2Overview Immunosuppression Causes of Allograft Failure Medical ComorbiditesMalignanciesPregnancy/Sexual Function
3Figure 1. Timeline for the introduction of immunosuppression medications. Immunosuppression in Liver Transplantation. Post et al. LiverTransplantation, Vol 11, No 11,2005: pp
4Figure 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
10Tac vs Csa Dyslipidemia and Gingival hyperplasia – more common in Csa Diabetes – more common in TacRejection – less common in TacRenal Dysfunction – similar
11SirolimusBinds to same immunophilin as Tac (FKBP12) but with a different mechanism of actionblocks 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 thisMeta-analysis of 11 studies suggests a numerical/non-significant improvement in renal function.Hepatology Oct;52(4):
12Sirolimus 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.
13SirolimusBlack 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.
15Mycophenylate Mofetil (MMF)/ Mycophenolic Acid (MPA) inhibit the de novo purine nucleotide synthesis via abrogation of the inosine monophosphate dehydrogenase and the production of guanosine nucleotidesLeads to blockage of DNA replication in T and B lymphocytes (can’t use salvage pathways).MPA is a delayed release form of MMFDosing –mg bid MMF orBID MPA
16Side effects of MMF/MPA Nausea, vomiting, diarrheaAnemiaLeukopeniaWeight lossThrombocytopenia
17Immunosuppression – Drug Interactions Cytochrome P-450 3AP-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 levelsGrapefruit – can increase levels of CNIs – mechanism not totally clear
18Drug InteractionsAmerican Journal of Transplantation 2009; 9: 1988–2003
19Drug InteractionsAmerican Journal of Transplantation 2009; 9: 1988–2003
20Antibody Induction Antithymocyte Globulin – induction/rejection. Polyclonal antilymphocyte globulin – multiple epitopes on T cell receptor – lead to apoptosis of T-cellsATGAM (of equine origin)Thymoglobulin (of rabbit origin)Monoclonal anti T-Cell antibodies – induction/rejectionMuromonab-CD3 (OKT3) – binds CD3 Antigen on T-Cell receptor – inactivates adjacent T-Cell – leads to rapid drop in T-CellsIL-2 Receptor Antibodies – inductionBasiliximab (Simulect)daclizumab (Zenapax).
21Causes of Allograft Failure Primary Nonfunction – slightly more common in Living DonorsVascular Complications – 10% of patientsHepatic Artery Thrombosis/StricturePortal Vein Thrombosis/StrictureHepatic Vein Thrombosis/StrictureBiliary Complications –Donors after Cardiac DeathLiving DonorsAnastomotic vs nonanastomotic strictures
22Causes of Allograft Failure- Rejection Antibody Mediated Rejection – hours to days10-20% Acute RejectionRisk 1st 3months>1st year>subsequent yearsChronic Rejection – a primary RF is prior episodes of Acute Rejection.Acute vs Chronic –time coursepattern of liver enzyme abnormalitiesresponse to therapy
23Acute Rejection Banff Grading System – each factor 1-3 scale Portal InflammationBile Duct Inflammation/damageVenous Endothelial Inflammation
26Chronic Rejection Early CR Late CR Small Bile ducts Duct loss <50% portal triadsDuct loss>50% portal triadsTerminal hepatic venules/zone 3 hepatocytesZone 3 necrosis/inflammationMild perivenular fibrosisFocal obliterationSevere fibrosis – central-central bridging fibrosisPortal tract hepatic arteriolesloss <25% portal triadsloss >25% portal triadsAdapted/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.
27Infections that can lead to graft failure CMV – 1-4 months post-OLT, increased risk of rejectionOther herpes family viruses similar course to lesser extentHCV1 in 3 cirrhotic at 5 years5-10% fibrosing cholestatic HCVHBVControlled in era of HBIG and oral therapies
28Causes of Allograft Failure – Recurrent Disease AIH, PBC, PSC – 10-20%EtOH – 20% with recurrent usemajority 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
29Renal Dysfunction 18% Rate of CRF (GFR <30) by 5 years Pretransplant Factors –female, HCV, Renal disease pretransplantImmunosuppression – dose dependentReversible – vasoconstriction of Intrarenal VesselsIrreversible – tubulointerstitial fibrosisHypertensionDiabetes
30Diabetes Prevalence – 33% RF – obesity, steroids, high TAC doses, pretransplant DM, HCVDe novo post transplant diabetes27% year 19% year 21% year 3Treat in a similar manner as non-OLT patients – lifestyle changes, minimize steroids and lower Tac dosing.OLT can cure Diabetes in some patients56% pretransplant DM, resolved DM in one cohort study1Steinmuller TH,. Liver transplantation and diabetes mellitus. Exp Clin Endocrinol Diabetes 2000; 108: 401–405.
31Hypertension 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
32Dyslipidemia Prevalence 16-43% RF – Female, Cholestatic liver disease, DM, Obesity, pretransplant dyslipidemiaEffects on Lipids:CSA, Steroids Sirolimus – greatest effectTAC – minor effectMMF/AZA – no effectTreatment – 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
33Obesity 22% Nonobese patients pre-OLT become obese post Pre-OLT obese gain more weight than non-obeseRF for recurrent (or de novo) NASHTX – the usualOrlistat can decrease absorption of CsA
34Gout Dec Uric Acid excretion by CNIs RFs – thiazides, ASA, Nicotinic AcidProphylaxis – Allopurinol (except if on AZA)TX – colchicine, steroidsAvoid NSAIDS (nephrotoxic with CNIs)
35Bone Disease Nadir in Bone Density 6 months Post Bone density 1 year post similar to bone density at time of OLT13% fracture rate within 2 years of OLTRFs for OsteoporosisETOHTobaccoLow TestosteronePhysical Inactivitycholestatic liver disease –unconjug bili inhibits osteoblast proliferationPatients also at risk of Osteonecrosis of Femoral Head
36Bone Disease Treatment of Osteoporosis Calcium 1500mg +vitamin D 800 IUBisphosphonates well studiedOther classes not as well studied but no obvious contraindicationsCalcitonins, Parathyroid hormone, Selective Estrogen Receptor-Modulators
38VaccinesTheoretical 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
39Dental CareImportant – can be source of sepsis in peri/post-OLT settingGingival Hyperplasia – unique to CSA, may require oral surgery and/or switch to TacAntibiotic Prophylaxis for Dental Work - revisedAs 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.
41THCIn Nontransplant Patients – reports of increased steatosis/fibrosis in THC usersContamination with fungal spores – theoretical increased risk of fungal infections.
42Malignancies – Skin Cancer 100x over general populationSquamous Cell (SCC)> Basal Cell > MelanomaSCC – multiple, more aggressive, more likely to be associated with metastasis35% lifetime riskRec –annual Dermatology exam,minimize immunosuppression in setting of diagnosed skin canceruse sunscreen/avoid sun exposure
43Malignancies - PTLD 2% Adults, 15% Kids 80-90% EBV associated Usually within 1 year post-OLT2 less common forms (CD20 negative)Plasmacytic form (similar to multiple myeloma)T-Cell malignancyTreatmentReduce immunsuppresionRituximab if CD20 positive, Chemotherapy if CD20 negative
44Malignancies - GIUpper aerodigestive tract – increased in those with Risk Factors – ETOH, TobaccoColon cancer – increased risk in those with preexisting RFs – ie PSC/UC patients –Annual colonoscopy with surveillance biopsies
45Malignancies - OtherBreast, Prostate, Lung, Colon cancer – no definite increased risk (in those without risk factors)Follow age-appropriate cancer screening guidelinesRole of decreased immunosuppression less clear in these cancers than in virally mediated malignancies (EBV, Kaposi’s, HPV associated (anogenital) malignances)
46Sexual FunctionESLD is bad for fertility (50% amenorrhea) and for sexual dysfunction (both libido and erectile dysfunction).>90% recover sexual function post-OLTUse Contraception!50% of females transplanted are of child bearing age
47Pregnancy Wait 1 year post-OLT Most drugs category C (MMF/AZA category D)National Transplantation Pregnancy Registry (NTPR) – 2700 pregnanciesLive birth Rate 70%Congenital anomolies 4-5% vs 3% general populationPremature/Low Birth weights range 10-55%Tac – lower rates of hypertension/preeclampsia vs CsA
48Pregnancy – Risk of Rejection Increased serum proteins that lead to increased binding of CNI’s and decreased levels10% rate of rejectionClose monitoring of CNI levels throughout pregnancy
49SummaryCsA, Tac or Sirolimus are the backbone of maintenance immunosuppresionAddition 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.
50SummaryTechnical Factors and early recurrent Disease responsible for allograft failure in first yearWith 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).
51ReadingMcGuire BM et al. Long-term Management of the Liver Transplant Patient: Recommendations for the Primary Care Doctor American Journal of Transplantation 2009; 9: 1988–2003Post DJ. Immunosuppression in Liver Transplantation. Liver Transplantation, 2005; 11: