Publications
225 results found
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
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.
Kousios A, Blakey S, Moran L, et al., 2023, Non-crystalline light chain proximal tubulopathy, a morphologically protean entity., Nephrology Dialysis Transplantation, 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.
de Nattes T, Beadle J, Toulza F, et al., 2023, A Simple Molecular Tool for the Assessment of Kidney Transplant Biopsies., Clin J Am Soc Nephrol, Vol: 18, Pages: 499-509
BACKGROUND: The Banff Classification for Allograft Pathology recommendations for the diagnosis of kidney transplant rejection includes molecular assessment of the transplant biopsy. However, implementation of molecular tools in clinical practice is still limited, partly due to the required expertise and financial investment. The reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) assay is a simple, rapid, and inexpensive assay that permits simultaneous evaluation of a restricted gene panel using paraffin-embedded tissue blocks. The aim of this study was to develop and validate a RT-MLPA assay for diagnosis and classification of rejection. METHODS: A retrospective cohort of 220 kidney transplant biopsies from two centers, which included 52 antibody-mediated rejection, 51 T-cell-mediated rejection, and 117 no-rejection controls, was assessed. A 17-gene panel was identified on the basis of relevant pathophysiological pathways. A support vector machine classifier was developed. A subset of 109 biopsies was also assessed using the Nanostring Banff Human Organ Transplant panel to compare the two assays. RESULTS: The support vector machine classifier train and test accuracy scores were 0.84 and 0.83, respectively. In the test cohort, the F1 score for antibody-mediated rejection, T-cell-mediated rejection, and control were 0.88, 0.86, and 0.69, respectively. Using receiver-operating characteristic curves, the area under the curve for class predictions was 0.96, 0.89, and 0.91, respectively, with a weighted average at 0.94. Classifiers' performances were highest for antibody-mediated rejection diagnosis with 94% correct predictions, compared with 88% correct predictions for control biopsies and 60% for T-cell-mediated rejection biopsies. Gene expression levels assessed by RT-MLPA and Nanostring were correlated: r = 0.68, P < 0.001. Equivalent gene expression profiles were obtained with both assays in 81% of the samples. CONCLUSIONS: The 17-gen
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.
Gama R, Murphy E, Salisbury J, et al., 2022, A rare case of nephrotic syndrome and Tangier disease, CEN CASE REPORTS, ISSN: 2192-4449
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.
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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- Citations: 3
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.
Gray-Rodriguez S, Jensen MP, Otero-Jimenez M, et al., 2022, Multisystem screening reveals SARS-CoV-2 in neurons of the myenteric plexus and in megakaryocytes, Journal of Pathology, Vol: 257, ISSN: 0022-3417
SARS-CoV-2, the causative agent of COVID-19, typically manifests as a respiratory illness although extrapulmonary involvement, such as in the gastrointestinal tract and nervous system, as well as frequent thrombotic events, are increasingly recognised. How this maps onto SARS-CoV-2 organ tropism at the histological level, however, remains unclear. Here, we perform a comprehensive validation of a monoclonal antibody against the SARS-CoV-2 nucleocapsid protein (NP) followed by systematic multisystem organ immunohistochemistry analysis of the viral cellular tropism in tissue from 36 patients, 16 post-mortem cases and 16 biopsies with polymerase chain reaction (PCR)-confirmed SARS-CoV-2 status from the peaks of the pandemic in 2020 and four pre-COVID post-mortem controls. SARS-CoV-2 anti-NP staining in the post-mortem cases revealed broad multiorgan involvement of the respiratory, digestive, haematopoietic, genitourinary and nervous systems, with a typical pattern of staining characterised by punctate paranuclear and apical cytoplasmic labelling. The average time from symptom onset to time of death was shorter in positively versus negatively stained post-mortem cases (mean = 10.3 days versus mean = 20.3 days, p = 0.0416, with no cases showing definitive staining if the interval exceeded 15 days). One striking finding was the widespread presence of SARS-CoV-2 NP in neurons of the myenteric plexus, a site of high ACE-2 expression, the entry receptor for SARS-CoV-2, and one of the earliest affected cells in Parkinson's disease. In the bone marrow, we observed viral SARS-CoV-2 NP within megakaryocytes, key cells in platelet production and thrombus formation. In 15 tracheal biopsies performed in patients requiring ventilation, there was a near complete concordance between immunohistochemistry and PCR swab results. Going forward, our findings have relevance to correlating clinical symptoms to the organ tropism of
Dodd P, Roufosse C, Harber M, 2022, Renal Transplant Rejection, Primer on Nephrology, Second Edition, Pages: 1589-1604, ISBN: 9783030764180
Once the technical difficulties of surgical implantation were overcome, live donor transplants between HLA-identical twins demonstrated not only that renal transplantation was feasible but effectively a “wonder cure”. However, when transplants were attempted across blood group or HLA mismatches, especially in the setting of sensitization with preformed antibodies, the immune response to the transplant became the principle barrier to success. Initial attempts at controlling the immune response relied on massive doses of steroids and were associated with severe side effects as well as very poor graft and patient survival. Over the following half a century, the development of tissue-typing as well as identification and quantification of donor-specific antibodies has eliminated hyper-acute rejection and dramatically reduced unanticipated accelerated rejection. In parallel the development of induction agents and more powerful, less toxic, maintenance immunosuppression has dramatically reduced acute rejection rates from >50% to single figures in units that use lymphocyte depleting antibodies as induction agents. However, while acute rejection rates have fallen, rejection remains a critical issue in transplantation. Despite modern immunosuppression, acute rejection remains a significant cause of graft dysfunction and premature failure, and chronic rejection is now recognized as the commonest cause of graft loss. Yet infection and malignancy related to immunosuppression administered to prevent or treat rejection are important causes of death. Preventing both over and under immunosuppression often requires individualized treatment and care with careful attention to the risks of both.
Arturs C, Roufosse C, 2021, Forging the tools for a computer-aided workflow in transplant pathology, LANCET DIGITAL HEALTH, Vol: 4, Pages: E2-E3
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Aguiar PV, Ramirez-Bajo MJ, Sanchez Salom L, et al., 2021, P.156: Transcriptomic Profile in Pancreas Biopsies for Monitoring Graft Rejection., Transplantation, Vol: 105
Aguiar PV, Ramirez-Bajo MJ, Salom LS, et al., 2021, Transcriptomic Profile in Pancreas Biopsies for Monitoring Graft Rejection, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: S64-S64, ISSN: 0041-1337
Kapp ME, Fogo AB, Roufouse C, et al., 2021, Renal Considerations in COVID-19: Biology, Pathology, and Pathophysiology., ASAIO J, Vol: 67, Pages: 1087-1096
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has emerged into a worldwide pandemic of epic proportion. Beyond pulmonary involvement in coronavirus disease 2019 (COVID-19), a significant subset of patients experiences acute kidney injury. Patients who die from severe disease most notably show diffuse acute tubular injury on postmortem examination with a possible contribution of focal macro- and microvascular thrombi. Renal biopsies in patients with proteinuria and hematuria have demonstrated a glomerular dominant pattern of injury, most notably a collapsing glomerulopathy reminiscent of findings seen in human immunodeficiency virus (HIV) in individuals with apolipoprotein L-1 (APOL1) risk allele variants. Although various mechanisms have been proposed for the pathogenesis of acute kidney injury in SARS-CoV-2 infection, direct renal cell infection has not been definitively demonstrated and our understanding of the spectrum of renal involvement remains incomplete. Herein we discuss the biology, pathology, and pathogenesis of SARS-CoV-2 infection and associated renal involvement. We discuss the molecular biology, risk factors, and pathophysiology of renal injury associated with SARS-CoV-2 infection. We highlight the characteristics of specific renal pathologies based on native kidney biopsy and autopsy. Additionally, a brief discussion on ancillary studies and challenges in the diagnosis of SARS-CoV-2 is presented.
Prendecki M, Gulati K, Turner-Stokes T, et al., 2021, Characterisation of an enhanced preclinical model of experimental MPO-ANCA autoimmune vasculitis, Journal of Pathology, Vol: 255, Pages: 107-119, ISSN: 0022-3417
Experimental autoimmune vasculitis (EAV) is a model of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) induced by immunisation of susceptible rat strains with myeloperoxidase (MPO). Animals develop circulating MPO-ANCA, pulmonary haemorrhage and glomerulonephritis, although renal injury is mild and recovers spontaneously without treatment. In this study we aimed to augment the severity of glomerulonephritis. Following induction of EAV on day 0, a sub-nephritogenic dose of nephrotoxic serum (NTS) containing heterologous antibodies to glomerular basement membrane was administered on day 14. This resulted in a significant increase in disease severity at day 28 compared to MPO immunisation alone - with more urinary abnormalities, infiltrating glomerular leucocytes, and crescent formation that progressed to glomerular and tubulointerstitial scarring by day 56, recapitulating important features of human disease. Importantly, the glomerulonephritis remained pauci-immune, and was strictly dependent on the presence of autoimmunity to MPO, as there was no evidence of renal disease following administration of sub-nephritogenic NTS alone or after immunisation with a control protein in place of MPO. Detailed phenotyping of glomerular leucocytes identified an early infiltrate of non-classical monocytes following NTS administration that, in the presence of autoimmunity to MPO, may initiate the subsequent influx of classical monocytes which augment glomerular injury. We also showed that this model can be used to test novel therapeutics by using a small molecule kinase inhibitor (fostamatinib) that rapidly attenuated both glomerular and pulmonary injury over a four-day treatment period. We believe that this enhanced model of MPO-AAV will prove useful for the study of glomerular leucocyte behaviour and novel therapeutics in AAV in the future. This article is protected by copyright. All rights reserved.
Adam BA, Murakami N, Reid G, et al., 2021, Gene Expression Profiling in Kidney Transplants with Immune Checkpoint Inhibitor?Associated Adverse Events, CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 16, Pages: 1376-1386, ISSN: 1555-9041
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- Citations: 7
Singh S, Roufosse C, Smith A, et al., 2021, An Audit of Electron Microscopic Evaluation of Native Renal Biopsies, Publisher: WILEY, Pages: S47-S47, ISSN: 0022-3417
Roufosse C, 2021, Super-Resolved Imaging for Translational Research and Diagnosis in Renal Pathology, 13th Joint Meeting of the British-Division-of-The-International-Academy-of-Pathology and The-Pathological-Society-of-Great-Britain-and-Ireland (Manchester Pathology), Publisher: WILEY, Pages: S11-S11, ISSN: 0022-3417
Roufosse C, 2021, Fibrillary Glomerulonephritis: the Diagnostic Role of DNAJB9, 13th Joint Meeting of the British-Division-of-The-International-Academy-of-Pathology and The-Pathological-Society-of-Great-Britain-and-Ireland (Manchester Pathology), Publisher: WILEY, Pages: S11-S11, ISSN: 0022-3417
Barba T, Oberbarnscheidt MH, Rabeyrin M, et al., 2021, THE BIATHLETE'S DILEMMA: UNRAVELLING THE MOLECULAR MECHANISMS OF THE IMMUNE PRIVILEGE OF GRAFT ENDOTHELIUM DURING TCMR, Publisher: WILEY, Pages: 9-9, ISSN: 0934-0874
Garcia E, Lightley J, Kumar S, et al., 2021, Application of direct stochastic optical reconstruction microscopy (dSTORM) to the histological analysis of human glomerular disease, Publisher: SPRINGER, Pages: S142-S142, ISSN: 0945-6317
Singh S, Roufosse C, Smith A, et al., 2021, An audit of Electron Microscopic (EM) evaluation of native renal biopsies, Publisher: SPRINGER, Pages: S42-S43, ISSN: 0945-6317
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