Do we still need corticosteroids for maintenance immunosuppression after renal transplantation? Con Burkhard Tönshoff University Children‘s Hospital Heidelberg,

Do we still need corticosteroids for maintenance immunosuppression

after renal transplantation?Con

Burkhard Tönshoff University Children‘s Hospital

Heidelberg, Germany

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

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”)

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.

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

Overview of strategies for steroid minimization

Steroid avoidanceEarly steroid withdrawalLate steroid withdrawal

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

Overview of strategies for steroid minimization

Steroid avoidanceEarly steroid withdrawalLate steroid withdrawal

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

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.

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

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.

*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


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

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.

Nu

mb

er o

f an

tih

yper

ten

sive

dru

gs

0.0

0.5

1.0

1.5

Antihypertensive drugs


0 9 15Time [months]

3 6 12

##

# ##


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]

Allograft function: 2-year data (n = 28)


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

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

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

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

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.

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.

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.

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.

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.

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

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.

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.

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

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

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

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.

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.

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.

*p<0.05 vs. control group**p<0.01 vs. control group #p<0.001 vs. baseline


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

Tri

gly

ceri

des

[m

g/d

L]

0

50

100

150

200

Serum triglycerides


0 9 15Time [months]

n.s.

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)


*p<0.01 vs. control group **p<0.001 vs. control group


#

##

##

***

n = 20

n = 16

Blood pressure: 2-year data (n = 28)


*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

Hem

og

lob

in [

g/d

L]

0

2

4

6

8

10

12

14

Hemoglobin


0 9 15Time [months]

3 6 12

#

# #

*p<0.01 vs. control group**p<0.001 vs. control group


* **

Leu

cocy

tes

[cel

ls/µ

L]

0

2000

4000

6000

8000

10000

Leucocytes


0 9 15Time [months]

3 6 12


*

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)


0 15

Time [months]

0 15


##p<0.001 vs. baseline

###

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)


0 15

Time [months]

0 15


#

27 27

#

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

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.

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

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.

*p<0.05 vs. control group #p<0.05 vs. baseline


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

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


n.s.

n = 20

n = 16

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

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)


0 15Time [months]

n.s.

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)


0 27Time [months]

n.s.

15

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


Longitudinal growth: 1-year data in prepubertal patients (n = 18)

n = 11

n = 7

* *#

##

#

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


Longitudinal growth: 1-year data pubertal patients (n = 18)

n = 9

n = 9

n.s.

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

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]

#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


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


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


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

Time [months]

0 3 6 9 12 15

MA

P S

DS

0.0

0.5

1.0

1.5

2.0

2.5




# #

#

#

n = 20

n = 16

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




*

n = 14

n = 14

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

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

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

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

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%)

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)

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

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

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

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

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

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

TWIST-Study

INVESTIGATOR MEETING

FG-506-02-43 TWIST – STUDY

London, 01st August 2008

Do we still need corticosteroids for maintenance immunosuppression after renal transplantation? Con Burkhard Tönshoff University Children‘s Hospital Heidelberg,

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