Publications by authors named "Candice Roufosse"

56 Publications

Masked crystalline light chain tubulopathy and podocytopathy with focal segmental glomerulosclerosis: a rare MGRS-associated renal lesion.

Histopathology 2021 Mar 5. Epub 2021 Mar 5.

Department of Cellular Pathology, North West London Pathology, Imperial College Healthcare NHS Trust, London, USA.

Monoclonal Gammopathy of Renal Significance (MGRS) encompasses a wide spectrum of histopathology. Characterizing rare forms of MGRS-related renal pathology remains work in progress. Light chain crystalline podocytopathy in the context of MGRS, either in isolation or combined with proximal tubulopathy (LCPT) has rarely been described. Unravelling MGRS pathologies is critical for patient management and often requires ancillary techniques for antigen retrieval to demonstrate light chain (LC) restriction on immunofluorescence (IF).
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http://dx.doi.org/10.1111/his.14363DOI Listing
March 2021

The Effect of Kidney Biopsy on Glomerular Filtration Rate: A Frequent Patient Concern.

Am J Nephrol 2020 Dec 11:1-4. Epub 2020 Dec 11.

Renal and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom.

The effect of percutaneous kidney biopsy on glomerular filtration rate has never been identified, though it is frequently a concern raised by patients. Following a clinical interaction with an inquisitive patient undergoing her fifth biopsy, we attempted to estimate the effect using retrospective data. In a cohort of patients with stable kidney function undergoing transplant biopsy without clinical indication (as part of a surveillance programme) the effect of biopsy was observed as a step change in glomerular filtration rate. Reassuringly, the loss of glomerular filtration rate resulting from a biopsy, has a 1-sided 95% confidence interval of <1.4 mL/min.
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http://dx.doi.org/10.1159/000511798DOI Listing
December 2020

Does the definition of chronic active T cell-mediated rejection need revisiting?

Am J Transplant 2020 Nov 29. Epub 2020 Nov 29.

Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, Canada.

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http://dx.doi.org/10.1111/ajt.16419DOI Listing
November 2020

Anticoagulant-Related Nephropathy in a Renal Transplant Recipient.

Kidney Int Rep 2020 Nov 14;5(11):2089-2096. Epub 2020 Aug 14.

Department of Cellular Pathology, North West London Pathology, Imperial College Healthcare NHS Trust, London, UK.

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http://dx.doi.org/10.1016/j.ekir.2020.08.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609890PMC
November 2020

Ultrastructure of cell trafficking pathways and coronavirus: how to recognise the wolf amongst the sheep.

J Pathol 2020 12 22;252(4):346-357. Epub 2020 Oct 22.

North West London Pathology, Imperial College Healthcare NHS Trust, London, UK.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has resulted in an urgent need to understand the pathophysiology of SARS-CoV-2 infection, to assist in the identification of treatment strategies. Viral tissue tropism is an active area of investigation, one approach to which is identification of virus within tissues by electron microscopy of post-mortem and surgical specimens. Most diagnostic histopathologists have limited understanding of the ultrastructural features of normal cell trafficking pathways, which can resemble intra- and extracellular coronavirus; in addition, viral replication pathways make use of these trafficking pathways. Herein, we review these pathways and their ultrastructural appearances, with emphasis on structures which may be confused with coronavirus. In particular, we draw attention to the fact that, when using routine fixation and processing, the typical 'crown' that characterises a coronavirus is not readily identified on intracellular virions, which are located in membrane-bound vacuoles. In addition, the viral nucleocapsid is seen as black dots within the virion and is more discriminatory in differentiating virions from other cellular structures. The identification of the viral replication organelle, a collection of membranous structures (convoluted membranes) seen at a relatively low scanning power, may help to draw attention to infected cells, which can be sparse. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5547DOI Listing
December 2020

Live Imaging of Monocyte Subsets in Immune Complex-Mediated Glomerulonephritis Reveals Distinct Phenotypes and Effector Functions.

J Am Soc Nephrol 2020 11 31;31(11):2523-2542. Epub 2020 Aug 31.

Centre for Inflammatory Disease, Imperial College London, London, UK

Background: Immune complexes within glomerular capillary walls cause crescentic GN (CrGN). Monocytes and macrophages are important in mediating CrGN, but little work has been done to phenotype the subpopulations involved and determine their respective contributions to glomerular inflammation.

Methods: Live glomerular imaging using confocal microscopy monitored intravascular monocyte subset behavior during nephrotoxic nephritis (NTN) in a novel WKY-hCD68-GFP monocyte/macrophage reporter rat strain. Flow cytometry and qPCR further analyzed the glomerular leukocyte infiltrate during NTN.

Results: Non-classical monocytes surveyed the glomerular endothelium lymphocyte function-associated antigen 1 (LFA-1) in the steady state. During NTN, non-classical monocytes were recruited first, but subsequent recruitment and retention of classical monocytes was associated with glomerular damage. Monocytes recruited to the glomerular vasculature did not undergo transendothelial migration. This finding suggests that inflammation in immune complex-mediated CrGN is predominantly intravascular, driven by dynamic interactions between intravascular blood monocytes and the endothelium. Glomerular endothelium and non-classical monocytes overexpressed a distinct chemokine axis, which may orchestrate inflammatory myeloid cell recruitment and expression of damage mediators. Reduced classical monocyte recruitment in Lewis rats during NTN confirmed a role for CD16 in mediating glomerular damage.

Conclusions: Monocyte subsets with distinct phenotypes and effector functions may be important in driving inflammation in experimental CrGN resulting from immune complexes formed within the glomerular capillary wall. LFA-1-dependent endothelial surveillance by non-classical monocytes may detect immune complexes through CD16, orchestrating the inflammatory response through intravascular retention of classical monocytes, which results in glomerular damage and proteinuria.
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http://dx.doi.org/10.1681/ASN.2019121326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608972PMC
November 2020

Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study.

Lancet Microbe 2020 Oct 20;1(6):e245-e253. Epub 2020 Aug 20.

Department of Cellular Pathology, Northwest London Pathology, Imperial College London NHS Trust, London, UK.

Background: Severe COVID-19 has a high mortality rate. Comprehensive pathological descriptions of COVID-19 are scarce and limited in scope. We aimed to describe the histopathological findings and viral tropism in patients who died of severe COVID-19.

Methods: In this case series, patients were considered eligible if they were older than 18 years, with premortem diagnosis of severe acute respiratory syndrome coronavirus 2 infection and COVID-19 listed clinically as the direct cause of death. Between March 1 and April 30, 2020, full post-mortem examinations were done on nine patients with confirmed COVID-19, including sampling of all major organs. A limited autopsy was done on one additional patient. Histochemical and immunohistochemical analyses were done, and histopathological findings were reported by subspecialist pathologists. Viral quantitative RT-PCR analysis was done on tissue samples from a subset of patients.

Findings: The median age at death of our cohort of ten patients was 73 years (IQR 52-79). Thrombotic features were observed in at least one major organ in all full autopsies, predominantly in the lung (eight [89%] of nine patients), heart (five [56%]), and kidney (four [44%]). Diffuse alveolar damage was the most consistent lung finding (all ten patients); however, organisation was noted in patients with a longer clinical course. We documented lymphocyte depletion (particularly CD8-positive T cells) in haematological organs and haemophagocytosis. Evidence of acute tubular injury was noted in all nine patients examined. Major unexpected findings were acute pancreatitis (two [22%] of nine patients), adrenal micro-infarction (three [33%]), pericarditis (two [22%]), disseminated mucormycosis (one [10%] of ten patients), aortic dissection (one [11%] of nine patients), and marantic endocarditis (one [11%]). Viral genomes were detected outside of the respiratory tract in four of five patients. The presence of subgenomic viral RNA transcripts provided evidence of active viral replication outside the respiratory tract in three of five patients.

Interpretation: Our series supports clinical data showing that the four dominant interrelated pathological processes in severe COVID-19 are diffuse alveolar damage, thrombosis, haemophagocytosis, and immune cell depletion. Additionally, we report here several novel autopsy findings including pancreatitis, pericarditis, adrenal micro-infarction, secondary disseminated mucormycosis, and brain microglial activation, which require additional investigation to understand their role in COVID-19.

Funding: Imperial Biomedical Research Centre, Wellcome Trust, Biotechnology and Biological Sciences Research Council.
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http://dx.doi.org/10.1016/S2666-5247(20)30115-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7440861PMC
October 2020

Molecular assessment of antibody-mediated rejection in human pancreas allograft biopsies.

Clin Transplant 2020 Nov 30;34(11):e14065. Epub 2020 Aug 30.

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.

Pancreas transplant longevity is limited by immune rejection, which is diagnosed by graft biopsy using the Banff Classification. The histological criteria for antibody-mediated rejection (AMR) are poorly reproducible and inconsistently associated with outcome. We hypothesized that a 34-gene set associated with antibody-mediated rejection in other solid organ transplants could improve diagnosis in pancreas grafts. The AMR 34-gene set, comprising endothelial, natural killer cell and inflammatory genes, was quantified using the NanoString platform in 52 formalin-fixed, paraffin-embedded pancreas transplant biopsies from 41 patients: 15 with pure AMR or mixed rejection, 22 with T cell-mediated rejection/borderline and 15 without rejection. The AMR 34-gene set was significantly increased in pure AMR and mixed rejection (P = .001) vs no rejection. The gene set predicted histological AMR with an area under the receiver operating characteristic curve (ROC AUC) of 0.714 (P = .004). The AMR 34-gene set was the only biopsy feature significantly predictive of allograft failure in univariate analysis (P = .048). Adding gene expression to DSA and histology increased ROC AUC for the prediction of failure from 0.736 to 0.770, but this difference did not meet statistical significance. In conclusion, assessment of transcripts has the potential to improve diagnosis and outcome prediction in pancreas graft biopsies.
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http://dx.doi.org/10.1111/ctr.14065DOI Listing
November 2020

Anti-glomerular basement membrane disease during the COVID-19 pandemic.

Kidney Int 2020 09 26;98(3):780-781. Epub 2020 Jun 26.

Centre for Inflammatory Disease, Imperial College London, London, UK; Renal Medicine, Imperial College Healthcare NHS Trust, London, UK. Electronic address:

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http://dx.doi.org/10.1016/j.kint.2020.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318989PMC
September 2020

The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell- and antibody-mediated rejection.

Am J Transplant 2020 09 28;20(9):2318-2331. Epub 2020 May 28.

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada.

The XV. Banff conference for allograft pathology was held in conjunction with the annual meeting of the American Society for Histocompatibility and Immunogenetics in Pittsburgh, PA (USA) and focused on refining recent updates to the classification, advances from the Banff working groups, and standardization of molecular diagnostics. This report on kidney transplant pathology details clarifications and refinements to the criteria for chronic active (CA) T cell-mediated rejection (TCMR), borderline, and antibody-mediated rejection (ABMR). The main focus of kidney sessions was on how to address biopsies meeting criteria for CA TCMR plus borderline or acute TCMR. Recent studies on the clinical impact of borderline infiltrates were also presented to clarify whether the threshold for interstitial inflammation in diagnosis of borderline should be i0 or i1. Sessions on ABMR focused on biopsies showing microvascular inflammation in the absence of C4d staining or detectable donor-specific antibodies; the potential value of molecular diagnostics in such cases and recommendations for use of the latter in the setting of solid organ transplantation are presented in the accompanying meeting report. Finally, several speakers discussed the capabilities of artificial intelligence and the potential for use of machine learning algorithms in diagnosis and personalized therapeutics in solid organ transplantation.
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http://dx.doi.org/10.1111/ajt.15898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496245PMC
September 2020

Electron microscopic investigations in COVID-19: not all crowns are coronas.

Kidney Int 2020 08 22;98(2):505-506. Epub 2020 May 22.

Department of Renal Histopathology, Queen Elizabeth Hospital Birmingham, Birmingham, West Midlands, UK.

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http://dx.doi.org/10.1016/j.kint.2020.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242192PMC
August 2020

Banff 2019 Meeting Report: Molecular diagnostics in solid organ transplantation-Consensus for the Banff Human Organ Transplant (B-HOT) gene panel and open source multicenter validation.

Am J Transplant 2020 09 27;20(9):2305-2317. Epub 2020 Jun 27.

Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.

This meeting report from the XV Banff conference describes the creation of a multiorgan transplant gene panel by the Banff Molecular Diagnostics Working Group (MDWG). This Banff Human Organ Transplant (B-HOT) panel is the culmination of previous work by the MDWG to identify a broadly useful gene panel based on whole transcriptome technology. A data-driven process distilled a gene list from peer-reviewed comprehensive microarray studies that discovered and validated their use in kidney, liver, heart, and lung transplant biopsies. These were supplemented by genes that define relevant cellular pathways and cell types plus 12 reference genes used for normalization. The 770 gene B-HOT panel includes the most pertinent genes related to rejection, tolerance, viral infections, and innate and adaptive immune responses. This commercially available panel uses the NanoString platform, which can quantitate transcripts from formalin-fixed paraffin-embedded samples. The B-HOT panel will facilitate multicenter collaborative clinical research using archival samples and permit the development of an open source large database of standardized analyses, thereby expediting clinical validation studies. The MDWG believes that a pathogenesis and pathway based molecular approach will be valuable for investigators and promote therapeutic decision-making and clinical trials.
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http://dx.doi.org/10.1111/ajt.16059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496585PMC
September 2020

Convalescent donor SARS-COV-2-specific cytotoxic T lymphocyte infusion as a possible treatment option for COVID-19 patients with severe disease has not received enough attention till date.

Br J Haematol 2020 06 19;189(6):1062-1063. Epub 2020 May 19.

Department of Cellular & Molecular Pathology, Northwest London Pathology, Imperial College Healthcare NHS Trust & Department of Immunology & Inflammation, Imperial College London, London, UK.

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http://dx.doi.org/10.1111/bjh.16780DOI Listing
June 2020

Effect of Optimized Immunosuppression (Including Rituximab) on Anti-Donor Alloresponses in Patients With Chronically Rejecting Renal Allografts.

Front Immunol 2020 5;11:79. Epub 2020 Feb 5.

Department of Inflammation Biology, MRC Centre for Transplantation, Guy's Hospital, King's College London, London, United Kingdom.

RituxiCAN-C4 combined an open-labeled randomized controlled trial (RCT) in 7 UK centers to assess whether rituximab could stabilize kidney function in patients with chronic rejection, with an exploratory analysis of how B cell-depletion influenced T cell anti-donor responses relative to outcome. Between January 2007 and March 2015, 59 recruits were enrolled after screening, 23 of whom consented to the embedded RCT. Recruitment was halted when in a pre-specified per protocol interim analysis, the RCT was discovered to be significantly underpowered. This report therefore focuses on the exploratory analysis, in which we confirmed that when B cells promoted CD4+ anti-donor IFNγ production assessed by ELISPOT, this associated with inferior clinical outcome; these patterns were inhibited by optimized immunosuppression but not rituximab. B cell suppression of IFNγ production, which associated with number of transitional B cells and correlated with slower declines in kidney function was abolished by rituximab, which depleted transitional B cells for prolonged periods. We conclude that in this patient population, optimized immunosuppression but not rituximab promotes anti-donor alloresponses associated with favorable outcomes. Registered with EudraCT (2006-002330-38) and www.ClinicalTrials.gov, identifier: NCT00476164.
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http://dx.doi.org/10.3389/fimmu.2020.00079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012933PMC
March 2021

Autologous Stem Cell Transplant for the Treatment of Type I Crystal Cryoglobulinemic Glomerulonephritis Caused by Monoclonal Gammopathy of Renal Significance (MGRS).

Kidney Int Rep 2019 Sep 22;4(9):1342-1348. Epub 2019 May 22.

Centre for Haematology, Department of Medicine, Imperial College London and Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom.

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http://dx.doi.org/10.1016/j.ekir.2019.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732723PMC
September 2019

Mycophenolate mofetil and tacrolimus versus tacrolimus alone for the treatment of idiopathic membranous glomerulonephritis: a randomised controlled trial.

BMC Nephrol 2019 09 6;20(1):352. Epub 2019 Sep 6.

Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, W12 0NN, UK.

Background: Tacrolimus (TAC) is effective in treating membranous nephropathy (MN); however relapses are frequent after treatment cessation. We conducted a randomised controlled trial to examine whether the addition of mycophenolate mofetil (MMF) to TAC would reduce relapse rate.

Methods: Forty patients with biopsy proven idiopathic MN and nephrotic syndrome were randomly assigned to receive either TAC monotherapy (n = 20) or TAC combined with MMF (n = 20) for 12 months. When patients had been in remission for 1 year on treatment the MMF was stopped and the TAC gradually withdrawn in both groups over 6 months. Patients also received supportive treatment with angiotensin blockade, statins, diuretics and anticoagulation as needed. Primary endpoint was relapse rate following treatment withdrawal. Secondary outcomes were remission rate, time to remission and change in renal function.

Results: 16/20 (80%) of patients in the TAC group achieved remission compared to 19/20 (95%) in the TAC/MMF group (p = 0.34). The median time to remission in the TAC group was 54 weeks compared to 40 weeks in the TAC/MMF group (p = 0.46). There was no difference in the relapse rate between the groups: 8/16 (50%) patients in the TAC group relapsed compared to 8/19 (42%) in the TAC/MMF group (p = 0.7). The addition of MMF to TAC did not adversely affect the safety of the treatment.

Conclusions: Addition of MMF to TAC does not alter the relapse rate of nephrotic syndrome in patients with MN.

Trial Registration: This trial is registered with EudraCTN2008-001009-41 . Trial registration date 2008-10-08.
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http://dx.doi.org/10.1186/s12882-019-1539-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6731553PMC
September 2019

Predicting long-term renal and patient survival by clinicopathological features in elderly patients undergoing a renal biopsy in a UK cohort.

Clin Kidney J 2019 Aug 28;12(4):512-520. Epub 2019 Feb 28.

Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, London, UK.

Background: Several publications have demonstrated the use of renal biopsy in elderly patients in establishing a diagnosis and enabling directed therapy. However, evidence on the long-term outcomes following biopsies is lacking. The aim of this study is to describe the renal and patient outcomes in elderly patients according to indication for biopsy, clinical parameters and the histological diagnosis.

Methods: We performed a retrospective cohort study of 463 patients >70 years old who underwent a renal biopsy at our centre between 2006 and 2015.

Results: The median age of the patients was 74.8 (range 70.0-89.6) years. The most frequent primary diagnoses were pauci-immune crescentic glomerulonephritis (GN; 12%), acute interstitial nephritis (10.8%) and membranous GN (7.1%). Death-censored renal survival at 1 and 5 years following the index biopsy was 85.2 and 75.9%, respectively, and patient survival at 1 and 5 years was 92.2 and 71.6%, respectively. Patients who progressed to end-stage renal disease (ESRD) were at higher risk of dying compared with patients who did not require dialysis [hazard ratio 2.41 (95% confidence interval 1.58-3.68; P < 0.001]. On multivariate analysis, factors associated with the risk of progression to ESRD were creatinine (P < 0.001), heavy proteinuria (P = 0.002) and a non-chronic kidney disease (CKD) biopsy indication (P = 0.006). A histological diagnosis of primary GN (P = 0.001) or tubulointerstitial nephritis (P = 0.008) was associated with a favourable renal outcome, while patients with vasculitis and paraprotein-related renal disease (PPRD) had the highest risk of requiring dialysis (P = 0.0002 and P = 0.003, respectively). PPRD was also an independent risk factor for death.

Conclusions: This study demonstrates that renal biopsies in the elderly not only enable directed therapy, but also provide prognostic information on renal and patient survival.
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http://dx.doi.org/10.1093/ckj/sfz006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672059PMC
August 2019

Clinical-pathological correlations in post-transplant thrombotic microangiopathy.

Histopathology 2019 Jul;75(1):88-103

Faculty of Medicine, Imperial College, London, UK.

Aims: Post-transplant thrombotic microangiopathy (TMA) is a rare and clinically challenging finding in renal transplant biopsies. In addition to recurrent atypical haemolytic uraemic syndrome, TMA in renal transplants is associated with various conditions, such as calcineurin inhibitor (CNI) treatment, antibody-mediated rejection (ABMR), viral infections, sepsis, pregnancy, malignancies, and surgery. The therapeutic implications of this diagnosis are considerable. In order to better understand post-transplant TMA and to identify histological or clinical differences between associated causes, we conducted a multicentre retrospective study.

Methods And Results: Clinical parameters and transplant renal biopsy findings from 81 patients with TMA were analysed. Biopsies from 38 patients were also analysed with electron microscopy. On the basis of clinical-pathological correlation, TMA was attributed to a main aetiology, whenever possible. TMA occurred at a median of 30 days post-transplantation. Systemic features of TMA were present in only 18% of cases. Twenty-two per cent of cases were attributed to CNI and 11% to ABMR. Although other potentially contributing factors were found in 56% of patients, in most cases (63%) no clearly attributable cause of TMA was identified. Histological differences between groups were minimal. The detection of ultrastructural features that are usually associated with ABMR may help to establish ABMR as the cause of TMA.

Conclusions: Although CNI and ABMR appear to be the main contributors to post-transplant TMA, the aetiology of most cases is probably multifactorial, and TMA cannot be unequivocally attributed to a single underlying aetiology. Morphological features of TMA are not discriminating, but electron microscopy may help to identify ABMR-associated TMA.
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http://dx.doi.org/10.1111/his.13855DOI Listing
July 2019

Proliferative glomerulonephritis with monoclonal Ig deposits (PGNMID): diagnostic and treatment challenges for the nephrologist!

Kidney Int 2019 02;95(2):467-468

Department of Nephrology, Hammersmith Hospital, West London Renal and Transplant Centre, Imperial College Healthcare NHS Trust, London, UK.

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http://dx.doi.org/10.1016/j.kint.2018.10.016DOI Listing
February 2019

Successful management of post-transplant focal segmental glomerulosclerosis with therapeutic plasma exchange and rituximab.

Clin Exp Nephrol 2019 May 14;23(5):700-709. Epub 2019 Jan 14.

Imperial College Kidney and Transplant Centre, London, UK.

Background: Post-transplant focal segmental glomerulosclerosis (FSGS) is associated with renal allograft loss. Currently, optimal treatment remains controversial.

Methods: The aim of our study was to examine the efficacy and safety of therapeutic plasma exchange (TPE), and rituximab (RTX), in the management of post-transplant FSGS. The treatment protocol consisted of RTX and monthly cycles of 5 plasma exchanges for 6 months. We treated 10 transplant recipients with biopsy-proven post-transplant FSGS. Lastly, we compared the studied group to a historic control group of nine patients with post-transplant FSGS.

Results: 9 out of 10 patients achieved remission after the conclusion of treatment (4 complete and 5 partial), while 1 patient did not respond to treatment. During the follow-up period, there was one graft loss and one patient died while in remission from unrelated complications. There was a significant reduction in mean uPCR between diagnosis (517.4 ± 524.2 mg/mmol) and last follow-up (87 ± 121.6 mg/mmol) in the patients with sustained remission (p = 0.026). There was no significant decline in eGFR in the eight relapse-free responders at the end of follow-up. (54.4 ± 16.7 from 49.8 ± 20.4 ml/min) (p = 0.6) An increased response rate to the combined TPE and RTX treatment was demonstrated, when compared to a historic control group of nine patients with post-transplant FSGS, as only five out of nine patients achieved remission (two complete and three partial) in that group.

Conclusions: In this study, treatment with TPE and RTX appears to be safe, well tolerated and effective in the management of patients with post-transplant FSGS.
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http://dx.doi.org/10.1007/s10157-019-01690-0DOI Listing
May 2019

Molecular Assessment of C4d-Positive Renal Transplant Biopsies Without Evidence of Rejection.

Kidney Int Rep 2019 Jan 18;4(1):148-158. Epub 2018 Sep 18.

Centre for Inflammatory Diseases, Imperial College, London, UK.

Introduction: Immunohistochemical staining for C4d in peritubular capillaries has been part of antibody-mediated rejection (AbMR) definition in the Banff Classification for Allograft Pathology since 2003. However, it has limited sensitivity and specificity, therefore the clinical significance of C4d-positive biopsies without evidence of rejection (C4d+ WER) is unknown. We investigated the transcript levels of genes associated with AbMR in C4d+ WER biopsies from both ABO-compatible and incompatible renal transplant patients.

Methods: RNA was extracted from formalin-fixed paraffin-embedded renal transplant biopsies ( = 125) and gene expression analysis of 35 AbMR-associated transcripts carried out using the NanoString nCounter system.

Results: AbMR-associated transcripts were significantly increased in samples with AbMR or suspicious AbMR. A subgroup of 17 of 35 transcripts that best distinguished AbMR from C4d-negative biopsies without evidence of rejection was used to study C4d+ WER samples. There was no differential expression between C4d-negative and C4d+ WER from both ABO-incompatible and -compatible transplants. The geometric mean of 17 differentially expressed genes was used to assign the C4d+ WER biopsies a high- or low-AbMR transcript score. Follow-up biopsies showed AbMR within 1 year of initial biopsy in 5 of 7 high-AbMR transcript patients but only 2 of 46 low-AbMR transcript patients. In multivariate logistic regression analysis, elevated transcript levels in a C4d+ WER biopsy were associated with increased odds for biopsy-proven AbMR on follow-up ( = 0.032, odds ratio 16.318), whereas factors including donor-specific antibody (DSA) status and time since transplantation were not.

Conclusion: Gene expression analysis in C4d+ WER samples has the potential to identify patients at higher risk of developing AbMR.
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http://dx.doi.org/10.1016/j.ekir.2018.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6308373PMC
January 2019

Shared alloimmune responses against blood and transplant donors result in adverse clinical outcomes following blood transfusion post-renal transplantation.

Am J Transplant 2019 06 28;19(6):1720-1729. Epub 2019 Jan 28.

Renal and Transplant Centre, Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, UK.

De novo HLA donor-specific antibodies (DSA) following transplantation are associated with alloimmune injury and allograft failure. Blood transfusions are allogeneic, and when given posttransplant (PTBT) they may independently increase the risk of HLA antibody development. This study aims to analyze the development of HLA transfusion-specific antibodies (TSA) to blood donors of transfusions given posttransplant and examine the impact on clinical outcomes. A total of 244 blood donors of transfusions received by 86 transplant patients (46 who developed a DSA post transfusion and 40 who remained DSA negative) were HLA typed. De novo TSA developed against 150/244 (61.5%) blood donors. In 70/150 (46.7%) cases the TSA was of shared HLA antibody specificity with a DSA response in the recipient (DSA+ = TSA+). This occurred when there was a greater overall HLA match between the blood and transplant donor. DSA+ = TSA+ patients had increased risk of allograft failure (P = .0025) and AMR (P = .02) compared with the DSA+ ≠ TSA+ patients. To conclude, PTBT may elicit de novo HLA antibodies. Enhanced HLA matching between the blood and transplant donor is more likely to result in a DSA and TSA of shared antibody specificities. Transfusion avoidance or the use of HLA matched or selected blood may reduce this risk and improve outcomes.
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http://dx.doi.org/10.1111/ajt.15233DOI Listing
June 2019

Smoldering Myeloma Presenting with Renal Histopathology of Monoclonal Gammopathy of Renal Significance: Adding to the Complexity.

J Am Soc Nephrol 2018 12 30;29(12):2901. Epub 2018 Oct 30.

Department of Cellular Pathology, Hammersmith Hospital, Imperial College National Health Service Trust, London, United Kingdom.

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http://dx.doi.org/10.1681/ASN.2018080864DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6287868PMC
December 2018

The expanding spectrum of antibody-mediated rejection: Should we include cases where no anti-HLA donor-specific antibody is detected?

Am J Transplant 2019 03 1;19(3):622-624. Epub 2018 Oct 1.

Center for Inflammatory Diseases, Imperial College, London, UK.

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http://dx.doi.org/10.1111/ajt.15114DOI Listing
March 2019

A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology.

Transplantation 2018 11;102(11):1795-1814

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.

The Banff Classification of Allograft Pathology is an international consensus classification for the reporting of biopsies from solid organ transplants. Since its initial conception in 1991 for renal transplants, it has undergone review every 2 years, with attendant updated publications. The rapid expansion of knowledge in the field has led to numerous revisions of the classification. The resultant dispersal of relevant content makes it difficult for novices and experienced pathologists to faithfully apply the classification in routine diagnostic work and in clinical trials. This review shall provide a complete and simple illustrated reference guide of the Banff Classification of Kidney Allograft Pathology based on all publications including the 2017 update. It is intended as a concise desktop reference for pathologists and clinicians, providing definitions, Banff Lesion Scores and Banff Diagnostic Categories. An online website reference guide hosted by the Banff Foundation for Allograft Pathology (www.banfffoundation.org) is being developed, which will be updated with future refinement of the Banff Classification from 2019 onward.
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http://dx.doi.org/10.1097/TP.0000000000002366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7597974PMC
November 2018

Mycophenolate mofetil therapy in immunoglobulin A nephropathy: histological changes after treatment.

Nephrol Dial Transplant 2017 01;32(suppl_1):i123-i128

Imperial College Healthcare NHS Trust Renal and Transplant Centre, Hammersmith Hospital, London, UK.

Background: Endocapillary hypercellularity independently predicts renal outcome in immunoglobulin A nephropathy (IgAN). Mycophenolate mofetil (MMF) treatment is offered to patients presenting to the Imperial College Renal and Transplant Centre with IgAN and histological evidence of endocapillary hypercellularity. Clinical trials of MMF in IgAN have been inconclusive and have been limited by a lack of specific histological inclusion and exclusion criteria when recruiting patients. Evidence of histological improvement following MMF treatment would support its therapeutic use. We therefore reviewed histological changes after MMF therapy in a cohort of IgAN patients.

Method: Eighteen IgAN patients with native renal biopsies before and after repeated MMF treatment were identified. Patients were excluded if they had received any other immunosuppressive therapy, including corticosteroids. On the basis of the Oxford Classification of IgAN, we reviewed histological changes after MMF treatment.

Results: Nine patients (50%) were male. At diagnostic renal biopsy, the median age was 35 years [interquartile range (IQR) 30-41], serum creatinine was 97 µmol/L (IQR 79-153) and urine protein creatinine ratio (UPCR) was 146 mg/mmol (IQR 98-212). The median time between biopsies was 24 months (range 9-41). Following MMF treatment, repeat biopsy demonstrated statistically significant improvement in the mean percentage of glomeruli showing endocapillary hypercellularity and cellular/fibrocellular crescents. There was no change in mesangial hypercellularity, segmental sclerosis or tubular atrophy scores. Mesangial IgA deposition was also significantly reduced. Histopathological improvement persisted after the cessation of MMF therapy, suggesting that 2 years of treatment is adequate for benefit. The median serum creatinine remained stable at 3 years follow-up at 104 µmol/L (IQR 79-147).

Conclusion: MMF treatment is associated with histopathological improvement in IgAN.
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http://dx.doi.org/10.1093/ndt/gfw326DOI Listing
January 2017

The natural history of immunoglobulin M nephropathy in adults.

Nephrol Dial Transplant 2017 May;32(5):823-829

Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London W12 0NN, UK.

Background: Immunoglobulin M (IgM) nephropathy is an idiopathic glomerulonephritis characterized by diffuse mesangial deposition of IgM. IgM nephropathy has been a controversial diagnosis since it was first reported, and there are few data identifying specific pathological features that predict the risk of progression of renal disease.

Methods: We identified 57 cases of IgM nephropathy among 3220 adults undergoing renal biopsy at our institution. Biopsies had to satisfy the following three criteria to meet the definition of IgM nephropathy in this study: (i) dominant mesangial staining for IgM, (ii) mesangial deposits on electron microscopy (EM) and (iii) exclusion of systemic disease.

Results: The median age was 42 years and 24 patients were male. Thirty-nine per cent of patients presented with the nephrotic syndrome, 49% presented with non-nephrotic proteinuria and 39% had eGFR <60 mL/min. The median post-biopsy follow-up was 40 months and serum creatinine had doubled in 31% by 5 years. Of histological parameters, glomerular sclerosis and tubular atrophy, but not mesangial proliferation, were risk factors for renal insufficiency. Thirty-nine per cent of nephrotic patients achieved complete remission, and outcome was significantly worse in those who did not respond to treatment. Focal segmental glomerulosclerosis was diagnosed in 80% of those undergoing repeat renal biopsy, despite ongoing mesangial IgM deposition.

Conclusions: We propose criteria for a consensus definition of IgM nephropathy.
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http://dx.doi.org/10.1093/ndt/gfw063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5837784PMC
May 2017

Immune Complex-Type Deposits in the Fischer-344 to Lewis Rat Model of Renal Transplantation and a Subset of Human Transplant Glomerulopathy.

Transplantation 2016 05;100(5):1004-14

1 Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, Giessen, Germany. 2 Institute of Pathology, University Hospital of Cologne, Cologne, Germany. 3 Institute of Transfusion Medicine, Hannover Medical School, Hannover, Germany. 4 Institute of Pathology, Department of Nephropathology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany. 5 Institute of Pathology, Hannover Medical School, Hannover, Germany. 6 PATHOCOM, Rheine, Germany. 7 Department of General and Thoracic Surgery, Justus-Liebig-University Giessen, Giessen, Germany. 8 Medical Clinic III, University Hospital Hamburg-Eppendorf, Hamburg, Germany. 9 Department of General, Visceral and Cancer Surgery, Transplant Center Cologne, University of Cologne, Cologne, Germany. 10 Imperial College Kidney and Transplant Centre, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom. 11 Department of Cellular Pathology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom.

Background: Antibody-mediated rejection is a leading cause for renal transplant loss. Rodent models are useful to dissect pathomechanisms and to develop treatment strategies. Although used for decades as a model, glomerular histopathological findings of Fischer-344 kidneys transplanted into Lewis rats have never been comprehensively described.

Methods: Kidneys from Fischer-344 rats were transplanted into Lewis rats as life-sustaining allografts without immunosuppression. Lewis isografts and normal Fischer-344 kidneys served as controls. Grafts were harvested at 9 days, 6 and 26 weeks. Histopathological examination included light microscopy, immunohistochemistry, and morphometry. Findings were compared with 51 human biopsies with transplant glomerulopathy.

Results: Most glomerular findings in rat allografts resembled human acute and chronic antibody-mediated rejection with glomerulitis, microthrombosis, microaneurysms, glomerular hypertrophy, podocyte loss, glomerular basement membrane splitting, and secondary focal and segmental glomerulosclerosis. In line with previous reports on nonendothelial antigens, glomerular immunoglobulin and C4d deposition was mostly nonendothelial. Only in 26-week allografts, we found mesangial and subendothelial immune complex-type electron-dense deposits. Similar deposits were found in 8 of 51 human biopsies with transplant glomerulopathy after rigorous exclusion of immune complexes of other cause, particularly recurrent glomerulonephritis and hepatitis C.

Conclusions: Thus, our model closely reflects the glomerular changes of acute antibody-mediated rejection in humans and of a special subset of human transplant glomerulopathy. The significance of alloimmune immune complex-type deposits in human transplants deserves further investigation.
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http://dx.doi.org/10.1097/TP.0000000000001068DOI Listing
May 2016

Multiplexed color-coded probe-based gene expression assessment for clinical molecular diagnostics in formalin-fixed paraffin-embedded human renal allograft tissue.

Clin Transplant 2016 Mar 3;30(3):295-305. Epub 2016 Feb 3.

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada.

Histopathologic diagnoses in transplantation can be improved with molecular testing. Preferably, molecular diagnostics should fit into standard-of-care workflows for transplant biopsies, that is, formalin-fixed paraffin-embedded (FFPE) processing. The NanoString(®) gene expression platform has recently been shown to work with FFPE samples. We aimed to evaluate its methodological robustness and feasibility for gene expression studies in human FFPE renal allograft samples. A literature-derived antibody-mediated rejection (ABMR) 34-gene set, comprised of endothelial, NK cell, and inflammation transcripts, was analyzed in different retrospective biopsy cohorts and showed potential to molecularly discriminate ABMR cases, including FFPE samples. NanoString(®) results were reproducible across a range of RNA input quantities (r = 0.998), with different operators (r = 0.998), and between different reagent lots (r = 0.983). There was moderate correlation between NanoString(®) with FFPE tissue and quantitative reverse transcription polymerase chain reaction (qRT-PCR) with corresponding dedicated fresh-stabilized tissue (r = 0.487). Better overall correlation with histology was observed with NanoString(®) (r = 0.354) than with qRT-PCR (r = 0.146). Our results demonstrate the feasibility of multiplexed gene expression quantification from FFPE renal allograft tissue. This represents a method for prospective and retrospective validation of molecular diagnostics and its adoption in clinical transplantation pathology.
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http://dx.doi.org/10.1111/ctr.12689DOI Listing
March 2016