CNI toxicity and mTOR inhibitors or the old switcheroo

or the old switcheroo

51F ESRF Li nephrotoxicityuP:Cr 151 late 07BG depression, hypertensionPD 6/12LR renal allograft Apr 09

4/6 mismatchCMV+ donor, CMV- recipient1500mL blood loss Induction:

Basiliximab Tacrolimus Mycophenolate

Cr 110 Tac3/2 (level 8), MMF 750 bd, Pred

10NODAT on gliclazide MRHypertension BP148/91 on

lercanidipineMild leucopaenia PTH 35 uP:Cr 100

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

49MESRF IgA disease1 year CAPDCardiomyopathyCadaveric heart and kidney

transplant 93

Recurrent IgA 01Proteinuria 300mg daily DyslipidaemiaStatin induced myositis, atorvastatin

okGoutSCC +++ including faceHernia repair

Cr 120Good LV functionuP:Cr 12CsA 50 bd, MMF 750/500, pred 5

Biopsy…

Prominent arteriolar hyaline thickening

Mild tubular atrophy“Favours cyclosporine toxicity”C4d, BK negative

Switch to everolimus

Immunosuppression biologyCalcineurin inhibitorsCNI toxicitymTOR inhibitorsSwitching

Suppress rejectionUndesired immunodeficiency

Infection Cancer

Non-immune toxicity

CyclosporinTacrolimus

HypertensionHyperlipidaemiaGum hypertrophyHirsutismTremorNODAT

NephrotoxicityHUS

NODATTremorHypertensionHyperlipidaemiaCosmetic changes

NephrotoxicityHUS

Acute• Vasoconstriction• ATN

Chronic• Arteriolar hyalinosis• Striped fibrosis• Tubular vacuolisation

SirolimusEverolimus

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

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)

Derivative of sirolimusVery similar profile

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

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

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

small

Two trials this year (n=137)Biopsy proven chronic CNI toxicitySwitched 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

Inhibitors of mTOR are safe, effective Valid alternative for CNI toxicityOutside this group renal benefits

small: Non-renal benefits may be persuasive

Go early if you go at allVigilant for side effects