This document discusses post liver transplantation complications and immunosuppression. It begins with a brief history of liver transplantation and then discusses various complications that can occur including technical complications, medical complications, graft dysfunction, rejection, and infections. It also covers long term complications and special scenarios related to immunosuppression in liver transplant patients.

1. Post Liver transplantation
complications and
Immunosuppression
Dr.Gowtham

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

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

4. 1.Technical complications
 Overall prevalance – 26 %
A) 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 1st month
 Either due to technical errors / Ischaemia
 Or it can present even in 3rd 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 %
a) HTN- Drugs, Pain, Hypervolaemia
b) Dyselectrolaemia – Na,K,Ca,Mg
c) Arrythmias- M/c- Bradycardia, SVT
d) Respiratory – Pleural leakage (low alb,high creat,IVF)
e) Renal Dysfunction: Bleeding,Clamping,Drugs,Sepsis,Dysfunction of graft
Cr >2.3/increase by >50 % of baseline
Usually between 2nd and 4th 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
 1st 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
1st month : Nosocomial
Hepatic abscess,Extra hepatic abscess,Cholangitis
2nd 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
1) 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 1st 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-
1. Continuous exposure to gut derived pathogens
2. Antigenic metabolic products
3. 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-
1. Steroid
2. ATG/ALG
3. 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 1st 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 1st 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 1st 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

39. 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

41. 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

42. 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

43. 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

44. 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

45. 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 concerns still remain
III

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

47. 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

48. 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

49. 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 liver
transplantation III
There are no published RCTs evaluating the effect of
mTOR inhibitors in preventing nor treating de novo
malignancy after liver transplantation
III

50. Patients with AIH

51. 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

52. Summary