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• W1923404879 abstract "This study examined outcomes beyond 1 year in eculizumab-treated (EC) positive crossmatch kidney transplants (+XMKTx) compared to a historical control group. +XMKTx received desensitization with either plasma exchange (PE) alone (N = 48) or PE and EC (N = 30). EC, given for at least 1 month, was continued in the setting of persistently high DSA (B flow cytometric crossmatch [BFXM] >200) including: 4 weeks (n = 14); 9 weeks (n = 6), 6 months (n = 2), and 12 months (n = 8). All patients had at least 2 years follow-up. The incidence of acute clinical ABMR was lower in the EC group than controls (6.7% vs. 43.8% p < 0.01). Death-censored allograft survival was similar between groups. Chronic ABMR was the main cause of graft loss. On 1-year protocol biopsies, no differences were noted between EC and controls including: cg score >0, 26.7% versus 31.9% (p = 0.62), ptc score ≥ 2, 60.0% versus 60.0% (p = 1.00), or C4d + , 33.8% versus 13.5% (p = 0.08). A persistently high BFXM in EC-treated patients was associated with cg score >0 at 1 year, while EC appeared to protect against cg if the BFXM remained low. We conclude that despite decreasing acute clinical ABMR rates, EC treatment does not prevent chronic ABMR in recipients with persistently high BFXM after +XMKTx. This study examined outcomes beyond 1 year in eculizumab-treated (EC) positive crossmatch kidney transplants (+XMKTx) compared to a historical control group. +XMKTx received desensitization with either plasma exchange (PE) alone (N = 48) or PE and EC (N = 30). EC, given for at least 1 month, was continued in the setting of persistently high DSA (B flow cytometric crossmatch [BFXM] >200) including: 4 weeks (n = 14); 9 weeks (n = 6), 6 months (n = 2), and 12 months (n = 8). All patients had at least 2 years follow-up. The incidence of acute clinical ABMR was lower in the EC group than controls (6.7% vs. 43.8% p < 0.01). Death-censored allograft survival was similar between groups. Chronic ABMR was the main cause of graft loss. On 1-year protocol biopsies, no differences were noted between EC and controls including: cg score >0, 26.7% versus 31.9% (p = 0.62), ptc score ≥ 2, 60.0% versus 60.0% (p = 1.00), or C4d + , 33.8% versus 13.5% (p = 0.08). A persistently high BFXM in EC-treated patients was associated with cg score >0 at 1 year, while EC appeared to protect against cg if the BFXM remained low. We conclude that despite decreasing acute clinical ABMR rates, EC treatment does not prevent chronic ABMR in recipients with persistently high BFXM after +XMKTx. Renal transplant candidates with high levels of antibody against a broad spectrum of HLA are very difficult to transplant. Despite receiving high priority for deceased donor kidneys and the increased implementation of kidney paired donation, they rarely receive a kidney transplant against which they do not have donor specific alloantibody (DSA) (1.Cecka JM Kucheryavaya AY Reinsmoen NL Leffell MS Calculated PRA:. Initial results show benefits for sensitized patients and a reduction in positive crossmatches.Am J Transplant. 2011; 11: 719-724Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar,2.Li H, Stegall MD, Dean PG, et al. Assessing the efficacy of kidney paired donation-performance of an integrated three-site program. Transplantation 2014.Google Scholar). “Desensitization” and the performance of a kidney transplant despite the presence of DSA remains an important option for these highly sensitized candidates (3.Montgomery RA Lonze BE King KE Desensitization in HLA-incompatible kidney recipients and survival.N Engl J Med. 2011; 365 (et al): 318-326Crossref PubMed Scopus (503) Google Scholar). Unfortunately, in patients who have DSA levels that cause a positive crossmatch against their donor at baseline (termed positive crossmatch kidney transplants, +XMKTx), the immunologic hurdles to a successful transplant are significant. Clinically significant antibody-mediated rejection (ABMR) in the first few weeks after transplantation is common and can lead to early graft loss (4.Gloor JM Winters JL Cornell LD Baseline donor-specific antibody levels and outcomes in positive crossmatch kidney transplantation.Am J Transplant. 2010; 10 (et al): 582-589Crossref PubMed Scopus (225) Google Scholar). Even when clinical ABMR is avoided or successfully treated, chronic graft loss is common, and 5-year graft survival is significantly lower than that of kidneys without DSA (5.Bentall A Cornell LD Gloor JM Five-year outcomes in living donor kidney transplants with a positive crossmatch.Am J Transplant. 2013; 13 (et al): 76-85Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar). We have shown that blockade of terminal complement with the anti-C5 antibody eculizumab (EC) decreases in the incidence of acute clinical ABMR after +XMKTx (6.Stegall MD Diwan T Raghavaiah S Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients.Am J Transplant. 2011; 11 (et al): 2405-2413Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar). The aim of the current study was to examine the outcomes and allograft histology of EC-treated patients beyond 1 year. This unique cohort allows us to test the hypothesis if early acute ABMR contributes to chronic ABMR. Furthermore, since patients with high levels of DSA remained on EC for up to a year, we also can begin to assess the role of terminal complement in chronic ABMR. This study was approved by the Mayo Clinic Institutional Review Board. Positive-crossmatch, ABO-compatible renal allograft recipients were included in a clinical trial using EC for the prevention of acute clinical ABMR. The EC group consisted of 30 living donor kidney recipients transplanted between June 2008 and October 2011; a historical control group without EC consisted of 48 consecutive +XM renal allograft recipients transplanted between January 2005 and September 2007. We previously published clinical characteristics, treatment protocols, and 1 year outcomes of the first 26 patients who received eculizumab (6.Stegall MD Diwan T Raghavaiah S Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients.Am J Transplant. 2011; 11 (et al): 2405-2413Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar). The current study extends these data to 30 patients (including the 26 original), all of whom had at least 2 years follow-up. Inclusion criteria were age >18 years old and a baseline B flow cytometric crossmatch (BFXM) channel shift <450 and ≥200 against the recipient’s living donor. During the study period, eligible patients evaluated for potential positive-crossmatch kidney transplantation were approached for inclusion in this protocol and were enrolled consecutively. Recipients with a channel shift ≥300 underwent pretransplant plasmapheresis to achieve both T- and B-flow crossmatch channel shifts <300 on the day of transplant (7.Burns JM Cornell LD Perry DK Alloantibody levels and acute humoral rejection early after positive crossmatch kidney transplantation.Am J Transplant. 2008; 8 (et al): 2684-2694Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar). The BFXM was used because it estimates total DSA against both class I and class II HLA. A solid-phase assay (LABscreen, One Lambda, Canoga Park, CA) was also used to verify alloantibody specificities and levels (reported as the highest mean fluorescence index [MFI] against donor HLA). DSA levels were measured at baseline (prior to any therapy), the day prior to transplant (after multiple plasmapheresis in patients undergoing pretransplant plasmapheresis) and posttransplant on days 4, 7, 14, 21 and 28, 90, 180, and 365. Patients underwent induction therapy with anti-thymocyte globulin; and maintenance immunosuppression consisted of tacrolimus, mycophenolate mofetil, and prednisone. Percutaneous surveillance renal allograft biopsies were obtained in EC-treated patients on posttransplant days 0, 4, 7, 14, 28, and months 3–4, 6, 12, and 24. Historical control group patients underwent surveillance biopsy at posttransplant months 3–4, 12, and 24. Additional biopsies in both groups were performed at other time points for clinical indication in a subset of patients. The EC dosing regimen, as previously reported (6.Stegall MD Diwan T Raghavaiah S Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients.Am J Transplant. 2011; 11 (et al): 2405-2413Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar), consisted of 1200 mg immediately prior to transplantation, 600 mg on postoperative day 1, and 600 mg weekly thereafter for 4 weeks. At week 4, assessment of DSA levels was performed. Eculizumab was discontinued in patients whose DSA had significantly decreased (BFXM <200). In patients with persistently high DSA (BFXM >200), EC treatment continued (1200 mg week 5, and then every 2 weeks). DSA assessments were performed at weeks 4, 9, 26, and 39. Eculizumab was discontinued at those time points if the B flow crossmatch channel shift was <200. Three patients received plasmapheresis posttransplant, and an additional dose of EC (600 mg) was administered immediately after plasmapheresis to ensure EC levels were sufficient to block completely terminal complement activity. The pharmacokinetics of EC were determined in two ways: (i) Serum drug levels were determined using a validated enzyme-linked immunosorbent assay that detects both free and C5-bound eculizumab (8.Thomas TC Rollins SA Rother RP Inhibition of complement activity by humanized anti-C5 antibody and single-chain Fv.Mol Immunol. 1996; 33 (et al): 1389-1401Crossref PubMed Scopus (276) Google Scholar) and (ii) activity was determined as the ability of the EC-treated patient’s serum to lyse chicken erythrocytes in a validated total human serum–complement hemolytic assay (9.Rinder CS Rinder HM Smith BR Blockade of C5a and C5b-9 generation inhibits leukocyte and platelet activation during extracorporeal circulation.J Clin Invest. 1995; 96 (et al): 1564-1572Crossref PubMed Scopus (206) Google Scholar). The dosing regimen generally was sufficient to completely block terminal complement throughout the treatment period. Kidney biopsy tissue from the EC treated patients was processed for light microscopy and stained by immunofluorescence with polyclonal FITC-conjugated antibodies to IgG, IgM, IgA, C3, C1q, kappa, lambda, fibrinogen, albumin (Dako Corp.), and C4d (AbD Serotec). Immunoperoxidase staining for C4d (American Research Products, Inc., Belmont, MA) was performed if immunofluorescence tissue was unavailable or inadequate. Light microscopy features of biopsies were scored by Banff criteria (10.Solez K Colvin RB Racusen LC Banff 07 classification of renal allograft pathology: Updates and future directions.Am J Transplant. 2008; 8 (et al): 753-760Abstract Full Text Full Text PDF PubMed Scopus (1621) Google Scholar, 11.Solez K Colvin RB Racusen LC Banff ’05 meeting report: Differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy (‘CAN’).Am J Transplant. 2007; 7 (et al): 518-526Abstract Full Text Full Text PDF PubMed Scopus (927) Google Scholar, 12.Racusen LC Solez K Colvin RB The Banff 97 working classification of renal allograft pathology.Kidney Int. 1999; 55 (et al): 713-723Abstract Full Text Full Text PDF PubMed Scopus (2773) Google Scholar, 13.Haas M Sis B Racusen LC Banff 2013 meeting report: Inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions.Am J Transplant. 2014; 14 (et al): 272-283Abstract Full Text Full Text PDF PubMed Scopus (1066) Google Scholar) on all biopsies. C4d positivity was defined as at least focal (>/ = 10%) peritubular capillary staining (Banff c4d score >1). Acute/active ABMR was scored using the 2013 Banff Criteria (12.Racusen LC Solez K Colvin RB The Banff 97 working classification of renal allograft pathology.Kidney Int. 1999; 55 (et al): 713-723Abstract Full Text Full Text PDF PubMed Scopus (2773) Google Scholar). The criteria include: (i) serologic evidence of DSAs; (ii) histologic evidence of acute tissue injury (g > 0 and/or ptc > 0 when recurrent/de novo glomerulonephritis excluded; acute thrombotic microangiopathy or acute tubular injury); and (iii) evidence of current/recurrent antibody interaction with the vascular endothelium including at least one of the following: (a) linear C4d staining in peritubular capillaries—c4d score >1 by IF on frozen section; (b) moderate microvascular either: ptc + g score >2, C4d may be negative. Since almost all biopsies in this study were obtained as protocol surveillance biopsies in patients with stable renal function, acute/active ABMR in that setting was considered “subclinical” ABMR. Per Banff 2013, any biopsy with transplant glomerulopathy (cg) was considered chronic (or chronic, active) ABMR. Biopsy scores were compared between EC patients and controls at the 3–4, 12, and 24 month biopsy time points. We present both individual scores and a composite diagnosis of subclinical ABMR. Statistical analysis was performed on JMPv10. (SAS, Cary, NC). Results were expressed as mean +/− standard deviation of the mean. Quantitative variables were compared using t-tests/ANOVA (variables with normal distribution), Wilcoxon/Kruskal Wallis (variables without normal distribution). Categorical variables were compared using the Chi-Square or two-tailed Fisher’s exact test. Patient and organ survival were evaluated by the Kaplan–Meier method, and comparisons were made using the Log–Rank test. For all groups, graft survival was analyzed as death-censored. For all comparisons, a two-tailed p-value of <0.05 was considered as statistically significant. Thirty patients received eculizumab from June 2008 to October 2011. Forty-eight historical controls were transplanted using a similar PE + IVIG based “desensitization” protocol without EC between January 2005 and September 2007. No difference in demographics or baseline immunologic parameters was noted Table 1.Table 1Baseline characteristicsEculizumab group n = 30Control group n = 48p-valueAge at transplant47.8 (±1.2.7)47.9 (±11.0)p = 0.91Female (%)71.0%78.0%p = 0.36Race1Race or ethnic group was self-reported. (%)p = 0.24Caucasian96.8%91.1%African American0%6.7%Hispanic0%2.2%Asian3.2%0%Cause of renal failure (%)p = 0.14Glornerulonephritis29.0%33.3%Other25.8%24.4%Cystic kidney disease12.9%13.3%Diabetes mellitus9.7%15.6%Hypertension9.7%0%Congenital6.5%8.9%Urological6.5%4.4%Baseline B flow crossmatch mean ± SD305.5 ± 91.8322.9 ± 78.5p = 0.35HLA mismatch mean ± SD3.9 ± 1.33.3 ± 1.4p = 0.34Retransplant (%)54.8%42.0%p = 0.52Class I DSA36.7%38.6%p = 0.89Class II DSA30.0%25.0%Class I+II DSA33.3%36.4%Class I DSA MFI2 mean ± SD4193.3 ± 4889.04556.68 ± 5083.0p = 0.76Class 2 DSA MFI mean ± SD4037.07 ± 5183.33128 ± 4141.2P = 0.40Total DSA MFI mean ± SD11 905.0 ± 8985.329592.51 ± 7806.15p = 0.24Number of pretransplant plasmapheresis mean ± SD4.6 ± 1.34.4 ± 1.4p = 0.78Length of follow-up (months) mean ± SD (range)38.2 ± 10.2 (24.1–59.8)73.0 ± 2.5.0 (41.3–105.0)p = 0.011 Race or ethnic group was self-reported. Open table in a new tab The mean age at transplant was similar in both groups. The majority of patients were female (71.0% in EC group and 78.0% in controls) and Caucasian (96.8% vs. 91.1%). The most common cause of renal failure in both groups was glomerulonephritis. The two groups were similar with respect to: (i) baseline B flow crossmatch (305.5 ± 91.8 vs. 322.9 ± 78.5 channel shift, p = 0.35), mean number of HLA mismatches (3.9 ± 1.3 vs. 3.3 ± 1.4, p = 0.34), and percent of patients that were “retransplants” (54.8% vs. 42.0%, p = 0.52). There was no difference in mean baseline DSA MFI, class of DSA, or number of pretransplant plasma exchanges. The control group was followed longer (p < 0.01). The mean follow-up in the control group was 73.0 +/− 25.0 months (range 41.3–105.4) and was 38.2 + /−14.2 months (range 24.1–63.1) in the EC group. No patients were lost to follow-up for at least 2 years. The primary endpoint of the original published study was the incidence of clinically apparent acute ABMR, defined as an increase in serum creatinine ≥0.3 mg/dL from nadir accompanied by histopathologic features of acute tissue injury attributable to alloantibody, in the first 3 months after transplantation (6.Stegall MD Diwan T Raghavaiah S Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients.Am J Transplant. 2011; 11 (et al): 2405-2413Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar). In this expanded cohort, the incidence of this primary endpoint again was found to be lower in the EC-treated patients compared to historical controls (6.67% vs. 43.8% p < 0.01) over a mean follow-up of 38.2 months and 73.0 months, respectively. Important for the interpretation of these results is the fact that EC was administered for a minimum of 1 month and was continued in patients with persistently high DSA (i.e. BFXM >200) for up to 1 year. Thus, per protocol, the length of treatment with EC varied. The duration of EC treatment was 4 weeks (n = 14); 9 weeks (n = 6), 6 months (n = 2), and 12 months (n = 8). Death-censored renal allograft survival was similar in patients who received EC compared to historical controls (p = 0.26, Figure 1A). The actual renal allograft survival at 1 year was 100% (EC) versus 98.0% (control, p = 1.0); at 2 years 89.7% (EC) versus 95.8% (control, p = 0.37); and at 3 years 85.6% (EC) versus 95.8% (control, p = 0.18). Over mean follow-up of 38.2 months, 16.7% of EC treated patients lost their grafts. In the control group, 28.6% of grafts were lost over a mean of 73.0 months. Transplant glomerulopathy was the most common histologic abnormality identified prior to graft loss accounting for 83.3% (5/6) of graft losses in the EC group and 58.8% (10/17) of losses in the control group p = 0.37. (Figure 1B). Death with function accounted for 17.6% (3/17) of graft losses in the control group and 16.6% (1/6) of losses in EC group, p = 1.0. Of the five death-censored allograft losses in the EC group with TG, none had an episode of acute clinical ABMR. However, by 6 months, three of those patients had TG and the other two had subclinical ABMR. Three of these patients received EC for 1 year posttransplant, and two had stopped EC at 1 month. At 1 year, all of these patients had anti-Class II DSA, all had peritubular capillaritis and advanced TG (Banff cg score >2) on protocol biopsy, yet only one of these was C4d+. The earliest graft loss occurred 409 days posttransplant. At 1 year, there were no differences between the two groups in the mean: serum creatinine (1.6 ± 0.9 vs. 1.3 ± 0.4 mg/dL, EC vs. control, p = 0.12), glomerular filtration rate (GFR) as measured by iothalamate clearance (46.7 ± 16.0 vs. 52.6 ± 10.6 mL/min, EC vs control, p = 0.3), or 24 h urine protein excretion (574.8 ± 146.4 vs. 637.5 ± 1589.5 mg EC vs. control, p = 0.28, Figure 2). More patients in the EC group had positive C4d staining scores >1 at 3–4 months after transplant compared to historical controls (46.4% vs. 17.9% p = 0.02). At 1 and 2 years, C4d staining continued to be numerically higher in the EC group, but was not statistically significant at 1 year, 33.3% EC versus 13.5% control (p = 0.08), and 2 years 31.8% EC versus 20.7% control (p = 0.52, Figure 3A). In the EC group, patients who remained on EC due to persistently high BFXM had a higher prevalence of C4d staining at 3 and 6 months compared to those who were able to stop drug, Figure 3B. Since almost all biopsies obtained between 3 months and 2 years were obtained as protocol surveillance biopsies in patients with stable renal function, the Banff category of “acute/active ABMR” diagnosed histologically in this setting was considered subclinical ABMR. Thus, the incidence of subclinical ABMR was similar in EC and control patients: at 3–4 months: 35.7% EC versus 42.6% controls (p = 0.46); at 1 year: 36.7% EC versus 36.8% control (p = 1.0); and at 2 years: 27.3% EC versus 15.1% control (p = 0.32, Figure 4A). The incidence of subclinical ABMR was higher in those on EC at 3–4 months (persistently high BFXM at >200) than those who had stopped EC (BFXM <200), 66.7% versus 21.1%, respectively (p = 0.03, Figure 4B). However, at 6 months, 1 year, and 2 years, the incidence of subclinical ABMR was similar whether or not the patient had discontinued EC (Figure 4B). While the Banff criteria for acute/active ABMR uses any ptc score >0 with C4d deposition and excludes any biopsies with cg, we also were interested in assessing the presence of moderate-to-severe peritubular capillaritis as this might reflect more persistent active injury. Thus, we also examined biopsies for a ptc score ≥2 with or without cg. This more severe form of inflammation was quite common and was similar in both EC and control patients: at 3–4 months, 25.0% in EC versus 34.1% in historical controls (p = 0.59); 1 year posttransplant, 60.0% in EC versus 60.0% in controls (p = 1.0); or at 2 years, 45.4% in EC versus 60.0% controls (p = 0.39) (Figure 5A). In the EC group, moderate-to-severe peritubular capillaritis was increasingly detected over time by light microscopy (Figure 5B). In the EC group, patients who remained on EC due to persistently high BFXM, the rate of peritubular capillaritis tended to be numerically higher, but only reached statistical significance at 6 months. The incidence of transplant glomerulopathy (TG, Banff cg score >0, also known as chronic ABMR) was similar in EC and control patients at 3–4 months (0% vs. 9.3% p = 0.15), 1 year (26.7% vs. 39.5%, p = 0.31), and at 2 years (45.4% vs 63.6% vs. p = 0.27, Figure 6A). TG was not detected until at least 6 months in the EC group. The incidence of TG was numerically lower in patients who stopped EC (i.e. had a BFXM <200 at some point) compared to those that remained on drug at 6 months (5.0% vs. 22.2%, p = 0.22) and at 12 months (18.1% vs. 50.0%, p = 0.16), but this did not reach statistical significance, Figure 6B. At 24 months posttransplant, when all patients had been off EC for at least 12 months, the incidence of TG in the EC group was 45.4%. The prevalence of interstitial fibrosis (Banff ci score >0) was similar in EC versus control patients at 1 years (63.3% vs. 55.0%, p = 0.62) and at 2 years (68.2% vs. 71.0%, p = 1.0) (Supplemental Table S1). The prevalence of moderate-to-severe fibrosis (ci > 2) was also similar between groups; (16.7% vs. 12.5%, p = 0.73) at 1 year and (19.4% vs. 18.2%, p = 1.0) at 2 years. This study used the BFXM for entry criteria and to determine the length of EC treatment. We use the BFXM primarily because it yields one number and thus can account for patients with multiple DSAs (e.g. both Class I and Class II DSA or multiple DSAs against one class). Using this data, we next examined the association between DSA (BFXM) at 6 months and the subsequent development of cg at 1 year (Figure 7). The important points to be made here are: (i) all patients had a high BFXM (>200) at baseline, but only a subset of patients had a persistently high BFXM at 6 months Figure 7A,B (40.5% [17/42] in controls and 46.1% [12/26] in EC group, p = 0.80); (ii) in both groups, there was no correlation between an early episode of clinical ABMR (denoted by an asterisk*) and persistently high BFXM levels or the development of TG at 1 year; (iii) patients with persistently high BFXM that was due to anti-Class I DSA alone had a very low incidence of TG at 1 year (Figure 7C,D); and (iv) patients in the EC group whose BFXM decreased to <200 had a low incidence of TG (Figure 7B,D,F). In contrast, in the control group even low levels of BFXM carried a risk for TG, especially in setting of Class II or I + II DSA (Figure 7A,C,E). Of note, clinically apparent acute ABMR was rare in the eculizumab-treated group. The incidence of TG at 1 year in patients with BFXM >200 was 50% (6/12) in the EC group and 35.7% (5/14) in the control group, p = 0.75. In those patients with BFXM >200 and any anti-Class II DSA, the incidence of TG was 50.0% (5/10) in the EC group and 42.9% (3/7) in the control group, p = 1.0. These data suggest that EC does not protect against TG at 1 year in patients with anti-Class II DSA and a high BFXM. However, in patients with BFXM <200 at 6 months, TG was absent (0/14) in the EC group at 1 year, but was in 42.3% (11/15) of allografts in the control group, p = 0.004. Furthermore, in the patients with BFXM <200 and any anti-Class II DSA, the incidence of TG was 0.0% (0/6) in the EC group vs. 50.0% (7/14) at 1 year in controls, p = 0.05. This suggests that a short-term early course of EC might be protective against the development of TG at 1 year in patients who subsequently develop low levels of DSA (BFXM < 200). These data also demonstrate the variability of alloantibody measurements over time. For example, more than half of the patients with a BFXM >200 at baseline, had levels lower than that at 6 months. One patient in the EC group had a BFXM >600 at 6 months and another who earlier had a low BFXM (<200) and was taken off EC had a higher BFXM at 6 months. This study extends the results of our prior study showing that early acute clinical ABMR commonly observed after +XMKTx (severe antibody-mediated injury characterized by glomeruli microthrombi, microvascular inflammation, and C4d deposition leading to graft dysfunction) is dependent on C5. Treatment with eculizumab markedly decreased its incidence. All episodes of clinical ABMR occurred in the first 3 months. Subclinical histologic findings found on protocol biopsy at later time points up to 2 years including acute/active ABMR, C4d staining, and moderate-to-severe peritubular capillaritis were relatively common and present at similar rates in EC and control patients. This clearly suggests that antibody-mediated effects are present in patients treated with EC. Chronic ABMR (cg score >0) also was equally common in EC and controls. Importantly, most of these subclinical changes were more common in patients with persistently high levels of DSA (BFXM >200) suggesting that this may be a major driver of these processes despite C5 blockade. This study also provides new insight into the mechanisms of chronic ABMR. For example, these data demonstrate that the prevention of early clinical ABMR does not completely prevent chronic ABMR, at least in EC-treated patients. Although early acute ABMR and chronic injury are associated as demonstrated by prior studies (14.Gloor J Cosio F Lager DJ Stegall MD. The spectrum of antibody-mediated renal allograft injury: implications for treatment.Am J Transplant. 2008; 8: 1367-1373Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar,15.Gloor JM Cosio FG Rea DJ Histologic findings one year after positive crossmatch or ABO blood group incompatible living donor kidney transplantation.Am J Transplant. 2006; 6 (et al): 1841-1847Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar), early acute ABMR is not necessary or causal for the development of chronic ABMR. In fact, this study suggests that major risk factor for TG at 1 year was a persistently high BFXM and that blockade of C5 is insufficient to prevent chronic injury in this setting. In contrast, in patients with lower levels of DSA (low BFXM), even a short-course of EC appeared to decrease TG at 1 year. Since this group typically has a very low incidence of early ABMR (7.Burns JM Cornell LD Perry DK Alloantibody levels and acute humoral rejection early after positive crossmatch kidney transplantation.Am J Transplant. 2008; 8 (et al): 2684-2694Abstract Full Text Full Text PDF PubMed Scopus (180) Google Scholar,16.Lefaucheur C Loupy A Hill GS Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation.J Am Soc Nephrol. 2010; 21 (et al): 1398-1406Crossref PubMed Scopus (634) Google Scholar), we expected that this group would be less likely to benefit from EC. However, this unexpected finding suggests that early C5 activity may be critically important to the development of chronic injury at 1 year in patients with low levels of DSA. However, we caution against over-interpretation of this result. A detailed description of DSA data including MFIs over time, antibody subclasses including C1q binding is beyond the scope of this report. Even the BFXM data presented here illustrates the complexity of DSA data and its interpretation using small numbers of patients. While beyond the scope of the current study, the use of aggressive antibody reduction therapy either at the time of transplantation or after transplant might alter the progression of chronic injury and deserves further study (17.Jordan SC Quartel AW Czer LS Posttransplant therapy using high-dose human immunoglobulin (intravenous gammaglobulin) to control acute humoral rejection in renal and cardiac allograft recipients and potential mechanism of action.Transplantation. 1998; 66 (et al): 800-805Crossref PubMed Scopus (226) Google Scholar, 18.Wong W Lee RA Saidman SL Smith RN Zorn E. Bortezomib in kidney transplant recipients with antibody mediated rejection: Three case reports.Clin Transpl. 2009; : 401-405PubMed Google Scholar, 19.Brown CM Abraham KA O’Kelly P Conlon PJ Walshe JJ. Long-term experience of plasmapheresis in antibody-mediated rejection in renal transplantation.Transplant Proc. 2009; 41: 3690-3692Crossref PubMed Scopus (25) Google Scholar, 20.Everly JJ Walsh RC Alloway RR Woodle ES. Proteasome inhibition for antibody-mediated rejection.Curr Opin Organ Transplant. 2009; 14: 662-666Crossref PubMed Scopus (76) Google Scholar). The histologic changes that were observed despite EC therapy could be due to low levels of C5 activation that were not detectable (multiple attempts at demonstrating MAC staining were unsuccessful and we cannot rule out this possibility). There also are several pathways “proximal” to C5 that may be sufficient to cause the observed subclinical and chronic injury and these could be targets for further study. C3a is a potent chemotactic molecule that may stimulate an inflammatory response in the allograft independent of the blockade of C5 (21.Dunkelberger JR Song WC. Complement and its role in innate and adaptive immune responses.Cell research. 2010; 20: 34-50Crossref PubMed Scopus (981) Google Scholar,22.Klos A Tenner AJ Johswich KO Ager RR Reis ES Kohl J. The role of the anaphylatoxins in health and disease.Mol Immunol. 2009; 46: 2753-2766Crossref PubMed Scopus (486) Google Scholar). Complement deposition (C4d+ staining) and complement binding DSA (C1q+), both relevant to activation of the proximal complement pathway, have been associated with chronic ABMR (23.Schmidtko J Wang R Wu CL Posttransplant lymphoproliferative disorder associated with an Epstein-Barr-related virus in cynomolgus monkeys.Della Pelle P. 2002; 73 (et al): 1431-1439Google Scholar, 24.Mauiyyedi S Pelle PD Saidman S Chronic humoral rejection: Identification of antibody-mediated chronic renal allograft rejection by C4d deposits in peritubular capillaries.J Am Soc Nephrol. 2001; 12 (et al): 574-582Crossref PubMed Google Scholar, 25.Loupy A Lefaucheur C Vernerey D Complement-binding anti-HLA antibodies and kidney-allograft survival.N Engl J Med. 2013; 369 (et al): 1215-1226Crossref PubMed Scopus (650) Google Scholar). Thus, more proximal blockade of complement might ameliorate chronic injury. There also may be complement-independent mechanisms sufficient to cause injury. NK cells can infiltrate the graft via binding to the Fcγ portion of DSA (26.Akiyoshi T Hirohashi T Alessandrini A Role of complement and NK cells in antibody mediated rejection.Neal Smith R. 2012; 73 (et al): 1226-1232Google Scholar). Depletion of NK cells in a cardiac transplant mouse model reduces chronic ABMR with or without complement fixing donor specific antibody (27.Hirohashi T Chase CM Della Pelle A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody.Am J Transplant. 2012; 12 (et al): 313-321Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar). In humans, renal allografts with known chronic ABMR have increased infiltration of NK cells and NK cell specific transcripts (28.Hidalgo LG Sis B Sellares J NK cell transcripts and NK cells in kidney biopsies from patients with donor-specific antibodies: Evidence for NK cell involvement in antibody-mediated rejection.Am J Transplant. 2010; 10 (et al): 1812-1822Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar). Finally, DSA alone can activate endothelial cells via HLA-mediated signaling, as has been observed in vitro (29.Bian H Harris PE Mulder A Reed EF. Anti-HLA antibody ligation to HLA class I molecules expressed by endothelial cells stimulates tyrosine phosphorylation, inositol phosphate generation, and proliferation.Hum Immunol. 1997; 53: 90-97Crossref PubMed Scopus (62) Google Scholar), which may lead to some of the manifestations of chronic injury. Activated endothelial cells also release pro-inflammatory cytokines that could mediate microvascular inflammation (e.g. peritubular capillaritis and glomerulitis) by NK cells, macrophages and other leukocytes (29.Bian H Harris PE Mulder A Reed EF. Anti-HLA antibody ligation to HLA class I molecules expressed by endothelial cells stimulates tyrosine phosphorylation, inositol phosphate generation, and proliferation.Hum Immunol. 1997; 53: 90-97Crossref PubMed Scopus (62) Google Scholar, 30.Jin YP Jindra PT Gong KW Lepin EJ Reed EF. Anti-HLA class I antibodies activate endothelial cells and promote chronic rejection.Transplantation. 2005; 79: S19-S21Crossref PubMed Scopus (71) Google Scholar, 31.Akiyoshi T Hirohashi T Alessandrini A Role of complement and NK cells in antibody mediated rejection.Hum Immunol. 2012; 73 (et al): 1226-1232Crossref PubMed Scopus (55) Google Scholar, 32.Hirohashi T Chase CM Della Pelle A novel pathway of chronic allograft rejection mediated by NK cells and alloantibody.Am J Transplant. 2012; 12 (et al): 313-321Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar). It may be that a persistent intracapillary cellular infiltrate is a mechanism of graft injury in patients with preformed DSA, independent of the concurrent presence of high DSA levels or terminal complement activation. Most studies of chronic ABMR in the literature have involved patients with a negative crossmatch at baseline who develop de novo DSA. Many of these patients develop DSA following a cell-mediated rejection and many have a combined cellular and antibody mediated rejection in the posttransplant course (33.Lerut E Kuypers DR Verbeken E Acute rejection in non-compliant renal allograft recipients: A distinct morphology.Clin Transplant. 2007; 21 (et al): 344-351Crossref PubMed Scopus (41) Google Scholar, 34.El Ters Grande M Keddis JP Kidney allograft survival after acute rejection, the value of follow-up biopsies.Am J Transplant. 2013; 13 (et al): 2334-2341Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 35.Halloran PF de Freitas DG Einecke G An integrated view of molecular changes, histopathology and outcomes in kidney transplants.Am J Transplant. 2010; 10 (et al): 2223-2230Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar, 36.Everly MJ Rebellato LM Haisch CE Incidence and impact of de novo donor-specific alloantibody in primary renal allografts.Transplantation. 2013; 95 (et al): 410-417Crossref PubMed Scopus (297) Google Scholar). Thus, chronic injury in this setting may not be solely due to DSA. In contrast, the patients in this study have a “purer” form ABMR (cell-mediated rejection was a rare finding on protocol biopsy). We thus encourage caution when making comparisons between these two types of chronic ABMR. Finally, the current study has several important limitations that deserve mention. One caveat in interpreting these results is that this study was not designed to prevent chronic ABMR and patients received different posttransplant treatments. In both groups, the number of patients developing chronic injury and graft loss was quite small and thus detailed analyses of risk factors for these outcomes is difficult. In addition, while EC decreased the incidence and severity of acute clinical ABMR allowing us to reduce the number of posttransplant PE treatment and splenectomies, it is possible that these more invasive therapies employed to prevent early graft loss also helped to decrease chronic injury rates. While beyond the scope of the current study, the use of aggressive antibody reduction therapy either at the time of transplantation or after transplant might alter the progression of chronic injury and deserves further study. Finally, given the complexity of these patients, it is quite difficult to develop matched controls for analyses and our use of the entire historical control group has obvious limitations. The question remains if more prolonged treatment with EC would result in a significant difference in chronic changes. Early acute ABMR is a difficult clinical management problem in +XMKTx and the ability of EC to prevent this complication is a significant improvement in this area. However, the fact that chronic ABMR occurred in patients with persistently high DSA despite EC highlights the need for further therapy in +XMKTx. The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. MDS, CAS, and LDC have a research contract with Alexion Pharmaceuticals (sponsor for this study). MG and WK have no conflicts of interest to disclose. Additional Supporting Information may be found in the online version of this article. Download .jpg (.11 MB) Help with files Table S1: The prevalence of interstitial fibrosis on protocol biopsies at 1 and 2 years EC and control patients. (A) Any fibrosis (ci > 0) and (B) Moderate-to-severe fibrosis ci score > 2. Fisher’s exact test." @default.
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