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Do we still need corticosteroids for maintenance immunosuppression after renal transplantation ?

Do we still need corticosteroids for maintenance immunosuppression after renal transplantation ?. Luca Dello Strologo Bambino Gesù Children’s Hospital Institute for Scientific Research Rome Italy. Steroids side effects. Growth impairment Fluid and electrolyte abnormalities Hypertension

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Do we still need corticosteroids for maintenance immunosuppression after renal transplantation ?

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  1. Do we still need corticosteroids for maintenance immunosuppression after renal transplantation ? Luca Dello Strologo Bambino Gesù Children’s Hospital Institute for Scientific Research Rome Italy

  2. Steroids side effects • Growth impairment • Fluid and electrolyte abnormalities • Hypertension • Hyperglycemia • Increased susceptibility to infection • Osteoporosis • Myopathy • Behavioural disturbances • Cataracts • Possible risk of peptic ulcers • Characteristic habitus including • fat redistribution • striae • ecchymoses • acne • hirsutism

  3. CNI side effects

  4. CNI: “Minor” side effects Drugs 2000 59:323-389

  5. Which poison is worse?

  6. Steroids side effects • Growth impairment • Fluid and electrolyte abnormalities • Hypertension • Hyperglycemia • Increases susceptibility to infection • Osteoporosis • Myopathy • Behavioural disturbances • Cataracts • Possible risk of peptic ulcers • Characteristic habitus including • fat redistribution • striae • ecchymoses • acne • hirsutism

  7. 1995-2006 • 153 tp • 38 pts older than 17 • 23 with syndromes associated with poor growth (cystinosis, Laurence Moon Biedl, other genetic syndromes, etc.)

  8. -0,9 -1,0 -1,1 -1,2 -1,3 -1,4 SDS for Height -1,5 -1,6 -1,7 -1,8 -1,9 -2,0 0 10 20 30 40 50 60 post-transplant follow up, months

  9. -0,9 n:51 -1,0 -1,1 -1,2 2001-2006 -1,3 -1,4 -1,5 Height SDS -1,6 -1,7 1995-2000 -1,8 -1,9 n:42 -2,0 0 10 20 30 40 50 60 Time post-transplant (months)

  10. 0,5 0,0 -0,5 < 7 years of age at transplant -1,0 -1,5 HSDS > 7 years of age at transplant -2,0 -2,5 -3,0 -3,5 0 10 20 30 40 50 60 months, post transplantation

  11. 18 16 14 12 p: n.s. 10 age at transplantation 8 6 4 2 0 1995-2000 2001-2006 period of transplantation

  12. Patients < 7 years of age at tp 2001-2006 1995-2000 Height SDS Time post-transplant (months)

  13. Patients > 7 years of age at tp -0,8 -1,0 -1,2 2001-2006 -1,4 -1,6 -1,8 Height SDS -2,0 1995-2000 -2,2 -2,4 -2,6 0 10 20 30 40 50 60 Time post-transplant (months)

  14. 5 P<0.001 4 P: 0.035 3 Time to alternate day steroids Post transplant years 2 1 0 2003-2006 1995-2000 2001-2006

  15. Rejection free rate 100 N: 75 90 80 70 N: 45 60 % 50 40 ALG + azathioprine 30 basiliximab + MMF 20 10 0 0 50 100 150 200 250 300 350 400 post-transplant follow up, days

  16. Am J Transplant 2008; 8: 574–585

  17. Rejection treatment: 500 – 1000 mg ev for three days Am J Transpl 2008; 8: 307–316

  18. Long term outcome without steroids • 1992: significant worse outcome 5 year after withdrawal (Sinclair Can Med Assoc J:147(5)645-657) • 2005: outcome comparable to historical cohort (different drugs!) (Matas Am J transplant 5:2473-8)

  19. osteopenia • Similar bone density 3 months after transplantation (low dosage steroid vs no steroid) (Transpl int 2003. 16:82-7) • Very mild benefit on the lumbar spine after one year (Transplantation 2004. 78 101-6)

  20. CNI nephrotoxicity

  21. Renal function in CsA treated heart transplanted children 140 120 2 100 ml/min/1.73 m 80 60 40 0 20 40 60 80 100 120 follow up, months Dello Strologo et al Pediatr Nephrol. 2006 21:561-5

  22. CNI minimization protocols • 2004 105 pts MMF + steroids and stop or reduce CsA or TAC(Weir: Am J Nephrol. ;24 :379-86) • 2004: 110 pts CsA + Everolimus + steroids(Nashan Transplantation. 2004 Nov 15;78(9):1332-40) • 2007: 1645 pts: MMF + steroids and low dose CsA/TAC or sirolimus(Ekberg New Engl J Med 357:2562-75) • 2007: 536 pts: MMF + steroids + CsA minimization(Ekberg Am J Transpl 7: 560–570) • 2008: 19 children everolimus + CsA +steroids(Ettenger Pediatr Transplantation 12: 456–463

  23. nephrotoxicity • Animal models suggest prednisone may protect from CNI-induced nephrotoxicity (Exp. Nephrol 1997 5:61-8) • A randomized study in humans showed a lower incidence of CNI-induced nephrotoxicity in patients on steroid maintenance (n:34) vs patients with early steroid withdrawal (n:35) (Surgery 2005 137:364-71)

  24. nephrotoxicity • CNI + MMF • PSI + low dose (or without) CNI + steroid • Which kidney will last longer?

  25. summary • IS is needed to protect the graft • All IS drugs have side effects • Steroids provide a low rejection rate even when used to a low dose • Rejections are treated with high dosages of steroids • Steroids are used in a wide range of diseases and we have learned to manage their toxicity.

  26. conclusions • We should aim at a steroid-free IS in the future • Currently, low doses of steroids on alternate day are effective and have limited side effects. • Steroids allow to minimize the dosages of the other immunosuppressive drugs

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