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Individualising

immunosuppression in response

to renal, cardiovascular,

metabolic and other long-termthreats to health and longevity

John OGrady

Kings College Hospital

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Recipient populationAverage age 47 years

Significant paediatric populationTypically non-smoking, non-drinking

Increasingly expecting near normal life-expectancy

rather than a few bonus years Planning life and family decisions on the

expectation of longevity

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Threats to health and longevityMalignant disease

Renal failureCardiovascular disease

Metabolic disease

ObesityBone disease

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Malignant disease PTLD

- risk correlates with overall intensity of

immunosuppression

- estimate of 0.5% per year

- cases seen at 16-23 years

- very poor prognosis unless amenable tosurgery

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Malignant disease 2-3% skin cancers

Oro-pharyngeal tumours, especially in patientstransplanted for alcoholic liver disease

Increased risk of colonic carcinoma in UC/PSCpatients

- 1% risk per year- 21% dysplasia rates by 8 years -

annual colonoscopy recommended

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Renal dysfunction and failureCalcineurin inhibitors (cyclosporine and

tacrolimus) associated with renal dysfunction

Up to 5% in UK of long-term survivors progressedto dialysis or renal transplantation

40% have serum creatinine >120 or creatinine

clearance

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Maintaining healthy kidneysCNI exposure in first 3 months very important

Avoid NSAIDs and other nephrotoxic drugs ifpossible

Screen for early deterioration with creatinine

clearance

Decrease or eliminate CNI with mycophenolate or

sirolimus

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Abnormal Glucose Metabolism Pretransplant diabetes mellitus

Very common early phenomenonLong-term diabetes mellitus

- increase in treatment intensity

- de novo diabetes mellitus

Some cases of improvement in DM

4-20% of patients have significant problem

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Diabetes mellitus - TMC studyFirst 3 month

Tacrolimus CyclosporineInsulin 47% 38%

Drug 13% 4%

Diet 16% 7%

Any 51% 39%

Change 22% 13%

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Diabetes mellitus - TMC studyDiabetes mellitus after 3 months more common in

tacrolimus group

- RR 2.06 (1.36-3.12; p = 0.0006)

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Tailoring immunosuppression because

of diabetes mellitusLittle evidence that it is practiced

Acceptable and manageable risk

Historically steroids viewed as culprit

Short-term studies do not demonstrate increased

morbidityWill long-term studies reveal complication profile

justifying tailoring?

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HyperlipidemiaHypercholesterolemia 17-43%

Hypertriglyceridemia 40-59%

Implicated drugs - cyclosporine, corticosteroidsand tacrolimus

Cyclosporine Vs Tacrolimus

140 to 202 151 to 164 mg/dl (mean) Steroid withdrawal 223 to 188 mg/dl

Pravastatin 251 to 208 mg/dl

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Risk Factors for Hyperlipidemia Cholesterol

Pretransplant level

Cholestatic liver disease

Female gender

Corticosteroids

Triglycerides

Hepatocellular liver

disease

Renal dysfunction

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Tailoring immunosuppression for

hyperlipidaemiaEarly steroid withdrawal

Switch from cyclosporine to tacrolimus -

Cambridge study

Avoid sirolimus

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Osteopenia 50% of PBC and PSC patients have bone densities

below fracture threshold

22-38% have atraumatic fractures

Bone density deteriorates in 90% of patients overfirst 6 months after transplantation

Corticosteroids main offending drugCyclosporine and tacrolimus implicated in animal

studies only

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Obesity 21.6% of patients developed de novo obesity after

liver transplantation

Mean body mass index increased from 24.8 kg/m2

to 28.1 kg/m2 at 2 years

Corticosteroids and cyclosporine main responsible

drugs

Tacrolimus may suppress appetite

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What is this?Hypertensive

Obese

Diabetic

Hyperlipidemic

Answer: a heart-attack waiting to happen

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Hypertension Implicated drugs include cyclosporine, tacrolimus

and corticosteroids

US and European trial showed comparable rates in

the range of 36-56%

Highest rates reported were 82% for cyclosporine

and 64% for tacrolimus

Good studies have yet to be reformed

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Obesity 21.6% of patients developed de novo obesity after

liver transplantation

Mean body mass index increased from 24.8 kg/m2

to 28.1 kg/m2 at 2 years

Corticosteroids and cyclosporine main responsible

drugs

Tacrolimus may suppress appetite

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ConclusionGood rationale for tailoring immunosuppression

Low application in this situation

Steroid minimisation/avoidance main

manifestation

Need model of overall riskNeed for well-patient clinics

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PHILOSOPHY

The excellent results ofliver transplantation have

now put into focus the

long term health profiles

of liver recipients and put

the onus on clinicians to

plan for up to 80 years or

more of life. The time hascome to worry now about

the small details that may

matter in that time span