Download Recurrence of disease after liver transplantation

Long-term Complications of
Immune suppression after liver
transplantation
Isabelle Colle MD PhD
Dept. of Hepatology and Gastroenterology
Ghent University Hospital
Ghent 10th of March 2005
UNIVERSITEIT
GENT
1. Metabolic and endocrinological disorders
- Diabetes mellitus => increased mortality after 2y
- Metabolic bone disease
- Obesity
- Hyperlipidemia => 40%
2. Cardiovascular diseases => 0-20% mortality after 3y
3. Renal failure after LTx => ESRD: 4.6 x increased risk of death
4. Malignancies
- solid tumors
- lymphoma and PTLD
- skin tumors
5. Infectious complications => 68% cause of death
Overall Summary of Safety
SAFETY PROFILE OF CURRENTLY APPROVED
IMMUNOSUPPRESSIVE MEDICATIONS VS SIROLIMUS
Drug
Nephrotoxicity
Neurotoxicity
Hypertension
Hyperlipidemia
Diabetes
Hepatotoxicity
Gum hyperplasia
Hirsutism
Diarrhea
Leukopenia
Thrombocytopenia
CsA
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-
Tacrolimus
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-
MMF
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AZA
+
+
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+
Steroids
+
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-
Physician’s Desk Reference
Kahan DB and Ponticelli, C. Principles and Practice of Renal Transplantation, ed Martin Dunitz, 2000
Sirolimus
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Metabolic complications
after liver transplantation
-Diabetes
-Metabolic bone disorders
-Obesity
-Hyperlipidemia
Diabetes mellitus
• DM if present before LTx => more infectious, renal and
cardiovascular complications, more malignancies, 5y
survival is less (34% in DM vs 67% in non-DM).
John. Hepatology 2001.
• 1/3 have transient glucose intolerance within 1°y
• 13-30% develop de novo DM
Eur FK506 multicentre Liver study group. Lancet 1994. Stegall. Transplantation 1995. Heisel. Am J
Transplantation 2004.
Reasons:
-Ciclosporin A (8%) < tacrolimus (18%):
 insulin resistance,  insulin secretion
- Prednisolone: withdrawal => better glucose metabolism
- Weight gain
Obesity
• Obesity occurs early after LTx
• 20 - 40% develop BMI > 30 kg/m2
Stegall. Transplantation 1995. Everhart. Liver Tx Surg 1998. Munoz. Transplant Proc 1991
Causes: ?
- Hepatic denervation
- Hunger feeling
- Increased sense of taste and smelling
- Ciclosporin A > tacrolimus: ?
- Prednisolone: no difference in dose
Treatment: dietary counseling, daily exercise
(2 miles within 25 min)
Hyperlipidemia
(1)
• Hypercholesterolemia > 250mg/dl
- 24% in ciclosporin
- 5% in tacrolimus
• High levels of Tg > 500mg/dl =>  plasma Cl of ciclo
• Sirolimus: blocks insulin-stimulated lipoprotein lipase,
reduction in catabolism of apoB100-containing lipoproteins
• Corticosteroids: hyperinsulinemia mediated stimulation
VLDL synthesis + down-regulation LDL-receptors
• Cyclosporin:  total and LDL chol and  HDL chol
Adverse effects of hyperlipidemia:
- heart attack: especially in KTx and HTx
- stroke
Mor E. Transpl Proc 1995. Canzanello. Liver Transpl Surg 1997. Kraemer. Metabolism 1998.
Hoogeveen. Tx 2001. Groth. Tx 1999. Kreis. Tx 2000.
Cardiovascular
complications after liver
transplantation
Arterial hypertension (AHT)
• AHT very common after LTx
• 80% exhibit AHT at one timepoint after LTx
• 50% patients require chronic antihypertensive
treatment
Cause:
- direct effects of IS on vascular endothelium:  SVR
- drug induced renal changes:  RVR
- cyclo 62% > FK 38%
- corticosteroids, weight gain
Sheiner. Transplantation 2000. Eur FK506 multicentre Liver study group. Lancet 1994. Rabkin. Am J Surg
2002. US FK506 multicentre Liver study group. NEJM 1994. Canzanello. Liver Tx Surg 1998.
Heart disease
• Heart disease occurs often within 6 – 12 m after LTx:
21% die of CV complications
• Silent coronary artery disease in older patients, DM
patients
• Hyperlipidemia and AHT plays important role
• Death due to cardiovascular disease at 3y:
20% vs 0% in ciclo vs tacrolimus
Table of events
(Rabkin. Am J Surg 2002)
Pruthi. Liver Transplant 2001.
Rabkin. Am J Surg 2002.
Renal complications after
liver transplantation
Survival after Liver Tx
• Survival in patients with HRS before Tx is
lower than no HRS => renal failure improves
but 7-10% will develop ESRD
• Patients with pre-LTx renal failure => 10% need
hemodialysis post-LTx vs 2% who did not have
renal failure before
• Indication combined KTx and LTx:
=> proven parenchymal kidney disease
=> genetic diseases: oxalosis; polycystic disease
N = 37 000 LTx
Risk factors for CRF:
-CN Inhibitors
-Older age
-Low preTx GFR
-Female
-Postop ARF
-DM, AHT
-hepC
-Tx before 1998
-Ciclo = FK?? in CRF
Chronic renal failure:
GFR < 29ml/min:
- 14% at 3 y
- 18% at 5y
=> 4.6 fold increased risk of death
Ojo. NEJM 2003
Renal failure after Liver Tx
(1)
1. Ciclosporin toxicity:
- Causes dose related decrease in RBF and GFR
- Endothelial dysfunction =>  VD and  of TXA2
and ET => VC on efferent and afferent arteriolus
=> tubular damage and even ATN
- Increased sympathetic tone
- Direct proximal tubulus toxin: osteopontin =>
interstitial fibrosis
- Contraction of mesangial cell
Burdmann. Semin Neprol 2003. Lanese. J Clin Invest 1993. Ruggenenti. Kidney Int 1993.
Mihatsch. Transpl Proc 1988
EFFECTS OF CYCLOSPORINE/FK506 ON
GLOMERULAR CIRCULATION IN THE
RAT1
ET-1, TX-A2, SNS 
NO, PG 
Control
1. English et al. Transplantation 1987; 44: 135-141.
Vasoconstricted arteriole (arrow) after
14 days of oral cyclosporine therapy
Renal failure after Liver Tx
(2)
1. Ciclosporin toxicity:
- Acute nephrotoxicity:
endothelial damage, fibrin thrombi in capillary
loops, eo’s, patchy necrosis of SMC  malignant
HT, thrombotic thrombocytopenic purpura
Renal failure after Liver Tx
- Chronic ciclosporin nephrotoxicity:
interstitial fibrosis striped pattern, tubular
atrophy (apoptosis), degenerative hyalin in
arterial walls (obliterative arteriolopathy)
(2)
Renal failure after Liver Tx
2. Tacrolimus toxicity:
- Same toxicity as cyclosporin
- In Ojo: FK less nephrotoxicity in LTx, = in
other organ Tx
3. Recurrence initial disease: hep C
Ojo. NEJM 2003. Eur FK506 multicentre Liver study group. Lancet 1994.
US FK506 multicentre Liver study group. NEJM 1994
(3)
Malignancies after liver
transplantation
-Solid tumors
-Lymphoma and PTLD: 57% of all tumors
-Skin cancers: 15 - 38%
Malignancies: general
• Tx recipients have higher risk than age-matched
controls
• Risk increases with:
- longer duration and better survival
- dose of immune suppression
- type of immune suppression (OKT3, ciclosporin and FK
by TGF-beta and VEGF expression  sirolimus:
anti-VEGF, IL10, cyclins)
- co-existing viral infection: EBV, HHV-8, HPV
Adami. Br J Cancer 2003. Penn. NEJM 1990. Guba. Transplantation 2004. Maluccio. Transplantation 2003
Malignancies: solid tumors
•
•
•
•
Breast cancer: especially in PBC pts
Head and neck tumors: alcohol, tabacco
Lung
Colorectal cancer:
- familial history
- Inflammatory bowel disease
- PSC
=> annual colonoscopy
Stewart. Lancet 1995. Aseni. Liver Tx 2001. Campistol. Transplantation 2004. Duman. NDT 2002.
• Kaposi sarcoma: 4%: associated with HHV-8
- occurs +/- 21m after Tx
- related to the amount of IS
- violaceous plaques-nodules on skin, mucosa, viscera
- partial or complete remission if IS is decreased,
switch to sirolimus
Lymphoma and Post Transplant
Lymphoproliferative Disorder (PTLD)
• Prevalence:
1-3% in adult LTx
20% in pediatric LTx within 2 y of LTx
• Most are of host origin
3 types of EBV-related PTLD:
- Mononucleosa like syndrome: benign polyclonal proliferation
- MN syndrome + polyclonal Bcell proliferation with early
malignant transformation
- Localised NH-lymphoma => diffuse progressive and fatal
Weissmann. Am J Clin Pathol 1995. Hanto. Annu Rev Med 1995. Petit. Transplantation 2002.
Hjelle. Transplantation 1989. Nalesnik. Am J Pathol 1988
(1)
Lymphoma and PTLD
(2)
• Risk factors for PTLD:
- EBV seronegative preTx => primo EBV infection
- CMV infection
- High dose IS, especially antilymphocyte Ab OKT3
Walker. Clin Infect Dis 1995. Swinnen. NEJM 1990.
Mechanism:
- IS => defective cytotoxic CD8 cells => proliferation EBV =>
TNF activation => EBV infects B-cells => transformed B-cells
Uncontrolled expansion of B-cells => PTLD
- 2% - 12% lymphoma are of T-cell origin
- EBV negative disease can occur => later, more virulent
Leblond. J Clin Oncol 1998. Mosialos. Cell 1995. Izumi. Proc Natl Acad Sci USA 1997. Liebowitz.NEJM 1998
Lymphoma and PTLD
(3)
Nalesnik. Am J Pathol 1988.
Localisation: often extranodal (70%)
- brain
- head and neck
- 44% liver
Treatment:
- prevention!
- decrease IS
- antiviral ganciclovir, acyclovir, foscarnet?
- chemo (CHOP, ProMACE-CytaBOM) and radiotherapy
- anti-CD20 = rituximab => 61% remission
- Interferon alfa
Rees. Lancet 1998. Oertel. Transplantation 1999. Schmidt. NEJM 2000. Cook. Lancet 1999.
Verschuuren. Transplantation 2002. Berney. Transplantation 2002.
Skin tumours: 38%
• Sqamous cell carcinoma:
- 250 times increased risk
- more invasive and more metastasis
- depends on dosage IS: heart TX > KTx > LTx
• Basal cell carcinoma:
- 10 times increased risk
Euvrard. NEJM 2003. Ramsay. J Am Acad Dermatol 2003. Jensen. J Am Acad Dermatol 1999.
Jemec. Transplantation 2003.
Skin tumours
Risk factors:
- Sun light exposure
- Light skin type
- Actinic keratosis
- HPV -warts
Treatment:
- Treat warts early
- Treat actinic keratosis early
- Decrease IS
- Retinoids (acitretine): preventive
Euvrard. NEJM 2003. Ramsay. J Am Acad Dermatol 2003. Jensen. J Am Acad Dermatol 1999.
Jemec. Transplantation 2003. Harwood. J Med Virol 2000. Smit. J Am Acad Dermatol 2004. Kelly.Lancet 1991
Infectious complications
after liver transplantation
Infectious complications
• Leading cause of mortality => 68% of deaths
- 48% bacterial
- 22% fungal
- 12% viral
• Serious infections mostly within first 3m
• Long term high IS => opportunistic infections
Torbenson. Mod pathol 1998. Fishman. NEJM 1998. Winston. Clin Infect Dis 1995.
Sequence of Infections After SOT
Bacterial infections
• Legionella: pneumonia, diarrhea, pulmonary
cavitations
• Listeria: in milk, meat
=> bacteremia, meningitis
=> ampicillin
• Nocardia: lung, CNS, skin => sulfonamide
• TBC: 0.9 – 2.3% after LTx
Torbenson. Mod pathol 1998. Fishman. NEJM 1998. Winston. Clin Infect Dis 1995.
Fungal infections
Risk factors for fungal infections:
- Re-transplantation
- High need of peroperative blood transfusion
- Creatinine > 2mg/dl
- Bilirubin > 10 mg/dl
- Choledocho-jejunostomy
- Previous colonisation
• Candida: abdominal infections
• Aspergillus: lung and brain =>
profylaxis fluconazole: 23% => 5.6%
• Pneumocystic carinii: 2-6m post-Tx
dyspnea, hypoxia, fever, cough =>TMP/SMZ,dapsone,pentamidine
Collins. J Infect Dis 1994. Paya. Clin Infect Dis 1993. Fishman. NEJM 1998. Winston. Clin Infect Dis 1995.
Viral infections
(1)
• CMV:
- Primo infection by donated allograft or sero+ blood
products
- Reactivation endogenous CMV
• Risk for CMV infection:
- D+ /R- High IS, especially antilymphocyte OKT3
• Mechanism:
infection, rejection, IS , OKT3 => increase in TNFalfa => reactivation CMV => direct
immunosuppressive properties => increased risk for
bacterial, fungal and EBV infection +  risk rejection
Torbenson. Mod pathol 1998. Fishman. NEJM 1998. Winston. Clin Infect Dis 1995. Paya. J Hepatol 1993.
Viral infections
(1)
• CMV:
Mechanism:
Torbenson. Mod pathol 1998. Fishman. NEJM 1998. Winston. Clin Infect Dis 1995. Paya. J Hepatol 1993.
Viral infections
(2)
• EBV:
- Primo infection in seronegative patient
- Reactivation endogenous EBV
 Increased risk to develop PTLD
• Human herpes virus HHV-6
=> attacks CD4 cells, risk factor for CMV
• Human herpes virus HHV-8
=> Kaposi sarcoma
• Human papiloma virus HPV-16-18-31-33
=> warts, sqamous cell ca, cervical dysplasia and carcinoma
• Varicella zoster
The paradox of transplantation
REJECTION
UNDERIMMUNOSUPPRESSION
INFECTIONS
TUMORS
CV and renal complications
OVERIMMUNOSUPPRESSION
Immune tolerance
REJECTION 
less
IMMUNOSUPPRESSION
INFECTIONS 
TUMORS 
CV and renal complications 
less
IMMUNOSUPPRESSION
Renal function measurements
• Creatinine:
false low due to muscle atrophy
=> Cockeroft and Gault: overestimation of GFR
• Cr EDTA
Neurological complications
after liver transplantation
Neurological disorders
• 10-50% neurological complications post LTx first week
Etiologies:
- Vascular events: 52%
- Infections: 18%
- IS associated leuko-encephalopathy: 12%
- Central pontine myelinolyse: 8%
- Malignancy: 3%
- Miscellaneous: 7%
Bonham. Transplantation 1998. Adams. Lancet 1987
Neurological disorders
Causes:
- IV administration immune suppression
- Postop hypercoagulability
- Periop cardiovascular instability
Symptoms:
-ciclo / FK: peripheral neuropathie:
tremor, shooting pain in limbs, carpal tunnel
syndrome (6% in PBC)
- headache/migraine: not always relieved by  IS
Treatment:
Calcium antagonists, beta-blockers, tricyclic antidepressants
Hematological complications
after liver transplantation
Hematological complications
(1)
Hematological complications
(2)
• Cytopenia: 1/3 of patients postLTx
• Anemia: microcytic, macrocytic, hemolysis
(ABO mismatch; azathioprine: folic acid)
• Hypersplenism persists: leucopenia,
thrombopenia
=> partial embolisation spleen
• Trombopenia: think of CMV, parvovirus
Suggested guidelines for cancer screening after SOT
Metabolic bone disorders
(1)
• PreLTx: osteopenic bone disorders due to:
- cholestasis
- alcohol abuse
- hypogonadism
- malnutrition
• Post LTx:
- Bone mass density (BMD) decreases during first 3 m
- BMD returns to preLTx levels after 6 – 12m
- BMD normalizes after 2 – 5 y
Floreani. Liver Tx Surg 1998. Eastell. Hepatology 1991. Rosen. Hepatology 1995. Hay. Gastroenterology 1995
Metabolic bone disorders
(2)
• Fractures: maximal in first 12m:
- vertebrae and ribs >> femur
- especially in PBC, PSC patients
• Osteonecrosis of hip: 10-15% => long-term steroid
Reasons:
Ciclosporin A and tacrolimus:  bone turn-over
Prednisolone: inhibit bone formation + activates resorption
AZA, MMF, sirolimus: no effect on bone mass
Treatment: Ca++, Vit D, antiresorptive treatment
with calcitonin, biphosphonates, oestrogens, exercise
Eastell. Hepatology 1991. Valero. Calcif Tissue Int 1995. Fan. JASoN 1996.
Ramsey-Goldman. J Bone Miner Res 1999.
Hyperlipidemia
(2)
Treatment:
- dietary counseling, exercise, weight reduction
- switch cyclo => tacrolimus:  in LDL and Tg
Hyper Tg:
- Fibrates
Hypercholesterolemia: goal LDL < 100 mg/dL (< 70mg/dL)
- Statins (HMG-CoA reductase inhibitors):
fluvastatin ALERT study (Lescol), atorvastatin (Lipitor)
- start low dose
- can go to a maximum of ½ dose
- cave rabdomyolysis in cyclo, also in FK: P450 3A4 =>  [statin]
- follow CK levels at W2, W6 and every consult
- cholestyramine: no => influence intestinal absorption
- gemfibrozil: hepatotoxicity
Holdaas. Lancet 2003
Treatment cardiovascular problems
• Obesity: weight reduction
• Exercise
• Lower hyperlipidemia
• Ca++ antagonists => effects on endothelial cells
Amlodipine, nifedipine, isradipine
Verapamil, diltiazem: check ciclo – FK level =>  metabolism
• Beta-blockers
• ACE-inhibitors => hyper kaliemia
• Clonidine
Pre-liver transplant renal failure
1. Renal failure due to the same disease as
causes liver failure:
- polycystosis
- hep B and C related: MGN, GN
2. Parenchymal disease due to AHT and DM
3. Functional renal failure:
- hepato-renal syndrome
- IV contrast use
- diuretics, hypovolemia
HRS = functional renal disease, can be reversible
Chance to develop HRS in cirrhosis + ascites: 32% 2y 41% 5y
Treatment: Ca-antagonists, replacement of cyclo
Ca++ channel blockers
- prevent cyclo-induced renal VC
- do not prevent ET-1 release
- effect on long-term not clear
Sequence of Infections After SOT
Community-acquired,
Conventional
Nosocomial
Opportunistic,
Unconventional or opportunistic infections
chronic viral
infections
Viral
CMV Retinitis or colitis
CMV Onset
HSV
EBV VZV Papova Adenovirus
TB
Fungal
Papillomavirus, PTLD
Pneumocystis
CNS
Listeria
Aspergillus, Nocardia, Toxoplasma
Cryptococcus
Bacterial
Wound
Pneumonia
Line-Related
Onset of hepatitis B and C
UTI, Relatively
Benign
UTI, Bacteremia, Pyelitis, Relapse
0
Transplantation
1
2
3
4
5
6
Months
J. Fishman.NEJM 1998; 24: 1741
Renal failure after Liver Tx
(3)
2. Tacrolimus toxicity:
- Same toxicity as cyclosporin
- In Ojo: FK less nephrotoxicity in LTx, = in
other organ Tx
3. Recurrence initial disease: hep C
4. Hyperkalemia:  U K+ excretion,  efficacy of aldosterone
5. Hyperuricemia and gout:  U uric acid excretion
6. Metabolic acidosis:  acid excretion, hyperchloremic
7. Hypophosphatemia, hypercalciuria and hypoMg++
Ojo. NEJM 2003. Eur FK506 multicentre Liver study group. Lancet 1994.
US FK506 multicentre Liver study group. NEJM 1994