Individualising immunosuppression in response to renal, cardiovascular, metabolic and other longterm

1
Individualising immunosuppression in response to
renal, cardiovascular, metabolic and other
long-term threats to health and longevity

• John OGrady
• Kings 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 gt120 or creatinine
  clearance lt60 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

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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

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Diabetes mellitus - TMC study

• First 3 month
• Tacrolimus Cyclosporine Insulin 47 38 D
  rug 13 4 Diet 16 7 Any 51 39
• Change 22 13

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Diabetes Mellitus - TMC study

• 4-12 months Tacrolimus Cyclosporine Insul
  in 13 7 Drug 7 2 Diet 11 16 An
  y 19 11
• Change 11 5

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Diabetes mellitus - TMC study

• Diabetes 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
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?

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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

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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 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

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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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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

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• 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.