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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
Gabriel M.Danovitch.Hand book of transplantation Fifth Edition
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
Gabriel M.Danovitch.Hand book of transplantation Fifth Edition
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
Carmen Lefaucheur. J Am Soc Nephrol 21: 1398–1406, 2010
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
Carmen Lefaucheur. J Am Soc Nephrol 21: 1398–1406, 2010
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
NephSAP Transplant, november 2011
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.
NephSAP Transplant, november 2011
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
NephSAP Transplant, november 2011
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
Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 2011
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
Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 2011
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.
Enver Akalin. Clin J Am Soc Nephrol 3: 1160–1167, 2008
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
Enver Akalin. Clin J Am Soc Nephrol 3: 1160–1167, 2008
◦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.
Enver Akalin. Clin J Am Soc Nephrol 3: 1160–1167, 2008
Immunosuppressive Treatment Protocol
Strong MFI> 6000Moderate MFI 4000 to 5999Weak MFI 1500 to 3999.
Clinical outcomes
Enver Akalin. Clin J Am Soc Nephrol 3: 1160–1167, 2008
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.
A. Loupya. American Journal of Transplantation 2009; 9: 2561–2570
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%
A. Loupya. American Journal of Transplantation 2009; 9: 2561–2570
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
Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 2011
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
Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 2011
Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 2011
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
C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
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.
C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
Baseline characteristic
C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
Pathologic correlations with patient phenotypes at the time of dnDSA detection
C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
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
C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
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.
Intravenous Immunoglobulin
Chethan Puttarajappa, Journal of Transplantation Volume 2012
Side effects◦Aseptic meningitis◦Volume overload◦AKI possible to high osmotic load
Intravenous Immunoglobulin
Chethan Puttarajappa, Journal of Transplantation Volume 2012
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
Chethan Puttarajappa, Journal of Transplantation Volume 2012
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
Chethan Puttarajappa, Journal of Transplantation Volume 2012
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
Lefaucheur.American Journal of Transplantation 2009; 9: 1099–1107
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
Lefaucheur.American Journal of Transplantation 2009; 9: 1099–1107
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
Rajeev Raghavan,Journal of Transplantation Volume 2010
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
Rajeev Raghavan,Journal of Transplantation Volume 2010
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:
Flechner et al. Transplantation • Volume 90, Number 12, December 27, 2010
•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.
Flechner et al. Transplantation • Volume 90, Number 12, December 27, 2010
Neurotoxicity 30 % Thrombocytopenia 28% Neutropenia 11 % Nausea 55% Diarrhea 44% Fatigue 12%
Side effects of Bortezomib
Rajeev Raghavan,Journal of Transplantation Volume 2010
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
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