Antituberculosis Antituberculosis drugsdrugs RifampinRifampin RifabutinRifabutin IsoniazidIsoniazid

AnticonvulsantsAnticonvulsants BarbituratesBarbiturates PhenytoinPhenytoin CarbamazepineCarbamazepine

Herbal preparationsHerbal preparations Saint John’s wortSaint John’s wort

AntibioticsAntibiotics NafcillinNafcillin IV trimethoprimIV trimethoprim IV sulfadimidineIV sulfadimidine ImipenemImipenem CephalosporinesCephalosporines TerbinafineTerbinafine CiprofloxacinCiprofloxacin

Other drugsOther drugs TiclopidineTiclopidine OctreotideOctreotide NefazodoneNefazodone

Nonmetabolic Interactions With Nonmetabolic Interactions With CNIsCNIs

Drug TypeDrug Type CommentsComments Nephrotoxic agentsNephrotoxic agents

NSAIDsNSAIDs VancomycinVancomycin GanciclovirGanciclovir AminoglycosidesAminoglycosides

Monitor renal functionMonitor renal function NSAIDs may have increased NSAIDs may have increased

nephrotoxicity with hepatic nephrotoxicity with hepatic impairmentimpairment

Potassium-sparing Potassium-sparing diureticsdiuretics

Hyperkalemia has been reportedHyperkalemia has been reported

AntacidsAntacids Magnesium and aluminum Magnesium and aluminum antacids may inhibit absorption antacids may inhibit absorption of CNIsof CNIs

If necessary, should be taken 2 If necessary, should be taken 2 hours after CNI dosehours after CNI dose

HMG-CoA reductase HMG-CoA reductase

inhibitors (statins)inhibitors (statins) Increased risk of Increased risk of

rhabdomyolysis, bone marrow rhabdomyolysis, bone marrow suppressionsuppression

CNICNI

Tacrolimus v. SandimmuneTacrolimus v. Sandimmune

acute rejection may be less with tacrolimus.acute rejection may be less with tacrolimus. similar graft survivalsimilar graft survival

Tacrolimus v. NeoralTacrolimus v. Neoral

In some studies, tacrolimus has reportedly had lower In some studies, tacrolimus has reportedly had lower acute rejection rates.acute rejection rates.

Despite this, both agents are associated with Despite this, both agents are associated with similarly excellent allograft survival rates, although similarly excellent allograft survival rates, although some studies report an advantage of one agent over some studies report an advantage of one agent over the other. the other.

CNICNI

In a meta-analysis and meta-regression study of 123 In a meta-analysis and meta-regression study of 123 reports from 30 trials (4102 patients), the followings reports from 30 trials (4102 patients), the followings were found. were found.

At six months, graft loss was significantly reduced in At six months, graft loss was significantly reduced in tacrolimus treated recipients and this effect tacrolimus treated recipients and this effect persisted up to three years.persisted up to three years.

At one year, tacrolimus treated patients had less At one year, tacrolimus treated patients had less acute rejection.acute rejection.

Treating 100 recipients with tacrolimus instead of Treating 100 recipients with tacrolimus instead of cyclosporin for the first year after transplantation cyclosporin for the first year after transplantation avoids 12 patients having acute rejection and two avoids 12 patients having acute rejection and two losing their graft but causes an extra five patients to losing their graft but causes an extra five patients to develop insulin dependent diabetes. develop insulin dependent diabetes.

Webster AC. Et al. BMJ 2005 Oct 8;331(7520):810

Dosing of Adjuvant AgentsDosing of Adjuvant Agents

AgentAgent Daily DoseDaily Dose MonitoringMonitoring

AzathioprineAzathioprine 1-3 mg/kg qd1-3 mg/kg qd None availableNone available

MMF (Cellcept)MMF (Cellcept) 750 mg-1.5 g bid750 mg-1.5 g bid MPA:1.6 – 2.75 MPA:1.6 – 2.75 mg/L*mg/L*

SirolimusSirolimus 2-5 mg qd2-5 mg qd 5-15 ng/mL (whole 5-15 ng/mL (whole blood trough level)blood trough level)

CorticosteroidsCorticosteroids 5-10 mg qd5-10 mg qd None availableNone available

*Borrows R, et al. Am J Transplant 2006(6):12-128

Antiproliferative AgentsAntiproliferative Agents

AgentAgent Daily DoseDaily Dose MonitoringMonitoring

Azathioprine Azathioprine (Imuran)(Imuran)

1-3 mg/kg qd1-3 mg/kg qd None availableNone available

Mycophenolate Mycophenolate mofetilmofetil (MMF, (MMF, CellceptCellcept))

750 mg-1.5 g bid750 mg-1.5 g bid

Not requiredNot required

MPA:1.6 – 2.75 MPA:1.6 – 2.75 mg/L*mg/L*

*Borrows R, et al. Am J Transplant 2006(6):12-128

Side Effects of Antiproliferative Side Effects of Antiproliferative AgentsAgents

Drug and Side Drug and Side EffectsEffects

Clinical ImplicationsClinical Implications

AzathioprineAzathioprine LeukopeniaLeukopenia AnemiaAnemia ThrombocytopeniaThrombocytopenia HepatitisHepatitis CholestasisCholestasis PancreatitisPancreatitis

Complete blood counts Complete blood counts should be performed should be performed regularly to monitor for regularly to monitor for hematologic side effectshematologic side effects

MMFMMF LeukopeniaLeukopenia AnemiaAnemia ThrombocytopeniaThrombocytopenia DiarrheaDiarrhea NauseaNausea Bloating dyspepsiaBloating dyspepsia VomitingVomiting EsophagitisEsophagitis GastritisGastritis

Complete blood counts Complete blood counts should be performed should be performed regularly to monitor for regularly to monitor for hematologic side effectshematologic side effects

GI side effects are more GI side effects are more common when dose exceeds common when dose exceeds 1 g bid and respond to dose 1 g bid and respond to dose reduction or more frequent reduction or more frequent administration of smaller administration of smaller dosesdoses

Drug Interactions With Drug Interactions With Antiproliferative AgentsAntiproliferative Agents

DrugDrug InteractionsInteractionsAzathiopriAzathioprinene

Coadministration with ganciclovir, ACE Coadministration with ganciclovir, ACE inhibitors, carbamazepine, clozapine, or inhibitors, carbamazepine, clozapine, or cotrimoxazole can lead to the cotrimoxazole can lead to the exacerbation of hematologic toxicityexacerbation of hematologic toxicity

Allopurinol is contraindicated, as Allopurinol is contraindicated, as concomitant administration can lead to concomitant administration can lead to life-threatening myelosuppressionlife-threatening myelosuppression

MMFMMF Coadministration with ganciclovir, ACE Coadministration with ganciclovir, ACE inhibitors, carbamazepine, clozapine, or inhibitors, carbamazepine, clozapine, or co-trimoxazole can lead to the co-trimoxazole can lead to the exacerbation of hematologic toxicityexacerbation of hematologic toxicity

Administration with tacrolimus may Administration with tacrolimus may potentiate GI side effectspotentiate GI side effects

MyforticMyfortic

Enteric-coated MMFEnteric-coated MMF

Intended to reduce GI side effects but has not been proved Intended to reduce GI side effects but has not been proved in clinical trialsin clinical trials

Dose equivalentDose equivalent 180 mg Myfortic = 500 mg MMF180 mg Myfortic = 500 mg MMF

Mycophenolate v. AzathioprineMycophenolate v. Azathioprine

Several studies, particularly some initial pivotal reports, Several studies, particularly some initial pivotal reports, found that acute rejection rates were lower with found that acute rejection rates were lower with mycophenolate. However, these studies may be flawed.mycophenolate. However, these studies may be flawed.

Given current evidence, azathioprine and mycophenolate Given current evidence, azathioprine and mycophenolate mofetil appear to be similar in terms of acute rejection mofetil appear to be similar in terms of acute rejection rates and long-term allograft survival rates. rates and long-term allograft survival rates.

Mycophenolate v. AzathioprineMycophenolate v. Azathioprine

MYSS TrialMYSS Trial

336 patients undergoing a deceased donor renal 336 patients undergoing a deceased donor renal transplant transplant

randomly assigned to mycophenolate mofetil or randomly assigned to mycophenolate mofetil or azathioprineazathioprine

both groups also receiving cyclosporine microemulsion both groups also receiving cyclosporine microemulsion and corticosteroids. Corticosteroids were continued for and corticosteroids. Corticosteroids were continued for the first six months (phase A), after which they were the first six months (phase A), after which they were slowly withdrawn and patients were followed for slowly withdrawn and patients were followed for another 15 or more months (phase B).another 15 or more months (phase B).

Remuzzi G. et al. Lancet 2004 Aug 7;364(9433):503-12.

Mycophenolate v. AzathioprineMycophenolate v. Azathioprine

MYSS TrialMYSS Trial

The incidence of clinical rejection was the same for The incidence of clinical rejection was the same for both mycophenolate and azathioprine in phase A (34 both mycophenolate and azathioprine in phase A (34 and 35 percent, respectively) and phase B (16 and and 35 percent, respectively) and phase B (16 and 12 percent, respectively). 12 percent, respectively).

Rates of allograft loss, and serum creatinine Rates of allograft loss, and serum creatinine concentration were the same in both groups. concentration were the same in both groups.

However, mycophenolate was approximately 15 However, mycophenolate was approximately 15 times more expensive than azathioprinetimes more expensive than azathioprine

Remuzzi G. et al. Lancet 2004 Aug 7;364(9433):503-12.

Mycophenolate v. AzathioprineMycophenolate v. Azathioprine

MYSS Follow-up Study

Remuzzi G. et al. J Am Soc Nephrol. 2007 June; 18: 1973–1985.

Mycophenolate v. AzathioprineMycophenolate v. Azathioprine

the long-term risk/benefit profile of MMF and azathioprine the long-term risk/benefit profile of MMF and azathioprine therapy in combination with cyclosporine Neoral is similar. therapy in combination with cyclosporine Neoral is similar.

In view of the cost, standard immunosuppression regimens In view of the cost, standard immunosuppression regimens for kidney transplantation should perhaps include for kidney transplantation should perhaps include azathioprine rather than MMF.azathioprine rather than MMF.

mTOR InhibitormTOR Inhibitor

Sirolimus (Rapamune / Rapamycin)Sirolimus (Rapamune / Rapamycin)

Dosage: 2-5 mg qdDosage: 2-5 mg qd

Level: 5-15 ng/mL (whole blood trough level)Level: 5-15 ng/mL (whole blood trough level)

Side Effects of SirolimusSide Effects of Sirolimus

Drug and Side Drug and Side EffectsEffects

Clinical ImplicationsClinical Implications

SirolimusSirolimus HypercholesterolemiaHypercholesterolemia HypertriglyceridemiaHypertriglyceridemia HypertensionHypertension RashRash LeukopeniaLeukopenia AnemiaAnemia ThrombocytopeniaThrombocytopenia Interstitial pneumonitisInterstitial pneumonitis Delayed wound healingDelayed wound healing Mouth ulcersMouth ulcers ProteinuriaProteinuria EdemaEdema

Pneumonitis occasionally Pneumonitis occasionally resolved in resolved in discontinuation of discontinuation of sirolimussirolimus

Drug Interactions With Drug Interactions With SirolimusSirolimus

As sirolimus is metabolized by the same pathway as the As sirolimus is metabolized by the same pathway as the CNIs (P-450 3A4), interactions are the same CNIs (P-450 3A4), interactions are the same

Sirolimus has been shown to raise blood levels of Sirolimus has been shown to raise blood levels of cyclosporine and MMFcyclosporine and MMF Sirolimus should be administered 4 hours after Sirolimus should be administered 4 hours after

cyclosporine or tacrolimuscyclosporine or tacrolimus

Sirolimus blood levels are raised by cyclosporineSirolimus blood levels are raised by cyclosporine Proper monitoring is advised Proper monitoring is advised

SteroidsSteroids

PrednisonePrednisone MethylprednisoneMethylprednisone Decreased activity with anti-TB and anti-seizure Decreased activity with anti-TB and anti-seizure

medicationsmedications Increased activity with estrogen, OCP, Increased activity with estrogen, OCP,

erythromycinerythromycin

SteroidsSteroids

Side Effects of CorticosteroidsSide Effects of Corticosteroids

Drug and Side Drug and Side EffectsEffects

Clinical ImplicationsClinical Implications

CorticosteroidsCorticosteroids AcneAcne Cushingoid facial Cushingoid facial

appearanceappearance HirsutismHirsutism Mood disordersMood disorders Hypertension Hypertension Glucose intoleranceGlucose intolerance CataractsCataracts OsteoporosisOsteoporosis Growth retardation in Growth retardation in

childrenchildren

May potentiate May potentiate adverse events of adverse events of CNIsCNIs

Tailoring Drug RegimensTailoring Drug Regimens

Refractory rejectionRefractory rejection Changing from cyclosporine to tacrolimus has proven Changing from cyclosporine to tacrolimus has proven

successful in reversing rejectionsuccessful in reversing rejection

Cardiovascular diseaseCardiovascular disease High blood pressure and high cholesterol may be High blood pressure and high cholesterol may be

lowered with changes from cyclosporine to tacrolimuslowered with changes from cyclosporine to tacrolimus High cholesterol may also be lowered by replacing High cholesterol may also be lowered by replacing

sirolimus with MMFsirolimus with MMF

DiabetesDiabetes De novoDe novo presentation of diabetes may improve with presentation of diabetes may improve with

lowering of steroid dose lowering of steroid dose Rarely, patients switched from tacrolimus to Rarely, patients switched from tacrolimus to

cyclosporine may see improvements of glucose cyclosporine may see improvements of glucose metabolism metabolism

HirsutismHirsutism Changing from cyclosporine to tacrolimus generally Changing from cyclosporine to tacrolimus generally

reverses hirsutism reverses hirsutism Gingival hyperplasia Gingival hyperplasia

Replacing cyclosporine with tacrolimus can alleviate Replacing cyclosporine with tacrolimus can alleviate gingival hyperplasia gingival hyperplasia

Withdrawing calcium channel blockers may also lead to Withdrawing calcium channel blockers may also lead to improvements in gingival tissueimprovements in gingival tissue

TremorTremor If dose reduction of the CNI does not stop tremor, If dose reduction of the CNI does not stop tremor,

consider switching to the alternate therapyconsider switching to the alternate therapy Gout Gout

Convert azathioprine to MMF if allopurinol must be usedConvert azathioprine to MMF if allopurinol must be used

Tailoring Drug RegimensTailoring Drug Regimens

Deficiencies with Deficiencies with Immunosuppressive TherapyImmunosuppressive Therapy

Patient’s compliance and adherencePatient’s compliance and adherence

Side effects of long-term exposureSide effects of long-term exposure

Long-term comorbidities induced by these agentsLong-term comorbidities induced by these agents

Need to continue these agents for lifeNeed to continue these agents for life

Inability to induce toleranceInability to induce tolerance

ConclusionConclusion

Proper immunosuppression is critical to the survival of Proper immunosuppression is critical to the survival of the renal allograftthe renal allograft

Understanding proper dosing and monitoring becomes Understanding proper dosing and monitoring becomes especially critical when comorbid conditions are involvedespecially critical when comorbid conditions are involved

Some side effects are inherent with a suppressed immune Some side effects are inherent with a suppressed immune system; others occur as the result of specific agentssystem; others occur as the result of specific agents

Experimental drug protocols that eliminate or withdraw Experimental drug protocols that eliminate or withdraw steroids and CNIs remain untested in the long term and steroids and CNIs remain untested in the long term and must be eyed with cautionmust be eyed with caution

Patient education regarding compliance should be Patient education regarding compliance should be ongoing throughout the life of the transplantongoing throughout the life of the transplant