New Horizons in Kidney Transplant: Preventing Antibody-Mediated Rejection in Sensitized Patients

New Horizons in Kidney Transplant: Preventing Antibody-Mediated Rejection in Sensitized Patients Denis Glotz, MD, PhD Saint-Louis Hospital Paris, France Robert A. Montgomery, MD, DPhil, FACS The Johns Hopkins Hospital Baltimore, Maryland In conjunction with the 2014 World Transplant Congress, July 26-31, 2014, in San Francisco, California.

Faculty Disclosures Denis Glotz, MD, PhD, has a financial interest/relationship or affiliation in the form of: Grant/Research Support from CSL Behring and Thermo Fisher Scientific Inc. Speakers Bureau participant with Alexion; F. Hoffmann-Roche; Sanofi; and Thermo Fisher Scientific Inc. This activity has been jointly sponsored by the University of New Mexico School of Medicine, Office of Continuing Medical Education, and PVI, PeerView Institute for Medical Education. This activity is supported by an unrestricted educational grant from Alexion Pharmaceuticals. This symposium is not part of the WTC official educational program and the sessions and content are not endorsed by WTC.

Faculty Disclosures Robert A. Montgomery, MD, DPhil, FACS, has a financial interest/relationship or affiliation in the form of: Consultant for ipierian Inc. Grant/Research Support from Alexion; Genzyme Corporation, a Sanofi company; and ViroPharma Incorporated, a wholly owned subsidiary of Shire, PLC. Scientific Advisory for Astellas Pharma US, Inc.; and Gambro. This activity has been jointly sponsored by the University of New Mexico School of Medicine, Office of Continuing Medical Education, and PVI, PeerView Institute for Medical Education. This activity is supported by an unrestricted educational grant from Alexion Pharmaceuticals. This symposium is not part of the WTC official educational program and the sessions and content are not endorsed by WTC.

Presentation 1: Antibody-Mediated Rejection: Clinical Phenotypes Photo Pending Denis Glotz, MD, PhD Saint-Louis Hospital Paris, France

Rejection Is an Antibody Process 1 CDC: complement-dependent cytotoxicity; Ig: immunoglobulin. 1. Taylor CJ et al. Transplantation. 1989;48:953-958.

Hyperacute Rejection 1 1. Courtesy of Denis Glotz, MD, PhD.

Patterns of Gene Expression 1 Rejection A : 50% graft loss Rejection B: Toxicity; infection Rejection C: CAN Rejection D: Normal CAN: chronic allograft nephropathy rejection type III. 1. Sarwal M et al. N Engl J Med. 2003;349:125-138.

Patterns of Gene Expression 1 AR: acute rejection; HLA: human leukocyte antigen: IL: interleukin; IFN: interferon; NK: natural killer. 1. Sarwal M et al. N Engl J Med. 2003;349:125-38

Laboratory Diagnosis of DSA: Luminex Assay 1 High sensitivity and specificity for HLA antibody detection Detects many more antibodies than are observed by the less sensitive and less specific CDC assay AMR: antibody-mediated rejection. 1. Chen G et al. Methods Mol Biol. 2013;1034:305-311.

Immunohistochemistry Versus Immunofluorescence 1 Kidney IF IHC IFV: immunofluorescence; IH: immunohistochemistry:. 1. Courtesy of Dominique Nochy.

AMR in Renal Transplant 1 Histological lesions ATN PTC, glomerulopathy, thrombosis Arteritis C4d+ DSA ATN: acute tubular necrosis; DSA: donor-specific antibody; PTC: peritubular capillaritis.. 1. Racusen LC et al. Am J Transplant. 2003 Jun;3(6):708-14.

C4d Positivity in Various Treatment Centers Authors Biopsies/Pts Indication C4d+ (% Pt) Feucht 1993 93/93 Renal failure 46% Lederer 2001 310/218 Renal failure 46%-72% Regele 2001 102/61 Renal failure 51% Bohmig 2002 113/58 Renal failure 28% Nickeleit 2002 398/265 Renal failure 35% Herzenberg 2002 126/93 Rejection 37% Mauiyyedi 2002 67/67 Renal failure 30% Regele 2002 213/213 Renal failure 34% Sund 2003 37/37 Protocol 30% Koo 2004 96/48 Protocol 13% 1. Courtesy of Denis Glotz, MD, PhD.

AMR in KTRs: Biopsies for Cause 1 KTR: kidney transplant recipient. 1. Lefaucheur C et al. J Am Soc Nephrol. 2010.21:1398-1406.

AMR: An Evolutive Process 1 Bringing together the pieces of the puzzle Quantitation DSA pre-tx graft survival Histology and graft survival? MFI: mean fluorescence intensity. 1. Lefaucheur C et al. J Am Soc Nephrol. 2010.21: 1398 1406.

Subclinical AMR Function Pathology Usefulness of Abs/screening biopsies+++ Ab: antibody.

Defining Subclinical AMR 1-3 Patient in a steady state: Stable GFR Evidence for Ab injury: glomerulitis+/ptc+ Evidence for Ab action in PTC: C4d+ Evidence for serologic Ab: DSA+ GFR: glomerular filtration rate. 1. Gloor J et al. Am J Transplant. 2007;7:2124-2132. 2. Haas M et al. Am J Transplant. 2007;7:576-585. 3. Lerut E at al. Translantation 2007;83:1416-1422.

Anti-HLA Antibodies and Late Allograft Loss 1 GFR: glomerular filtration rate. 1. Lee PC et al. Transplantation. 2002.27;74(8):1192-4.

Proteinuria is the Hallmark of Glomerular Injury 1 The relationship between HLA Ab and proteinuria in KTR developing DSA and NDSA a Control group never developed antibodies. NDSA: non donor-specific antibodies. 1. Fotheringham J et al. Transplantation. 2011. 15;91(9):991-6.

It All Starts With Proteinuria 1 egfr: estimated glomerular filtration rate. 1. Fotheringham J et al. Transplantation. 2011;15:991-996.

Presence of DSA Frequent in Late Biopsies For Cause 1 DSA distribution in pts undergoing late biopsies for clinical indication PRA: panel-reactive antibody. 1. Hidalgo LG et al. Am J Transplant. 2009;9(11):2532-41.

Development of De Novo DSA Is Associated With Allograft Loss 1 Graft survival of patients with de novo DSA versus those without Time From Transplant, y 1. Wiebe C et al. Am J Transplant. 2012;12:1157-1167.

Nature History of Subclinical AMR 1 Evolution of chronic lesions in DSA+ patients according to time of screening biopsy a CG a Mean +/- SEM, data including nine additional screening biopsies performed at 3 y. CG: chronic glomerulopathy; IF: interstitial fibrosis; SEM: standard error of measurement; TA: tubular atrophy. 1. Loupe A et al. Am J Transplant. 2009; 9: 2561-2570.

AMR Is the Leading Cause of Late Graft Failure 1 PVN 7% Missing data 5% Medical conditions 10% GN 13% ABMR AMR 47% Nonadherent 48% Adherent 52% Mixed 5% Probable AMR 13% 65% of subsequent failures could be attributed to AMR, probable AMR, or mixed; 48% were nonadherent GN: glomerulonephritis; PVN: polyomavirus nephropathy. 1. Sellarés J et al. Am J Transplant. 2012;12:388-399.

The Spectrum of Clinical Phenotypes 1 Hyperacute Acute Caused when high titers of DSA are present Happens within min to d Rare (due to crossmatching) Occurs in 5%-7% of KTRs Causes 20%-48% of acute-rejection episodes in presensitized crossmatched patients Manifests over days as a result of DSA Chronic Antibody mediated Characteristically seen as TG on kidney biopsy TG prevalence in protocol biopsies varies from 5% at 1 y to 20% at 5 y Manifestations Early stages: asymptomatic Advanced stages: nephrotic-range proteinuria Hypertension Allograft dysfunction; progression may be fairly rapid TG: transplant glomerulopathy. 1. Puttarajappa C et al. J Transplant.2012;2012:193724

80 DSA+ KTRs: 157 Protocol Biopsies 1 C4d status fluctuates during the first-year post-transplant, reflecting a dynamic process C4d = 3 C4d = 2 C4d = 1 C4d = 0 1. Loupy A et al. Am J Transplant. 2009;9:2561-2570.

Is Complement Necessary for Antibody-Mediated Lesions? 1 Specificity/sensitivity/positive predictive and negative predictive values for C4d Sensitivity = 0.69 Specificity = 0.83 PPV = 0.93 NPV = 0.44 C4d+ (n = 90) KTRs with preformed DSA (n = 80) Protocol biopsies at 3-mo and 1-y post-transplant (n = 157) C4d- (n = 67) Microvascular inflammation + (n = 84) Microvascular inflammation (n = 6) Microvascular inflammation + (n = 37) NPV: negative predictive value; PPV: positive predictive value. 1. Loupy A et al. Am J Transplant. 2011;11:652-660. Microvascular inflammation (n = 30)

Banff 2013: Inclusion of C4d- AMR and Antibody-Associated Arterial Lesions Full-blown acute AMR (acute AMR type 1) Acute AMR without evident complement deposition (acute AMR type 2) C4d-positive subclinical AMR (subclinical AMR type 1) Subclinical AMR without evident complement deposition (subclinical AMR type 2) C4d-positive chronic AMR (chronic AMR type 1) Chronic AMR without evident complement deposition (chronic AMR type 2) C4d staining without histologic evidence of rejection 1. Haas M et al. Am J Transplant. 2014;14:272-283.

Diagnostic Criteria for Acute AMR in KTR: Clinical Phenotypes: C4d+ vs C4d- 1 C4d+ Serological evidence DSA present Immunopathic evidence IF: diffuse-positive C4d in PTC IHC: diffuse of focal-positive C4d in PTC Histological evidence ATN-like changes and/or PTC and/or Glomerulitis and/or Thrombotic microangiopathy and/or Arterial fibrinoid necrosis and No evidence of chronic capillary injury a C4d- Serological evidence DSA present Immunopathic evidence Negative C4d staining and Endothelial activation, detected by increased mrna expression of endothelial genes and/or Evidence for glomerular and/or capillary endothelial cycling Histological evidence PTC and/or Glomerulitis and/or Thrombotic microenglopathy and/or Arterial fibrinoid necrosis and No evidence of chronic capillary injury a a Reduplication and/or multilayering of glomerular and PTC basement membranes. ATN: acute tubular necrosis; DSA: donor-specific antigen; IHC: Immunohistochemistry; IF: interstitial fibrosis; KTR: kidney transplant recipient; PTC: peritubular capillaritis.. 1. Mengel M et al. Transpl Int. 2012;25:611-622.

Diagnostic Criteria for Chronic AMR in KTR: Clinical Phenotypes: C4d+ vs C4d- 1 C4d+ C4d- Serological evidence DSA present Immunopathic evidence IF: diffuse-positive C4d in PTC IHC: diffuse of focal-positive C4d in PTC Histological evidence Transplant glomerulopathy and/or PTC basement membrane multilamination and/or IF with tubular atrophy and/or Fibrous intimal thickening of arteries Glomerulitis and/or capillaritis may accompany 1. Mengel M et al. Transpl Int. 2012;25:611-622. Serological evidence DSA present Immunopathic evidence Negative C4d staining and Endothelial activation, detected by increased mrna expression of endothelial genes and/or Evidence for glomerular and/or capillary endothelial cycling Histological evidence Transplant glomerulopathy and/or PTC basement membrane multilamination and/or IF with tubular atrophy and/or Fibrous intimal thickening of arteries Glomerulitis and/or capillaritis may accompany

Low Positive Predictive Value of DSA for AMR 1 Specificity/sensitivity/PPV/NPV for AMR Method N PPV Sensitivity (%) Specificity (%) CXM 24 54.2 40.6 97 DSA ELISA 46 41.3 59.4 92.7 DSA Luminex 83 34.9 90.6 85.4 CXM: crossmatch. 1. Courtesy of Denis Glotz, MD, PhD.

Solid-Phase Assays for Antibodies 1 Complement-fixing C1q assay on the HLA SAB that combines sensitivity, specificity, and functional potential SAB: single-antigen bead. 1. Chen G et al. Hum Immunol. 2011;72:849-858.

Post Treatment DSA: Outcomes 1 DSA+/C1q+ = higher risk of graft loss 1. Loupy A et al. N Engl J Med. 2013;369:1215-1226.

Presentation 2: The Role of Complement Inhibition in Preventing and Treating AMR Robert A. Montgomery, MD, DPhil, FACS The Johns Hopkins Hospital Baltimore, Maryland

AMR: Pathogenesis of the Humoral Immune Response 1 Plasmablasts Plasma cells HLA antibody Clonal expansion T cell Complement activation Memory B cells LLPC Bone marrow LLPC: long-lived plasma cell. 1. Montgomery RA et al. Semin Immunol. 2011;23:224-234. Coagulative necrosis

AMR: Therapeutic Targets for Interrupting the Humoral Immune Response 1 Proteosomal Inhibitors HLA antibody IVIg and Plasmapheresis Anti-CD20 Clonal expansion Plasmablasts Plasma cells Splenectomy T-Cell ATG, Steroids Memory B cells Complement Inhibitors Complement Activation LLPC Bone marrow ATG: anti-thymocyte globulin; IVIg: intravenous immunoglobulin 1. Montgomery et al. Seminars in Immunology. 2011. 23:224-234. Coagulative necrosis

Does Rituximab Prevent An Anamnestic Response 1 Made Antibody to Tetramer Antigen b Post-Transplant Antibody Production to Antigens With Elevated B-Cell Frequencies a Treated With Rituximab Yes No Yes 0 13 Χ 2 1= 16.2 P =.00006 No 10 3 Tetramers used to determine the frequencies of B cells with HLA specificities that are not producing soluble antibody Tetramers are available only for a limited number of HLA molecules a There was not detectable antibody to the tested tetramer antigen prior to transplantation. b Made antibody to the tetramer antigen after transplantation. 1. Zachary AA et al. Transplantation. 2013;95:701-704.

Placebo-Controlled, Randomized Trial of SOC ± Rituximab For Treatment of AMR 1 Primary endpoint: a composite criterion (graft loss or absence of improvement of renal function at d 12) Results: Among the 38 patients included with AMR, 52.6% (10/19) met the primary endpoint in the rituximab group vs 57.9% (11/19) in the placebo group (P =.744); there were no differences in SCr, proteinuria, and glomerulitis at 1, 6, or 12 mo SCr: serum creatinine. 1. Sautenet B et al. 2013 American Transplant Congress (ATC 2013). Abstract 226.

Desensitization Protocol For +XM 1 FK506 (0.1 mg/kg/d) MMF (2 gm/d) Steroids ATG Anti-CD20 Continue FK506 Continue MMF (2 gm/d) Prednisone Taper -10-9 -8-7 -6-5 -4-3 -2-1 0 1 2 3 4 5 6 7 8 9 10 Preoperative PP/IVIG TXP Postoperative PP/IVIG Goal Is a ( ) Cyto XM Goal Is a ( ) Flow XM ATG: anti-thymocyte globulin; MMF: mycophenolate mofetil. 1. Montgomery RA. Am J Transplant. 2010;10:449-457.

AMR in HLA-Incompatible Transplants 1 Type of AMR Incidence (%) Treatment Response Severe oliguric AMR 8.9% Not responsive to PP/IVIg/anti-CD20 AMR 15.8% Responds to PP/IVIg/anti-CD20 No AMR 75.3% No treatment beyond protocol CMR: cell-mediated rejection. 1. Orandi BJ et al. Am J Transplant. 2014. In press.

PP/IVIg Treatment Protocol for Acute AMR 1 Anti-CD20 Steroid bolus or α-thymocyte globulin PP: single plasma volume exchange IVIg: 100 mg/kg following each PP treatment (CMV hyperimmune globulin) PP/IVIg PP/IVIg PP/IVIg PP/IVIg PP/IVIg AMR diagnosis 2 4 6 8 CMV: cytomegalovirus. 1. Montgomery RA et al. Transplantation. 2000;70:887-895.

Severe Oliguric AMR and the Impact of Rescue Splenectomy 1 1. Locke JE et al. Am J Transplant. 2007;7:842-846

Severe Oliguric AMR and the Impact of Rescue Splenectomy 1 1. Locke JE et al. Am J Transplant. 2007;7:842-846

Classical Complement Pathway in Acute AMR in Sensitized KTRs 1 ECULIZUMAB a a FDA approved for PNH and ahus. ahus: atypical hemolytic uremic syndrome; DAF: decay-accelerating factor; PNH: paroxysmal nocturnal hemoglobinuria; Y-CVF, Yunnan-cobra venom factor. 1. Stegall MD et al. Nat Rev Nephrol. 2012;8:670 678.

Treatment Protocol for Severe Oliguric Acute AMR 1,2 Anti-CD20 Steroid bolus or α-thymocyte globulin Heparin D/C FK 506 PP/IVIg AMR diagnosis PP/IVIg PP/IVIg PP/IVIg PP/IVIg 1 2 3 4 Eculizumab Eculizumab 1,200 mg 600 mg Splenectomy Eculizumab 600 mg Eculizumab 600 mg Eculizumab 600 mg 1. Locke JE et al. Am J Transplant. 2009;9:231-235. 2. Iyer HS et al.curr Opin Nephrol Hypertens. 2013;22:681-688.

Graft Survival After Severe AMR By Intervention 1 1. Orandi BJ et al. Am J Transplant. 2014. In press.

Transplant Glomerulopathy in Early Severe Oliguric AMR 1 Graft Loss/Died Missing 3 2 1 0 CG: chronic glomerulopathy. 1. Orandi BJ et al. Am J Transplant. 2014. In press.

Prevention Of AMR In Desensitized Patients With Eculizumab 1 PreTx BFXM <300 MESF <19,300 BFXM <200 MESF <10,000 STOP MESF 10,000 0 1,200 1 600 2 600 3 600 4 600 5 1,200 6 7 1,200 8 9 1,200 STOP No post-transplant PP/biopsy/Ab levels at 4, 7, 14, 28, and 90 BFXM: B-cell flow cytometric crossmatch; MESF: molecules of equivalent soluble fluorochrome. 1. Stegall MD et al. Am J Transplant. 2011;11:2405-2413.

Prevention Of AMR In Desensitized Patients 1 Category Follow-up (mean mo + SD, range) Eculizumab (n = 26) 11.9 + 6.1 (3.0-27.5) Control (n = 51) 48.8 + 14.1 (7.8-69.8) Graft survival at 1 y (n, %) 16/16 (100) 49/51 (97) 1.00 AMR 3 mo (n, %) 2 (7.7) 21 (41).0031 Patients developing high DSA levels 3 mo a 13 (50) 22 (43).63 High DSA biopsies C4d+ (n, %) 13 (100) 20 (91).52 High DSA and C4d+ biopsies showing AMR (n, %) P N/A 2 (15) 20 (100) <.0001 Cellular rejection 3 mo (n, %) 1 (6.2) 1 (2).42 a B flow XM channel shift >350 at any time point in the first 3 mo. 1. Stegall MD et al. Am J Transplant. 2011;11:2405-2413

Approaches to the Use of Eculizumab: Hopkins Versus Mayo Approach 1 Hopkins Approach Eculizumab along with PP (and splenectomy) used to rescue kidneys with severe AMR phenotype (8.9% occurs POD 5- POD 7) Rationale 75% of patients will not have AMR; this approach avoids the cost of treating them Protecting the kidney from complement-mediated damage while removing DSA might improve outcomes (reduce risk for immediate graft loss and TG) POD: postoperative day. 1. Courtesy of Robert A. Montgomery, MD, DPhil, FACS. Mayo Approach Eculizumab used as prophylaxis to reduce the incidence (from 41% to 7.7%; P =.003) and severity of early AMR Done without the use of posttransplant PP In some cases, remaining DSA disappears; in others it persists beyond the discontinuation of the agent, with many of these patients developing TG

AMR: C1 Esterase Inhibitor a Mechanistically Attractive Due To Proximal Complement Blockade 1 A FDA approved for hereditary angioedema. C1-INH: C1 esterase inhibitor; FDP: fibrin degradation product; HMWK: high molecular weight kininogen; IL: interleukin; KK: kallikrein; MASP: MBP-associated serine protease; MBP: mannosebinding protein; TNF: tumor necrosis factor; tpa: tissue plasminogen activator. 1. Levy J, O Donnell P. Expert Opin Investig Drugs. 2006;15:1077-1090.

Conclusions The rate of AMR after desensitization is 24.7%, of which 8.9% is severe and nonresponsive to standard therapy and 15.8% is not graft-threatening and is responsive to PP; both phenotypes at risk for TG Rituximab has an attractive mechanism and, when B-cell precursor rates are high, prevents anamnestic responses; however, this does not seem to translate into efficacy for the prevention or treatment of AMR Splenectomy is effective in rescuing kidneys with the severe AMR phenotype but does not protect against TG A combination of splenectomy, PP/IVIg, and eculizumab is good rescue therapy and appears to prevent TG in the severe AMR phenotype Eculizumab is very effective in reducing the rate of AMR in the first 3 mo after desensitization but, if high levels of DSA persist, there is a likelihood of chronic AMR/TG C1 esterase inhibitor provides more proximal complement blockade, and endogenous levels are depleted by PP

Panel Discussion: Review of Clinical Cases Denis Glotz, MD, PhD Saint-Louis Hospital Paris, France Robert A. Montgomery, MD, DPhil, FACS The Johns Hopkins Hospital Baltimore, Maryland

Prophylaxis of AMR: F.T.

F.T.: Transplant Status Potential living donor: sister Donor Status 4 MM: A24, B35, DR4, DQ8 Positive cytotoxic crossmatch T, IgG F.T. s Status 3 DSAs (MFI >15000): A24, DR4, DQ8

Patient Report Cytotox PRA: 93% vpra: 100% 1 donor /5 y

Prophylaxis of AMR: Treatment Considerations for F.T. IVIg high dose (Glotz, Jordan) PP/IVIg (Montgomery) acd20/ivig (Jordan) Bortezomib protocols (Woodle)

Prophylaxis of AMR: Desensitization Desensitization (1): lower cytotoxicity and obtain a negative cytotoxic crossmatch Desensitization (2): lower MFIs and negativate (as much as possible) the flow crossmatch

Prophylaxis of AMR: Desensitization (Cont d) Desensitization (1): lower cytotoxicity and obtain a negative cytotoxic crossmatch 6 monthly cures of IVIg high dose Desensitization (2): lower MFIs and negativate (as much as possible) the flow crossmatch 4 PP/IVIg sessions just before Tx

Prophylaxis of AMR Negative cytotoxic and flow crossmatches with low DSAs (<1,500) Transplantation, immediate function But AMR at day 10!

TT by C5 Inhibition: LD Tx HD Bx Bx Bx PP IVIg Cy 1. Courtesy of Denis Glotz, MD, PhD.

TT by C5 Inhibition: LD Tx (Cont d) 1. Courtesy of Denis Glotz, MD, PhD. Eculizumab

Kidney Transplantation Compared With Dialysis: Clinically Relevant Outcomes A systematic review of 110 studies (1,961,904 participants) with kidney failure Key findings Kidney transplantation was associated with» Reduced risk of mortality and cardiovascular events» Improved quality of life (vs chronic dialysis) Benefits of transplant (vs chronic dialysis) increased over time despite increased age and comorbidities of KTRs Results were consistent» For different dialysis modalities» For deceased and living donors» Across countries with differing health care systems Results confirm that kidney transplantation is the preferred modality of treatment for chronic kidney failure 1. Tonelli M et al. Am J Transplant. 2011;11:2093-2109.

Preventing AMR in Sensitized Deceased-Donor KTRs 1 Open-label, single-arm, multicenter phase 2 trial: 9-wk preliminary results Primary endpoint: post-transplantation treatment failure rate at wk 9, defined by biopsy-proven AMR, graft loss, patient death, and/or loss to follow-up Ec 1,200 mg Ec 1,200 mg Ec 900 mg Ec 1,200 mg Ec 1,200 mg D 0 D 1, 7, 14, 28 Wk 5 Wk 7 Wk 9 Induction: rabbit ATG EC: eculizumab. Maintenance: prednisone, tacrolimus, mycophenolate 1. Glotz D et al. 16th Congress of the European Society for Organ Transplantation (ESOT 2013). Abstract 2071.

Preventing AMR in Sensitized Deceased-Donor KTRs 1 Outcome Post-transplant failure rate Primary composite endpoint including 1) biopsyproven AMR (grade II or III), 2) graft loss, 3) patient death, and 4) loss to follow-up. Eculizumab (N=47) n (%) 5 (10.6); (3.5, 23.1) Biopsy-proven AMR 3 (6.4) Graft loss and/or death 2 (4.3) Lost to follow-up 0 (0) Data from local laboratory instead of the central laboratory 1. Glotz D et al. ESOT 2013. Abstract 2071.

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