Do we still need Do we still need corticosteroids for corticosteroids for

maintenance maintenance immunosuppression after immunosuppression after renal transplantation ?renal transplantation ?

Luca Dello StrologoLuca Dello StrologoBambino Gesù Children’s HospitalBambino Gesù Children’s HospitalInstitute for Scientific Research Institute for Scientific Research

Rome ItalyRome Italy

Steroids side effectsSteroids side effects Growth impairmentGrowth impairment Fluid and electrolyte abnormalities Fluid and electrolyte abnormalities Hypertension Hypertension HyperglycemiaHyperglycemia Increased susceptibility to infectionIncreased susceptibility to infection OsteoporosisOsteoporosis MyopathyMyopathy Behavioural disturbancesBehavioural disturbances CataractsCataracts Possible risk of peptic ulcersPossible risk of peptic ulcers Characteristic habitus including Characteristic habitus including

fat redistributionfat redistribution striae striae ecchymoses ecchymoses acne acne hirsutismhirsutism

CNI side effectsCNI side effects

TACTAC CsACsA

NephrotoxicitNephrotoxicityy

++++ ++++++

NeurotoxicityNeurotoxicity ++++ ++

DiabetesDiabetes ++++ ++

HypertensionHypertension ++++ ++++++

HyperlipidemiHyperlipidemiaa

±± ++++

CNI: “Minor” side effects CNI: “Minor” side effects

Side EffectSide EffectCsACsA

(%)(%)TACTAC

(%)(%)

AcneAcne 1010 33 CsA > TACCsA > TAC

AlopeciaAlopecia 1-61-6 11-2011-20 CsA < TACCsA < TAC

AnaemiaAnaemia 17-3817-38 17-4717-47 CsA = TACCsA = TAC

GUM GUM Hyperplasia Hyperplasia 5-65-6 0.5-10.5-1 CsA > TACCsA > TAC

HirsutismHirsutism 9-319-31 0-70-7 CsA > TACCsA > TAC

PruritusPruritus 7-207-20 15-3615-36 CsA < TACCsA < TAC

TremorTremor 12-4612-46 35-35-5656 CsA < TACCsA < TAC

Drugs 2000 59:323-389

Which poison is worse?Which poison is worse?

Steroids side effectsSteroids side effects Growth impairment Growth impairment Fluid and electrolyte abnormalities Fluid and electrolyte abnormalities Hypertension Hypertension HyperglycemiaHyperglycemia Increases susceptibility to infectionIncreases susceptibility to infection OsteoporosisOsteoporosis MyopathyMyopathy Behavioural disturbancesBehavioural disturbances CataractsCataracts Possible risk of peptic ulcersPossible risk of peptic ulcers Characteristic habitus including Characteristic habitus including

fat redistributionfat redistribution striae striae ecchymoses ecchymoses acne acne hirsutismhirsutism

1995-20061995-2006

153 tp153 tp 38 pts older than 1738 pts older than 17 23 with syndromes associated with 23 with syndromes associated with

poor growth (cystinosis, Laurence poor growth (cystinosis, Laurence Moon Biedl, other genetic Moon Biedl, other genetic syndromes, etc.)syndromes, etc.)

0 10 20 30 40 50 60

-2,0

-1,9

-1,8

-1,7

-1,6

-1,5

-1,4

-1,3

-1,2

-1,1

-1,0

-0,9S

DS

for

He

igh

t

post-transplant follow up, months

1995-2000

2001-2006

0 10 20 30 40 50 60

-2,0

-1,9

-1,8

-1,7

-1,6

-1,5

-1,4

-1,3

-1,2

-1,1

-1,0

-0,9H

eig

ht S

DS

Time post-transplant (months)

n:51

n:42

0 10 20 30 40 50 60

-3,5

-3,0

-2,5

-2,0

-1,5

-1,0

-0,5

0,0

0,5H

SD

S

months, post transplantation

< 7 years of age at transplant

> 7 years of age at transplant

0

2

4

6

8

10

12

14

16

18ag

e at

tra

nspl

anta

tion

period of transplantation

1995-2000 2001-2006

p: n.s.

0 10 20 30 40 50 60-1,4

-1,2

-1,0

-0,8

-0,6

-0,4

-0,2

0,0

0,2

1995-2000

2001-2006

He

igh

t SD

S

Time post-transplant (months)

Patients < 7 years of age at tp

0 10 20 30 40 50 60

-2,6

-2,4

-2,2

-2,0

-1,8

-1,6

-1,4

-1,2

-1,0

-0,8

1995-2000

2001-2006

He

igh

t SD

S

Time post-transplant (months)

Patients > 7 years of age at tp

P<0.001

P: 0.035

0

1

2

3

4

5

Pos

t tr

ansp

lant

yea

rs

Tim

e to

alte

rnat

e da

y st

eroi

ds

1995-2000 2001-2006 2003-2006

0 50 100 150 200 250 300 350 4000

10

20

30

40

50

60

70

80

90

100%

post-transplant follow up, days

ALG + azathioprine

basiliximab + MMF

Rejection free rateN: 75N: 75

N: 45N: 45

Am J Transplant 2008; 8: 574–585

Am J Transpl 2008; 8: 307–316

Rejection treatment: 500 – 1000 mg ev for three daysRejection treatment: 500 – 1000 mg ev for three days

Long term outcome without Long term outcome without steroidssteroids

1992: significant worse outcome 5 1992: significant worse outcome 5 year after withdrawal year after withdrawal (Sinclair Can Med Assoc J:147(5)645-657)(Sinclair Can Med Assoc J:147(5)645-657)

2005: outcome comparable to 2005: outcome comparable to historical cohort (different drugs!)historical cohort (different drugs!)(Matas Am J transplant 5:2473-8)(Matas Am J transplant 5:2473-8)

osteopeniaosteopenia

Similar bone density 3 months after Similar bone density 3 months after transplantation (low dosage steroid transplantation (low dosage steroid vs no steroid) vs no steroid) (Transpl int 2003. 16:82-7)(Transpl int 2003. 16:82-7)

Very mild benefit on the lumbar Very mild benefit on the lumbar spine after one year spine after one year (Transplantation (Transplantation 2004. 78 101-6)2004. 78 101-6)

CNI nephrotoxicityCNI nephrotoxicity

0 20 40 60 80 100 12040

60

80

100

120

140m

l/min

/1.7

3 m

2

follow up, monthsDello Strologo et al Pediatr Nephrol. 2006 21:561-5

Renal function in CsA treated heart transplanted children

CNI minimization protocolsCNI minimization protocols

2004 105 pts MMF + 2004 105 pts MMF + steroidssteroids and stop or reduce CsA and stop or reduce CsA or TACor TAC (Weir: (Weir: Am J Nephrol. ;24 :379-86)Am J Nephrol. ;24 :379-86)

2004: 110 pts CsA + Everolimus + 2004: 110 pts CsA + Everolimus + steroidssteroids (Nashan (Nashan Transplantation. 2004 Nov 15;78(9):1332-40)Transplantation. 2004 Nov 15;78(9):1332-40)

2007: 1645 pts: MMF + 2007: 1645 pts: MMF + steroidssteroids and low dose and low dose CsA/TAC or sirolimusCsA/TAC or sirolimus (Ekberg New Engl J Med 357:2562-75)(Ekberg New Engl J Med 357:2562-75)

2007: 536 pts: MMF + 2007: 536 pts: MMF + steroids steroids + CsA minimization+ CsA minimization (Ekberg (Ekberg Am J Transpl 7: 560–570)Am J Transpl 7: 560–570)

2008: 19 children everolimus + CsA +2008: 19 children everolimus + CsA +steroidssteroids (Ettenger (Ettenger Pediatr Transplantation 12: 456–463Pediatr Transplantation 12: 456–463

nephrotoxicitynephrotoxicity

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

A randomized study in humans A randomized study in humans showed a lower incidence of CNI-showed a lower incidence of CNI-induced nephrotoxicity in patients on induced nephrotoxicity in patients on steroid maintenance (n:34) vs steroid maintenance (n:34) vs patients with early steroid withdrawal patients with early steroid withdrawal (n:35) (n:35) (Surgery 2005 137:364-71)(Surgery 2005 137:364-71)

nephrotoxicitynephrotoxicity

CNI + MMFCNI + MMF PSI + low dose (or without) CNI + PSI + low dose (or without) CNI +

steroidsteroid Which kidney will last longer?Which kidney will last longer?

summarysummary IS is needed to protect the graftIS is needed to protect the graft All IS drugs have side effectsAll IS drugs have side effects Steroids provide a low rejection rate even Steroids provide a low rejection rate even

when used to a low dosewhen used to a low dose Rejections are treated with high dosages Rejections are treated with high dosages

of steroidsof steroids Steroids are used in a wide range of Steroids are used in a wide range of

diseases and we have learned to manage diseases and we have learned to manage their toxicity. their toxicity.

conclusionsconclusions

We should aim at a steroid-free IS in the We should aim at a steroid-free IS in the futurefuture

Currently, low doses of steroids on Currently, low doses of steroids on alternate day are effective and have alternate day are effective and have limited side effects. limited side effects.

Steroids allow to minimize the dosages of Steroids allow to minimize the dosages of the the other other immunosuppressive drugs immunosuppressive drugs