Professor Of Nephrology

1
HEPATIC PROBLEMS IN RENAL TRANSPLANTATION
Dr. ESSAM M. KHEDR

• Professor Of Nephrology
• Ain Shams University
• Nasser Institute for Research Treatment

2
Hepatic Problems In Renal Transplantation

• Pre-transplant. Problems
• Schistosomal infection.
• Hepatitis.
• Malignancies.
• Granulomas.
• Gall stones.
• Hemosiderosis.

• Post-transplant. Problems
• Schistosomal infection.
• Hepatitis.
• Malignancies.
• Granulomas.
• Gall stones.
• Drug hepatotoxicity.

3

• Pre-transplant. Problems
• Schistosomal infection.
• Hepatitis.
• Malignancies.
• Granulomas.
• Gall stones.
• Hemosiderosis.
• Post-transplant. Problems
• Schistosomal infection.
• Hepatitis.
• Malignancies.
• Granulomas.
• Gall stones.
• Drug hepatotoxicity.

4
Pre-transplantation hepatic problems

• Schistosomal infection.
• Hepatitis.
• Granulomas.
• Malignancies.
• Gall stones.
• Hemosiderosis.

5
Schistosomal Infection (Hepatic schisto.)

• Schistosomal infected patients are suitable
  recipients donors.
• Schistosomal infection should be eradicated
  first. Barroue et al.,J.Urol.1997
• Schistosomal nephropathy can recur in
  transplanted kidney.

6

• Schistosomal Infection
• Evaluation
• Rectal biopsy.
• Indirect hemoagglutination assay(IHA)
• Radiological evaluation for
• Bladder calcification.
• Hepatosplenomegaly or periportal fibrosis.
• Ureteric stricture.
• Retrograde pyelography.
• Endoscopic evaluation
• Urethrocystoscopy biopsy from visible lesions
• Upper GIT endoscopy for varices.

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• Schistosomal Infection
• Treatment
• Praziquantil (15 mg/kg) single oral dose.
• Oxamniquine (40-60mg/kg) two divided doses-
  3successive days.
• At least one month before transplantation.
• 
  Mahmoud et al., NDT.2001

8
HBV Infection

• Decision for transplantation should be made with
  atmost care.
• Immunosuppression allows rapid replication of the
  virus following transplantation.
• HBV-DNA, HBeAg did not correlate with occurrence
  of chronic hepatitis post-transplantation.
• Hang et
  al.,transplant.,1990

9
HBV Infection

• Liver biopsy to every patient likely to suffer
  life threatening hepatitis after renal
  transplantation.
• Renal transplantation is not recommended in
  severe hepatitis or cirrhosisRoo et al.,
  Am.J.Kid.Dis1993
• In mild hepatitis(Knodll scorelt5),
  transplantation can be done.
• No gaurantee that liver disease can not go on.
  
• Kossico et al.,
  J.Am.Soc.Nephrol.1995
• High mortality from CLD even in asymptomatic HBV
  carrier. Mathurin et al.,
  Hepatol.1999

10
HBV Infection

• Treatment
• Interferon
• To date it represents the best
• treatment option.
• Lamivudine
• A potent inhibitor of HBV replication.
• Can be used in patients with chronic hepatitis
  pre-transplantation.
• Dose100-150mg/day for 6-30 months
  pre-transplantation. Beerari et al.,
  Transpl.1997

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HCV Infection

• Consequences of HCV infection in renal transplant
  recipients (only 10 years follow up)
• CAH ? 59.
• Cirrhosis ? 3-7.
• Liver cancer ? 0. Berthoux et al.,NDT.,2000
• HCV seropositivity is not a contraindication for
  renal transplantation. Haem et al.,
  NDT.1996

12

• HCV Infection
• Stable transaminases before transplantation
• can not exclude chronic liver disease later
  on.
• 
  Gentil et al., NDT.1999
  
• Poor correlation between transaminases level and
  liver biopsy in dialysis patients and
  transplantation candidates.
• Liver biopsy is the only definitive way of
  diagnosing CLD in those patients.
• 
  Simon et al., Kid.Int.1996
• Severe CAH and cirrhosis patints should not
  receive a graft.

13

• HCV Infection
• 46 of HCV-RNA ve patients have normal
  transaminases.
• Fabrizi et
  al., NDT.1996
• 27 of HCV-Ab positive patients are HCV-PCR
  negative
• Patient recovered from HCV infection.
• Flactuating level of viremia.
• Undetectable level by PCR.

14

• HCV Infection
• Level of HCV-RNA increases usually
  post-transplantion. Chan et al.,
  Transpl. 1999
• HCV genotype correlates with severity of liver
  disease and response to treatment.
  Fabrizi et al., NDT.1996

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HCV infection

• Treatment
• Standard therapy of HCV is
• a combination of interferon and ribavirin.
• Roynand
  et al.,lancet.,1999
• Ribavirin is contraindicated in HD patients
• Hemolytic anemia. Mc hutchinson, New Engl.
  J.Med.1998

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HCV infection

• Treatment
• Interferon should be given as monotherapy in HD
  patients
• 3MU S.C. 3 times weekly after each dialysis.
• Efficacy
• Normalisation of transaminases.
• HCV-RNA negative by PCR.
• Koeing et
  al.,Kid.Int.,1994

17
HCV infection

• Treatment
• Histological response is common even in absence
  of virological efficacy.
• Haurib et
  al.,Am.J.Kid.Dis.,1999
• Sustained response means negative HCV-RNA during
  therapy and follow up period in 20-90 of cases.
• 
  Izopet et al., Kid.Int. 1997

18
HCV infection

• Treatment
• Transient response means ve HCV RNA during
  therapy but returns with stopping the drug.
• Poor tolerance occurs in 20-40 of cases
• Anemia.
• Epo resistance.
• Cardiovascular side effects.
• 
  Reichard et al., Lancet.1998

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The natural history of HCV infection
20

• Other hepatic viruses
• Cytomegalovirus(CMV).
• Herpes Zoster virus.
• Herpes simplex virus.
• Epstein barr virus (EBV).

21

• CMV infection
• Avoid CMV primary infection in seronegative
  recipients
• No blood transfusion to HD patients.
• CMV ve kidneys not to be transplanted to
  seronegative patients.
• Give living attenuated vaccine for seronegative
  patients.

22

• CMV infection
• Avoid CMV secondary infection (reinfection or
  reactivation)
• Choose least aggressive immunosuppressives.
• Passive immunization with high titre CMV plasma
  or immunoglobulins.
• Normal intravenous immunoglobulins.
• High dose acyclovir (800-3200mg).
• Prophylactic dose ganciclovir (pre empitive)

23

• Herpes zoster virus
• Live attenuated vaccine pre-transplantation.
• Zoster immunoglobulins
• Immunocompromised patients.
• No detectable VZV antibodies.

24

• Hepatic granulomas
• Tuberculosis
• TB granuloma in the liver is rare.
• Hematogenous(miliaryTB).
• Lymphatic spread.
• Extrapulmonary TB is higher in organ transplant
  recepients Rubin
  et al., Kid. Int. 1994
• 31 in the study of Yildiz et al., NDT.1998.
• Tuberculous patients can be transplanted after
  6-9 months of treatment, longer period is needed
  in extrapulmonary TB.
• Pre-transplant splenectomy should be avoided in
  TB patients.

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• Hepatic granulomas
• Sarcoidosis
• Liver is involved in 60-90 of cases.
• 20-30 of patients have hepatomegaly.
• Cholestasis, elevated bilirubin and ALP.
• Rarely cirrhosis and portal hypertension.
• Kidney transplantation is an accepted treatment
  for sarcoid patients with renal failure.
  Padilla et al., Lung Dis.1997

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• Gall stones
• There is no need for pre-transplant
  cholecystectomy in asymptomatic cholelithiasis.
• Acute cholecystitis occurring after renal
  transplantation should be treated surgically.

27

• Hemosiderosis
• Frequent blood transfusion in dialysis patients.
• In HCV ve patients, iron deposits in liver are
  found in 18 of cases
• Cirrhosis was found in 50 of those patients.
• Treatment
• Intermittent phlebotomies.
• Avoidance of blood transfusion.
• Frequent iron studies.

28
Post-transplantation hepatic problems

• Impact of
• Schistosomal infection.
• Hepatitis viruses.
• Malignancies.
• Granulomatous diseases.
• Drug hepatotoxicity.

29
Schistosomal infection

• Recurrence
• Recurrence of schisto. nephropathy in the graft
  can occur if it was the cause of renal failure.
• Azevedo et al.,
  Transplant., 1987
• Falco and Gould reported that schisto.
  nephropathy might recur.
• Ann.
  Int. Med., 1975

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Schistosomal infection

• Effect on immunosuppression
• Cyclosporin A (significantly higher doses)
• Periportal fibrosis.
• Reduction of bile flow.
• Impaired intestinal absorption.
• 
  Sobh et al., NDT., 1992
• 
  Mahmoud et al.,
  NDT., 2001
• Altered elimination of CsA due to periportal
  fibrosis.
• Takaya
  et al.,Transplant.,1987
• Azathioprine no significant dose change in
  schistosomal infected recipients.
  Mahmoud et al., NDT., 2001

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Schistosomal infection

• Graft rejection
• Although schistosomal infection
  causes a state of suppression
  of immune response . Copran et al., Nature.,
  1975
• 
  
• No significant difference in incidence and
  frequency of early and late rejection.
• 
  Mahmoud et al., NDT., 2001
• 
  
  

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Schistosomal infection

• Progression of hepatic disease
• HBsAg serum level is higher in schistosomal
  infected patients.
• Complications as
• 1.liver cell failure.
  4.Malignancies(bladder).
• 2.Varices.
  5.Hypertension.
• 3.Hepatic dysfunction. 6.Diabetes.
• are not significantly higher Mahmoud et
  al.,NDT.2001
• Death in schisto. infected recipients was not
• due to liver cirrhosis or liver cell failure.

33
Schistosomal infection

• Survival
• Schistosomal Infection had no impact on patient
  or graft survival at 10 years.
• There was no schistosomal reinfection.
  Mahmoud et al., NDT., 2001
• 
  

34
HBV infection

• Progression of hepatic disease
• High rate of histological deterioration 85.3
• Liver cirrhosis.
• HCC. Fonairon et
  al., Transpl.1996
• 50 0f HBsAg ve patients had a clinical
  pathological signs of active hepatic dysfunction
  even if normal histology and liver functions at
  time of transplantation. Park et
  al., NDT.2001
• 60 of HBsAg ve patients progressed to CAH or
  cirrhosis, 50 died from liver cell failure.
• 
  Parfery et al.,
  Kid.Int.1985

35
HBV infection

• Progression of hepatic disease
• Fibrosing cholestatic hepatitis leading to fatal
  hepatitis was reported Kairaitis.,NDT.1985
• At autopsy
• Cholestasis.
• Fibrosis extending from the portal tracts.
• HBsAg HBcAg in hepatocytes
• Both 10 years graft and patient survival were
  significantly lower, patient survival was 55.
  Mathurin et al., Hepatology.1999

36
HBV infection

• Lumivudine treatment
• Lamivudine was not effective in clearing the
  virus from the patients.
• 
  
  Roastig et al., Transpl.1997
• HBV-DNA remained ve in 20-30 of patients
  following lamivudine treatment.
  Kletzmayr et al., Transpl.2000
• With prolonged therapy resistance to the drug is
  a major concern.
• 
  Fontaine et al., Transpl.2000

37
HBV infection

• Lamivudine treatment
• 15-30 rebound in HBV-DNA after initial response
  explained by
• Non compliance.
• Drug resistance. Schlom et al.,
  Lancet.1997
• Combining lamivudine with other antiviral agents
  can prevent resistance.
• HBV reactivation in 70 of patients after
  discontinuing the drug.
• 
  
  Dieastag et al., Kid.Int. 1995
• Fulminative hepatic failure was reported.
• 
  Peters et al., Transpl.1999

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• HCV infection
• Progression of hepatic disease
• Majority of post-transplant hepatic problems are
  related to HCV infection.
• HCV positive recipients do better with
  transplantation than with dialysis.
• 21 of deaths in HCV ve patients were related to
  liver disease, liver cirrhosis and liver cell
  failure.
• 
  Roa et al., Am.J.Med.1993
  
  
• 
  
  
  

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HCV infection

• Fibrosing cholestatic hepatitis
• Early and severe complication of renal
  transplantation in HCV ve recipients under
  azathioprine therapy.
• 
  Munoz et al., Soc.Nephrol.1998

40
HCV infection

• With hepatitis G virus infection
• HGV-RNA ve and HCV-RNA ve recipients have a
  higher rate of acute rejection.
• HGV has no impact on liver enzymes or liver
  histology in HCV ve recipients.
  Roastig et al., Transpl.1999

41
HCV infection

• Treatment
• NO effective and safe therapy to date.
• Ribavirin monotherapy gives some improvement in
  liver histology.
• 
  Gane et al., New.Eng.J.Med.1996
• Ribavirin with a very small dose of interferon (1
  MU 3 times/ week) to avoid increase in the Th1
  cytokines and occurrence of rejection.
• Brillanti et al.,
  It.J.Gastroent.Hepatol.1999
• 
  

42
HCV infection

• Effect on survival
• In denovo HCV infection
• following renal transplatation
• No difference in survival compared to HCV
  negative recipients.
• In pre-existing pre-transplant. HCV ve
  recipients
• Increased incidence of graft loss and death rate.
• Bouthot et
  al., Transplant.1999
• 
  

43
HCV infection

• Effect on survival
• 10 years patient survival
• 80 in HCV ve recipients.
• 65 in HCV ve recipients.
• 
  Mathurin et al.,Hepatol.1999
• 
  
• HCV positivity have insignificant impact on graft
  survival during the first 5 years.
• The effect is seen during subsequent follow up.
  Roy.first.M.,
  NDT.2000

44
Graft survival
45
Patient survival
46
HCV infection
Effect on survivalGentil et al ., NDT. 1999
47
HCV infection

• Graft rejection
• Decreased rate of rejection and increased rate of
  infection in some studies.
• 
  Roth et
  al., Am.J.Kidney Dis.1999
• But not in others. Ali et
  al., Transpl.1998
• 
  Ponz et al.,Kid.Int.1991
• 
  
  
• HCV ve recipients can tolerate reduction in
  immunosuppression without increased rate of
  rejection.
• Azathioprine is usually withdrawn.
• HCV increases susceptibility to CsA
  hepatotoxicity.
• 
  Honira et al.,Transpl.1993

48

• Other hepatic viruses
• Cytomegalovirus (CMV)
• Herpes simplex virus
• Herpes zoster virus
• Epstein barr virus (EBV)

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• CMV hepatitis
• Weeks after transplantation.
• Self limited.
• Good prognosis.
• Serious liver disease in disseminated CMV
  infection.
• Does not lead to chronic hepatitis.
• Increased rate of rejection.
• Fever, chills, increased transaminases,
  leukopenia, no jaundice.

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• Herpes simplex hepatitis
• Rare.
• Can lead to fulminate liver disease.
• Reactivation of latent HSV lead to severe
  mucocutaneous herpes simplex and hepatitis
• Extensive hepatic necrosis.
• Cowdrys nuclear inclusion.
• Early treatment with acyclovir is indicated.

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• Varicella Zoster Hepatitis
• Disseminated infection
• pneumonia.
• Encephalitis or meningitis.
• Hemorrhagic rash.
• Grave prognosis.

52
Epstein Barr virus(EBV)

• Due to primary infection with EBV in seronegative
  renal transplant recipients.
• Fever.
• Lymphadenopathy.
• Hepatitis.
• Rare severe organ complications.

53

• Drug hepatoxicity
• Azathioprine
• Cyclosporin A
• Other drugs
• Alpha methyl dopa
• Isoniazide
• Allopurinol
• Nitrofuradantine
• Sulphonamide

54

• Azathioprine
• Dose dependent cholestatic syndrome
• Within 6 months post-transplantation.
• Reversible with dose reduction.
• Increase ALP, Bilirubin and/or transaminases.
• Jaundice, pruritis and dark urine.
• 
  Alder
  et al., NDT.1987
• Dose of Azathioprine should be reduced in
  patients with HCV or HBV infections.

55

• Azathioprine
• Hepatic veno-occlusive disease
• Endothelial cell injury ?
• Not dose related.
• Rare.
• 1-2 years after drug therapy.
• Mainly males.
• With CMV infection.
• Jaundice, ascitis and other signs of portal
  hypertension.

56

• Azathioprine
• Hepatic veno-occlusive disease
• Serious complications(poor prognosis)
• Progressive portal hypertension and esophageal
  varices.
• Progressive chronic liver failure.
• Nodular regenerative hyperplasia and
  veno-occlusive disease (risk factor for HCC).
• Liver biopsy done at first sign of mild hepatic
  dysfunction.

57

• Azathioprine
• Hepatic veno-occlusive disease
• Treatment
• Discontinuation of the drug.
• Anticoagulation.
• Portocaval shunt.
• Defibrotide
• 35-40 mg/kg/day.
• IV.
• for 21 days. Azouly et al.,
  Clin.Hepatol.1998

58

• Cyclosporin A
• Dose dependent cholestatic syndrome (With usual
  doses)
• Increased bilirubin, mild increase in
  transaminases and ALP.
• Very high blood level of CsAgt1000ng/L.
• No clinical significance.
• No histological changes in liver biopsy.

59

• Cyclosporin A
• With very high doses of CsA (gt15mg/kg)
• Centrilobular necrosis lead to liver failure.
• 1st month post transplantation.
• Manifestations occur at lower doses in CLD.

60

• Malignancies
• Hepatobiliary tumours.
• Visceral kaposis sarcoma.
• Lymphomas.

61

• Hepatobiliary tumours
• 20-38 fold increase in incidence.
• Hepatoma is the most prevalent tumour in HBV
  recipients.
• Other risk factors include
• HCV.
• Schistosomal infection.
• Azathioprine.
• Veno-occlusive liver diseases.

62
Granulomas

• Tuberculosis
• Sarcoidosis

63
Tuberculosis

• Anti-TB drugs are hepatotoxic specially INH.
• Hepatotoxicity of INH increases by 8 when given
  with rifampicin, fatal hepatitis reported in
  4.6.
• Antony et al.,
  Clinic.Transpl.1997
• With rifampicin dose of CsA should be increased
  to 50-400 to achieve a therapeutic level.
  Yildiz et al NDT.1998

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Tuberculosis

• Rifampicin increases clearance of prednisolone
  and increases the risk of rejection.
• Dose of prednisolone should be increased by 50
  when starting rifampicin therapy.
• Policy of INH prophylaxis is doubtful.

65
Sarcoidosis

• Survival and complications are similar to those
  of patients undergoing transplantation for other
  indications.
• Recurrence of sarcoidosis is often asymptomatic
  and does not affect graft function or patients
  survival.
• Exacerbation of sarcoidosis occurs with intense
  immunosuppression.
• 
  Padilla et al., lung Dis.1999

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