Immunosuppression post liver transplant
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Transcript of Immunosuppression post liver transplant
Post liver transplant immunosuppression
Shankar Zanwar
First successful organ transplant
Liver transplant • First human liver transplant – 1963 – Dr Thomas Starlz Colorado – Canada
• First 1 year survival – 1967
• Introduction of Calcineurin inhibitors in liver Tx
• First successful liver transplant in India – 1998
Liver – distinction in transplants• A huge load of antigens exposed to liver – pathogens, toxins tumor cells dietary and non dietary proteins
• Compared with other organ transplants• Immunologically privileged• Rarity of hyper-acute rejection despite positive T cell
cross match• Low incidence of graft loss due to chronic rejection• Potential of regeneration of liver cells after tissue
injury
Immunological basis of rejection -
1. Alloantigen recognition – • The graft antigen is
recognized as foreign by antigen presenting cells
• This recognition as foreign is presented to the T -lymphocytes along with major histocompatibility complex
• The antigen from MHC binds T-cells receptors
2. Lymphocyte activation – co-stimulation
• T cell activation – needs co-stimulation
• Ligands on APC binds to receptors on T cells – CD28, CD154, CD2, CD11a & CD54
• Receptor ligand complex activates immunophilin stimulates calcineurin nuclear factor of T cells IL-2 transcription.
3.Clonal expansion•Newly synthesized IL-2 by T cells binds to IL-2 receptors on the cells surface
• Stimulates T-cells in autocrine manner cell proliferation
• Finally this T- cell proliferation cell mediated cytotoxicity and secretion of cytokines, chemokines that attracts other attacker cells.
• Result in inflammatory environment and graft cell death.
Acute rejection•Occurs in 10-70% of patients depending on primary immunosuppression used, indication of transplant and definition of rejection
Neuberger J Hepatology 1998
• Early acute rejection –within 90 days• Late acute rejection after more than 180 days• Clinical presentation• Fever• Malaise • Abdominal pain , H/S megaly and rarely splenomegaly
Criteria• Clinical – in absence of no other obvious causes• Increase in ALT >50 U/l• And or Bilirubin > 6 mg/dl• Changes reversed by antirejection therapy
Schlitt, Transplantation 1992
•Despite many biomarkers (microRNAs), histology is gold standard, 3 classic findings• Mixed inflammatory infiltrate in portal triad• Nonsuppurative cholangitis • Endothelitis
Banff grading of ACR• Mild – Inflammatory infiltrate in the portal triad and around the bile duct limited to a minority of the triads/ducts - 1
• Moderate – Infiltrate involving most or all of the triads/ducts -2
• Severe – Spill over in the periportal areas, mod-sev endothelitis, perivenular extension and necrosis of hepatocytes – 3
Demetris et al Hepatology 1997
• Rejection activity index(RAI) - <4 Mild
• Though indicator of severity, RAI doesn't correlate steroid response or graft survival
Horolodt Liver transplant 2006
•Differential diagnosis of ACR• Recurrent HCV infection• Functional cholestasis – subcellular organelle damage
– cold ischemia time• Cyclosporine toxicity – ↑LFT a/w unexplained ↑ creat• Massive hemorrhagic necrosis - rare
Pharmacotherapy of immunosuppression•Drug classes• Signal I - Alloantigen recognition – Antilymphocyte/thymocyte
antibodies
• Signal II- Lymphocyte co-stimulation – inhibits signal transduction – Calcineurin inhibitors – Cyclosporine and Tacrolimus
• Signal III- Clonal expansion – IL-2R blockers – Basiliximab/Sirolimus
• DNA synthesis inhibitors – Mycophenolate and azathioprine
• Steroids
Antibodies – Induction therapy• Polyclonal antibodies – Thymoglobulin used commonly
•Use – induction or steroid resistant rejection
• 1st dose is given in intra-op – anhepatic phase
•May lead to cytokine release(flu like) syndrome, leucopenia and thrombocytopenia
• In metaanalysis of 19 trials – reduces acute rejection when compared to placebo, RR 0.85
• But overall no difference in mortality, graft loss or mortality
Penniga L, Ab induction vs placebo Cochrane Datab sys rev, 2014
Steroids•Glucocorticoids • suppress antibody and complement binding,• Upregulate IL-10 (anti-inflammatory)• Downregulate IL-2 and IL-6 (proinflammatory)• IFN-Y synthesis inhibition
• Commonly used steroids• Hydrocortisone• Prednisolone• Prednisone• Methylprednisolone
Baylor college steroid protocol
•No agreement on protocol amongst different centers
• Tapering to zero is usually is achieved over 3-6months but most centers leave 5mg/d indefinitely
• Side effects - known to all
• Budesonide – a possible alternative, reduced systemic effects d/t high first pass
•One study has used this with apparent success in post LTx pts. with significant success – further RCTs required
Bhat M Liver transplant 2012
HCV and glucocorticoids• Steroid ↑ HCV replication in post LTx HCV infection
• 3 options • Maintain low dose steroid 5mg/d indefinitely• Taper slowly• Avoid steroids
•Majority use slow tapering
• Rapid tapering ↑ chance of fibrosisVivarelli J Hepatology 2007
• Steroid free regimen can be tried – Multiple options available
• Latest trial – of 75 pts. compared tac + steroid with tac + Mycophenolate – Event free survival at 1 and 5 year similar in both group.
Takada, Liver Tx, 2013
• Caution – aggressive immunosuppression - late consequences as post Tx lymphoproliferative dis.
Calcineurin inhibitors
Cyclosporine• Administration – IV, oral tabs or suspension
• Peak blood levels in 2-4 hours
• Avg t ½ - 15 hours
• Cleared from bile, hepatic metabolism – CYP3A4
•Dosing • initially - 8-10mg/kg/d,• maintenance – 2-6mg/kg/d
• Initially daily monitoring with reducing frequency after graft function stabilization
•Multiple drugs interact with cyclosporine.
• Target level initial 3 mons 200-250ng/ml, tapered down to 12 months to 80-120ng/ml
•Microemulsion fromulations better – ↑ bioavailability, faster acting and less variability
Tacrolimus•Macrolide isolated from Streptomyces
• Inhibits IL-2 and IFN-Y production, 100X more potent than cyclosporine
•Metabolized in liver same enzyme as Cyclo
•Not removed by dialysis
• Tacrolimus dosing should be individualized – to start with 0.5 to 1mg 12 hours on POD 1
• Aim target of 7-10ng/dl by end of 1 week
• A level 6ng/ml is satisfactory at 6 mons and 4-6ng/ml beyond 1 year
• Slightly higher levels are better for autoimmune, PBC and PSC
• Lower doses are appropriate alcohol and hemochromatosis.
OD tacrolimus•Many studies now recommend prolonged release Tacrolimus over the twice daily regime
• Trial • n= 34 pt switched from BD to OD regimen• Median conversion period median 38 (range 8-211)• No difference in the mean trough levels• Renal function – GFR increased in OD dosing regimen
67ml/min vs 73ml/min mean p=0.003Valente G Transplant 2013
•OD dosing in stable pts. improves quality of care and renal function and adherence to immunosupp.
S/e of calcineurin inhibitors• Hepatotoxicity• Cardiovascular• HTN(C>T)• Hypercholesterolemia
• Glucose intolerance(T>C)• Neurotoxicity(T>C)• Tremors, myoclonus• Headache, seizures• Insomnia, hallucinations• Paresthesia • Dysarthria,
polyneuropathy
• Nephrotoxicity• Striped fibrosis• HyperK, hypomag.• Type IV RTA
• Cosmetic • Gingival hypertrophy(C>T)• Hirsutism(C>T)• Alopecia(T>C)
•Malignancy • Skin cancers• Cervical cancers• Lymphoproliferative
disorders• GI upset(T>C)
Interactions with other drugs• That ↑ levels• CCBs• Azole antifungals• Sirolumus• Methyl prednisolone• Macrolide antibiotics• Protease inhibitors
(ART)• Grape juice
• That ↓ levels• ATT (INH and Rif)• Anticonvulsants – older• Imipenem• Ciproflox• Cephalosporin• Ticlopedine
Cyclosporine Vs Tacrolimus • Landmark study – O’ Grady – Lancet 2002• RCT with 606 pts.
• All results statistically significant• All results studied at end 1 year• Tacrolimus scores more!
Outcomes Microem Cyclosporine TacrolimusDeath 32% 21%MODS 10% 10%Treatment failure 4% 2%Renal dysfunction and need for antihypertensive equal in both group
• Another metaanalysis of 16 trials – treating 100pts with tac vs cyclo would avoid rejection in 9 pt and death in 2 but would create 4 extra diabete
McAlister Am J Transplant 2006
Sirolimus
Sirolimus•Macrolide antibiotic from Streptomyces
•Works synergistically with Tacrolimus
•May be useful as substitute in CNI intoleranceBeckebaum Clin Transpl 2004, Watson CJ Liver transplant 2007
•Dosing • 2-5 mg once daiy• Level should be maintained at 5-15ng/ml
• S/e - Similar to CNI, may also have pancytopenia, interstitial pneumonia, Hep AT, delayed healing
• Benefits in renal failure are not clear
• Some initial improvement in GFR but may not sustain in long term
DuBay Liver transplant 2008
•May be of benefit in patients with HCC – since antiproliferative action
Zimmerman Liver transplant 2008
• Because of many side effects FDA warning – do not use in de-novo in liver transplant recipients
Stamp release on first successful liver transplant survivor in India
Everolimus•Hydroxyethyl derivative of sirolimus
• Starting dose 0.75mg BD, levels at 3-8ng/dl maintenance
• In a study with 3 groups, n= 719(after 1 month tac post LTx)• Everolimus with tac elimination (EVR)• Everolimus + low dose Tacrolimus (EVR + TAC)• Standard dose TAC
De Simone Am J Trans 2012
• Everlolimus facilitates early Tacrolimus minimization, with comparable efficacy and superior renal function compared with std. tac regimen at 1 year
DNA synthesis inhibitors
Mycophenolate• Derrived from penicillium
• Oral dose but poor absorption
• Inhibits enzyme for guanine nucleotide formation inhibit DNA synthesis
• Lymphocyte lack a salvage pathway of guanine nucleotide formation succumb
• Usual dose 1gm BD (Myfortic 720mg), level to be maintained – 1.6-2.75mg/dl
• S/e – Pancytopenia and GI upset
• Role of MMF is similar to siroliminus i.e. reduce or discontinue CNI dosing to treat side effects
• In a RCT with 150pts., CNI vs MMF(alone) 5 year follow-up• No significant difference in ACR, higher rejection freq. in
MMF• No significant difference CVS, GI and CNS S/e• Renal functions improved significantly when switched to
MMF from CNI Schmeding, Transplantation 2011
• Azathioprine vs MMF almost similar except for expenses (MMF costlier),but AZA less studied in LTx
Antibody therapy• Monoclonal antibodies• Muromonab –CD3(OKT3) – 1st MAB approved for transplant
• Blocks cytotoxic t cells in graft
• Standard dose 5mg IV daily for 10-14 days
• Initital few doses flu like syndrome – managed with hydrocort, avil and PCM
• Successful OKT3 treatment – rapid decline in CCD3+ T cells – from 60 5%
• Long term side effect Lymphoproliferative disease – 3%HC Devarbhavi Am J Transplant 2006
•Muromonab – • Main utility is for steroid resistant rejection• Trial - steroid resistant rejection
• n=28, steroid continuation vs OKT3, with cross over if failed• Steroid group - 3/13 responded, 10 switched to OKT
• 9/10 switched responded with median improvement for 8months• OKT group 11/15 responded, 2 rescued by steroid 1 retransplant,
1 death• OKT3 is superior to higher dose steroids in reversing
allograft rejection in failed steroid therapyCosimi AB Transplantation 1987
Other MABs
Other MABs• Basiliximab and daclizumab –• Humanized MABs block IL-2 receptors
• Less immunogenic than OKT3(though not relevant here)
• Longer T ½ and better tolerated
• Similar efficacy for both agents
• Dosing –• Basiliximab 20mg IV preop and POD4• Daclizumab 1mg/kg preop and every week X 6 doses
•Main role of these is for renal sparing induction regimen
• Abs can reduce CNI use in pts. with preOLT renal disesase
• These may also be used in to minimize steroid use
• Trial - RCT • Tac + steroid (n=347) vs Tac + daclizumab (n=351)• Steroid resistant ACR incidence 6 vs 3• Adverse events were similar
Boillot Liver Transplant 2005
• But these agents can’t be used as for treating rejection
Experimental Agents• Belatacept – CD80/86 binder – • Proven beneficial in renal transplant• Increased rate of PTLPD• Clear data in liver transplant are awaited
• Efalizumab – CD11a inhibitor• Stabilizes APC-T cell complex• One trial has shown benefit• More data needed to prove efficacy
• Alemtuzumab – anti CD52 • In LTx it has been used as agent to reduce CNI/steroid use• Infectious complications are prominent
Balancing act – immunosuppression in renal impairment
Renal sparing regimens• Significant renal dysfunction – 40% of LTx,
• AKI occurs in 15% post op cases, worsens mid or long term survival
• CNI cause dose related and reversible ↓ in GFR
• CNI induced nephrotoxicity caused by intense arteriolar vasoconstrictions prerenal dysfunction
• Chronic renal dysfunction impacts long term survivalDuvoux, J of Hepatology 2011
Approach in early post op period
Duvoux, J of Hepatology 2011
Mid & long term renal protection
Duvoux, J of Hepatology 2011
Immunosuppression in post transplant HCV• Steroids and Antilymphocyte therapies are a/w severe HCV recurrence
• Tacrolimus and cyclosporine similar in recurrence, but graft and pt. survival better with Tacrolimus
• Benefits from low dose and slow tapering of steroids and long term azathioprine are seen
• Rapid changes in regimens may be deleterious
•Weaning off the immunosuppression is appealing but not yet practical.
Dimitrios J of Hepatology 2012
Immunosuppression - HCC• Recurrence rates post transplant 3.5-21%
• CNI may pose risk of recurrence
• Cyclosporine better than Tacrolimus – lesser risk
• CNI and mTtor regimen better since sirolimus has anti tumor activity due to anti VEGF action
•Metaanalysis substantiates role if sirolimus contain regimen
Liang W Liver transplant 2012
Neuberger, Clinical and experimental Immunology 2005
Immunosuppression for surgical candidates• Continue ongoing medications, route may be changed
• IV administration of CNI is more cytotoxic avoid if possible
• Check drug interactions
• IV steroids as an addition in routine dose in steroid based regimen since they are likely to have hypothalamo-pituitary axis
Stopping immunosuppression • Some pts develop tolerance and may be able to stop immunosuppression
• In a study discontinuation was tried in 24 pts.,• 63% were tolerant at 14 moths(median)• Remaining had acute or chronic rejections
Srobe Liver transplant 2013
• Complete weaning – still a far fetched dream
Thank You