Individualising immunosuppression in response to renal, cardiovascular, metabolic and other long-term threats to health and longevity

John OGrady Kings College Hospital

Success of liver transplantation

90+%

surgical success 600 new recipients join recipient pool annually Minimal late loss to rejection Hepatitis C only MAJOR threat of recurrent disease No intrinsic attrition rate (unlike kidneys)

Recipient population
Average

age 47 years Significant paediatric population Typically 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

Threats to health and longevity

Malignant

disease Renal failure Cardiovascular disease Metabolic disease Obesity Bone disease

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 to surgery

Malignant disease
2-3%

skin cancers Oro-pharyngeal tumours, especially in patients transplanted for alcoholic liver disease Increased risk of colonic carcinoma in UC/PSC patients - 1% risk per year - 21% dysplasia rates by 8 years annual colonoscopy recommended

Renal dysfunction and failure

Calcineurin

inhibitors (cyclosporine and tacrolimus) associated with renal dysfunction Up to 5% in UK of long-term survivors progressed to dialysis or renal transplantation 40% have serum creatinine >120 or creatinine clearance <60 ml.min NEJM study showed ESRD occurred at 1-1.5% per year

Maintaining healthy kidneys

CNI

exposure in first 3 months very important Avoid NSAIDs and other nephrotoxic drugs if possible Screen for early deterioration with creatinine clearance Decrease or eliminate CNI with mycophenolate or sirolimus

Abnormal Glucose Metabolism

Pretransplant

diabetes mellitus Very common early phenomenon Long-term diabetes mellitus - increase in treatment intensity - de novo diabetes mellitus Some cases of improvement in DM 4-20% of patients have significant problem

Diabetes mellitus - TMC study

First

3 month Tacrolimus Insulin 47% Drug 13% Diet 16% Any 51% Change 22%

Cyclosporine 38% 4% 7% 39% 13%

Diabetes Mellitus - TMC study

4-12

months Tacrolimus Cyclosporine Insulin 13% 7% Drug 7% 2% Diet 11% 16% Any 19% 11% Change 11% 5%

Diabetes mellitus - TMC study

Diabetes

mellitus after 3 months more common in tacrolimus group - RR 2.06 (1.36-3.12; p = 0.0006)

Tailoring immunosuppression because of diabetes mellitus

Little

evidence that it is practiced Acceptable and manageable risk Historically steroids viewed as culprit Short-term studies do not demonstrate increased morbidity Will long-term studies reveal complication profile justifying tailoring?

Hyperlipidemia
Hypercholesterolemia

17-43% Hypertriglyceridemia 40-59% Implicated drugs - cyclosporine, corticosteroids and 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

Risk Factors for Hyperlipidemia

Cholesterol Pretransplant level Cholestatic liver disease Female gender Corticosteroids

Triglycerides Hepatocellular liver disease Renal dysfunction

Tailoring immunosuppression for hyperlipidaemia

Early

steroid withdrawal

Switch

from cyclosporine to tacrolimus Cambridge study sirolimus

Avoid

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 over first 6 months after transplantation Corticosteroids main offending drug Cyclosporine and tacrolimus implicated in animal studies only

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

What is this?
Hypertensive Obese Diabetic

Hyperlipidemic

Answer: a heart-attack waiting to happen

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

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

Conclusion
Good

rationale for tailoring immunosuppression Low application in this situation Steroid minimisation/avoidance main manifestation Need model of overall risk Need for well-patient clinics

PHILOSOPHY
The excellent results of liver 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 has come to worry now about the small details that may matter in that time span.