1 / 35

CNI toxicity and mTOR inhibitors

CNI toxicity and mTOR inhibitors. or the old switcheroo. Case 1: MV. 51F ESRF Li nephrotoxicity uP:Cr 151 late 07 BG depression, hypertension PD 6/12 LR renal allograft Apr 09. Transplantation. 4/6 mismatch CMV+ donor, CMV- recipient 1500mL blood loss Induction: Basiliximab

lundy
Télécharger la présentation

CNI toxicity and mTOR inhibitors

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. CNI toxicity and mTOR inhibitors or the old switcheroo

  2. Case 1: MV 51F ESRF Li nephrotoxicity uP:Cr 151 late 07 BG depression, hypertension PD 6/12 LR renal allograft Apr 09

  3. Transplantation • 4/6 mismatch • CMV+ donor, CMV- recipient • 1500mL blood loss • Induction: • Basiliximab • Tacrolimus • Mycophenolate

  4. @ 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 uP:Cr 100

  5. 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

  6. Case 2: SD 49M ESRF IgA disease 1 year CAPD Cardiomyopathy Cadaveric heart and kidney transplant 93

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

  8. State of play Cr 120 Good LV function uP:Cr 12 CsA 50 bd, MMF 750/500, pred 5 Biopsy…

  9. Biopsy Prominent arteriolar hyaline thickening Mild tubular atrophy “Favours cyclosporine toxicity” C4d, BK negative Switch to everolimus

  10. Immunosuppression biology Calcineurin inhibitors CNI toxicity mTOR inhibitors Switching

  11. Acute cellular rejection

  12. C4d staining

  13. Immunosuppression effects • Suppress rejection • Undesired immunodeficiency • Infection • Cancer • Non-immune toxicity

  14. Calcineurin inhibitors Cyclosporin Tacrolimus

  15. Cyclosporine side effects Hypertension Hyperlipidaemia Gum hypertrophy Hirsutism Tremor NODAT Nephrotoxicity HUS

  16. Tacrolimus side effects NODAT Tremor Hypertension Hyperlipidaemia Cosmetic changes Nephrotoxicity HUS

  17. CNI toxicity • Acute • Vasoconstriction • ATN • Chronic • Arteriolar hyalinosis • Striped fibrosis • Tubular vacuolisation

  18. CNI vasculopathy

  19. “striped fibrosis”

  20. CNI tubulopathy

  21. Inhibitors of mTOR Sirolimus Everolimus

  22. 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

  23. 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)

  24. Everolimus (Certican) Derivative of sirolimus Very similar profile

  25. Switching • 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

  26. 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

  27. Conclusion • If you are going to switch, do it early • GFR >40 • No proteinuria • Benefits in terms of renal function are small

  28. Switching for CNI toxicity • 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

  29. The hidden cost

  30. 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

More Related