CNI toxicity and mTOR inhibitors

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

14. Acute cellular rejection

15. C4d staining

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

17. Calcineurin inhibitors Cyclosporin Tacrolimus

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

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

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

22. CNI vasculopathy

23. “striped fibrosis”

24. CNI tubulopathy

25. Inhibitors of mTOR Sirolimus Everolimus

27. 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

28. 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)

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

30. 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

31. 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

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

33. 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

34. The hidden cost

35. 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