ABO Antibody Titer and Risk of Antibody-Mediated Rejection in ABO-Incompatible Renal Transplantation
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1 American Journal of Transplantation 2010; 10: Wiley Periodicals Inc. C 2010 The Authors Journal compilation C 2010 The American Society of Transplantation and the American Society of Transplant Surgeons doi: /j x ABO Antibody Titer and Risk of Antibody-Mediated Rejection in ABO-Incompatible Renal Transplantation A. A. R. Tobian a, *,R.S.Shirey a, R. A. Montgomery b,w.cai a, M. Haas c, P. M. Ness a and K. E. King a a Department of Pathology and b Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD c Department of Pathology & Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA *Corresponding author: Aaron Tobian, atobian1@jhmi.edu Therapeutic plasma exchange (TPE) preconditioning with immunosuppressive therapy reduces ABO antibody titers, permitting engraftment of ABOincompatible (ABO-I) kidney transplants. The posttransplant predictive role of ABO antibody titers for antibody-mediated rejection (AMR) is unknown. This retrospective study evaluated 46 individuals who received TPE to permit ABO-I kidney transplantation. ABO antibody titers were performed using donor-type indicator red cells. Seven individuals (15.2%) experienced clinical or subclinical AMR. There was no significant difference between recipient blood group, number of pretransplant TPE and baseline titer between those with and without AMR. At 1 2 weeks posttransplant the median titer was 64 (range 4 512) among individuals with AMR and 16 (range 2 256) among individuals without AMR. Total agglutination reactivity score was significantly higher among individuals with AMR (p = 0.046). The risk of AMR was significantly higher among individuals with an elevated posttransplant titer of 64 (p = 0.006). The sensitivity of an elevated posttransplant titer was 57.1% with a specificity of 79.5%. The positive predictive value was 33.3% and the negative predictive value was 91.2%. Most individuals with AMR have an elevated titer, however, the positive predictive value of a high titer for AMR is poor. Key words: ABO antibodies, ABO incompatible, antibody-mediated rejection (AMR), antibody rebound, plasmapheresis, renal transplantation, therapeutic plasma exchange (TPE) Received 16 October 2009, revised 29 January 2010 and accepted for publication 18 February 2010 Introduction ABO blood group antigens are expressed throughout the body (1), including embryonic kidney cells (2), vascular endothelium, convoluted distal tubules and collecting tubules (3). Key mediators of antibody-mediated rejection (AMR) that prevent renal transplantation across ABO barriers are the naturally occurring antibodies directed against ABO antigens (4,5). In hyperacute rejection, it is the preexisting circulating antibodies directed against ABO, HLA or other alloantibody-to-donor endothelial surface antigens that usually lead to rejection within minutes to hours. The alloantibodies bind to peritubular and glomerular capillaries and activate complement (4). AMR resulting from the generation of newly formed anti-donor antibodies can occur weeks to years after transplantation, and can lead to the development of chronic rejection, characterized most specifically by transplant glomerulopathy (TG) and multilayering of peritubular capillary (PTC) basement membranes (6,7). The optimal treatment of end-stage renal failure is kidney transplantation, but a shortage of donors has significantly limited this practice. ABO-incompatible (ABO-I) renal transplantation has the potential to significantly increase the donor pool (8,9). Transplants are occurring through a preparative regimen including the use of either therapeutic plasma exchange (TPE) or immunoadsorption and immunosuppressive therapy in order to reduce circulating ABO antibody titers to 16, permitting engraftment of ABO-I kidney transplants (10,11). ABO-I is currently an American Society for Apheresis (ASFA) category II indication for TPE (12). All individuals undergoing ABO-I renal transplantation at Johns Hopkins Hospital receive posttransplant TPE to prevent rebound of anti-a and/or anti-b titers. The majority (>75%) of individuals have posttransplant ABO antibody titers that remain at low levels (titer 16) (13). Other institutions have documented that high posttransplant ABO antibody titers correlate with increased graft loss (14,15). However, it is unknown how well posttransplant ABO antibody titers correlate with AMR. In addition, the previous studies have only evaluated titer levels in individuals who had a splenectomy. Since 2000, significant improvements have occurred with the immunosuppressive regimen to reduce AMR and splenectomy is no longer standard of care. 1247
2 Tobian et al. Thus, it is unknown whether posttransplant ABO antibody titers predict AMR. Materials and Methods This retrospective study evaluated 46 individuals who had ABO-I renal transplants with follow-up biopsies using a protocol that has been approved by the Johns Hopkins Medical Institutions Institutional Review Board. The study included all individuals that received an ABO-I renal transplant between 1999 and The only participants that were excluded from the study were individuals with donor-specific anti-hla antibodies. The 46 individuals in this study have participated in the Johns Hopkins Hospital Incompatible Kidney Transplant Program. Previous studies that have included many of these patients have demonstrated the utility of TPE to decrease ABO titers and enable successful long-term engraftment (10,11,13). Briefly, the TPE treatment plan was based on the anti-a and anti-b titers with the goal of achieving a preoperative ABO antibody titer of 16 at the anti-human globulin (AHG) phase. Following each TPE procedure, low-dose (100 mg/kg) CMVIg (Cytogam, MedImmune Inc., Gaithersburg, MD) was given (TPE/CMVIg). Pretransplant therapy consisted of every other day TPE followed immediately by CMVIg. The COBE Spectra (CaridianBCT, Lakewood, CO) was used for TPE. Each TPE session consisted of one plasma volume exchange replaced at 100% volume with 5% serum albumin; supplemental plasma replacement was used when patients were at an increased risk of bleeding. All patients received several posttransplant TPE/CMVIg treatments by protocol. The number of posttransplant treatments was based on the initial antibody titer and the perceived level of risk of antibody rebound and AMR. For example, patients with higher initial antibody levels or rebounding titers between treatments received more TPE by protocol. Once TPE is discontinued, it was reinstituted based on an integration of clinical data including changes in serum creatinine, biopsy results and ABO titer. Histopathologic analysis of biopsies and diagnosis of rejection Biopsies were obtained when clinically indicated or by protocol, as previously described (11). Surveillance biopsies were performed at 1, 3, 6 and 12 months after transplantation. All biopsies were analyzed by routine light microscopy using hematoxylin-eosin, periodic acid-schiff, methenamine silver and Masson s trichrome stains. For all biopsies, a small (3 4 mm) piece of cortical or medullary tissue was also taken for C4d staining, which was performed by indirect immunofluorescence on cryostat sections using a mouse monoclonal anti-human C4d antibody (Quidel, San Diego, CA) at 1:40 dilution, followed by fluorescein isothiocyanate conjugated goat anti-mouse IgG (Jackson Immunoresearch Laboratories, West Grove, PA) (16,17). Staining for C4d in PTCs was graded as diffuse (positive in >50% of specimen), focal (>10% of specimen, but <50%) or absent. Clinical and subclinical acute cellular rejections were graded according to Banff 97 criteria (18). AMR (clinical or subclinical) was diagnosed as being present when the following criteria were met (19): (1) positive (diffuse or focal) C4d staining in PTC; and (2) at least one of the following: marginated leukocytes (neutrophils or mononuclear cells) in at least 10% of cortical PTC, moderate or severe glomerulitis (Banff g score >2), or transmural necrotizing arteritis. Individuals were defined as having clinical AMR, subclinical AMR or combined AMR and cellular rejection. For the clinical AMR, a biopsy was performed for a clinical indication (e.g. an increase in creatinine, decrease in urine output, increase in antibody titer). Subclinical AMR was identified among individuals with no clinical symptoms but underwent a scheduled protocol biopsy as noted above. Some individuals had combined antibodymediated and cellular rejection. Individuals with cellular rejection alone were not evaluated in this study. Titers Antibody titers were determined before and after each posttransplant TPE/CMVIg treatment, 72 h after the last planned treatment, at weekly intervals for the first month and at 2, 3, 6 and 12 months. The titration procedure (i.e. serial dilutions of the patient s plasma in normal saline) was similar to the methods previously described (13,20,21). ABO antibody titers were performed using donor-type indicator red cells and incubation at phases that include room temperature (22 C) test phase for 30 minutes, followed by 30 minutes at 37 C and conversion to the AHG phase for optimal detection of IgG antibody. However, this study only reports the AHG phase. All titers were performed in parallel with a known control. The titer endpoint was the reciprocal of the highest dilution demonstrating macroscopic agglutination. For individuals who had multiple titers within the 1 2 weeks or 3 6 month range, the highest titer was utilized. Titer agglutination reactivity was scored using the Marsh scoring system (22). The scores at each titer dilution ranged from 0 (no agglutination) to 12 (all cells agglutinated). The reactivity scores in the manuscript represent the sum of agglutination scores recorded for each plasma dilution. Human leukocyte antigen (HLA) crossmatch techniques including antiglobulin-enhanced lymphocytotoxicity (AHG-complement dependent cytotoxicity [CDC]) with T cells, one-wash CDC (1wCDC) with B cells, and flow cytometry with T and B cells were performed as previously described (23). A crossmatch was considered positive when (1) cell death with the patient s serum was more than or equal to 10% above background in cytotoxicity assays or (2) the ratio of median channel obtained with a patient s serum was more than or equal to 3 times that obtained with negative control serum in a flow crossmatch. When present, anti-hla class I and II donor-specific antibodies (DSA) were identified by (1) ELISA using soluble HLA antigens as targets, specifically, GTI Quik-ID and GTI Quick-ID class II (GTI Diagnostics, Brookfield, WI) were used, or (2) using a color-coded multianalyte bead immunoassay on the Luminex platform, which uses beads coated with soluble HLA molecules as targets (Life Screen, Life Match I for Class I and Life Match ID for class II, Tepnel Lifecodes, Stanford, CT, and Single Antigen Beads, One Lambda, Canoga Park, CA). The multianalyte immunoassays were performed according to the manufacturer s instructions as reported elsewhere (23,24). In this study, the patients from 1999 to mid 2003 were tested by ELISA; all subsequently were tested by Luminex. All patients had a negative flow crossmatch and no detectable DSA by solid phase assay. Statistical analysis Statistical analyses were performed using STATA, v9.2 (StataCorp, College Station, TX) and Microsoft Excel (Redmond, WA). Hypothesis testing was performed with Student s t-tests for continuous variables, chi-square test for dichotomous variables and Fisher s exact chi-square test for dichotomous variables with expected cell sizes less than five. The t-tests were two-tailed and performed assuming unequal variance. Results The Johns Hopkins Incompatible Kidney Transplant Program (InKTP) performed 46 ABO-I, HLA crossmatch compatible renal transplants between 1999 and Of these individuals, only seven (15.2%) experienced clinical (5/46, 10.9%) or subclinical (2/46, 4.3%) AMR. There were no episodes of hyperacute rejection. Of the seven individuals with AMR, TPE was stopped prematurely for one individual after she contracted West Nile Virus encephalitis and died within the first month of transplantation. She had a functioning graft prior to death. Thus, the 1-year 1248 American Journal of Transplantation 2010; 10:
3 Table 1: Characteristics of individuals with and without antibody-mediated rejection (AMR) ABO Titer and Antibody-Mediated Rejection AMR No AMR Characteristics (n = 7) (n = 39) p-value Age (mean, SD) 46.6 ± ± Female 5 (71.4%) 16 (41.0%) 0.14 Recipient Blood Group O 6 (85.7%) 34 (87.2%) 0.92 Immunosuppresive regimen Splenectomy 4 (57.1%) 7 (17.9%) anti-cd20 1 (14.3%) 8 (20.5%) 0.70 Both splenectomy and anti-cd20 0 (0.0%) 2 (5.1%) 0.78 Neither splenectomy nor anti-cd20 2 (28.6%) 22 (56.4%) 0.23 Number of pre-transplant TPE (mean, SD) 6.4 ± ± Baseline ABO titer (median, range) 128 (64 256) 64 (4 1024) Total agglutination reactivity (mean, SD) 65.4 ± ± Day prior to transplantation ABO titer (median, range) 8 (2 16) 8 (2 16) Total agglutination reactivity (mean, SD) 35.3 ± ± weeks post-transplantation ABO titer (median, range) 64 (4 512) 16 (2 256) Total agglutination reactivity (mean, SD) 58.0 ± ± months post-transplantation ABO titer (median, range) 16 (8 256) 8 (1 256) Total agglutination reactivity (mean, SD) 49.0 ± ± The immunosuppressive regimen also included TPE, CMVIg, tacrolimus (FK506), mycophenolate mofetil (MMF), steroids and daclizumab. death-censored graft survival was 100%; with a 1-year patient survival of 97.8%. Individuals who experienced either clinical or subclinical AMR had similar characteristics of those without AMR (Table 1). There was no significant difference between age, sex, recipient blood group, number of pretransplant TPE procedures and baseline titer between the two groups. As previously described, the Johns Hopkins ABOi program evolved over time with the initial patients receiving an immunosuppressive regimen that included splenectomy and/or anti-cd20 to more recent patients that did not receive either intervention (11). The rest of the immunosuppressive regimen has remained constant and included: TPE, CMVIg, tacrolimus (FK506), mycophenolate mofetil (MMF), steroids and daclizumab. There was a marginally significant difference between the two groups with a higher proportion of individuals with AMR having had a splenectomy (Table 1). The numbers, however, are small. AMR was not different among the other groups (anti-cd20 and the no splenectomy/no anti-cd20) (Table 1). None of the patients in either group had donor-specific anti- HLA class I or class II antibodies. The median titer was reduced to 8 on the day prior to transplant in both individuals with and without AMR. At 1 2 weeks posttransplant, however, the median titer was 64 (range 4 512) among individuals that had AMR and was 16 (range 2 256) among individuals without AMR. The mean total agglutination reactivity score was significantly higher among individuals with AMR (p = 0.046) at 1 2 weeks. There was no difference in mean reactivity score between the two groups at 3 6 months posttransplant (p = 0.20). The risk of AMR was significantly higher among individuals with elevated ( 64) posttransplant titer at any point during the first 12 months (p = 0.006). To evaluate whether posttransplantation ABO titer correlates with AMR, individuals were assessed based on their highest titer (either before documented AMR or at any time point for those that did not experience AMR) (Table 2). The sensitivity of an elevated posttransplant titer ( 64) to predict AMR was 57.1% with a specificity of 79.5%. There were two individuals with AMR that did not have a posttransplant titer 64. The positive predictive value was 33.3% and the negative predictive value was 91.2%. With a titer 32, the sensitivity increased to 85.7%, but the specificity was only 46.2%. With a titer 128, the sensitivity was only 42.9%, but the specificity increased to 89.7%. As represented in Figure 1 of the time course of the elevated titers and AMR, one individual had documented AMR at a titer of 32 and subsequently increased to a titer of 64. The majority of individuals (76.9%, 10/13) with an elevated posttransplant titer ( 64) at any point during the first 12 months experienced an increase in antibody Table 2: Elevated posttransplant ABO antibody titer and the correlation to antibody-mediated rejection AMR No AMR Elevated titer ( 64) 4 8 Titer within normal limits ( 32) 3 31 American Journal of Transplantation 2010; 10:
4 Tobian et al. Figure 1: The ABO titer against the donor kidney after transplantation with respect to TPE and AMR. This figure represents the seven individuals that experienced AMR. The titer is represented by an (- -). On days the individual also had TPE, the titer is represented by a square (- -). The titer on the day of biopsy showing AMR is represented by the at sign (-@-). The ABO transplant barrier in each panel is the donor and then recipient ABO blood group, respectively. level by 1 2 weeks after transplantation (Figure 1 and Table 3). However, only 5 (38.5%) of the 13 individuals with an elevated titer had either clinical AMR, subclinical AMR, or combined antibody-mediated and cellular rejection (Table 3). The one individual with combined antibodymediated and cell-mediated rejection had clinical renal dysfunction. There was no consistent trend in timing of an elevated titer (within the first few weeks or months later) between those with or without AMR. In addition, of those with an elevated titer, there was no difference in sex among those who developed AMR (p = 0.57). Discussion ABO incompatibility after preconditioning is no longer considered a contraindication to renal transplantation. TPE/CMVIg significantly reduces ABO antibody titers prior to transplantation and these titers generally continue to remain suppressed at 3 6 months posttransplantation (10). Naturally occurring antibodies that are produced against ABO antigens that are not present in one s own tissues are key mediators of AMR (16,25). In this study, the incidence of AMR was 15.2% (clinical 10.9% and subclinical 4.3%). In addition, most individuals with AMR had an elevated titer prior to rejection, but a high titer had a poor positive predictive value for AMR. The role of the ABO titer in AMR has historically been unclear. The physicians at Tokyo Women s Medical University demonstrated that high posttransplantation ABO antibody titers correlate with increased graft loss (14). The same group and also one group in the United States found that initial high ABO antibody titers are associated with a 1250 American Journal of Transplantation 2010; 10:
5 Table 3: Characteristics of individuals with elevated titers ( 64) ABO Titer and Antibody-Mediated Rejection Immunosuppressive Baseline Pre-tx Post-tx 1 2 wk post-tx 3 6 mo post-tx Antibody ABO regimen (Splenectomy titer titer titer titer titer mediated Transplant Sex or anti-cd20) (score) (score) (score) (score) (score) rejection A1 - O F Neither 32 (50) 8 (42) 16 (31) 64 (60) 32 (51) None A1 - O M Neither 128 (55) 16 (33) 16 (32) 32 (58) 64 (51) None A1 - O M Splenectomy 64 (54) 8 (26) 2 (8) 64 (56) 128 (67) None A1 - O F Splenectomy & anti-cd (94) 16 (40) 32 (46) 128 (55) 256 (71) None A2 - O M Neither 256 (70) 4 (12) 64 (51) 64 (57) 32 (40) None A2 - O M anti-cd20 32 (44) 16 (41) 64 (52) 16 (37) 32 (56) None A2 - O F Neither 128 (63) 8 (18) 32 (37) 256 (75) 64 (60) None B - O F Neither 512 (92) 8 (26) 16 (37) 16 (37) 64 (64) None A1 - O F Splenectomy 256 (87) 16 (43) 32 (55) 64 (67) 64 (71) Combined A1 - O F Splenectomy 256 (79) 16 (43) 8 (40) 512 (90) Clinical A1B - A F Neither 64 (51) 4 (18) 8 (29) 64 (60) 32 (44) Clinical A1B - O M Splenectomy 128 (50) 4 (40) 8 (39) 16 (32) 64 (57) Subclinical B - O F Splenectomy 256 (72) 8 (30) 16 (32) 128 (81) 8 (30) Clinical The ABO transplant barrier reflects the donor and then recipient ABO blood group, respectively. The immunosuppressive regimen also included TPE, CMVIg, tacrolimus (FK506), mycophenolate mofetil (MMF), steroids, and daclizumab. Titer agglutination reactivity scores represent the sum of the agglutination scores recorded for each plasma dilution. The highest titer is highlighted in bold. Antibody-mediated rejection can be either clinical (symptomatic and biopsy proven), subclinical (asymptomatic but biopsy proven) or combined (both antibody-mediated and T-cell-mediated rejection). requirement for posttransplant TPE and an increased incidence of humoral rejection (15,26,27). After the Japanese group changed from their original quintuple immunosuppressive therapy to tacrolimus, MMF and steroids, however, they did not find a correlation between preoperative ABO antibody titer and graft survival (28). In this study, there was no significant difference in baseline ABO antibody titers between those with and without AMR. The incidence of AMR at 1 year in our study is similar to other institutions; we reported an incidence of 15.2%. In the most recent era, the incidence of AMR at the Tokyo Women s Medical University was 12% (29). The Mayo Clinic reported AMR in 18% of nonsplenectomized and 30% in splenectomized patients (30). The European groups report AMR in a range of 0 50% (31 33). The European groups also report a low level of antibody titer posttransplantation (31,32). The variability in AMR and titers posttransplantation across institutions may be due to differences in the diagnosis of histologic AMR, differences of titers and crossmatch sensitivities among laboratories and programs, differences in use of protocol biopsies and differences in immunosuppression and apheresis protocols. This study also demonstrated that the clinical significance of an elevated posttransplantation ABO antibody titer is variable and there was no consistent clinical correlation for AMR. The negative predictive value of a low titer was 91.2%, but there were two individuals with AMR who did not have an ABO antibody titer 64. The positive predictive value of a high ABO antibody titer was only 33.3%. While many individuals with AMR had elevated titers within 1 2 weeks, some individuals with AMR did not have an increase in titer until 3 6 months. Thus, the timing of increase in an ABO antibody titer (i.e. acute versus chronic) also does not assist in predicting AMR. Overall, a high titer is generally necessary but is not sufficient for AMR. In the 1980s, there was some success in the transplantation of A 2 kidneys into O recipients without TPE (34,35). The most common subgroups of blood group A are A 1 and A 2. While both subgroups react strongly with anti-a in direct agglutination testing, there are both qualitative and quantitative differences (36). Approximately, 80% of the Western population is A 1 and the remaining 20% is A 2 (36). Since the A 1 -transferase is more efficient at converting H substance into A antigen and capable of making repetitive Type 3 or Type 4 A structures, there are approximately five times more A antigen sites on A 1 erythrocytes than A 2 erythrocytes (36,37). Type 4 A structures are the dominant compound expressed on kidneys (37,38). Due to the difference in antigen production, A 2 kidneys may be more compatible in O recipients. With current immunosuppression regimens, crossing the A1 blood group has been very successful (11,39). In this study, there were individuals with elevated anti-a titers posttransplantation. However, only recipients of A1 kidneys developed AMR histology, indicating that at equal antibody strength A1 donor kidneys may be more likely to reject. One limitation of this study is the evolving classification of rejection in ABOi allografts. Of the seven individuals with histologic AMR, only five had elevated ( 64) ABO titers at any point during the first 12 months. Of the other two individuals, one had a titer of 32 posttransplantation American Journal of Transplantation 2010; 10:
6 Tobian et al. that may have contributed to AMR, but the other individual had consistently low titers ( 8). Cell-mediated rejection did not play any role in the rejection episode of the individual with consistently low titers. In addition, none of the individuals in this study had donor-specific HLA antibodies. Histologic diagnosis of AMR on biopsies of ABOincompatible renal allografts can be difficult compared to biopsies of conventional, ABO-compatible grafts. PTC C4d staining is present in the great majority of biopsies of ABOincompatible grafts, including protocol biopsies (16,40), thus limiting the usefulness of C4d in the diagnosis of AMR. Unlike the case in compatible renal allografts (41), C4d staining in ABO-incompatible grafts is often seen in the absence of histologic features of AMR (16,40), and this latter C4d staining has not been associated with the development of TG or other chronic changes, at least during the first year posttransplantation (17). In the recipients of ABO-incompatible grafts in this study, the diagnosis of AMR was based on histologic criteria as described in the updated Banff classification (19), and were clearly met; and all seven patients with AMR in this study had margination of leukocytes (neutrophils and mononuclear cells) in >10% of cortical PTCs. Recently, it has been demonstrated that endothelium microcirculation injury is a major target of AMR (42). Thus, it has been suggested that evaluation of endothelial gene expression may be a necessary addition to the histopathologic diagnosis of AMR (43). Thus, further work is necessary to continue to evaluate the optimal diagnostic criteria for AMR. It is hypothesized that posttransplant TPE is helpful in preventing rebound of anti-a and anti-b titers until tolerance or accommodation occurs. However, there is a lack of understanding of the immunological mechanism for a reduction of ABO antibody titer to permit organ survival. While the presence of high titer ABO antibodies at the time of transplantation most often leads to hyperacute rejection, antibodies can rebound to high levels after engraftment without renal dysfunction or evidence of AMR, a state termed accommodation. The mechanisms of accommodation remain uncertain, but one possible explanation is an increase in resistance of graft endothelial cells to injury mediated by the host immune system (44), perhaps involving upregulation of complement regulatory proteins such as CD55 and CD59 (45). The exact mechanism of increasing antibody titers is also unknown, but it has been demonstrated that antibody synthesis is not the primary mechanism for rebound (46). Thus, further research in understanding the mechanisms of antibody rebound and accommodation is critically needed. While the incidence of AMR in this study was 15%, the 1- year death-censored graft survival was 100%. Thus, AMR can be reversed with TPE/CMVIg treatments, although it is well documented that AMR is strongly correlated with subsequent development of TG, the latter being associated with diminished long-term graft survival (47,48). Posttransplant TPE/CMVIg treatments may be helpful in preventing rebound of anti-a and anti-b titers until tolerance or accommodation occurs. There are groups, however, that have achieved good results that have not routinely performed posttransplant TPE/CMVIg. This study demonstrates that the ABO antibody titer alone cannot predict AMR. Thus, the initiation of posttransplant TPE should be based on the clinical criteria of urine output, creatinine levels and biopsy results in addition to the ABO antibody titer. Acknowledgments We gratefully appreciate the assistance provided by the laboratory medical technologists who performed the titers and the apheresis nurses. 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Detection of HLA class I-specific antibodies by the QuikScreen enzymelinked immunosorbent assay. Clin Diagn Lab Immunol 1997; 4: Zachary AA, Ratner LE, Graziani JA, Lucas DP, Delaney NL, Leffell MS. Characterization of HLA class I specific antibodies by ELISA using solubilized antigen targets: II. Clinical relevance. Hum Immunol 2001; 62: Montgomery RA, Zachary AA. Transplanting patients with a positive donor-specific crossmatch: A single center s perspective. Pediatr Transplant 2004; 8: Shimmura H, Tanabe K, Ishikawa N, Tokumoto T, Takahashi K, Toma H. Role of anti-a/b antibody titers in results of ABOincompatible kidney transplantation. Transplantation 2000; 70: Sivakumaran P, Vo AA, Villicana R et al. Therapeutic plasma exchange for desensitization prior to transplantation in ABOincompatible renal allografts. J Clin Apheresis 2009; 24: Shimmura H, Tanabe K, Ishida H et al. 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Am J Transplant 2008; 8: Goldammer A, Derfler K, Herkner K, Bradwell AR, Horl WH, Haas M. Influence of plasma immunoglobulin level on antibody synthesis. Blood 2002; 100: Sis B, Campbell PM, Mueller T et al. Transplant glomerulopathy, late antibody-mediated rejection and the ABCD tetrad in kidney allograft biopsies for cause. Am J Transplant 2007; 7: Gloor JM, Sethi S, Stegall MD et al. Transplant glomerulopathy: Subclinical incidence and association with alloantibody. Am J Transplant 2007; 7: American Journal of Transplantation 2010; 10:
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