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