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Annual Meeting Immunology/Transplantation PRN and American Society of Transplantation Focus Session— Symposium on the Management of Complications After Organ Transplantation Activity No. 0217-0000-11-096-L01-P (Knowledge-Based Activity) Tuesday, October 18 1:30 p.m.–4:30 p.m. Convention Center: Spirit of Pittsburgh Ballroom B Moderators: Steven Gabardi, Pharm.D., FCCP, BCPS Abdominal Organ Transplant Specialist, Program Director, PGY2 Organ Transplant Pharmacology Residency, Brigham and Women’s Hospital; Department of Transplant Surgery/Renal Division; Instructor of Medicine, Harvard Medical School, Boston, Massachusetts and Eric M. Tichy, Pharm.D., BCPS Clinical Pharmacy Specialist, Solid Organ Transplant, Yale-New Haven Hospital, New Haven, Connecticut Agenda 1:30 p.m. Significant Infectious Disease Issues After Transplantation Michael Green, M.D., MPH Professor of Medicine, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 2:15 p.m. Management of Cardiovascular Disease in Transplantation Donald Hricik, M.D. Professor of Medicine, University Hospitals and the School of Medicine, Case Western Reserve University, Cleveland, Ohio 2:45 p.m. Post Transplant Lymphoproliferative Disease and Malignancy Steve Webber, M.D. Professor of Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania 3:30 p.m. Prevention and Treatment of Allograft Rejection E. Steve Woodle, M.D., FACS Professor of Surgery, Director of Division of Transplantation; Director, Israel Penn International Transplant Tumor Registry, University of Cincinnati, Cincinnati, Ohio 4:00 p.m. Immunosuppressants: What Every Clinical Pharmacist Should Know Lisa McDevitt-Potter, Pharm.D., BCPS Senior Clinical Pharmacy Specialist, Organ Transplantation, Tufts Medical Center, Boston, Massachusetts Symposium on the Management of Complications After Organ Transplantation 1

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Page 1: Immunology/Transplantation PRN and American … Meeting Immunology/Transplantation PRN and American Society of Transplantation Focus Session— Symposium on the Management of Complications

Annual Meeting

Immunology/Transplantation PRN and American Society of Transplantation Focus Session—Symposium on the Management of Complications After Organ Transplantation Activity No. 0217-0000-11-096-L01-P (Knowledge-Based Activity) Tuesday, October 18 1:30 p.m.–4:30 p.m. Convention Center: Spirit of Pittsburgh Ballroom B Moderators: Steven Gabardi, Pharm.D., FCCP, BCPS Abdominal Organ Transplant Specialist, Program Director, PGY2 Organ Transplant Pharmacology Residency, Brigham and Women’s Hospital; Department of Transplant Surgery/Renal Division; Instructor of Medicine, Harvard Medical School, Boston, Massachusetts and Eric M. Tichy, Pharm.D., BCPS Clinical Pharmacy Specialist, Solid Organ Transplant, Yale-New Haven Hospital, New Haven, Connecticut Agenda 1:30 p.m. Significant Infectious Disease Issues After Transplantation

Michael Green, M.D., MPH Professor of Medicine, Children’s Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania

2:15 p.m. Management of Cardiovascular Disease in Transplantation Donald Hricik, M.D. Professor of Medicine, University Hospitals and the School of Medicine, Case Western Reserve University, Cleveland, Ohio

2:45 p.m. Post Transplant Lymphoproliferative Disease and Malignancy Steve Webber, M.D. Professor of Medicine, University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania

3:30 p.m. Prevention and Treatment of Allograft Rejection E. Steve Woodle, M.D., FACS Professor of Surgery, Director of Division of Transplantation; Director, Israel Penn International Transplant Tumor Registry, University of Cincinnati, Cincinnati, Ohio

4:00 p.m. Immunosuppressants: What Every Clinical Pharmacist Should Know Lisa McDevitt-Potter, Pharm.D., BCPS Senior Clinical Pharmacy Specialist, Organ Transplantation, Tufts Medical Center, Boston, Massachusetts

Symposium on the Management of Complications After Organ Transplantation 1

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Annual Meeting

Faculty Conflict of Interest Disclosures Michael Green: consultant/member of advisory board for Bristol Myers Squibb. Donald Hricik: speaker’s bureau for Novartis, Genentech; received grant funding/research support from Astellas. Lisa McDevitt-Potter: clinical investigator for Genentech, Astellas, and LifeCycle.Steve Webber: no conflicts to disclose. E. Steve Woodle: consultant/member of advisory board for Genzyme, Wyeth, Novartis; received grant funding research support from Genzyme, Wyeth, Novartis. Learning Objectives

1. Participants will be able to identify risk factors associated with having an increased risk of developing CMV and BKV infections after solid organ transplantation.

2. At the end of this presentation, attendees will be able to compare and contrast the available strategies for the prevention of CMV disease

3. Participants will be able to recognize that the use of antifungal prophylaxis varies with the type of organ transplant procedure that patients undergo.

4. Participants will understand the relative advantages and disadvantages (including potential drug-drug interactions and toxicity profiles) associated with the use of different classes of anti-fungal agents in solid organ transplant recipients.

5. Recognize the prevalence and long-term impact of overall cardiovascular disease, specifically hypertension, dyslipidemias and metabolic syndrome, in transplant recipients.

6. Describe the risk factors for cardiovascular disease in this patient population. 7. Identify the effects of immunosuppressive drugs on the development of cardiovascular disease. 8. Outline the modifications to immunosuppressive regimens to help manage these disease states. 9. Discuss the interventions for the management of cardiovascular disease in organ transplant

recipients. 10. Determine the incidence of post transplant malignancy in transplantation and identify cancer

types having the highest risk of post transplant occurrence. 11. Describe the impact of individual immunosuppressive agents on risk of post transplant

malignancy. 12. Explain the potential of mTOR inhibitors in the management of pos transplant malignancies. 13. Discuss the various therapies for the treatment of PTLD. 14. Describe the physiological cascades that lead to organ rejection in transplant recipients. 15. Compare and contrast cellular and antibody-mediated rejection. 16. Choose appropriate pharmacotherapy for the management of cellular rejection. 17. Discuss the current therapies for the treatment of antibody-mediated rejection. 18. Evaluate the quality of the clinical data evaluating therapy for the management antibody-

mediated rejection. 19. Summarize the options available for the prevention and management of chronic allograft

rejection. 20. Outline the potential for pharmacokinetic and pharmacodynamic drug-drug interactions with the

maintenance immunosuppressants. 21. List the long-term complications of maintenance immunosuppression and their potential impacts

on transplant outcomes. 22. Evaluate the short- and long-term impact of nonadherence on the transplanted organ and

transplant recipient.

Symposium on the Management of Complications After Organ Transplantation 2

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Annual Meeting

Self-Assessment Questions Self-assessment questions are available online at www.accp.com/am

Symposium on the Management of Complications After Organ Transplantation 3

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Significant Infectious Disease Significant Infectious Disease Issues After Solid Organ Issues After Solid Organ

TransplantationTransplantation

Michael Green, Michael Green, M.D., M.D., MPHMPHProfessor of Pediatrics, Surgery & Clinical and Professor of Pediatrics, Surgery & Clinical and

Translation ScienceTranslation ScienceUniversity of Pittsburgh School of MedicineUniversity of Pittsburgh School of Medicine

Division of Infectious DiseasesDivision of Infectious DiseasesChildren’s Hospital of Pittsburgh of UPMCChildren’s Hospital of Pittsburgh of UPMC

DisclaimersDisclaimers

I am a consultant for Bristol Myers SquibbI am a consultant for Bristol Myers Squibb

I may discuss offI may discuss off--label use of antimicrobial label use of antimicrobial medications during this talkmedications during this talk

Based Upon My Assignment, Based Upon My Assignment, My Learning Objectives are: My Learning Objectives are:

Participants will be able to identify risk factors Participants will be able to identify risk factors associated with having an increased risk of developing associated with having an increased risk of developing CMVCMV and and BKVBKV infections after solid organ infections after solid organ transplantationtransplantation

At the end of this presentation, attendees will be able to At the end of this presentation, attendees will be able to compare and contrast the available strategies for thecompare and contrast the available strategies for thecompare and contrast the available strategies for the compare and contrast the available strategies for the prevention of prevention of CMVCMV diseasedisease

Participants will be able to recognize that the use of Participants will be able to recognize that the use of antiantifungalfungal prophylaxis varies with the type of organ prophylaxis varies with the type of organ transplant procedure that patients undergotransplant procedure that patients undergo

Participants will understand the relative advantages and Participants will understand the relative advantages and disadvantages (including potential drugdisadvantages (including potential drug--drug interactions drug interactions and toxicity profiles) associated with the use of different and toxicity profiles) associated with the use of different classes of anticlasses of antifungalfungal agents in solid organ transplant agents in solid organ transplant recipientsrecipients

CytomegalovirusCytomegalovirusCytomegalovirusCytomegalovirus

CMV InfectionCMV Infection

Historically, most frequent and important postHistorically, most frequent and important post--transplant opportunistic infection transplant opportunistic infection

Primary infection or reactivation/reinfectionPrimary infection or reactivation/reinfection

Donor organ source of primary infection & Donor organ source of primary infection & reinfection reinfection

Primary infection associated with increased Primary infection associated with increased morbidity and mortalitymorbidity and mortality

Severe disease with heavy immunosuppressionSevere disease with heavy immunosuppression

CMV InfectionCMV Infection

Typical presentation: 30 to 90 d postTypical presentation: 30 to 90 d post--Tx Tx

Asymptomatic vs symptomatic infectionAsymptomatic vs symptomatic infection CMV syndrome: fever, leukopenia & atypical CMV syndrome: fever, leukopenia & atypical

lymphocytosislymphocytosis

Invasive CMV: liver, gastrointestinal tract or Invasive CMV: liver, gastrointestinal tract or lungslungs

Use of prophylaxis results in:Use of prophylaxis results in: Prevention Prevention

Modification of timing & presentationModification of timing & presentation

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Invasive CMV DiseaseInvasive CMV Disease

CMV Hepatitis

CMV Pneumonitis

Who Is at Risk for CMV?Who Is at Risk for CMV?

Donor/Recipient FactorsDonor/Recipient FactorsCMV serology status of donor/recipient (D+/RCMV serology status of donor/recipient (D+/R--))Organ transplantedOrgan transplantedLung/small bowel > pancreas, heart > liver, kidneyLung/small bowel > pancreas, heart > liver, kidneyPatient factors (age, comorbidities)Patient factors (age, comorbidities)Exogenous immunosuppressionExogenous immunosuppression——induction, routine, rejectioninduction, routine, rejectiong ppg pp , , j, , jHighHigh--volume transfusion of blood productsvolume transfusion of blood productsCD4+, CD8+ TCD4+, CD8+ T--cell (general and specific), NK cell, Bcell (general and specific), NK cell, B--cellcellPolymorphisms of TollPolymorphisms of Toll--like receptorlike receptor--2 and Toll2 and Toll--like receptorlike receptor--4 4 Deficiencies of complement proteins and mannoseDeficiencies of complement proteins and mannose--binding lectinbinding lectin

Viral FactorsViral FactorsReplication dynamicsReplication dynamicsCoCo--infection with other viruses (EBV, HHVinfection with other viruses (EBV, HHV--6, HHV6, HHV--7)7)Immunologic evasionImmunologic evasionViral heterogeneityViral heterogeneity

Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S86.

Treatment of CMV DiseaseTreatment of CMV DiseaseAfter Organ TransplantationAfter Organ Transplantation

Ganciclovir effective in majority of casesGanciclovir effective in majority of cases Clinical responses in 5 to 7 daysClinical responses in 5 to 7 days Fall in viral load may lag behind clinical responseFall in viral load may lag behind clinical response Valganciclovir can be used for mild to moderate Valganciclovir can be used for mild to moderate

diseasedisease Consider modification of immune suppressionConsider modification of immune suppression Consider modification of immune suppressionConsider modification of immune suppression Recurrent episodes in about 20% of treated Recurrent episodes in about 20% of treated

patientspatients Foscarnet or cidofovir for “truly” ganciclovirFoscarnet or cidofovir for “truly” ganciclovir--

resistant CMV (rare)resistant CMV (rare) Consider for persistence of symptoms and/or CMV loadConsider for persistence of symptoms and/or CMV load Confirm presence of resistance mutationsConfirm presence of resistance mutations

Duration of therapy based on clearance of the Duration of therapy based on clearance of the CMV viral load (pp65 antigen or DNAemia)CMV viral load (pp65 antigen or DNAemia)

Treatment of CMV:Treatment of CMV:Additional CommentAdditional Comment

Ancillary Treatment with CMVAncillary Treatment with CMV--IVIGIVIG Generally recommended for treatment of CMV pneumonitisGenerally recommended for treatment of CMV pneumonitis

Some experts also recommend for CMV enteritisSome experts also recommend for CMV enteritis

D i f CMVD i f CMV IVIG f f di bli h d bIVIG f f di bli h d b Dosing of CMVDosing of CMV--IVIG for treatment of disease not established by IVIG for treatment of disease not established by randomized trialrandomized trial Single publication use 100 mg/kg for 7 doses qod for 14 daysSingle publication use 100 mg/kg for 7 doses qod for 14 days

Role of secondary prophylaxis after completion of Role of secondary prophylaxis after completion of treatment of CMV diseasetreatment of CMV disease Recommended by some expertsRecommended by some experts

Lack of definitive data to determine relative benefit Lack of definitive data to determine relative benefit

Paradigms for PreventionParadigms for Prevention

Universal (chemo)prophylaxisUniversal (chemo)prophylaxis Administration of antiviral medication to all Administration of antiviral medication to all

“at“at--risk” patients (or a specified subset) starting < 10 risk” patients (or a specified subset) starting < 10 days after transplant for a defined duration days after transplant for a defined duration y py p

Preemptive therapyPreemptive therapy Patients monitored regularly and treatment dose Patients monitored regularly and treatment dose

antiviral medications begun if positive, optimally antiviral medications begun if positive, optimally before symptomsbefore symptoms

Chemoprophylaxis Recommendations Chemoprophylaxis Recommendations (AST/TTS)(AST/TTS)

The duration of prophylaxis in D+/RThe duration of prophylaxis in D+/R-- should be generally should be generally between 3between 3--6 months (I) 6 months (I)

Decision may depend on degree of immunosuppressionDecision may depend on degree of immunosuppression

6 months (minimum) is recommended for lung (II6 months (minimum) is recommended for lung (II--2) 2) and small intestine (III) SOTsand small intestine (III) SOTs

Recommendation based on “expert opinion”Recommendation based on “expert opinion”

Little to no supportive data for ITx recipientsLittle to no supportive data for ITx recipients

Some centers add CMV immunoglobulin (CMV Ig) Some centers add CMV immunoglobulin (CMV Ig) for heart, lung, and bowel transplants (III)for heart, lung, and bowel transplants (III)

AST: Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S86.TTS: Kotton CN et al. Transplantation. 2010;89:779-795.

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PREEMPTIVE THERAPYPREEMPTIVE THERAPYPREEMPTIVE THERAPYPREEMPTIVE THERAPY

CMV diseaseCMV disease

++__

++ ++ ++ ++______

++ ++__

00 44 88 12 weeks12 weeks

Could have initiated preemptive therapyCould have initiated preemptive therapy

TESTTEST

Preemptive Therapy: MetaPreemptive Therapy: Meta--AnalysesAnalysesPreemptive Therapy: MetaPreemptive Therapy: Meta--AnalysesAnalyses

Study AuthorStudy AuthorCMV DiseaseCMV DiseaseRelative RiskRelative Risk

(95% CI)(95% CI)

All Cause MortalityAll Cause MortalityRelative RiskRelative Risk

(95% CI)(95% CI)

Strippoli GF et al. Strippoli GF et al. Cochrane Cochrane Database Syst Rev.Database Syst Rev. 2006 2006 J 25 (1) CD005133J 25 (1) CD005133

0.290.29(0.11 (0.11 –– 0.80)0.80)

1.231.23(0.35 (0.35 –– 4.30)4.30)

Jan 25;(1):CD005133.Jan 25;(1):CD005133.(( )) (( ))

Kalil et al. Kalil et al. Ann Intern MedAnn Intern Med. . 2005;143:8702005;143:870--880.880.

0.280.28(0.11 (0.11 –– 0.69)0.69)

0.940.94(0.32 (0.32 –– 2.76)2.76)

Small et al. Small et al. Clin Infect Dis. Clin Infect Dis. 2006;43:8692006;43:869--880.880.

0.300.30(0.15 (0.15 –– 0.60)0.60)

0.940.94(0.43 (0.43 –– 2.07)2.07)

Preemptive Preemptive TherapyTherapy vs Prophylaxisvs ProphylaxisPreemptive Preemptive TherapyTherapy vs Prophylaxisvs Prophylaxis

There are very few comparative randomized trials There are very few comparative randomized trials comparing preemptive therapy vs prophylaxis comparing preemptive therapy vs prophylaxis

In 2 separate trials, Khoury et al (n=98 kidney In 2 separate trials, Khoury et al (n=98 kidney transplant) and Reischig et al (n=70 kidney transplant) transplant) and Reischig et al (n=70 kidney transplant) randomized to preemptive therapy vs prophylaxis randomized to preemptive therapy vs prophylaxis

Equally effective in preventing CMV diseaseEqually effective in preventing CMV disease

Kliem et al: randomized 148 renal transplant patients Kliem et al: randomized 148 renal transplant patients to preemptive therapy (IV ganciclovir) vs prophylaxis to preemptive therapy (IV ganciclovir) vs prophylaxis (3 months oral ganciclovir)(3 months oral ganciclovir)

LongLong--term graft survival at 4term graft survival at 4--years posttransplant years posttransplant was significantly improved in the prophylaxis groupwas significantly improved in the prophylaxis group

Khoury JA et al. Am J Transplant. 2006;6:2134-2143.Kliem V et al. Am J Transplant. 2008;8:975-983.Reischig T et al. Am J Transplant. 2008;8:69-77.

Preemptive Preemptive TherapyTherapy vs Prophylaxis: vs Prophylaxis: LongLong--Term OutcomeTerm Outcome

Preemptive Preemptive TherapyTherapy vs Prophylaxis: vs Prophylaxis: LongLong--Term OutcomeTerm Outcome

50

60

70

80

90

100

(Un

cen

sore

d f

or

Dea

th)

[%]

N=130 Graft Loss (Failure Rates)

O-GP

IV-PT

Kliem V et al. Am J Transplant. 2008;8:975-983.

ITT=Intent-to-treatIV-PT=Intravenous preemptive therapyO-GP=Oral ganciclovir prophylaxis

0

10

20

30

40

50

0 1 2 3 4Years After Transplantation

Fre

edo

m f

rom

Gra

ft L

oss

( N=130 Graft Loss (Failure Rates)

P Value(Log rank test)

0.0425

0.83470.00350.9693

ITT

D+/R-D+/R+D-/R+

O-GP[%]

7.8

14.80.0

14.3

IV-PT[%]

21.7

18.226.815.4

HYBRID APPROACHESHYBRID APPROACHESHYBRID APPROACHESHYBRID APPROACHES

++ ++ ++__ ++ ____ __ ++ __

CMV diseaseCMV disease

TESTTEST

00 44 88 12 months12 months

Could have initiated preemptive therapyCould have initiated preemptive therapyProphylaxis

THIS STRATEGY REQUIRES MONITORING AT VERY FREQUENT INTERVALS AFTER STOPPING PROPHYLAXIS

Humar A et al. Am J Transplant. 2004;4:644-649.TTS: Kotton CN et al. Transplantation. 2010;89:779-795.

Prophylaxis vs Preemptive TherapyProphylaxis vs Preemptive TherapyProphylaxis vs Preemptive TherapyProphylaxis vs Preemptive Therapy

ProphylaxisProphylaxis PreemptivePreemptiveEvidence of efficacyEvidence of efficacy ++++++ ++++

Indirect effects/mortalityIndirect effects/mortality ++++ ++

Other virusesOther viruses + for some+ for some ??Other virusesOther viruses + for some+ for some ??

EaseEase ++++ +/+/--

LateLate--onset diseaseonset disease ++++ --

ResistanceResistance LowLow LowLow

Adapted from Kotton CN et al. Transplantation. 2010;89:779-795.

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GUIDELINES GUIDELINES –– Kidney, Liver, Kidney, Liver, Pancreas, and HeartPancreas, and Heart

GUIDELINES GUIDELINES –– Kidney, Liver, Kidney, Liver, Pancreas, and HeartPancreas, and Heart

D+/RD+/R-- Universal prophylaxis preferred (II/III)Universal prophylaxis preferred (II/III)

V l i l i (FDA ti i li b t tV l i l i (FDA ti i li b t t Valganciclovir (FDA caution in livers but some experts Valganciclovir (FDA caution in livers but some experts still use), oral ganciclovir, IV ganciclovir, or valacyclovir still use), oral ganciclovir, IV ganciclovir, or valacyclovir (kidney) (I, except II(kidney) (I, except II--2 for pancreas) 2 for pancreas)

Start by day 10 until 3Start by day 10 until 3--6 months (I)6 months (I)

Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S86.Kotton CN et al. Transplantation. 2010;89:779-795.

GUIDELINES GUIDELINES –– Kidney, Liver, Kidney, Liver, Pancreas, and Heart (Cont’d)Pancreas, and Heart (Cont’d)GUIDELINES GUIDELINES –– Kidney, Liver, Kidney, Liver,

Pancreas, and Heart (Cont’d)Pancreas, and Heart (Cont’d)

R+ Patients:R+ Patients:

Prophylaxis: ganciclovir, valganciclovir (FDA caution in Prophylaxis: ganciclovir, valganciclovir (FDA caution in livers), valacyclovir (kidneys) (I/II)livers), valacyclovir (kidneys) (I/II)

oror

Preemptive therapy Preemptive therapy –– pp65 antigen test or molecular pp65 antigen test or molecular diagnostic test (IIdiagnostic test (II--2); IV ganciclovir or valganciclovir for 2); IV ganciclovir or valganciclovir for positive test (I)positive test (I)

Humar A et al. Am J Transplant. 2009;9(suppl 4):S78-S86.Kotton CN et al. Transplantation. 2010;89:779-795.

Antiviral Dosing For Prevention& Antiviral Dosing For Prevention& Treatment of CMVTreatment of CMV

PreventionPrevention

(Adult) (Adult)

PreventionPrevention

(Pediatric)(Pediatric)

TreatmentTreatment

GanciclovirGanciclovir N/AN/A 10 mg/kg/day I.V. 10 mg/kg/day I.V. di id ddi id d

10 mg/kg/day I.V. 10 mg/kg/day I.V. di id ddi id ddivided BID divided BID divided BID divided BID

ValganciclovirValganciclovir 900 mg P.O. 900 mg P.O. once daily once daily

Dose (mg) = 7 x Dose (mg) = 7 x BSA x ClcrBSA x Clcr

900 mg twice 900 mg twice daily daily

FoscarnetFoscarnet N/AN/A N/AN/A 180 mg/kg/day 180 mg/kg/day divided every 8 divided every 8 hours (induction)hours (induction)

BKVBKVBKVBKV

Background InformationBackground Information

BK Virus (BKV) is one of two human polyoma viruses, BK Virus (BKV) is one of two human polyoma viruses, discovered in 1971. discovered in 1971. Originally isolated from urine of KTx recipient with ureteral Originally isolated from urine of KTx recipient with ureteral

stenosisstenosis

Primary infection with BKV is usually asymptomatic & Primary infection with BKV is usually asymptomatic & occurs in first decade of lifeoccurs in first decade of life 11oo infections harmless in immunocompetent, but lead to viral infections harmless in immunocompetent, but lead to viral

latency within and intermittent shedding from the kidney.latency within and intermittent shedding from the kidney.

Urinary shedding of BKV is increased in the Urinary shedding of BKV is increased in the immunocompromised person.immunocompromised person.

BKV infections and viruria have been associated with BKV infections and viruria have been associated with hemorrhagic cystitis, ureteral strictures & interstitial hemorrhagic cystitis, ureteral strictures & interstitial nephritis in some immunosuppressed individualsnephritis in some immunosuppressed individuals

Relationship between viral load & likelihood of diseaseRelationship between viral load & likelihood of disease

BK Virus & Organ TransplantationBK Virus & Organ Transplantation

Although there is potential role for BKV in ALL SOT Although there is potential role for BKV in ALL SOT recipients experience to date identifies KTx recipients recipients experience to date identifies KTx recipients as being the primarily affected populationas being the primarily affected population

Imbalance between BKV replication & host immune Imbalance between BKV replication & host immune ppresponse key element in pathogenesis of diseaseresponse key element in pathogenesis of disease 3030--50% of KTx recipients with high50% of KTx recipients with high--level viruria progress to level viruria progress to

viremia and BKV associated nephropathy (BKVAN)viremia and BKV associated nephropathy (BKVAN)

BKVAN is the major manifestation after KTxBKVAN is the major manifestation after KTx

Ureteral stenosis or stricture in up to 3% of cases of BKV Ureteral stenosis or stricture in up to 3% of cases of BKV disease in RTx recipientsdisease in RTx recipients

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BKV & KTxBKV & KTx

Majority of BKV infections secondary to reactivation Majority of BKV infections secondary to reactivation of latent viral infectionof latent viral infection As many as 90% of cases asymptomaticAs many as 90% of cases asymptomatic Reactivation documented 5 weeks to 17 mos postReactivation documented 5 weeks to 17 mos post--TxTx

Primary infection associated with increased risk of Primary infection associated with increased risk of yyBKV diseaseBKV disease Documented 10 days to 6 weeks postDocumented 10 days to 6 weeks post--TxTx

Median time to onset BKVN: 9Median time to onset BKVN: 9--14 months14 months Some authors describe bimodal presentation: 4Some authors describe bimodal presentation: 4--8 weeks 8 weeks

and months to yearsand months to years Not enough pediatric data to determine if infection Not enough pediatric data to determine if infection

following primary infection occurs earlierfollowing primary infection occurs earlier

Risk Factors for BKVRisk Factors for BKV

Recipient of kidney transplantRecipient of kidney transplant Donor characteristicsDonor characteristics

Female gender, deceased donation, ischemiaFemale gender, deceased donation, ischemia--perfusion injury, perfusion injury, recent BKV exposure as measured by high antibody titer, HLA recent BKV exposure as measured by high antibody titer, HLA mismatches, African American ethnicitymismatches, African American ethnicity

R i i h i iR i i h i i Recipient characteristicsRecipient characteristics Older age, male gender, low or absent BKVOlder age, male gender, low or absent BKV--specific Tspecific T--cell cell

activityactivity

PostPost--transplant factorstransplant factors Acute rejection & higher levels of immunosuppressionAcute rejection & higher levels of immunosuppression

Cumulative steroid exposureCumulative steroid exposure Exposure to antiExposure to anti--lymphocyte antibodieslymphocyte antibodies Tacrolimus exposure compared to cyclosporine or mTor inhibitorsTacrolimus exposure compared to cyclosporine or mTor inhibitors

BKV Nephropathy:BKV Nephropathy:DiagnosisDiagnosis

Affected patients may initially appear Affected patients may initially appear asymptomaticasymptomatic

Rising creatinine is a late sign of infection & Rising creatinine is a late sign of infection & diseasedisease Often confused with rejectionOften confused with rejection

Patients with BKVAN should have BKV Patients with BKVAN should have BKV viremia detectable by PCR of bloodviremia detectable by PCR of blood

Definitive diagnosis require histologyDefinitive diagnosis require histology Presence of viral inclusionsPresence of viral inclusionsConfirmation via immunhistochemistry with Confirmation via immunhistochemistry with

SV40 TSV40 T--antigenantigenAlternate role for EM or PCRAlternate role for EM or PCR

Immunoperoxidase staining with anti-SV40 antibody showing BK virus antigens within infected nuclei of tubular epithelium.

Management of BKVNManagement of BKVN Immunosuppression should be reduced in KTx Immunosuppression should be reduced in KTx

patients with BKVAN patients with BKVAN Alternative strategies have includedAlternative strategies have included

Switching from tacrolimus to lowSwitching from tacrolimus to low--dose cyclosporinedose cyclosporine Switching from mycophenalate to leflunomideSwitching from mycophenalate to leflunomide Switching from calcineurin inhibitor to lowSwitching from calcineurin inhibitor to low--dose sirolimusdose sirolimusgg

Potential therapeutic benefits of “antiPotential therapeutic benefits of “anti--viral therapy” viral therapy” for those with persistent BKV load despite adequate for those with persistent BKV load despite adequate reduction in immunesuppression though no definitive reduction in immunesuppression though no definitive evidence supporting efficacy of these agentsevidence supporting efficacy of these agents CidofovirCidofovir LeflunomideLeflunomide IVIGIVIG QuinolonesQuinolones

BKV PreventionBKV Prevention

Preemptive strategies proposed based on Preemptive strategies proposed based on anecdotal & single center seriesanecdotal & single center series

Monitoring of BKV load recommended to Monitoring of BKV load recommended to inform preemptive interventioninform preemptive interventioninform preemptive interventioninform preemptive intervention Presence of BK viremia prompts actionPresence of BK viremia prompts action

Current guidelines suggest reduction of immune Current guidelines suggest reduction of immune suppressionsuppression

Unsure role for antiviral therapyUnsure role for antiviral therapy

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What Some Experts Recommend For Antiviral What Some Experts Recommend For Antiviral Dosing For Prevention& Treatment of BKVDosing For Prevention& Treatment of BKV

PreventionPrevention Treatment Treatment

CidofovirCidofovir 0.3 mg/kg/dose I.V. 0.3 mg/kg/dose I.V. once (range 0.25once (range 0.25--0.75 0.75 mg/kg/dose) given mg/kg/dose) given

0.3 mg/kg/dose I.V. 0.3 mg/kg/dose I.V. once (range 0.25once (range 0.25--0.75 0.75 mg/kg/dose) given mg/kg/dose) given

every week every week

(CHP)(CHP)--not proven not proven

every week every week

(CHP) not(CHP) not--proven proven

LeflunomideLeflunomide No Proven Dose or No Proven Dose or EfficacyEfficacy

? Dose based on levels? Dose based on levels

CiprofloxacinCiprofloxacin No proven Dose No proven Dose No Proven DoseNo Proven Dose

? 500 mg BID ? 500 mg BID

Invasive Fungal Invasive Fungal InfectionsInfections

Fungal Infections After SOTFungal Infections After SOT

Wide variety of potential fungal infections Wide variety of potential fungal infections following SOTfollowing SOT

Incidence of invasive mycoses following SOT Incidence of invasive mycoses following SOT ranges from 5 to 42% depending upon organ ranges from 5 to 42% depending upon organ g p g p gg p g p gtransplantedtransplanted Highest incidence in lung transplant recipientsHighest incidence in lung transplant recipients

Associated with high overall mortality ratesAssociated with high overall mortality rates Candida & Aspergillus spp account for Candida & Aspergillus spp account for

majority of invasive fungal infectionsmajority of invasive fungal infections

Risk Factors for Invasive Mycoses Risk Factors for Invasive Mycoses after SOTafter SOT

Invasive fungal infections (IFI) are concentrated in Invasive fungal infections (IFI) are concentrated in specific subpopulations of SOTspecific subpopulations of SOT High risk populations differ with each organ transplantedHigh risk populations differ with each organ transplanted

S f l ALL SOT i iS f l ALL SOT i i Some factors apply to ALL SOT recipientsSome factors apply to ALL SOT recipients

Lung transplant recipients appear to be at highest risk Lung transplant recipients appear to be at highest risk Association with history of Cystic FibrosisAssociation with history of Cystic Fibrosis

Frequently seen in patients with obliterative bronchiolitisFrequently seen in patients with obliterative bronchiolitis

Risk Factors for Early vs Late Risk Factors for Early vs Late AspergillusAspergillus

Risk factors for Early Risk factors for Early Aspergillus (< 3 mos)Aspergillus (< 3 mos) Complicated postComplicated post--op op

coursecourse

Risk factors for Late Risk factors for Late Aspergillus (> 3 mos) Aspergillus (> 3 mos) Advanced ageAdvanced age Renal failureRenal failure

Repeated bacterial Repeated bacterial infectioninfection

CMV infectionCMV infection Renal replacement Renal replacement

therapy therapy Underlying diagnosis of Underlying diagnosis of

Cystic FibrosisCystic Fibrosis Hospital constructionHospital construction

Increased immune Increased immune suppressionsuppression

Risk Factors for IFI:Risk Factors for IFI:Organ SpecificOrgan Specific

Liver TransplantLiver Transplant RetransplantationRetransplantation ReoperationReoperation Renal dysfunctionRenal dysfunction

F l i t h ti f ilF l i t h ti f il

Heart TransplantHeart Transplant Hx of ventricular assist Hx of ventricular assist

devicedevice ReoperationReoperation CMV diseaseCMV disease Fulminant hepatic failureFulminant hepatic failure

CMV diseaseCMV disease

Lung TransplantLung Transplant History of CFHistory of CF CMV diseaseCMV disease Obliterative bronchiolitisObliterative bronchiolitis

CMV diseaseCMV disease PostPost--tx hemodialysistx hemodialysis

Kidney Transplant Kidney Transplant ReoperationReoperation CMV diseaseCMV disease PostPost--tx hemodialysistx hemodialysis

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Candida infections after SOTCandida infections after SOT

Species of candida associated with infection after Species of candida associated with infection after SOT evolvingSOT evolving Up to 33% of infections postUp to 33% of infections post--OLTx due to nonOLTx due to non--albicans albicans

speciesspecies NonNon--candida species associated with worse outcomecandida species associated with worse outcome Implications for choice of antifungal treatmentImplications for choice of antifungal treatment

Frequent presence of Candida as “colonizing” flora Frequent presence of Candida as “colonizing” flora can confuse diagnosiscan confuse diagnosis

Candidemia related to presence of central venous Candidemia related to presence of central venous catheters is most common cause of infection due to catheters is most common cause of infection due to candida early after SOTcandida early after SOT

Additional sites can vary by organ transplantedAdditional sites can vary by organ transplanted

Invasive Candidiasis:Invasive Candidiasis:TreatmentTreatment

Treatment of invasive candidiasis for SOT recipients Treatment of invasive candidiasis for SOT recipients similar to treatment among most other patients as similar to treatment among most other patients as outlined in 2009 IDSA guidelinesoutlined in 2009 IDSA guidelines (2009 AST ID Guidelines) (2009 AST ID Guidelines)

No randomized trials in SOT to inform recommendationsNo randomized trials in SOT to inform recommendations Can use amphotericin B preparations, echinocandins or Can use amphotericin B preparations, echinocandins or

l d di d i l f il d di d i l f iazoles depending upon recovered species, renal function azoles depending upon recovered species, renal function & concern for drug& concern for drug--drug interactionsdrug interactions Some experts prefer echinocadins for invasive candidiasis due Some experts prefer echinocadins for invasive candidiasis due

to less toxicity, fungicidal activity & less significant drugto less toxicity, fungicidal activity & less significant drug--drug drug interactionsinteractions

Transient elevations in transaminases in patients receiving Transient elevations in transaminases in patients receiving cyclosporine & caspofungin in Phase I clinical trials led FDA to cyclosporine & caspofungin in Phase I clinical trials led FDA to limit use to those setting where “benefit outweighs potential limit use to those setting where “benefit outweighs potential risk”risk” (see later comments) (see later comments)

Prophylaxis Against CandidaProphylaxis Against Candida

Antifungal prophylaxis against Candida in Antifungal prophylaxis against Candida in SOT is very controversialSOT is very controversial

Poor quality and limited number of studiesPoor quality and limited number of studies

A if l h l i h ld b d fA if l h l i h ld b d f Antifungal prophylaxis should be reserved for Antifungal prophylaxis should be reserved for those at highest risk of developing diseasethose at highest risk of developing disease

Informed choice of agents limited by lack of Informed choice of agents limited by lack of datadata

Prophylaxis for Candida*Prophylaxis for Candida*

Pappas et al, AST ID Guidelines, Am J Transplantation, 2009

*Recommendations not really applicable to pediatric recipients

Aspergillus Infection after SOTAspergillus Infection after SOT Invasive aspergillosis seen in relatively uncommonly Invasive aspergillosis seen in relatively uncommonly

in SOT recipientsin SOT recipients Incidence range of 1Incidence range of 1--10% for Liver, Heart, Renal Tx 10% for Liver, Heart, Renal Tx

recipients while rates as high as 23% seen in lung recipients while rates as high as 23% seen in lung recipientsrecipients

Presentation tends to be early most SOT recipients Presentation tends to be early most SOT recipients but can be later for lung recipientsbut can be later for lung recipientsg pg p

General treatment of SOT recipients similar to other General treatment of SOT recipients similar to other patient population as outlined in IDSA Guidelinespatient population as outlined in IDSA Guidelines Voriconazole is drug of choice with growing published Voriconazole is drug of choice with growing published

experience in SOTexperience in SOT ((Singh, AST ID Guidelines, Am J Transplant, 2009)Singh, AST ID Guidelines, Am J Transplant, 2009)

Role of combination therapy not fully definedRole of combination therapy not fully defined Many clinicians and experts use two or more drugs for Many clinicians and experts use two or more drugs for

proven invasive diseaseproven invasive disease Use of voriconazole + echinocadin highlighted for primary Use of voriconazole + echinocadin highlighted for primary

therapy by AST ID Guidelines therapy by AST ID Guidelines

Prophylaxis Against AspergillusProphylaxis Against AspergillusHigh Risk PopulationsHigh Risk Populations

Lung transplant recipientsLung transplant recipients Voriconazole for lung recipients for 4 months Voriconazole for lung recipients for 4 months

HighHigh--risk liver transplant recipientsrisk liver transplant recipients AST ID Guidelines includes those experiencing retransplantation, AST ID Guidelines includes those experiencing retransplantation,

renal replacement therapy (pre or post LTx), reoperation and renal replacement therapy (pre or post LTx), reoperation and transplantation for fulminant hepatic failure or CF as potential transplantation for fulminant hepatic failure or CF as potential

did f h l idid f h l icandidates for prophylaxiscandidates for prophylaxis Use of lipid amphotericin B or echinocadin recommended (no duration Use of lipid amphotericin B or echinocadin recommended (no duration

provided) provided)

HighHigh--risk heart transplant recipients risk heart transplant recipients Those with recovery of aspergillus, reoperation, CMV disease, postThose with recovery of aspergillus, reoperation, CMV disease, post--tx tx

dialysis or presence of invasive aspergillosis in program 2 months dialysis or presence of invasive aspergillosis in program 2 months before or after this transplantbefore or after this transplant

Use of itraconazole or voriconazole recommended (no duration Use of itraconazole or voriconazole recommended (no duration provided) provided)

Singh, AST ID Guidelines, Am J Transplant, 2009Singh, AST ID Guidelines, Am J Transplant, 2009

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Drug Drug Interactions:Drug Drug Interactions:AntiAnti--infectious Agents in SOTinfectious Agents in SOT

Increased use of antimicrobial agents early after SOT Increased use of antimicrobial agents early after SOT (for treatment or prevention of infection) makes this (for treatment or prevention of infection) makes this highest risk period of concern for drughighest risk period of concern for drug--drug drug interactions related to these therapiesinteractions related to these therapies

Optimal treatment of specific infections should be Optimal treatment of specific infections should be guided not only by knowledge of pathogen’s guided not only by knowledge of pathogen’s susceptibility to antimicrobials but also by the effects susceptibility to antimicrobials but also by the effects of these agents on PK of immunosuppressants & of these agents on PK of immunosuppressants & potential for additive or synergistic toxicitiespotential for additive or synergistic toxicities

Thomas et al., AST ID Guidelines, 2009

Interactions that Raise Calcineurin & mTOR Interactions that Raise Calcineurin & mTOR Inhibitor LevelsInhibitor Levels

Macrolide antibiotics (except azithromycin) are strong inhibitors of Macrolide antibiotics (except azithromycin) are strong inhibitors of CYP3A4 increasing levels of CyA, Tac and sirolimusCYP3A4 increasing levels of CyA, Tac and sirolimus Greatest effect on sirolimus & least effect on CyAGreatest effect on sirolimus & least effect on CyA Rapid onset of 3Rapid onset of 3--10 fold increase in immunosuppressant concentration or 10 fold increase in immunosuppressant concentration or

AUCAUC Rare case reports of effect of azithromycin on CyARare case reports of effect of azithromycin on CyA

All azole antifungal agents decrease metabolism of calcineurin All azole antifungal agents decrease metabolism of calcineurin inhibitors and sirolimusinhibitors and sirolimusinhibitors and sirolimusinhibitors and sirolimus Modest to profound increases in serum concentration and AUCModest to profound increases in serum concentration and AUC Interaction increases from fluconazole →itraconazole → posoconazole → Interaction increases from fluconazole →itraconazole → posoconazole →

ketoconazole → voriconazole ketoconazole → voriconazole Interactions can be both dose and drug dependentInteractions can be both dose and drug dependent Voriconazole prescribing recommendations suggest cutting Tac dose by 1/3Voriconazole prescribing recommendations suggest cutting Tac dose by 1/3 Concomitant use voriconazole and sirolimus contraindicated Concomitant use voriconazole and sirolimus contraindicated

Eichinocadins lack significant interactions with calcineurin Eichinocadins lack significant interactions with calcineurin inhibitorsinhibitors ? Of risk of hepatoxicity with use of caspofungin + CsA not substantiated by ? Of risk of hepatoxicity with use of caspofungin + CsA not substantiated by

subsequent studiessubsequent studiesThomas et al., AST ID Guidelines, 2009

Interactions that Decrease Calcineurin & Interactions that Decrease Calcineurin & mTOR Inhibitor LevelsmTOR Inhibitor Levels

All rifamycins are strong inducers of CYP3A4 All rifamycins are strong inducers of CYP3A4 resulting in dramatic decrease in levels of calcineurin resulting in dramatic decrease in levels of calcineurin inhibitors and sirolimusinhibitors and sirolimus Use should be avoided if possibleUse should be avoided if possible

If m st se dose sho ld be initiall do bled ithIf m st se dose sho ld be initiall do bled ith If must use, dose should be initially doubled with If must use, dose should be initially doubled with rapid subsequent increases (up to 10rapid subsequent increases (up to 10--fold reported) & fold reported) & careful f/u of levelscareful f/u of levels

Much less dramatic effect of rifampin on MMF Much less dramatic effect of rifampin on MMF reportedreported Manufacturer still recommends avoiding this combinationManufacturer still recommends avoiding this combination

Thomas et al., AST ID Guidelines, 2009

Pharmacodynamic InteractionsPharmacodynamic Interactions

Increased nephrotoxicity with use of Increased nephrotoxicity with use of amphotericin B products or cidofovir & amphotericin B products or cidofovir & calcineurin inhibitorscalcineurin inhibitors

Increased marrow suppression with use ofIncreased marrow suppression with use of Increased marrow suppression with use of Increased marrow suppression with use of ganciclovir or acyclovir & rapamycin or ganciclovir or acyclovir & rapamycin or mycophenolate or azathioprinemycophenolate or azathioprine

Guidelines for the Prevention Guidelines for the Prevention and Management of Infections and Management of Infections Complications of Solid Organ Complications of Solid Organ

TransplantationTransplantation

AST Handbook of Transplant Infections

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Management of Cardiovascular Disease after Kidney Transplantation

Donald E. Hricik, M.D.Chief, Division of Nephrology

Case Western Reserve UniversityUniversity Hospitals Case Medical Center

60

65

8590 90

96

80

65

6060

80

100

cen

t Cyclosporine

• OKT3

• Cyclosporine Emulsion

• Tacrolimus

• MMF

• Dicluzimab

Cadaveric Renal Allograft Survival

• Radiation• Prednisone• 6-MP

45 45

25

15

40

35

0

20

40Perc

Rejection <12 mo

1 Year Survival

‘60 ‘65 ‘70 ‘75 ‘80 ‘85 ‘90 ‘95 ‘00

• Basiliximab

• Thymoglobulin• Sirolimus

YearAdapted from Stewart F, Organ Transplantation, 1999

• AZA

•ATGAM

Causes of Late Kidney Allograft Loss

Late allograft loss(>1 yr after

transplantation)

50%Chronic renal allograft

40%Death with

functioning graft

50%Cardiovascular

4

gdysfunction

Cardiovascular disease

10%–20%Other diagnoses

Chronic rejectionNon-specific fibrosis,

tubular atrophy

Drug toxicity

New diseases

Recurrent diseases

Acute rejection

Pascual M et al. N Engl J Med. 2002;346:580-590.

30%–40%Chronic allograft

nephropathy

Cardiovascular Mortality in Renal Transplant Recipients

Cardiovascular Annual Mortality

General 0.28 %

Hemodialysis 9.12%

Peritoneal dialysis 9.24 %

Renal transplant 0 54 %

Cerebrovasculardisease

7%

Infection20%

Malignancy13%

Cardiovasculardisease

48%

Infection17%

Cerebrovasculardisease

10%

USRDS database, 2001.Foley, et al. J Am Soc Nephrol. 1998;9(suppl):S16.Foley, et al. Am J Kidney Dis. 1998;32(suppl 3):S112.

Renal transplant 0.54 %

Other23%Cardiovascular

disease 37%

N = 47,581

All Patients

Malignancy6%

Other19%

N = 16,231

Diabetic Patients

Kidney Transplantation Reduces CVD Risk in Patients With ESRD

28

36

41

30

35

40

45

CV death rate on waiting list

CV death rate after DD transplant

atie

nt

year

s

6Meier-Kriesche HU et al. Am J Transplant. 2004;4:1662-1668.

35

8

17

2825

21

6 5 57 7

11 10

0

5

10

15

20

25

30

Rat

es p

er 1

00

0 p

a

0-3 3-6

Months

6-12 12-24 24-36 36-48 48-60 60+

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Independent Risk Factors forPost-transplant Cardiovascular Events

6

8

10

ativ

e ri

sk

*

*P < 0.0001; †P < 0.01; ‡P < 0.05Error bars represent 95% CI

Single-center retrospective study (N = 427)Aker S et al. Int Urol Nephrol. 1998;30:777–788.

0

2

4

Diabetesmellitus

Rel

a

Age attransplant

(> 50 y)

Body massindex

(> 25 kg/m2)

Smoking LDL-C(> 180 mg/dL)

Uric acid(> 6.5 mg/dL)

‡† ‡ ‡‡

Risk Factors for Cardiovascular Disease

• Kidney Disease• Obesity• Dyslipidemia• Diabetes

Metabolic Syndrome(30-60% kidney pts)Diabetes

• HTN• Tobacco• Physical inactivity• Family history• Age

(30 60% kidney pts)

What is Metabolic Syndrome?

NCEP-ATP III(any 3)

IDF(obesity+2)

Central obesityTriglycerides HDLBP

> 40”(m); 35”(f)> 150 mg/dl< 40 mg/dl> 130/85

> 37”(m); 31”(f)> 150 mg/dl< 40 mg/dl> 130/85

DiabetesMellitus

Kidney (Allograft)Dysfunction

ChronicInflammation

CardiovascularDisease

BP Fasting glucose

> 130/85> 100 mg/dl

> 130/85> 100 mg/dl

CyA Tac SRL Ster MMF

Hypertension ++ + ++ Hyperglycemia + ++ +++ Renal insufficiency ++ ++ Hyperlipidemia ++ + ++ ++

Immunosuppression Long-Term Side Effect Profiles

Hyperkalemia +++ +++ Tremor + Hirsutism + Gingival hyperplasia + Hypophosphatemia ++ ++ + Osteoporosis +++ Malignancy + + ? +

CyA = cyclosporine; Tac = tacrolimus; SRL = sirolimus+++ = severe; – = opposite; + = mild; ++ = moderate; = none; ? = unknown

The Pitfalls of Immunosuppression Incidence of Hypertension at 1 Year Post-transplantation (N = 29,751)

9.5%

SBP values (mm Hg)

< 120

120–1299 8%

4.1% 4.2%

SBP = systolic blood pressureOpelz G et al. Kidney Int. 1998;53:217–222.

130–139

140–149

150–159

160–169

170–179

180

15.2%

20.2%22.6%

15.0%

9.8%

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Association of Hypertension at 1 YearWith Decreased Graft Survival

surv

ivin

g

70

80

90

100

SBP No. pts

< 120 2,805120–129 4,488130–139 5,961140 149 6 670

SBP = systolic blood pressureOpelz G et al. Kidney Int. 1998;53:217–222.

% g

raft

s

50

60

70

0

0 1 2 3 4 5 6 7

Years post-transplantation

140–149 6,670

150–159 4,443

160–169 2,925170–179 1,217

180 1,242

Pathogenesis of Hypertensionin Renal Transplant Recipients

• Pre-existing essential hypertension

• General-population risk factors(obesity, smoking, alcohol, excessive salt intake)

• Renal dysfunction/rejection

Mailloux LU et al. Am J Kidney Dis. 1998;32(suppl 3):S120–S141.Kew CE II et al. J Renal Nutrition. 2000;10:3–6.

Renal dysfunction/rejection

• Renal-transplant artery stenosis

• Effects of native kidneys

• Hypertensive donor

• Immunosuppressive drugs

Posttransplant Hypertension: Treatment

• All antihypertensive drugs work!

• No established algorithm, but consider:

– Interactions between immunosuppressive meds and BP ppmeds.

– “Nephrotoxicity” of BP meds– Side effects of BP meds– Cost and number of medications!– HTN is a side effect of IS medications

ACEIs and ARBs in Kidney Transplantation

Antiproteinuric

? Renal? Renal Protection

Hyperkalemia

Acute Renal Failure (rare)

Anemia

Kaplan-Meier estimates of patient survival ACEIs/ARBs Do not Influence Graft or Patient Survival

Opelz G, et al. J Am Soc Nephrol 2006;17:3257-3262

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Pathogenesis of Hyperlipidemiain Renal Transplant Recipients

• High prevalence of predisposing factors1

– Age– Diabetes– Obesity

• Impaired renal function2

R l i ffi i– Renal insufficiency– Proteinuria

• Drugs3

– Diuretics, beta-blockers– Immunosuppressive agents

1. Keane WF. Miner Electrolyte Metab. 1997;23:166–169.2. Kasiske BL. Am J Kidney Dis. 1998;32(suppl 3):S142–S156.3. Aakhus S et al. J Intern Med. 1996;239:407–415.

Dyslipidemia in the Transplant Recipient

Definitions and Prevalence

Dyslipidemia

Level

(mg/dl)

Prevalence

(%)

Total Cholesterol > 200 51-97

LDL Cholesterol > 100 72-97

Triglycerides > 150 36

HDL Cholesterol < 40 14-48

Kasiske B, et al. Am J Transplant. 2004Kasiske BL, et al. J Am Soc Nephrol. 2000

Hyperlipidemia in Kidney Recipients

Risk Factors and Implications

Hyperlipidemia

ObesityCorticosteroids CV disease

Chronic graft dysfunction

ort costero dsSirolimusCyADiuretics-blockersDMproteinuria

V d sease

240

220

200tero

l (m

g/d

L)

Cyclosporine vs Tacrolimus

Mean Total Cholesterol Level Over TimeCyclosporine

Tacrolimus230

194

226

199

210

198

P < 0.001P < 0.001

P = 0.07

200

180

160

140Mea

n t

ota

l ch

ole

st

Randomized, multicenter trial with traditional formulation of cyclosporinePirsch JD et al. Presented at Transplant 2000; Chicago, Illinois; May 13–17, 2000.

(n = 189)

150

(n = 192)

144

Baseline(n = 104)

194

1 Year(n = 129)

3 Years(n = 94)

5 Years(n = 98) (n = 93) (n = 64)

Effect of Sirolimus on Aortic Atherosclerosis in ApoE-Deficient Mice

Adelman SJ et al. Presented at Transplant 2001; Chicago, Illinois: May 11–16, 2001.

Control 8 mg/kg/d x 2 d

Beneficial Effects of Statins

• Lower lipid levels• Reduce systemic inflammation• Immunomodulatory• Increase insulin sensitivity• Anti-oxidant effects• Enhance endothelial function

1. Mason JC, Curr Opin Nephrol Hypertens. 2005;14:17-24. 2. Jardine AG, et al. Am J Transplant. 2004;4:988-995.

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ALERT Trial (n=2102)*Cumulative Incidence of Cardiac Death or

Nonfatal definite MI - Core Study15

10 PlaceboP = 0.005

35%

Proportion of patients with event

(%)

Holdaas et al Lancet 2003;361:2024

Years since randomization

1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0

5

0

Fluvastatin

0.50.0

(%)

*Fluvastatin 40-80 mg/day

Mean follow-up 5 years

Total cardiac events not reduced significantly

Adjuncts to Statins in Txp Recipients

• Fibrates (e.g fenofibrate, gemfibrozil)– Reduce creatinine clearance– Usually reversible

• Ezetimibe• Ezetimibe– Benefit unknown– Lowers LDL effectively– Appears to be safe in txp pts– Interactions with CNI unknown

Management of Dyslipidemia in Kidney Recipients

Djamali A, Clin J Am Soc Nephrol 2006

Diabetes in Transplant Recipients

~30% of renal transplant patients have pre-existing type-I or -II diabetes1

New onset glucose intolerance develops in 20% of transplant patients2

Di b i l i h 2 3 f ld hi h Diabetic transplant patients have a 2- to 3-fold higher incidence of post-transplant infectious complications3-5

Increased risk of cardiovascular and peripheral vascular complications2

1. USRDS 2001 Annual Data Report; 2. Kasiske. In: Handbook of Kidney Transplantation, 3rd ed,2001; 3. Steinmuller, et al. Exp Clin Endocrinol Diabetes. 2000;108:401; 4. Stratta. Surgery.1998;124:823; 5. Brann, et al. J Heart Lung Transplant. 1998;17:374.

Survival Free of Posttransplant DiabetesBased on Medicare Claims

70

80

90

100

20

30

40

50

60

70

0 3 6 9 12 15 18 21 24 27 30 33 36

3 months (9.1%) 12 months (16%) 36 months (24

Adapted from Kasiske B, et al Am J Transplantation 2003; 3:178-85

Classification of Diabetes MellitusCategory ADA 2004 WHO 1999

Normal <100 <110

Impaired Fasting 100-125 110-125Impaired Fasting Glucose

100 125 110 125

Impaired Glucose Tolerance

2h PPG 140-199 2h PPG 140-199

Diabetes Mellitus FPG > 126 or

2h PPG > 200

FPG > 126 or

2h PPG > 200

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Effect of Diabetes Mellitus (DM) and PTDM on Patient Survival

No DM

100

80

60

40t cu

mu

lati

ve

rviv

al (

%)

PTDM

0 2 4 6 8

40

20

0

Years post-transplantation

Pat

ien

sur

10 12 14

Type-1 DM

10-year survival: PTDM (49%) and type-1 DM (39%) P 0.001 vs no DM (75%)PTDM = post-transplant diabetes mellitusSingle-center, retrospective study (N = 939)Revanur VK et al. Clin Transplant. 2001;15:89–94.

Cardiovascular Events and Glycemic Status at 1 Year Post-transplantation

Cosio FG et al. Kidney Int. 2005;67:2415-2421.

Risk Factors for NODAT

Black, Hispanic Age >40 yrs Male gender ADPKD HCV infection1

Corticosteroid Tacrolimus Cyclosporine

ModifiableNon-modifiable

Immunosuppression

Potentially modifiable

ADPKD HLA mismatches Acute rejection FH Diabetes

CMV infection2

Pre-TxIGT3

Cyclosporine Sirolimus

Obesity/metabolicsyndrome

Adapted from Pham PTT et al. Endocrinol Metab Clin N Am 2007

Hypomagnesemia?

Tacrolimus is more diabetogenic than cyclosporine

14%

(Kasiske et al. AJT 3:178, 2003)

22%

PTDM: Independent Risk Factors

Clinical Factor Relative RiskAge > 60 2.60Age 49-59 1 90Age 49 59 1.90BMI > 30 1.73African American 1.68Tacrolimus 1.35Hepatitis C Antibodies 1.33

Kasiske et al. AJT 2003 3: 178

Sirolimus and Increased NODAT in Kidney Recipients

Johnston et al, J. Am Soc Nephrol 2008n=20,124 Medicare kidney recipients

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Nonpharmacologic Therapy

(Weight Loss; Exercise)

Oral Hypoglycemic Agent Monotherapy

Combination of Oral Agents

? Manipulation of Immunosuppression

STEPWISE APPROACH TO

TREATMENT OF NODAT

Combination of Oral Agents

Insulin Plus Oral Agents

Insulin Monotherapy

Non-Insulin Drug Therapy for NODATClass Principle

Mechanismof Action

Example SideEffects

Metabolism/Elimination

Altered Dosing in CKD

Sulfonylureas Insulin secretagogue

GlipizideGlyburideGlimepiride

Hypoglycemia Hepatic No

Meglitinides Insulin secretagogue

RepaglinideNateglinide

Hypoglycemia CYP2C8/3A4 Yes

Biguanides hepatic gluc production

Metformin Nausea, Lactic acidosis

Renal tubular secretion

Yes

TZDs insulin sensitivity

PioglitazoneRosiglitazone

Wt gain, Fluid retention

CYP2C8CYP3A4

No

α-glucosidaseInhibitors

intestinal gluc absorption

Acarbose Nausea, Flatulence

Major-FecalMinor-Renal

Yes

GLP-1ReceptorAgonists

(i) gluc med insulin secretion(ii) glucagon(iii) weight loss

Exenatide Nausea,other GI Major-Renal Yes

DPP-IVInhibitors

GLP-1 Sitagliptin Minimal RenalCYP3A4, 2C8

Yes

Cardiovascular Death by sCr at 1 Year Posttranplant

Serum Creatinine @ 1 Year CV death-free survival rate

< 1.3 97%

1.3-1.4 96%

1.5-1.6 95.5

1.7-1.8 94

1.9-2.1 93.5

2.2-2.5 93

2.6-4.0 91Meier-Kriesche at al. Transplantation 2003; 75: 1291

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