ABMR pam

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  • Acitivation of complement leads to lysis of endothelial cells and acute rejectionIncomplete inhibition of complement might prevent endothelial cell lysis but not complement activation leading to endothelial cell C4 is a component of the complement system, and is cleaved by C1 after antibody binds to antigen. As C4d is bound to the kidney, it's a local marker of inflammationT cells initiate and maintain primary and memory B cell responses
  • Ref 10 Nepsap
  • คนไข้ที NIF & ARE  positive HLA Abมากกว่าคนที่ IF & no ARE อย่าง significantPRA>50% ก็เช่นกันแต่ไม่ sig
  • ABMR pam

    1. 1. Sumanee Prakobsuk 10/07/2012
    2. 2.  Pathophysiology and Pathology. Diagnosis criteria. Major Histocompatibility Complex (MHC) molecule . Transplantation in the Presence of Antidonor HLA Antibodies (sensitized patients). Treatment Acute ABMR.
    3. 3.  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.
    4. 4. Donor Organ 4 Damaged C1 CapillaryEndothelial Cell Releases complex  cell platelet aggregatio C4Formation n of factors, cyt  Antigen- okines Ab C4b  complex C4d Endothelial cell necrosis C4d is by-product and marker of complement activation Schwartz, NEJM 2010
    5. 5. Glomerulitis Peritubular capillaritis C4d +
    6. 6. Transplant glomerulopathy-Thickened of GBM-Double contours C4d + Multilamination of GBM,PTC
    7. 7. 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)
    8. 8.  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
    9. 9.  Suspicious for antibody-mediated rejection if - C4d or - Alloantibody Not demonstrated in the presence of morphologic evidence of tissue injury.
    10. 10.  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
    11. 11. Gabriel M.Danovitch.Hand book of transplantation Fifth Edition
    12. 12. Class I Class II On the surface of all  Antigen-presenting cells nucleated cells (APCs), monocyte, macro phage, Kuffer cell, dendritic Density of HLA class I cells, alveolar type2 expression cells, renal mesangial Plt > B cell > T cell cells, and B lymphocyte A, B, C, E, F, G, MICA, MI  DP,DQ, DR, DM,DO CB Present Ag peptides to  Present Ag peptide to CD8 T cells CD4 T cells Gabriel M.Danovitch.Hand book of transplantation Fifth Edition
    13. 13.  Increased risk of: 1. Hyperacute rejection 2. Memory B cell response leading to early ABMR 3. Chronic active ABMR
    14. 14. Pretransplant immunologic evaluationAs always, we are doing three key tests ◦ Tissue typing  ABO typing  HLA typing ◦ HLA antibody screening ◦ T and B cell crossmatching
    15. 15.  HLA typing
    16. 16. Panel Reactive Antibody Determine the state of pre-sensitization of the transplant Predict cross match result Predict waiting time
    17. 17. Technologies used to detect HLA antibodies (sensitization)2 main methodologies: Complement-dependent cytotoxicity (CDC) Serology CDC-anti-human globulin (CDC- AHG) Enzyme-linked immunosorbent assay (ELISA) Solid Flow phase cytometry Single antigen beads Luminex
    18. 18. Lymphocytes (T cells, usually)Patientserum + rabbit complement Red = dead CANNOT Green = alive DIFFERENTIATE IgG FROM IgM
    19. 19. LymphocytesPatientserum Enhance with anti-human globulin (AHG) + rabbit complement
    20. 20. MCS=median channel shift MFI=mean fluorescence intensity Luis G. Hidalgo,UAH Histocompatibility Laboratory
    21. 21. Luis G. Hidalgo,UAH Histocompatibility Laboratory
    22. 22.  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 Gebel and Bray. Transplantation Reviews 20: 189-194, 2006
    23. 23.  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
    24. 24. Year of Waiting List RegistrationPeak 2000 2003 2005 2007 2009 PRA0-9% 10- 16.5%79%OPTN/SRTR 2010 Annual Report
    25. 25. Year of TransplantPeak 2000 2003 2005 2007 2009 PRA0-9% 10-79% OPTN/SRTR 2010 Annual Report
    26. 26. Peak 3 1 years 5 years 10 This has led to the problem of determiningPRAthreshold level and characteristics years the month (Tx2007 (Tx2003 of s -2008) -2008) (Tx1998 donor-specific HLAab (DSA HLA-ab) that have -2008) (Tx200 a meaningful impact on clinical outcomes 7-2008)0-9% 10- OPTN/SRTR 2010 Annual Report79%
    27. 27.  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.
    28. 28. Patients with NIF or ARE were positive forHLAclass I and II Abtibodies in theirpretransplantation serum than patientswithout NIF or ARE
    29. 29. Strong relationship between the presence of HLAab and  poor immediate graft function  acute rejectionHowever, there was reduce graft survival  no determination of whether the HLAabs were DSA
    30. 30.  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 months Carmen Lefaucheur. J Am Soc Nephrol 21: 1398–1406, 2010
    31. 31. AntiHLA+ DSA+61% AntiHLA- DSA - 84% AntiHLA+DSA- 93%The presence of HLA-DSAs on the highest rankpregraft serum associates with a significantlydecreased graft survival (A),regardless of whether HLA-DSAs were class I or II (B).
    32. 32. Carmen Lefaucheur. J Am Soc Nephrol 21: 1398–1406, 2010
    33. 33. Total Transplant Pt Without ABMR Pt Carmen Lefaucheur. J Am Soc Nephrol 21: 1398–1406, 2010
    34. 34.  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. Carmen Lefaucheur. J Am Soc Nephrol 21: 1398–1406, 2010
    35. 35.  Proteins other than HLA antigens can also serve as targets of AMR. MICA : MHC Class I chain A. Antiangiotensin type I receptor antibody. NephSAP Transplant, november 2011
    36. 36.  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. NephSAP Transplant, november 2011
    37. 37.  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
    38. 38.  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.
    39. 39. 93 0.6 % 88.3 2.2 %P=0.01 11.4 %
    40. 40.  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. Yizhou Zou, M.D.N Engl J Med 2007;357:1293-300.
    41. 41.  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
    42. 42. Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 2011
    43. 43. PP/low-dose IVIGauthor No Pts Inducti F/U AR/AM Pt Graft on Months R survival survival (%) (%)Schweitz 11 OKT3 13 36/27 100 100we2000Magee 28 Thymo/ 22 71/39 93 892008 Basilixim ab/RituxThielke 51 Thymo/ 23 33/24 95 932009 RituxHaririan 41 OKT3 or 47 24/12 78 662009 Thymo Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 2011
    44. 44. High-dose IVIGauthor No Pts Induct F/U AR/ Pt Graft ion Month AMR surviv surviv s (%) al(%) al(%)Glotz 13 Thymo 12 8/8 100 932002Jondan 42 Daclizu 24 31/31 98 892003 mabMai200 20 Thymo 36 50/30 94 899Bachler 37 Thymo 24 38/38 95 872010 Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 2011
    45. 45. M.D. Stegalla. American Journal of Transplantation 2006; 6: 346–351
    46. 46. negative crossmatch Acute ABMRPP/low-dose IVIG and rituximabdemonstrated more success in abrogating positivecross-match and lower acute rejection rates
    47. 47.  To investigate the effects of desensitization protocols using IVIg with or without plasmapheresis in patients with donor-specific anti-HLA antibodies on prevention of antibody-mediated rejection and downregulation of donor-specific antibodies. Enver Akalin. Clin J Am Soc Nephrol 3: 1160–1167, 2008
    48. 48.  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
    49. 49.  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. Enver Akalin. Clin J Am Soc Nephrol 3: 1160–1167, 2008
    50. 50. ◦ 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 on postoperative day 1. Strong MFI> 6000 Moderate MFI 4000 to 5999 Weak MFI 1500 to 3999. Enver Akalin. Clin J Am Soc Nephrol 3: 1160–1167, 2008
    51. 51.  Group 1 , Seven ( 70%) patients lost DSA completely Group 2, four (44%) patients lost DSA Completely Group 3, six (43%) patients lost DSA completely Enver Akalin. Clin J Am Soc Nephrol 3: 1160–1167, 2008
    52. 52.  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
    53. 53.  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
    54. 54. Group A (n = 54 )DSA positive 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. Screening onward, the final 18 patients From 2006 Kidney Bx and measured glomerular filtrationat day 4(GFR) at 3 months and dose of 375 ◦ Received additional prophylactic Rituximab at a mg/m2 rate 1 year. Together with plasmapheresis performed immediately posttransplant then three times per week for 3 weeks. Group B (n = 83)without preformed DSA 20 mg intravenous Basiliximab Day 0,4
    55. 55. A. Loupya. American Journal of Transplantation 2009; 9: 2561–2570
    56. 56. At 3 months after transplant31 % Subclinical AMR in DSA + At 1 year  Score higher IF/TA 100 % vs 33 %  TG 43% vs 0%
    57. 57.  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 ?? A. Loupya. American Journal of Transplantation 2009; 9: 2561–2570
    58. 58. Our review article demonstrates theimportance of the strength of DSAs fordevelopment of AMR.Currently, we screen all transplantcandidates for anti-HLA antibodiesusing Luminex single-antigen beads forthe specificity and the strength ofantibodies Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 2011 Renal Division, Albert Einstin College of Medicine MontefioreMedicalCenter,Bronx, New York
    59. 59. Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 2011
    60. 60. Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 2011
    61. 61. 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,* 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. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
    62. 62. DSA screening was performed using FlowPRAbeads representing HLA-A,-B, -Cw, -DR, -DQand -DP antigensHLA antibody specificities was performed usingFlowPRA single antigen class I and II beads C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
    63. 63.  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
    64. 64. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
    65. 65. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
    66. 66. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
    67. 67. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
    68. 68. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
    69. 69.  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. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
    70. 70.  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) BL Kasiske et al.: KDIGO guideline 2009 for kidney transplant recipients
    71. 71. 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) BL Kasiske et al.: KDIGO guideline 2009 for kidney transplant recipients
    72. 72. IAN R. M ACKAY, M.D., N Engl J Med, Vol. 345, No. 10 September 6, 2001
    73. 73. 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
    74. 74.  Side effects ◦ Aseptic meningitis ◦ Volume overload ◦ AKI possible to high osmotic load Chethan Puttarajappa, Journal of Transplantation Volume 2012
    75. 75.  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 the level of antibodies has dropped to safe levels along with improvement in renal function. Chethan Puttarajappa, Journal of Transplantation Volume 2012
    76. 76.  The mechanism of action of Rituximab in AMR is not clear, however, the depletion of CD20-positive subset of B-cells may attenuate the antibody generation process. Side effects ◦ Acute infusion reactions ◦ Reactivation of latent viruses such as hepatitis B, C, CMV, and TB Chethan Puttarajappa, Journal of Transplantation Volume 2012
    77. 77.  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
    78. 78. • At the end of each PP cycleRituximab(375 mg/m2).Induction:•simulect•High risk PRA>20%,African,re-transplant:Thymoglobulin
    79. 79. Graft survival rates at 2 years group A 90% group B 60%Beneficial effect was observed with PP inaddition to treatment with rituximab in AMR
    80. 80. Kaposztas et al.Clin Transplant 2009: 23: 63–73
    81. 81.  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
    82. 82.  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)
    83. 83. PP /IVIg/anti-CD20 High-dose IVIg regimenGraft survival at 36 monthsfollowing the episode of AMR•50% in group A•91.7% in group B Lefaucheur.American Journal of Transplantation 2009; 9: 1099–1107
    84. 84. High-dose IVIg regimen PP /IVIg/anti-CD20
    85. 85.  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. Lefaucheur.American Journal of Transplantation 2009; 9: 1099–1107
    86. 86.  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. Rajeev Raghavan,Journal of Transplantation Volume 2010
    87. 87. Author Center N Complete Results summary therapy Idica et al. 2008 - 13 Detail not apparent (i) 10 of 13 had significant decrease (reversal) of DSA + (ii) 100% had reduced MFI of antibodies Raghavan et al. Houston, TX, 1 (i) 4 cycles bortezomib, one (i) Reduced PRA (55% → 30%) and significant reduction of + USA dose rituximab, class I antibodies daily (ii) Successful transplant with mycophenolate good allograft function at 6- months - Wahrmann Vienna, 2 (i) 2 cycles (i) cPRA mildly decreased in et al.2010 Austria bortezomib at both patients intervals of 3- (ii) Overall, no significant and effect on the levels of 4-months, both antigen-specific IgG or ABO given with blood group antibodies steroidsRajeev Raghavan,Journal of Transplantation Volume 2010
    88. 88. Author Center N Complete therapy Result summary Walsh et al. Cincinnati 2 (i) 1 cycle bortezomib (ii) ongoing (i) Immediate significant reduction + Ohio, USA plasmapheresis, of DSA rituximab, (ii) Good allograft intravenous steroids function at 5- and (iii) pheresis done at 6-months follow-up least 72 hours post- (iii) One patient had bortezomib re-elevation of DSA which responded to a second course of treatment Sberro- Soussan Paris, France 4 (i) 1 cycle bortezomib (solo therapy) (i) No effect on anti- HLA antibodies - et al. 2010 within 40 subsequent days, and at 150 days follow-up.Rajeev Raghavan,Journal of Transplantation Volume 2010
    89. 89.  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
    90. 90. American Journal of Transplantation 2010; 10: 681–686
    91. 91.  Bortezomib failed to decrease DSA intensity within the 150-day follow-up period in all patients.They concluded that a single cycle of bortezomibdoes not seem to exert an effect on any long-livedantibody levels (further than 1 year post-transplant)
    92. 92.  20 patients with AMR and DSA + a mean of 19 months after transplantation. Flechner et al. Transplantation • Volume 90, Number 12, December 27, 2010
    93. 93. 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. Flechner et al. Transplantation • Volume 90, Number 12, December 27, 2010
    94. 94. For the entire group, patient survival is100%, and graft survival is 85% with amean follow-up of 9.8 months They found that • patients with SCr< 3 for combining There is a rational mg/dl had better plasmapheresis, as it Bortezomib with response more effective in eliminating may be plasma cell that produceing high levels of antibody. •The mean decrease from peak- nadir MESF/MFI of the most dominant DSA was 55% . •only 25 % had undetectable DSA after treatment. Flechner et al. Transplantation • Volume 90, Number 12, December 27, 2010
    95. 95.  Neurotoxicity 30 % Thrombocytopenia 28% Neutropenia 11 % Nausea 55% Diarrhea 44% Fatigue 12% Rajeev Raghavan,Journal of Transplantation Volume 2010
    96. 96.  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).
    97. 97.  Antibody-mediated rejection is an important cause of acute and chronic graft failure. Improvements in HLA technology revolutionized the understanding of this important entity. Transplantation of sensitized patients remains a difficult problem. However, developments such as paired kidney donation and desensitization protocols are continuously improving the rates of transplantation in this difficult to transplant population.
    98. 98.  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

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