cni toxicity and mtor inhibitors or the old switcheroo
TRANSCRIPT
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or the old switcheroo
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51F ESRF Li nephrotoxicityuP:Cr 151 late 07BG depression, hypertensionPD 6/12LR renal allograft Apr 09
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4/6 mismatchCMV+ donor, CMV- recipient1500mL blood loss Induction:
Basiliximab Tacrolimus Mycophenolate
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Cr 110 Tac3/2 (level 8), MMF 750 bd, Pred
10NODAT on gliclazide MRHypertension BP148/91 on
lercanidipineMild leucopaenia PTH 35 uP:Cr 100
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Cr 99 to 132 = Biopsy:
ATN, mild interstitial fibrosis, tubular atrophy
C4d, BK negative No rejection/CNI tox
ACEI (normal doppler) and ↑Ca but…Switch to sirolimus
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49MESRF IgA disease1 year CAPDCardiomyopathyCadaveric heart and kidney
transplant 93
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Recurrent IgA 01Proteinuria 300mg daily DyslipidaemiaStatin induced myositis, atorvastatin
okGoutSCC +++ including faceHernia repair
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Cr 120Good LV functionuP:Cr 12CsA 50 bd, MMF 750/500, pred 5
Biopsy…
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Prominent arteriolar hyaline thickening
Mild tubular atrophy“Favours cyclosporine toxicity”C4d, BK negative
Switch to everolimus
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Immunosuppression biologyCalcineurin inhibitorsCNI toxicitymTOR inhibitorsSwitching
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Suppress rejectionUndesired immunodeficiency
Infection Cancer
Non-immune toxicity
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CyclosporinTacrolimus
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HypertensionHyperlipidaemiaGum hypertrophyHirsutismTremorNODAT
NephrotoxicityHUS
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NODATTremorHypertensionHyperlipidaemiaCosmetic changes
NephrotoxicityHUS
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Acute• Vasoconstriction• ATN
Chronic• Arteriolar hyalinosis• Striped fibrosis• Tubular vacuolisation
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SirolimusEverolimus
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SIDE EFFECTS Hyperlipidaemia Thrombocytopaenia Anaemia Diarrhoea Impaired wound
healing Lymphocoele Proteinuria Mouth ulcers Oedema Acne Pneumonitis
BENEFITS Antineoplastic Arterial protection May reduce CMV
No CNI toxicity
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Renal transplantation With CNI CNI-free or CNI-sparing regimen Switching from CNI
Non-renal uses Transplant: heart, lung, liver, islet cell GVHD prophylaxis (HSCT) Drug eluting stents Thrombotic microangiopathy Oncology (temsirolimus)
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Derivative of sirolimusVery similar profile
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The CONVERT trial (Transplantation Jan 09) >800 patients >6/12 post transplant On CsA or Tac Continue 1 : 2 Convert
Primary endpoints GFR BCAR Graft loss Death
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BENEFITS Equivalent:
GFR (ITT) BCAR Patient survival Graft survival
Malignancy decreased Total (3.8 v 11%) Skin (2.2 v 7.7%)
NEGATIVES Proteinuria Infection
Pneumonia (12.7 v 5.1%)
HSV (8.7 v 4.4%) Anaemia (36.3 v
16.5%) Thrombocytopaenia
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If you are going to switch, do it early GFR >40 No proteinuria Benefits in terms of renal function are
small
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Two trials this year (n=137)Biopsy proven chronic CNI toxicitySwitched to SRL+MMF+pred (no
loading)Outcomes:
Best for GFR>40, mild CNI toxicity 90% graft survival but many adverse
events
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Drug Annual cost ($)
Pred negligible
MMF (500 bd) 3,000
CsA (200mg daily) 4,750
Tac (4mg daily) 6,000
SRL (3mg daily) 8,400
Ritux (4 doses) 13,500
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Inhibitors of mTOR are safe, effective Valid alternative for CNI toxicityOutside this group renal benefits
small: Non-renal benefits may be persuasive
Go early if you go at allVigilant for side effects