Imperial College London

DrCandiceRoufosse

Faculty of MedicineDepartment of Immunology and Inflammation

Clinical Senior Lecturer
 
 
 
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Contact

 

+44 (0)20 3313 3280c.roufosse

 
 
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Location

 

Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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179 results found

Adam BA, Murakami N, Reid G, Du K, Jasim R, Boils CL, Bu L, Hill PD, Murray AG, Renaudin K, Roufosse C, Weins A, Wen K, Riella LV, Mengel Met al., 2021, Gene Expression Profiling in Kidney Transplants with Immune Checkpoint Inhibitor-Associated Adverse Events., Clin J Am Soc Nephrol, Vol: 16, Pages: 1376-1386

BACKGROUND AND OBJECTIVES: Immune checkpoint inhibitors are increasingly used to treat various malignancies, but their application in patients with kidney transplants is complicated by high allograft rejection rates. Immune checkpoint inhibitor-associated rejection is a novel, poorly understood entity demonstrating overlapping histopathologic features with immune checkpoint inhibitor-associated acute interstitial nephritis, which poses a challenge for diagnosis and clinical management. We sought to improve the understanding of these entities through biopsy-based gene expression analysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: NanoString was used to measure and compare the expression of 725 immune-related genes in 75 archival kidney biopsies, including a 25-sample discovery cohort comprising pure T cell-mediated rejection and immune checkpoint inhibitor-associated acute interstitial nephritis and an independent 50-sample validation cohort comprising immune checkpoint inhibitor-associated acute interstitial nephritis, immune checkpoint inhibitor-associated T cell-mediated rejection, immune checkpoint inhibitor-associated crescentic GN, drug-induced acute interstitial nephritis, BK virus nephropathy, and normal biopsies. RESULTS: Significant molecular overlap was observed between immune checkpoint inhibitor-associated acute interstitial nephritis and T cell-mediated rejection. Nevertheless, IFI27, an IFN-α-induced transcript, was identified and validated as a novel biomarker for differentiating immune checkpoint inhibitor-associated T cell-mediated rejection from immune checkpoint inhibitor-associated acute interstitial nephritis (validation cohort: P<0.001, area under the receiver operating characteristic curve =100%, accuracy =86%). Principal component analysis revealed heterogeneity in inflammatory gene expression patterns within sample groups; however, immune checkpoint inhibitor-associated T cell-mediated rejection and immune checkpoint inhibi

Journal article

Kousios A, Mcadoo S, Blakey S, Moran L, Atta M, Tam FW, Cook HT, Chaidos A, Roufosse Cet al., 2021, Masked crystalline light chain tubulopathy and podocytopathy with focal segmental glomerulosclerosis: a rare MGRS-associated renal lesion, Histopathology, Vol: 79, Pages: 265-268, ISSN: 1365-2559

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).

Journal article

Prendecki M, Gulati K, Turner-Stokes T, Bhangal G, Chiappo D, Woollard K, Cook HT, Tam FW, Roufosse C, Pusey CD, McAdoo SPet al., 2021, Characterisation of an enhanced preclinical model of experimental MPO-ANCA autoimmune vasculitis, Journal of Pathology, 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.

Journal article

Gulati K, Roufosse C, McAdoo SP, 2021, Diffuse crescentic glomerulonephritis presenting with preserved renal function, RHEUMATOLOGY, Vol: 60, Pages: 18-20, ISSN: 1462-0324

Journal article

Garcia E, Lightley J, Kumar S, Kalita R, Gorlitz F, Alexandrov Y, Cook T, Dunsby C, Neil MAA, Roufosse CA, French PMWet al., 2021, Application of direct stochastic optical reconstruction microscopy (dSTORM) to the histological analysis of human glomerular disease, JOURNAL OF PATHOLOGY CLINICAL RESEARCH, Vol: 7, Pages: 438-445

Journal article

Nikolopoulou A, Teixeira C, Cook H, Roufosse C, Cairns THD, Levy JB, Pusey C, Griffith MEet al., 2021, Membranous nephropathy associated with viral infection, Clinical Kidney Journal, Vol: 14, Pages: 876-883, ISSN: 2048-8505

BackgroundMembranous nephropathy (MN) can be associated with hepatitis infection and less commonly with human immunodeficiency virus (HIV) infection. The significance of anti-phospholipase A2 receptor (PLA2R) and anti-thrombospondin type 1 domain-containing 7A (THSD7A) antibodies in this setting is unclear.MethodsWe describe the clinical, histopathological and outcome data of 19 patients with MN and hepatitis B virus (HBV), hepatitis C virus (HCV) or HIV infection identified through our renal biopsy database and the association with anti-PLA2R antibodies and anti-THSD7A antibodies.ResultsThe cohort consisted of 19 patients, 8 male and 11 female, with a median age of 42 years (range 23–74). HBV infection was found in six cases, HCV in four and HIV in nine (two HIV patients had HBV co-infection and one HCV co-infection). PLA2R staining on biopsy was positive in 10/19 patients: 4 with HBV-MN, 3 with HCV-MN and 3 with HIV-MN and circulating anti-PLA2R antibodies were detected in 7/10 cases. THSD7A staining on biopsy was positive in three PLA2R-negative cases, one with HBV-MN and two with HIV-MN. Mean proteinuria was higher in the PLA2R-positive group and the median urinary protein:creatinine ratio (uPCR) was 963 mg/mmol (range 22–2406) compared with the PLA2R-negative group [median uPCR 548 mg/mmol (range 65–1898); P = 0.18 Mann–Whitney]. Spontaneous remission occurred in 6/19 patients and after-treatment remission occurred in 7/11 patients. Renal function was preserved in all but two patients who required haemodialysis 2 and 11 years from diagnosis.ConclusionsWe describe a cohort of patients with MN associated with viral infection, including rare cases of HIV-MN with PLA2R and THSD7A positivity. The mechanism of coincidental or viral-related MN needs to be investigated further.

Journal article

Naesens M, Haas M, Loupy A, Roufosse C, Mengel Met al., 2020, Does the definition of chronic active T cell-mediated rejection need revisiting?, AMERICAN JOURNAL OF TRANSPLANTATION, Vol: 21, Pages: 1689-1690, ISSN: 1600-6135

Journal article

Dattani R, Corbett RW, Galliford J, Hill P, Cairns T, Cook HT, Roufosse C, Ashby DRet al., 2020, The Effect of Kidney Biopsy on Glomerular Filtration Rate: A Frequent Patient Concern, AMERICAN JOURNAL OF NEPHROLOGY, Vol: 51, Pages: 903-906, ISSN: 0250-8095

Journal article

Tennekoon HD, Kousios A, Gardiner R, Moran L, Goodall D, Galliford J, Taube D, Roufosse Cet al., 2020, Anticoagulant-related nephropathy in a renal transplant recipient., Kidney International Reports, Vol: 5, Pages: 2089-2096, ISSN: 2468-0249

Journal article

Roufosse C, Drachenberg C, Renaudin K, Willicombe M, Toulza F, Dominy K, McLean A, Simmonds N, de Kort H, Cantarovitch D, Scalea J, Mengel M, Adam Bet al., 2020, Molecular assessment of antibody-mediated rejection in human pancreas allograft biopsies, Clinical Transplantation, Vol: 34, Pages: 1-13, ISSN: 0902-0063

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.

Journal article

Neil D, Moran L, Horsfield C, Curtis E, Swann O, Barclay W, Hanley B, Hollinshead M, Roufosse Cet al., 2020, Ultrastructure of cell trafficking pathways and coronavirus: how to recognise the wolf amongst the sheep, JOURNAL OF PATHOLOGY, Vol: 252, Pages: 346-357, ISSN: 0022-3417

Journal article

Toulza F, Dominy K, Cook H, Galliford J, Beadle J, McLean A, Roufosse Cet al., 2020, Technical considerations when designing a gene expression panel for renal transplant diagnosis, Scientific Reports, Vol: 10, ISSN: 2045-2322

Gene expression analysis is emerging as a new diagnostic tool in transplant pathology, in particular for the diagnosis of antibody-mediated rejection. Diagnostic gene expression panels are defined on the basis of their pathophysiological relevance, but also need to be tested for their robustness across different preservatives and analysis platforms. The aim of this study is the investigate the effect of tissue sampling and preservation on candidate genes included in a renal transplant diagnostic panel. Using the NanoString platform, we compared the expression of 219 genes in 51 samples, split for formalin-fixation and paraffin-embedding (FFPE) and RNAlater preservation (RNAlater). We found that overall, gene expression significantly correlated between FFPE and RNAlater samples. However, at the individual gene level, 46 of the 219 genes did not correlate across the 51 matched FFPE and RNAlater samples. Comparing gene expression results using NanoString and qRT-PCR for 18 genes in the same pool of RNA (RNAlater), we found a significant correlation in 17/18 genes. Our study indicates that, in samples from the same routine diagnostic renal transplant biopsy procedure split for FFPE and RNAlater, 21% of 219 genes of potential biological significance do not correlate in expression. Whether this is due to fixatives or tissue sampling, selection of gene panels for routine diagnosis should take this information into consideration.

Journal article

Hanley B, Naresh KN, Roufosse C, Nicholson AG, Weir J, Cooke GS, Thursz M, Manousou P, Corbett R, Goldin R, Al-Sarraj S, Abdolrasouli A, Swann OC, Baillon L, Penn R, Barclay WS, Viola P, Osborn Met al., 2020, Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: a post-mortem study, The Lancet Microbe, Vol: 1, Pages: e245-e253, ISSN: 2666-5247

BackgroundSevere 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.MethodsIn 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.FindingsThe 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

Journal article

Mengel M, Loupy A, Haas M, Roufosse C, Naesens M, Akalin E, Clahsen-van Groningen MC, J Dagobert, Demetris AJ, Duong van Huyen JP, Gueguen J, Issa F, Robin B, Rosales I, Von der Thüsen JH, Sanchez-Fueyo A, Smith RN, Wood K, Adam B, Colvin RBet al., 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, American Journal of Transplantation, Vol: 20, ISSN: 1600-6135

This Meeting Report from the XVth Banff conference describes the creation of a multi-organ 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 analyzes, 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.

Journal article

Loupy A, Haas M, Roufosse C, Naesens M, Adam B, Afrouzian M, Akalin E, Alachkar N, Bagnasco S, Becker JU, Cornell LD, Clahsen-van Groningen MC, Demetris AJ, Dragun D, Duong van Huyen J-P, Farris AB, Fogo AB, Gibson IW, Glotz D, Gueguen J, Kikic Z, Kozakowski N, Kraus E, Lefaucheur C, Liapis H, Mannon RB, Montgomery RA, Nankivell BJ, Nickeleit V, Nickerson P, Rabant M, Racusen L, Randhawa P, Robin B, Rosales IA, Sapir-Pichhadze R, Schinstock CA, Seron D, Singh HK, Smith RN, Stegall MD, Zeevi A, Solez K, Colvin RB, Mengel Met al., 2020, The banff 2019 kidney meeting report (I): updates on and clarification of criteria for T cell- and antibody-mediated rejection., American Journal of Transplantation, Vol: 20, Pages: 2318-2331, ISSN: 1600-6135

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.

Journal article

Turner-Stokes T, Garcia Diaz A, Pinheiro D, Prendecki M, McAdoo SP, Roufosse C, Cook HT, Pusey CD, Woollard KJet al., 2020, Live imaging of monocyte subsets in immune complex-mediated glomerulonephritis reveals distinct phenotypes and effector functions., Journal of the American Society of Nephrology, Vol: 31, Pages: 1-1, ISSN: 1046-6673

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 ex vivo the glomerular leukocyte infiltrate during NTN. RESULTS: Non-classical monocytes surveyed the glomerular endothelium via 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.

Journal article

Roufosse C, Curtis E, Moran L, Hollinshead M, Cook T, Hanley B, Horsfield C, Neil Det al., 2020, Electron microscopic investigations in COVID-19: not all crowns are coronas, Kidney International, Vol: 98, Pages: 505-506, ISSN: 0085-2538

Journal article

Prendecki M, Clarke C, Cairns T, Cook T, Roufosse C, Thomas D, Willicombe M, Pusey CD, McAdoo SPet al., 2020, Anti-glomerular basement membrane disease during the COVID-19 pandemic, Kidney International, ISSN: 0085-2538

Journal article

Shiu KY, Stringer D, McLaughlin L, Shaw O, Brookes P, Burton H, Wilkinson H, Douthwaite H, Tsui T-L, Mclean A, Hilton R, Griffin S, Geddes C, Ball S, Baker R, Roufosse C, Horsfield C, Dorling Aet al., 2020, Effect of optimized immunosuppression (including rituximab) on anti-donor alloresponses in patients with chronically rejecting renal allografts, Frontiers in Immunology, Vol: 11, Pages: 1-16, ISSN: 1664-3224

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.

Journal article

Kousios A, Roufosse C, 2019, An update on paraprotein-related renal pathology, Diagnostic Histopathology, Vol: 25, Pages: 408-421, ISSN: 1756-2317

Paraproteins are intact monoclonal immunoglobulins (MIg) or isolated MIg heavy or light chains, detected in the blood or urine and caused by a clonal proliferation of B cells or plasma cells. Paraproteins often cause renal injury, referred to here as paraprotein-related renal disease (PPRD), whether the underlying clonal disorder is characterized by high tumour burden requiring treatment or low tumour burden and thus not requiring immediate treatment from the haematological standpoint. For the latter, an important recent update is the introduction of the concept of Monoclonal Gammopathy of Renal Significance (MGRS), in which the renal pathology in itself may justify the use of clone-directed therapies targeting the nephrotoxic clone, in order to preserve renal function. A bewildering array of renal pathology can be caused by paraproteins, affecting all compartments of the kidney – glomeruli, tubules, interstitium and blood vessels. This review aims to provide an overview of the different renal lesions that can be seen, organized by predominant compartment affected, with guidance on how to spot them and classify them.

Journal article

Poo SX, Tham CSW, Smith C, Lee J, Cairns T, Galliford J, Hamdulay S, Jacyna M, Levy JB, McAdoo S, Roufosse C, Wernig F, Mason J, Pusey C, Tam F, Tomlinson Jet al., 2019, IgG4-related disease in a multi-ethnic community: Clinical characteristics and association with malignancy, QJM: An International Journal of Medicine, Vol: 112, Pages: 763-769, ISSN: 1460-2393

BackgroundImmunoglobulin-G4-related disease (IgG4-RD) is a recently recognised fibro-inflammatory condition that can affect multiple organs. Despite growing interest in this condition, the natural history and management of IgG4-RD remain poorly understood.AimTo describe the clinical characteristics, treatment and outcomes of IgG4-RD in a multi-ethnic UK cohort, and investigate its possible association with malignancy.DesignRetrospective analysis of case-note and electronic data.MethodsCases were identified from sub-specialty cohorts and a systematic search of an NHS trust histopathology database using ‘IgG4’ or ‘inflammatory pseudotumour’ as search terms. Electronic records, imaging and histopathology reports were reviewed.Results66 identified cases of IgG4-RD showed a similar multi-ethnic spread to the local population of North West London. The median age was 59 years and 71% of patients were male. Presenting symptoms relating to mass effect of a lesion were present in 48% of cases and the mean number of organs involved was 2.4. 10 patients had reported malignancies with 6 of these being haematological. 83% of those treated with steroids had good initial response, however 50% had relapsing-remitting disease. Rituximab was administered in 11 cases and all achieved an initial serological response. Despite this, 7 patients subsequently relapsed after a mean duration of 11 months and 4 progressed despite treatment.ConclusionsWe report a large UK-based cohort of IgG4-RD that shows no clear ethnic predisposition and a wide range of affected organs. We discuss the use of serum IgG4 concentrations as a disease marker in IgG4-RD, the association with malignant disease and outcomes according to differing treatment regimens.

Journal article

Nikolopoulou A, Condon M, Turner-Stokes T, Cook HT, Duncan N, Galliford J, Levy J, Lightstone L, Pusey C, Roufosse C, Cairns T, Griffith Met al., 2019, Mycophenolate mofetil and tacrolimus versus tacrolimus alone for the treatment of idiopathic membranous glomerulonephritis: A randomised controlled trial., BMC Nephrology, Vol: 20, Pages: 1-9, ISSN: 1471-2369

Background: Tacrolimus (TAC) is effective in treating membranous nephropathy (MN);however relapses are frequent after treatment cessation. We conducted a randomisedcontrolled trial to examine whether the addition of mycophenolate mofetil (MMF) to TACwould reduce relapse rate.Methods: 40 patients with biopsy proven idiopathic MN and nephrotic syndrome wererandomly 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 MMFwas stopped and the TAC gradually withdrawn in both groups over 6 months. Patients alsoreceived supportive treatment with angiotensin blockade, statins, diuretics andanticoagulation as needed. Primary endpoint was relapse rate following treatmentwithdrawal. Secondary outcomes were remission rate, time to remission and change in renalfunction.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 groupwas 54 weeks compared to 40 weeks in the TAC/MMF group (p=0.46). There was nodifference in the relapse rate between the groups: 8/16 (50%) patients in the TAC grouprelapsed compared to 8/19 (42%) in the TAC/MMF group (p=0.7). The addition of MMF toTAC did not adversely affect the safety of the treatment.Conclusions: Addition of MMF to TAC does not alter the relapse rate of nephrotic syndromein patients with MN.

Journal article

Kousios A, Duncan N, Charif R, Tam FWK, Levy J, Cook HT, Pusey CD, Roufosse C, Chaidos Aet al., 2019, Autologous stem cell transplant for the treatment of type I crystal cryoglobulinaemic glomerulonephritis caused by monoclonal gammopathy of renal significance (MGRS), Kidney International Reports, Vol: 4, Pages: 1342-1348, ISSN: 2468-0249

Cryoglobulins (CGs) are immunoglobulins that precipitate at temperatures below 37°C and dissolve again after rewarming. Cryoglobulinemia may be asymptomatic or cause end-organ damage by CG precipitation in small- to medium-sized blood vessels.1 In their seminal work, Brouet et al.2 classify cryoglobulinemias into 3 subgroups according to CG composition and clonality. In type II cryoglobulinemia there is a mixture of monoclonal IgM with rheumatoid factor activity and polyclonal IgG. In type III, CGs consist of polyclonal IgM and IgG.1 Type II and III cryoglobulinemias are also referred to as mixed cryoglobulinemias and are often caused by chronic hepatitis C infection and less frequently by autoimmune diseases or other viral infections (hepatitis B infection, HIV).3CGs in type I cryoglobulinemia are monoclonal Igs (MIg), also known as paraproteins, commonly IgG, IgM subtypes, or free light chains. The underlying pathological process is a plasma cell or B-cell lymphoproliferative disease, such as multiple myeloma (MM), Waldenström macroglobulinemia, chronic lymphocytic leukemia, or other B-cell non-Hodgkin lymphoma. However, in approximately 40% of symptomatic cases, the plasma cell or B-cell clone is too small to fulfill the diagnostic criteria of MM or overt lymphoma. The term monoclonal gammopathy of undetermined significance (MGUS) used for these cases is a misnomer, as the MIg causes disease regardless of the size and tumor burden.4 For cases with renal involvement, the International Kidney and Monoclonal Gammopathy Research Group introduced the term monoclonal gammopathies of renal significance (MGRS).5 The updated MGRS definition includes monoclonal gammopathies that cause renal disease but have low tumor burden and thus treatment from the hematological standpoint is not imminently indicated.6 These patients may have fewer than 10% plasma cells in bone marrow biopsy, smoldering myeloma, or low-grade lymphomas.7 MGRSs are not of undetermined significanc

Journal article

Navaratnarajah A, Sambasivan K, Cook TH, Pusey C, Roufosse C, Willicombe Met al., 2019, Predicting long-term renal and patient survival by clinicopathological features in elderly patients undergoing a renal biopsy in a UK cohort, Clinical Kidney Journal, Vol: 12, Pages: 512-520, ISSN: 2048-8505

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 i

Journal article

Broecker V, Bardsley V, Torpey N, Perera R, Montero R, Dorling A, Bentall A, Neil D, Willicombe M, Berry M, Roufosse Cet al., 2019, Clinical-pathological correlations in post-transplant thrombotic microangiopathy, Histopathology, Vol: 75, Pages: 88-103, ISSN: 0309-0167

AimsPost‐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 resultsClinical 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.ConclusionsAlthough 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.

Journal article

Hassan S, Regan F, Brown C, Harmer A, Anderson N, Beckwith H, Roufosse C, Santos-Nunez E, Brookes P, Taube D, Willicombe Met al., 2019, Shared alloimmune responses against blood and transplant donors result in adverse clinical outcomes following blood transfusion post renal transplantation, American Journal of Transplantation, Vol: 19, Pages: 1720-1729, ISSN: 1600-6135

De novo HLA donor specific antibodies (DSA) following transplantation are associated with alloimmune injury and allograft failure. Blood transfusions are allogeneic, and when given post-transplant (PTBT) they may independently increase the risk of HLA antibody development. This study aims to analyse the development of HLA transfusion specific antibodies (TSA) to blood donors of transfusions given post-transplant and examine the impact on clinical outcomes. 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=0·0025] and AMR [p=0·02] 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.

Journal article

Kousios A, Storey R, Troy-Barnes E, Hamady M, Salisbury E, Duncan N, Charif R, Tam F, Cook T, Crane J, Chaidos A, Roufosse C, Flora Ret al., 2019, Plasmacytoma-like post-transplant lymphoproliferative disease in a disused arterio-venous fistula: the importance of histopathology., Kidney International Reports, Vol: 4, Pages: 749-755, ISSN: 2468-0249

Common causes of swelling in arteriovenous fistulae (AVFs) include thrombosis, infection, aneurysm, and superior vena cava (SVC) obstruction secondary to previous dialysis vascular catheter use. Malignancies confined in AVFs are rare and have been described in case series and case reports, mostly in immunosuppressed patients.1 Patients who undergo transplantation frequently have functioning or nonfunctioning AVFs. The risk of malignancy is increased in this patient group and thus should be considered in patients presenting with symptomatic AVF. The most common histopathological diagnosis is angiosarcoma.1, 2 Plasmacytoma-like posttransplant lymphoproliferative disease (PTLD) confined in an AVF has not been previously described.

Journal article

Randhawa P, Roufosse C, 2019, The expanding spectrum of antibody-mediated rejection: should we include cases where no anti-HLA donor-specific antibody is detected?, American Journal of Transplantation, Vol: 19, Pages: 622-624, ISSN: 1600-6135

Antibody-mediated rejection (ABMR) in a renal transplant biopsy is most often diagnosed by a combination of microvascular injury (MVI), C4d deposition and presence of circulating DSA. MVI designates the leucocyte margination reaction in glomeruli (glomerulitis, Banff score g) and in peritubular capillaries (peritubular capillaritis, Banff score ptc). MVI (sum of Banff scores g+ptc) is a morphological feature rather than a diagnosis, and is not specific for ABMR.

Journal article

Kousios A, Duncan N, Tam FWK, Chaidos A, Cook HT, Roufosse C, Charif Ret al., 2019, Proliferative glomerulonephritis with monoclonal Ig deposits (PGNMID): diagnostic and treatment challenges for the nephrologist!, Kidney International, Vol: 95, Pages: 467-468, ISSN: 0085-2538

Journal article

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