Publications
239 results found
Naesens M, Roufosse C, Haas M, et al., 2024, The Banff 2022 Kidney Meeting Report: Reappraisal of microvascular inflammation and the role of biopsy-based transcript diagnostics., Am J Transplant, Vol: 24, Pages: 338-349
The XVI-th Banff Meeting for Allograft Pathology was held at Banff, Alberta, Canada, from 19th to 23rd September 2022, as a joint meeting with the Canadian Society of Transplantation. To mark the 30th anniversary of the first Banff Classification, premeeting discussions were held on the past, present, and future of the Banff Classification. This report is a summary of the meeting highlights that were most important in terms of their effect on the Classification, including discussions around microvascular inflammation and biopsy-based transcript analysis for diagnosis. In a postmeeting survey, agreement was reached on the delineation of the following phenotypes: (1) "Probable antibody-mediated rejection (AMR)," which represents donor-specific antibodies (DSA)-positive cases with some histologic features of AMR but below current thresholds for a definitive AMR diagnosis; and (2) "Microvascular inflammation, DSA-negative and C4d-negative," a phenotype of unclear cause requiring further study, which represents cases with microvascular inflammation not explained by DSA. Although biopsy-based transcript diagnostics are considered promising and remain an integral part of the Banff Classification (limited to diagnosis of AMR), further work needs to be done to agree on the exact classifiers, thresholds, and clinical context of use.
Drachenberg CB, Buettner-Herold M, Aguiar PV, et al., 2024, Banff 2022 pancreas transplantation multidisciplinary report: Refinement of guidelines for T cell-mediated rejection, antibody-mediated rejection and islet pathology. Assessment of duodenal cuff biopsies and noninvasive diagnostic methods., Am J Transplant, Vol: 24, Pages: 362-379
The Banff pancreas working schema for diagnosis and grading of rejection is widely used for treatment guidance and risk stratification in centers that perform pancreas allograft biopsies. Since the last update, various studies have provided additional insight regarding the application of the schema and enhanced our understanding of additional clinicopathologic entities. This update aims to clarify terminology and lesion description for T cell-mediated and antibody-mediated allograft rejections, in both active and chronic forms. In addition, morphologic and immunohistochemical tools are described to help distinguish rejection from nonrejection pathologies. For the first time, a clinicopathologic approach to islet pathology in the early and late posttransplant periods is discussed. This update also includes a discussion and recommendations on the utilization of endoscopic duodenal donor cuff biopsies as surrogates for pancreas biopsies in various clinical settings. Finally, an analysis and recommendations on the use of donor-derived cell-free DNA for monitoring pancreas graft recipients are provided. This multidisciplinary effort assesses the current role of pancreas allograft biopsies and offers practical guidelines that can be helpful to pancreas transplant practitioners as well as experienced pathologists and pathologists in training.
Roufosse C, Naesens M, Haas M, et al., 2024, The Banff 2022 Kidney Meeting Work Plan: Data-driven refinement of the Banff Classification for renal allografts., Am J Transplant, Vol: 24, Pages: 350-361
The XVIth Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from September 19 to 23, 2022, as a joint meeting with the Canadian Society of Transplantation. In addition to a key focus on the impact of microvascular inflammation and biopsy-based transcript analysis on the Banff Classification, further sessions were devoted to other aspects of kidney transplant pathology, in particular T cell-mediated rejection, activity and chronicity indices, digital pathology, xenotransplantation, clinical trials, and surrogate endpoints. Although the output of these sessions has not led to any changes in the classification, the key role of Banff Working Groups in phrasing unanswered questions, and coordinating and disseminating results of investigations addressing these unanswered questions was emphasized. This paper summarizes the key Banff Meeting 2022 sessions not covered in the Banff Kidney Meeting 2022 Report paper and also provides an update on other Banff Working Group activities relevant to kidney allografts.
Santos E, Spensley K, Gunby N, et al., 2024, Application of HLA molecular level mismatching in ethnically diverse kidney transplant recipients receiving a steroid-sparing immunosuppression protocol., Am J Transplant
Defining HLA mismatch at the molecular compared with the antigen level has been shown to be superior in predicting alloimmune responses, although data from across different patient populations are lacking. Using HLA-Matchmaker, HLA-EMMA and PIRCHE-II, this study reports on the association between molecular mismatch (MolMM) and de novo donor-specific antibody (dnDSA) in an ethnically diverse kidney transplant population receiving a steroid-sparing immunosuppression protocol. Of the 419 patients, 51 (12.2%) patients had dnDSA. De novo DSA were seen more frequently with males, primary transplants, patients receiving tacrolimus monotherapy, and unfavorably HLA-matched transplants. There was a strong correlation between MolMM load and antigen mismatch, although significant variation of MolMM load existed at each antigen mismatch. MolMM loads differed significantly by recipient ethnicity, although ethnicity alone was not associated with dnDSA. On multivariate analysis, increasing MolMM loads associated with dnDSA, whereas antigen mismatch did not. De novo DSA against 8 specific epitopes occurred at high frequency; of the 51 patients, 47 (92.1%) patients with dnDSA underwent a pretreatment biopsy, with 21 (44.7%) having evidence of alloimmune injury. MolMM has higher specificity than antigen mismatching at identifying recipients who are at low risk of dnDSA while receiving minimalist immunosuppression. Immunogenicity consideration is important, with more work needed on identification, especially across different ethnic groups.
de Nattes T, Beadle J, Roufosse C, 2024, Biopsy-based transcriptomics in the diagnosis of kidney transplant rejection, Current Opinion in Nephrology and Hypertension, ISSN: 1062-4821
PURPOSE OF REVIEW: The last year has seen considerable progress in translational research exploring the clinical utility of biopsy-based transcriptomics of kidney transplant biopsies to enhance the diagnosis of rejection. This review will summarize recent findings with a focus on different platforms, potential clinical applications, and barriers to clinical adoption. RECENT FINDINGS: Recent literature has focussed on using biopsy-based transcriptomics to improve diagnosis of rejection, in particular antibody-mediated rejection. Different techniques of gene expression analysis (reverse transcriptase quantitative PCR, microarrays, probe-based techniques) have been used either on separate samples with ideally preserved RNA, or on left over tissue from routine biopsy processing. Despite remarkable consistency in overall patterns of gene expression, there is no consensus on acceptable indications, or whether biopsy-based transcriptomics adds significant value at reasonable cost to current diagnostic practice. SUMMARY: Access to biopsy-based transcriptomics will widen as regulatory approvals for platforms and gene expression models develop. Clinicians need more evidence and guidance to inform decisions on how to use precious biopsy samples for biopsy-based transcriptomics, and how to integrate results with standard histology-based diagnosis.
Seneschall C, Law S, Roufosse C, et al., 2024, Tocilizumab (anti-IL-6) treatment for AA renal amyloidosis in a patient with advanced chronic kidney disease, a case report., J Nephrol
Systemic amyloid A amyloidosis is a progressive condition in which sustained elevation of serum amyloid A protein concentration leads to widespread amyloid deposition resulting in multiorgan failure without treatment. The kidney is the most commonly affected organ, and renal amyloid A amyloidosis can cause nephrotic syndrome and chronic kidney disease (CKD) leading to end stage kidney disease (ESKD). Serum Amyloid A protein is produced in the liver in response to chronic inflammation, specifically by inflammatory cytokines, especially IL-6. Tocilizumab, a monoclonal antibody that targets the interleukin-6 receptor, has increasingly been of interest in treating amyloid A amyloidosis. We present a case of a 79-year-old male with long-term seronegative polyarthritis who was referred with gradual decline in kidney function and nephrotic range proteinuria. His renal biopsy showed amyloid A amyloidosis with significant interstitial fibrosis and tubular atrophy. He was commenced on monthly tocilizumab infusions and peritoneal dialysis with good clinical response and rapid resolution of his nephrotic state. This case adds to the current literature on the benefits of tocilizumab in treating amyloid A amyloidosis in patients with advanced CKD.
Chauveau B, Gibier J-B, Olagne J, et al., 2024, Atypical Anti-Glomerular Basement Membrane Nephritis: A Case Series From the French Nephropathology Group., Am J Kidney Dis
RATIONALE & OBJECTIVE: Atypical anti-glomerular basement membrane (GBM) nephritis is characterized by a bright linear immunoglobulin staining along the GBM by immunofluorescence without a diffuse crescentic glomerulonephritis nor serum anti-GBM antibodies by conventional enzyme-linked immunosorbent assay (ELISA). We characterized a series of patients with atypical anti-GBM disease. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Patients identified by the French Nephropathology Group as having atypical anti-GBM nephritis between 2003 and 2022. FINDINGS: Among 38 potential cases, 25 were included, of whom 14 (56%) were female and 23 (92%) had hematuria. The median serum creatinine at diagnosis was 150 (IQR, 102-203) μmol/L and median urine protein-creatinine ratio (UPCR) was 2.4 (IQR, 1.3-5.2) g/g. Nine patients (36%) had endocapillary proliferative glomerulonephritis (GN), 4 (16%) had mesangial proliferative GN, 4 (16%) had membranoproliferative GN, 2 (8%) had pure and focal crescentic GN, 1 (4%) had focal segmental glomerulosclerosis, and 5 had glomeruli that were unremarkable on histopathology. Nine patients (36%) had crescents, involving a median of 9% of glomeruli. Bright linear staining for IgG was seen in 22 cases (88%) and for IgA in 3 cases (12%). The 9 patients (38%) who had a monotypic staining pattern tended to be older with less proteinuria and rarely had crescents. Kidney survival rate at 1 year was 83% and did not appear to be associated with the light chain restriction. LIMITATIONS: Retrospective case series with a limited number of biopsies including electron microscopy. CONCLUSIONS: Compared with typical anti-GBM disease, atypical anti-GBM nephritis frequently presents with an endocapillary or mesangial proliferative glomerulonephritis pattern and appears to have a slower disease progression. Further studies are needed to fully characterize its pathophysiology and associated clinical outcomes. PLAIN-LANGUAGE SUMMARY: Atypical
Cechnicka S, Ball J, Reynaud H, et al., 2024, Realistic Data Enrichment for Robust Image Segmentation in Histopathology, Pages: 63-72, ISSN: 0302-9743
Poor performance of quantitative analysis in histopathological Whole Slide Images (WSI) has been a significant obstacle in clinical practice. Annotating large-scale WSIs manually is a demanding and time-consuming task, unlikely to yield the expected results when used for fully supervised learning systems. Rarely observed disease patterns and large differences in object scales are difficult to model through conventional patient intake. Prior methods either fall back to direct disease classification, which only requires learning a few factors per image, or report on average image segmentation performance, which is highly biased towards majority observations. Geometric image augmentation is commonly used to improve robustness for average case predictions and to enrich limited datasets. So far no method provided sampling of a realistic posterior distribution to improve stability, e.g. for the segmentation of imbalanced objects within images. Therefore, we propose a new approach, based on diffusion models, which can enrich an imbalanced dataset with plausible examples from underrepresented groups by conditioning on segmentation maps. Our method can simply expand limited clinical datasets making them suitable to train machine learning pipelines, and provides an interpretable and human-controllable way of generating histopathology images that are indistinguishable from real ones to human experts. We validate our findings on two datasets, one from the public domain and one from a Kidney Transplant study. 1 (The source code and trained models will be publicly available at the time of the conference, on huggingface and github. )
Tam FWK, Tumlin J, Barratt J, et al., 2023, Randomized trial on the effect of an oral spleen tyrosine kinase inhibitor in the treatment of IgA nephropathy, Kidney International Reports, Vol: 8, Pages: 2546-2556, ISSN: 2468-0249
IntroductionWe reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells.MethodsThis study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors. The primary end point was reduction of proteinuria. Secondary end points included change from baseline in estimated glomerular filtration rate (eGFR) and kidney histology.ResultsAlthough we could not detect significant reduction in proteinuria with fostamatinib overall, in a predetermined subgroup analysis, there was a trend for dose-dependent reduction in median proteinuria (from baseline to 24 weeks by 14%, 27%, and 36% in the placebo, fostamatinib 100 mg, and 150 mg groups, respectively) in patients with baseline urinary protein-to-creatinine ratios (UPCR) more than 1000 mg/g. Kidney function (eGFR) remained stable in all groups. Fostamatinib was well-tolerated. Side effects included diarrhea, hypertension, and increased liver enzymes. Thirty-nine patients underwent repeat biopsy showing reductions in SYK staining associated with therapy at low dose (−1.5 vs. 1.7 SYK+ cells/glomerulus in the placebo group, P < 0.05).ConclusionsThere was a trend toward reduction in proteinuria with fostamatinib in a predefined analysis of high risk patients with IgAN despite maximal care, as defined by baseline UPCR greater than 1000 mg/g. Further study may be warranted.
Kousios A, Blakey S, Moran L, et al., 2023, Non-crystalline light chain proximal tubulopathy, a morphologically protean entity., Nephrology Dialysis Transplantation, Vol: 38, Pages: 2576-2588, ISSN: 0931-0509
BACKGROUND: Light chain proximal tubulopathy (LCPT) is a rare form of paraprotein-related disease, occurring in two main histopathological forms; crystalline and non-crystalline. The clinicopathological features, treatment strategies and outcomes, especially of the non-crystalline form, are not well described. METHODS: Single-centre retrospective case series of 12 LCPT patients, 5 crystalline and 7 non-crystalline, between 2005-2021. OBSERVATIONS: Median age was 69.5 years (range, 47-80). 10 patients presented with CKD and significant proteinuria (median eGFR of 43.5 ml/min/1.73m2; uPCR 328 mg/mmol). Only 6 patients had known haematological disease at the time of renal biopsy. Multiple myeloma (MM) was diagnosed in 7 cases and MGRS in 5. A clone was detected in all cases combining serum/urine electrophoresis and free LC assays. Crystalline and non-crystalline variants had similar clinical presentations. For the non-crystalline variant, a diagnosis was reached based on combination of CKD without other cause, haematological work-up, LC restriction on IF and abnormalities on EM. Nine of 12 patients received clone-directed treatment. Patients who achieved haematological response (including all non-crystalline LCPT) had improved renal outcomes over a median follow-up of 79 months. CONCLUSIONS: The non-crystalline variant may go unrecognised because of its subtle histopathological features and requires EM to distinguish it from "excessive LC resorption without tubular injury". Clone-directed treatment with good haematological response improves renal outcomes in both variants but limited data exist in MGRS. Multi-centre prospective studies are needed to better define the clinico-pathological characteristics associated with poor outcomes and optimize treatment strategies in patients with MGRS.
Van Loon E, Callemeyn J, Roufosse C, 2023, Automating kidney transplant rejection diagnosis: a simple solution for a complex problem?, Clin Kidney J, Vol: 16, Pages: 1720-1722, ISSN: 2048-8505
Lightley J, Kumar S, Lim MQ, et al., 2023, <i>openFrame</i>: A modular, sustainable, open microscopy platform with single-shot, dual-axis optical autofocus module providing high precision and long range of operation, JOURNAL OF MICROSCOPY, ISSN: 0022-2720
Beadle J, Papadaki A, Toulza F, et al., 2023, Application of the Banff Human Organ Transplant Panel to kidney transplant biopsies with features suspicious for antibody-mediated rejection, Kidney International, Vol: 104, Pages: 526-541, ISSN: 0085-2538
The Banff Classification for Allograft Pathology includes the use of gene expression in the diagnosis of antibody-mediated rejection (AMR) of kidney transplants, but a predictive set of genes for classifying biopsies with 'incomplete' phenotypes has not yet been studied. Here, we developed and assessed a gene score that, when applied to biopsies with features of AMR, would identify cases with a higher risk of allograft loss. To do this, RNA was extracted from a continuous retrospective cohort of 349 biopsies randomized 2:1 to include 220 biopsies in a discovery cohort and 129 biopsies in a validation cohort. The biopsies were divided into three groups: 31 that fulfilled the 2019 Banff Criteria for active AMR, 50 with histological features of AMR but not meeting the full criteria (Suspicious-AMR), and 269 with no features of active AMR (No-AMR). Gene expression analysis using the 770 gene Banff Human Organ Transplant NanoString panel was carried out with LASSO Regression performed to identify a parsimonious set of genes predictive of AMR. We identified a nine gene score that was highly predictive of active AMR (accuracy 0.92 in the validation cohort) and was strongly correlated with histological features of AMR. In biopsies suspicious for AMR, our gene score was strongly associated with risk of allograft loss and independently associated with allograft loss in multivariable analysis. Thus, we show that a gene expression signature in kidney allograft biopsy samples can help classify biopsies with incomplete AMR phenotypes into groups that correlate strongly with histological features and outcomes.
Jones BP, Vali S, Saso S, et al., 2023, Living donor uterus transplant in the UK: A case report, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, ISSN: 1470-0328
Gama R, Murphy E, Salisbury J, et al., 2023, A rare case of nephrotic syndrome and Tangier disease, CEN CASE REPORTS, Vol: 12, Pages: 265-269, ISSN: 2192-4449
Whittington AM, Turner FS, Baark F, et al., 2023, An acidic microenvironment in Tuberculosis increases extracellular matrix degradation by regulating macrophage inflammatory responses, PLoS Pathogens, Vol: 19, Pages: 1-25, ISSN: 1553-7366
Mycobacterium tuberculosis (M.tb) infection causes marked tissue inflammation leading to lung destruction and morbidity. The inflammatory extracellular microenvironment is acidic, however the effect of this acidosis on the immune response to M.tb is unknown. Using RNA-seq we show that acidosis produces system level transcriptional change in M.tb infected human macrophages regulating almost 4000 genes. Acidosis specifically upregulated extracellular matrix (ECM) degradation pathways with increased expression of Matrix metalloproteinases (MMPs) which mediate lung destruction in Tuberculosis. Macrophage MMP-1 and -3 secretion was increased by acidosis in a cellular model. Acidosis markedly suppresses several cytokines central to control of M.tb infection including TNF-α and IFN-γ. Murine studies demonstrated expression of known acidosis signaling G-protein coupled receptors OGR-1 and TDAG-8 in Tuberculosis which are shown to mediate the immune effects of decreased pH. Receptors were then demonstrated to be expressed in patients with TB lymphadenitis. Collectively, our findings show that an acidic microenvironment modulates immune function to reduce protective inflammatory responses and increase extracellular matrix degradation in Tuberculosis. Acidosis receptors are therefore potential targets for host directed therapy in patients.
Santos E, Spensley K, Gunby N, et al., 2023, Steroid sparing maintenance immunosuppression in highly sensitised patients receiving Alemtuzumab induction, Transplant International, Vol: 36, Pages: 1-11, ISSN: 0934-0874
This analysis reports on the outcomes of two different steroid sparing immunosuppression protocols used in the management of 120 highly sensitised patients (HSPs) with cRF>85% receiving Alemtuzumab induction, 53 maintained on tacrolimus (FK) monotherapy and 67 tacrolimus plus mycophenolate mofetil (FK+MMF). There was no difference in the median cRF or mode ofsensitisation between the 2 groups, although the FK+MMF cohort received more poorly matched grafts. There was no difference in one-year patient or allograft survival, however rejection free survival was inferior with FK monotherapy compared with FK+MMF at 65.4% and 91.4% respectively, p<0.01. DSA-free survival was comparable. Whilst there was no difference in rates of BK between the cohorts, CMV-free survival was inferior in the FK+MMF group at 86.0% compared with 98.1% in the FK group, p=0.026. One-year post-transplant diabetes free survival was 89.6% and 100.0% in the FK and FK+MMF group respectively, p=0.027, thedifference attributed to the use of prednisolone to treat rejection in the FK cohort, p=0.006. We report good outcomes in HSPs utilising a steroid sparing protocol with Alemtuzumab induction and FK+MMF maintenance and provide granular data on immunological and infectious complications to inform steroid avoidance in these patient groups.
Gleeson S, Beadle J, Moran L, et al., 2023, TUBULORETICULAR INCLUSIONS: A NEW PROGNOSTIC BIOMARKER IN KIDNEY TRANSPLANTATION, 60th ERA Congress, Publisher: OXFORD UNIV PRESS, Pages: I171-I171, ISSN: 0931-0509
Drachenberg CB, Büttner-Herold M, Ventura-Aguiar P, et al., 2023, Banff 2022 Pancreas Transplantation Multidisciplinary Report: Refinement of Guidelines for TCMR, AMR, Islet and Non-Rejection Pathologies. Assessment of Duodenal Cuff Biopsies and Non-Invasive Diagnostic Methods
de Nattes T, Beadle J, Toulza F, et al., 2023, A Simple Molecular Tool for the Assessment of Kidney Transplant Biopsies, CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 18, Pages: 499-509, ISSN: 1555-9041
Jesuthasan A, Roufosse C, Ramaswami A, 2023, Biopsy-proven fungal pyelonephritis complicating delayed graft function in a renal transplant patient, BMJ CASE REPORTS, Vol: 16
Prendecki M, Gulati K, Pisacano N, et al., 2023, Syk activation in circulating and tissue innate immune cells in antineutrophil cytoplasmic antibody-associated vasculitis, Arthritis and Rheumatology, Vol: 75, Pages: 84-97, ISSN: 2326-5205
OBJECTIVE: Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG-mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA-induced myeloid cell activation and vasculitis pathogenesis. METHODS: Phosphorylation of Syk in myeloid cells from healthy controls and ANCA-associated vasculitis (AAV) patients was analyzed using flow cytometry. The effect of Syk inhibition on myeloperoxidase (MPO)-ANCA IgG activation of cells was investigated using functional assays (interleukin-8 and reactive oxygen species production) and targeted gene analysis with NanoString. Total and phosphorylated Syk at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridization. RESULTS: We identified increased phosphorylated Syk at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to patients with disease in remission or healthy controls. Syk was phosphorylated in vitro following MPO-ANCA IgG stimulation, and Syk inhibition was able to prevent ANCA-mediated cellular responses. Using targeted gene expression analysis, we identified up-regulation of FcR- and Syk-dependent signaling pathways following MPO-ANCA IgG stimulation. Finally, we showed that Syk is expressed and phosphorylated in tissue leukocytes at sites of organ inflammation in AAV. CONCLUSION: These findings indicate that Syk plays a critical role in MPO-ANCA IgG-induced myeloid cell responses and that Syk is activated in circulating immune cells and tissue immune cells in AAV; therefore, Syk inhibition may be a potential therapeutic option.
Toulza F, Santos E, Spensley K, et al., 2022, Histological findings in a prospective cohort of transplant patients with screening for development of donor-specific antibodies, Publisher: SPRINGER, Pages: S310-S311, ISSN: 0945-6317
Roufosse C, Cook H, Dominy K, et al., 2022, Diagnostic application of transcripts associated with antibody-mediated rejection in kidney transplant biopsies, Nephrology Dialysis Transplantation, Vol: 37, Pages: 1576-1584, ISSN: 0931-0509
BackgroundThe diagnosis of antibody-mediated rejection (AMR) is reached using the Banff Classification for Allograft Pathology, which now includes gene expression analysis. In this study, we investigate the application of “Increased Expression Of Thoroughly Validated Gene Transcripts/Classifiers Strongly Associated With AMR” as a diagnostic criteria.MethodWe used qRT-PCR for 10 genes associated with AMR in a retrospective cohort of 297 transplant biopsies, including biopsies that met the full diagnostic criteria for AMR, even without molecular data (AMR, n = 27); biopsies that showed features of AMR, but that would only meet criteria for AMR with increased transcripts (AMRsusp, n = 49) and biopsies that would never meet criteria for AMR (No-AMR, n = 221).ResultsA 10-gene AMR score trained by a receiver-operating characteristic to identify AMR found 16 cases with a high score amongst the AMRsusp cases (AMRsusp-high) that had significantly worse graft survival than those with a low score (AMRsusp-low) (n = 33). In both univariate and multivariate Cox regression analysis, the AMR 10-gene score was significantly associated with an increased hazard ratio for graft loss in the AMRsusp group (HR 1.109, p = 0.004 and HR 1.138, p = 0.012), but not in the whole cohort. Net reclassification index and integrated discrimination improvement analyses demonstrated improved risk classification and superior discrimination respectively for graft loss when considering the gene score in addition to histological and serological data, but only in the AMRsusp group, not the whole cohort.ConclusionsThis study provides evidence that a gene score strongly associated with AMR helps identify cases at higher risk of graft loss in biopsies that are suspicious for AMR but don’t meet full criteria.
Aguiar R, Bourmpaki E, Bunce C, et al., 2022, Incidence, risk factors, and effect on allograft survival of glomerulonephritis post-transplantation in a United Kingdom population: cohort study, Frontiers in Nephrology, Vol: 2, Pages: 1-11, ISSN: 2813-0626
BACKGROUND: Post-transplant glomerulonephritis (PTGN) has been associated with inferior long-term allograft survival, and its incidence varies widely in the literature. METHODS: This is a cohort study of 7,623 patients transplanted between 2005 and 2016 at four major transplant UK centres. The diagnosis of glomerulonephritis (GN) in the allograft was extracted from histology reports aided by the use of text-mining software. The incidence of the four most common GN post-transplantation was calculated, and the risk factors for disease and allograft outcomes were analyzed. RESULTS: In total, 214 patients (2.8%) presented with PTGN. IgA nephropathy (IgAN), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and membranoproliferative/mesangiocapillary GN (MPGN/MCGN) were the four most common forms of post-transplant GN. Living donation, HLA DR match, mixed race, and other ethnic minority groups were associated with an increased risk of developing a PTGN. Patients with PTGN showed a similar allograft survival to those without in the first 8 years of post-transplantation, but the results suggest that they do less well after that timepoint. IgAN was associated with the best allograft survival and FSGS with the worst allograft survival. CONCLUSIONS: PTGN has an important impact on long-term allograft survival. Significant challenges can be encountered when attempting to analyze large-scale data involving unstructured or complex data points, and the use of computational analysis can assist.
Seron D, Rabant M, Becker JU, et al., 2022, Proposed Definitions of T Cell-Mediated Rejection and Tubulointerstitial Inflammation as Clinical Trial Endpoints in Kidney Transplantation, TRANSPLANT INTERNATIONAL, Vol: 35, ISSN: 0934-0874
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Roufosse C, Becker JU, Rabant M, et al., 2022, Proposed Definitions of Antibody-Mediated Rejection for Use as a Clinical Trial Endpoint in Kidney Transplantation, TRANSPLANT INTERNATIONAL, Vol: 35, ISSN: 0934-0874
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Becker JU, Seron D, Rabant M, et al., 2022, Evolution of the Definition of Rejection in Kidney Transplantation and Its Use as an Endpoint in Clinical Trials, TRANSPLANT INTERNATIONAL, Vol: 35, ISSN: 0934-0874
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Gray-Rodriguez S, Jensen M, Otero-Jimenez M, et al., 2022, Detection of SARS-CoV-2 within enteric neurons and in brain, Publisher: WILEY, ISSN: 0305-1846
Tempest-Roe S, Prendecki M, McAdoo S, et al., 2022, Inhibition of spleen tyrosine kinase decreases donor specific antibody levels in a rat model of sensitization, Scientific Reports, Vol: 12, ISSN: 2045-2322
Antibody mediated rejection is a major cause of renal allograft loss. Circulating preformed donor specific antibodies (DSA) can result as a consequence of blood transfusion, pregnancy or prior transplantation. Current treatment strategies are limited due to partial or transient efficacy, adverse side-effects or patient unsuitability. Previous in vivo studies exploring autoimmune diseases have shown that spleen tyrosine kinase (SYK) signalling is involved in the development of pathogenic autoantibody. The role of SYK in allogenic antibody production is unknown, and we investigated this in a rodent model of sensitization, established by the transfusion of F344 whole blood into LEW rats. Two-week treatment of sensitized rats with selective SYK inhibitor fostamatinib strongly blocked circulating DSA production without affecting overall total immunoglobulin levels, and inhibition was sustained up to 5 weeks post-completion of the treatment regimen. Fostamatinib treatment did not affect mature B cell subset or plasma cell levels, which remained similar between non-treated controls, vehicle treated and fostamatinib treated animals. Our data indicate fostamatinib may provide an alternative therapeutic option for patients who are at risk of sensitization following blood transfusion while awaiting renal transplant.
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