• 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. Arterial—v3 (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: 1398–1406, 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: 1398–1406, 2010
  • 33. Total Transplant Pt Without ABMR Pt Carmen Lefaucheur. J Am Soc Nephrol 21: 1398–1406, 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: 1398–1406, 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: 922–936, 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: 922–936, 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: 922–936, 2011
  • 45. M.D. Stegalla. American Journal of Transplantation 2006; 6: 346–351
  • 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: 1160–1167, 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: 1160–1167, 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: 1160–1167, 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: 1160–1167, 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: 1160–1167, 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: 1160–1167, 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: 2561–2570
  • 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 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: 2561–2570
  • 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: 2561–2570
  • 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. Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 2011
  • 60. Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 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: 1157–1167
  • 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: 1157–1167
  • 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: 1157–1167
  • 64. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
  • 65. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
  • 66. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
  • 67. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
  • 68. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
  • 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: 1157–1167
  • 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: 63–73
  • 78. • At the end of each PP cycleRituximab(375 mg/m2).Induction:•simulect•High 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: 63–73
  • 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 atthe time of transplantation as prophylaxis against acute rejection (2g/kg days 0–1, 20–21 and 40–41).Lefaucheur.American Journal of Transplantation 2009; 9: 1099–1107
  • 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 AMR•50% in group A•91.7% in group B Lefaucheur.American Journal of Transplantation 2009; 9: 1099–1107
  • 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: 1099–1107
  • 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: 681–686
  • 90. American Journal of Transplantation 2010; 10: 681–686
  • 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 (C5–9).
  • 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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    • 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. Arterial—v3 (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: 1398–1406, 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: 1398–1406, 2010
  • 33. Total Transplant Pt Without ABMR Pt Carmen Lefaucheur. J Am Soc Nephrol 21: 1398–1406, 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: 1398–1406, 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: 922–936, 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: 922–936, 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: 922–936, 2011
  • 45. M.D. Stegalla. American Journal of Transplantation 2006; 6: 346–351
  • 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: 1160–1167, 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: 1160–1167, 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: 1160–1167, 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: 1160–1167, 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: 1160–1167, 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: 1160–1167, 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: 2561–2570
  • 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 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: 2561–2570
  • 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: 2561–2570
  • 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. Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 2011
  • 60. Kwaku Marfo.Clin J Am Soc Nephrol 6: 922–936, 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: 1157–1167
  • 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: 1157–1167
  • 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: 1157–1167
  • 64. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
  • 65. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
  • 66. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
  • 67. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
  • 68. C. Wiebe. American Journal of Transplantation 2012; 12: 1157–1167
  • 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: 1157–1167
  • 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: 63–73
  • 78. • At the end of each PP cycleRituximab(375 mg/m2).Induction:•simulect•High 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: 63–73
  • 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 atthe time of transplantation as prophylaxis against acute rejection (2g/kg days 0–1, 20–21 and 40–41).Lefaucheur.American Journal of Transplantation 2009; 9: 1099–1107
  • 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 AMR•50% in group A•91.7% in group B Lefaucheur.American Journal of Transplantation 2009; 9: 1099–1107
  • 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: 1099–1107
  • 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: 681–686
  • 90. American Journal of Transplantation 2010; 10: 681–686
  • 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 (C5–9).
  • 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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