care of the post-olt patient george makar. overview immunosuppression causes of allograft failure...
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Care of the Post-OLT Patient
George Makar
Overview
• Immunosuppression• Causes of Allograft Failure• Medical Comorbidites• Malignancies• Pregnancy/Sexual Function
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
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
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
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 <100
Cyclosporine – Adverse Effects
• Hypertension• Renal dysfunction• Hirsutism• Hyperkalemia• Gingival hyperplasia• Hypomagnesemia
http://jorthod.maneyjournals.org/content/vol30/issue1/images/large/ClocFig1b.jpeg
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– >6 Months – 5-7 (variable)
Tacrolimus – Adverse Effects
• Posttransplant diabetes mellitus• Nausea, vomiting, diarrhea• Hyperkalemia• Tremor• Hypertension• Hypomagnesemia• Headache• Renal dysfunction
Tac vs Csa
• Dyslipidemia and Gingival hyperplasia – more common in Csa
• Diabetes – more common in Tac• Rejection – less common in Tac• Renal Dysfunction – similar
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 Oct;52(4):1360-70.
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.
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.
Sirolimus – Adverse Effects• Anemia• Hypercholesterolemia• Hypertriglyceridemia• Leukopenia• Hyperlipidemia• Interstitial lung disease• Thrombocytopenia• Peripheral edema• Wound dehiscence• Hepatic Artery Thrombosis
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 (can’t use salvage pathways).
• MPA is a delayed release form of MMF • Dosing –
– 1000-1500mg bid MMF or – 360-720 BID MPA
Side effects of MMF/MPA
• Nausea, vomiting, diarrhea• Anemia• Leukopenia• Weight loss• Thrombocytopenia
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
Drug Interactions
American Journal of Transplantation 2009; 9: 1988–2003
Drug Interactions
American Journal of Transplantation 2009; 9: 1988–2003
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).
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
Causes of Allograft Failure- Rejection
• Antibody Mediated Rejection – hours to days• 10-20% Acute Rejection
– Risk 1st 3months>1st year>subsequent 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
Acute Rejection
• Banff Grading System – each factor 1-3 scale– Portal Inflammation– Bile Duct Inflammation/damage– Venous Endothelial Inflammation
Wyatt (2010) Histopathology 57, 333–341
Acute Rejection
• RFs – – young recipient, – “healthier” recipients, – HLA-DR mismatch, – PSC/PBC/AIH, – long cold ischemia time, – older donor.
• Late (>1 year) acute rejection – inadequate immunosuppression.
Chronic Rejection
Early CR Late CRSmall Bile ducts Duct loss <50% portal triads Duct loss>50% portal triads
Terminal hepatic venules/zone 3 hepatocytes
Zone 3 necrosis/inflammationMild perivenular fibrosis
Focal obliterationSevere fibrosis – central-central bridging fibrosis
Portal tract hepatic arterioles
loss <25% portal triads loss >25% portal triads
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.
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
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
Renal Dysfunction
• 18% Rate of CRF (GFR <30) by 5 years• Pretransplant Factors –
– female, HCV, Renal disease pretransplant
• Immunosuppression – dose dependent– Reversible – vasoconstriction of Intrarenal Vessels– Irreversible – tubulointerstitial fibrosis
• Hypertension• Diabetes
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: 401–405.
Hypertension
• CsA (25-82%) > Tac (17-64%)• Goal BP <=130/80• 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
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/toxicities. – Note – bile acids cannot be used if also on MMF/AZA
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
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)
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
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
Vaccines
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 don’t use)•Use inactivated virus whenever possible
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.
Tobacco
• Increased rates of – CAD– Stroke – Esophageal/upper aerodigestive Cancer– liver vascular events (Hepatic Artery
Thrombosis/Stenosis, Portal Vein Stenosis, DVT)
THC
• In Nontransplant Patients – reports of increased steatosis/fibrosis in THC users
• Contamination with fungal spores – theoretical increased risk of fungal infections.
Malignancies – Skin Cancer
• 100x over general population– Squamous Cell (SCC)> Basal Cell > 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
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
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
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, Kaposi’s, HPV associated (anogenital) malignances)
Sexual Function
• ESLD is bad for fertility (50% amenorrhea) and for sexual dysfunction (both libido and erectile dysfunction).
• >90% recover sexual function post-OLT• Use Contraception!
– 50% of females transplanted are of child bearing age
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
Pregnancy – Risk of Rejection
• Increased serum proteins that lead to increased binding of CNI’s and decreased levels
• 10% rate of rejection• Close monitoring of CNI levels throughout
pregnancy
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.
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).
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: 1988–2003
• Post DJ. Immunosuppression in Liver Transplantation. Liver Transplantation, 2005; 11: 1307-1314