John O’Grady King’s College Hospital

1. Individualising immunosuppression in response to renal, cardiovascular, metabolic and other long-term threats to health and longevity John O’Grady King’s College Hospital

2. 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)

3. 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

4. Threats to health and longevity • Malignant disease • Renal failure • Cardiovascular disease • Metabolic disease • Obesity • Bone disease

5. 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

6. 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

7. 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

8. 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

9. 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

10. Diabetes mellitus - TMC study • First 3 month • Tacrolimus Cyclosporine Insulin 47% 38% Drug 13% 4% Diet 16% 7% Any 51% 39% • Change 22% 13%

11. Diabetes Mellitus - TMC study • 4-12 months Tacrolimus Cyclosporine Insulin 13% 7% Drug 7% 2% Diet 11% 16% Any 19% 11% • Change 11% 5%

12. Diabetes mellitus - TMC study • Diabetes mellitus after 3 months more common in tacrolimus group - RR 2.06 (1.36-3.12; p = 0.0006)

13. 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?

14. 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

15. Cholesterol Pretransplant level Cholestatic liver disease Female gender Corticosteroids Triglycerides Hepatocellular liver disease Renal dysfunction Risk Factors for Hyperlipidemia

16. Tailoring immunosuppression for hyperlipidaemia • Early steroid withdrawal • Switch from cyclosporine to tacrolimus - Cambridge study • Avoid sirolimus

17. 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

18. 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

19. What is this? • Hypertensive • Obese • Diabetic • Hyperlipidemic Answer: a heart-attack waiting to happen

20. 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

21. 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

22. 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

23. 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.