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1. Sumanee Prakobsuk10/07/2012 2. Pathophysiology and Pathology. Diagnosis criteria. Major Histocompatibility Complex (MHC)molecule . Transplantation in the Presence of AntidonorHLA Antibodies (sensitized patients). Treatment Acute ABMR. 3. Graft rejection caused by Abtibodies directedagainst HLA molecules, ABO antigens orendothelial cell antigens. Most recipients do not have antibodiesagainst HLA molecules before transplantationunless they were sensitized by exposure toalloantigens through Pregnancy Blood transfusion, Previous transplantation. 4. DonorOrgan 4 Damaged C1 CapillaryEndothelialCell Releasescomplex cell plateletaggregatio C4Formationnoffactors, cyt Antigen- okinesAb C4b complex C4dEndothelial cell necrosis C4d is by-product and marker of complement activation Schwartz, NEJM 2010 5. GlomerulitisPeritubularcapillaritis C4d + 6. Transplant glomerulopathy-Thickened of GBM-Double contours C4d + Multilamination of GBM,PTC 7. Triad C4d+ Presence of circulating antidonor antibodies Morphologic evidence of acute tissue injury, suchas (Type/Grade): I. ATN-like minimal inflammation II. Capillary and or glomerular inflammation (ptc/g >0) and/or thromboses III. Arterialv3 (tranmural arteritis/fibrinoid necrosis) 8. C4d+ Presence of circulating antidonor antibodies Morphologic evidence of chronic tissue injury Glomerular double contours Peritubular capillary basement membranemultilayering Interstitial fibrosis/tubular atrophy Fibrous intimal thickening in arteries 9. Suspicious for antibody-mediated rejection if - C4dor- AlloantibodyNot demonstrated in the presence ofmorphologic evidence of tissue injury. 10. Major molecule for selfvs. non-selfdetermining process Very high antigenicity In human = humanleukocyte Ag (HLA )Gabriel M.Danovitch.Hand book of transplantation Fifth Edition 11. Gabriel M.Danovitch.Hand book of transplantation Fifth Edition 12. Class I Class II On the surface of all Antigen-presenting cellsnucleated cells (APCs), monocyte, macrophage, Kuffercell, dendritic Density of HLA class Icells, alveolar type2expressioncells, renal mesangial Plt > B cell > T cell cells, and B lymphocyte A, B, C, E, F, G, MICA, MI DP,DQ, DR, DM,DOCB Present Ag peptides to Present Ag peptide toCD8 T cells CD4 T cells Gabriel M.Danovitch.Hand book of transplantation Fifth Edition 13. Increased risk of: 1. Hyperacute rejection 2. Memory B cell response leading to early ABMR 3. Chronic active ABMR 14. Pretransplant immunologicevaluationAs always, we are doing three key tests Tissue typing ABO typing HLA typing HLA antibody screening T and B cell crossmatching 15. HLA typing 16. Panel Reactive Antibody Determine the state of pre-sensitization of the transplant Predict cross match result Predict waiting time 17. Technologies used to detect HLA antibodies (sensitization)2 main methodologies:Complement-dependentcytotoxicity (CDC)Serology CDC-anti-human globulin (CDC- AHG) Enzyme-linked immunosorbent assay (ELISA) Solid Flow phase cytometry Single antigen beadsLuminex 18. Lymphocytes (T cells, usually)Patientserum+ rabbitcomplementRed = dead CANNOT Green = aliveDIFFERENTIATEIgG FROM IgM 19. LymphocytesPatientserum Enhance withanti-humanglobulin (AHG)+ rabbitcomplement 20. MCS=median channel shift MFI=mean fluorescence intensity Luis G. Hidalgo,UAH Histocompatibility Laboratory 21. Luis G. Hidalgo,UAH Histocompatibility Laboratory 22. Most anti-HLA Ab are IgG. Donor specific antibody against HLA Class Ior II IgG were clinically relevant conferringboth 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. 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. Year of Waiting ListRegistrationPeak 2000 2003 2005 2007 2009 PRA0-9% 10- 16.5%79%OPTN/SRTR 2010 Annual Report 25. Year of TransplantPeak 2000 2003 2005 2007 2009 PRA0-9% 10-79%OPTN/SRTR 2010 Annual Report 26. Peak 3 1 years 5 years 10 This has led to the problem of determiningPRAthreshold level and characteristics yearsthe month (Tx2007 (Tx2003of s -2008) -2008) (Tx1998donor-specific HLAab (DSA HLA-ab) that have -2008) (Tx200a meaningful impact on clinical outcomes 7-2008)0-9% 10- OPTN/SRTR 2010 Annual Report79% 27. Retrospective review. DDKT, 18 centers To investigate the relationship between thepretransplant presence of HLA class I andclassII antibodies and the development of noimmediate function and Acute rejectionepisode. 28. Patients with NIF or ARE were positive forHLAclass I and II Abtibodies in theirpretransplantation serum than patientswithout NIF or ARE 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. Observational study Single-center study of 402 consecutive DDKT. Examined the impact of the strength of HLA-DSAdetected on the risk for AMR and graft survival inDDKT 1998-2006 DSA HLAab by Luminex single antigen bead assay Mean F/U 51.4+- 30.6 monthsCarmen Lefaucheur. J Am Soc Nephrol 21: 13981406, 2010 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. Carmen Lefaucheur. J Am Soc Nephrol 21: 13981406, 2010 33. Total Transplant Pt Without ABMR Pt Carmen Lefaucheur. J Am Soc Nephrol 21: 13981406, 2010 34. long term graft survival was significantly inferiorfor patients who had any detectable preexistingDSA Luminex peak MFI predicted AMR and graftsurvival. MFI > 3000 appeared to the cutoff for significantdecrease in graft survival and whether an episodeof ABMR occurred.Carmen Lefaucheur. J Am Soc Nephrol 21: 13981406, 2010 35. Proteins other than HLA antigens can alsoserve as targets of AMR. MICA : MHC Class I chain A. Antiangiotensin type I receptor antibody.NephSAP Transplant, november 2011 36. MICA antigens are expressed on endothelialcells, dendritic cells, fibroblasts, epithelial cells, andmany tumors But not on peripheral-blood lymphocytes. MICA protein do not associate with B2 micoglobulinas do MHC class I antigens and not serve topresent antigen to T cell They are instead ligands for NK cells.NephSAP Transplant, november 2011 37. Since MICA antigens are not expressed onlymphocytes,the cells commonly used forcross-matching Antibodies directed against MICA are notdetected with the methods generally used.NephSAP Transplant, november 2011 38. To determine whether an immune response to MICAantigens might play a role in the failure of kidneyallografts. 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. 93 0.6 %88.3 2.2 %P=0.01 11.4 % 40. Presensitization of kidney-transplantrecipients against MICA antigens isassociated with an increased frequency ofgraft loss and might contribute to allograftloss among recipients who are well matchedfor HLA.Yizhou Zou, M.D.N Engl J Med 2007;357:1293-300. 41. These studies are unable at this time toprovide any absolute thresholds for thedecision to transplat with a given organ or not. But do provide data to begin to define level ofrisk NephSAP Transplant, november 2011 42. Kwaku Marfo.Clin J Am Soc Nephrol 6: 922936, 2011 43. PP/low-dose IVIGauthor No Pts Inducti F/UAR/AMPt GraftonMonths Rsurvival survival(%)(%)Schweitz 11 OKT313 36/27100100we2000Magee28 Thymo/ 2271/3993 892008Basiliximab/RituxThielke51 Thymo/23 33/2495 932009RituxHaririan 41 OKT3 or 47 24/1278 662009Thymo Kwaku Marfo.Clin J Am Soc Nephrol 6: 922936, 2011 44. High-dose IVIGauthor No Pts Induct F/U AR/ Pt GraftionMonth AMR surviv surviv s (%) al(%)al(%)Glotz 13 Thymo 12 8/8100932002Jondan42 Daclizu 24 31/3198 892003 mabMai20020 Thymo 36 50/3094 899Bachler 37 Thymo 24 38/3895 872010 Kwaku Marfo.Clin J Am Soc Nephrol 6: 922936, 2011 45. M.D. Stegalla. American Journal of Transplantation 2006; 6: 346351 46. negative crossmatchAcute ABMRPP/low-dose IVIG and rituximabdemonstrated more success in abrogating positivecross-match and lower acute rejection rates 47. To investigate the effects of desensitizationprotocols using IVIg with or withoutplasmapheresis in patients with donor-specificanti-HLA antibodies on prevention ofantibody-mediated rejection and downregulationof donor-specific antibodies. Enver Akalin. Clin J Am Soc Nephrol 3: 11601167, 2008 48. Pretransplantation DSA, negative CDC cross-match. Anti-HLA antibodies were studied by Luminexsingle Beads . Biopsies were performed for an increase increatinine level and/or proteinuria. Enver Akalin. Clin J Am Soc Nephrol 3: 11601167, 2008 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 duringtransplant surgery and 500 mg/kg on each ofpostoperative days 1 and 2.Enver Akalin. Clin J Am Soc Nephrol 3: 11601167, 2008 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: 11601167, 2008 51. Group 1 , Seven ( 70%) patients lost DSA completely Group 2, four (44%) patients lost DSA Completely Group 3, six (43%) patients lost DSA completelyEnver Akalin. Clin J Am Soc Nephrol 3: 11601167, 2008 52. Kidney transplant recipients with DSA are at higherrisk for developing early acute AMR despite negativeCDC T cell cross-match and require desensitization. Not only should the presence of DSA bedocumented, but also the strength or titers of thealloantibodies should be determined to decide thetype of the desensitization protocol. Highdosage IVIG alone dose not prevent AMR inpatients with strong DSA Aaddition of peritransplantation PP significantly decreases the incidence of AMR. Enver Akalin. Clin J Am Soc Nephrol 3: 11601167, 2008 53. Assessed the histological lesions at 3 months and 1 year in patients receiving DDKT, comparingthose 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: 25612570 54. Group A (n = 54 )DSA positiveInduction :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 glomerularfiltrationat day 4(GFR) at 3 months and dose of 375 Received additional prophylactic Rituximab at amg/m2 rate 1 year.Together with plasmapheresis performed immediately posttransplant then three times per week for 3 weeks. Group B (n = 83)without preformed DSA20 mg intravenous Basiliximab Day 0,4 55. A. Loupya. American Journal of Transplantation 2009; 9: 25612570 56. At 3 months after transplant31 % Subclinical AMR in DSA +At 1 year Score higher IF/TA100 % vs 33 % TG 43% vs 0% 57. If these findings are comfirmed in a large series of patients. Protocol Biopsies may be a valuable tool in the management of thispopulation ?? Treatment protocol ??A. Loupya. American Journal of Transplantation 2009; 9: 25612570 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: 922936, 2011 Renal Division, Albert Einstin College of Medicine MontefioreMedicalCenter,Bronx, New York 59. Kwaku Marfo.Clin J Am Soc Nephrol 6: 922936, 2011 60. Kwaku Marfo.Clin J Am Soc Nephrol 6: 922936, 2011 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 aconsecutive cohort of kidney transplants. Risk factors for dnDSA development Correlation of dnDSA with clinical pathologicand outcome. C. Wiebe. American Journal of Transplantation 2012; 12: 11571167 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 beadsC. Wiebe. American Journal of Transplantation 2012; 12: 11571167 63. Kidney biopsy Six-month protocol biopsies. Newly detected dnDSA patients since January2008 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: 11571167 64. C. Wiebe. American Journal of Transplantation 2012; 12: 11571167 65. C. Wiebe. American Journal of Transplantation 2012; 12: 11571167 66. C. Wiebe. American Journal of Transplantation 2012; 12: 11571167 67. C. Wiebe. American Journal of Transplantation 2012; 12: 11571167 68. C. Wiebe. American Journal of Transplantation 2012; 12: 11571167 69. dnDSA develops in 15% of low risk renal transplantrecipients 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 ofproteinuria or rise creatinie. C. Wiebe. American Journal of Transplantation 2012; 12: 11571167 70. 6: TREATMENT OF ACUTE REJECTION 6.1: We recommend biopsy before treatingacute rejection, unless the biopsy willsubstantially delay treatment. (1C) 6.2: We suggest treating subclinical andborderline acute rejection. (2D)BL Kasiske et al.: KDIGO guideline 2009 for kidney transplant recipients 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 receivingmycophenolate or azathioprine, or switching azathioprine to mycophenolate. (2D) BL Kasiske et al.: KDIGO guideline 2009 for kidney transplant recipients 72. IAN R. M ACKAY, M.D., N Engl J Med, Vol. 345, No. 10 September 6, 2001 73. Routinely used High dose: 2 gm/kg Low dose: 100 mg/kg per session Low-dose IVIG is mostly used in combinationwith plasmapheresis where it may help replenishdepleted IGs.Initial studies used IVIG at high-doses withoutplasmapheresis and described a fair degree ofsuccess in desensitization prior to transplant andalso for treating antibody-mediated rejection.Chethan Puttarajappa, Journal of Transplantation Volume 2012 74. Side effects Aseptic meningitis Volume overload AKI possible to high osmotic load Chethan Puttarajappa, Journal of Transplantation Volume 2012 75. Plasmapheresis is very effective in reducing theantibody load but needs to be used inconjunction with other therapies that target theantibody producing mechanisms. DSAs are monitored along with renal function todocument the effectiveness of the therapy. Treatment, if successful, is continued until thelevel of antibodies has dropped to safe levelsalong with improvement in renal function.Chethan Puttarajappa, Journal of Transplantation Volume 2012 76. The mechanism of action of Rituximab in AMR isnot clear, however, the depletion of CD20-positivesubset of B-cells may attenuatethe antibody generation process. Side effects Acute infusion reactions Reactivation of latent viruses such as hepatitisB, C, CMV, and TB Chethan Puttarajappa, Journal of Transplantation Volume 2012 77. The retrospective 2001-2006 Compared the outcomes of a PP-based vs. aPP plus rituximab regimen to treat patientsexperiencing AMR and resistant to steroidplus anti-lymphocyte globulin treatment.Kaposztas et al.Clin Transplant 2009: 23: 6373 78. At the end of each PP cycleRituximab(375 mg/m2).Induction:simulectHigh risk PRA>20%,African,re-transplant:Thymoglobulin 79. Graft survival rates at 2 yearsgroup A 90%group B 60%Beneficial effect was observed with PP inaddition to treatment with rituximab in AMR 80. Kaposztas et al.Clin Transplant 2009: 23: 6373 81. DDKT Biopsy prove AMR & DSA+ Negative current CDC crossmatch All patients received induction with thymoglobulin (1.5 mg/kg/day 710 doses) Maintenance immunosuppression steroids +Cellcept+tacrolimus /cyclosporine Patients with remote positive IgG T- and B-cell CXM received IVIg atthe time of transplantation as prophylaxis against acute rejection (2g/kg days 01, 2021 and 4041).Lefaucheur.American Journal of Transplantation 2009; 9: 10991107 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 3weeks, 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 doseof IVIg (100 mg/kg) *4-After the last PP-high-dose IVIg as described above (2 g/kg every3 weeks, 4 doses)-two weekly doses of rituximab (375 mg/m2) 83. PP /IVIg/anti-CD20High-dose IVIgregimenGraft survival at 36 monthsfollowing the episode of AMR50% in group A91.7% in group B Lefaucheur.American Journal of Transplantation 2009; 9: 10991107 84. High-dose IVIg regimen PP /IVIg/anti-CD20 85. PP/IVIg/anti-CD20 leads to improved graftsurvival 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 significantlygreater in patients treated by the associationof PP/IVIg/anti-CD20 as compared to thosetreated by IVIg.Lefaucheur.American Journal of Transplantation 2009; 9: 10991107 86. Bortezomib is a novel proteosome inhibitor that is approved for the treatment of multiplemyeloma. Inhibition of proteasomes can lead to decreasednuclear factor-Kappa B activation, cell cyclearrest, endoplasmic reticulum stress, and increasedcell apoptosis . This action is pronounced in plasma cells likelybecause of the high antibody turnover and highendoplasmic reticulum activity.Rajeev Raghavan,Journal of Transplantation Volume 2010 87. Author Center N CompleteResults summarytherapyIdica et al.2008 -13Detail notapparent(i) 10 of 13 had significantdecrease (reversal) of DSA+(ii) 100% had reduced MFI ofantibodiesRaghavan etal. Houston, TX,1 (i) 4 cyclesbortezomib, one(i) Reduced PRA (55% 30%)and significant reduction of+ USAdose rituximab, class I antibodiesdaily (ii) Successful transplant withmycophenolate good allograft function at 6-months-Wahrmann Vienna,2 (i) 2 cycles(i) cPRA mildly decreased inet al.2010 Austriabortezomib at both patientsintervals of 3- (ii) Overall, no significantand effect on the levels of4-months, bothantigen-specific IgG or ABOgiven withblood group antibodiessteroidsRajeev Raghavan,Journal of Transplantation Volume 2010 88. Author Center N Complete therapy Result summaryWalsh et al. Cincinnati 2 (i) 1 cycle bortezomib(ii) ongoing (i) Immediate significant reduction+ Ohio, USAplasmapheresis,of DSArituximab, (ii) Good allograftintravenous steroids function at 5- and(iii) pheresis done at 6-months follow-upleast 72 hours post- (iii) One patient hadbortezomib re-elevation of DSA which responded to a second course of treatmentSberro-Soussan Paris, France4 (i) 1 cycle bortezomib(solo therapy) (i) No effect on anti- HLA antibodies -et al. 2010within 40 subsequent days, and at 150 days follow-up.Rajeev Raghavan,Journal of Transplantation Volume 2010 89. case series of four renal transplant recipients in whomgraft biopsy disclosed ABMR , accompanied bypersistent DSA. All patients received bortezomib (1.3 mg/m2) on days1, 4,8 and 11 as sole desensitization therapy withoutany modification of their maintenanceimmunosuppressive treatment.American Journal of Transplantation 2010; 10: 681686 90. American Journal of Transplantation 2010; 10: 681686 91. Bortezomibfailed todecrease DSAintensity withinthe 150-dayfollow-upperiod in allpatients.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. 20 patients with AMR and DSA + a mean of19 months after transplantation. Flechner et al. Transplantation Volume 90, Number 12, December 27, 2010 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 todays 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 of2 g/kg IVIG (0.5 g/kg in four divided treatments) wasgiven to the majority of recipients. Flechner et al. Transplantation Volume 90, Number 12, December 27, 2010 94. For the entire group, patient survival is100%, and graft survival is 85% with amean follow-up of 9.8 monthsThey found that patients with SCr< 3 for combining There is a rationalmg/dl had better plasmapheresis, as it Bortezomib withresponse more effective in eliminating may be plasma cell that produceing high levels of antibody.The mean decrease from peak-nadir MESF/MFI of the mostdominant DSA was 55% .only 25 % had undetectableDSA after treatment.Flechner et al. Transplantation Volume 90, Number 12,December 27, 2010 95. Neurotoxicity 30 % Thrombocytopenia 28% Neutropenia 11 % Nausea 55% Diarrhea 44% Fatigue 12%Rajeev Raghavan,Journal of TransplantationVolume 2010 96. Humanized monoclonal antibody directed againstcomplement protein C5. Thereby inhibiting conversion of C5 to C5b andpreventing formation of the membrane attackcomplex (C59). 97. Antibody-mediated rejection is an important cause ofacute and chronic graft failure. Improvements in HLA technologyrevolutionized the understanding of this important entity. Transplantation of sensitized patients remains a difficultproblem. However, developments such as paired kidney donationand desensitization protocolsare continuously improving the rates of transplantation inthis difficult to transplant population. 98. Therapies for AMR are still not optimal with highrates of graft loss leading to poor patient outcomes. Newer therapies, such as bortezomib and eculizumabthat target novel pathways in the AMR process arepromising but will need further randomized studiesbefore becoming widely used. Studies will need to be performed to determine thebest use, either alone or in combination, of themyriad number of therapies currently available


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