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Do we still need corticosteroids for maintenance immunosuppression after renal transplantation ? Luca Dello Strologo Bambino Gesù Childrens Hospital Institute.

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Presentation on theme: "Do we still need corticosteroids for maintenance immunosuppression after renal transplantation ? Luca Dello Strologo Bambino Gesù Childrens Hospital Institute."— Presentation transcript:

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

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

3 CNI side effects TACCsA Nephrotoxicity+++++ Neurotoxicity+++ Diabetes+++ Hypertension+++++ Hyperlipidemia±++

4 CNI: Minor side effects Side Effect CsA(%)TAC(%) Acne103 CsA > TAC Alopecia1-611-20 CsA < TAC Anaemia17-3817-47 CsA = TAC GUM Hyperplasia 5-60.5-1 CsA > TAC Hirsutism9-310-7 Pruritus7-2015-36 CsA < TAC Tremor12-4635-56 Drugs 2000 59:323-389

5 Which poison is worse?

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

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

8 0102030405060 -2,0 -1,9 -1,8 -1,7 -1,6 -1,5 -1,4 -1,3 -1,2 -1,1 -1,0 -0,9 SDS for Height post-transplant follow up, months

9 1995-2000 2001-2006 0102030405060 -2,0 -1,9 -1,8 -1,7 -1,6 -1,5 -1,4 -1,3 -1,2 -1,1 -1,0 -0,9 Height SDS Time post-transplant (months) n:51 n:42

10 0102030405060 -3,5 -3,0 -2,5 -2,0 -1,5 -1,0 -0,5 0,0 0,5 HSDS months, post transplantation < 7 years of age at transplant > 7 years of age at transplant

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

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

13 0102030405060 -2,6 -2,4 -2,2 -2,0 -1,8 -1,6 -1,4 -1,2 -1,0 -0,8 1995-2000 2001-2006 Height SDS Time post-transplant (months) Patients > 7 years of age at tp

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

15 050100150200250300350400 0 10 20 30 40 50 60 70 80 90 100 % post-transplant follow up, days ALG + azathioprine basiliximab + MMF Rejection free rate N: 75 N: 45

16

17 Am J Transplant 2008; 8: 574–585

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

19 Long term outcome without steroids 1992: significant worse outcome 5 year after withdrawal 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!) 2005: outcome comparable to historical cohort (different drugs!) (Matas Am J transplant 5:2473-8)

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

21 CNI nephrotoxicity

22 020406080100120 40 60 80 100 120 140 ml/min/1.73 m 2 follow up, months Dello Strologo et al Pediatr Nephrol. 2006 21:561-5 Renal function in CsA treated heart transplanted children

23 CNI minimization protocols 2004 105 pts MMF + steroids and stop or reduce CsA or TAC (Weir: Am J Nephrol. ;24 :379-86) 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) 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: 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) 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 2008: 19 children everolimus + CsA +steroids (Ettenger Pediatr Transplantation 12: 456–463

24 nephrotoxicity Animal models suggest prednisone may protect from CNI-induced nephrotoxicity (Exp. Nephrol 1997 5:61-8) 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) 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)

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

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

27 conclusions We should aim at a steroid-free IS in the future 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. 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 Steroids allow to minimize the dosages of the other immunosuppressive drugs


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