abmr pam

Antibody-Mediated Rejection in Kidney Transplant

Sumanee Prakobsuk10/07/2012

Pathophysiology and Pathology. Diagnosis criteria. Major Histocompatibility Complex (MHC)

molecule . Transplantation in the Presence of

Antidonor HLA Antibodies (sensitized patients).

Treatment Acute ABMR.

Content

Graft rejection caused by Abtibodies directed against HLA molecules, ABO antigens or endothelial cell antigens.

Most recipients do not have antibodies against HLA molecules before transplantation unless they were sensitized by exposure to alloantigens through ◦ Pregnancy◦ Blood transfusion,◦ Previous transplantation.

Antibody-Mediated Rejection

Types of ABMR

Pathophysiology of Antibody Mediated Rejection

DonorOrgan

Capillary Endothelia

l cell

Formation of

Antigen-Ab complex

DonorOrgan

Capillary Endothelia

l cell

Formation of

Antigen-Ab complex

C1 complex

Pathophysiology of AMR

Damaged Cell

Releases platelet

aggregation

factors, cytokines

Damaged Cell

Releases platelet

aggregation

factors, cytokines

Endothelial cell

necrosis

Endothelial cell

necrosis

Schwartz, NEJM 2010

C4

C4b C4d

C4d is by-product and marker of complement activation

4

Pathways to C4d deposition

Pathology of Acute ABMR

Glomerulitis Peritubular capillaritis

C4d +

Pathology of Chronic ABMR

Transplant glomerulopathy-Thickened of GBM-Double contours

C4d +Multilamination of GBM,PTC

Triad C4d+ Presence of circulating antidonor antibodies Morphologic evidence of acute tissue injury,

such as (Type/Grade):◦ I. ATN-like minimal inflammation◦ II. Capillary and or glomerular inflammation (ptc/g >0)

and/or thromboses◦ III. Arterial—v3 (tranmural arteritis/fibrinoid necrosis)

Diagnosis of Acute ABMR: Banff2007

C4d+ Presence of circulating antidonor antibodies Morphologic evidence of chronic tissue injury

◦ Glomerular double contours ◦ Peritubular capillary basement membrane

multilayering ◦ Interstitial fibrosis/tubular atrophy ◦ Fibrous intimal thickening in arteries

Diagnosis of Chronic ABMR:Banff2007

Suspicious for antibody-mediated rejection if - C4d or - Alloantibody

Not demonstrated in the presence of morphologic evidence of tissue injury.

Major Histocompatibility Complex (MHC) molecule

Major molecule for self vs. non-self determining process

Very high antigenicity

In human = human leukocyte Ag (HLA )

Gabriel M.Danovitch.Hand book of transplantation Fifth Edition

Chromosome 6


Major Histocompatibility Complex (MHC) molecule

Class I Class II On the surface of all

nucleated cells

Density of HLA class I expression

Plt > B cell > T cell A, B, C, E, F, G, MICA,

MICB Present Ag peptides to

CD8 T cells

Antigen-presenting cells (APCs), monocyte, macrophage, Kuffer cell, dendritic cells, alveolar type2 cells, renal mesangial cells, and B lymphocyte

DP,DQ, DR, DM,DO

Present Ag peptide to CD4 T cells


Memory B cell response

How does HLA sensitization occur?

Increased risk of: 1. Hyperacute rejection 2. Memory B cell response leading to early

ABMR 3. Chronic active ABMR

Why is being sensitized dangerous?

As always, we are doing three key tests

◦ Tissue typing ABO typing HLA typing

◦ HLA antibody screening◦ T and B cell crossmatching

Pretransplant immunologic evaluation

HLA typing

HLA mismatch ภาพ HLA typing

HLA antibody specificity testing

Panel Reactive Antibody Determine the state of pre-sensitization of the transplant Predict cross match result Predict waiting time

Technologies used to detect HLA antibodies (sensitization)

2 main methodologies:Complement-dependent

cytotoxicity (CDC)

CDC-anti-human globulin (CDC-AHG)

Serology

Flow cytometry

Luminex

Solid phase

Single antigen beads

Enzyme-linked immunosorbent assay (ELISA)

CDC-based assays

Lymphocytes (T cells, usually)

Patient serum

+ rabbit complement

Red = deadGreen = alive

CANNOT DIFFERENTIATE IgG FROM

IgM

Enhanced CDC-based assays

Enhance with anti-human

globulin

(AHG)

Lymphocytes

Patient serum

+ rabbit complement

The level of green fluorescence determines strength of reaction of allo-antibody

Luis G. Hidalgo,UAH Histocompatibility Laboratory

MCS=median channel shift MFI=mean fluorescence intensity

Luis G. Hidalgo,UAH Histocompatibility Laboratory

Cross-match

Most anti-HLA Ab are IgG.

Donor specific antibody against HLA Class I or II IgG were clinically relevant conferring both short and long term risk to the patients.

IgM HLA ab are not clinically relevant.

All CDC + IgG (either B or T cell ) contraindication for transplantation

CDC, CDC-AHG, Flow Crossmatch

Gebel and Bray. Transplantation Reviews 20: 189-194, 2006

CDC – and AHG +◦ no hyperacute rejection but may result in

early(1-2wk) acute rejection and graft loss

CDC – and FCXM + ◦ High risk in

Retransplant with previous early graft loss PRA >10% both primary and regraft

◦ Low risk in Current PRA< 10% both primary and regraft

Gebel and Bray. Transplantation Reviews 20: 189-194, 2006

Transplantation in the Presence of Antidonor HLA

Antibodies

Year of Waiting List Registration

Peak PRA

2000 2003 2005 2007 2009

0-9%

2,550

4,633

9,245

13,413

13,922

10-79%

1,082

1,807‚

3,210

4,792

5,817

>80%

765 1,249

2,156

3,29

9

3,919

Organ procurement and Transplant network : Annual Report

16.5%OPTN/SRTR 2010 Annual Report

Year of Transplant

Peak PRA

2000 2003 2005 2007 2009

0-9%

82.9%

80.5%

77.3%

75.6%

67.8%

10-79%

11.8%‚

11.7%

12.9%

13.7%‚

18.0%‚

>80%

3.1%‚

3.8%

4.8%

5.7%

7.9%‚

Transplant Recipient Characteristics, 2000 to 2009 Recipients of Deceased Donor

Kidneys

OPTN/SRTR 2010 Annual Report

Peak PRA

3 month

s(Tx2007-2008)

1 years(Tx200

7-2008)

5 years(Tx200

3-2008)

10 years(Tx199

8-2008)

0-9% 95.7%

91.9%

71.2%‚

45.3%

10-79%

95.4%

91.3%

69.9%

43.4%

>80% 94.9%

90.0%

69.2%

42.1%

Unadjusted Graft Survival, Deceased Donor Kidney Transplants Survival

at 3 Months, 1 Year, 5 Years, and 10 Years

OPTN/SRTR 2010 Annual Report

This has led to the problem of determining the threshold level and characteristics of donor-specific HLAab (DSA HLA-ab) that have a meaningful impact on clinical outcomes

Retrospective review. DDKT, 18 centers To investigate the relationship between the

pretransplant presence of HLA class I and classII antibodies and the development of no immediate function and Acute rejection episode.

Patients with NIF or ARE were positive for HLAclass I and II Abtibodies in their pretransplantation serum than patients without NIF or ARE

Conclusion

Strong relationship between the presence of HLAab and

poor immediate graft function

acute rejection reduce graft survivalHowever, there was no determination

of whether the HLAabs were DSA

Observational study Single-center study of 402 consecutive DDKT. Examined the impact of the strength of HLA-DSA

detected on the risk for AMR and graft survival in DDKT 1998-2006

DSA HLAab by Luminex single antigen bead assay

Mean F/U 51.4+- 30.6 monthsCarmen Lefaucheur. J Am Soc Nephrol 21: 1398–1406, 2010

Graft survival

The presence of HLA-DSAs on the highest rank pregraft serum associates with a significantly decreased graft survival (A),regardless of whether HLA-DSAs were class I or II (B).

AntiHLA+ DSA+61%AntiHLA- DSA - 84%AntiHLA+DSA- 93%

RR for acute AMR according to the MFI ofhighest pregraft ranked DSA detected by

Luminex

Carmen Lefaucheur. J Am Soc Nephrol 21: 1398–1406, 2010

Total Transplant Pt Without ABMR Pt


long term graft survival was significantly inferior for patients who had any detectable preexisting DSA

Luminex peak MFI predicted AMR and graft survival.

MFI > 3000 appeared to the cutoff for significant decrease in graft survival and whether an episode of ABMR occurred.

Conclusions


Proteins other than HLA antigens can also serve as targets of AMR.

MICA : MHC Class I chain A. Antiangiotensin type I receptor antibody.

Non-HLA abtibodies

NephSAP Transplant, november 2011

MICA antigens are expressed on endothelial cells, dendritic cells, fibroblasts, epithelial cells, and many tumors

But not on peripheral-blood lymphocytes.

MICA protein do not associate with B2 micoglobulin as do MHC class I antigens and not serve to present antigen to T cell

They are instead ligands for NK cells.

MICA-Antibody


Since MICA antigens are not expressed on lymphocytes,the cells commonly used for cross-matching

Antibodies directed against MICA are not detected with the methods generally used.


MICA-Antibody

To determine whether an immune response to MICA antigens might play a role in the failure of kidney allografts.

Pretransplantation serum samples from 1910 DDKT. Between 1990 and 2004 20 centers in 13 countries. IgG anti-HLA class I & II test : ELISA kits Tests for IgG antibodies against MICA

antigens :microbeads (Luminex)Yizhou Zou, M.D.N Engl J Med 2007;357:1293-300.

1

11.4 %P=0.01

93 ±0.6 %

88.3 ±2.2 %

Presensitization of kidney-transplant recipients against MICA antigens is associated with an increased frequency of graft loss and might contribute to allograft loss among recipients who are well matched for HLA.

Conclusions

Yizhou Zou, M.D.N Engl J Med 2007;357:1293-300.

These studies are unable at this time to provide any absolute thresholds for the decision to transplat with a given organ or not.

But do provide data to begin to define level of risk


Desensitization Protocols

Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 2011

author No Pts Induction

F/UMonths

AR/AMR

Pt survival(%)

Graft survival(%)

Schweitzwe2000

11 OKT3 13 36/27 100 100

Magee2008

28 Thymo/Basiliximab/Ritux

22 71/39 93 89

Thielke2009

51 Thymo/Ritux

23 33/24 95 93

Haririan2009

41 OKT3 or Thymo

47 24/12 78 66

Desesitization protocols and clinical outcomesPP/low-dose IVIG


author

No Pts

Induction

F/UMonths

AR/AMR(%)

Pt survival(%)

Graft survival(%)

Glotz2002

13 Thymo 12 8/8 100 93

Jondan2003

42 Daclizumab

24 31/31 98 89

Mai2009

20 Thymo 36 50/30 94 89

Bachler2010

37 Thymo 24 38/38 95 87

High-dose IVIG


M.D. Stegalla. American Journal of Transplantation 2006; 6: 346–351

0

20

40

60

80

100

38

84 8880

3729

negative crossmatchAcute ABMR

Results

PP/low-dose IVIG and rituximabdemonstrated more success in abrogating positive cross-match and lower acute rejection rates

To investigate the effects of desensitization protocols using IVIg with or without plasmapheresis in patients with donor-specific anti-HLA antibodies on prevention ofantibody-mediated rejection and downregulation of donor-specific antibodies.

Enver Akalin. Clin J Am Soc Nephrol 3: 1160–1167, 2008

Pretransplantation DSA, negative CDC cross-match.

Anti-HLA antibodies were studied by Luminex single Beads .

Biopsies were performed for an increase in creatinine level and/or proteinuria.


Induction:Thymoglobulin 1.5 mg/kg per d for 5 d Maintenamce: tacrolimus, mycophenolate mofetil,and a steroid taper.

All patients received high-dosage IVIG 1.0 g/kg during transplant surgery and 500 mg/kg on each of postoperative days 1 and 2.

Immunosuppressive Treatment Protocol


◦LRKT candidates with strong class I DSA 4-8 sessions of pretransplantation PP over 2 to 3 wk underwent transplantation after their DSA strength

decreased to moderate or weak.

◦DDKT recipients with DSA 3 sessions of PP every other day starting onpostoperative day 1.


Immunosuppressive Treatment Protocol

Strong MFI> 6000Moderate MFI 4000 to 5999Weak MFI 1500 to 3999.

Clinical outcomes


Group 1 , Seven ( 70%) patients lost DSA completely Group 2, four (44%) patients lost DSA Completely Group 3, six (43%) patients lost DSA completely

CONCLUSIONS Kidney transplant recipients with DSA are at higher risk

for developing early acute AMR despite negative CDC T cell cross-match and require desensitization.

Not only should the presence of DSA be documented, but also the strength or titers of the alloantibodies should be determined to decide the type of the desensitization protocol.

Highdosage IVIG alone dose not prevent AMR in patients with strong DSA

Aaddition of peritransplantation PP significantly decreases the incidence of AMR.Enver Akalin. Clin J Am Soc Nephrol 3: 1160–1167, 2008

Assessed the histological lesions at 3 months and 1 year in patients receiving DDKT,

comparing those with preformed DSA to those without. Second, we evaluated the presence and extent of SAMR. From January 2002 to March 2007

A. Loupya. American Journal of Transplantation 2009; 9: 2561–2570

Group A (n = 54 )DSA positive

Group B (n = 83)without preformed DSA

Induction :10-day course of ATG a dose of 75 mg/d.

4 courses of IVIg a dose of 2 g/kg administered over 96 h ◦ first course started before reperfusion,◦ subsequent courses being given on days 21, 42 and 63.

From 2006 onward, the final 18 patients◦ Received additional prophylactic Rituximab at a dose of 375

mg/m2 at day 4 Together with plasmapheresis performed immediately

posttransplant then three times per week for 3 weeks.

20 mg intravenous Basiliximab Day 0,4

Screening Kidney Bx and measured glomerular filtration rate (GFR) at 3 months and 1 year.

3-month and 1-year screening biopsies results according to the presence or absence of DSA

At 3 months after transplant 31 % Subclinical AMR in DSA +

At 1 year Score higher IF/TA

100 % vs 33 %

TG 43% vs 0%


If these findings are comfirmed in a large series of patients. Protocol Biopsies may be a valuable tool in the management of this

population ?? Treatment protocol ??

Approach to Sensitized Patients


Our review article demonstrates the importance of the strength of DSAs for development of AMR.

Currently, we screen all transplant candidates for anti-HLA antibodiesusing Luminex single-antigen beads for the specificity and the strength of antibodies

Renal Division,Albert Einstin College of MedicineMontefioreMedicalCenter,Bronx, New York

De Novo DSA

Sequential evaluation of sera for dnDSA in a consecutive cohort of kidney transplants.

Risk factors for dnDSA development Correlation of dnDSA with clinical pathologic

and outcome.

C. Wiebea,†, I. W. Gibsonb,c,†,T. D. Blydt-Hansend, M. Karpinskie, J. Hoe,L. J. Storsleye, A. Goldbergd, P. E. Birkd,D. N. Rushe and P. W. Nickersona,c,*

C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167

DSA screening was performed using FlowPRA beads representing HLA-A,-B, -Cw, -DR, -DQ and -DP antigensHLA antibody specificities was performed using FlowPRA single antigen class I and II beads


Kidney biopsy ◦ Six-month protocol biopsies.

◦ Newly detected dnDSA patients since January 2008 as standard of care

◦ Clinically indicated allograft biopsy. proteinuria was ≥0.5 g/day Cr rose ≥25% from baseline without a known cause.


Baseline characteristic


Pathologic correlations with patient phenotypes at the time of dnDSA detection


dnDSA develops in 15% of low risk renal transplant recipients

Mean 4.6 +- 3 years posttransplant

Graft survival at 10 years reduce by 40% Independent risk factors for dnDSA development

◦ HLA-DRB1 MM ◦ nonadherence ◦ cellular rejection before dnDSA onset

The dnDSA typically arises before the onset of proteinuria or rise creatinie.

The principal finding of this study


6: TREATMENT OF ACUTE REJECTION

6.1: We recommend biopsy before treating acute rejection, unless the biopsy will substantially delay treatment. (1C)

6.2: We suggest treating subclinical and borderline acute rejection. (2D)

Treatment ABMR

BL Kasiske et al.: KDIGO guideline 2009 for kidney transplant recipients

6.4: We suggest treating antibody-mediated acute rejectionwith one or more of the following alternatives, with orwithout corticosteroids (2C): Plasma exchange Intravenous immunoglobulin anti-CD20 antibody lymphocyte-depleting antibody.

6.5: For patients who have a rejection episode, we suggest Adding mycophenolate if the patient is not receiving

mycophenolate or azathioprine, or switching azathioprine to mycophenolate. (2D)

Treatment ABMR

BL Kasiske et al.: KDIGO guideline 2009 for kidney transplant recipients

Intravenous Immunoglobulin

IAN R. M ACKAY, M.D., N Engl J Med, Vol. 345, No. 10 September 6, 2001

Routinely used High dose: 2 gm/kg Low dose: 100 mg/kg per session

Low-dose IVIG is mostly used in combination with plasmapheresis where it may help replenish depleted IGs.

Initial studies used IVIG at high-doses without plasmapheresis and described a fair degree of success in desensitization prior to transplant and also for treating antibody-mediated rejection.


Chethan Puttarajappa, Journal of Transplantation Volume 2012

Side effects◦Aseptic meningitis◦Volume overload◦AKI possible to high osmotic load



Plasmapheresis is very effective in reducing the antibody load but needs to be used in conjunction with other therapies that target the antibody producing mechanisms.

DSAs are monitored along with renal function to document the effectiveness of the therapy.

Treatment, if successful, is continued until thelevel of antibodies has dropped to safe levels along with improvement in renal function.

Plasmapheresis


The mechanism of action of Rituximab in AMR is not clear, however, the depletion of CD20-positive subset of B-cells may attenuatethe antibody generation process.

Side effects◦ Acute infusion reactions◦ Reactivation of latent viruses such as hepatitis B, C,

CMV, and TB

Rituximab


The retrospective 2001-2006 Compared the outcomes of a PP-based vs. a

PP plus rituximab regimen to treat patients experiencing AMR and resistant to steroid plus anti-lymphocyte globulin treatment.

Kaposztas et al.Clin Transplant 2009: 23: 63–73

Induction: •simulect•High risk PRA>20%,African,re-transplant:Thymoglobulin

• At the end of each PP cycleRituximab(375 mg/m2).

Graft survival rates at 2 years group A 90%group B 60%

Beneficial effect was observed with PP in addition to treatment with rituximab in AMR

Kaposztas et al.Clin Transplant 2009: 23: 63–73

DDKT Biopsy prove AMR & DSA+ Negative current CDC crossmatch All patients received induction with

◦ thymoglobulin (1.5 mg/kg/day × 7–10 doses) Maintenance immunosuppression

◦ steroids +Cellcept+tacrolimus /cyclosporine Patients with remote positive IgG T- and B-cell CXM received IVIg

at the time of transplantation as prophylaxis against acute rejection (2 g/kg days 0–1, 20–21 and 40–41).

Lefaucheur.American Journal of Transplantation 2009; 9: 1099–1107

High-dose IVIg regimen (group A) ◦ 12 patients with AMR/DSA+◦ diagnosed between January 2000 and December

2003◦ 2 g/kg IVIg, administered over 2 days every 3

weeks, × 4 doses

• Plasmapheresis /IVIg/anti-CD20 regimen (group B)

- 12 patients with AMR/DSA+- diagnosed between January 2004-December 2005. - daily 1-PV followed by administration of low dose of

IVIg (100 mg/kg) *4- After the last PP

- high-dose IVIg as described above (2 g/kg every 3 weeks, × 4 doses)

- two weekly doses of rituximab (375 mg/m2)

Graft survival at 36 months following the episode of AMR•50% in group A•91.7% in group B

High-dose IVIg regimen

PP /IVIg/anti-CD20


High-dose IVIg regimen PP /IVIg/anti-CD20

8465 ± 6560

2671 ± 2189

PP/IVIg/anti-CD20 leads to improved graft survival over protocols using IVIg alone.

Graft survival at 36 months was◦ 91.7% PP/IVIg/anti-CD20 regimen◦ 50% in IVIg.

Diminution of DSAs levels is significantly greater in patients treated by the association of PP/IVIg/anti-CD20 as compared to those treated by IVIg.

Conclusion


Bortezomib is a novel proteosome inhibitor that is approved for the treatment of multiple

myeloma.

Inhibition of proteasomes can lead to decreased nuclear factor-Kappa B activation, cell cycle arrest, endoplasmic reticulum stress, and increased cell apoptosis .

This action is pronounced in plasma cells likely because of the high antibody turnover and high endoplasmic reticulum activity.

Bortezomib (Velcade)

Rajeev Raghavan,Journal of Transplantation Volume 2010

Author Center

N Complete therapy

Results summary

Idica et al. 2008

- 13 Detail not apparent

(i) 10 of 13 had significant decrease (reversal) of DSA(ii) 100% had reduced MFI ofantibodies

+

Raghavan et al.2009

Houston, TX,USA

1 (i) 4 cycles bortezomib, one dose rituximab, dailymycophenolate

(i) Reduced PRA (55% → 30%) and significant reduction of class I antibodies(ii) Successful transplant with good allograft function at 6-months

+

Wahrmann et al.2010

Vienna,Austria

2 (i) 2 cycles bortezomib atintervals of 3- and4-months, both given withsteroids

(i) cPRA mildly decreased in both patients(ii) Overall, no significant effect on the levels of antigen-specific IgG or ABO blood group antibodies

-

Clinical and outcomes of published Desensitization protocols using

Bortezomib


Author Center N Complete therapy

Result summary

Walsh et al.2010 [

CincinnatiOhio, USA

2 (i) 1 cycle bortezomib(ii) ongoingplasmapheresis, rituximab,intravenous steroids(iii) pheresis done at least 72 hours post-bortezomib

(i) Immediate significant reduction of DSA(ii) Good allograft function at 5- and 6-months follow-up(iii) One patient had re-elevation of DSA which responded to a secondcourse of treatment

+

Sberro-Soussanet al. 2010

Paris, France

4 (i) 1 cycle bortezomib (solo therapy)

(i) No effect on anti-HLA antibodieswithin 40 subsequent days, and at 150days follow-up.

-

Clinical and outcomes of published Rejection protocols using

Bortezomib


case series of four renal transplant recipients in whom graft biopsy disclosed ABMR , accompanied by persistent DSA.

All patients received bortezomib (1.3 mg/m2) on days 1, 4,8 and 11 as sole desensitization therapy without any modification of their maintenance immunosuppressive treatment.

American Journal of Transplantation 2010; 10: 681–686

American Journal of Transplantation 2010; 10: 681–686

Bortezomib failed to decrease DSA intensity within the 150-day follow-up period in all patients.

They concluded that a single cycle of bortezomib does not seem to exert an effect on any long-lived antibody levels (further than 1 year post-transplant)

20 patients with AMR and DSA + a mean of 19 months after transplantation.

Flechner et al. Transplantation • Volume 90, Number 12, December 27, 2010

1. For acute cellular rejection, Banff scored grade 1A/B:initial pulse steroid treatment with 15 to 20 mg/kg IV methylprednisolone given in three divided daily doses (500 mg three times).

2. Initiation of plasmapheresis twice weekly for two weeks (total four treatments). Treatments were spaced to days 1-4-8-11.

3. IV bortezomib given as 1.3 mg/m2 after each plasmapheresis (total four treatments).

4. When the plasmapheresis was completed, the addition of 2 g/kg IVIG (0.5 g/kg in four divided treatments) was given to the majority of recipients.

The treatment of AMR was given in a 2-week cycle that included:


•The mean decrease from peak-nadir MESF/MFI of the most dominant DSA was 55% .•only 25 % had undetectable DSA after treatment.

For the entire group, patient survival is 100%, and graft survival is 85% with a mean follow-up of 9.8 months

They found that patients with SCr< 3 mg/dl had better response

• There is a rational for combining Bortezomib with plasmapheresis, as it may be more effective in eliminating plasma cell that produceing high levels of antibody.


Neurotoxicity 30 % Thrombocytopenia 28% Neutropenia 11 % Nausea 55% Diarrhea 44% Fatigue 12%

Side effects of Bortezomib


Humanized monoclonal antibody directed against complement protein C5.

Thereby inhibiting conversion of C5 to C5b and preventing formation of the membrane attack complex (C5–9).

Eculizumab

Antibody-mediated rejection is an important cause of acute and chronic graft failure.

Improvements in HLA technologyrevolutionized the understanding of this important entity.

Transplantation of sensitized patients remains a difficult problem.

However, developments such as paired kidney donation and desensitization protocolsare continuously improving the rates of transplantation in this difficult to transplant population.

Take Home Messages

Therapies for AMR are still not optimal with high rates of graft loss leading to poor patient outcomes.

Newer therapies, such as bortezomib and eculizumab that target novel pathways in the AMR process are promising but will need further randomized studies before becoming widely used.

Studies will need to be performed to determine the best use, either alone or in combination, of the myriad number of therapies currently available

Take Home Messages

THANK YOUTHANK YOU

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