This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier’s archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright Author's personal copy The Use of Immunoglobulin Therapy for Patients Undergoing Solid Organ Transplantation: An Evidence-Based Practice Guideline Nadine Shehata, Valerie A. Palda, Ralph M. Meyer, Tom D. Blydt-Hansen, Patricia Campbell, Carl Cardella, Steven Martin, Peter Nickerson, Kevork Peltekian, Heather Ross, Tom K. Waddell, Lori West, David Anderson, John Freedman, and Heather Hume This guideline for the use of immunoglobulin (IG) for sensitized patients undergoing solid organ transplantation (SOT) is an initiative of the Canadian Blood Services and the National Advisory Committee on Blood and Blood Products of Canada to (1) provide guidance for Canadian practitioners involved in the care of patients undergoing SOT and transfusion medicine specialists on the use of IG and (2) standardize care, limit adverse events, and optimize patient care. A systematic expert and bibliography literature search up to July 2008 was conducted, with 791 literature citations and 45 reports reviewed. To validate the recommendations, the guideline was sent to physicians involved in SOT in Canada and a patient representative. The recommendations identify (1) sensitized patients undergoing SOT that would have a better survival and decreased morbidity by receiving IG preoperatively, postoperatively, and for the treatment of organ rejection; (2) patients who may not have any benefit from receiving IG; and (3) potential adversities to IG. © 2010 Elsevier Inc. All rights reserved. T HE RISK OF human leukocyte antigen (HLA) antibody-mediated graft rejection/loss or ABO incompatibility is a barrier to solid organ transplantation for many patients in need of this therapy. Although the optimal approach to this problem is to develop strategies to increase the availability of compatible donors and/or organs for transplantation, transplant physicians continue to investigate treatment options to decrease the rejection/loss rate in sensitized patients. The administration of intravenous immunoglobulin (IVIG) is among the immunomodulatory therapies that are currently being used to overcome these barriers. However, the use of IVIG in this setting is not a licensed indication for IVIG and, to our knowledge, has not previously been reviewed in the medical literature. Since 2004, the Canadian Blood Services and Canada's National Advisory Committee on Blood and Blood Products have been involved in a joint initiative to develop guidelines for IVIG utilization. The history and rationale for the involvement of these two bodies in IVIG guideline development are described in the introductory article of this supplement.1 Given the increasing use in Canada of IVIG in the setting of solid organ transplantation, this setting was chosen for the development of the fourth set of guidelines in this series. The first two guidelines, which From the Department of Medicine, University of Toronto, St. Michael's Hospital, Canadian Blood Services, Toronto, Ontario, Canada; Departments of Medicine and Health Policy Evaluation, University of Toronto, St. Michael's Hospital, Toronto, Ontario, Canada; National Cancer Institute of Canada Clinical Trials Group and Departments of Oncology, Medicine and Community Health and Epidemiology, Queen's University, Kingston, Ontario, Canada; Department of Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada; Department of Medicine, University of Manitoba, Canadian Blood Services, Winnipeg, Manitoba, Canada; Division of Pediatric Nephrology, Children's Hospital, Winnipeg, Manitoba, Canada; Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada; Department of Medicine, University of Toronto, University Health Network, Toronto, Ontario, Canada; Department of Pediatrics, Université de Montréal, Hôpital Ste Justine, Montreal, Quebec, Canada; Department of Surgery, University of Toronto, University Health Network, Toronto, Ontario, Canada; Li Ka Shing Knowledge Institute, Canada; Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada; Departments of Medicine, Community Health and Epidemiology and Pathology Dalhousie University, Halifax, Nova Scotia, Canada, and Canadian Blood Services, Ottawa, Ontario, Hôpital Sainte Justine, Montreal, Quebec, Canada. STATEMENT OF CONFLICT OF INTEREST: Dr L West receives research funding from the US National Institutes of Health (Grant P01-HL079067). Drs Nadine Shehata and Peter Nickerson are employees of Canadian Blood Services, as were Drs Heather Hume and John Freedman during the period of the development of these guidelines. Funding was provided from an unrestricted education grant from Bayer, Inc, to Canadian Blood Services. Bayer did not have any role in the selection of panel members, the literature search, the selection of articles, or the development of the recommendations. Address reprint requests to Nadine Shehata, MD, Queen Wing, 2-080, St. Michael's Hospital, 30 Bond Street, Toronto, Ontario, Canada M5B 1W8. E-mail: [email protected] 0887-7963/09/$ - see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.tmrv.2009.09.010 Transfusion Medicine Reviews, Vol 24, No 1, Suppl 1 (January), 2010: pp S7-S27 S7 Author's personal copy S8 SHEHATA ET AL addressed IVIG use in hematologic and neurologic disorders, were published in a supplement of Transfusion Medicine Reviews in 2007; and the third guideline, for the use of immunoglobulin in primary immune deficiencies, is published along with this guideline in the current Transfusion Medicine Reviews supplement.2-4 SCOPE AND PURPOSE OF THE GUIDELINE AND TARGET AUDIENCE The specific objectives of this guideline are (1) to examine the evidence for the use of IVIG in patients who are candidates for solid organ transplantation and are sensitized to HLAs or ABO antigens, (2) to provide guidance for physicians in Canada (and potentially elsewhere) involved in the care of these patients on the optimal utilization of IVIG therapy in this setting, (3) to identify areas where further research is required, and (4) to provide assurance for funders of the Canadian blood system that the effectiveness of immunoglobulin therapy is being assessed. These guidelines are intended for use (1) for adult and pediatric patients who are sensitized to HLA or ABO antigens and are scheduled for kidney, heart, liver, or lung transplantation; (2) for adult and pediatric patients who experience acute and chronic rejection after solid organ transplantation; and (3) by physicians responsible for evaluating requests for IVIG or involved in the development of transfusion policy. DEVELOPMENT OF THE GUIDELINE In 2007, a panel consisting of solid organ (kidney, heart, lung, and liver) transplantation experts, guideline methodologists, and members from Canada's National Advisory Committee on Blood and Blood Products was convened to develop an evidence-based practice guideline for the use of IVIG in patients undergoing solid organ transplantation. The panel did not include a patient representative; however, the experts' knowledge of patient tolerances and preferences of immunoglobulin therapy was considered in the development of recommendations. The panel identified clinical areas of solid organ transplantation that would benefit from treatment with IVIG and generated pertinent clinical questions. The questions were developed via electronic correspondence and teleconferences using a modified Delphi process. Methodologists attended all meet- ings to ensure methodological rigor. Each expert was assigned a question to review and generate a recommendation. The questions were used to identify search terms. The data were abstracted to evidence tables that described the characteristics and quality of the studies and pertinent clinical outcomes. The tables were distributed to the panel before a consensus meeting where each panel member presented their recommendations. Recommendations were developed based on the best evidence available. The levels of evidence and grading of recommendations were adapted from the Canadian Task Force on Preventative Health Care (available at http:// www.ctfphc.org/). The levels of evidence describe the methodological rigor of the study, whereas the grades of recommendation comprise the level of evidence and clinical expertise. If the evidence was insufficient for a recommendation, the consensus section describes the rationale for the recommendation. Areas of disagreement were resolved through consensus verification with all committee members. National experts from the Canadian Society of Transplantation and a patient representative from the Kidney Foundation of Canada reviewed the final guideline to validate the relevance of the guideline and recommendations. Their agreement to each recommendation and their evaluation of the entire guideline were elicited. The National Advisory Committee on Blood and Blood Products will ensure adequate dissemination of the guideline to Canadian physicians involved in the care of patients undergoing solid organ transplantation; will assess the utilization of the guideline; and will perform periodic revisions of the guideline to ensure that recommendations reflect current practices, expertise, and evidence. Identification and Selection of Studies A systematic search was conducted of the MEDLINE (to October 2007), In Process (to October 2007), Cochrane Clinical Trials (to issue 3, 2007), and Embase (1980 to week 45, 2007) databases. The search was updated to July 2008. The search terms are illustrated in Appendix A. We included studies that met the following inclusion criteria: (1) an original report; (2) published in English; and (3) a randomized controlled trial, cohort/case series, systematic review, or guideline. We excluded studies that (1) Author's personal copy IMMUNOGLOBULIN IN SOLID ORGAN TRANSPLANTATION did not report a clinical outcome, (2) were abstracts or letters, or (3) had five or fewer patients. One reviewer (NS) assessed the citations for inclusion and extracted data to generate tables containing information about trial design, quality, and outcome results. These tables were used as a basis for discussion by the panel. The guideline is organized according to the organ transplantation specialty, that is, kidney, heart, lung, and liver and for each specialty, by clinical question. As the evidence for the use of IVIG is limited for heart, lung, and liver transplantation, these sections focused on the use of IVIG where evidence was available. The relevant background, a summary and critical appraisal of the evidence, the consensus process, and the recommendation statement accompanied by a level of evidence and grade of recommendation follow each question. The evidence is shown in detail in Tables 2 to 9. Literature Search Results Seven hundred ninety-one citations were retrieved, and panel members identified three additional citations. Five studies were excluded for the following reasons: the primary objective of one study was to study the effect of IVIG on autoregulatory antibodies5; one study described survival for patients who received cytomegalovirus immunoglobulin (CMVIG) for the treatment of CMV disease6; two studies addressed the effect of IVIG on the development of alloimmunization7,8; and one study was a report of preliminary results of unpublished data.9 Forty-four reports were used for this guideline.10-53 A summary of the categorization of the reports is found in Table 1. One additional report examined adverse events only and Table 1. Characterization of Studies Disease category HLA desensitization for kidney transplantation ABO-incompatible kidney transplants Rejection after kidney transplantation Desensitization for heart transplantation Desensitization for lung transplantation Desensitization for liver transplantation Randomized controlled trials (n) Observational studies (n) 2 17 0 6 1 10 0 6 0 1 0 1 S9 was also included.54 Tables 2 to 9 describe the characteristics and results of the reports included in this guideline. KIDNEY TRANSPLANTATION Is there evidence that the use of IVIG for patients who are sensitized (HLA or ABO) and are undergoing kidney transplantation decreases sensitization, improves access to transplantation, and/or improves any of the following outcomes: the frequency of acute rejection, graft survival, and overall survival? The incidence and prevalence of end-stage renal disease continue to rise in Canada.55-57 The options for management are dialysis and transplantation. The annual expenditure to the health care system for a patient receiving hemodialysis is $104 277 per year, whereas the annual expenditure beyond the first year for transplantation is $32 196 per year.55,58 The number of patients receiving transplantation has, however, decreased over time,56 although the life expectancy for patients with renal failure who receive a transplanted kidney is double the life expectancy without transplantation.55,59 Up to 30% of patients with end-stage renal disease waiting for transplantation in Canada have HLA panel-reactive antibodies of 20% or more and receive fewer than 5% of transplants in Canada.55 These patients have been exposed to HLAs from pregnancy, prior transfusion, or prior transplantation and have preformed antibodies. Thus, they are sensitized, increasing their risk for early rejection and graft loss.55 Overall, 32% of patients are excluded from receiving a transplanted kidney from a living donor because of an HLA-positive crossmatch; and 22% are excluded because of ABO antibodies.60 All recipients require pretransplant immunologic risk assessment (ie, determination of prior exposure to HLA antigens and donor ABO compatibility) and management, which before 2005 had not been standardized in Canada.55 Currently in Canada, transplant programs have moved to standardize pretransplant immunologic risk assessment in heart, lung, and kidney patients using sensitive flow cytometric–based technologies for determination of the presence and specificity of an HLA antibody. Immunomodulation of the sensitized patient is a highly specialized evolving field that borders on research, which may either represent a “care gap” or make it hard to “provide guidance” because of the lack of well-designed randomized controlled trials. Author's personal copy S10 SHEHATA ET AL Table 2. Characteristics of the Studies for the Use of Immunoglobulin for Desensitization in Kidney Transplantation 1st author, year Study design Randomized controlled trials Jordan SC, 200410 Multicenter RCT, DB, PC Peraldi, MN, 199611 Single-center RCT Observational studies Case series Vo AA, 200853 Anglicheau D, 200712 Prospective case series Living or deceased donor Method to determine sensitization Definition of sensitization NR 30 mo Negative CXM 20 mo FXM, CDC CXM, T-cell CDC-PRA Mean prestudy PRA 77%, or had DSA 12 mo T- and B-cell CDC and AHG-CDC/ PRA using MLA FXM CDC CXM (1) Negative T-CDC CXM at 1:2 dilution, (2) negative T-cell FXM or positive (with a mean flow-channel shift of b250), or (3) both. NR Positive T-cell AHG CXM and/or DSA (negative CXM at Tx) DSA but negative Lack of rejection/ CXM graft loss PRA ≥20% Transplantation PRA using MLA Second deceased T and B CXM PRA Both Deceased Bielman D, 200713 Prospective case series Mahmoud KM, Prospective 200714 case series Prospective Kayler L, 200629 case series Both Living CDC CXM, PRA by ELISA T-AHG-CDC, B-CDC, FXM, anti-A IgG antibody for non-A2 Stegall MD, 200615 Cohort Living FC T-AHG-CDC Thielke J, 200516 Case series Living FXM Akalin E, 200517 Case series Living FXM, CDC Mahmoud K, 200418 Akalin E, 200319 Case series Living Prospective case series Prospective case series Both PRA-ELISA CDC CXM AHG-CDC, FXM Prospective Jordan SC, case series 200321 Zachary A, 200322 Case series Both PRA using frozen lymphocyte antibody panel and T-cell AHG-CDC PRA using MLA NR Both CDC and FXM Glotz D, 200223 Prospective case series Both PRA using MLA or T-cell IgG CXM Sonnenday CJ, 200224 Schweitzer EJ, 200025 Retrospective Living case series Prospective Living case series AHG-CDC or FXM Glotz D 199526 Prospective case series PRA Gloor JM, 200320 Living NR Follow-up PRA ≥50% monthly × 3 mo NR Both Living Definition of response AHG-CDC Positive (N10%) T-AHG-CDC or B-CDC or T or B FXM (15 and 30) or IAT Mean channel fluorescence shift N52 for T-cells and N106 for B-cells Channel shifts for T-cells N+20 and B-cells N+40 Positive T- and B-cell FXM or CDC PRA ≥20% Negative CXM or IgG titer ≤1:8 Positive AHG-CDC or FXM NR mean peak PRA-69% NR 6 mo Before transplantation Mean = 16 mo Negative T-AHG-CXM 1y Negative CXM 18 mo NR 6-34 mo NR 6 wk Positive B-cell CDC NR and B- or T-cell FXM T-cell AHG-CDC Negative CXM FXM: median channel ratio N3; CDC: N10% cell death PRA N50% or positive T-cell CXM 25 mo Negative or “acceptable” CDC CXM NR 15 mo 15 mo 2y 2-90 mo Deceased: 50% 1y decrease in antibodies; living: negative CXM Negative CXM 17 mo Negative AHG-CDC; no donor-specific reactivity by ELISA NR 3-26 mo NR Author's personal copy IMMUNOGLOBULIN IN SOLID ORGAN TRANSPLANTATION S11 Table 2 (continued) 1st author, year ABO incompatible Tyden G, 200727 Tyden G, 200628 Tyden G, 200530 Winters JL, 200431 Sonnenday CJ, 200432 Gloor JM, 200333 Study design Prospective cohort Prospective case series Case series Prospective case series Retrospective case series Retrospective case series Method to determine sensitization Definition of sensitization Saline method (IgM), IAT (IgG) DAT and IAT ABO incompatible Saline method for IgM and IAT for IgG IAT, AHG-T-cell cytotoxicity assay IAT Mean acceptable titer b1:128 ABO incompatibility DAT and IAT, method for PRA NR ABO incompatible Definition of response Preoperative IgG titer b1:8 IgG and IgM titer b1:8 Titer b1:8 Follow-up 2-61 mo 1-49 mo 3-34 mo Mean = 13 mo ABO incompatibility AHG titer ≤16 until 2001 then b4 Titer ≤1:16 ABO incompatibility NR 1y Median = 1 y Abbreviations: CXM, crossmatch; DB, double blind; DAT, direct antiglobulin test; DSA, donor-specific antibodies; ELISA, enzyme-linked immunosorbent assay; FC, flow cytometry; FXM, flow cytometry crossmatch; IAT, indirect Coomb test; MLA, microlymphocytoxicity assay; NA, not applicable; NR, not reported; PC, placebo controlled; PRA, panel-reactive antibody; RCT, randomized controlled trial; T-AHG-CDC, T-cell antiglobulin enhanced complement-dependent cytotoxicity crossmatch; Tx, transplantation. The treatment options for sensitized patients are (1) immunomodulation, that is, reduction/removal of HLA antibodies, or (2) the development of strategies to find a donor to whom the sensitized recipient has not developed antibodies (ie, living donor paired exchange or mandated allocation of organs to sensitized patients when an acceptable mismatch becomes available). Intravenous immunoglobulin has been used for desensitization for patients who have HLA antibodies and has been also used perioperatively in combination with other immunomodulating agents in this patient population to (1) directly block the ability of donor-specific HLA antibodies to activate complement, (2) neutralize donor-specific antibodies via anti-idiotypic HLA antibodies contained in IVIG, or (3) down-regulate HLA antibody production by donor-specific B-cells. Intravenous immunoglobulin has also been used for ABO-incompatible renal transplantation, although its use for this indication is an emerging clinical entity and these transplants are only being conducted in a small number of centers. Most desensitization protocols for patients receiving an ABO-incompatible transplant use IVIG as a cointervention. HLA Sensitization Tables 2 and 3 illustrate the characteristics and results of the studies for the use of immunoglobulins for desensitization for HLA antibodies. There were 2 randomized controlled trials6,11 and 17 cohort/case series12-26,29,53 for the use of IVIG for HLA-sensitized renal transplant recipients and seven cohort/case series27-33 for the use of IVIG in ABO-incompatible transplantation. Only one of the two randomized controlled trials was a double-blind trial (Tables 2 and 3).6 Both reports indicated that the groups were comparable.6,11 None of the trials specified whether there was concealment of allocation or whether intent-totreat analysis was used. Jordan and colleagues reported a trend in improvement in desensitization rates and a statistically significant decrease in time to transplantation for patients treated with IVIG.10 However, acute rejection occurred more frequently in patients treated with IVIG; and there was no information provided on donor/recipient compatibility or HLA antibody titer. A standardized immune suppression protocol was not used peritransplantation, and an analysis between living and deceased donors was not provided. Peraldi and colleagues11 randomized patients having a second deceased donor transplant. It was unclear whether donor-specific antibodies were present because only the panel-reactive antibody test was used. Five-year survival was not different between the groups; however, graft survival was superior in patients treated with IVIG. Most of the remaining reports were case series. Three were publications in non–peer-reviewed journals.16,18,24 Author's personal copy S12 SHEHATA ET AL Table 3. Results of the Studies for the Use of Immunoglobulin for Desensitization in Kidney Transplantation 1st author, year Patients Randomized controlled trials Adult Jordan SC, 200410 Peraldi MN, 199611 Adult Observational studies Adult Vo AA, 200853 Anglicheau D, 200712 Adult Bielman D, 200713 Mahmoud KM, 200714 Adults Kayler L, 200629 Adult HLA and ABO incompatible Stegall MD, 200615 Adult Adults Thielke J, 200516 Adult † Akalin E, 200517 NR Mahmoud K, 200418 Adult N Transplant regimen 48 IVIG 2 g/kg q 4 wk × 4 mo, at 12 and 24 mo if not transplanted 50 Placebo Immunosuppression determined by center 21 IVIG 400 mg/(kg d) days 0-4 20 No IVIG; all received steroids, AZA, CYA, ATG/OKT3 20 IVIG 2g/kg day 0 and day 30, rituximab 1g day 7 and day 22 + alemtuzumab, MMF, steroids, TAC 38 IVIG 2 g/kg days 0, 21, 42, and 63; TG or basiliximab, TAC or CYA, MMF, steroids 9 IVIG 400 mg/(kg d) days 1-4, TG, TAC, MMF, prednisone 11 IVIG 500 mg/kg × 6 doses in 2 wk, and after 2 mo, simvastatin 20 mg/d × 2 mo 12 PP 2-7 d then CMVIG 100 mg/kg + MMF, TAC, steroids, daclizumab; splenectomy (for ABO, n = 3), PP/CMVIG post-Tx 32 PP/IVIG (100 mg/kg) daily, rituximab, splenectomy (n = 19) 13 IVIG 2 g/kg × 1 before Tx (n = 2, 3 g/kg) 16 PP/IVIG (100 mg/kg) daily, rituximab 375 mg/m2 × 1, TG, then PP/IVIG day post-Tx & posttransplant, DSA monitoring, +PP/IVIG days 1-3 post-Tx, TG, TAC, MMF, prednisone 16 PP + IVIG (100 mg/kg) q 2nd day 1 wk before Tx, Rituxan (n = 6; Genentech, USA); post-Tx: PP, IVIG q 2nd day × 1 wk + TAC, TG, MMF, steroids 7 IVIG (100 mg/kg) × 3 d, TG, CYA (n = 5), TAC + MMF + prednisone (n = 2) 11 IVIG 500 mg/kg × 6 doses Success of desensitization 17/48 (35%) 10/50 (20%) (P = .07) received a transplant No difference in reduction of PRA Humoral rejection 9/17 (53%) (& cellular) 1/10 (10%) (P = .04) Graft survival 12/16 (75%) 5/8 (62%) Survival 4 Patients died 8 Patients died (P = .29) No difference 5 y 68% in acute vs 50%, rejection P = .002 episodes 5 y 90% vs 95% 16/20 (80%) 16% 94% (n = 16) 100% (n = 16) ≈30%-40% % reduction in PRA in n = 27 who had PRA at Tx NR 4/38 (11%) 36/38 (95%) 37/38 (97%) 4/9 (44%) NR NR PRA 39% ± 18% before IVIG vs 37% ± 17% post-IVIG (P = .36); 0% was crossmatch negative 100% NR NR NR 4/12 (30%) 1 y 100% 1 y 100% 27/32 (84%) 11/30 (37%) NR ⁎ NR ⁎ 5/13 (36%) 4/5 (80%) 14/16 (88%) 4/14 (29%) 12/16 (75%) 3/12 (25%) 100% 100% NR 2/7 (28%) 6/7 (86%) 100% 0% NR NR NR Author's personal copy IMMUNOGLOBULIN IN SOLID ORGAN TRANSPLANTATION S13 Table 3 (continued) 1st author, year Patients Akalin E, 200319 Adult Gloor JM, 200320 Adult Jordan SC, 200321 Adult and pediatric renal, cardiac, liver ‡ Zachary A, 200322 NR Glotz D, 200223 Adult Sonnenday CJ, 200224 Adult Schweitzer EJ, 200025 Adult NR Glotz D, 199526 ABO incompatible Tyden G, Adult and 200727 children ABO incompatible ABO compatible NR Tyden G, 200628 Tyden G, 200530 Adult and pediatric Winter JL, 200431 NR N Transplant regimen 8 IVIG 100 mg/kg day 0, 2 doses between days 1-4; TG, CYA, MMF (n = 7), rapamycin (n = 1), steroids 14 PP/IVIG 100 mg/kg days −4, −3, −1, 0, +1, +3, FFP day +1, rituximab day −4, + splenectomy + TG, MMF, TAC, prednisone 26 IVIG 2 g/kg for living donor 17 IVIG 2g/kg q month × 4 and 1 mo after Tx for deceased heart (2) or kidney; all patients received Zenapax (Roche Pharmaceuticals, USA), TAC, MMF, steroids 49 ║ PP q 2nd day + CMVIG 100 mg/kg + TAC, steroids, MMF, daclizumab 15 IVIG 2 g/kg/4 wk for 12 wk pre-Tx, then IVIG 2 g/kg, MMF, steroids, TG, TAC at Tx, then IVIG 2 g/kg days 20 and 40 18 PP and CMVIG 100 mg/kg q 2nd day until response, + TAC, MMF, prednisone, daclizumab 15 ¶ MMF, TAC, prednisone, PP 3×/wk in weeks 2 and 3, IVIG 500 mg/kg over 7 d week 2, OKT3 PO days 1-10 10 IVIG 400 mg/kg × 4 d 60 Rituximab, TAC, MMF, steroid, IA × 4, IVIG 0.5 g/kg Success of desensitization Humoral rejection Survival NR 1/8 (12%) 7/8 (88%) 100% 100% 6/14 (43%) 11/14 (79%) 12/14 (86%) 100% (n = 2 required more IVIG) 16/17 (94%) 13/42 (31%) § 89% 98% 63% lost Not clear antibody to donor HLA, 27% lost antibody to 3rd-party HLA 13/15 (87%) 1/13 (7%) Not clear NR 10/13 (77%) 11/13 (85%) 100% 5/18 (28%) 17/18 (94%) NR 11/15 (73%) 11/11 (100%) NR 4/10 3 (27%) Humoral, 1 (9%) cellular 0/4 4/4 4/4 100% 0 97% 98% 95% 98% 274 NR 21 IA × 4 pre-Tx and × 3 post-Tx, IVIG 500 mg/kg × 1, rituximab, TAC, MMF, prednisone 11 Rituximab, TAC, MMF, prednisone, IA + IVIG 500 mg/kg after last session, IA × 3 PO 26 PP days −4, −2, −1, 0 followed by IVIG 100 mg/kg days −4, −2, −1, FFP day 0, TG, TAC, MMF, prednisone, + splenectomy Graft survival 100% 0 20/21 (95%) 100% 100% 0 100% 100% 100% 12/26 (46%) 22/26% (85%) 24/26 (92%) (continued on next page) Author's personal copy S14 SHEHATA ET AL Table 3 (continued) 1st author, year Patients Sonnenday C, Adult 200432 Gloor JM, 200333 Adult ABO incompatible Adult ABO compatible N Transplant regimen 6 PP + CMVIG 100 mg/kg × 5 q 2nd day pre-Tx and × 3 post + TAC, MMF, steroids, rituximab, daclizumab, 18 TG, TAC, MMF, steroids (8 did not receive pre-Tx conditioning) + PP; PP and IVIG (10 g/d) for patients replaced with albumin, splenectomy for non-A2 81 HC: TAC, MMF, steroids Success of desensitization Humoral rejection Graft survival Survival 100% 0 100% NR NR 5/18 (28%) 89% 94% NR 96% 99% Abbreviations: ATG, antilymphocyte globulin; AZA, azathioprine; CYA, cyclosporine A; FFP, fresh frozen plasma; HC, historical controls; IA, immunoadsorption; MMF, mycophenolate mofetil, PO, postoperatively; q, every; TAC, tacrolimus, TG, thymoglobulin. ⁎ Survival was only reported for the entire cohort. † One patient received a kidney and pancreas transplant. ‡ All patients had to have had in vitro evidence that IVIG could reduce cytotoxicity. § The type of rejection was not specified. ║ The authors also included patients with ABO-incompatible transplants and patients treated for rejection with PP and CMVIG. ¶ Two individuals had kidney and pancreas transplantation. These transplants were unsuccessful. One report compared single-dose IVIG to two regimens containing IVIG and plasmapheresis (PP). The pretransplant regimen also included the use of rituximab and thymoglobulin.15 Successful desensitization was defined as a negative anti-human globulin complement-dependent cytotoxicity (AHG-CDC) crossmatch pretransplantation. Intravenous immunoglobulin as a single agent was associated with inferior desensitization rates and higher rates of rejection. This report, although with a few patients, described the success of desensitization based on the preimmunomodulation AHG-CDC crossmatch titer of donor-specific HLA antibody. Patients who had an AHG-CDC titer of 1:32 or more predesensitization were less likely to achieve a negative AHG-CDC crossmatch independent of the desensitization regimen. One small observational report used low-dose IVIG 500 mg/kg only.14 Desensitization with this protocol was unsuccessful.14 Seven reports used lower-dose (ie, 100-500 mg/kg) IVIG/CMVIG in combination with PP and various immunosuppressive regimens.15,16,20,22,24,25,29 A total of 201 patients were included in these studies. The success of desensitization ranged from 63% to 100%. The frequency of antibody-mediated rejection ranged from 25% to 43%, and graft survival was from 79% to 100% (Table 2). Five reports,12,15,21,23,53 including 177 adult patients, used higher doses of IVIG (ie, 2 g/kg). Rates of desensitization ranged from 36% to 100%, and the frequency of antibody-mediated rejection occurred in 7% to 80% of patients transplanted (Table 2). ABO-Incompatible Kidney Transplantation Seven observational reports described the use of IVIG/CMVIG in patients undergoing ABOincompatible renal transplantation (Tables 2 and 3). 27-33 All reports used IVIG concurrently with other immune modulating agents. Graft survival ranged from 80% to 100%, and patient survival was greater than 90%. Two reports compared graft survival and overall survival with patients receiving ABO-compatible transplants and reported comparable outcomes (Tables 2 and 3).27,33 Is there evidence that the perioperative use (ie, prophylactic use) of IVIG for sensitized (HLA or ABO) patients who have been desensitized or who have a positive crossmatch and are undergoing kidney transplantation decreases the frequency of acute rejection and chronic rejection, and improves graft survival and overall survival? Four reports addressed the administration of IVIG peritransplantation; three included patients with a positive crossmatch at transplantation, 12,17,19 and one included patients with donor-specific Author's personal copy IMMUNOGLOBULIN IN SOLID ORGAN TRANSPLANTATION antibodies.13 High graft survival and overall survival rates with IVIG were reported in three reports (Tables 1 and 2).12,17,19 What are the adverse effects of IVIG in patients undergoing kidney transplantation? The use of IVIG has been associated with several adverse events such as thrombosis, hemolytic anemia, renal failure, and aseptic meningitis.61 Few reports in the renal transplantation population discussed complications associated specifically with IVIG. One study did not find any differences in viral or bacterial infections in patients treated with IVIG or OKT3.34 Headaches were described in two reports,6,12 and aseptic meningitis associated with IVIG was reported in one individual.43 Renal failure was not found to occur in any patient treated with IVIG in the latter study.43 Other adverse events reported in patients who received both IVIG and other immune-suppressive agents include CMV disease,12,33,34,40 BK virus,12 bacterial infection,12,33 fungal infection,33,40 and thrombosis.12 The contribution of IVIG specifically to these events could not be conclusively attributed. One retrospective review addressed adverse events associated with IVIG in 279 patients at a single center and included 180 sensitized patients who were treated with IVIG before solid organ transplantation.54 Three products were used: Gamimune-N 10% (Bayer Biological, USA), Carimune (CSL Behring, USA), and Polygam (Baxter Hyland Immuno, USA). Significant adverse events, defined as acute myocardial infarction and acute renal failure, were noted with Polygam and Carimune, respectively. In addition, thrombotic events occurred in 4.7% of patients receiving Polygam compared with 0% in patients who received Carimune and Gamimune. The acute renal failure was attributed to sucrose in Carimune, and the high sodium chloride base of Polygam (ie, an osmolality of 1250 mosm/L in the 10% preparation) was postulated to be the factor resulting in thrombotic events. Headaches were the most frequent adverse events reported with Gamimune-N 10%. CONSENSUS FOR KIDNEY TRANSPLANTATION HLA Desensitization Although there were a number of reports describing the use of IVIG for sensitized patients undergoing renal transplantation, there were several S15 limitations. The definition of sensitization was not consistent among the studies, and the type and titer of the antibody were often not reported. The assays to detect HLA antibodies were variable; that is, some used flow cytometric assays, others used enzyme-linked immunosorbent assays. Several studies failed to provide sufficient methodological details to permit interpretation of the data. Thus, the true immunologic risk of the recipients was difficult to evaluate. The definition of response and the proportion of patients who responded were often not indicated. Of the reports that described a definition of response, most indicated a negative AHG-CDC crossmatch was equivalent to response. The dose of IVIG and timing of IVIG were also variable. Nonetheless, the use of IVIG was associated with acceptable outcomes, that is, acute rejection and short-term graft and patient outcomes. Details on long-term outcomes were limited, but evidence is mounting that patients who have persistently positive crossmatches at the time of transplantation or have too high a titer of donor-specific HLA antibodies (ie, AHG-CDC crossmatch titer N1:32) to start desensitization have inferior outcomes in the long term.15 However, as these patients may not have been able to receive a transplant and as they have a high risk for morbidity and mortality while receiving dialysis, many physicians consider graft survival and overall survival acceptable compared with dialysis. For patients who are sensitized as defined by a positive CDC crossmatch, IVIG 2 g/(kg mo) for 4 months and PP/IVIG (100 mg/kg) in the perioperative period to achieve a negative cytotoxicity crossmatch pretransplant were considered equivalent treatment modalities. Although higher doses of IVIG have been used in combination with PP in a few reports, there is no evidence to suggest that higher doses are superior to 100 mg/kg. For patients who were sensitized as defined by a positive crossmatch by flow cytometry, IVIG 2 g/kg once and PP/IVIG (100 mg/kg) to achieve a negative flow crossmatch pretransplant were considered equivalent options. Although the maximum dosage of IVIG has not been determined, the panel felt that based on previous studies,6,36 IVIG should be administered at a maximum single dose of 2 g/kg and not exceed 180 g, as the efficacy and safety of higher doses have not been evaluated. Author's personal copy S16 ABO-Incompatible Transplantation There is uncertainty about the best strategy for these patients. Outcomes cannot be separated by a single therapeutic modality because there are usually several therapeutic agents used concurrently. Intravenous immunoglobulin is used as part of a regimen by several centers for ABO-incompatible renal transplantation; however, whether it plays an essential role in immune modulation in these cases has yet to be determined. Perioperative Use of IVIG There is limited literature available on the perioperative use of IVIG in the transplantation setting, and the use of IVIG in the perioperative setting is often center dependent. Intravenous immunoglobulin is used perioperatively for patients who have donor-specific antibodies detected by solid-phase assays or who have undergone desensitization and whose AHG-CDC crossmatch is negative pretransplant. These patients may still have a positive crossmatch by flow cytometry at transplantation; and as the treatment of these patients is center dependent, some centers may not proceed with transplantation with a crossmatch that is positive by flow cytometry. Given the favorable graft survival and overall survival, IVIG was recommended as a treatment option, that is, IVIG 2 g/kg once or PP followed by IVIG (100 mg/kg) in the first week after transplantation. It has been previously recommended in Canada that, after transplantation, solid-phase–based HLA antibody assessment and pathology monitoring be performed routinely in these high-risk patients.55 Adverse Events There are several formulations of IVIG available in Canada; however; there is no evidence to suggest that there is a difference in outcomes or adverse events according to the formulation. In addition, Carimune and Polygam are no longer available in Canada. Patients with renal disease are susceptible to vascular complications and are also susceptible to infections due to the various immunosuppressive agents used perioperatively. There are insufficient data to confirm whether IVIG further increases the thrombosis risk associated with renal disease; but as this population often has significant SHEHATA ET AL vascular disease, there may potentially be an increased risk of thrombosis with IVIG. The committee did not consider IVIG to contribute to infectious risk. RECOMMENDATIONS HLA Sensitization 1. When transplantation will involve use of a kidney from a living donor to whom the patient is sensitized, IVIG is recommended to decrease donor-specific sensitization. Level of evidence: I-II 2-3 Grade of recommendation: B Clinical considerations: For patients who are sensitized to their donor as defined by a positive CDC crossmatch, give IVIG 2g/(kg mo) for 4 months to achieve a negative AHG-CDC crossmatch before transplantation. The committee is also aware that alternate strategies such as PP followed by IVIG (100 mg/kg) have also been used and consider these acceptable strategies. The use of PP followed by IVIG (100 mg/kg per dose) is generally restricted to the perioperative period. Aim for a negative AHG-CDC crossmatch or negative flow cytometric crossmatch and not a change in the percentage of panel-reactive antibody. Emerging studies suggest that high-titer (ie, AHG-CDC crossmatch N1:16) donor-specific HLA antibodies may limit the effectiveness of desensitization.12 Although the data are not derived from the pediatric population, the committee felt that it was reasonable to use IVIG similarly in the pediatric population. With respect to clinical efficacy and adverse events, there is insufficient evidence to recommend one formulation of IVIG over another. Qualifying statement: For sensitized patients who have received a transplant from a deceased donor, desensitization with IVIG is generally not used in Canada because of limited availability of deceased donors. Although the evidence from this systematic review supports the use of IVIG for desensitization before transplantation for highly sensitized patients receiving kidneys from deceased donors, the routine use of IVIG might result in unnecessary wastage, as it is not guaranteed that recipients will have access to donors within 2 years. The recommendation against the use of IVIG for recipients of deceased donor transplants is subject to the availability of deceased donors. Should deceased donor kidneys become Author's personal copy IMMUNOGLOBULIN IN SOLID ORGAN TRANSPLANTATION S17 there is insufficient evidence to recommend one formulation of IVIG over another for currently available products. 4. Intravenous immunoglobulin is not recommended for patients who do not have donor-specific antibodies. Level of evidence: III Grade of recommendation: D readily available, IVIG would be recommended for the sensitized recipient. 2. There is insufficient evidence to make a recommendation for or against the use of IVIG for ABO-incompatible kidney transplantation; however, other factors may influence decision-making. Level of evidence: II-2-III Grade of recommendation: B 3. Intravenous immunoglobulin is recommended for patients undergoing kidney transplantation who have donor-specific antibodies perioperatively to reduce the incidence of acute antibody-mediated rejection. Level of evidence: III Grade of recommendation: B Clinical considerations: There is insufficient evidence to recommend one treatment regimen. With respect to clinical efficacy and adverse events, In patients with acute rejection or chronic rejection, is there evidence that the use of IVIG improves graft survival or overall survival? Rejection after transplantation is a significant and frequently occurring problem associated with substantial morbidity. Rejection of the renal allograft is associated with peritransplant immunosuppression and can be categorized as (1) acute antibody-mediated rejection, (2) steroid-resistant Table 4. Characteristics of the Studies for the Use of IVIG for Kidney Transplant Rejection 1st author, year Study design Living or deceased donor Randomized controlled trials Single-center Both Casadei D, RCT 200134 Observational Studies Vasilescu ER, Retrospective Deceased 200635 case series Both Type of rejection Mean PRA CYA, AZA, steroids NR 2y Antibody mediated NR † NR 1y Antibody mediated (C4d+) Acute humoral 67% ± 25% NR White NB, 200438 Retrospective Both case series Acute humoral NR Rocha P, 200339 Retrospective Both case series T: 47 ± 11; B: 31 ± 10 Luke PPW, 200140 Retrospective NR case series Montgomery RA, 200041 Casadei D, 199842 Jordan SC, 199843 Casadei D, 199644 Retrospective Living case series Cohort NR Acute humoral and acute cellular rejection Steroid or antilymphocyte antibody-resistant rejection Acute humoral Steroid-resistant rejection Acute humoral ± cellular rejection Steroid-resistant rejection Both Retrospective Both case series Follow-up NA Case series Case series Definition of response Steroid-resistant rejection ⁎ Jordan SC, 200536 Lehrich RW, 200537 Retrospective Both case series Maintenance immunosuppression T: 39% ± 8.7%; TAC/CYA, MMF, B: 43% ± 8.9% prednisone Basiliximab, TAC, prednisone, sirolimus (n = 6), MMF (n = 3) TAC/CYA, MMF, MP Return to nearnormal creatinine or loss of DSA NR 4y Return to normal Mean renal replacement 29 mo therapy NR 1y Outcome of renal allograft 1.5 y NR MMF (n = 6), TAC (n = 16), CYA (n = 1) Reversal of rejection Mean 22 mo NR NR NR TAC, MMF, prednisone NR NR Mean 30 mo 2 mo NR NR NR 5 mo-5 y NR CYA + AZA + prednisone NR 1 mo Abbreviation: MP, methylprednisone. ⁎ Steroid-resistant rejection defined as failure to improve renal function within 7 days of pulse methylprednisone. † No correlation between antibody-mediated rejection and panel-reactive antibodies. Author's personal copy S18 SHEHATA ET AL acute cellular rejection, (3) “simple” acute cellular rejection, and (4) chronic active antibody-mediated rejection. A mixed picture may also occur. Intravenous immunoglobulin is commonly used to treat antibody-mediated rejection. There were seven case series that included a total of 166 patients with antibody-mediated rejection (Tables 4 and 5).35-39,41,43 All but one43 of these studies used a combination of IVIG and PP. However, various additional immunosuppressive agents were also used in the treatment of these patients. Definitions of acute humoral rejection differed. The doses of IVIG administered ranged from 100 mg/kg to 2 g/kg. Graft survival ranged from 60% to 100%, and patient survival was from 90% to 100%. The survival rate is comparable with 3-month graft survival of historical controls that has been reported at 50%, despite treatment with antilymphocyte antibody preparations in 92% of patients.62 For patients at increased immunologic risk (sensitized recipient having undergone desensitiza- tion protocols to achieve transplantation) with acute antibody-mediated rejection, one case series with 18 patients reported a 60% graft survival using IVIG and steroid treatment.36 In those who did not respond, addition of thymoglobulin and plasma exchange could not rescue the organ. Two other case series with a combined total of 39 patients that also included patients who were sensitized reported favorable results (Tables 4 and 5).37,39 One randomized controlled trial,34 one cohort study,42 and two case series40,44 addressed the use of IVIG in patients having steroid-resistant rejection. The cohort study may have been a preliminary report of the randomized controlled trial.42 Patients in the randomized controlled trial were treated with IVIG or OKT3. Comparable graft and patient survivals were reported (Table 5).34 A lower recurrence rate of acute rejection occurred with IVIG (46% with IVIG compared with 75% with OKT3, P = .4).34 In one case series, graft survival was similar to that observed in the randomized controlled trial (71%).40 This is comparable to historical data in patients treated with a Table 5. Results of Studies for the Use of IVIG for Kidney Transplant Rejection 1st author, year Patients Randomized controlled trials Adult Casadei D, 200134 N Graft survival Survival 80% 80% 78/80 (98%) 78/80 (98%) NR 72% 20/23 (87%) 11/18 (61%) NR 20/23 (87%) 22/23 (96%) 8/9 (89%) 8/9 (89%) 15/16 (93%) 13/16 (81%) 15/16 (93%) Jordan SC, 199843 PP, IVIG/CMVIG 100 mg/kg until response q 2nd day + MP, MMF, TAC NR 18 IVIG 2 g/kg, pulse steroids ± PP or TG Adult 23 4 Daily PP followed by IVIG 2g/kg (variable dose); PP only (n = 1), + MP (n = 11), +TG or OKT3 (n = 7) Adult 9 PP followed by IVIG 250/500 mg/kg q 2nd day +MP Adult, ± 16 4 Daily PP followed by IVIG 2 g/kg; pancreas PP only (n = 1), IVIG only (n = 1) + MP + OKT3 (n = 3) + TG (n = 1) NR 17 IVIG 2 g/kg over 2-10 d (additional IVIG, n = 4) + steroids (n = 10), + MMF (n = 7), 7 were 10 Rejection; PP + IVIG/CMVIG adults 100 mg/(kg d) q 2nd day until improvement or no DSA NR 11 IVIG 500 mg/kg × 7 d 12 OKT3 5 mg/d for 14 d NR 10 ⁎ IVIG 2 g/kg + MP ± OKT3 ± CY ± TAC Casadei D, 199644 NR Jordan SC, 200536 Lehrich RW, 200537 White NB, 200438 Rocha P, 200339 Luke PPW, 200140 Montgomery RA, 200041 Casadei D, 199842 IVIG 500 mg/(kg d) × 7 d OKT3 5 mg/kg × 14 d Response rate 11/15 (73%) 13/15 (87%) Observational studies Vasilescu ER, 200635 Adult 15 15 Treatment regimen 80 22 IVIG 500 mg/kg ×7 d Abbreviation: CY, cyclophosphamide. ⁎ Three patients had heart transplantation. 87% 92% NR Resolution of 12/17 (71%) 16/17 (95%) rejection = 9/17 (53%) NR 9/10 NR 8/11 (73%) 10/12 (83%) 100% NR NR 21/25 (84%) NR 100% 100% 1/3 Cardiac (33%), not reported for kidney NR Author's personal copy IMMUNOGLOBULIN IN SOLID ORGAN TRANSPLANTATION calcineurin inhibitor-based immunosuppression protocol, where 6-month graft survival is reported to be 59%.63 There were no studies with a sufficient sample size (ie, N5 patients) that addressed the use of IVIG for the treatment of simple acute cell-mediated rejection or chronic active antibody-mediated rejection. Consensus There is sufficient evidence to propose that IVIG be used for the treatment of patients with acute antibody-mediated rejection. There are insufficient data to draw conclusions regarding treatment of antibody-mediated rejection using IVIG alone, without the use of concomitant PP. In most published reports, IVIG is used after PP. Cytomegalovirus immunoglobulin has also been administered at some centers with PP; however, there are no data to indicate that CMVIG is superior to other IVIG preparations. In addition, there are no trials that compare IVIG and PP to other rejection therapies or that compare IVIG alone to PP. Randomized controlled trials are required to compare these treatment options. There are limited data on the use of IVIG in patients with increased immunologic risk who experience acute antibody-mediated rejection, and there are no data comparing the use of IVIG in the patient with increased immunologic risk to its use in the standardrisk patient. Nonetheless, because immune mechanisms of rejection are similar in such patients, IVIG use was also considered a treatment option in these patients, although they may be less responsive. Intravenous immunoglobulin is not presently considered as first-line therapy for the treatment of steroid-resistant rejection, as there are no data to indicate that IVIG is superior to alternate therapies. Comparative studies of IVIG are promising, but have not included current standard polyclonal antilymphocyte antibody treatments, which are better tolerated than previous monoclonal antilymphocyte preparations. The use of IVIG may be reserved for situations where standard treatments have been ineffective or are contraindicated. Intravenous immunoglobulin has less toxicity associated with its use compared with other standard therapies and should be studied further. There are also limited data on the use of IVIG for chronic active antibody-mediated rejection. Randomized controlled trials are required to define the role of IVIG in this patient population. S19 There are little pediatric data. The immunologic mechanisms of acute humoral rejection and steroid-resistant rejection are similar, and children are expected to have a similar benefit from IVIG treatment. Recommendations 5. Give IVIG after PP for patients who have received a living donor or deceased kidney donor transplant and who have acute antibody-mediated rejection to improve graft survival. Level of evidence: II-3 Grade of recommendation: B Clinical considerations: Intravenous immunoglobulin is typically administered as part of a treatment protocol that includes PP. Regimens for administration of IVIG include IVIG after each PP treatment (100 mg/kg per treatment day) or as a set dose of 2 g/kg total, after the final PP treatment. There are no comparative data to indicate which of these approaches is superior. Cytomegalovirus immunoglobulin has also been administered at a dose of 100 mg/kg after each PP treatment. The optimal number and frequency of PP treatments needed are beyond the scope of these recommendations. With respect to clinical efficacy and adverse events, there is insufficient evidence to recommend one formulation of IVIG over another for currently available products. 6. In patients who have received a living/ deceased donor kidney transplant and who have steroid-resistant rejection, consider IVIG to improve graft survival when other therapies are deemed unacceptable or ineffective. Level of evidence: I, II-2, III Grade of recommendation: B Clinical considerations: Intravenous immunoglobulin can be administered over a period of up to 10 consecutive days, at a total dose of 2 to 3.5 g/kg. Longer administration periods with smaller doses can be used in selected patients where fluid overload is a potential risk. Assessment of treatment response should include measurement of renal function and reassessment of renal histology. There is insufficient evidence to recommend one formulation of IVIG over another. 7. There is insufficient evidence to make a recommendation for or against the routine use of IVIG for other forms of rejection. Level of evidence: III Grade of recommendation: I Author's personal copy S20 SHEHATA ET AL CARDIAC TRANSPLANTATION There remains a great deal of controversy over quantification, evaluation, and management of the sensitized potential cardiac transplant recipient. What is certain is that highly sensitized patients, including those with donor-specific antibodies, have an increased risk of antibody-mediated rejection, cardiac allograft vasculopathy, and early graft loss after transplantation.64,65 In addition, the use of mechanical circulatory support as a bridge to transplantation has been associated with an increasing incidence of de novo sensitization (approximately 30% depending on the definitions used) due in part to transfusions, especially platelets, at the time of implantation.66 Multiple strategies to desensitize the potential cardiac transplant recipient have been proposed including treatment with mycophenolate mofetil or cyclophosphamide, PP, IVIG, rituximab in isolation or in combination with other agents, before transplantation, perioperatively, or immediately after transplantation. Results have been variable, and the interpretation of analyses is limited by inconsistent use of classification of outcomes. Six observational studies reported on the use of IVIG in cardiac transplantation (Tables 6 and 7).45-50 Three studies included the same cohort of patients who were treated with IVIG for desensitization aiming for a negative crossmatch.47,48,50 Four reports did not define response to treatment.45,46,48,49 The reduction of antibody level with IVIG as a single modality was not measured in any report. A decreased panel-reactive antibody was detected in two reports,45,49 and four reports did not show a change in panel-reactive antibodies.46-48,50 Three reports demonstrated a reduced time to transplantation but included the same patient co- hort.47,48,49 One small study showed a survival benefit in sensitized heart transplant recipients who received pretransplant treatment with PP and IVIG.45 One report included a pediatric population, and outcomes were not improved with the use of IVIG.46 Only one study reported complications associated with IVIG.48 The use of IVIG resulted in immune complex disease (ie, fevers, arthralgias, and maculopapular rash) in four patients (15%). Four patients also experienced reversible renal insufficiency defined as a 50% increase in serum creatinine level. The renal insufficiency resolved in all patients 3 weeks after IVIG infusion.48 Consensus There were several limitations in the available literature. Different methodologies were used for the detection of panel-reactive antibodies. The reports that included rejection as an outcome reported both acute cellular and antibody-mediated rejection and did not use the current International Society for Heart and Lung Transplantation's standardized definition of antibody-mediated rejection. The use of other interventions with IVIG such as PP and other immunosuppressive agents precluded assessment of the impact of any given therapy. There was also a paucity of data for transplantation rates and outcomes. Although one report found a survival benefit,45 these results have not been reproduced, the numbers are small, and no data on donor-specific antibody were given. The available literature on renal transplantation suggests that transplantation in the setting of an acceptable antigen mismatch (ie, in the presence of an HLA antibody but not directed against the donor HLA type) is associated with comparable Table 6. Characteristics of the Studies for the Use of IVIG for Desensitization for Cardiac Transplantation 1st author, year Study design Leech SH, 200645 Jacobs J, 200446 Case series Retrospective cohort Retrospective cohort Retrospective cohort Retrospective cohort Prospective cohort John R, 200347 Itescu S, 200248 Pisani BA, 199949 John R, 199950 Method to determine sensitization Definition of sensitization Definition of response CDC CXM, PRA by FC Cytotoxic PRA PRA N10% PRA N10% NR NR Mean 21 mo 17 d-8 y Follow-up Lymphocytotoxic CXM Lymphocytotoxic assay AHG CDC NR Negative CXM 1y NR NR 12 mo PRA N10% NR Mean 22 mo CDC Anti-HLA reactivity N20% Negative CDC CXM NR Author's personal copy IMMUNOGLOBULIN IN SOLID ORGAN TRANSPLANTATION S21 Table 7. Results of the Studies for the Use of IVIG for Desensitization for Cardiac Transplantation 1st author, year Leech SH, 200645 Jacobs J, 200446 John R ‡, 200347 Patients Sensitized post LVAD John R ‡, 199950 Transplant regimen Sensitized adults 35 PP and IVIG 20 g × 5 or for OHT ⁎ PP × 1 then IVIG 20 g Nonsensitized 277 All received MMF, MP, adults TG TAC ± basiliximab Sensitized 8 IVIG weekly (dose NR) + children for OHT PP + CY + MMF Nonsensitized 52 No treatment; all 60–IVIG, steroids, TG as induction, then TAC/CYA, AZA/MMF Sensitized 26 1-3 monthly CY, IVIG 2 g/kg + post-LVAD AZA, CYA, steroids CY and MMF posttransplantation Sensitized 45 No IVIG + AZA, post-LVAD CYA, steroids Itescu S ‡, Sensitized 200248 post-LVAD Pisani BA, 199949 N Sensitized adults for OHT Nonsensitized Sensitized post-LVAD Sensitized post-LVAD Not sensitized post-LVAD 26 1-3 monthly CY, IVIG 2 g/kg 44 No treatment 16 102 16 4 28 All received triple immune suppression + AZA/MMF PP +IVIG (20g), preoperatively No treatment All received MP, CYA + AZA + OKT3 (n = 3) 1-3 monthly IVIG 2 g/kg (n = 6, IVIG 3g/kg), monthly CY 1-3 monthly, IVIG 2 g/kg + PP 2-3×/wk × 1-2 mo, monthly CY No treatment Success of desensitization Decrease in PRA Humoral rejection 7/35 (20%) vs NR NR 1 Rejection episode/pt vs 0.7/pt † (P = .2) 54% NR vs 33% vs 48% transplanted (P = .04) within 2 mo 0% died awaiting NR ¶ transplantation (n = 23) vs 14% (P = .08) 88% vs 84% (P = NS) 1/16 (6%) NR NR NR 87% vs 10/102 (10%) (P = NS) TTT reduced 3.3 mo NR Survival 85% (P = .04) 22% TTT reduced to 3.3 mo (n = 23) ║ 20% reduction in PRA after PP Graft survival 32/35 (91%) 31/35 (88%) vs NR vs 58% (P = .04) NR 50% vs NR vs (84%) (P = NS) NR NR 7.1 mo, P b .05 Abbreviations: LVAD, left ventricular assist device; NS, not significant, OHT, orthotopic heart transplantation; pt, patient; TTT, time to transplantation. §The time to transplantation was 1.7 months for individuals who were treated with IVIG vs 2.8 months for individuals not treated (P b .01). ⁎ Two patients also received a kidney transplant. † The type of rejection was not specified. ‡ The same patient population was used for all studies. ║ There was a 33% reduction in immunoglobulin G anti-HLA I/II. ¶ The results were not reported according to subgroup. outcomes to patients without any HLA antibody present. Hence, in the absence of data on donorspecific antibodies, it is difficult to formulate recommendations based on the results of this study.45 Thus, the panel considered that there were insufficient data to formulate a recommendation on the routine use of IVIG for desensitization in cardiac transplantation. Recommendation There is insufficient evidence to recommend for or against the routine use of IVIG for desensitization for Table 8. Characteristics of the Studies for the Use of IVIG for Desensitization in Lung and Liver Transplantation 1st author, year Study design Appel JZ ⁎, 200551 Urbani L, 200852 Retrospective cohort Retrospective case series Method to determine sensitization Definition of sensitization Definition of response Follow-up FC for PRA NR NR ABO incompatible NR NR 3y 18 mo ⁎ The study excluded patients not surviving until hospital discharge or longer than 90 days. Author's personal copy S22 SHEHATA ET AL patients undergoing heart transplantation to improve graft/overall survival or to treat rejection; however, other factors may influence decision-making. Level of evidence: II-2-III Grade of recommendation: I rejection; however, other factors may influence decision-making. Level of evidence: II-3 Grade of recommendation: I LIVER TRANSPLANTATION LUNG TRANSPLANTATION The role of IVIG or any other desensitization therapy in patients undergoing lung transplantation who are sensitized to HLA antigens is unknown. Recent studies have identified increased morbidity and mortality associated with HLA sensitization, whereas earlier reports did not.67-70 Interpretation of these reports is difficult given different diagnostic techniques. There has been only one report on the use of IVIG in lung transplantation (Tables 8 and 9).51 Twelve patients were treated with IVIG and extracorporeal immunoadsorption for removal of preformed antibodies beginning from the time of transplantation. There were no statistically significant differences in freedom from bronchiolitis obliterans or acute rejection. An additional 8 patients who developed de novo antibodies and declining graft function were treated with IVIG 500 mg weekly as “rescue therapy.” There was no statistically significant effect on declining lung function. There have been no other studies to substantiate these results. Recommendation There is insufficient evidence to make a recommendation for or against the routine use of IVIG for desensitization for patients undergoing lung transplantation or for the treatment of Antibody-mediated rejection is rare after liver transplantation, and evaluation of recipients for HLA antibody formation is not routinely performed. Consequently, desensitizing protocols with IVIG have not been required. Intravenous immunoglobulin has been used as specific therapy for posttransplant complications including hypogammaglobulinemia,71 thrombocytopenia,72 and demyelinating polyradiculoneuropathy.73 In adults receiving ABO-incompatible liver transplants, IVIG has been incorporated into successful protocols but always added to various combinations of immunosuppressive agents such as PP, extracorporeal photopheresis, and anti-CD20 antibody therapy.74 Benefits from the immunomodulatory effects of IVIG have been proposed in the existing literature; that is, CMVIG prophylaxis appeared to offer a survival benefit independent of its antiviral effect in one report.75 However, there have been no studies specifically designed to prospectively assess the role of IVIG/CMVIG in rejection and survival after liver transplantation. One observational report fulfilled inclusion criteria (Tables 8 and 9).52 This report52 focused on the use of IVIG for ABO-incompatible liver transplantation and reported favorable graft and overall survival and reduced rejection rates in patients treated with IVIG. However, the group that received IVIG also received extracorporeal photopheresis. Table 9. Results of Studies for the Use of IVIG for Desensitization in Lung and Liver Transplantation 1st author, year Appel JZ, 200551 Urbani L, 200852 Patients N Transplant regimen Sensitized patients 12 IVIG 2 g/kg at transplant, 500 mg/kg weeks 1-4 + taper weeks 5-24 ECI at transplant, daily week 1, weekly weeks 2-4 Sensitized patients 23 No treatment Adult undergoing ABO-incompatible transplantation 11 PP Success of desensitization Rejection Graft survival Freedom from BOS 95% 0.4 vs 50%, P = .32 NR vs 1.2 (P = .05) 72% 46% 63% vs 0 vs 88% (P = .01) (P ≤ .001) vs 86% (P = NR) 8 PP, IVIG 1 g/kg during anhepatic phase and for 14 d if anti-ABO titer N8, ECI days 2, 4, 6, weekly × 4 wk then depending on liver function tests Abbreviations: BOS, bronchiolitis obliterans syndrome; ECI, extracorporeal immunoadsorption. NR Survival NR Author's personal copy IMMUNOGLOBULIN IN SOLID ORGAN TRANSPLANTATION S23 Table 10. Responses From Reviewers to General Statement Regarding the Guideline Item n (%) Generally, I do not think practice guidelines are useful. The rationale for developing this guideline, as stated in the “Introduction” section of the report, is clear. There is a need for a guideline on this topic. The literature search is relevant and complete. The results of the trials described in the report are interpreted according to my understanding of the data. The draft recommendations in the report are clear. This report should be approved as a practice guideline. If this report were to become a practice guideline, how likely would you be to make use of it in your own practice? Agree 1 10 Neither agree nor disagree Disagree 9 8 8 8 2 2 2 9 7 1 2 1 Unsure 3 Unlikely 1 Likely 5⁎ NOTE. Reviewers were asked to check one box to signify their agreement with the statements. ⁎One individual did not respond to this question. Table 11. Responses From Reviewers Regarding Their Agreement With Guideline Recommendations Agreement Recommendation 1. When transplantation will involve use of a kidney from a living donor to whom the patient is sensitized, IVIG is recommended to decrease donor-specific sensitization. 2. There is insufficient evidence to make a recommendation for or against the use of IVIG for ABO-incompatible transplantation; however, other factors may influence decision-making. 3. IVIG is recommended perioperatively for patients who have donor-specific antibodies to reduce the incidence of accelerated acute humoral rejection. 4. IVIG is not recommended for patients who do not have donor-specific antibodies. 5. Give IVIG with plasmapheresis for patients who have received a living donor or deceased donor transplant and who have acute antibody-mediated rejection to improve graft survival. 6. In patients who have received a living/deceased donor transplant and who have steroid-resistant rejection, consider IVIG to improve graft survival when other therapies are deemed unacceptable or ineffective. 7. There is insufficient evidence to make a recommendation for or against the routine use of IVIG for other forms of rejection. 8. There is insufficient evidence to recommend for or against the routine use of IVIG for desensitization for patients undergoing heart transplantation to improve graft/overall survival or to treat rejection; however, other factors may influence decision-making. 9. There is insufficient evidence to recommend for or against the routine use of IVIG for desensitization for patients undergoing lung transplantation to improve graft/overall survival or to treat rejection; however, other factors may influence decision-making. 10. There is insufficient evidence to recommend for or against the routine use of IVIG for desensitization for patients undergoing liver transplantation to improve graft/overall survival or to treat rejection; however, other factors may influence decision-making. This is not my area of expertise (n) Agree (n) Neither agree nor disagree (n) 3 5 1 2 6 1 3 5 1 3 5 2 5 1 2 6 1 2 7 4 5 3 6 3 6 Disagree (n) 1 1 NOTE. Reviewers were asked to check one box to signify their agreement with the recommendations. One individual did not respond to this section. Author's personal copy S24 Recommendation There is insufficient evidence to make a recommendation for or against the routine use of IVIG for patients undergoing liver transplantation or for the treatment of rejection/ABO-incompatible liver transplantation. Level of evidence: III Grade of recommendation: I Guideline Appraisal The guideline was sent to 11 national experts in transplantation and transfusion medicine as well as a patient representative to appraise the guideline. Ten reviews were received. The reviewers were asked to evaluate the guideline and to rate their agreement to each of the recommendations. Tables 10 and 11 illustrate a summary of the responses to questions. The reviewers' comments and the panel's responses to the comments are available upon request. Future Research There is limited methodologically rigorous evidence for the use of IVIG for solid organ transplantation. Future studies are needed to delineate the effect of IVIG on desensitization using standardized methods for desensitization; the effect of IVIG on acute rejection rates, graft survival, and overall survival; the use of the combined modality IVIG and PP compared either to PP or IVIG alone; and the optimum dosage of IVIG. When immunoglobulin is used for renal, cardiac, lung, or liver transplantation, the committee recommends the following elements for data capture: impact on antibody specificity and titers, transplant rates, time to transplantation, graft function, graft survival, and frequency and outcomes of rejection (cellular and antibody mediated). Disclaimer Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances or seek the supervision of a qualified clinician. The National Advisory Committee on Blood and Blood Products and the Canadian Blood Services make no representation or warranties of any kind whatsoever regarding their content or use SHEHATA ET AL or application and disclaim any responsibility for their application or use in any way. ACKNOWLEDGMENTS We thank Drs P Acott, A Dipchand, J Hannon, D Lane, V Ng, J Pendergast, L Shepherd, L Singer, and K Tinckham and Ms B Baerwald for reviewing the guideline and their insightful comments. We thank Corinne Holubowich for conducting the literature searches and Dolly Cordi, Colleen Bruneau, and Jennifer Joly for their administrative assistance. APPENDIX A. SEARCH TERMS The following search terms were used: intravenous immunoglobulin$.mp., immunoglobuolin$, intravenous.mp., IVIG.mp., carimune.mp., endobulin$.mp., flebogamma.mp., gamastan.mp., gamimmun$.mp., gamimun$.mp., gamulin rh.mp., gamunex.mp., gammabulin$.mp., gammagard$.mp., gammar?P$.mp., gammar-Iv.mp., gammonativ$.mp., gammunex.mp., globulin-n.mp., immune globulin, intravenous.mp., intraglobin$.mp, intravenous antibod$.mp., intravenous ig.mp., IV-IgG.mp., iv immunoglobulin$.mp., iveegam$.mp., modified immune globulin$.mp, sandoglobulin$.mp., venimmune$.mp., venoglobulin$. mp., vivaglobin$.mp., cytogam$.mp., CMV-IGIV$. mp., cytomegalovirus immune globulin$.mp., cytomegalovirus immunoglobulin$.mp., transplants.sh., transplantation.sh., cell transplantation.sh., cell transplant$.mp., organ graft$.mp., organ transplant $.mp., tissue graft$.mp., tissue transplant$.mp., recipient, transplant$.mp., tissue transplantation. sh., organ transplantation.sh., transplant$, recipient$.mp., transplant$, cell$.mp., islets of langerhans transplantation.sh., islets of langerhans transplant$. mp., graft$, islets of langerhans.mp., ransplant$, islets of langerhans.mp., transplant$, pancreatic islet $.mp., islet$ transplant$.mp., transplant$, island$ of langerhans.mp., transplant$, islet$.mp., graft$, organ.mp., transplant$, organ$.mp., bone transplantation.sh., bone transplant$.mp., graft$, bone$.mp., transplant$, bone$.mp., bone-patellar tendon-bone graft.sh., tendon$, para-articular.mp., heart transplantation.sh., cardiac transplant$.mp., graft$, heart.mp., transplant$, cardiac.mp., heart transplant$.mp., transplant$, heart.mp., kidney transplantation.sh., kidney transplant$.mp., graft$, kidney. mp., renal transplant$.mp., transplant$, kidney.mp., transplant$, renal.mp., heart-lung transplantation. Author's personal copy IMMUNOGLOBULIN IN SOLID ORGAN TRANSPLANTATION sh., heart-lung transplant$.mp., graft$, heart-lung. mp, transplant$, heart-lung.mp., liver transplantation.sh., liver transplant$.mp., graft$, liver.mp., hepatic transplant$.mp., transplant$, hepatic.mp., transplant$, liver.mp., graft$, lung.mp., lung transplantation.sh., lung transplant$.mp., transplant$, lung.mp., pancreas transplantation.sh., pancreas transplant$.mp., graft$, pancreas.mp., transplant$, pancreas.mp., bone-patellar tendon-bone graft$.mp., replantation.mp., reimplantation.sh., reimplantation.mp.tooth replantation.sh. tooth replantation. mp., reimplantation, tooth.mp., replantation, tooth. mp., tooth reimplantation.mp., tissue transplantation.sh., tissue transplant$.mp., graft$, tissue.mp., transplant$, tissue.mp., brain tissue transplantation. sh., brain tissue transplant$.mp., graft$, brain tissue.mp., transplant$, brain tissue.mp., brain S25 transplantation.sh., brain transplant$.mp., corneal transplantation.sh., cornea$ transplant$.mp., graft $, cornea$.mp., transplant$, cornea$.mp., keratoplasty.mp., keratoplasty.sh., epikeratophakia.sh., epiketophakia.mp., fetal tissue transplantation.sh., fetal tissue transplant$.mp., graft$, fetal tissue.mp., transplant$, fetal tissue.mp., fetal tissue donation$. mp., skin transplantation.mp., skin transplant$.mp., transplant$, skin.mp., dermatoplasty.mp., graft$, skin.mp., transplantation, homologous.sh., transplant$, homologous.mp., allograft.mp., homograft. mp., transplant$, allogeneic.mp., allogeneic transplant$.mp., homologous transplant$.mp., transplant $, isogeneic.mp., homograft, isogeneic.mp., homograft, syngeneic.mp., isograft.mp., transplant$, syngeneic.mp., isogeneic transplant$.mp., syngeneic transplant$.mp. 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