immunosuppressive strategies for improved long-term outcomes in renal transplantation jeremy chapman...

Immunosuppressive strategies for improved long-term outcomes in

renal transplantation

Jeremy Chapman Centre for Transplant and Renal Research

Millennium InstituteUniversity of SydneyWestmead Hospital

SYDNEY

Immunosuppressive strategies for improved long-term outcomes in

renal transplantation

Jeremy Chapman Centre for Transplant and Renal Research

Millennium InstituteUniversity of SydneyWestmead Hospital

SYDNEY

Mortality

Two Log orders of improvement needed

One Log order of improvement needed

We have to do something differently

We have to do something differently

The timeline for destruction of a kidney

Tx

Interstitial FibrosisInterstitial FibrosisTubularAtrophy TubularAtrophy

AcuteRejectionAcuteRejection

IschaemiaIschaemiaSubclinical Rejection/Chronic Humoral Rejection Subclinical Rejection/Chronic Humoral Rejection

ArteriosclerosisArteriosclerosis

Chronic Donor Disease

Acute Donor Disease


Acute Donor Disease

Arteriolar HyalinosisArteriolar Hyalinosis

CNI ToxicityCNI Toxicity

Glomerular SclerosisGlomerular Sclerosis

GR

AF

T L

OS

S

Rising Creatinine

Chapman JR et al. J Am Soc Nephrol 2005; 16: 3015–3026.

0

0.5

1

1.5

2

Mean Banff score

0 2 4 6 8 10

Years after transplantation

tubular atrophy (ct)

chronic interstitial fibrosis (ci)

CNI Toxicity

Allograft Rejection

The Problem simplified

CNI Toxicity

Allograft Rejection


Manage Toxicity

Manage Immune Response

Years

CNI Toxicity

Allograft Rejection


Manage Toxicity


Years

EARLY

Symphony Study designSymphony Study design1645 patients, 15 countries1645 patients, 15 countries

TxTx 6 mo6 mo 12 mo 12 mo

DaclizumabDaclizumabLow-dose CsALow-dose CsAMMFMMFSteroidsSteroids

50–100 ng/ml50–100 ng/ml

Low-dose sirolimusLow-dose sirolimusMMFMMFSteroidsSteroids

DaclizumabDaclizumab4-8 ng/ml4-8 ng/ml

Low-dose tacrolimusLow-dose tacrolimusMMFMMFSteroidsSteroids

DaclizumabDaclizumab3-7 ng/ml3-7 ng/ml

150-300 ng/ml for 3 months150-300 ng/ml for 3 months100-200 ng/ml thereafter 100-200 ng/ml thereafter

Standard-dose CsAStandard-dose CsAMMFMMFSteroidsSteroids

Standard-Standard-CsA CsA

Low-Low-CsACsA

Low-Low-TacTac

Low-Low-SRLSRL

Biopsy Proven Acute Rejection Biopsy Proven Acute Rejection at 1 yearat 1 year(ITT, Excluding Borderline)(ITT, Excluding Borderline)

26%26%24%24%

12%12%

37%37%

p<0.0001p<0.0001

p<0.0001p<0.0001

00

1010

2020

3030

4040

5050

12 months post-Tx12 months post-Tx

BP

AR

(%

of

pa

tien

ts)

BP

AR

(%

of

pa

tien

ts)

Standard-dose CsAStandard-dose CsA

Low-dose CsALow-dose CsA

Low-dose TACLow-dose TAC

Low-dose SRLLow-dose SRL

Cummulative Meta analysis of Il2r versus placebo

Biopsy proven

rejection

episodes

Relative Risk.4 .5 .6 .8 1 1.2 1.4

Yussim 2004

Fangmann 2004

Bernarde 2004

Ekberg 2004

Sheashaa 2003

Ahsan 2002

de Boccardo 2002

Ponticelli 2001

Pisani 2001

Folkmane 2001

Davies 2000

DDT 1999

Kahan 1999

DTT 1998

Nashan 1997

IL2Ra v placebo: Graft loss or death at 6 m

2003 Meta analysis: 7 Trials, 1081 Participants

2006 update: 13 Trials, 2516 Participants

How long has graft survival benefit been evident?

• Cumulative

meta-analysis

1.4

1.6

1.8

2

0 2 4 6 8 10

1.4

1.6

1.8

2

0 2 4 6 8 10

YEARS BEYOND MAIN STUDY

log survival

T 1/2: 11.1 ys

T 1/2: 19.2 ysT 1/2: 15.8 ys

T 1/2: 7.8 ys

log survival

Half-Life Estimates in Patients without and with Acute Rejection

TACROLIMUS CYCLOSPORIN

p<0.05

p<0.05

Long term Evaluation of the European Multicenter Trial Comparing Tacrolimus and Cyclosporin

Messages:

• Early - Low Risk Pts – IL2r, Tacro, Mycophenolate, Steroids

CNI Toxicity

Allograft Rejection


Manage Toxicity


Years

EARLY

CNI Toxicity

Allograft Rejection


Manage Toxicity


Years

Beyond 3 Months

CAESAR study: higher rejection rate (13%) after CsA withdrawal at month 3

0.90.80.7

0.60.50.40.30.20.1

0.0

Ev

ent-

fre

e p

rob

ab

ility

0 60 120 180 240 300 360 420 480 540 600

Time (days)

A: Low /no CsA

B: Low CsA

C: Norm CsA

H Ekberg et al Caesar Study Group AJT 2007

CsA withdrawal

A v B and A v C at 12 months p < 0.05

BPAR (excluding borderline, ITT population)

∆ 13%

CsA too low? (100ng/ml)

IL-2 Ab

Pilot study with MMF, Steroids and Daclizumab – high rejection rate

Vincenti F et al. Transplantation 2001; 71:1282–7.

n = 98

Cu

mu

lati

ve in

cid

enc

e (%

)

Kaplan-Meier estimates

0

10

20

30

40

50

60

70

80

Time from transplantation to event (months)

0 1 2 3 4 5 6 7 8 9 10 11 12

48% after 6 Months

53% after 12 Months

BPAR

310 - Study Design

Sirolimus*

3 months + 2 weeks

Sirolimus* (>5 ng/mL) CsA (75-200 ng/mL)

Steroids

CsA Stopped

(25% per week)

+CsA

Sirolimus* (20-30 ng/mL < 1 yr) (15-25 ng/mL > 1 yr)

Steroids

+ Steroids

n=525

SRL+ CsAn=215

SRL n=215

DiscontinuedBefore randomizationn=95

*Tablets

3m

Incidence of First Biopsy-Confirmed Acute Rejection*

* Intent-to-treat analysis.

Months0 6 12 18 24 30 36 42 48

Acu

te R

ejec

tio

n (

%)

0

5

10

15

20

25

30

0

5

10

15

20

25

30

SRL SRL + CsARandomization

*Log Rank Test = 0.205

*SRL+CsA vs SRL

Acute Rejection RateKaplan-Meier Estimates

TREATMENT REGIMENSTREATMENT REGIMENS

125-250ng/mL

SRL 8-12ng/mL

Induction Phase Maintenance Phase

CsA6-8mg/kg/d

(+/- Induction per local standard)

50-100ng/mL 50-75ng/mL

13 52Week 22

SRL + CsA Minimization + CCS*

Taper 25%/week to off by month 4

17

125-250ng/mL

SRL + CsA Elimination + CCS*

SRL LD 6mg SRL MD 2mg

CsA6-8mg/kg/d

12-20ng/mLSRL 8-12ng/mL 10-20ng/mL

*CCS per local standard

SRL LD 6mg SRL MD 2mg

30

35

40

45

50

55

60

65

70

Day 5 Month 1 Month 3 Month 6 Month 9 Month 12

Minimization

Elimination

RENAL FUNCTION: NANKIVELL GFR* RENAL FUNCTION: NANKIVELL GFR*

(ON THERAPY)(ON THERAPY)

*p = NS for all comparisons (t test). ITT analysis at 12 mo: 49.5 vs 51.6 mL/min, Minimization (n=105) vs Elimination (n=102), p=0.603; GFR=0 for missing values, graft loss, or death.

Minimization, n = 105 100 94 83 74 71

Elimination, n = 100 94 85 71 67 65

44.2

61.1

GFR

, mL/

min

55.8 56.4 61.559.5

39.9

50.1

56.0

63.4 62.4 65.2

RATES OF GRAFT AND PATIENT SURVIVAL RATES OF GRAFT AND PATIENT SURVIVAL AND DISCONTINUATIONS AT 12 MONTHSAND DISCONTINUATIONS AT 12 MONTHS

Minimization Elimination p-Value*

ITT Population, n (%)Graft survival* 92/105 (87.6) 90/102 (88.2) 1.000

Graft survival, death censored

103/105 (98.1) 96/102 (94.1) 0.166

Patient survival 94/105 (89.5) 94/102 (92.2) 0.632

Discontinuations, n (%)

- adverse event

- lack of efficacy/graft loss

34/105 (32.4)

13/105 (12.4)

5/105 (4.8)

37/102 (36.3)

13/102 (12.8)

15/102 (14.7)

0.562

1.000

0.018

*Includes death with a functioning graft

12.4 12.414.3

16.7

21.6 22.5

0

5

10

15

20

25

30

Month 3 Month 6 Month 12

% B

CA

R

Minimization, n=105

Elimination, n=102

BIOPSY-CONFIRMED ACUTE REJECTION*BIOPSY-CONFIRMED ACUTE REJECTION*

n = 13 17 13 22 15 23

p=0.433

p=0.096 p=0.152

*ITT analysis

CONCEPT studyTransplantation

n = 235

Sirolimus (SRL) Neoral (CsA)

DACLIZUMAB+

MMF+

NEORAL+

STEROIDS

Week 12randomisation

n=192

Group An=95

Group Bn=97

STEROIDS WITHDRAWN AT MONTH 8

Lebranchu Y Am J Transplant 2009

Before randomisati

on

After randomisation

MMF + SRL

(n = 95)

MMF + CsA (n = 97)

Graft loss 3 1 (1%)

Death 1

Graft and patient survival

One year results


6%

72%

3%

68%

78%

60%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

W35 W39 W52

MMF+SRL (n=95)

MMF+CsA (n=97)

MMF + SRL MMF + CsA Total

Mean duration of treatment prior to steroid withdrawal (months)

8.6 ± 2.4 8.8 ± 2.0 8.7 ± 2.2

One year results

Corticosteroid withdrawal (ITT)%

of

pati

en

ts


61.8±16.8 59.3

±13.6

67.3±14.2

60.3±14.4

30

40

50

60

70

Randomisation W52

SRL CsAp=0.004

p=ns

ml/m

in

One year results:Iohexol clearance

n=59 n=75

Lebranchu Y. Transplantation Proceedings 2008;40:S57–S59.

MMF + SRL (n = 95)

MMF + CsA

(n = 97)

P-value

BPAR (grade ≥1) Banff classification Grade I Grade II Grade III

17 / 16 (17%)

1700

10 / 8 (8%)

541

0.07

Acute rejection after randomisation

One year results


75.9%

87.0%

16.7%

8.7%

3.7%1.5% 3.7% 2.9%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

< 0.5g 0.5 - 1 g 1 - 2 g > 2 g

MMF+SRL MMF+CsA

Proteinuria at one year (g/day)


Spare The Nephron Trial design

Spare The Nephron Trial design

MMF + tacrolimus

MMF + cyclosporine

MMF + tacrolimus

MMF + cyclosporine

MMF + sirolimus

MMF + sirolimus

Post-randomization

Patient screening and enrollment

1 year 2 years

30 – 180

DAYS

POST-TX

Pre-randomization

Sirolimus2 to 10 mg loading dose Maintain trough levels of 5 to 10 ng/mL

Key exclusion criteria

• Corticosteroid-resistant, biopsy-proven acute rejection or treated for acute rejection with antibody therapy within 90 days prior to randomization

• Corticosteroid-sensitive acute rejection 30 days prior to randomization

• >1 biopsy-proven acute rejection prior to study entry• SCr >2.5 mg/dL or CrCl <30 mL/min (Cockroft-Gault) at

study entry• Total cholesterol levels >300 mg/dL or triglycerides >350

mg/dL

Randomized N=298

MMF/CNIN=150

MMF/SRLN=148

TacrolimusWithdrawal

N=122

CyclosporineWithdrawal

N=26

CyclosporineN=31

*81% received tacrolimus and 19% received cyclosporine

Patient allocation (ITT)*

TacrolimusN=119

Patient demographics

MMF/CNI

MMF/SRL N=148

TotalN=150

MMF/TACN=119

Sex, n (%)*

Male Female

93 (63%)55 (37%)

95 (63%)55 (37%)

75 (63%)44 (37%)

Ethnicity, n (%)*

Caucasian 74 (50%) 74 (49%) 58 (49%)

African American 48 (32%) 50 (33%) 40 (34%)

Other 26 (18%) 26 (17%) 21 (18%)

Age (years)*

Mean SD 48.7 12.9 48.7 12.7 48.4 12.5

*P = NS for MMF/SRL vs MMF/CNI and for MMF/TAC vs MMF/CsA

Baseline characteristics MMF/CNI

MMF/SRL N=148

TotalN=150

MMF/TACN=119

Type of donor, n (%)*

Living related 41 (28%) 38 (25%) 29 (24%)

Living unrelated 19 (13%) 21 (14%) 19 (16%)

Deceased donor 88 (60%) 91 (61%) 71 (60%)

PRA level (highest assessment), n (%)*

0% 93 (63%) 91 (61%) 70 (59%)

1-19% 31 (21%) 27 (18%) 24 (20%)

>20% 21 (14%) 27 (18%) 22 (19%)

Not known/missing 3 (2%) 5 (3%) 3 (3%)

Time posttransplant to randomization*

Mean ± SD, Days 113 ± 54 116 ± 49

*P = NS for MMF/SRL vs MMF/CNI and for MMF/TAC vs MMF/CsA

Induction therapy, n (%)

MMF/CNI

MMF/SRLN=151

TotalN=150

MMF/TACN=119

Antithymocyte globulin 53 (35%) 53 (35%) 44 (37%)

Basiliximab 35 (23%) 44 (29%) 32 (27%)

Daclizumab 20 (13%) 13 (9%) 8 (7%)

MMF/SRL MMF/CNI

Mea

n do

se (

mg)

± S

D

BaselineN=140 N=139

Post-Randomization 1 MonthN=114 N=129

6 MonthsN=116 N=123

12 MonthsN=122 N=112

Mycophenolate mofetil dose

Sirolimus trough levelsM

ean

siro

limus

con

cent

ratio

nng

/mL

(± S

EM

)

Day 7N=123

1 MonthN=112

6 MonthsN=104

12 MonthsN=102

Post-Randomization

Treatment failure, n (%)MMF/CNI

MMF/SRLN=148

TotalN=150

MMF/TACN=119

Treatment failure* 44 (30%) 35 (23%) 30 (25%)

Reason for treatment failure

Death 0 (0%) 2 (1%) 1 (1%)

Withdrawal due to AE 23 (16%) 10 (7%) 8 (7%)

Need to resume CNI 5 (3%) 0 (0%) 0 (0%)

Need to withdraw therapy 5 (3%) 11 (7%) 11 (9%)

Lost to follow-up 10 (7%) 12 (8%) 10 (8%)

Withdrew consent 1 (1%) 0 (0%) 0 (0%)

*Events are mutually exclusive; only the first event counted per patient*P = NS for MMF/SRL vs. MMF/CNI

Adverse events post-randomization in >10% of patients, n (%)

MMF/SRLN=148

MMF/CNIN=153

Diarrhea 50 (34%) 47 (31%)

Peripheral edema 39 (26%) 20 (13%)

Hyperlipidemia 35 (24%) 13 (8%)

Leukopenia 33 (22%) 29 (19%)

Anemia 23 (16%) 18 (12%)

Hypertension 23 (16%) 12 (8%)

Mouth ulceration 21 (14%) 0 (0%)

Hypokalemia 20 (14%) 6 (4%)

Upper respiratory tract infection 19 (13%) 16 (10%)

Cough 16 (11%) 16 (10%)

Serum creatinine increased 13 (9%) 31 (20%)

Urinary tract infections 20 (14%) 30 (20%)

Opportunistic infections 16 (11%) 27 (18%)

Efficacy outcomes, n (%)

MMF/CNI

MMF/SRL*N=148

Total*N=150

MMF/TACN=119

Biopsy-proven acute rejection 10 (7%) 9 (6%) 7 (6%)

Death 0 (0%) 3 (2%) 2 (2%)

Graft loss 3 (2%) 4 (3%) 3 (3%)

*P = NS for MMF/SRL vs. MMF/CNI

Baseline to month 12

N = 118 N = 109

0

5

10

15

20

25

30

35

Mea

n P

erce

nt

Ch

ang

e ±

SE

MMMF/SRL

MMF/CNI

7.8

Baseline GFRmL/min/1.7 m2 SEM 59.5 2.0 58.7 2.2

-5

P=0.013

25.7

Mean % change in measured GFR

Messages:


• 3-12 months– TOR inhibitors have a place

• Proteinuria <1gm/d

• GFR >40ml/min

• No SubClinical Rejection

CNI Toxicity

Allograft Rejection


Manage Toxicity


Years

Beyond 3 Months

CNI Toxicity

Allograft Rejection


Manage Toxicity


Years

Late

Measuring renal function

020406080

100120140160180200

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

years

crea

tini

ne

0102030405060708090100

GF

R

Creatinine GFR

Adapted from Chapman JR et al. J Am Soc Nephrol 2005; 16: 3015–3026.

020406080

100120140160180200

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

years

crea

tini

ne

0102030405060708090100

GF

R

Creatinine GFR

Adapted from Chapman JR et al. J Am Soc Nephrol 2005; 16: 3015–3026.

SCR – Aza changed to

Mycophenolate

Measuring renal function

Smak Gregoor PJH, JASN 2002, 13(5): 1365-1373

Dutch study:high rejection rate after CsA withdrawal

at 6 months

Acute Rejection: MMF/Pred MMF/CsA TripleAfter 3 mo 14 (22%) 3 (4%) 1 (1.4%) >Banff I 9 1 0

No difference in renal function, better blood pressure after steroids stopped

• Rejection 16% (8% in the 1st yr) vs. 1% (p<0.002)• 5.7ml/min difference in renal function (p=0.05)

4 year follow up after CNI withdrawal in stable patients at 12-30 months

Graft loss and acute rejection renal function

Abramowicz, D. et al. J Am Soc Nephrol 2005;16:2234-2240

• Prospective randomized study (187 patients)

Abramowicz D et al. Transplantation 2002; 74:1725-34;

CNI withdrawal in renal transplant patients with stable renal function at 12-30 monthsstable renal function at 12-30 months

Triple therapy

CsA withdrawn

Rejection risk after CNI withdrawal with MMF depends on the time post-transplant

Tx

Pre-adaptation Post-adaptation Stable12 30

risk of AR Vincenti 53%

CAESAR +13%Dutch +22%

Abramowicz + 8% (16%)

Weir 2.5%Dudley 0%Suwelack 0%

Zeit

Messages:


• 3-12 months– TOR inhibitors have a place

• Late (?Too Late)– MMF/Pred is not enough for most patients– Individualise depending upon

• baseline therapy• pathology• function and proteinuria

Mortality

Cancer and heart disease are the main causes of death in the transplant population in Australia

0

10

20

30

40

50

60

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006

Cancer

Cardiac

InfectionVascularOther Social

ANZDATA Registry, 2006

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30

Years Post Transplant

0%

20%

40%

60%

80%

100% Any Cancer Skin Non Skin Age-Matched Gen. Pop

Cancer Occurs in 80% of transplanted patients by 30

yearsPatients at Risk (8,881) Australia and NZ

2436

370

118

Cancer in CKD – Individual Cancers

•What are the Risk Factors?

•What is the Prognosis?

•How should we treat these patients

•How should we screen for these cancers

•What are the Risk Factors?

•What is the Prognosis?

•How should we treat these patients

•How should we screen for these cancers

All cancersUnspecifiedLeukaemia

Non-Hodgkin lymphomaHodgkin disease

ThyroidBrain

EyeTestis

ProstatePenisOvary

Corpus uteriCervix uteri

VulvaBreast

Connective tissueKaposi sarcoma

MesotheliomaMelanoma

LungLarynx

PancreasGallbladder

LiverAnus

RectumColon

Small intestineStomach

OesophagusSalivary gland

MouthTongue

Lip

.01 .1 1 10 100 1000 .01 .1 1 10 100 1000 .01 .1 1 10 100 1000

Prior to RRT During dialysis After transplantation

Site

SIR



ThyroidBrain

EyeTestis

ProstatePenisOvary


VulvaBreast



LungLarynx

PancreasGallbladder

LiverAnus

RectumColon



MouthTongue

Lip

.01 .1 1 10 100 1000 .01 .1 1 10 100 1000 .01 .1 1 10 100 1000


Site

SIR



ThyroidBrain

EyeTestis

ProstatePenisOvary


VulvaBreast



LungLarynx

PancreasGallbladder

LiverAnus

RectumColon



MouthTongue

Lip

.01 .1 1 10 100 1000 .01 .1 1 10 100 1000 .01 .1 1 10 100 1000


Site

SIR

PRE Dx POST Dx POST Tx

Months0 6 12 18 24 30 36 42 48 54 60

Fir

st

No

n-s

kin

Ca

rcin

om

a(%

Pa

tie

nts

)

0

2

4

6

8

10

12

0

2

4

6

8

10

12

*Log-Rank Test, p = 0.094

*SRL-CsA-ST vs SRL-ST

SRL-CsA-ST

SRL-STRandomization

Protocol Extension to 60 Months

Amendment toDiscontinue

SRL-CsA-ST PatientsA

Months0 6 12 18 24 30 36 42 48 54 60

Fir

st

No

n-s

kin

Ca

rcin

om

a(%

Pa

tie

nts

)

0

2

4

6

8

10

12

0

2

4

6

8

10

12



SRL-CsA-ST

SRL-STRandomization



SRL-CsA-ST PatientsA Non skin

Months0 6 12 18 24 30 36 42 48 54 60

Ski

n C

ance

rs (

Eve

nts

)

0

20

40

60

80

100

120

0

20

40

60

80

100

120

SRL-CsA-ST

SRL-STRandomization

BRelative Risk = 0.346

(p < 0.001)

Months0 6 12 18 24 30 36 42 48 54 60

Ski

n C

ance

rs (

Eve

nts

)

0

20

40

60

80

100

120

0

20

40

60

80

100

120

SRL-CsA-ST

SRL-STRandomization

BRelative Risk = 0.346

(p < 0.001)

SkinMonths

0 6 12 18 24 30 36 42 48 54 60

Fir

st C

ance

r (%

Pat

ien

ts)

0

5

10

15

20

0

5

10

15

20



SRL-CsA-ST

SRL-STRandomization



SRL-CsA-ST PatientsA

Months0 6 12 18 24 30 36 42 48 54 60

Fir

st C

ance

r (%

Pat

ien

ts)

0

5

10

15

20

0

5

10

15

20



SRL-CsA-ST

SRL-STRandomization



SRL-CsA-ST PatientsAll Cancers

Sirolimus

3 months + 2 weeks

+CsA+ Steroids

N=525

SRL-CsA-STSRL-CsA-STn=215n=215

SRL-STSRL-ST n=215n=215

CONVERT Study:Significantly Lower Malignancy Rates

0.20.40.9

1.4

2.2

0

3.3

5.1

0

5

10SRL CNI

Total Skin PTLD All Others

p = 0.004

p = 0.019

p = 1.000

(n=555) (n=274)

p = 0.006Rat

e,%

The timeline for destruction of a kidney

Tx

Interstitial FibrosisInterstitial FibrosisTubularAtrophy TubularAtrophy

AcuteRejectionAcuteRejection

IschaemiaIschaemiaSubclinical Rejection/Chronic Humoral Rejection Subclinical Rejection/Chronic Humoral Rejection

ArteriosclerosisArteriosclerosis


Acute Donor Disease


Acute Donor Disease

Arteriolar HyalinosisArteriolar Hyalinosis

CNI ToxicityCNI Toxicity

Glomerular SclerosisGlomerular Sclerosis

GR

AF

T L

OS

S

Rising Creatinine

Chapman JR et al. J Am Soc Nephrol 2005; 16: 3015–3026.

Predict

&

Prevent

0

20

40

60

80

100

120

140

160

180

200

Direct Pathway(donor-specific)

300

350

400

Direct Pathway(Third Party)

Indirect Pathway(donor-specific)

Indirect Pathway(Third Party)

Elispots / 300,000 PBMC

p = 0.001

61.2 9.6

20 21

82 85

14.3 20

59% pos 60% pos

Circulating alloreactive T cellsCirculating alloreactive T cells

Bestard et al.J Am Soc Nephrol, 2008; 19: 1419-29

Direct pathway 3 times higher Direct pathway 3 times higher than indirect responsesthan indirect responses

0 100 200 300

Direct Elispot / 300,000 PBMC

1

2

3

4

5

Serum Creatinine (mg/dL)

r = 0.551, p = 0.001

Direct T-cell alloreactivity is related to graft function

NO (n=22)

YES (n=12)

Late Acute Rejection

0

50

100

150

200

250

300

350

Direct Elispot / 300,000 PBMC

p = 0.016

*


NO (n=19) YES (n=15)

Proteinuria

20

40

60

80

Indirect Elispots / 300,000 PBMC*

p = 0.022

Indirect pathway T-cell alloresponse is related to proteinuria and time after transplantation

12 24 36 48 60 72 84 96 108 120 132

Time after transplantation (months)

0

10

20

40

60

Indirect Elispots / 300,000 PBMC

80

r = 0.351, p = 0.045


cDNA details

1 month gene expression 3 month gene expression

Name M Adj. P B Name M Adj. P B

hemoglobin. beta 4.34 5.94E-07 14.59 hemoglobin. beta 4.63 2.58E-10 21.85

hemoglobin. alpha 2 3.86 5.94E-07 13.96 hemoglobin. alpha 2 3.78 1.85E-09 19.43

dual specificity phosphatase 1 -1.71 2.50E-06 11.99 collagen. type I. alpha 2 3.21 1.02E-07 15.33

cysteine-rich. angiogenic inducer. 61 -1.78 2.50E-06 11.97transforming growth factor beta-stimulated

protein TSC-22 -0.97 1.93E-07 14.48

51F12;No Annotation 0.79 8.29E-06 10.65 dual specificity phosphatase 1 -1.75 2.46E-07 14.02

mannose receptor. C type 1 0.81 1.69E-05 9.79 prostaglandin E receptor 3 -1.09 1.04E-06 12.34

collagen. type I. alpha 2 2.86 1.83E-05 9.36 spondin 2. extracellular matrix protein 1.23 1.04E-06 12.28

collagen. type III. alpha 1 (Ehlers-Danlos syndrome type IV) 3.05 1.83E-05 9.35 cysteine-rich. angiogenic inducer. 61 -1.95 1.04E-06 12.19

sushi-repeat-containing protein. X chromosome 1.29 1.83E-05 9.06collagen. type III. alpha 1 (Ehlers-Danlos

syndrome type IV) 3.25 1.92E-06 11.44

ribonuclease. RNase A family. k6 0.74 2.22E-05 9.05 early growth response 1 -2.36 1.92E-06 11.42

solute carrier family 21 (organic anion transporter). member 9 1.12 2.22E-05 8.99 von Willebrand factor 1.18 2.08E-06 11.25

early growth response 1 -2.29 2.34E-05 8.85 procollagen C-endopeptidase enhancer 1.36 4.67E-06 10.30

p53 regulated PA26 nuclear protein 0.66 3.56E-05 8.31 dermatopontin 2.22 4.67E-06 10.29

bridging integrator 1 0.80 3.14E-05 8.18 secreted frizzled-related protein 4 2.44 4.67E-06 10.25

gene for serine/threonine protein kinase -0.99 4.07E-05 8.07 BTG family. member 3 -0.57 5.81E-06 9.97

glycoprotein 2 (zymogen granule membrane) -0.58 4.07E-05 8.06 collagen. type VI. alpha 2 0.93 8.78E-06 9.51

cartilage intermediate layer protein. nucleotide pyrophosphohydrolase 1.78 6.45E-05 7.53 Microfibril-associated glycoprotein-2 2.64 9.60E-06 9.34

zinc finger protein 145 (Kruppel-like) 1.13 6.90E-05 7.44chondroitin sulfate proteoglycan 2

(versican) 1.31 9.60E-06 9.25

sialyltransferase 1 (beta-galactoside alpha-2.6-sialytransferase) -1.10 6.90E-05 7.35 matrix metalloproteinase 23B 1.04 9.60E-06 9.21

Up

2-fold

Down

2-fold

1mth

CAN 3mth

Normal 3mth

1mth Gene expression 3mth “normal” gene expression

3mth “CAN” gene expression

6

2

245

232 genes 138 genes

65 genes

25

1

6

39

4

61

17

70

12

3

0

4

25

22

9

33

Up

2-fold

Down

2-fold

1mth

CAN 3mth

Normal 3mth

1mth Gene expression 3mth normal gene expression

3mth CAN gene expression

6

2

245

232 genes 138 genes

65 genes

25

1

6

39

4

61

17

70

12

3

0

4

25

22

9

33

Fingerprint?

PBTs predictive of Rejection

Cytotoxic T cell and Interferon PBT correlate with rejectionAnd associated with markers of Tubular Injury

Phil Halloran

PBTs for T-cell mediated, antibody mediated and mixed rejection were similar

ATAGCATAGC

0.0

10.0

20.0

30.0

40.0

50.0

60.0

70.0

80.0

90.0

100.0

i-Banff Banff t-score i-IFTA IFTA nodular

% c

on

trib

uti

on

not otherwise annotated

Endothel activation

B-cell / Ig associated

Injury and repair associated

Kidney parenchyma associated

Macrophage associated

Interferon-γ dependent

T-cell associated

IFTA correlates with different genes than i IFTA correlates with different genes than i and t scoresand t scores

484 probesets

249 probesets

172 probesets

34 probesets

202 probesets

*cut off: r>0.4, p<0.001

Vancouver 2010

Vancouver 2010

immunosuppressive strategies for improved long-term outcomes in renal transplantation jeremy chapman...

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