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Paediatric Renal Transplantation

Paediatric Renal Transplantation. Angela Lamb Paediatric Renal Pharmacist Yorkhill Hospital Glasgow. Summary. History of kidney transplants Kidney transplantation History Immunosuppression Immunosuppressive NICE guidelines on immunosuppression therapy

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Paediatric Renal Transplantation

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  1. Paediatric Renal Transplantation Angela Lamb Paediatric Renal Pharmacist Yorkhill Hospital Glasgow

  2. Summary • History of kidney transplants • Kidney transplantation • History Immunosuppression • Immunosuppressive • NICE guidelines on immunosuppression therapy • Renal unit guidelines for Kidney Transplant • Role of pharmacist • Future

  3. History of Kidney Transplant • 1954 • First successful kidney transplantation took place in Brigham hospital in Boston in identical twins • 1959 • First successful kidney transplantation non-identical individuals • 1960 • First UK living donor kidney Tx took place in Edinburgh • 1965 • First recorded cadaver kidney Tx in UK

  4. Paediatric Transplantation • 1950 • RHSC Glasgow was the first regional referral unit for children with renal disease in the UK • 1960s • Peritoneal Dialysis was pioneered in RHSC Glasgow for acute renal failure • 1971 • New purpose built Renal Unit which led to the use of PD for ESRF

  5. Paediatric Transplantation • 1970s(early) • Guys in London & Royal Manchester Children's Hospital first Paediatric Haemodialysis units in the UK • Dr Anna Murphy • HD unit at RHSC Glasgow • 1977 (March) • First paediatric renal Tx took place in RHSC Glasgow • 1990s • One specialist paediatric renal unit in Scotland

  6. Transplants saves lives: • Information from UK Transplant website 2006-2007 : • 1,933 kidney Tx of which 676 (35%) were given their kidney by a friend or relative (living related donor LRD) • Most recent figures on 15/4/07 • 6,359patients were listed as actively waiting for a transplant of which 99 are children <18years

  7. Kidney Transplant • Renal replacement therapy • Cadaver - last for 10-12 years • Living related donor – last for 12-14 years • First choice for children • Planned • Better donor match • Require 2-3 kidneys in a lifetime

  8. Kidney Transplant • Leave the native kidneys • Remove if primary disease cause long-term problem • Tx kidney located low in the abdomen

  9. Problems post transplant • Rejection • Infection • Dehydration • Drug toxicity • Obstruction • Graft vascular thrombosis

  10. Transplant Rejection Three types: • Hyperacute • this occurs within hours of transplant and is mediated by preformed allo-antibodies • Acute • usually seen within a few months of transplant. Cellular or vascular. • Chronic • a progressive decline in graft function over months or years.

  11. Immune Response • Immune system goes into a “search out and destroy” mode when it recognises a foreign antigen • Antigen is an enormous range of substances that can be bound by an antibody and induce some kind of immune response

  12. Cells in the immune system

  13. Immune Response

  14. History of Immunosuppression • Organ Tx first attempted at the turn of the last century- failure • 1944 Sir Peter Medawar – graft loss was a result of host vs graft immune response • Skin graft model – discovered that the immune system recognised the Tx as non-self

  15. History of Immunosuppression • 1956 Billingham & colleagues • skin grafts were co-Tx with allogenic bone marrow cells into irradiated mice • Hume • extended these observation in kidney & BMTx in irradiated dogs • Extended • to humans giving sub-lethal doses of total body irradiation before kidney Tx

  16. History of Immunosuppression • Goodwin & colleagues used myeloablative agents such as nitrogen mustard and also chlorambucil & prednisolone • Technical difficulties • High rate of infection • 100% mortality • This early work established • Organ cooling • Minimal ischaemic time • Matching of donor & recipient

  17. History of Immunosuppression • Over the next 30 years three types of drugs were developed: • Aim of limiting B-cell & T-cell proliferation mediating rejection • Inhibitors of DNA synthesis • Lymphocyte depleting agents • Cytokine modulators

  18. Immunosuppressants • 1962 Azathioprine • 1963 Prednisolone • 1967 Anti-human polyclonal antibodies: • equine ATGAM • rabbit Thymoglobulin (ATG) • 1978 Ciclosporin • 1980s Muromonab (OKT3) • 1990 Tacrolimus • 1995 Mycophenolate mofetil • 2000 Monoclonal antibodies • 2000 Sirolimus

  19. Azathioprine • First drug to be used to prevent graft rejection • Mechanism of action • Well absorbed and quickly metabolised to 6-mercaptopurine (6-MP) • 6-MP is further metabolised to thioguanine nucleotides which disrupt the cellular synthesis of RNA & DNA • Preventing mitosis and thus proliferation of B & T cells

  20. Azathioprine • Dosage: • Started pre-Tx just before TH • Once daily dose 2mg/kg (max 100mg daily) • Side effects: • Reversible, dose dependent BMS • GI upset give with meals • Advice • Not to crush or split tablets • Tablet will disperse in water

  21. Prednisolone • Mechanism of Action • Mechanism of action not fully understood • Inhibit production of a number of T cells and macrophage cytokines (IL, IF, TNF-ɑ) • This results in a non-specific effect in disrupting the response of the immune system • High doses act as immunosuppressant and anti-inflammatory

  22. Prednisolone • Dosage: • Given at anastomosis 600mg/m² as IV methylprednisolone • Changed to oral prednisolone asap starting at 60mg/m² in two divided doses (max 60mg),then on a reducing dose • Side effects: •  BP • electrolyte balance •  appetite • GI • fat distribution • Advice: • Do not use EC tablets

  23. Mycophenolate Mofetil (MMF) • Alternative anti-purine agent • Mechanism of action: • MMF is a prodrug of mycophenolate acid which was produced by the mould penicillium glaucum • MMF is a non-competitive, reversible inhibitor of purine synthesis which leads to inhibition of both B & T cell proliferation

  24. Mycophenolate Mofetil (MMF) • Dosage: • Dose 600mg/m² bd (max 1g bd) with ciclosporin • Dose 600mg/m² bd (max 1g bd) for 1 week then 300mg/m² bd (max 1g bd) with tacrolimus • Side effects • Cause BMS • Main problem GI upset – diarrhoea • Advice • Liquid is available • Other information • Mycophenolate sodium

  25. Ciclosporin • First inhibitor of cytokine synthesis • Mechanism of action • Originally isolated from the fungus tolypocldium inflatum • Ciclopsorin forms a complex with cycophyllin which binds to the enzyme calcineurin – Calcineurin inhibitor • This complex inhibits newly activated T cells from transcribing the genes that code for IL-2 • Halting cytokine production inhibits the T cell driven immune response • Metabolism • Cytochrome P450 3A4

  26. Ciclosporin • Dosage: • Can be started pre-Tx • Dose oral 5mg/kg bd then adjust according to 12 hour trough level • 0-3months 175-225nmol/l • 1-3months 150-200nmol/l • 3-12months 125-175nmol/l • >12months 100-150nmol/l • Side effects • Renal dysfunction •  BP • Hypertrichosis • Gingival hyperplasia, • Hyperlipidaemia • Other information • Liquid available

  27. Tacrolimus • Calcineurin inhibitor • It is a macrolide discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. • Mechanism of action • Tacrolimus binds to the intracellular protein FK506 binding protein-12 (FKBP12) this forms a complex with Ca²+ and calmodulin. This complex inhibits calcineurin • This complex inhibits newly activated T cells from transcribing the genes that code for IL-2 • Halting cytokine production inhibits the T cell driven immune response • Metabolism • Cytochrome P450 3A4

  28. Tacrolimus • Dosage: • Can be started pre-Tx • Dose oral 0.15mg/kg bd then adjust according to 12 hour trough level • 0-2months 10-15ng/ml • 2-12months 5-10ng/ml • >12months 3-7ng/ml • Side effects • Renal dysfunction •  BP • Glucose intolerance • Neurotoxicity • Tremor • Alopecia

  29. Sirolimus • Latest immunosuppressant to be licensed for kidney Tx • Sirolimus is a macrolide antibiotic first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from an island called Rapa Nui • Mechanism of action • binds to the intracellular protein FKBP12 in a similar way to tacrolimus • sirolimus-FKBP12 complex inhibits the mammalian target of rapamycin (mTOR) • This blocks the proliferation of lymphocytes by blocking the cells response to IL-2 • Metabolism • Cytochrome P450 3A4

  30. Sirolimus • Dosage: • Dose oral 1-4mg then adjust according to 24 hour trough level 4-12ng/ml • Dosage & timing depends on co-administration with ciclosporin • Side effects • Hyperlipidaemia • Delayed wound healing •  LDH • Thrombocytopenia • Hypokalaemia • Lymphocoele formation • Other information • Liquid available

  31. Monoclonal antibodies (mAbs) • CD25 mAbs • Basiliximab & Daclizumab • Mechanism of action • Block IL-2 from binding to the IL-2Rɑ(CD25) • Reduce proliferation of T-cells by IL-2 cytokine pathway

  32. Monoclonal antibodies (mAbs) • Dosage - Basiliximab • Only 2 doses given • Day 0 (2 hours before Th) • Day 4 • IV • 35kg 20mg each dose • <35kg 10mg each dose • Side effects • Hypersensitivity reactions (same CD25) • Other Information • IL-2R (CD25) blockade for 4-6weeks • Reduce Acute Cellular Rejection (ACR)

  33. Prednisolone mAbs Azathioprine MMF Ciclosporin Tacrolimus Sirolimus

  34. Prophylactic Medication • PCP • Co-trimoxazole • Anti-coagulation • Dalteparin (anti Xa levels 0.2-0.4) then aspirin • GI cover • Ranitidine • Infection • Cefotoxime • CMV • Ganciclovir/ valganciclovir

  35. Supplements • Magnesium • Magasorb magnesium citrate • Phosphate • Phosphate sandoz 

  36. NICE guidelines: Immunosuppressive therapy for renal transplantation in children and adolescents April 2006 • Basiliximab or Daclizumab • used as part of ciclosporin-based immunosuppressive regimen • Tacrolimus • alternative to ciclosporin (side effect profile)

  37. NICE guidelines: • MMF -option ONLY when: • Proven intolerance to CNI especially nephrotoxicity • There is a very high risk of nephrotoxicity requiring the min or avoidance of CNI until risk has passed • MMF- RCT for steroid reduction/ withdrawal regimen • MPS- not recommended • Sirolimus- not recommended unless: • Proven intolerance to CNI (complete withdrawal)

  38. RHSC Renal Unit Transplant Guidelines • Azathioprine/ Prednisolone & Tacrolimus • +/- Basiliximab • MMF/ Prednisolone(rapid reduction) & Ciclosporin • +/- Basiliximab

  39. Role of Paediatric Renal Pharmacist • Transplant work-up • See everyone in the multidisciplinary team • Discuss medication • Complete change of medicines pre & post Tx • Meet once or twice pre Tx • Carefully monitor dosage post Tx • Meet as part of discharge plan from ward update RMB

  40. Twist Study • Steroid sparing regimen • see the effect on growth • Arm one • Daclizumab/ Tacrolimus/ MMF & 4 days of prednisolone post Tx • Arm two • Tacrolimus/ MMF & normal prednisolone regimen post Tx

  41. Future • Aim of immunosuppression over the next 30 years • The addition of new immunosuppressive agents in routine use • mArbs will becomes routine practice in paediatric transplantation • Steroid use will change

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