International Renal Renal Meeting Meeting International and Mayo - - PowerPoint PPT Presentation

International International Renal Renal Meeting Meeting and and Mayo Mayo Clinic Day Clinic Day in in Sardinia Sardinia

Cagliari (Italy), Cagliari (Italy), April April 30 30-

• May 3, 2011

May 3, 2011

Immunosuppressive Immunosuppressive Induction Induction Regimen Regimen in in Renal Renal Transplantation Transplantation

Donato Donati Donato Donati

Azienda Azienda Ospedaliera Ospedaliera-

• Universitaria

Universitaria, , Varese Varese -

• Italy

Italy

Th1

IFN-γ

Tc

IL-10 IFN-γ IL-2 IL-4

Rejection

TNF-α,IL-6 IL-1.

Th2

APC

MHC

TCR CD28 B7-1/2

Tcell

CD40L CD40 CD4+25+ FoxP3

B Abs Mo

IL-2

T cell:

Commander in-chief

• rchestrating

alloimmunity

Adapted from: Sayegh and Turka. NEJM 1998;338:1813

Th17 IL-17, IL-21 IL-2, IFN-y

Tolerance

Anti -T Lymphocyte Antibodies

selective to extracellular targets on T cells

• Non Depletional

Depletional

Basiliximab ATGs Daclizumab Muromonab Belatacept Alemtuzumab

CD CD-

• 28

28

Belatacept Muromonab

x The IL-2/IL-2r interplay is crucial for T cell proliferation and response

Basiliximab blocks the

chain chain (CD25) (CD25)

• f the
• f the IL-2 receptor

The CD25 antigen is expressed on circulating CD4+ and on all subsets of activated T lymphocytes

Basiliximab Basiliximab

by by large large the best the best selling selling induction induction agent agent in Italy in Italy

Efficient Efficient in in preventing preventing acute acute rejection rejection ( (-

• 10/15% vs. placebo)

10/15% vs. placebo)

• Kahan

Kahan BD, BD, et et al.

• al. Transplantation

Transplantation 67:276, 1999 67:276, 1999

• Ponticelli C,

Ponticelli C, et et al. Transplantation 72: 126, 2001

• al. Transplantation 72: 126, 2001
• Lawen JG, et al. Transplantation 75:37,2003

Lawen JG, et al. Transplantation 75:37,2003

• Adu D, et al. BMJ 326:789, 2003 (

Adu D, et al. BMJ 326:789, 2003 (metanalysis metanalysis) )

Expectations from Induction by means of anti-T Lymphocyte antibodies

• Prevention of damages from I/R injury

Prevention of damages from I/R injury

• Reduction of rate of acute rejection

Reduction of rate of acute rejection

• Promotion of (sort of) tolerance

Promotion of (sort of) tolerance

• Minimization of chronic

Minimization of chronic immunosuppression immunosuppression

TGF-β1 PDGF

ICAM-1

MHC II MØ and T cell

infiltration

TNF-α, IFN-γ, IL Endothelin Ox radicals, Free radicals

• x LDL

NO

I R

Chemochines

Adhesion molecules (leukocytes and endothelial cells)

Tx vasculopathy=

Graft Failure

T cell infiltration in I/R injury T cell infiltration in I/R injury

CD4+ KO mice CD4+ KO mice CD4+ T cell adoptive transfer CD4+ T cell adoptive transfer

NO Injury Injury

Model of Model of Leucocyte Leucocyte/ /Endothelium Endothelium Interaction Interaction

Glycoprotein

• r glycolipid

Fluid Shear Stress PSGL-1 L-selectin

• M

2

integrin

Mediators of chemotaxis

E-selectin P-selectin P-NAd MAdCAM-1 VCAM-1 MAdCAM-1 VCAM-1

Sticking Rolling Activation Arrest

sLex sLex sLex sLex sLex sLex

Y Y

sLex

ICAM-3 CD50 LPAM-1

• 4

7

CCR5 CXCR4 CCR7 ICAM-1 CD54 ICAM-2 CD102 VLA-4

CD49/CD29

LFA-1

• 1

2

LPAM-1

• 4

7

(activated)

VLA-4

CD49/CD29 (activated) CD195 CD184 CD197

Cellular distribution of RATG target antigens

Granulocytes

CD4, LFA-1, HLA I CD45, CD86, CD126,

VLA-4, LPAM-1 (integrins)

B cells T cells

CD3/TCR, CD2, CD4, CD5, CD6, CD7, CD8, CD25,CD28, CD30, CD45, CD80, CD86, CTLA-4, VLA-4, LFA-1, LPAM-1, CCR5, CCR7, CXCR4 (chemochine receptors), HLA I, 2-M CD19, CD20, CD25, CD27, CD30, CD32, CD38, CD40, CD45, CD86, CD95, HLA-DR CD138

Monocytes Endothelium

ICAM-1, ICAM-2, ICAM-3

NK cells

CD2, CD45, CD56

Plasmacells

Study of microcirculation in primates with Study of microcirculation in primates with ischemia/reperfusion injury of ischemia/reperfusion injury of estremities estremities effect of effect of ATG ATG (

(ATG ATG-

• F and Thymoglobulin)

F and Thymoglobulin)

Blood speed Leukocytes rolling Leukocytes flow Adhesion of leukocytes to endothelial walls

Chappell D, et al.Transplantation 2006; 81: 552-8

with ATGs:

DGF DGF with

with ATG ATG-

• F

F vs vs Basiliximab Basiliximab

3 groups of patients 3 groups of patients

• ATG

ATG-

• F (53)

F (53)

• Basiliximab

Basiliximab (58) (58)

• No induction (44)

No induction (44)

10 20 %

Kyllonen Kyllonen LE, et al. Transplantation 2007; 84:75 LE, et al. Transplantation 2007; 84:75-

• 82

82

Brennan DC, et al. NEJM 2006; 355:1967 Brennan DC, et al. NEJM 2006; 355:1967-

• 1977

1977

Thymoglobulin Thymoglobulin (n= 141) (n= 141) vs vs Basiliximab Basiliximab (n= 137) (n= 137) AR % AR % SRAR SRAR DGF % DGF %

15.6 25.5 1 8 40 44

Brennan DC, et al. NEJM 2006; 355:1967 Brennan DC, et al. NEJM 2006; 355:1967-

• 1977

1977

Thymoglobulin Thymoglobulin (n= 141) (n= 141) vs vs Basiliximab Basiliximab (n= 137) (n= 137)

• Similar, but extremely high rate of

Similar, but extremely high rate of DGF (40 DGF (40-

• 44%) but

44%) but CIT longer than 24 hours

Reduced rate and and severity of acute rejection with Thymo

Thymo

• comparable GS and PS

comparable GS and PS

Lebranchu Lebranchu et al. Am J Transplant 2002; 2: 48 et al. Am J Transplant 2002; 2: 48-

• 58

58

Thymoglobulin Thymoglobulin vs vs Basiliximab

Basiliximab

Transplantation with Transplantation with CIT shorter than 24 hours

DGF with Thymo 6% (vs 14%) SRAR with Thymo 8% (vs 14%)

Intra Intra-

• operative vs. Post
• perative vs. Post-
• operative
• perative

Thymoglobulin induction Thymoglobulin induction

Intra Intra-

• op
• p Post

Post-

• op
• p

Dose Dose of Thymo (cumulative)

• f Thymo (cumulative)

4.6 mg/Kg 4.6 mg/Kg 4.8 mg/Kg 4.8 mg/Kg

DGF DGF 4 4 11 11 Rejections Rejections 1 1 5 5

• W. Goggins et al, Transplantation 2003
• W. Goggins et al, Transplantation 2003

Expectations from Induction by means of anti-T Lymphocyte antibodies

• Prevention of damages from I/R injury

Prevention of damages from I/R injury

• Reduction of rate of acute rejection

Reduction of rate of acute rejection

• Promotion of (sort of) tolerance

Promotion of (sort of) tolerance

• Minimization of chronic

Minimization of chronic immunosuppression immunosuppression

Meccanisms of Tolerance induction

Clonal deletion total elimination of T and B cells i.e. lymphocyte depletion which has to be profound, both in the blood and in the lymphoid tissues Clonal suppression regolatory T cells (CD4+CD25+) which suppress activation and response against antigen Clonal anergy lymphocytes are present but don t act i.e. block of co-stimulation (signal 1 without signal 2)

Changes of number of peripheral lymphocytes with RATG (dose dependent)

1 2 3

• 1 1

3 5 7 9 11 13 15 17 19 0.4 0.8 1.2 0.5 1 1.5 2 1 2 3 0.5 1 1.5 2

• 1 1

3 5 7 9 11 13 15 17 19

• 1 1

3 5 7 9 11 13 15 17 19

• 1 1

3 5 7 9 11 13 15 17 19

• 1 1

3 5 7 9 11 13 15 17 19

Days

CD3+ CD4+ CD8+ CD2+ CD20+

Lymphocyte Counts (giga/L) Days

Control LOD HID sVHID lVHID

Préville X, et al. Transplantation. 2001;71:460-468

2 4 6

CD3+

1 2 3 4 5

CD20+

1 2 3 4

CD4+

1 2 3

CD8+

2 4 6

CD2+

1 2 3

CD56+ (NK)

CNTRL LOD HID sVHID lVHID

nd nd

CNTRL LOD HID sVHID lVHID CNTRL LOD HID sVHID lVHID

nd nd nd nd

Lymphocytes (no. × 108/g of tissue)

lymphocyte depletion in spleen with RATG

Préville X, et al. Transplantation. 2001;71:460-468

1 2 0.2 0.4 0.6 0.5 1 1.5 0.5 1 1.5 1 2 0.2 0.4

CNTRL LOD HID sVHID lVHID CNTRL LOD HID sVHID lVHID CNTRL LOD HID sVHID lVHID

CD3+ CD20+ CD4+ CD8+ CD2+ CD56+ (NK) Lymphocytes (no. × 109/g of tissue)

Lymphocyte depletion in lymph nodes with RATG (dose dependent)

Préville X, et al. Transplantation. 2001;71:460-468

T reg CD4 CD 25 FoxP3

CTLA-4

T reg+ cells

IL-2

Transcription factor forkhead box p3 Control gene of development and function

• f T reg
• chain of IL-2 receptor, required for

generation, survival and development of T reg constitutive, not induced as it is on effector T cells Crucial for generation and maintenance of T reg (CD4+CD25+ are severely impaired in IL-2 KO mice)

0 hrs 24 hrs

5%

Thymo Rabbit Ig

4% 28%

CD4+ CD25+ CD25+ CD4+ CD25+

49% 24% 50%

In vitro data

Expansion of CD4+ T cells expressing CD25 with Thymoglobulin

Lopez M, et al. J Am Soc Nephrol. 2006

Thymoglobulin-induced CD4+CD25+ cells have a Treg Phenotype

15 30

7% 1%

CD4+CD25HI

2% 22% 24% 8%

GITRCTLA-4 Foxp3

P =0.001 P =0.001 P =0.008 P <0.0001

Percent

Thymoglobulin Rabbit IgG

Adapted from Lopez M, et al. J Am Soc Nephrol. 2006

Other T cell Depleting and Non Depleting agents Other T cell Depleting and Non Depleting agents do not cause expansion of CD4 do not cause expansion of CD4+

+CD25

CD25+

+ T cells

T cells

Lopez M, et al. J Am Soc Nephrol. 2006;17(10) Epub Aug 16.

Campath-1H Basiliximab Daclizumab

unst rIL-2 unst rIL-2

PHA induced T lymphoblasts

Control Thymo

Thymoglobulin effects on T cell responses in vitro Thymo Thymo impairs the ability of T cells to proliferate

BUT BUT

up-regulates high-affiniy IL-2R

Donati Donati D, et al. 4th International Conference on New Trends in Clinica D, et al. 4th International Conference on New Trends in Clinical and l and Experimental Experimental Immunosuppression

• Immunosuppression. Geneva, Switzerland, February 2000

. Geneva, Switzerland, February 2000

Resting T lymphocytes do not proliferate in the presence of recombinant IL-2

Alemtuzumab Alemtuzumab (Campath (Campath-

• 1H)

1H)

Humanized monoclonal Humanized monoclonal antibody directed against antibody directed against CD52 antigen

• Expressed on B & T

Expressed on B & T lymphocytes lymphocytes

• Not expressed on bone

Not expressed on bone marrow progenitor cells marrow progenitor cells

• Induces more profound

Induces more profound lymphodepletion lymphodepletion than ATG than ATG

Human IgG1 construct

Murine CDRs

Carbohydrate

KIDNEY TRANSPLANTATION WITH RECIPIENT PRETREATMENT, LOW-DOSE POST-TRANSPLANT IMMUNOSUPPRESSION, AND SUBSEQUENT WEANING

Shapiro R, et al

Thymoglobulin 5mg/kg pre-operatively, or Campath 1H 30 mg 1-2 gm IV methylprednisolone Tacrolimus Monotherapy Started POD 1 Target trough levels - 10 ng/ml x 3 - 4 mo.

Ann Surg. 2003 October; 238(4): 520 525

0% 20% 40% 60% 80% 100%

Thymo Campath Reference

1 2 3 Years

Graft Survival

Thymoglobulin N Time to Weaning (months) 119/138 (86%) 6.0 + 2.5 86/94 (91%) 6.2 + 1.2 Campath

Weaning

Spaced Mono 79% Daily Mono 8% Multi 13% Multi 61% Daily Mono 39%

Campath Pretreated Thymoglobulin Pretreated Reference

Outcome (1.5 - 2.5 years)

Alemtuzumab Alemtuzumab (CAMPATH (CAMPATH-

• 1H) induction therapy

1H) induction therapy in cadaveric kidney transplantation Cyclosporine monotherapy

Efficacy and Safety at 5 years Efficacy and Safety at 5 years

• Single

Single center center study study

• Uncontrolled pilot study

Uncontrolled pilot study

• Adult primary renal transplant recipients

Adult primary renal transplant recipients

• Cadaveric

Cadaveric donors donors

• Alemtuzumab

Alemtuzumab (n=33) (n=33) vs vs Control group (n=66) Control group (n=66)

Immunosuppression Immunosuppression

• CsA

CsA, , whole blood trough concentration between 75 and

whole blood trough concentration between 75 and 125 125 ng ng/ml /ml

• Two doses of 20 mg of

Two doses of 20 mg of Alemtuzumab Alemtuzumab: first dose at the time : first dose at the time

• f surgery and the second 24 h later
• f surgery and the second 24 h later

Watson CJE et al. Am J Transplantation 5:1347, 2005 .

Results at 5 years

Watson CJE et al. Am J Transplantation 5:1347, 2005

33.6% 76% 85% Control n.s 31.5%

Acute Rejection

.58 74%

Graft Survival

.48 83%

Patient Survival

p-value Campath 1H CsA mono

The progressive nature of The progressive nature of calcineurin calcineurin-

• inhibitor

inhibitor nephrotoxicity nephrotoxicity

Nankivell BJ et al. N Engl J Med. 2003 100 75 50 25

Years after transplantation

0.5 0.25 0.75 1 2 3 4 5 6 7 8 9 10

Calcineurin nephrotoxicity (%)

PS % GS % AR % GFR ml/min 50 100 MMF-St Dacl-MMF-St Dacl-MMF-St Dacl-MMF-St CsA 100-200 CsA 50-100 Tacrolimus Sirolimus

Symphony Study 1 year; pts 1645

Larson Larson TS TS et et al. Am J

• al. Am J Transplant

Transplant 2006; 6: 514 2006; 6: 514 Patient Patient survival survival at 1 at 1 year year 98% 98% 96% 96% Deaths at 3 years Deaths at 3 years 5 5 7 7 Graft survival at 1 year Graft survival at 1 year 94% 94% 92% 92% at 3 years at 3 years 85% 85% 85% 85% Rejections Rejections 10/80 10/80 8/82 8/82 Subclinical rejections Subclinical rejections 6 6 6 6

Srl + MMF + Ster Tac + MMF + Ster

Thymoglobulin

Larson Larson TS TS et et al. Am J

• al. Am J Transplant

Transplant 2006; 6: 514 2006; 6: 514

Srl + MMF + Ster Tac + MMF + Ster

clearance clearance at 1 at 1 month month 67 ml/min 67 ml/min 58 ml/min 58 ml/min at 1 at 1 year year 63 63 61 61 at 2 year 61 at 2 year 61 61 61 Hystology Hystology Int Int Fibrosis Fibrosis = = Tub Tub Atrophy Atrophy = = Glom Glom sclerosis sclerosis = = Vasc Vasc Lesions Lesions ++ ++

Thymo Steroids MMF Srl Tx 5 90 150

• n

Varese Hospital Immunosuppressive Protocol (D Donati)

(32 cadaveric donor kidney tx)

days

2.5 mg/Kg 0.625 mg/Kg 1 g/day

Trough 10-15 Trough 8-12

D Donati, et al. Am J Transplant 2007: 160 (with modifications)

lymphodepletion T reg CD4+CD25+ memory T cells T reg CD4+CD25+

• DGF

DGF need of dialysis in the first week post

need of dialysis in the first week post-

• tx

tx:

: 3

3

including 1 case including 1 case di di ATN diagnosed in the donor ( ATN diagnosed in the donor (creatinine creatinine 3 mg/dl) 3 mg/dl) and 1 case of obstructive and 1 case of obstructive uropathy uropathy) )

• Rejections

Rejections: : 5 5

4 steroid sensible 4 steroid sensible 1 steroid resistant, antibodies sensible 1 steroid resistant, antibodies sensible

RESULTS

ADVERSE EVENTS ADVERSE EVENTS

(acute: post (acute: post-

• operative
• perative period

period)

)

• Leukopenia

Leukopenia: 15 : 15

• Thrombocytopenia

Thrombocytopenia : 12 : 12

• Anemia

Anemia : 11 : 11

• Infections

Infections (all (all patients patients received received prophylaxis prophylaxis with with

• ral
• ral gancyclovir

gancyclovir and and co co-

• trimoxazole

trimoxazole): ):

• No case of

No case of opportunistic

• pportunistic infections

infections

• 7 cases of bacterial infections

7 cases of bacterial infections including wound including wound and lymphocele and lymphocele

• 2 cases of fungal infections

2 cases of fungal infections (wound and (wound and lymphocele) lymphocele)

9 year Follow 9 year Follow-

• up

up

Deaths With Graft Function: Deaths With Graft Function:

1 death in the first year (digestive death in the first year (digestive hemorrhage hemorrhage) ) 1 death after 4 years (primary pulmonary hypertension) 1 death after 4 years (primary pulmonary hypertension) 1 1 death death after 8 after 8 years years ( (complications complications of

• f bowel obstruction)

bowel obstruction)

Graft losses: Graft losses:

2 in the first year: 2 in the first year: 1 late hemathoma, 1 late hemathoma, 1 for complications following wou 1 for complications following wound infections nd infections 1 after 4 years: 1 after 4 years: CAN CAN

STEROID WITHDRAWAL STEROID WITHDRAWAL 1 case of 1 case of hyposurrenalism hyposurrenalism 1 early death (*) 1 early death (*) 2 cases of mild increase of serum 2 cases of mild increase of serum creatinine creatinine 2 cases of rejection (**) 2 cases of rejection (**) 1 non compliance 1 non compliance MMF WITHDRAWAL MMF WITHDRAWAL 3 cases of mild increase of serum 3 cases of mild increase of serum creatinine creatinine 1 early death ( 1 early death (° °) ) CONVERSIONS TO CNI CONVERSIONS TO CNI 2 for rejections in re 2 for rejections in re-

• transplant patients (**)

transplant patients (**) 2 for severe 2 for severe lymphocele lymphocele

PROTOCOL VIOLATIONS 9 year Follow

9 year Follow-

• up

up 16 patients (out of 32) are currently on 16 patients (out of 32) are currently on sirolimus sirolimus monotherapy monotherapy

IMMUNOSUPPRESSIVE PROTOCOL IMMUNOSUPPRESSIVE PROTOCOL (CNI (CNI sparing sparing) )

Day 0 1 2 3 4 5 >6 R-ATG (mg/kg/day) 2.5 2 1.25 1 0.625-1 0.625-1 6-MP(mg/kg/day ) 10 7.5 5 3 2 1 tap to 8 mg/day MMF (g/day) = = = 2 2 2 2

DONORS: age > 65 years RECIPIENTS : age > 60 years

Donati D, et al. Transplant Proc. 2002 Aug;34(5):1678-80

RESULTS RESULTS

1-year 2.5-year

PATIENTS SURVIVAL: 100% 86% GRAFT SURVIVAL: 100% 86% DGF: 1/14 REJECTIONS: 2/14 biopsy proven (Banff IB and IIA)

steroid sensitive (1 pt converted to CsA)

Conclusions Conclusions

I Induction nduction with with depletional depletional anti anti-

• lymphocyte

lymphocyte antibodies antibodies

Low incidence of DGF: I/R damage Low incidence of rejection: ( I/R injury,

high immunosuppressive power by lymphodepletion)

Ability to minimize chronic immunosuppression Allows CNI avoidance by a likely tolerogenic effect However: not easy to handle

side effects from myeloinhibition

Induction Induction in in Hyperimmunized Hyperimmunized patients patients, , CDC CDC-

• Xm

Xm positive positive Transplantation Transplantation

• IgIv

IgIv

• Rituximab

Rituximab

• Plasma

Plasma-

• exchange

exchange

• Immuno

Immuno-

• adsorbtion

adsorbtion

• Eculizumab

Eculizumab

• Bortezomib

Bortezomib

• ATG,

ATG, Campath Campath, , Basiliximab Basiliximab

Hyperimmunized Hyperimmunized patients on waiting list for patients on waiting list for re re-

• transplantation (deceased donor) in Varese

transplantation (deceased donor) in Varese

Desensitation Desensitation Protocol Protocol

• IgIv

IgIv 2g/Kg 4 times on a monthly basis 2g/Kg 4 times on a monthly basis

• Rituximab

Rituximab 375 mg/m 375 mg/m2

2 one months after the last

• ne months after the last

administration of administration of IgIv IgIv Induction Regimen Induction Regimen

• Dual Induction: ATG

Dual Induction: ATG-

• F and

F and Basiliximab Basiliximab Maintenance Maintenance

• Tacrolimus

Tacrolimus + + Sirolimus Sirolimus + steroids + steroids

DR: DR: n= n= 4 4 DR: DR: n= n= 5 5

anti anti-

• HLA

HLA classe II classe II specificities specificities

34 34 54 54

%PRA %PRA

B12 B12 1:1 1:1 A31, B12 A31, B12 1:4 1:4

Specificities Specificities titer titer

15 15 25 25

%PRA %PRA B B lymphocytes lymphocytes

15 15

%PRA %PRA T T lymphocytes lymphocytes

A: A: n= n= 9 9 B: B: n= n= 5 5 A: A: n= n= 13 13 B: B: n= n= 9 9

anti anti-

• HLA

HLA class I class I specificities specificities

Luminex CDC

PRE-Desens POST-Desens

Case 1 male 43 y Tx Tx 01/06/2010

Specificities and MFI of DSA class I pre and post-Tx TX

Steroid Boluses

Specificities and MFI of DSA class II pre and post-Tx TX

Steroid Boluses

85 85 99 99

% PRA % PRA

Bw4 B22 Bw4 B22 A9, A19 A9, A19 1:64 1:64 B17 (1:32) B17 (1:32) Bw4 B22 Bw4 B22 A9, A19 A9, A19 1:64 1:64 B17 (1:128) B17 (1:128)

Specificities Specificities titer titer

70 70 90 90

%PRA %PRA B B lymphocytes lymphocytes

60 60 60 60

%PRA %PRA T T lymphocytes lymphocytes

DR: DR: n= n= 4 4 DQ: n=1 DQ: n=1 DR: DR: n= n= 4 4 DQ: n=1 DQ: n=1

anti anti-

• HLA

HLA class II class II specificities specificities

A: A: n= n= 7 7 B: B: n= n= 29 29 A: A: n= n= 10 10 B: B: n= n= 33 33

anti anti-

• HLA

HLA class I class I specificities specificities

Luminex CDC

PRE-Desens POST-Desens

Case 2: male 71 y Tx 02/07/2010

Specificities and MFI of DSA class I pre and post-Tx TX

ATG

Specificities and MFI of DSA class II pre and post-Tx TX

ATG

70 70 83 83

%PRA %PRA %PRA %PRA B B lymphocytes lymphocytes %PRA %PRA T T lymphocytes lymphocytes

DR: DR: n= n= 1 1 DQ: n=3 DQ: n=3 DR: DR: n= n= 1 1 DQ: DQ: n= n= 4 4

anti anti-

• HLA

HLA class II class II specificities specificities

A: A: n= n= 6 6 B: B: n= n= 15 15 A: A: n= n= 8 8 B: B: n= n= 18 18

anti anti-

• HLA

HLA class I class I specificities specificities

Luminex CDC

Case 3: female 53 y Tx Tx 19/08/2010

PRE-Desens POST-Desens

Specificities and MFI of DSA class I pre and post-Tx TX

Specificities and MFI of DSA class II pre and post-Tx

TX

Outcome Outcome

Fu (d) DGF AR fu creat side effects Fu (d) DGF AR fu creat side effects Pt 1 Pt 1 325 no 325 no no no 1.4 1.4 cmv cmv (pre (pre-

• empt

empt)

)

Pt 2 Pt 2 74 yes (20d) yes (IIB) 2 74 yes (20d) yes (IIB) 2 batteriemia batteriemia (Coli) (Coli) cmv cmv (disease) (disease) death (embolism) death (embolism) Pt 3 Pt 3 255 no no 1.3 no 255 no no 1.3 no

Conclusions Conclusions

• Results

Results are are not not consistent consistent

• However

However in in all all 3 the 3 the patients patients CDC CDC-

• Xm

Xm was was positive positive with with pre pre-

• desensitation

desensitation sera and sera and negative negative afterwards afterwards

• Given

Given the policy of the Nord Italia the policy of the Nord Italia Transplant Transplant program program those those hyperimmunizd hyperimmunizd patients patients would would hardly hardly have have found found a a suitable suitable donor donor to to be be transplanted transplanted