Transcript CNI toxicity and mTOR inhibitors by Dr Angus Ritchie

or the old switcheroo
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51F
ESRF Li nephrotoxicity
uP:Cr 151 late 07
BG depression, hypertension
PD 6/12
LR renal allograft Apr 09
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4/6 mismatch
CMV+ donor, CMV- recipient
1500mL blood loss
Induction:
 Basiliximab
 Tacrolimus
 Mycophenolate
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Cr 110
Tac3/2 (level 8), MMF 750 bd, Pred 10
NODAT on gliclazide MR
Hypertension BP148/91 on lercanidipine
Mild 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
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ACEI (normal doppler) and ↑Ca but…
Switch to sirolimus
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49M
ESRF IgA disease
1 year CAPD
Cardiomyopathy
Cadaveric heart and kidney transplant 93
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Recurrent IgA 01
Proteinuria 300mg daily
Dyslipidaemia
Statin induced myositis, atorvastatin ok
Gout
SCC +++ including face
Hernia repair
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Cr 120
Good LV function
uP:Cr 12
CsA 50 bd, MMF 750/500, pred 5
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Biopsy…
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Prominent arteriolar hyaline thickening
Mild tubular atrophy
“Favours cyclosporine toxicity”
C4d, BK negative
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Switch to everolimus
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Immunosuppression biology
Calcineurin inhibitors
CNI toxicity
mTOR inhibitors
Switching
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Suppress rejection
Undesired immunodeficiency
 Infection
 Cancer
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Non-immune toxicity
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Cyclosporin
Tacrolimus
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Hypertension
Hyperlipidaemia
Gum hypertrophy
Hirsutism
Tremor
NODAT
Nephrotoxicity
HUS
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NODAT
Tremor
Hypertension
Hyperlipidaemia
Cosmetic changes
Nephrotoxicity
HUS
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Acute
• Vasoconstriction
• ATN
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Chronic
• Arteriolar hyalinosis
• Striped fibrosis
• Tubular vacuolisation
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Sirolimus
Everolimus
SIDE EFFECTS
 Hyperlipidaemia
 Thrombocytopaenia
 Anaemia
 Diarrhoea
 Impaired wound healing
 Lymphocoele
 Proteinuria
 Mouth ulcers
 Oedema
 Acne
 Pneumonitis
BENEFITS
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Antineoplastic
Arterial protection
May reduce CMV
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No CNI toxicity
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Renal transplantation
 With CNI
 CNI-free or CNI-sparing regimen
 Switching from CNI
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Non-renal uses
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Transplant: heart, lung, liver, islet cell
GVHD prophylaxis (HSCT)
Drug eluting stents
Thrombotic microangiopathy
Oncology (temsirolimus)
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Derivative of sirolimus
Very similar profile
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The CONVERT trial (Transplantation Jan 09)
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>800 patients
>6/12 post transplant
On CsA or Tac
Continue 1 : 2 Convert
Primary endpoints
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GFR
BCAR
Graft loss
Death
BENEFITS
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Equivalent:
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 GFR (ITT)
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Proteinuria
Infection
 BCAR
 Pneumonia (12.7 v 5.1%)
 Patient survival
 HSV (8.7 v 4.4%)
 Graft survival
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NEGATIVES
Malignancy decreased
 Total (3.8 v 11%)
 Skin (2.2 v 7.7%)
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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 toxicity
Switched 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
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Inhibitors of mTOR are safe, effective
Valid alternative for CNI toxicity
Outside this group renal benefits small:
 Non-renal benefits may be persuasive
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Go early if you go at all
Vigilant for side effects