Modest Improvements in Refractory Antibody-Mediated Rejection After Prolonged Treatment.
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ABSTRACT:
SUBMITTER: Degner KR
PROVIDER: S-EPMC8116765 | biostudies-literature | 2021 May
REPOSITORIES: biostudies-literature
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Modest Improvements in Refractory Antibody-Mediated Rejection After Prolonged Treatment.
Degner Kenna R KR Parajuli Sandesh S Aziz Fahad F Garg Neetika N Mohamed Maha M Mandelbrot Didier A DA Panzer Sarah E SE Wilson Nancy A NA Reese Shannon R SR Van Hyfte Kristin K Zhong Weixiong W Hidalgo Luis G LG Nickerson Peter P Djamali Arjang A
Kidney international reports 20210223 5
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Project description:Purpose of reviewAntibody-mediated rejection (AMR) has emerged as the leading cause of late graft loss in kidney transplant recipients. Donor-specific antibodies are an independent risk factor for AMR and graft loss. However, not all donor-specific antibodies are pathogenic. AMR treatment is heterogeneous due to the lack of robust trials to support clinical decisions. This review provides an overview and comments on practical but relevant dilemmas physicians experience in managing kidney transplant recipients with AMR.Recent findingsActive AMR with donor-specific antibodies may be treated with plasmapheresis, intravenous immunoglobulin and corticosteroids with additional therapies considered on a case-by-case basis. On the contrary, no treatment has been shown to be effective against chronic active AMR. Various biomarkers and prediction models to assess the individual risk of graft failure and response to rejection treatment show promise.SummaryThe ability to personalize management for a given kidney transplant recipient and identify treatments that will improve their long-term outcome remains a critical unmet need. Earlier identification of AMR with noninvasive biomarkers and prediction models to assess the individual risk of graft failure should be considered. Enrolling patients with AMR in clinical trials to assess novel therapeutic agents is highly encouraged.
| S-EPMC9475491 | biostudies-literature
Project description:Tocilizumab (TCZ), an IL-6 inhibitor, has shown promise in the treatment of donor-specific antibodies (DSA) and chronic antibody-mediated rejection (AMR) in renal transplant recipients. However, its use in lung transplantation has not been described. This retrospective case-control study compared AMR treatments containing TCZ in 9 bilateral lung transplant recipients to 18 patients treated for AMR without TCZ. Treatment with TCZ resulted in more clearance of DSA, lower recurrence of DSA, lower incidence of new DSA, and lower rates of graft failure when compared to those treated for AMR without TCZ. The incidence of infusion reactions, elevation in transaminases, and infections were similar between the 2 groups. These data support a role for TCZ in pulmonary AMR and establish preliminary evidence to design a randomized controlled trial of IL-6 inhibition for the management of AMR.
| S-EPMC10529998 | biostudies-literature
Project description:BackgroundTreatment options for antibody-mediated rejection (AMR) are limited. Recent studies have shown that inhibition of interleukin-6 (IL-6)/interleukin-6 receptor (IL-6R) signaling can reduce inflammation and slow AMR progression.MethodsWe report our experience using monthly tocilizumab (anti-IL6R) in 25 pediatric renal transplant recipients with AMR, refractory to IVIg/Rituximab. From January 2013 to June 2019, a median (IQR) of 12 (6.019.0) doses of tocilizumab were given per patient. Serial assessments of renal function, biopsy findings, and HLA DSA (by immunodominant HLA DSA [iDSA] and relative intensity score [RIS]) were performed.ResultsMedian (IQR) time from transplant to AMR was 41.4 (24.367.7) months, and time from AMR to first tocilizumab was 10.6 (8.317.6) months. At median (IQR) follow up of 15.8 (8.435.7) months post-tocilizumab initiation, renal function was stable except for 1 allograft loss. There was no significant decrease in iDSA or RIS. Follow up biopsies showed reduction in peritubular capillaritis (p = .015) and C4d scoring (p = .009). The most frequent adverse events were cytopenias.ConclusionsTocilizumab in pediatric patients with refractory AMR was well tolerated and appeared to stabilize renal function. The utility of tocilizumab in the treatment of AMR in this population should be further explored.
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Project description:Background and objectivesActive antibody-mediated rejection is the main cause of kidney transplant loss, sharing with SLE the alloimmune response and the systemic activation of the IFN-α pathway. IgE-mediated immune response plays a key role in the development of SLE nephritis and is associated with IFN-α secretion. The aim of our study was to investigate IgE-mediated immune response in antibody-mediated rejection.Design, setting, participants, & measurementsThis was a cross-sectional study of 56 biopsy-proven antibody-mediated rejection study participants, 80 recipients with normal graft function/histology (control), 16 study participants with interstitial fibrosis/tubular atrophy, and six participants with SLE. We evaluated graft IgE deposition, tryptase (a mast cell marker), and CD203 (a specific marker of activated basophils) by immunofluorescence/confocal microscopy. In addition, we measured serum concentration of human myxovirus resistance protein 1, an IFN-α-induced protein, and anti-HLA IgE.ResultsWe observed a significantly higher IgE deposition in tubules and glomeruli in antibody-mediated rejection (1766±79 pixels) and SLE (1495±43 pixels) compared with interstitial fibrosis/tubular atrophy (582±122 pixels) and control (253±50 pixels). Patients with antibody-mediated rejection, but not control patients and patients with interstitial fibrosis/tubular atrophy, presented circulating anti-HLA IgE antibodies, although with a low mean fluorescence intensity. In addition, immunofluorescence revealed the presence of both mast cells and activated basophils in antibody-mediated rejection but not in control and interstitial fibrosis/tubular atrophy. The concentration of circulating basophils was significantly higher in antibody-mediated rejection compared with control and interstitial fibrosis/tubular atrophy. MxA serum levels were significantly higher in antibody-mediated rejection compared with control and correlated with the extent of IgE deposition.ConclusionsOur data suggest that IgE deposition and the subsequent recruitment of basophils and mast cells within the kidney transplant might play a role in antibody-mediated rejection.
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Project description:ObjectiveThis study aims to assess the efficacy of pharmacological interventions in mitigating graft injury in transplant patients with antibody-mediated rejection (AMR) through a network meta-analysis (NMA).MethodsA search was conducted on databases such as Cochrane Library, PubMed, EmBase, and Web of Science for randomized controlled trials (RCTs) on pharmacological interventions for alleviating graft injury following AMR. The search was performed for publications up to April 12, 2024. Two reviewers conducted independent reviews of the literature, extracted data, and assessed the risk of bias (ROB) in the included studies using the ROB assessment tool recommended by the Cochrane Handbook for Systematic Reviews of Interventions 5.1.0. A Bayesian NMA was conducted using R 4.4.0, RStudio software, and the GeMTC package to assess the outcomes in estimated glomerular filtration rate (eGFR), mean fluorescence intensity (MFI), g-score, and infection under pharmacological treatments.ResultsA total of 8 RCTs involving 215 patients and 6 different pharmacological treatments were included in this NMA. The results indicated that the increase in eGFR by eculizumab (SUCRA score: 81) appeared to be more promising. The decrease in MFI by bortezomib (SUCRA score: 72.3), rituximab (SUCRA score: 68.2), and clazakizumab (SUCRA score: 67.1) demonstrated better efficacy. The decrease in g-score by eculizumab (SUCRA score: 74.3), clazakizumab (SUCRA score: 72.2), and C1INH (SUCRA score: 63.6) appeared to have more likelihood. For infection reduction, clazakizumab (SUCRA score: 83.5) and bortezomib (SUCRA score: 66.8) might be better choices.ConclusionThe results of this study indicate that eculizumab has the potential to enhance eGFR and reduce g-score. Bortezomib demonstrates superior efficacy in reducing MFI. Clazakizumab appears to be more effective in reducing infections.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42024546483.
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Project description:Data supporting the use of carfilzomib (CFZ) for treatment of antibody-mediated rejection (AMR) in lung transplantation in combination with plasmapheresis and intravenous immunoglobulin suggest positive outcomes through donor-specific antibody (DSA) depletion or conversion to noncomplement-activating antibodies. Herein, we describe our center's experience treating AMR with CFZ.MethodsAll patients treated with CFZ for AMR from 2014 to 2019 were included. The primary outcome was a positive response to CFZ was defined as: (1) loss of DSA C1q-fixing ability after last CFZ dose; (2) clearance of de novo DSA; or (3) decrease in de novo DSA mean fluorescence intensity of >3000.ResultsTwenty-eight patients with 31 AMR episodes were treated with CFZ. A positive response was observed in 74.4% of AMR episodes and 82.1% of patients. This response was driven by loss of complement 1q fixation (70.6%), elimination of class I DSAs (78.6%), and reduction in both classes I (median 2815, 79.5% reduction from baseline) and II DSA mean fluorescence intensity (3171, 37.1%).ConclusionsCFZ shows potential for ameliorating AMR; however, additional studies are needed to define optimal time of administration.
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Project description:BackgroundChronic active antibody-mediated rejection (c-aABMR) is an important cause of allograft failure and graft loss in long-term kidney transplants.MethodsTo determine the efficacy and safety of combined therapy with rituximab, plasma exchange (PE) and intravenous immunoglobulins (IVIG), a cohort of patients with transplant glomerulopathy (TG) that met criteria of active cABMR, according to BANFF'17 classification, was identified.ResultsWe identified 62 patients with active c-aABMR and TG (cg ≥ 1). Twenty-three patients were treated with the combination therapy and, 39 patients did not receive treatment and were considered the control group. There were no significant differences in the graft survival between the two groups. The number of graft losses at 12 and 24 months and the decline of eGFR were not different and independent of the treatment. A decrease of eGFR≥13 ml/min between 6 months before and c-aABMR diagnosis, was an independent risk factor for graft loss at 24 months (OR = 5; P = 0.01). Infections that required hospitalization during the first year after c-aABMR diagnosis were significantly more frequent in treated patients (OR = 4.22; P = 0.013), with a ratio infection/patient-year of 0.65 and 0.20 respectively.ConclusionsTreatment with rituximab, PE, and IVIG in kidney transplants with c-aABMR did not improve graft survival and was associated with a significant increase in severe infectious complications.Trial registrationAgencia Española de Medicametos y Productos Sanitarios (AEMPS): 14566/RG 24161. Study code: UTR-INM-2017-01.
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Project description:Recent developments in intensive desensitization protocols have enabled kidney transplantation in human leukocyte antigen (HLA)-sensitized recipients. However, cases of active antibody-mediated rejection (AABMR), when they occur, are difficult to manage, graft failure being the worst-case scenario. We aimed to assess the impact of our desensitization and AABMR treatment regimen and identify risk factors for disease progression. Among 849 patients who underwent living-donor kidney transplantation between 2014 and 2021 at our institution, 59 were diagnosed with AABMR within 1 year after transplantation. All patients received combination therapy consisting of steroid pulse therapy, intravenous immunoglobulin, rituximab, and plasmapheresis. Multivariable analysis revealed unrelated donors and preformed donor-specific antibodies as independent risk factors for AABMR. Five-year death-censored graft survival rate was not significantly different between patients with and without AABMR although 27 of 59 patients with AABMR developed chronic AABMR (CABMR) during the study period. Multivariate Cox proportional hazard regression analysis revealed that a donor age greater than 59 years and microvascular inflammation (MVI) score (g + ptc) ≥4 at AABMR diagnosis were independent risk factors for CABMR. Our combination therapy ameliorated AABMR; however, further treatment options should be considered to prevent CABMR, especially in patients with old donors and severe MVI.
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