Chronic Active Antibody-mediated Rejection Research Articles

Early effects of first-line treatment with anti-interleukin-6 receptor antibody tocilizumab for chronic active antibody-mediated rejection in kidney transplantation.

Chronic active antibody-mediated rejection (cAMR) is a major determinant of late allograft failure. Rituximab/immunoglobulins (IVIg) + plasma exchange (PLEX) showed controversial results in cAMR treatment. Tocilizumab (TCZ), a humanized anti-interleukin 6 receptor antibody, has been recently used as rescue therapy in patients non-responsive to rituximab/IVIg/PLEX with favorable outcomes. Whether TCZ acts "per se" or requires a priming effect from previous treatments is currently unknown. Fifteen patients with cAMR were treated with TCZ as a first-line therapy and followed for a median time of 20.7months. Despite the majority of patients experiencing advanced transplant glomerulopathy (TG) at diagnosis (60% with cg3), glomerular filtration rate and proteinuria stabilized during the follow-up, with a significant reduction in donor-specific antibodies. Protocol biopsies after 6months demonstrated significant amelioration of microvascular inflammation and no TG, C4d deposition, or IF/TA progression. Gene-expression and immunofluorescence analysis showed upregulation of three genes (TJP-1, AKR1C3, and CASK) involved in podocyte, mesangial, and tubular restoration. Tocilizumab adopted as a first-line approach in cAMR was associated with early serological and histological improvements and functional stabilization even in advanced TG, suggesting a role for the use of TCZ alone with the avoidance of unnecessary previous immunosuppressants.

P1760EXTRACORPOREAL PHOTOPHERESIS AND KIDNEY ALLOGRAFT REJECTION

Abstract Background and Aims Extracorporeal photopheresis (ECP) is an apheresis modality that in the field of solid organ transplantation (SOT) has an indication in the treatment or prophylaxis of pulmonary, cardiac or hepatic graft rejection. The usefulness of ECP in renal transplantation (RTx) remains contradictory because of the few studies that evaluate the effectiveness and safety of this technique. Method Case series study of kidney transplant patients with histological diagnosis of rejection who have been treated with ECP during the 2013-2018 period (n = 8 patients). The technical characteristics of the ECP sessions (n = 89) were studied, including tolerance and complications in each of them. Results Demographic and clinical characteristics are shown in Table 1. The indication of FEC was the contraindication to conventional treatment (n = 4), mainly due to concomitant infection (50%), or refractoriness (n = 4) to the treatment prescribed in each case and it is specified in Table 1. The initial schedule was 2 consecutive weekly sessions for 5 weeks, with additional sessions depending on the evolution at the end of the first batch. The scheduled sessions could be completed in most patients (n = 5). The 3 reasons for discontinuation were the lack of response to treatment, hospital admission and thrombosis of the arteriovenous fistula (AVF). The improvement of graft function in terms of creatinine reduction at the end of therapy occurred among patients presenting with acute cellular rejection (ACR) (n = 4) and it remained 3 months after the end of the treatment. The only late ACR (> 3 months post-transplant) could not complete the initial programming. No graft with humoral component showed improvement in renal function. Graft loss and dialysis restart occurred in a patient with chronic active antibody-mediated rejection (cAMR). The other patient with cAMR is in a pre-dialysis situation. A total of 89 procedures were studied, all performed with the THERAKOS® CELLEX® Photopheresis System, with the administration of the methoxsalen solution (UVADEX®) and photoactivation with ultraviolet A light. Vascular access per session was the AVF (76% ) or the central vascular catheter (CVC) (24%), under no circumstances was peripheral access used. Each procedure lasted on average 112.72 +/- 13.85 minutes (range, 86-145). The volume of treatment (“buffy coat”) was 189.11 +/- 28.67 mL per session, and the total volume of fluids administered (NaCl and anticoagulation) was 559.40 +/- 41.17 mL. The complications observed during the sessions were fever (n = 2), thrombosis of the AVF (n = 1), coagulation of the extracorporeal system (n = 1) and anemization (n = 1). Interprocedure there was a case of urinary infection that conditioned hospital admission and discontinuation of therapy. One patient died of cardiovascular cause with a functioning graft 4 years after therapy. Conclusion The utility of the ECP seems to be in cases of cell rejection, probably related to the triggering of an immunomodulatory response of lymphocytes. It can be considered a well-tolerated and safe treatment. Special care should be taken with patients who require water restriction (infusion of 560 mL on average per session). We need more studies with a greater number of patients and a control group to be able to confirm the effectiveness and safety of PEC in RTx and to be considered a useful therapeutic tool as in other SOT.

Antibody-Mediated Rejection Due to Donor-Specific HLA-DQB1 and DQA1 Antibodies After Kidney Transplantation: A Case Report

BackgroundDonor-specific HLA antibody (DSA) is associated with the risk of allograft loss due to antibody-mediated rejection (ABMR). The majority of de novo DSA after kidney transplantation is directed toward donor HLA-DQ antigens. A HLA-DQ antigen is a heterodimer consisting of an alpha and beta chain. Traditionally, HLA-DQA1 typing has not been part of the pretransplant evaluation. Therefore, DQ alpha proteins are not usually taken into account in the interpretation of HLA-DQ antibody reactions. MethodsWe hereby present a case of a kidney transplant recipient with 0% pretransplant panel reactive antibody. She received kidney allograft from her husband. Two years after transplantation, she experienced abdominal swelling, and enlargement of transplanted kidney was identified. A biopsy of the allograft kidney demonstrated chronic active ABMR. DSAs were investigated using immunoglobulin G (IgG) and C1q single antigen bead (SAB) assay. HLAMatchmaker analysis was performed to identify eplets that explain the antibody reactivity patterns. ResultsThe IgG SAB analysis of a patient’s serum at the time of rejection showed positive reactions with all DQ2-carrying beads with mean fluorescence intensity (MFI) > 10000. However, the C1q assay demonstrated strong reaction to only HLA-DQA1∗05:01-DQB1∗02:01-carrying bead with MFI = 22462, whereas weak or no reactions against other HLA-DQ2-carrying beads were found. High-resolution HLA typing revealed that HLA-DQA1∗05:01 and DQB1∗02:01 were mismatched donor antigens. HLAMatchmaker analysis showed that the antibodies were reactive toward 40GR3 eplet on DQA1 and 45GE3 eplet on DQB1. ConclusionsThis case highlights the clinical significance of antibodies specific to both DQ alpha and DQ beta chains after kidney transplantation.

Increased urinary exosomal SYT17 levels in chronic active antibody-mediated rejection after kidney transplantation via the IL-6 amplifier.

Chronic active antibody-mediated rejection (CAAMR) is a particular problem in kidney transplantation (KTx), and ~25% of grafts are lost by CAAMR. Further, the pathogenesis remains unclear, and there is no effective cure or marker. We previously found that a hyper NFκB-activating mechanism in non-immune cells, called the IL-6 amplifier, is induced by the co-activation of NFκB and STAT3, and that this activation can develop various chronic inflammatory diseases. Here, we show that synaptotagmin-17 (SYT17) is increased in an exosomal fraction of the urine from CAAMR patients, and that this increase is associated with activation of the IL-6 amplifier. Immunohistochemistry showed that SYT17 protein expression was increased in renal tubule cells of the CAAMR group. While SYT17 protein was not detectable in whole-urine samples by western blotting, urinary exosomal SYT17 levels were significantly elevated in the CAAMR group compared to three other histology groups (normal, interstitial fibrosis and tubular atrophy, and calcineurin inhibitors toxicity) after KTx. On the other hand, current clinical laboratory data could not differentiate the CAAMR group from these groups. These data suggest that urinary exosomal SYT17 is a potential diagnostic marker for CAAMR.

Recommended Treatment for Antibody-mediated Rejection After Kidney Transplantation: The 2019 Expert Consensus From the Transplantion Society Working Group.

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.

Efficacy and Safety of Tocilizumab in the Treatment of Acute Active Antibody-mediated Rejection in Kidney Transplant Recipients.

Background.Antibody-mediated rejection (AMR) continues to have a deleterious impact on kidney allograft survival. Recent evidence supports use of tocilizumab for treatment of chronic active AMR, but it has not been assessed for treatment of acute active AMR.Methods.We performed a single-center, observational study of kidney transplant recipients who received at least 1 dose of tocilizumab in addition to conventional therapies for acute active AMR between October 2016 and October 2018 with follow-up through August 2019.Results.Seven patients were included. All 7 patients received tocilizumab 8 mg/kg (max dose, 800 mg) monthly. We noted a 50% or greater reduction in immunodominant donor-specific antibodies in 4 of 6 patients. Renal function improved or stabilized in all patients throughout the duration of therapy. One patient developed cytomegalovirus esophagitis and 1 had a potential hypersensitivity reaction. In the extended follow-up, 1 patient had mixed rejection and 2 patients had T-cell–mediated rejection, which occurred 6 to 24 mo after completion of therapy.Conclusions.Tocilizumab may be considered as an addition to conventional therapies for treatment of acute active AMR. More studies are needed to determine which patients may benefit from therapy and to examine the appropriate duration of treatment.

Immune Cell Infiltrate in Chronic-Active Antibody-Mediated Rejection.

Background: Little is known about immune cell infiltrate type in the kidney allograft of patients with chronic-active antibody-mediated rejection (c-aABMR).Methods: In this study, multiplex immunofluorescent staining was performed on 20 cases of biopsy-proven c-aABMR. T-cell subsets (CD3, CD8, Foxp3, and granzyme B), macrophages (CD68 and CD163), B cells (CD20), and natural killer cells (CD57) were identified and counted in the glomeruli (cells/glomerulus) and the tubulointerstitial (TI) compartment [cells/high-power field (HPF)].Results: In the glomerulus, T cells and macrophages were the dominant cell types with a mean of 5.5 CD3+ cells/glomerulus and 4 CD68+ cells/glomerulus. The majority of T cells was CD8+ (62%), and most macrophages were CD68+CD163+ (68%). The TI compartment showed a mean of 116 CD3+ cells/HPF, of which 54% were CD8+. Macrophage count was 21.5 cells/HPF with 39% CD68+CD163+. CD20+ cells were sporadically present in glomeruli, whereas B-cell aggregates in the TI compartment were frequently observed. Natural killer cells were rarely identified. Remarkably, increased numbers of CD3+FoxP3+ cells in the TI compartment were associated with decreased graft survival (p = 0.004).Conclusions: Renal allograft biopsies showing c-aABMR show a predominance of infiltrating CD8+ T cells, and increased numbers of interstitial FoxP3+ T cells are associated with inferior allograft survival.

Orosomucoid 1 is involved in the development of chronic allograft rejection after kidney transplantation.

Chronic allograft rejection is the most common cause of long-term allograft failure. One reason is that current diagnostics and therapeutics for chronic allograft rejection are very limited. We here show that enhanced NFκB signaling in kidney grafts contributes to chronic active antibody-mediated rejection (CAAMR), which is a major pathology of chronic kidney allograft rejections. Moreover, we found that urinary orosomucoid 1 (ORM1) is a candidate marker molecule and therapeutic target for CAAMR. Indeed, urinary ORM1 concentration was significantly higher in kidney transplant recipients pathologically diagnosed with CAAMR than in kidney transplant recipients with normal histology, calcineurin inhibitor toxicity, or interstitial fibrosis and tubular atrophy. Additionally, we found that kidney biopsy samples with CAAMR expressed more ORM1 and had higher NFκB and STAT3 activation in tubular cells than samples from non-CAAMR samples. Consistently, ORM1 production was induced after cytokine-mediated NFκB and STAT3 activation in primary kidney tubular cells. The loss- and gain-of-function of ORM1 suppressed and promoted NFκB activation, respectively. Finally, ORM1-enhanced NFκB-mediated inflammation development in vivo. These results suggest that an enhanced NFκB-dependent pathway following NFκB and STAT3 activation in the grafts is involved in the development of chronic allograft rejection after kidney transplantation and that ORM1 is a non-invasive candidate biomarker and possible therapeutic target for chronic kidney allograft rejection.

Treatment of chronic active antibody-mediated rejection in renal transplant recipients \u2013 a single center retrospective study

BackgroundChronic active antibody-mediated rejection is a major etiology of graft loss in renal transplant recipients. However, there is no consensus on the optimal treatment strategies.MethodsComputerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of chronic active antibody-mediated rejection. The patients were divided into two groups according to treatment strategy: Group 1 received aggressive treatment (double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy); and group 2 received supportive treatment.ResultsFrom February 2009 to December 2017, a total of 82 patients with biopsy-proven chronic antibody mediated rejection were identified. Kaplan-Meier analysis of death-censored graft survival showed a worse survival in group 2 (P = 0.015 by log-rank test). Adverse event-free survival was lower in group 1, whereas patient survival was not significantly different. Proteinuria and supportive treatment were independent risk factors for graft loss in multivariate analysis.ConclusionsAggressive treatment was associated with better graft outcome. However, higher incidence of adverse events merit personalized treatment, especially for those with higher risk of infection. Appropriate prophylactic antibiotics are recommended for patients undergoing aggressive treatment.

An in vitro model of antibody-mediated injury to glomerular endothelial cells: Upregulation of MHC class II and adhesion molecules

Chronic active antibody-mediated rejection is a major cause of allograft failure in kidney transplantation. Microvascular inflammation and transplant glomerulopathy are defining pathologic features of chronic active antibody-mediated rejection and are associated with allograft failure. However, the mechanisms of leukocyte infiltration and glomerular endothelial cell injury remain unclear. We hypothesized MHC class II ligation on glomerular endothelial cells (GEnC) would result in upregulation of adhesion molecules and production of chemoattractants. A model of endothelial cell activation in the presence of antibodies to MHC classes I and II was used to determine the expression of adhesion molecules and chemokines. Murine GEnC were activated with IFNγ, which upregulated gene expression of β2-microglobulin (MHC class I), ICAM1, VCAM1, CCL2, CCL5, and IL-6. IFNγ stimulation of GEnC increased surface expression of MHC class I, MHC class II, ICAM1, and VCAM1. Incubation with antibodies directed at MHC class I or class II did not further enhance adhesion molecule expression. Multispectral imaging flow cytometry and confocal microscopy demonstrated MHC molecules co-localized with the adhesion molecules ICAM1 and VCAM1 on the GEnC surface. GEnC secretion of chemoattractants, CCL2 and CCL5, was increased by IFNγ stimulation. CCL2 production was further enhanced by incubation with sensitized plasma. Endothelial activation induces de novo expression of MHC class II molecules and increases surface expression of MHC class I, ICAM1 and VCAM1, which are all co-localized together. Maintaining the integrity and functionality of the glomerular endothelium is necessary to ensure survival of the allograft. IFNγ stimulation of GEnC propagates an inflammatory response with production of chemokines and co-localization of MHC and adhesion molecules on the GEnC surface, contributing to endothelial cell function as antigen presenting cells and an active player in allograft injury.

Potential urinary extracellular vesicle protein biomarkers of chronic active antibody-mediated rejection in kidney transplant recipients

The aim of this study was to identify potential proteomic biomarkers for chronic active antibody-mediated rejection (CAMR) in kidney transplant recipients (KTRs). Among 385 KTRs enrolled in a cross-sectional multicenter study, 26 KTRs with biopsy-proven CAMR, 57 KTRs with long-term graft survival (LGS), and 10 rejection-free matched KTRs were included. A proteomic approach was employed to measure urinary extracellular vesicle (EV) changes in the KTRs. The urinary EVs were trypsin-digested using a gel-assisted protocol and quantified by label-free liquid chromatography with tandem mass spectrometry, using a data-dependent acquisition (DDA) mode. Western blot analysis was performed to confirm the protein levels for each candidate biomarker. Analysis of the isolated EV proteins revealed 93 and 97 proteins in the CAMR and LGS patients, respectively. Proteins that were identical in both groups were excluded and only high-significance proteins with a fold change of at least 1.5 were selected as candidate biomarkers. Six proteins (APOA1, TTR, PIGR, HPX, AZGP1, and CP) that were distinguishable between CAMR and LGS were selected. The proteins were confirmed by immunoblot analyses using independently acquired urinary EV samples. AZGP1 in particular was found to be a CAMR-specific proteomic biomarker that was distinguishable from the rejection-free control group with matching kidney function, duration of transplantation, and age. We identified and validated six proteomic biomarkers for CAMR and clarified one CAMR-specific proteomic biomarker in KTRs. Further clinical trials are needed before these rejection-specific biomarkers can be applied for the early prediction, diagnosis, and monitoring of the clinical response of KTRs to the treatment of CAMR.

Efficacy of Bortezomib as an Adjunctive Therapy for Refractory Chronic Active Antibody-Mediated Rejection in Kidney Transplant Patients: A Single-Center Experience

BackgroundChronic active antibody-mediated rejection (CAMR) has unsatisfactory prognosis in spite of intensive standard antihumoral treatment. Efficacy of additional bortezomib in CAMR remains uncertain. MethodsA retrospective chart review was conducted among kidney transplant patients with biopsy-proven CAMR. Our standard CAMR protocol included plasma exchange, intravenous immunoglobulin, and rituximab. Repeated treatment was provided for refractory cases. Patients receiving at least 1 course of bortezomib were enrolled as the bortezomib group. Allograft outcome was compared among patients receiving repeated standard protocol alone and the bortezomib group. ResultsThirteen and 15 patients were assigned to the bortezomib and control groups, respectively. Repeated bortezomib protocol was given for 1, 2, 3, and 4 courses in 6, 4, 1, and 2 patients, respectively. With a median follow-up time after treatment of 41.8 (18.3-47.4) months, the bortezomib group had a lower rate of glomerular filtration rate declination (-4.20 ± 4.89 mL/min/y vs -12.33 ± 10.44 mL/min/y; P = .014), a higher rate of disappearance of donor specific antibodies (69.2% vs 25%; P = .03), a lower rate of allograft loss (15.4% vs 66.7%; P = .006), and better allograft survival (P = .006). ConclusionIn CAMR, additional bortezomib treatment was more effective in eliminating donor specific antibodies and improving allograft survival than standard protocol treatment.

Long-term Trends in the Clinicopathologic Features of Kidney Transplant Recipients With Graft Dysfunction

BackgroundGraft biopsy is the gold standard for the differential diagnosis of graft dysfunction. The time interval between transplant surgery and biopsy often provides clinicians with diagnostic clues. However, the clinicopathologic features of late graft biopsy, especially those obtained at more than 5 years after kidney transplant, are not well understood. Materials and MethodsWe retrospectively collected graft biopsy tissues obtained from kidney transplant recipients who underwent indication biopsy between February 2012 and March 2017. Patients were divided according to their post-transplant period, and their clinical characteristics, pathologic diagnosis, and Banff scores were compared across groups. ResultsA total of 410 indication biopsy specimens obtained from 321 kidney transplant recipients were analyzed in this study. Overall, the incidence of T cell–mediated rejection, borderline rejection, and BK virus–associated nephropathy decreased while that of antibody-mediated rejection, nonspecific interstitial fibrosis and tubular atrophy, and glomerulonephritis increased over time. Most samples obtained over 5 years after kidney transplant exhibited chronic glomerular and tubulointerstitial injuries irrespective of their pathologic diagnosis. In patients whose post-transplant period was less than 5 years, urine protein-to-creatinine ratio was significantly elevated in the glomerulonephritis and chronic active antibody-mediated rejection groups only. In contrast, patients who underwent graft biopsy more than 5 years after kidney transplant showed significantly high levels of proteinuria irrespective of the pathologic diagnosis, and there was no statistical difference between groups. ConclusionWe demonstrated that the etiology of graft dysfunction is largely influenced by the biopsy time point.

Utility of immunohistochemistry with C3d in C3 glomerulopathy.

C3-dominance by immunofluorescence is a defining feature in the diagnosis of C3 glomerulopathy. Most pathologists stain for C3c, which has been reported as a trace/negative even in otherwise clear-cut cases of dense deposit disease. We investigated the usefulness of C3d immunohistochemistry in biopsies with C3 glomerulopathy as an ancillary diagnostic tool. All biopsies from patients diagnosed with C3 glomerulopathy in the period January 2005 to June 2017 in the Erasmus MC, Rotterdam were included (n = 14; 10 C3 glomerulonephritis, 4 dense deposit disease). The staining pattern of C3d and C4d by immunohistochemistry was analyzed. As controls, biopsies from patients with immune complex membranoproliferative glomerulonephritis (n = 2), infection-associated glomerulonephritis (n = 6), pauci-immune crescentic glomerulonephritis (n = 7), tubulointerstitial nephritis (n = 7) and chronic-active antibody-mediated rejection (n = 9) were included. All 14 biopsies with C3 glomerulopathy showed a C3d score of ≥2, including two clear-cut biopsies with C3 glomerulopathy originally showing a trace/negative staining for C3c. In the control group, a C3d score ≥2 was observed in 11 biopsies (35%; 2 with immune complex membranoproliferative glomerulonephritis (100%), 6 with infection-associated glomerulonephritis (100%), 1 with pauci-immune crescentic glomerulonephritis (14%), 1 with tubulointerstitial nephritis (14%) and 1 with chronic-active antibody-mediated rejection (11%)). C4d was positive in 71% of the biopsies with C3 glomerulopathy (10/14). In conclusion, C3d immunohistochemistry is a valuable tool in the diagnosis of C3 glomerulopathy, especially in cases in which C3c immunofluorescence shows a trace/negative. We recommend the use of C3d in addition to C3c in cases suspicious for C3 glomerulopathy.

Combination of Glomerular C4d and Morphologic Glomerular Lesions as a Possible Indicator in the Diagnosis of Acute or Chronic Active Antibody-Mediated Rejection

BackgroundLinear C4d staining in the peritubular capillaries is considered a sensitive and useful marker of active or chronic active antibody-mediated rejection (ABMR) in transplanted kidneys. However, the diagnostic significance of glomerular C4d deposits (gC4d) is still undetermined. The aim of this study is to evaluate the association of gC4d with clinicopathologic features and to assess its diagnostic value. MethodsFrom 2013 to 2018, a total of 158 cases of allograft kidney biopsy specimens were obtained from the Korea University Anam Hospital. The histologic features were evaluated according to the Banff classification. The gC4d were determined through immunohistochemical analyses and classified based on scores of 0 to 3 according to the extent of gC4d. ResultsA total of 73 cases (46.2%) showed gC4d, and 37 cases (23.4%), 23 cases (14.6%), and 13 cases (8.2%) were classified with a score of 1+, 2+, and 3+, respectively. The gC4d showed a significant correlation with antibody-associated histologic lesions, including peritubular capillaritis, glomerulitis, and transplant glomerulopathy (P < .001). However, gC4d showed no significant association with cell-mediated injuries such as tubulitis, interstitial inflammation, acute tubular necrosis, and thrombotic microangiopathy. Although positive gC4d alone was associated with nonspecific findings without ABMR, most cases of gC4d combined with glomerulitis or transplant glomerulopathy showed typical histologic features of ABMR, clinically with higher antibody titers and severe functional deterioration. ConclusionsGlomerular C4d deposits may be an alternate useful marker in the diagnosis of active or chronic active ABMR when combined with histologic features of glomerular lesions.

Effect of Rabbit Antithymocyte Globulin on Acute and Chronic Active Antibody-Mediated Rejection After Kidney Transplantation

BackgroundRabbit antithymocyte globulin (rATG) induction is associated with reduction in the occurrence of de novo donor-specific antibody (DSA) and antibody-mediated rejection (AMR). Therefore, rATG administration is considered as a treatment for AMR. However, only a few studies have investigated the treatment of AMR with rATG after kidney transplantation. MethodsBetween April 2013 and March 2018, 162 consecutive de novo kidney transplantations were performed with induction immunosuppressive therapy comprising tacrolimus, mycophenolate mofetil, methylprednisolone, and basiliximab. AMR was diagnosed on the basis of the presence of DSA and episode biopsy findings. For DSA-positive recipients, plasmapheresis was performed to remove DSA before rATG administration (1.5 mg/kg for 5 days). Patients treated with rATG against active AMR were retrospectively analyzed for graft function. ResultsA total of 13 kidney transplant recipients developed active AMR within 302 days after transplantation. After rATG administration, the mean serum creatinine and urine protein levels significantly declined from 3.03 mg/dL to 1.68 mg/dL (P = .002) within 46 days and from 3.01 g/gCr to 0.54 g/gCr (P = .006) within 106 days, respectively. The peripheral blood lymphocyte count rapidly decreased after rATG administration and remained low for 12 months. With regard to adverse events, fever (84.6%), cytomegaloviremia (84.6%), thrombocytopenia (61.5%), anemia (30.8%), and neutropenia (15.4%) occurred within 3 months after rATG administration. ConclusionsrATG improved graft function by suppressing peripheral blood lymphocytes in kidney transplant recipients with active AMR. The rATG administration as a treatment for active AMR may contribute to positive graft outcomes after kidney transplantation.

MON-164 CLINICAL AND PATHOLOGICAL ANALYSES IN CASES OF TRANSPLANT GLOMERULOPATHY AFTER KIDNEY TRANSPLANTATION IN MONGOLIA

Transplant glomerulopathy (TG) is included as one of the criteria of chronic active antibody-mediated rejection (c-AMR) in Banff 09 classification. TG is a morphologic lesion of renal allografts that is characterized histologically by duplication and/or multilayering of the glomerular basement membrane (GBM). TG is well documented to be associated with the presence of donor-specific antibodies (DSAs), most notably against HLA class II antigens, and in the majority of cases is felt to represent a morphologic manifestation of chronic antibody-mediated rejection (ABMR). The First Central Hospital of Mongolia is the only hospital that perform Kidney transplantation (KT) in Mongolia. We perform 20 KT per year and currently we performed total of 164 KT in end stage kidney disease patients in our hospital. In addition, we follow-up nearly 400 kidney transplanted patients in our clinic (including patients had transplantation in overseas). In this report, we discuss the clinical and pathological analyses of cases of TG after renal transplantation. TG was diagnosed in 10 renal allograft biopsy specimens (BS) obtained from transplant patients who was under follow up at our clinic between 2017 and 2018. We checked DSA and stained the specimens with H&E, masson's trichrome, PAS, silver staining and used Banff 09 classification. Immunofluorescence and C4d stainings were also done. Among the 10 patients,20% had a history of acute rejection (AR); of these,10% had acute antibody-mediated rejection (a-AMR).Among the 86 BS of TG,the TG was mild in 35 cases (cg1),moderate in 28 cases (cg2) and severe in 23 cases (cg3).Peritubular capillaritis was present in 74 bs (86%), transplant glomerulitis in 65 (76%),interstitial fibrosis and tubular atrophy (if/ta) in 71 (83%),thickening of the peritubular capillary (ptc) basement membrane in 72 (84%), and interstitial inflammation in 40 (47%).C4d deposition in the ptc was present in 49 bs (57%); 39 of these 49 bs showed diffuse c4d deposits in the ptc (c4d3),while the remaining 10 bs showed focal deposits (c4d2).Diffuse c4d deposition in the glomerular capillaries (GC) was seen in 70 bs (81%), while focal c4d deposition in the GC was seen in 9 (11%). In the assay using plastic beads coated with HLA antigen performed in 67 serum samples obtained in the peri-biopsy period, circulating ant-HLA alloantibody was detected in 55 (82%); in 33 of the 55 (49%) samples, donor-specific antibodies (DSA) were detected. Among our study, the findings in 22 bs (26%) fully met the criteria for c-AMR in banff '09 classification, including TG, c4d deposition in the ptc and presence of DSA, while those in 27 BS were suspicious of c-AMR. Deterioration of the renal allograft function after the biopsies was seen in 31 patients (62%). We suggest that histopathological changes of transplant glomerulopathy might be accompanied by inflammation of the microvasculature, such as transplant glomerulitis and peritubular capillaritis, thickening of the peritubular capillary basement membrane, and circulating anti-HLA antibodies. C4d deposition in the ptc is not always present in biopsy specimens of TG. Anti-HLA antibody class II, particularly when the antibody was DSA class II, appeared to be associated with the development of TG. The prognosis of grafts exhibiting TG was poor even under the currently used standard triple immunosuppressive regimen.

Fostamatinib in the Treatment of Chronic Active Antibody Mediated Rejection

Fostamatinib in the Treatment of Chronic Active Antibody Mediated Rejection

Treatment with intravenous immunoglobulins and methylprednisolone may significantly decrease loss of renal function in chronic-active antibody-mediated rejection

BackgroundChronic-active antibody mediated rejection (c-aABMR) is a major contributor to long-term kidney allograft loss. We conducted a retrospective analysis to establish the efficacy of treatment with intravenous immunoglobulins (IVIG) and pulse methylprednisolone (MP) of patients with c-aABMR.MethodsSixty-nine patients, in the period 2005–2017, with the diagnosis (suspicious for) c-aABMR that were treated with IVIG and MP were included. Patients were administered three doses of 1 g intravenous MP combined with a single dose of IVIG (1 g/kg body weight). Primary outcome was the decline in allograft function one year post treatment. Responders to IVIG-MP therapy were defined by an eGFR one year after treatment which was at least 25% above the projected allograft function.ResultsPatients showed an average decline in eGFR of 9.8 ml/min/1.73m2 the year prior to treatment. Following treatment, a significant reduction (p < 0.001) in eGFR decline was observed (6.3 ml/min/1.73m2). Furthermore, a significant improvement in proteinuria was observed upon treatment (p < 0.001). Sixty-two percent (n = 43) of the patients were considered a responder and showed considerable slowing of graft function deterioration in the year after treatment (p < 0.001). Three and 5-year graft survival was significantly superior in responders.ConclusionsMore than 60% of patients with c-aABMR with a progressive decline in eGFR respond favorably to treatment with IVIG-MP resulting in a significant improvement of graft survival (Sablik, Am J Transplant 18, 2018).

Everolimus-based Immunosuppression Possibly Suppresses Mean Fluorescence Intensity Values of De Novo Donor-specific Antibodies After Primary Kidney Transplantation

PurposeWe evaluated de novo donor-specific antibody (DSA) production of everolimus (EVR)-based immunosuppression for primary kidney transplant recipients involved in the A1202 study at our institute. MethodsFrom March 2008 to August 2009, 24 recipients were prospectively randomized into 2 groups. The EVR group received reduced cyclosporin A and EVR. The standard protocol (STD) group received standard cyclosporin A and mycophenolate mofetil. Both groups received basiliximab and steroids. De novo DSA was identified using LABScreen single antigen beads (One Lambda, Canoga Park, Calif., United States). Mean fluorescence intensity (MFI) values > 1000 were considered positive. P < .05 was considered significant. ResultsGraft survival was 100% in the EVR group and 90.9% in the STD group. All patients remained on the primary protocol in the EVR group, but 3 patients in the STD group (27.3%) were converted to tacrolimus due to DSA and non-adherence. Estimated glomerular filtration rate was similar in both groups. No EVR group recipients and 9.1% of STD group recipients were treated for T-cell-mediated rejection. No recipients of the EVR group exhibited peritubular capillaritis, while 9.1% in STD group developed chronic active antibody-mediated rejection. LABScreen revealed an accumulative class II DSA production rate of 15.4% in the EVR group and 18.3% in the STD group at 10 years. When the MFI cut-off level was set to 6000, anti-HLA antibody and de novo DSA-free survival was significantly better in the EVR group. ConclusionsEVR-based immunosuppression provided equivalent or even better clinical outcomes. EVR suppressed de novo DSA production at 10 years follow-up; however, further follow-up is inevitable.