Care of the Post-OLT Patient

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Care of the Post-OLT Patient

• George Makar

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Overview

• Immunosuppression
• Causes of Allograft Failure
• Medical Comorbidites
• Malignancies
• Pregnancy/Sexual Function

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Figure 1. Timeline for the introduction of
immunosuppression medications.

• Immunosuppression in Liver Transplantation. Post
  et al. LiverTransplantation, Vol 11, No 11,2005
  pp 1307-1314

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Figure 2. Illustration showing the activation of
a T lymphocyte (via 3-signal pathway) by an
antigen-presenting cell. Further detail includes
the specific sites targeted by the calcineurin
inhibitors (TAC and CyA) showing inhibition of
IL-2 production. Monoclonal antibodies
(basiliximab, daclizumab) target the IL-2
receptor, while OKT3 targets the T-cell receptor.
Sirolimus, MPA, MMF, azathioprine, and FK778
interfere with the proliferative phase in the
cell cycle. Novel agent FTY720 alters lymphocyte
trafficking/homing patterns through modulation of
cell surface adhesion receptors inducing a
lymphopenic effect.

• Immunosuppression in Liver Transplantation. Post
  et al. Liver Transplantation, Vol 11, No 11,2005
  pp 1307-1314

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Immunosuppression

• Early multiple meds, high doses
• Pred CNI /- (MMF/AZA)
• Late fewer (1) meds, lower doses
• Most patients CNI alone (usually Tac)
• Exceptions
• Autoimmune hepatitis, PSC, PBC (usually 2 drugs)
• Renal dysfunction (MMF/AZA lower CNI dose)

CNI calcineurin inhibitor CsA or Tac
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Cyclosporine

• Block Calcineurin? ?IL-2 ??T-Cell Activation
• Initial dosage 10 to 15 mg/kg/day divided into 2
  doses.
• Trough Goals
• Week 1-2 250-350 ng/mL
• Weeks 3-4 200-300
• Weeks 5-24 150-250 ng/mL
• Weeks 25 100-200 ng/mL
• Distant can tolerate levels lt100

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Cyclosporine Adverse Effects

• Hypertension
• Renal dysfunction
• Hirsutism
• Hyperkalemia
• Gingival hyperplasia
• Hypomagnesemia

http//jorthod.maneyjournals.org/content/vol30/iss
ue1/images/large/ClocFig1b.jpeg
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Tacrolimus

• MOA same as CsA
• Initial dose 0.1 to 0.15 mg/kg/day orally
• Trough Goals (variable per patient/disease)
• Early Post-OLT 10-15 ng/ml
• 3-6 Months 8-10
• gt6 Months 5-7 (variable)

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Tacrolimus Adverse Effects

• Posttransplant diabetes mellitus
• Nausea, vomiting, diarrhea
• Hyperkalemia
• Tremor
• Hypertension
• Hypomagnesemia
• Headache
• Renal dysfunction

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Tac vs Csa

• Dyslipidemia and Gingival hyperplasia more
  common in Csa
• Diabetes more common in Tac
• Rejection less common in Tac
• Renal Dysfunction similar

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Sirolimus

• Binds to same immunophilin as Tac (FKBP12) but
  with a different mechanism of action
• blocks response of T and B Cell Activation by
  cytokines prevents progression at the juncture
  of G1 and S phase in these cell lines.
• Theoretical (lab based) antineoplastic and
  antifungal effects.
• Early excitement about renal protective effect-
  subsequent studies have not confirmed this
• Meta-analysis of 11 studies suggests a
  numerical/non-significant improvement in renal
  function.

Hepatology. 2010 Oct52(4)1360-70.
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Sirolimus

• Not FDA approved for Liver Transplants
• The FDA is notifying healthcare professionals of
  clinical trial data that suggest increased
  mortality in stable liver transplant patients
  after conversion from a calcineurin inhibitor
  (CNI)-based immunosuppressive regimen to
  sirolimus (Rapamune). The trial was conducted by
  sirolimus manufacturer, Wyeth.

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Sirolimus

• Black Box warning possible increased risk of
  Hepatic Artery Thrombosis in immediate post-OLT
  setting usually wait up to 12 weeks post.
• Recent study of switch from CNI to SRL suggests
  possible increased mortality (FDA ALERT
  06/11/2009)
• Currently using in those intolerant to CNIs, and
  in some patients for theoretical antineoplastic
  and renoprotective (controversial) effects.

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Sirolimus Adverse Effects

• Anemia
• Hypercholesterolemia
• Hypertriglyceridemia
• Leukopenia
• Hyperlipidemia
• Interstitial lung disease
• Thrombocytopenia
• Peripheral edema
• Wound dehiscence
• Hepatic Artery Thrombosis

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Mycophenylate Mofetil (MMF)/Mycophenolic Acid
(MPA)

• inhibit the de novo purine nucleotide synthesis
  via abrogation of the inosine monophosphate
  dehydrogenase and the production of guanosine
  nucleotides
• Leads to blockage of DNA replication in T and B
  lymphocytes (cant use salvage pathways).
• MPA is a delayed release form of MMF
• Dosing
• 1000-1500mg bid MMF or
• 360-720 BID MPA

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Side effects of MMF/MPA

• Nausea, vomiting, diarrhea
• Anemia
• Leukopenia
• Weight loss
• Thrombocytopenia

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Immunosuppression Drug Interactions

• Cytochrome P-450 3A
• P-Glycoprotein cell membrane associated protein
  transports drugs and plays a role in both
  absorption (bowel) as well as elimination (liver
  and kidney)
• carvedilol inhibits p-plycoprotein pathway
  leading to increased CNI levels
• Grapefruit can increase levels of CNIs
  mechanism not totally clear

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Drug Interactions
American Journal of Transplantation 2009 9
19882003
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Drug Interactions
American Journal of Transplantation 2009 9
19882003
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Antibody Induction

• Antithymocyte Globulin induction/rejection.
• Polyclonal antilymphocyte globulin multiple
  epitopes on T cell receptor lead to apoptosis
  of T-cells
• ATGAM (of equine origin)
• Thymoglobulin (of rabbit origin)
• Monoclonal anti T-Cell antibodies
  induction/rejection
• Muromonab-CD3 (OKT3) binds CD3 Antigen on
  T-Cell receptor inactivates adjacent T-Cell
  leads to rapid drop in T-Cells
• IL-2 Receptor Antibodies induction
• Basiliximab (Simulect)
• daclizumab (Zenapax).

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Causes of Allograft Failure

• Primary Nonfunction slightly more common in
  Living Donors
• Vascular Complications 10 of patients
• Hepatic Artery Thrombosis/Stricture
• Portal Vein Thrombosis/Stricture
• Hepatic Vein Thrombosis/Stricture
• Biliary Complications
• Donors after Cardiac Death
• Living Donors
• Anastomotic vs nonanastomotic strictures

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Causes of Allograft Failure- Rejection

• Antibody Mediated Rejection hours to days
• 10-20 Acute Rejection
• Risk 1st 3monthsgt1st yeargtsubsequent years
• Chronic Rejection a primary RF is prior
  episodes of Acute Rejection.
• Acute vs Chronic
• time course
• pattern of liver enzyme abnormalities
• response to therapy

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Acute Rejection

• Banff Grading System each factor 1-3 scale
• Portal Inflammation
• Bile Duct Inflammation/damage
• Venous Endothelial Inflammation

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Wyatt (2010) Histopathology 57, 333341
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Acute Rejection

• RFs
• young recipient,
• healthier recipients,
• HLA-DR mismatch,
• PSC/PBC/AIH,
• long cold ischemia time,
• older donor.
• Late (gt1 year) acute rejection inadequate
  immunosuppression.

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Chronic Rejection
Adapted/abbreviated from Table 69-9 Features of
Early and Late Chronic liver allograft rejection.
Pg 1086, Transplantation of the Liver, Busuttil
and Klingman, 2nd Edition.
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Infections that can lead to graft failure

• CMV 1-4 months post-OLT, increased risk of
  rejection
• Other herpes family viruses similar course to
  lesser extent
• HCV
• 1 in 3 cirrhotic at 5 years
• 5-10 fibrosing cholestatic HCV
• HBV
• Controlled in era of HBIG and oral therapies

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Causes of Allograft Failure Recurrent Disease

• AIH, PBC, PSC 10-20
• EtOH 20 with recurrent use
• majority of recurrent use not associated with
  heavy Etoh ingestion or poor outcomes.
• HCC within Milan - 10 risk of recurrence
• - higher rates for outside of Milan Criteria

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Renal Dysfunction

• 18 Rate of CRF (GFR lt30) by 5 years
• Pretransplant Factors
• female, HCV, Renal disease pretransplant
• Immunosuppression dose dependent
• Reversible vasoconstriction of Intrarenal
  Vessels
• Irreversible tubulointerstitial fibrosis
• Hypertension
• Diabetes

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Diabetes

• Prevalence 33
• RF obesity, steroids, high TAC doses,
  pretransplant DM, HCV
• De novo post transplant diabetes
• 27 year 1
• 9 year 2
• 1 year 3
• Treat in a similar manner as non-OLT patients
  lifestyle changes, minimize steroids and lower
  Tac dosing.
• OLT can cure Diabetes in some patients
• 56 pretransplant DM, resolved DM in one cohort
  study1

Steinmuller TH,. Liver transplantation and
diabetes mellitus. Exp Clin Endocrinol Diabetes
2000 108 401405.
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Hypertension

• CsA (25-82) gt Tac (17-64)
• Goal BP lt130/80
• Thiazide, Loop (if edema)
• Calcium channel Blockers
• (not dilt,verapamil, nicardipine inc levels of
  CNIs).
• Later ACE/ARB, especially in DM (monitor K)
• Can use others doxazosin, clonidine, beta
  blockers (monitor levels with Coreg).

Can block intrarenal vasoconstriction caused by
CNIs
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Dyslipidemia

• Prevalence 16-43
• RF Female, Cholestatic liver disease, DM,
  Obesity, pretransplant dyslipidemia
• Effects on Lipids
• CSA, Steroids Sirolimus greatest effect
• TAC minor effect
• MMF/AZA no effect
• Treatment all classes of agents can be used
  each with potential for drug interactions/toxiciti
  es.
• Note bile acids cannot be used if also on
  MMF/AZA

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Obesity

• 22 Nonobese patients pre-OLT become obese post
• Pre-OLT obese gain more weight than non-obese
• RF for recurrent (or de novo) NASH
• TX the usual
• Orlistat can decrease absorption of CsA

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Gout

• Dec Uric Acid excretion by CNIs
• RFs thiazides, ASA, Nicotinic Acid
• Prophylaxis Allopurinol (except if on AZA)
• TX colchicine, steroids
• Avoid NSAIDS (nephrotoxic with CNIs)

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Bone Disease

• Nadir in Bone Density 6 months Post
• Bone density 1 year post similar to bone density
  at time of OLT
• 13 fracture rate within 2 years of OLT
• RFs for Osteoporosis
• ETOH
• Tobacco
• Low Testosterone
• Physical Inactivity
• cholestatic liver disease
• unconjug bili inhibits osteoblast proliferation
• Patients also at risk of Osteonecrosis of Femoral
  Head

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Bone Disease

• Treatment of Osteoporosis
• Calcium 1500mg vitamin D 800 IU
• Bisphosphonates well studied
• Other classes not as well studied but no obvious
  contraindications
• Calcitonins, Parathyroid hormone, Selective
  Estrogen Receptor-Modulators

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Vaccines
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Vaccines

• Theoretical Risks with Life Attenuated Vaccines
  due to potential risk of shedding of liver virus
  small studies suggest that many of these are
  safe.
• Transplant Center dependent decisions for these
  (we dont use)
• Use inactivated virus whenever possible

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Dental Care

• Important can be source of sepsis in
  peri/post-OLT setting
• Gingival Hyperplasia unique to CSA, may require
  oral surgery and/or switch to Tac
• Antibiotic Prophylaxis for Dental Work - revised
• As per AHA guidelines only if at increased risk
  of endocarditis (prior endocarditis, prosth
  valve, certain forms congenital heart dz).
• Many transplant programs (including ours) still
  provide antibiotics.

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Tobacco

• Increased rates of
• CAD
• Stroke
• Esophageal/upper aerodigestive Cancer
• liver vascular events (Hepatic Artery
  Thrombosis/Stenosis, Portal Vein Stenosis, DVT)

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THC

• In Nontransplant Patients reports of increased
  steatosis/fibrosis in THC users
• Contamination with fungal spores theoretical
  increased risk of fungal infections.

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Malignancies Skin Cancer

• 100x over general population
• Squamous Cell (SCC)gt Basal Cell gt Melanoma
• SCC multiple, more aggressive, more likely to
  be associated with metastasis
• 35 lifetime risk
• Rec
• annual Dermatology exam,
• minimize immunosuppression in setting of
  diagnosed skin cancer
• use sunscreen/avoid sun exposure

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Malignancies - PTLD

• 2 Adults, 15 Kids
• 80-90 EBV associated
• Usually within 1 year post-OLT
• 2 less common forms (CD20 negative)
• Plasmacytic form (similar to multiple myeloma)
• T-Cell malignancy
• Treatment
• Reduce immunsuppresion
• Rituximab if CD20 positive, Chemotherapy if CD20
  negative

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Malignancies - GI

• Upper aerodigestive tract increased in those
  with Risk Factors ETOH, Tobacco
• Colon cancer increased risk in those with
  preexisting RFs ie PSC/UC patients
• Annual colonoscopy with surveillance biopsies

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Malignancies - Other

• Breast, Prostate, Lung, Colon cancer no
  definite increased risk (in those without risk
  factors)
• Follow age-appropriate cancer screening
  guidelines
• Role of decreased immunosuppression less clear in
  these cancers than in virally mediated
  malignancies (EBV, Kaposis, HPV associated
  (anogenital) malignances)

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Sexual Function

• ESLD is bad for fertility (50 amenorrhea) and
  for sexual dysfunction (both libido and erectile
  dysfunction).
• gt90 recover sexual function post-OLT
• Use Contraception!
• 50 of females transplanted are of child bearing
  age

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Pregnancy

• Wait 1 year post-OLT
• Most drugs category C
• (MMF/AZA category D)
• National Transplantation Pregnancy Registry
  (NTPR) 2700 pregnancies
• Live birth Rate 70
• Congenital anomolies 4-5 vs 3 general
  population
• Premature/Low Birth weights range 10-55
• Tac lower rates of hypertension/preeclampsia vs
  CsA

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Pregnancy Risk of Rejection

• Increased serum proteins that lead to increased
  binding of CNIs and decreased levels
• 10 rate of rejection
• Close monitoring of CNI levels throughout
  pregnancy

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Summary

• CsA, Tac or Sirolimus are the backbone of
  maintenance immunosuppresion
• Addition of other agents (Steroids, MMF,
  Azathioprine) can be used to decrease risk of
  rejection or allow for lower doses of the primary
  agents.
• 50 of post-OLT deaths are directly/indirectly
  related to immunosuppressive medications.

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Summary

• Technical Factors and early recurrent Disease
  responsible for allograft failure in first year
• With the possible exception of HCV and HCC
  patients, after the first year, long-term
  survival more affected by CV disease and
  malignancy than allograft failure.
• Goal should be aggressive lifestyle measures to
  control weight and medical comorbidities and
  ensuring patients are up to date with cancer
  screening.
• Primary additional testing in long-term
  transplant patients annual dermatology exams and
  DEXA scans (especially for those on long-term
  steroid therapy).

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Reading

• McGuire BM et al. Long-term Management of the
  Liver Transplant Patient Recommendations for the
  Primary Care Doctor American Journal of
  Transplantation 2009 9 19882003
• Post DJ. Immunosuppression in Liver
  Transplantation. Liver Transplantation, 2005 11
  1307-1314