A clinician’s view of

Vascular Rejection D. Glotz, D. Nochy 2005

Seem more and more frequent....

• 10 à 20% historically

• Close to 30% or more today....

Vascular Rejections

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

1970 1980 1990 2000

A changing picture…

St S Rej

St S Rej

Rejections

A much better understanding..

• New Antibodies detection techniques

• New Cross-match techniques

• C4d

Vascular Rejections

Histological Définition

• Banff: score V (IIb, III)

• CCTT: individualisation

Vascular Rejections

TypesTypes

• Arteriolar, glomerular, capillaries

• Arteries

Vascular Rejections

Vascular Rejections

Pronostic Importance

293 Bx (J2-J35) of 382 pts Tx 1985 - 1989

Bates NDT 1999

6 months Survival 5 years Survival

Normal 20%

95% 78%Borderline 34%

ACR 18%

IIa 6%

IIb et III 15% 78% 61%

• 177 Bx of 134 transplants 1994-1996• 31% failures if vascular rejection (58)• 15% failures if interstitial rejection (65)

p<0,05

Mc Donald NDT 1999

Vascular Rejections

Pronostic Importance

Loucaidou Transpl 2003245 Tx 1995-2002

Vascular Rejections

Pronostic Importance

Vascular Rejection Treatment

- - +

33% 97%

AHR (DSA,C4d+) ACR (DSA,C4d-) Mild AR

n=18 n=30 n=30

Steroid Sensitivity

Antibody Sensitivity

Graft Surv. 6 mo 77,80% 96,70% 96,70%

232 Tx 1995-1999

Mauiyyedi JASN 2002

OKT3OKT3

RENALTRANSPLANTS BROUSSAIS 1987-1992RENALTRANSPLANTS BROUSSAIS 1989-1993

240 transplantations･Mean age: 42,3 years (18/64)･ 65% men

･Time on dialysis: 3,8 years (0,5/14)

･ Patients with PRA>0: 30% (36%)

･Thymoglobulin, Aza, Sandimmune, steroids

RENALTRANSPLANTS BROUSSAIS 1987-1992RENALTRANSPLANTS BROUSSAIS 1989-1993

1 5 10

Patient 97% 91% 82%

Graft 92% 77% 58%

Patient and Graft survivalPatient and Graft survival

years

RENAL TRANSPLANTS BROUSSAIS 1987-1992RENAL TRANSPLANTS BROUSSAIS 1989-1993

RejectionsRejections

･ < 1% during Thymo administration･ 22% at 6 months･ 29% at 12 months

･ of which 81% were Steroid-sensitive･ 10% of recurrent rejections

Vascular Rejections

17 Vascular rejections

•7,1% of all patients•76% steroid-resistant•4 treated with OKT3 as first-line TT •28% of all rejections

Vascular Rejections

Histology

•38% G3, only 24% G0•71% I1•59% T1 or T0•38% V3, 63% V2-V3

Vascular Rejections

17 Vascular rejections

•47% sensitized patients•82% first episode of rejection•Delay Tx-rejection: 89 days (53% 35 days, 47% >6 months)•Creatinin at rejection: 408 µM/l•Reversal: 75%

All treated with Steroid pulses and OKT3

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 1 2 3 4

PATIENTGRAFT

Vascular Rejections

Repeat biopsies (67% of patients)

Vascular Rejections

•100% reversal•No recurrent rejections•Extensive fibrosis

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0 10 20 30 40

PATIENTGRAFT

Vascular Rejections

A much better understanding..

• New Antibodies detection techniques

• New Cross-match techniques

• C4d

Vascular Rejections

Antibody associated Rejections

HistologyAbs + (n=24) Abs - (n=20) p

Glomerulitis 46% 10% 0,01

T0-T1 50% 5% 0,02

T2-T3 50% 95% 0,02

V0-V1 42% 90% 0,01

V2-V3 58% 10% 0,01

Graft loss 12 (50%) 3 (15%) 0,025

44/459 Tx 1987-1994 Trpkov Transpl 1996

76%

59%

41%

37%

63%

Our series

associated to the existence of DSA

• Unselected biopsies• Specificity: 93%• Sensitivity: 31%• P. Positive Value : 87%

Bohmig JASN 2002

C4d

associated to humoral rejection with DSA

• 232 pts Tx 1995 - 1999• 67 pts with rejet<3 months, IF and sérum• 30% C4d + (20/67)• 30% AHR, 45% AHR+ACR• 96% with DSA

Mauiyyedi JASN 2002

C4d

C V

58 35

C4d+ 31% 46%

C4d- 69% 54%

Graft loss C V58 35

38% C4d+ 33% 44%

7% C4d- 5% 11%

p<0,0001 p<0,001 p<0,05

Hertzenberg JASN 2002

C4d positive Rejections

Pronostic Importance

Humoral Rejection

DéfinitionDéfinition• Histological Lesions

• NTA

• CPT, glom, thromboses

• Arteritis• C4d positive• Donor specific Antibodies

Humoral Rejection

The Pompidou experience 1999-2004

•237 transplants•25% immunized/re-transplant patients•Thymoglobulin, Neoral, Cellcept, steroids•14,6% Rejections•9,7% Humoral Rejections

Humoral Rejection

The Pompidou experience 1999-2004

•23 patients, 56 Biopsies of A.H.R.•78% in immunized patients•Delay Tx-A.H.R. 16 days in 87% of cases•Creatinin at rejection 290 µM/l

Humoral Rejection

C4d and D.S.A. at 1st Biopsy

•C4d +, D.S.A. + 52,2% •C4d +, D.S.A. - 30,5%•C4d ?, D.S.A. + 8,7%•C4d -, D.S.A. - 8,7%

Humoral Rejection

Histological findings at 1st biopsy

•Glomerular neutrophils 78,6%•PTC dilatation 83,9%•PTC neutrophils 39,1%•Acute Tubular damage 65,2%•Glomerular TMA 30,4%•G1-3 94,6%•V1-2 56,5%

Who’s at risk of Humoral Rejection?

AHR (DSA,C4d+) ACR (DSA,C4d-) Mild AR

n=18 n=30 n=30

Peak pre-Tx PRA 56,50% 3% 3%

Re-Tx 38,90% 6,70% 6,70%

Crespo, Transpl 2001

Trpkov Transpl 1996

Abs + (n=24) Abs - (n=20)

Peak PRA 36,50% 24,50% NS

Pre-Tx PRA 11,30% 14,70% NS

Re-Tx 50% 10% p<0,01

Who’s at risk of Humoral Rejection?

The Pompidou experience 1999-2004

•30% A.H.R. in immunized vs 3% in non immunized patients

•D.S.A. pre-Tx (ELISA): 65,2%

•Historical positive crossmatch: 43,5%

Humoral Rejection Treatment

• IVIg

• IVIg/Plasmapheresis

IVIg Treatment

• 7 patients

• 6 resistant to anti-lymphocyte antibodies

• 7 short term success (<6months)

Jordan, Transpl 1998

Humoral Rejection Treatment

• 17 patients

• 13 rejections StR, 4 AbR

• Patient Survival 18 months: 94%

• Graft Survival 18 months: 71%Luke, Transpl 2001

IVIg Treatment

Humoral Rejection Treatment

IVIg/PP treatment

• 3 patients

• AHR with DSA

• 100% success

Montgomery, Transpl 2000

Humoral Rejection Treatment

• 16 patients

• 100% StR, 50% AbR

• Graft survival 1 year: 81% (84%)

Rocha, Transpl 2003

IVIg/PP treatment

Humoral Rejection Treatment

Humoral Rejection

The Pompidou experience 1999-2004

•Treatment with IVIg high dose and Steroid pulses•75% success, no deaths•Mean Follow-up 36 ± 21 months•Last creatinin 193 µM/l

2 periods in time, 2 definitions of rejection, 2 treatments…

Period 1989-1993 1999-2004

Type of rejection "Vascular" "Humoral"

% immunised patients 30% 25%

% rejection 29% 14,30%

% V/AHR 7,10% 9,70%

% V/AHR in rejections 25% 68%

% Immunized pats/rej 47% 78%

Delay Tx-rejection 35 days 16 days

Creatinin at rejection 406 µM/l 290µM/l

Treatment OKT3 IVIg

Success rate short term 75% 75%

And the same success rate….

Rejets Vasculaires

Vascular Rejections

Vascular Rejection « Cellular »Ab Anti-Lymphocytes

Humoral RejectionD.S.A.IVIg/PP