CNI toxicity and mTOR inhibitors or the old switcheroo.
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Transcript of CNI toxicity and mTOR inhibitors or the old switcheroo.
or the old switcheroo
51F ESRF Li nephrotoxicityuP:Cr 151 late 07BG depression, hypertensionPD 6/12LR renal allograft Apr 09
4/6 mismatchCMV+ donor, CMV- recipient1500mL blood loss Induction:
Basiliximab Tacrolimus Mycophenolate
Cr 110 Tac3/2 (level 8), MMF 750 bd, Pred
10NODAT on gliclazide MRHypertension BP148/91 on
lercanidipineMild leucopaenia PTH 35 uP:Cr 100
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
49MESRF IgA disease1 year CAPDCardiomyopathyCadaveric heart and kidney
transplant 93
Recurrent IgA 01Proteinuria 300mg daily DyslipidaemiaStatin induced myositis, atorvastatin
okGoutSCC +++ including faceHernia repair
Cr 120Good LV functionuP:Cr 12CsA 50 bd, MMF 750/500, pred 5
Biopsy…
Prominent arteriolar hyaline thickening
Mild tubular atrophy“Favours cyclosporine toxicity”C4d, BK negative
Switch to everolimus
Immunosuppression biologyCalcineurin inhibitorsCNI toxicitymTOR inhibitorsSwitching
Suppress rejectionUndesired immunodeficiency
Infection Cancer
Non-immune toxicity
CyclosporinTacrolimus
HypertensionHyperlipidaemiaGum hypertrophyHirsutismTremorNODAT
NephrotoxicityHUS
NODATTremorHypertensionHyperlipidaemiaCosmetic changes
NephrotoxicityHUS
Acute• Vasoconstriction• ATN
Chronic• Arteriolar hyalinosis• Striped fibrosis• Tubular vacuolisation
SirolimusEverolimus
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
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)
Derivative of sirolimusVery similar profile
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
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
If you are going to switch, do it early GFR >40 No proteinuria Benefits in terms of renal function are
small
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
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
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