Long-term Complications of Immune suppression after liver transplantation

Isabelle Colle MD PhD Dept. of Hepatology and Gastroenterology Ghent University Hospital Ghent 10 th 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

Drug

SAFETY PROFILE OF CURRENTLY APPROVED IMMUNOSUPPRESSIVE MEDICATIONS VS SIROLIMUS

Nephrotoxicity Neurotoxicity Hypertension Hyperlipidemia Diabetes Hepatotoxicity Gum hyperplasia Hirsutism Diarrhea Leukopenia Thrombocytopenia

CsA +++ ++ +++ ++ + + ++ ++ + - - Tacrolimus +++ +++ ++ + +++ + - - + - - MMF - - - - - - - - +++ +++ + AZA Steroids Sirolimus - - - - - - + +++ ++ ++ - - - +++ - + - - + +++ + - - + - - - + - - + + ++

Physician’s Desk Reference Kahan DB and Ponticelli, C. Principles and Practice of Renal Transplantation, ed Martin Dunitz, 2000

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/m

2 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 • High levels of Tg > 500mg/dl =>  - 5% in tacrolimus 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:  - drug induced renal changes:  RVR SVR - 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

Chronic renal failure:

GFR < 29ml/min: - 14% at 3 y - 18% at 5y => 4.6 fold increased risk of death 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 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 RAT 1 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

(2) - Chronic ciclosporin nephrotoxicity

: interstitial fibrosis striped pattern, tubular atrophy (apoptosis), degenerative hyalin in arterial walls (obliterative arteriolopathy)

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 Ojo. NEJM 2003. Eur FK506 multicentre Liver study group. Lancet 1994. US FK506 multicentre Liver study group. NEJM 1994

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)

(1)

• 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

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 TNF alfa => 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.

•

CMV:

Mechanism:

Viral infections

(1)

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 INFECTIONS TUMORS CV and renal complications UNDER IMMUNOSUPPRESSION OVER IMMUNOSUPPRESSION

Immune tolerance

REJECTION  INFECTIONS  TUMORS  CV and renal complications  less IMMUNOSUPPRESSION 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

Conventional Nosocomial infections

Viral HSV Fungal

Unconventional or opportunistic infections

TB

CMV Onset

EBV VZV Papova Adenovirus Pneumocystis CNS Listeria Aspergillus, Nocardia, Toxoplasma Bacterial

Wound Pneumonia Line-Related Community-acquired,

Cryptococcus

Opportunistic, chronic viral CMV Retinitis or colitis

Papillomavirus, PTLD 0 Transplantation

Onset of hepatitis B and C UTI, Bacteremia, Pyelitis, Relapse

1 2 3

Months

4 5 6

UTI, Relatively Benign 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