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Do we still need corticosteroids for maintenance immunosuppression
after renal transplantation?Con
Burkhard Tönshoff University Children‘s Hospital
Heidelberg, Germany
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The Steroid Problem: Multifaceted toxicity
Poor growth Cushingoid habitus, acne
as risk factors for non-adherence Calcium loss, bone demineralization Hypertension Lipid abnormalities, chronic graft atherosclerosis Diabetes mellitus Depression-mood swings Cataracts
Non-immune triggers of CR
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Treatment strategies to minimize glucocorticoids in pediatric renal transplantation
Steroid avoidance Early steroid withdrawal Late steroid withdrawal (>1 year posttransplant)
The success of corticosteroid withdrawal may depend in part upon the effectiveness of the remaining agents that constitute the immunosuppressive regimen and the right patients selection (“one size does not fit all”)
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NIH Multicenter Randomized Study of Steroid-Free vs. Steroid-Based Rx n=130; Stanford protocol; ATC 2008
130 unsensitized primary pediatric renal transplant recipients randomized 1:1 to:
1. Steroid-free arm: Daclizumab 10 mg/kg over 9 doses + Tacrolimus + MMF
2. Steroid-based arm: Daclizumab 5 mg/kg over 4 doses + Tacrolimus + MMF + Steroids
24.1% of steroid-free and 27.5% of steroid-based patients were African Americans.
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Steroid-freeN=60
Steroid-basedN=70
P value
Patient survival 100% 100% n.s.
Graft survival 96.7% 98.6% n.s.
Height SDS 0.34 SDS 0.34 SDS n.s.
BPAR 23.3% 21.4% n.s
Calculated GFRml/min/1.73 m²
90.0 90.6 n.s.
Percent first hospitalization
55% 70% n.s.
Neoplasms 0% 6.3% n.s.
PTDM 0% 4.5% n.s.
1 Year Results Sarwal et al, ATC 2008
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Overview of strategies for steroid minimization
Steroid avoidanceEarly steroid withdrawalLate steroid withdrawal
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European Study: TWIST study design
Renal Graft Pediatric RecipientsRandomisation
MAB (2x Daclizumab) + TAC + MMF
Methylprednisolone 4 days
TAC + MMF + Steroids
Regular steroid regimen(as in previous studies)
6 months follow-upEnd Point :
-Rejection rate-steroid specific side-effects
6 months follow-upEnd Point :
-Rejection rate-steroid specific side-effects
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Overview of strategies for steroid minimization
Steroid avoidanceEarly steroid withdrawalLate steroid withdrawal
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Multicenter, open-label, prospective, randomized study on late steroid
withdrawal in children with stable renal function
on a maintenance immunosuppressive therapy with CsA and MMF
Burkhard Tönshoff, Britta Höcker, Lutz WeberUniversity Children‘s Hospital
Heidelberg, Germany
on behalf of the German Study Group on Pediatric Renal Transplantation
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Rationale
Many centers at least in Europe practice late steroid withdrawal in selected pediatric renal transplant recipients, but this approach has never been rigorously tested in a controlled prospective clinical trial.
We therefore undertook this first prospective randomized open-label multicenter trial (investigator-initiated) to address this question.
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Inclusion and exclusion criteria
Inclusion criteria: Age < 18 years Bone age ≤ 15 years in boys and ≤ 13 years in girls Time posttransplant: 12 – 24 months First or second RTx, LD or CD Triple immunosuppression at study entry: CsA, MMF, steroids Written informed consent
Exclusion criteria: Irreversible AR of an previous graft within 6 months prior to study entry PRA > 80% within 12 months prior to study entry Steroid-resistant AR, > 2 AR after RTx or > 1 AR within the last 6 months GFR < 40 mL/min*1.73 m² Serum creatinine increase > 20% within the last 6 months Biopsy-proven chronic rejection Noncompliance Other immunosuppressants Growth hormone therapy
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Patient characteristics (n=41)
ParameterSteroid withdrawal
(n = 23)Control group
(n = 18)Statistical
significance
Gender 7 girls; 16 boys 7 girls; 11 boys n.s.
Prepubertal (n = 20) 13 7 n.s.
Pubertal (n = 21) 10 11 n.s.
Age at transplantation [yr] 8.4 ± 4.7 9.8 ± 3.2 n.s.
Living/cadaveric RTx 18 CD; 5 LD 13 CD; 5 LD n.s.
Age at study entry [yr] 10.0 ± 4.4 11.5 ± 3.1 n.s.
Time period between grafting and study entry [yr]
1.53 ± 0.48 1.65 ± 0.42 n.s.
Graft function [CCr] at study
entry [mL/min*1.73 m²]105 ± 37 94 ± 20 n.s.
Body Mass Index SDS 0.80 ± 0.22 0.37 ± 0.35 n.s.
CsA dose [mg/kg*day] 5.5 ± 2.2 5.6 ± 2.1 n.s.
CsA trough level [µg/mL] 107 ± 43 107 ± 34 n.s.
MMF dose [mg/m²*day] 944 ± 369 948 ± 221 n.s.
Prednisone dose [mg/m²*day] 4.4 ± 1.5 4.6 ± 1.3 n.s.
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*p<0.05 vs. control group**p<0.005 vs. control group #p<0.05 vs. baseline##p<0.005 vs. baseline
Steroid withdrawalControl group
Time [months]
0 3 6 9 12 15 18 21 24 27
H
eig
ht
SD
S
-1.0
-0.5
0.0
0.5
1.0
* * ** **
Primary endpoint:Longitudinal growth: 2-year data (n = 28)
#
## ####
## n = 14
n = 14
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Steroid withdrawalControl group
Time [months]
0 3 6 9 12 15 18 21 24 27
B
MI S
DS
-1.2
-0.8
-0.4
0.0
0.4
0.8
#
**
# ##
**
**** *** ***
*p<0.05 vs. control group **p<0.01 vs. control group***p<0.001 vs. control group
#p<0.05 vs. baseline
Change in body mass index: 2-year data (n = 28)
n = 14
n = 14
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Body mass index SDS(mean +/- SEM)
Time [months]
0 3 6 9 12
BM
I SD
S
0
1
2
Body Mass Index
* P = 0.008 versus baseline
Beforesteroid withdrawal
One year aftersteroid withdrawal
*
Steroid withdrawal
Control group
Andreas S.
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Nu
mb
er o
f an
tih
yper
ten
sive
dru
gs
0.0
0.5
1.0
1.5
Antihypertensive drugs
Steroid withdrawalControl group
0 9 15Time [months]
3 6 12
##
# ##
#p<0.005 vs. baseline
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Serum cholesterol
Ch
ole
ster
ol [
mg
/dL
]
0
50
100
150
200
250
*p<0.01 vs. baselineSteroid withdrawalControl group
* *
0 9 15Time [months]
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Allograft function: 2-year data (n = 28)
Steroid withdrawalControl group
Time [months]
0 3 6 9 12 15 18 21 24 27
CC
r [m
L/m
in*1
.73
m²]
0
20
40
60
80
100
120
140n.s.
n = 14n = 14
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Drop-outs and treatment failure
Drop-out reason / treatment failureSteroid withdrawal
(5/23 (22%))Control group
(3/18 (17%))
Switch to mTOR inhibitor 2 (month 1 and 6) 0
MMF discontinuation 1 (month 18) 1 (month 18)
Consent withdrawal 0 2 (month 0)
Assumed AR 1 (month 12) 0
Allograft loss due to noncompliance 1 (month 33) 0
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Histology (n = 41)
Histology Steroid withdrawal (n = 23)
Control group (n = 18)
Number of biopsies 6 (26%) 4 (22%)
BPAR
● Borderline 0 1 (month 9)
● Banff IIa 0 1 (month 21)
CAN ± CsA nephrotoxicity 5 1
CsA nephrotoxicity 1 0
Unspecific changes 0 1
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Summary: Late steroid withdrawal study
In this study, late steroid withdrawal (> 1 year posttransplant) in selected pediatric renal transplant recipients on CsA and MMF over an observation period of 2 years was– Safe: No increased rate of ARE, no difference in
calculated GFR and proteinuria
– Allowed significant catch-up growth: Height gain + 1 SDS in 2 years
– Improved cardiovascular risk factors: Decrease of serum cholesterol, blood pressure, BMI
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Steroid withdrawal and cardiovascular risk factors
Obesity, hyperlipidemia and arterial hypertension are well-known cardiovascular risk factors and closely associated with steroid therapy. Cardiovascular events are among the main causes of death for both pediatric (N Engl J Med 350, 2004) and adult (Am J Kidney Dis 38, 2001) renal transplant recipients in the long-run.
Vanrenterghem et al. (Transplantation 85, 2008) recently showed that an increased long-term total steroid dose is associated with increased cardiovascular morbidity.
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Steroid withdrawal and compliance/adherence
Moreover, the improvement of body disfigurement attributable to a marked cushingoid appearance, at least in individual patients, potentially enhances their adherence to taking immunosuppressive drugs (Transplantation 26, 1990), an essential prerequisite for long-term allograft survival.
Thus, a hidden cost of steroid-related side-effects may be increased graft loss.
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Renal transplant function as primary endpoint?
Theoretically, safety should be the primary endpoint and adequately powered to show at least non-inferiority of the proposed regimen.
In order to assess the feasibility of a non-inferiority study, we calculated the sample size to provide 90% power to detect non-inferiority of GFR, in the steroid-withdrawal group compared to the standard-steroids group.
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Renal transplant function as primary endpoint?
If one considers a difference in GFR of ≤5% after one year of steroid-free IS to be non-inferior with a 15% coefficient of variation based on values from former studies performed with a standard-steroid regimen, at least 196 patients per treatment arm would be necessary for between-group comparisons made at an adjusted significance level of 5%.
Given the small number of pediatric renal transplant patients available, such a study would be impossible to conduct.
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The impact of steroid-free IS on graft function and survival: Evidence from other studies
Long-term follow-up studies on late (≥ 1 year post-transplant) steroid withdrawal with an observation period of up to four years in pediatric renal transplant recipients (Transplantation 78, 2004) and up to 7 years in a large group (n = 1110) of adult Caucasian patients (AJT 5, 2005) indicate that the rates of acute rejection and renal dysfunction did not differ between steroid-free and steroid-continuation groups.
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81.9% vs. 75.3%, p = 0.0001
88.8% vs. 84.3%, p = 0.0016
91.8% vs. 87.9%, p = 0.0091
Long-Term Prospective Study of Steroid Withdrawal in Kidney and Heart Transplant Recipients
Opelz G et al, Am J Transpl 5: 720, 2005
• Steroids were withdrawn no earlier than 6 months post-transplant.• 94% CsA, 97% Caucasian
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The impact of steroid-free IS on graft function and survival: Evidence from other studies
Recently, the 5-year results of a randomized double-blind placebo-controlled trial of early corticosteroid cessation vs. chronic corticosteroids in adults on TAC and MMF revealed that no significant differences existed in allograft survival or graft function 5 years post-transplant, but steroid withdrawal provided cardiovascular risk and bone disease benefits (Woodle S, ATC meeting 2008).
It is important to note that these differences were found despite the low prednisone dose of 5 mg per day in the steroid maintenance group after 6 months post-transplant.
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Conclusions Late (> 12 months post-transplant) steroid withdrawal is
feasible in low immunological risk patients on newer immunosuppressive drugs (MMF, TAC).
Late steroid withdrawal has the advantage over steroid avoidance that immunological high-risk patients and those with unstable graft function can easily be identified beforehand and be excluded from steroid-free immunosuppression.
Early steroid withdrawal in patients receiving antilymphocyte induction therapy is promising.
Long-term follow up is required to decide which strategy (steroid avoidance, early steroid withdrawal or late steroid withdrawal) is superior for both graft survival and patient outcome.
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Randomized Prospective Steroid Withdrawal Study German Study Group on Pediatric Renal Transplantation
27 30 33 36 39 42
0 3 6 9 12 15 18 21 24 27 months
Randomi-zation
optional steroid withdrawal
Patients at least 1 year after kidney transplantation with stable transplant function
Immunosuppre-ssion withCsA, MMF, Predn.
Branch B:control group,daily steroids
1st study phase (controlled)
2nd study phase (uncontrolled)
Branch A:steroid withdrawal
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Randomized Prospective Steroid Withdrawal Study German Study Group on Pediatric Renal Transplantation
27 30 33 36 39 42
0 3 6 9 12 15 18 21 24 27 months
Randomi-zation
optional steroid withdrawal
Patients at least 1 year after kidney transplantation with stable transplant function
Immunosuppre-ssion withCsA, MMF, Predn.
Branch B:control group,daily steroids
1st study phase (controlled)
2nd study phase (uncontrolled)
Branch A:steroid withdrawal
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Steroid-free Protocol
Immunosuppression Dosing
Drugs
Pre-op
Post-op
Tacrolimus 0.15 mg/kg/dose Trough levels (ng/ml) bid Weeks 0-1: 12-14
Mo 3: 5-7 Year 1: 3-5
MMF 600-450 mg/m²/dose bid 300 mg/m2/dose, bid
Trough levels 2-4 mg/dl
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Conclusion
In this study, late steroid withdrawal (> 1 year posttransplant) in selected pediatric renal transplant recipients on CsA and MMF over an observation period of 2 years was– safe: no difference in calculated GFR and proteinuria
– allowed significant catch-up growth: height gain +1 SDS in 2 years
– improved cardiovascular risk factors: decrease of serum cholesterol, blood pressure, BMI
Long-term follow up is required to decide which strategy (steroid avoidance, early steroid withdrawal or late steroid withdrawal) is superior for both graft survival and patient outcome in pediatric renal transplant recipients.
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Protocol
Safety and efficacy of antithymocyte globulin or alemtuzumab preconditioning, steroid avoidance and reduced CNI immunosuppression in 34 children after RTx.
ATG (n=8) or alemtuzumab (n=26), followed by low-dose twice a day tacrolimus monotherapy with consolidation to once daily dosing by 6 months and once every other day dosing by 12 months.
Follow-up ranged from 0.5–2.9 years (mean 1.33 years), with a minimum of 6 months.
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Results
Both ATG and alemtuzumab were well tolerated. Lymphopenia occurred routinely and resolved after 3–6 months.
Acute cellular rejection in 9%, related to medical nonadherence in two patients and resulted in one graft loss at 1.5 years.
AE: Transient neutropenia in 10 children (none with serious infection), and autoimmune hemolytic anemia in two.
GFR stable (88 mL/min/1.73 m² at latest follow-up. 91% catch-up growth.
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*p<0.05 vs. control group**p<0.01 vs. control group #p<0.001 vs. baseline
Steroid withdrawalControl group
Time [months]
0 3 6 9 12 15
H
eig
ht
SD
S
-1.0
-0.5
0.0
0.5
1.0
## #
* **
Primary endpoint: Longitudinal growth: 1-year data (n = 36)
n = 20
n = 16
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Tri
gly
ceri
des
[m
g/d
L]
0
50
100
150
200
Serum triglycerides
Steroid withdrawalControl group
0 9 15Time [months]
n.s.
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Time [months]
0 3 6 9 12 15
M
AP
SD
S
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
Change in blood pressure: 1-year data (n = 36)
Steroid withdrawalControl group
*p<0.01 vs. control group **p<0.001 vs. control group
#p<0.05 vs. baseline
#
##
##
***
n = 20
n = 16
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Blood pressure: 2-year data (n = 28)
Steroid withdrawalControl group
*p<0.05 vs. control group
Time [months]
0 3 6 9 12 15 18 21 24 27
M
AP
SD
S
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
* ***
n = 14
n = 14
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Hem
og
lob
in [
g/d
L]
0
2
4
6
8
10
12
14
Hemoglobin
Steroid withdrawalControl group
0 9 15Time [months]
3 6 12
#
# #
*p<0.01 vs. control group**p<0.001 vs. control group
#p<0.05 vs. baseline
* **
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Leu
cocy
tes
[cel
ls/µ
L]
0
2000
4000
6000
8000
10000
Leucocytes
Steroid withdrawalControl group
0 9 15Time [months]
3 6 12
*p<0.05 vs. control group
*
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CsA
do
se [
mg
/kg
*day
]
0
1
2
3
4
5
6
7C
sA tro
ug
h level [n
g/m
L]
0
20
40
60
80
100
120
140
Cyclosporine A exposure: 1-year data (n = 36)
Steroid withdrawalControl group
0 15
Time [months]
0 15
#p<0.05 vs. baseline
##p<0.001 vs. baseline
###
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CsA
do
se [
mg
/kg
*day
]
0
1
2
3
4
5
6
7
CsA
trou
gh
level [ng
/mL
]
0
20
40
60
80
100
120
140
Cyclosporine A exposure: 2-year data (n = 28)
Steroid withdrawalControl group
0 15
Time [months]
0 15
#p<0.05 vs. baseline
#
27 27
#
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Clinical eventSteroid withdrawal (n = 23) Control group (n = 18)
Event per patient
Number of patients (%)
Event per patient
Number of patients (%)
Opportunistic infections 1.0 4 (17.4) 1.8 5 (27.8)
Diarrhea 1.6 7 (30.4) 1.6 7 (38.9)
Respiratory tract infections: Upper RTI Pneumonia
4.11.0
18 (78.3)5 (21.7)
5.31.0
12 (66.7)1 (5.6)
Urinary tract infections 3.6 5 (21.7) 2.8 4 (22.2)
Other infections 2.4 15 (65.2) 2.4 9 (50.0)
M. Addison 1.0 1 (4.3) 0 0
Pseudotumor cerebri 1.0 1 (4.3) 0 0
Gingival hyperplasia 1.0 4 (17.4) 1.0 1 (5.6)
Hypertrichosis 1.0 2 (8.7) 1.0 2 (11.1)
Adverse events
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Methods. In a retrospective case-control study, covering a mean follow-up period of 46 ± 2.3 months and 40 patientsaged 11.4 ± 4.9 years, we analyzed the safety and efficacy of steroid withdrawal in pediatric renal transplant recipients receiving CsA micoroemulsion, MMF, and low-dose prednisone treatment.
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Time [months]
CC
r [m
L/m
in/1
.73
m²]
40
60
80
100
120
140
0 3 6 9 12 24
* + +
46 2.3
Graft function
Steroid withdrawal
Control group*P < 0.05; +P < 0.01 vs. baseline
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Conclusions: Glucocorticoids
Late withdrawal: Feasible in pediatric renal transplant recipients with stable graft function. Facilitated by maintenance therapy with newer immunosuppressive drugs (tacrolimus, MMF).
Early withdrawal: IL2r antibody, steroids, CNI and Rapamycin are too immunosuppressive in at-risk population. Lesson: “Balance” must not be too far on the complication side.
Steroid avoidance (Stanford experience): successful, substantial benefits for children following kidney transplantation, but requires further validation in controlled randomized trials.
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*p<0.05 vs. control group #p<0.05 vs. baseline
Steroid withdrawalControl group
Time [months]
0 3 6 9 12 15
B
MI S
DS
-1.2
-0.8
-0.4
0.0
0.4
0.8
Change in body mass index: 1-year data (n = 36)
# # ##
#
* * * * *
n = 20
n = 16
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Allograft function: 1-year data (n = 36)
Time [months]
0 3 6 9 12 15
CC
r [m
L/m
in*1
.73
m²]
0
20
40
60
80
100
120
140
Steroid withdrawalControl group
n.s.
n = 20
n = 16
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Histology (n = 41)
Histology Steroid withdrawal (n = 23)
Control group (n = 18)
Number of biopsies 6 (26%) 4 (22%)
BPAR
● Borderline 0 1 (month 9)
● Banff IIa 0 1 (month 21)
CAN ± CsA nephrotoxicity 5 1
CsA nephrotoxicity 1 0
Unspecific changes 0 1
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Uri
nar
y p
rote
in e
xcre
tio
n [
mg
/m²*
day
]
0
20
40
60
80
100
120
Proteinuria: 1-year data (n = 36)
Steroid withdrawalControl group
0 15Time [months]
n.s.
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Uri
nar
y p
rote
in e
xcre
tio
n [
mg
/m²*
day
]
0
20
40
60
80
100
120
Proteinuria: 2-year data (n = 28)
Steroid withdrawalControl group
0 27Time [months]
n.s.
15
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Time [months]
0 3 6 9 12 15
H
eig
ht
SD
S
-0.4
-0.2
0.0
0.2
0.4
0.6
*p<0.01 vs. control group #p<0.05 vs. baseline
Steroid withdrawalControl group
Longitudinal growth: 1-year data in prepubertal patients (n = 18)
n = 11
n = 7
* *#
##
#
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Time [months]
0 3 6 9 12 15
H
eig
ht
SD
S
-0.6
-0.4
-0.2
0.0
0.2
0.4
Steroid withdrawalControl group
Longitudinal growth: 1-year data pubertal patients (n = 18)
n = 9
n = 9
n.s.
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Study endpoints
Primary endpoint: Longitudinal growth
Secondary endpoints: Alleviation of cardiovascular risk factors
Arterial hypertension Hyperlipidemia Body Mass Index
Safety aspects: Patient and graft survival Allograft function (CCr according to Schwartz)
Acute rejection episodes Proteinuria Myelosuppression
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Time [months]
0 3 6 9 12 15-4
-3
-2
-1
0
1
Longitudinal growth: 1-year data(prepubertal patients; n = 10)
Hei
gh
t S
DS
Time [months]
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#p<0.05 vs. baselineSteroid withdrawalControl group
Height SDS: 1-year data (n = 36)
Time [months]
0 3 6 9 12 15
Hei
gh
t S
DS
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
# # # n = 20
n = 16
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#p<0.05 vs. baselineSteroid withdrawalControl group
Height SDS: 2-year data (n = 28)
Time [months]
0 3 6 9 12 15 18 21 24 27
Hei
gh
t S
DS
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
##
# n = 14
n = 14
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#p<0.05 vs. baselineSteroid withdrawalControl group
Time [months]
0 3 6 9 12 15
BM
I SD
S
-0.4
0.0
0.4
0.8
1.2
Body mass index: 1-year data (n = 36)
# # ##
# n = 20
n = 16
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#p<0.05 vs. baselineSteroid withdrawalControl group
Time [months]
0 3 6 9 12 15 18 21 24 27
BM
I SD
S
-0.4
0.0
0.4
0.8
1.2
1.6
Body mass index: 2-year data (n = 28)
#
#
##
# n = 14n = 14
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Time [months]
0 3 6 9 12 15
MA
P S
DS
0.0
0.5
1.0
1.5
2.0
2.5
Blood pressure: 1-year data (n = 36)
Steroid withdrawalControl group
#p<0.05 vs. baseline
# #
#
#
n = 20
n = 16
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Time [months]
0 3 6 9 12 15 18 21 24 27
MA
P S
DS
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Blood pressure: 2-year data (n = 28)
Steroid withdrawalControl group
*p<0.05 vs. control group
*
n = 14
n = 14
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Standard vs Novel Extended Daclizumab
Induction
Months post-txp
Protocol biopsies
0 1 2 3 4 5 6
2mg/kg
1mg/kg every 2 weeks x 4; 3 weeks x 1; 4 weeks x 3
Total dose= 10 mg/kg vs 5 mg/kg6 months versus 2 months coverage
12
1mg/kg every 2 weeks x 4
Sta-Dac
1mg/kg
Ext-Dac
Safety Data for Extended Use:Nussenblatt et al, PNAS, 1999, 96(13), 7462
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Complete Steroid Avoidance vs Steroid Taper?
• Steroid ELIMINATION is the best option to improve growth– Lower daily dosing: growth+/-– Alternate day dosing: growth+, AR++, compliance-– Steroid Withdrawal: growth ++, AR+++, graft loss+
• Stronger Rx (maintenance/ induction) may allow safe steroid avoidance from the start
• Steroid avoidance may promote graft “acceptance”– “No steroids” immunologically safer- steroid
dependancy hypothesis?– Steroids inhibit Fas dependant peripheral tolerance– Steroids break experimental tolerance
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STANFORD STEROID FREE PROTOCOL
0 1 2 3 4 5 6 7 8 9 10 11 12 24
Months post-txp
Protocol biopsies
Rx
Daclizumab
MMF
Tacrolimus
•Sarwal et al, Rapid Comm., Transplantation, 2001n=10, 6 month analysis
•Sarwal et al, Transplantation, 2003n=50, 2 year analysis
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STEROID FREE PROTOCOL
Immunosuppression Dosing
Drugs
Pre-op
Post-op
Tacrolimus 0.15mg/kg/dose Trough levels (ng/ml) bid Weeks 0-1: 12-14
Mo 3: 5-7 Year 1: 3-5
MMF 600-450 mg/m2/dose bid 300 mg/m2/dose, bid
Trough levels 2-4 mg/dl
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Single Center Study AnalysisNovember 1999- July 2005
• 77 Steroid-Free (SF) pediatric transplant recipients• Efficacy and Dosing study• Follow-up: Range=16-66 months; Mean= 40 months
• 77 Steroid-Based (SB) historical (1/3) and prospective (2/3) pediatric transplant controls
• Pre-requisite for Inclusion: 100% graft survival at 2 years and no DGF
• Matched for age, sex, race, cause of ESRD, pre-txp dialysis, mean HLA match, CMV, EBV, Blood pressure, HCT, WBC, Lipids
• Immunosuppression: -Tacrolimus 100%- Induction 100% (Daclizumab 65%)
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Graft Survival at 3 YearsGraft Survival at 3 Years
• Graft survival– 95% in SF vs. 71% in SB (p=0.001)
• Death censored graft survival – 100% in SF vs. 87% in SB (p=0.0011)
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Acute Rejection : Acute Rejection : Improved in Improved in SF!SF!
• Acute Rejection (AR) in both groups– 1 year AR 6% in SF vs 22% in SB (p=0.0005)– Late AR (> 1 yr): 2% in SF vs. 8% in SB (p=0.01)
• Sub-clinical AR in SF (405 protocol biopsies)- data not available in SB– Banff ‘ungradable’– 13%– No steroid pulsing, graft function stable, follow-
up biopsy clear-? significance– Incidental drug toxicity at 1 year 25%
• 48% in first 20 patients vs 18% in last 20 patients
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ALLOGRAFT FUNCTIONSchwartz method in ml/min/1.73 m2
Steroid-free Steroid-based p value
Pre-transplant 13.5±5.9 14.5±7.9 0.48
6 months 99.4±31.9 85.3±29 0.03
12 months 90.7±22.8 76.4±26.1 0.01
24 months 103.4±39.5 74.1±31.8 0.009
36 months
48 months
92.7±27.3
89.4±24.6
72.2±25.6
69.7±30.3
0.01
0.01
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Pre-transplant Hypertension
60% 67.4% 0.1
Post-transplant Hypertension at 1 year
12.5%
91.6% <0.0001
New-onset Hypertension post-transplant
4% 36.3% <0.0001
Post-transplant Hypertension at 1 year with ≥ 2 drugs
4% 27.7% <0.0001
HYPERTENSION- less severe in SF
Steroid-Free Steroid-Based p value
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Hyperlipidemia:Hyperlipidemia: Less in SFLess in SF
Hypertriglyceridemia of SF vs SB
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
0 6 12Months Post-tx
mg
/dL
Steroid-Free
Steroid-Based
p=0.4 p=0.04 p=0.008
Hypercholesterolemia - SF vs SB
0%10%20%30%40%50%60%70%80%90%
100%
0 6 12Months Post-tx
% P
atie
nts
with
H
yper
chol
ster
olem
ia
Steroid-Free
Steroid-Based
p=0.73
p=0.0012
p=0.0014
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GrowthGrowth - I - Improved mproved ΔΔ Height z-score in SF Height z-score in SF
Age < 5
-1.2
-0.7
-0.2
0.3
0.8
1.3
1.8
2.3
6 12 18 24
Months Post-Tx
De
lta
Z-S
co
re
Steroid-Free
Steroid-Based
p<0.0001
p=0.004
p=0.66 p=0.01
Age 5-15
-0.8
-0.3
0.2
0.7
1.2
1.7
6 12 18 24
Months Post-Tx
Del
ta Z
-Sco
re
Steroid-Free
Steroid-Basedp=0.03
p=0.05
p=0.04p=0.02
Improved growth by 0.75-1.68 height SDS (p=0.0011) in SF 0-15 yrs age confirmed with 565 matched NAPRTCS SB 0-15 yr old patients
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German Study Group on Pediatric Renal TransplantationGerman Working Group for Pediatric Nephrology (APN)
Contributing investigators:
J Drube, L Pape, G Offner - Hannover
U John, J Misselwitz - Jena
H Fehrenbach - Memmingen
M Pohl - Freiburg
M Zimmering, J Gellermann, U Querfeld - Berlin
G Klaus – Marburg
S Fründ, M Bulla - Münster
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TWIST-Study
INVESTIGATOR MEETING
FG-506-02-43 TWIST – STUDY
London, 01st August 2008