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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
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
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
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
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 4
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.
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 5
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.
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 6
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
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 7
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
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 8
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
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 9
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
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 10
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
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 11
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+
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 12
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%
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 13
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
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 14
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.
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 15
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
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 16
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
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 17
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
2011 ACCP Annual Meeting
Symposium on the Management of Complications After Organ Transplantation 18