Post Liver transplantation complications and Immunosuppression (1)-1.pptx

Liver transplant

1. Post Liver transplantation complications and Immunosuppression Dr.Gowtham

2. History 1 st transplant – Welch – in dogs- 1995 Ist in Humans – Starlz – 1963 1 st succesful liver transplant in 1967 Survival for : One year – 90-95% 5 years – 70%

3. Complications Immediate : Graft Dysfunction and Acute Rejection Technical complications Infections Systemic problems (II) Long term : Immunosuppression related : DM,HTN,Bone,Neoplasia,Organ toxicity Chronic Rejection

4. 1.Technical complications Overall prevalance – 26 % Arterial : Hepatic artery thrombosis – 1.5 – 25 % M/c in children Symptoms – Variable Early – Ischaemia /Necrosis of Graft Late- Biliary complications- Intrahepatic bilomas , Biliary stenosis Diagnosis : Doppler,Arteriogram , CT- angio

5. Treatment : Acute – Thrombolysis / Thrombectomy /Re transplantation Chronic- Drainage of bilomas , Antibiotics, Bilo -enteric by pass Elective Re-transplantation 50- 70 % require Re- tranplantation B) Portal vein thrombosis : 2-3 % Related to pre-transplant PVT/ Spleenectomy,prior PHTN surgery

6. Acute: Presents like acute liver failure Chronic : Presents with complications of Portal hypertension Treatment : If only stenosis – Angiographic dilatation Surgery – Direct anastomosis +/- Graft c) Biliary complications : i ) Biliary fistula Mostly seen in 1 st month Either due to technical errors / Ischaemia Or it can present even in 3 rd month when T-tube is removed Presentation: No bile, Bilomas,leucocytosis,cholestatic jaundice

7. Treament : Open T-tube Antibiotics Endoscopic management with ERCP for Biliary drainage Percutaneous drainage Surgery – if all methods fail / presence of peritonitis ii) Biliary Obstruction : Anastomotic site stenosis Cholestatic jaundice – septic shock

8. d) Haemorrhage : 20 % incidence Usually within 48 hrs Re-surgery in 10-15 % Still Cause will not be found in 50 % of resurgeries

9. 2. Medical complications Mortality in early post-transplant – 5 – 10 % HTN- Drugs, Pain, Hypervolaemia Dyselectrolaemia – Na,K,Ca,Mg Arrythmias - M/c- Bradycardia , SVT Respiratory – Pleural leakage (low alb,high creat,IVF ) Renal Dysfunction: Bleeding,Clamping,Drugs,Sepsis,Dysfunction of graft Cr >2.3/increase by >50 % of baseline Usually between 2 nd and 4 th post-op day Adequate fluid replinishing and Early HD is the key f) Neuro - IC bleed,Anoxia - enceph Convulsions- drugs Myopathies /Neuropathies

10. 3.Graft Dysfunction – Early Graft related : Primary Dysfunction Non-specific cholestatic syndrome Rejection Surgery technique related : Vascular / Biliary Drug related – Cyclosporine Infections- CMV/Bacterial sepsis related

11. Primary Graft failure Retransplant required with in 7 days Elevated AST/ALT Coagulopathy Encephalopathy, No bile drainage 5-10 % Exact cause – Unknown Diagnosis : AST >5000, Fac V < 20 % , PT < 60 % inspite of plasma Scant Bile with encephalopathy Elevated ammonia and lactic acid levels

12. Biopsy : Ischaemic Hepatic Necrosis 1 st 48 hrs- Can start on Prostaglandins If no improvement in 24-48 hrs – Re-transplant

13. 4.Rejection- Acute Risk factor for Graft survival Particularly in HCV related Hyper acute : with in mins to hrs – Ab & complements – Irreversible Acute : Days to months – Cell mediated – Reversible Chronic : Span of months – Usually wont respond to treatment- Graft loss May be asymptomatic – with fatigue/Upper abd discomfort Transmanitis + sub therapeutic drug levels Needs Biopsy for Diagnosis

14. 5.Infections Cause >50 % deaths in transplant 1 st month : Nosocomial Hepatic abscess,Extra hepatic abscess,Cholangitis 2 nd month : Due to increased immunosuppression Viral (CMV> Rec of HCV>EBV> Adeno ) Fungi( Pneum.carni > Candida> Aspergillus >Cryptococcus) Bacterial( Mycobacterial > Nocordia & Listeria ) CMV-if No prophylaxis – 23-85 % (will have infections) – 10-40% disease

15. > 6 months – Haemophilus influenza and pneumococcal infection Similar to general population Prophylaxis for Bacteria infections: Selective intestinal decontamination Peri -op antibiotics Antibiotics before biliary interventions Personal hand washing High Risk: Seropositive donor , Rejection episodes,high BT,On steroids,AKI,ALF Ganciclovir – 3 gm/day Valganciclovir – 900mg/day For 100 days

16. II) Late complications Chronic Rejection : > 6 months Clinical & Biochemical cholestasis Liver Biopsy – Loss of small bile ducts & Obliterative angiopathy Early stage : looks like Acute rejection – Dense portal infiltration and bile duct endothelitis Foamy macropahge infiltration of arterial branches TB >10 – Unlikely response – Liver transplantation

17. 2) Renal Failure : CNI Mild- Decrease in CNI dose Severe- Replace with non nephro toxic drugs 3) HTN : 50-70 % in 1 st 6 months Less frequent with Tacrolimus than cyclosporine Vasoconstriction of afferrent arterioles & steroids CCB’s

18. 4) DM : De novo DM (4-20%) M/c in initial stages Alc / Hep C – they might have DM prior to Surgery 5) Dysplipidaemia : 17-40 % develop changes Steroids,CNI,Sirolimus HMG Co A reduce inhibitors- Pravastatin 6)Obesity : 15-40 % - 1 yr after transplant High with cyclosporine

19. 7) Bone : 20-40 % - atraumatic fracture – vertebrae and ribs 65 % with cholestatic disease and with Re-transplantation 8) Neuro : Increase in Tacrolimus Tremors – M/c – decrease in dose Headache,parasethesia,Insomnia 9)Malignancy: 5-15 % of solid organ transplantation Kaposis sarcoma > Lymphoproliferative – early cancers

20. Skin and Carcinoma of Vulva and perineum Alcoholic cirrhosis – Oropharyngeal carcinoma HCV- Lymphoproliferative cancers

21. How liver transplant is different than others? Largest Organ Least amount of Immunosuppression required Lowest incidence of chronic immune mediated rejection In dual organ transplants-the LT reduces the chance of rejection of the second organ Highly Immune Tolerogenic Due to- Continuous exposure to gut derived pathogens Antigenic metabolic products Need to eliminate microbial pathogen

22. Why liver is more tolerogenic than other organs? Normally  ( Dendritic dells/ Kuffers cell/Liver sinosoidal endothelial cells) All express pattern recognition receptors (PRR) Ligation of PRR by PAMPS proinflammatory cytokinesacute phase proteins by liver cellsRecruitement of leukocyteinflammationInjury But in Liver In liver activation by PAMPS and lipopolysachharide or other antigens leads to secretion of anti- infalmmatory cytokines- IL-10/TGF-B Stimulation of regulatory T cell Induction of cytotoxic T Cell apoptosis Hence less inflammation and injury

23. What are the other mechanism of Liver tolerance? Dulk et al (2003). Archivum immunologiae et therapiae experimentalis . 51. 29-44.

24. Mechanism of immune response after Transplantation

25. Details of T cell proliferation N Engl J Med 2004; 351:2715-2729

26. Immunosuppressant Drugs- Signal 1 blockers: (Anti TCR CD3 molecules) Cyclosporine Tacrolimus other anti CD3 molecules : OKT3 / ATG Signal 2 blockers: Belatacept (binds CD28) Signal 3 blockers: anti CD25 ab : Basiliximab mTOR . Inhibitors: Sirolimus / Everolimus

27. Drugs acting via other pathways Drugs that ↓ purine supply: Azathioprine / Mycophenolate mofetil Drugs that deplete necessary immune cells: ATG / OKT3 (Depletes and lyses T cells), anti CD 52 (Lyses B and T cells) Steroids

28. Antibody therapies Depleting antibodies Non-Depleting antibodies Polyclonal Rabbit-Derived Antithymocyte Globulin Monoclonal Muromonab-CD3 (OKT3) Alemtuzumab (anti CD-52) Rituximab (anti CD-20) IL-2 R antibodies Basliximab Daclizumab

29. Induction Phase of Immunosuppression What is Induction? The early post-transplant phase when the recipient immune system is inundated with alloantigen from the donor liver, and more intense Immunosuppression is needed in the first few days to prevent acute rejection and preserve graft Agents- Steroid ATG/ALG IL-2 receptor antagonist Immunosuppression in LT  usually with a CNI and corticosteroids with or without the use of an antimetabolite such as MPA Antibody mediated induction is less used

30. Is there a role of induction in LT? Induction Immunosuppression  clearly offers protection against acute cellular rejection (ACR) in kidney transplantation The risk-benefit of induction  less apparent in LT, (lower incidence of acute rejection than kidney transplantation/Almost negligible antibody mediated rejection <5%) Analysis of the UNOS database for induction agents (2003–2009)  induction immunosuppression in liver transplantation  significant improvements in graft and patient survival at 3 months, 1 year and 5 years post transplant

31. Induction to facilitate CNI minimisation

32. Options for Induction Steroids : 0.5 gm to 1 gm Methylpred for 3 days Rapidly taper to 10-20mg/day and maintained for 1 st 3-6 months Usually CNI/MPA/AZA is started early in combination with steroids to help immunosuppression

33. Antibodies Polyclonal - Equine Vs Rabbit – Rabbit ATG (most commonly used in kidney transplant) Monoclonal – Alemtuzumab Vs Muromonab – Alemt Caution- HCV ( Dhesi S et al – Curr opin Organ Transplant 2009) Non-depleting : Basiliximab Vs Dacilizumab – Both are equal ( Penniga et.al –Cochrane Database syst. Rev 2014) Non HCV- ATG, HCV- Dacili ( Outcome of Induction Immunosuppression for Liver Transplantation Comparing Anti- Thymocyte Globulin, Daclizumab , and Corticosteroid Tadahiro Uemura   1 ,  Eric Schaefer ,  Christopher S Hollenbeak ,  Akhtar Khan ,  Zakiyah Kadry )

34. Rising trends of use of Antibody mediated induction??

35. Maintainance Therapy Tacrolimus is superior to cyclosporine (Haddad EM et al –Cochrane database Syst Rev 2006) Started on 0.1 – 0.15 mg/kg in 2 divided doses on 1 st post op day/after 2-4 days Oral,S /L,IV available (caution- Seizures) Optimal trough levels : ! st 4-6vweeks – 10-15 ng /ml then 5-10 ng /ml

36. Cyclosporine Recommended dose : 10-15 mg/kg in 2 divided dose C0 - 250 ng /ml in early post op period and later on 150ng/ml C2 - 800-1400 for 1 st 3 months 600-1000 after 6 months 500-700 after 12 months Nephrotoxicity - Dose dependant and reversible Other – HTN,DM,Neurotoxicity,Risk of malignancies ,hyper lipidaemia Both are metabolised thr . Cyt P 450 Cyclosporine – Gingival hyperplasia and Hirusitism

37. MMF Usually used in along with CNI For withdrwal of steroids/ dec dose of CNI Dose – 1 gm every 12 hrly Non- linear pharmacokinetics Haematological and GI Serious adv effects- IBD like colitis and GVHD like enteropathy Protective against post transplant de novo malignancies No effect in preventing post transplant recurrence of HCC

38. mTOR inh TAC switched to mTORin mTORin + Low dose TAC Monotherapy Anti tumour effect - In HCC and for other malignancies Edema,hyperlipidaemia,Oral ulcers Proteinuria and glomerular injury , ARDS,pleural and pericardial effusions Impaired surgical wound healing Black box warning for Sirolimus in view of HAT(<30days) Everolimus – preferably start after one month

39. Special Scenario In renal impairment In HCV In HCC In De-Novo tumors ABO incompatible LT AIH and LT Metabolic syndrome During various infections- TB,CMV,Herpes,Sepsis

40. Renal impairment Chronic renal dysfunction* or ESRD is common after LT The cumulative incidence of post- LTx CKD at 5 years in patients with MELD < 20 and in those with MELD > 20 at LT was 17% and 37% respectively (136). Use of CNIs is the most important risk factor for nephrotoxicity

41. Induction regimens for minimising renal dysfunction rATG 0.75-1.5mg/kg for 10 days + MMF delayed CNI for 2 week Alemtuzumab  30mg IV OD Basiliximab 20mg Iv on day 1 & 4  delayed introduction of CNI after 1 week MMF 1000mg BD for 5 days allows avoiding CNI for 5 days recovery of renal function most cost effectiveincreased risk of rejection If the renal function recovers after a period of CNI avoidance, Tacrolimus can be initiated, with a dose achieving a level of 5 to 7 ng/mL along with high-dose MMF 1500 mg twice a day. If the renal function do not recover use a CNI-sparing approach with sirolimus achieving a level of 10 ng/mL along with high-dose MMF 1500 mg twice a day and a slow steroid taper

42. Long-Term Post-transplant Renal Dysfunction Chronic renal dysfunction* or ESRD occurs in ~18% of patients within 5 years of LT Use of CNIs is the most important risk factor for nephrotoxicity CNI Minimization: Dosing MMF at a maximum 1500 mg twice a day or mycophenolate sodium 1080 mg twice a day allows CNI minimization, with a tacrolimus serum level of 3 to 4 ng/mL CNI Free regimen: MMF with mTOR inhibitors, No CNI M. Rodriguez et al.  Tacrolimus trough levels, rejection and renal impairment in liver transplantation: a systematic review and meta-analysis.  Am J Transplant.  12:2797-2814 2012

43. Recommendations (EASL) Recommendations IL-2R antibodies with delayed and low-dose Tac plus MMF and steroids is safe and significantly improves renal function after LT I MMF monotherapy should not be used due to the risk of acute cellular rejection I MMF in combination with CNI reduction of at least 50% is associated with significant improvement in renal function and has a low risk of acute rejection I No RCTs have been performed comparing renal function with MMF and AZA III Conversion to SRL can be done safely and provide adequate immunosuppression without increased incidence of rejection, graft loss or infection I Early EVR-based, CNI-free immunosuppression seems to improve renal function after LT; however, this leads to an increased risk of acute rejection I RCTs with longer follow-up are needed. Safety c oncerns still remain III

44. HCV liver-transplanted patients Three options exists with respect to steroid- Maintain low dose steroid indefinitely (5mg/Day) Taper steroid slowly Avoid steroid Regarding CNI-debate between Cyclosprin and Tac HCV increases drug level of CNI

45. Recomendations (EASL) Recommendations There are no conclusive data showing a meaningful clinical difference between CNIs with respect to HCV recurrence after LT I A rapid decrease in steroid immunosuppression may determine a worse graft evolution in some patients I The ‘protective role’ of slow steroid withdrawal shown in several studies also requires further investigation III There is still controversy regarding the best antiproliferative agent for HCV recipients. Observational studies suggest that maintenance of AZA is associated with less fibrosis progression compared with MMF II-1 Only properly designed RCTs will confirm if mTOR inhibitors are useful in HCV transplant recipients. There are very few HCV-specific data on EVR III OKT3 and alemtuzumab are associated with severe HCV recurrence I Data for IL-2R antagonists are contradictory I

46. Patients with HCC Immunosuppression plays a central role in the increased risk of cancer after LT Including the recurrence of HCC A dose-dependent relationship between CNIs and HCC recurrence post LT has been reported Studies were retrospective Comparative data on CNIs are lacking and/or inconclusive Recommendations To date there is evidence that SRL does not improve long-term, recurrence-free survival beyond 5 years I Benefit of SRL is evident in 3–5 years in patients with HCC within Milan criteria I

47. Patients with de novo tumours There are few data on differential risk of immunosuppressive regimens Recommendations Risk of de novo malignancy should be considered similar in clinical practice with Tac or CsA-based immunosuppressive regimens II-2 The risk of malignancy related to CNIs in clinical practice may come from the dosage rather than the type of CNI used I There is no evidence suggesting a link between the use of MMF and de novo malignancy after l iver transplantation III There are no published RCTs evaluating the effect of mTOR inhibitors in preventing nor treating de novo malignancy after l iver transplantation III

48. Patients with AIH

49. Patients with Metabolic syndrome The risk of developing de novo Metabolic Syndrome following LT has been reported to be 33%, 27% and 40% at 3, 6, 12 months, respectively. The impact of steroid avoidance or minimization on weight gain post LT is likely favorable, though evidence has been mixed . The use of mTORi for CNI minimization or elimination is associated with less weight gain post LT than standard dose CNI regimens Pepe V, et al. Prevalence and Risk Factors of Metabolic Syndrome after Liver Transplantation. Journal of Hepatology 2015;62:S320

50. Summary