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  Tacrolimus  Mycophenolate

@ 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

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

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

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

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

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

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

Acute cellular rejection

C4d staining

Immunosuppression effects  Suppress rejection  Undesired immunodeficiency  Infection  Cancer  Non-immune toxicity

Calcineurin inhibitors  Cyclosporin  Tacrolimus

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

Tacrolimus side effects  NODAT  Tremor  Hypertension  Hyperlipidaemia  Cosmetic changes  Nephrotoxicity  HUS

CNI toxicity  Acute Vasoconstriction ATN  Chronic Arteriolar hyalinosis Striped fibrosis Tubular vacuolisation

CNI vasculopathy

“striped fibrosis”

CNI tubulopathy

Inhibitors of mTOR  Sirolimus  Everolimus

Sirolimus (Rapamune) 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

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)

Everolimus (Certican)  Derivative of sirolimus  Very similar profile

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

Outcomes: safe and effective 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

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

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

The hidden cost DrugAnnual cost ($) Prednegligible 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

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