CNI toxicity and mTOR inhibitors

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CNI toxicity and mTOR inhibitors

• or the old switcheroo

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Case 1 MV

• 51F
• ESRF Li nephrotoxicity
• uPCr 151 late 07
• BG depression, hypertension
• PD 6/12
• LR renal allograft Apr 09

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Transplantation

• 4/6 mismatch
• CMV donor, CMV- recipient
• 1500mL blood loss
• Induction
• Basiliximab
• Tacrolimus
• Mycophenolate

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_at_ 3 months

• Cr 110
• Tac3/2 (level 8), MMF 750 bd, Pred 10
• NODAT on gliclazide MR
• Hypertension BP148/91 on lercanidipine
• Mild leucopaenia
• PTH 35
• uPCr 100

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Bump along the way

• 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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Case 2 SD

• 49M
• ESRF IgA disease
• 1 year CAPD
• Cardiomyopathy
• Cadaveric heart and kidney transplant 93

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Progress

• Recurrent IgA 01
• Proteinuria 300mg daily
• Dyslipidaemia
• Statin induced myositis, atorvastatin ok
• Gout
• SCC including face
• Hernia repair

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State of play

• Cr 120
• Good LV function
• uPCr 12
• CsA 50 bd, MMF 750/500, pred 5
• Biopsy

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Biopsy

• Prominent arteriolar hyaline thickening
• Mild tubular atrophy
• Favours cyclosporine toxicity
• C4d, BK negative
• Switch to everolimus

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• Immunosuppression biology
• Calcineurin inhibitors
• CNI toxicity
• mTOR inhibitors
• Switching

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Acute cellular rejection
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C4d staining
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Immunosuppression effects

• Suppress rejection
• Undesired immunodeficiency
• Infection
• Cancer
• Non-immune toxicity

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Calcineurin inhibitors

• Cyclosporin
• Tacrolimus

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Cyclosporine side effects

• Hypertension
• Hyperlipidaemia
• Gum hypertrophy
• Hirsutism
• Tremor
• NODAT
• Nephrotoxicity
• HUS

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Tacrolimus side effects

• NODAT
• Tremor
• Hypertension
• Hyperlipidaemia
• Cosmetic changes
• Nephrotoxicity
• HUS

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CNI toxicity

• Acute
• Vasoconstriction
• ATN
• Chronic
• Arteriolar hyalinosis
• Striped fibrosis
• Tubular vacuolisation

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CNI vasculopathy
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striped fibrosis
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CNI tubulopathy
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Inhibitors of mTOR

• Sirolimus
• Everolimus

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Sirolimus (Rapamune)

• SIDE EFFECTS

• BENEFITS

• Hyperlipidaemia
• Thrombocytopaenia
• Anaemia
• Diarrhoea
• Impaired wound healing
• Lymphocoele
• Proteinuria
• Mouth ulcers
• Oedema
• Acne
• Pneumonitis

• Antineoplastic
• Arterial protection
• May reduce CMV
• No CNI toxicity

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Sirolimus usage

• 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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Everolimus (Certican)

• Derivative of sirolimus
• Very similar profile

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Switching

• The CONVERT trial (Transplantation Jan 09)
• gt800 patients
• gt6/12 post transplant
• On CsA or Tac
• Continue 1 2 Convert
• Primary endpoints
• GFR
• BCAR
• Graft loss
• Death

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Outcomes safe and effective

• BENEFITS

• NEGATIVES

• Equivalent
• GFR (ITT)
• BCAR
• Patient survival
• Graft survival
• Malignancy decreased
• Total (3.8 v 11)
• Skin (2.2 v 7.7)

• 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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Conclusion

• If you are going to switch, do it early
• GFR gt40
• No proteinuria
• Benefits in terms of renal function are small

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Switching for CNI toxicity

• Two trials this year (n137)
• Biopsy proven chronic CNI toxicity
• Switched to SRLMMFpred (no loading)
• Outcomes
• Best for GFRgt40, mild CNI toxicity
• 90 graft survival but many adverse events

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The hidden cost
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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Summary

• Inhibitors of mTOR are safe, effective
• Valid alternative for CNI toxicity
• Outside this group renal benefits small
• Non-renal benefits may be persuasive
• Go early if you go at all
• Vigilant for side effects