Publications
590 results found
Prendecki M, Cairns T, Pusey CD, 2016, Familial vasculitides: granulomatosis with polyangitis and microscopic polyangitis in two brothers with differing anti-neutrophil cytoplasm antibody specificity, Clinical Kidney Journal, Vol: 9, Pages: 429-431, ISSN: 2048-8513
Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a group of rare autoimmune diseases. Although the aetiology of AAV is uncertain, it is likely that genetic and environmental factors contribute. We report the unusual case of two brothers presenting with AAV with differing clinical pictures and differing ANCA specificity. There is a recently identified difference in genetic risk factors associated with ANCA specificity, making it surprising that first-degree relatives develop AAV with differing clinical and serological features. Our report illustrates the complex aetiology of AAV and suggests that further research on the interaction of genetic and environmental factors is needed.
Pusey CD, Connor TM, Aiello V, et al., 2016, The natural history of IgM nephropathy in adults, Nephrology Dialysis Transplantation, ISSN: 1460-2385
Background: Immunoglobulin M (IgM) nephropathy is an idiopathic glomerulonephritis characterised 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 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: (1) dominant mesangial staining for IgM, (2) mesangial deposits on EM, (3) exclusion of systemic disease.Results: The median age was 42 years and 24 patients were male. 39% of patients presented with the nephrotic syndrome, 49% patients presented with non-nephrotic proteinuria, and 39% had eGFR <60 ml/min. 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. 39% of nephrotic patients achieved complete remission, and outcome was significantly worse in those who did not respond to treatment. FSGS 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.
Moschidou D, Corcelli M, Hau K-L, et al., 2016, Human Chorionic Stem Cells: Podocyte Differentiation and Potential for the Treatment of Alport Syndrome, STEM CELLS AND DEVELOPMENT, Vol: 25, Pages: 395-404, ISSN: 1547-3287
- Author Web Link
- Cite
- Citations: 12
Kraaij T, Tengström FC, Kamerling SW, et al., 2016, A novel method for high-throughput detection and quantification of neutrophil extracellular traps reveals ROS-independent NET release with immune complexes, Autoimmunity Reviews, Vol: 15, Pages: 577-584, ISSN: 1873-0183
A newly-described first-line immune defence mechanism of neutrophils is the release of neutrophil extracellular traps (NETs). Immune complexes (ICxs) induce low level NET release. As such, the in vitro quantification of NETs is challenging with current methodologies. In order to investigate the role of NET release in ICx-mediated autoimmune diseases, we developed a highly sensitive and automated method for quantification of NETs. After labelling human neutrophils with PKH26 and extracellular DNA with Sytox green, cells are fixed and automatically imaged with 3-dimensional confocal laser scanning microscopy (3D-CLSM). NET release is then quantified with digital image analysis whereby the NET amount (Sytox green area) is corrected for the number of imaged neutrophils (PKH26 area). A high sensitivity of the assay is achieved by a) significantly augmenting the area of the well imaged (11%) as compared to conventional assays (0.5%) and b) using a 3D imaging technique for optimal capture of NETs, which are topologically superimposed on neutrophils. In this assay, we confirmed low levels of NET release upon human ICx stimulation which were positive for citrullinated histones and neutrophil elastase. In contrast to PMA-induced NET release, ICx-induced NET release was unchanged when co-incubated with diphenyleneiodonium (DPI). We were able to quantify NET release upon stimulation with serum from RA and SLE patients, which was not observed with normal human serum. To our knowledge, this is the first semi-automated assay capable of sensitive detection and quantification of NET release at a low threshold by using 3D CLSM. The assay is applicable in a high-throughput manner and allows the in vitro analysis of NET release in ICx-mediated autoimmune diseases.
Henderson SR, Shah A, Copley SJ, et al., 2015, Occam's razor or Hickam's dictum? Allergic bronchopulmonary aspergillosis and eosinophilic granulomatosis with polyangiitis, Thorax, Vol: 71, Pages: 193-195, ISSN: 1468-3296
Vallant N, Sandhu B, Woollard K, et al., 2015, MESENCHYMAL STEM CELLS IN MACHINE PERFUSION-THE PERFECT COMBINATION TO ATTENUATE ISCHEMIA-REPERFUSION INJURY IN SOLID ORGAN TRANSPLANTATION?, Publisher: WILEY-BLACKWELL, Pages: 811-811, ISSN: 0934-0874
- Author Web Link
- Cite
- Citations: 1
Tan LT, Davagnanam I, Isa H, et al., 2015, Clinical and Imaging Features of Lacrimal Gland Involvement in Granulomatosis with Polyangiitis, OPHTHALMOLOGY, Vol: 122, Pages: 2125-2129, ISSN: 0161-6420
- Author Web Link
- Cite
- Citations: 7
Isa H, Luthert P, Rose G, et al., 2015, Tissue Interleukin-17 and Interleukin-23 as Biomarkers for Orbital Granulomatosis with Polyangiitis, OPHTHALMOLOGY, Vol: 122, Pages: 2140-2142, ISSN: 0161-6420
- Author Web Link
- Cite
- Citations: 10
Hamour S, Gan P-Y, Pepper R, et al., 2015, Local IL-17 Production Exerts a Protective Role in Murine Experimental Glomerulonephritis, PLoS One, Vol: 10, ISSN: 1932-6203
IL-17 is a pro-inflammatory cytokine implicated in the pathogenesis of glomerulonephritis and IL-17 deficient mice are protected from nephrotoxic nephritis. However, a regulatory role for IL-17 has recently emerged. We describe a novel protective function for IL-17 in the kidney. Bone marrow chimeras were created using wild-type and IL-17 deficient mice and nephrotoxic nephritis was induced. IL-17 deficient hosts transplanted with wild-type bone marrow had worse disease by all indices compared to wild-type to wild-type bone marrow transplants (serum urea p<0.05; glomerular thrombosis p<0.05; tubular damage p<0.01), suggesting that in wild-type mice, IL-17 production by renal cells resistant to radiation is protective. IL-17 deficient mice transplanted with wild-type bone marrow also had a comparatively altered renal phenotype, with significant differences in renal cytokines (IL-10 p<0.01; IL-1β p<0.001; IL-23 p<0.01), and macrophage phenotype (expression of mannose receptor p<0.05; inducible nitric oxide synthase p<0.001). Finally we show that renal mast cells are resistant to radiation and produce IL-17, suggesting they are potential local mediators of disease protection. This is a novel role for intrinsic cells in the kidney that are radio-resistant and produce IL-17 to mediate protection in nephrotoxic nephritis. This has clinical significance as IL-17 blockade is being trialled as a therapeutic strategy in some autoimmune diseases.
Thiele M, Kerschbaumer RJ, Tam FW, et al., 2015, Selective Targeting of a Disease-Related Conformational Isoform of Macrophage Migration Inhibitory Factor Ameliorates Inflammatory Conditions., Journal of Immunology, ISSN: 1550-6606
Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine and counterregulator of glucocorticoids, is a potential therapeutic target. MIF is markedly different from other cytokines because it is constitutively expressed, stored in the cytoplasm, and present in the circulation of healthy subjects. Thus, the concept of targeting MIF for therapeutic intervention is challenging because of the need to neutralize a ubiquitous protein. In this article, we report that MIF occurs in two redox-dependent conformational isoforms. We show that one of the two isoforms of MIF, that is, oxidized MIF (oxMIF), is specifically recognized by three mAbs directed against MIF. Surprisingly, oxMIF is selectively expressed in the plasma and on the cell surface of immune cells of patients with different inflammatory diseases. In patients with acute infections or chronic inflammation, oxMIF expression correlated with inflammatory flare-ups. In addition, anti-oxMIF mAbs alleviated disease severity in mouse models of acute and chronic enterocolitis and improved, in synergy with glucocorticoids, renal function in a rat model of crescentic glomerulonephritis. We conclude that oxMIF represents the disease-related isoform of MIF; oxMIF is therefore a new diagnostic marker for inflammation and a relevant target for anti-inflammatory therapy.
McAdoo SP, Bhangal G, Page T, et al., 2015, Correlation of disease activity in proliferative glomerulonephritis with glomerular spleen tyrosine kinase expression, Kidney International, Vol: 88, Pages: 52-60, ISSN: 0085-2538
Spleen tyrosine kinase (SYK) is an important component of the intracellular signaling pathway for various immunoreceptors. Inhibition of SYK has shown promise in preclinical models of autoimmune and glomerular disease. However, the description of SYK expression in human renal tissue, which would be desirable ahead of clinical studies, is lacking. Here we conducted immunohistochemical analysis for total and phosphorylated SYK in biopsy specimens from >120 patients with a spectrum of renal pathologies, including thin basement membrane lesion, minimal change disease, membranous nephropathy, IgA nephropathy, lupus nephritis, ANCA-associated glomerulonephritis, antiglomerular basement membrane disease, and acute tubular necrosis. We found significant SYK expression in proliferative glomerulonephritis and that glomerular expression levels correlated with presenting serum creatinine and histological features of disease activity that predict outcome in IgA nephropathy, lupus nephritis, ANCA-associated glomerulonephritis, and antiglomerular basement membrane disease. SYK was phosphorylated within pathological lesions, such as areas of extracapillary and endocapillary proliferation, and appeared to localize to both infiltrating leucocytes and to resident renal cells within diseased glomeruli. Thus SYK is associated with the pathogenesis of proliferative glomerulonephritides, suggesting that these conditions may respond to SYK inhibitor treatment.
Weiner M, Goh SM, Mohammad AJ, et al., 2015, Outcome and Treatment of Elderly Patients with ANCA-Associated Vasculitis, CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 10, Pages: 1128-1135, ISSN: 1555-9041
- Author Web Link
- Cite
- Citations: 62
Tarzi RM, Liu J, Schneiter S, et al., 2015, CD14 expression is increased on monocytes in patients with anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis and correlates with the expression of ANCA autoantigens, CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol: 181, Pages: 65-75, ISSN: 0009-9104
- Author Web Link
- Cite
- Citations: 18
McAdoo SP, Tanna A, Randone O, et al., 2015, Necrotizing and crescentic glomerulonephritis presenting with preserved renal function in patients with underlying multisystem autoimmune disease: a retrospective case series, RHEUMATOLOGY, Vol: 54, Pages: 1025-1032, ISSN: 1462-0324
- Author Web Link
- Open Access Link
- Cite
- Citations: 11
Joshi L, Tanna A, McAdoo SP, et al., 2015, Long-term Outcomes of Rituximab Therapy in Ocular Granulomatosis with Polyangiitis <i>Impact on Localized and Nonlocalized Disease</i>, OPHTHALMOLOGY, Vol: 122, Pages: 1262-1268, ISSN: 0161-6420
- Author Web Link
- Cite
- Citations: 41
Behmoaras J, Diaz AG, Venda L, et al., 2015, Macrophage Epoxygenase Determines a Profibrotic Transcriptome Signature, Journal of Immunology, Vol: 194, Pages: 4705-4716, ISSN: 1550-6606
Epoxygenases belong to the cytochrome P450 family. They generate epoxyeicosatrienoic acids, which are known to have anti-inflammatory effects, but little is known about their role in macrophage function. By high-throughput sequencing of RNA in primary macrophages derived from rodents and humans, we establish the relative expression of epoxygenases in these cells. Zinc-finger nuclease-mediated targeted gene deletion of the major rat macrophage epoxygenase Cyp2j4 (ortholog of human CYP2J2) resulted in reduced epoxyeicosatrienoic acid synthesis. Cyp2j4−/− macrophages have relatively increased peroxisome proliferator-activated receptor-γ levels and show a profibrotic transcriptome, displaying overexpression of a specific subset of genes (260 transcripts) primarily involved in extracellular matrix, with fibronectin being the most abundantly expressed transcript. Fibronectin expression is under the control of epoxygenase activity in human and rat primary macrophages. In keeping with the in vitro findings, Cyp2j4−/− rats show upregulation of type I collagen following unilateral ureter obstruction of the kidney, and quantitative proteomics analysis (liquid chromatography–tandem mass spectrometry) showed increased renal type I collagen and fibronectin protein abundance resulting from experimentally induced crescentic glomerulonephritis in these rats. Taken together, these results identify the rat epoxygenase Cyp2j4 as a determinant of a profibrotic macrophage transcriptome that could have implications in various inflammatory conditions, depending on macrophage function.
Koutroutsos K, Charif R, Roufosse C, et al., 2015, Successful Management of Post Transplant Focal Segmental Glomerulosclerosis With Plasma Exchange and Rituximab, American Transplant Congress, Publisher: WILEY-BLACKWELL, ISSN: 1600-6135
Reynolds J, Preston GA, Pressler BM, et al., 2015, Autoimmunity to the alpha 3 chain of type IV collagen in glomerulonephritis is triggered by 'autoantigen complementarity', JOURNAL OF AUTOIMMUNITY, Vol: 59, Pages: 8-18, ISSN: 0896-8411
- Author Web Link
- Cite
- Citations: 11
Pepper RJ, Wang H-H, Rajakaruna GK, et al., 2015, S100A8/A9 (Calprotectin) Is Critical for Development of Glomerulonephritis and Promotes Inflammatory Leukocyte-Renal Cell Interactions, AMERICAN JOURNAL OF PATHOLOGY, Vol: 185, Pages: 1264-1274, ISSN: 0002-9440
- Author Web Link
- Cite
- Citations: 31
Rahmattulla C, van Wijngaarden RAFDL, Berden AE, et al., 2015, Renal function and ear, nose, throat involvement in anti-neutrophil cytoplasmic antibody-associated vasculitis: prospective data from the European Vasculitis Society clinical trials, RHEUMATOLOGY, Vol: 54, Pages: 899-907, ISSN: 1462-0324
- Author Web Link
- Cite
- Citations: 25
Power A, Usvyat L, Pusey C, et al., 2015, CONTRASTING WORLDWIDE TRENDS OF STROKE INCIDENCE IN HEMODIALYSIS - CAUSE FOR CONCERN, 52nd Congress of the European-Renal-Association-European-Dialysis-and-Transplant-Assocation, Publisher: OXFORD UNIV PRESS, ISSN: 0931-0509
Power A, Usvyat L, Marcelli D, et al., 2015, RISING GLOBAL INCIDENCE OF HEMORRHAGIC STROKE IN HEMODIALYSIS, 52nd Congress of the European-Renal-Association-European-Dialysis-and-Transplant-Assocation, Publisher: OXFORD UNIV PRESS, ISSN: 0931-0509
Croft AP, Smith SW, Carr S, et al., 2015, Successful outcome of pregnancy in patients with anti-neutrophil cytoplasm antibody-associated small vessel vasculitis, KIDNEY INTERNATIONAL, Vol: 87, Pages: 807-811, ISSN: 0085-2538
- Author Web Link
- Cite
- Citations: 19
Singh S, Procter S, Power A, et al., 2015, SURVEY OF STAFF OPINIONS ABOUT EXTENDED HAEMODIALYSIS TREATMENT TIME AND SERVICE IMPLICATIONS., Journal of Renal Care, Vol: 41, Pages: 162-167, ISSN: 1755-6686
We explored the potential impact of staff opinions and service provision upon patient's willingness to recruit to a clinical trial studying the effects of extended treatment time (TT) on haemodialysis (HD), six hours versus four hours for a period of twenty-four weeks.
Tanna A, Pusey C, 2015, CLINICAL TRIALS Rituximab for maintenance of remission in AAV, NATURE REVIEWS NEPHROLOGY, Vol: 11, Pages: 131-132, ISSN: 1759-5061
- Author Web Link
- Cite
- Citations: 5
Henderson SR, Copley SJ, Pusey CD, et al., 2014, Prolonged B cell depletion with rituximab is effective in treating refractory pulmonary granulomatous inflammation in granulomatosis with polyangiitis (GPA), Medicine, Vol: 93, ISSN: 0304-5412
Pulmonary nodule formation is a frequent feature of granulomatosis with polyangiitis (GPA). Traditional induction therapy includes methotrexate or cyclophosphamide, however, pulmonary nodules generally respond slower than vasculitic components of disease. Efficacy of rituximab (RTX) solely for the treatment of pulmonary nodules has not been assessed. In this observational cohort study, we report patient outcomes with RTX in GPA patients with pulmonary nodules who failed to achieve remission following conventional immunosuppression. Patients (n = 5) with persistent pulmonary nodules were identified from our clinic database and retrospectively evaluated. Systemic manifestations, inflammatory markers, disease activity, concurrent immunosuppression, and absolute B cell numbers were recorded pre-RTX and at 6 monthly intervals following treatment. Chest radiographs at each time point were scored by an experienced radiologist, blinded to clinical details. Five patients with GPA and PR3-ANCA were evaluated (2 male, 3 female), mean age 34 (22–52) years. Pulmonary nodules (median 4, range 2–6), with or without cavitation were present in all patients. RTX induced initial B cell depletion (<5 cells/μL) in all patients but re-population was observed in 3 patients. Repeated RTX treatment in these 3 and persistent B cell depletion in the whole cohort was associated with further significant radiological improvement. Radiographic scoring at each time interval showed reduction in both number of nodules (P = <0.0001) and largest nodule diameter (P = <0.0001) in all patients for at least 18 months following B cell depletion. In summary, RTX therapy induces resolution of pulmonary granulomatous inflammation in GPA following prolonged B cell depletion.
McAdoo SP, Reynolds J, Bhangal G, et al., 2014, Spleen tyrosine kinase inhibition attenuates autoantibody production and reverses experimental autoimmune GN, Journal of the American Society of Nephrology, Vol: 25, Pages: 2291-2302, ISSN: 1046-6673
Spleen tyrosine kinase (SYK) has an important role in immunoreceptor signaling, and SYK inhibition has accordingly attenuated immune-mediated injury in several in vivo models. However, the effect of SYK inhibition on autoantibody production remains unclear, and SYK inhibition has not been studied in an autoimmune model of renal disease. We, therefore, studied the effect of SYK inhibition in experimental autoimmune GN, a rodent model of antiglomerular basement membrane disease. We show glomerular SYK expression and activation by immunohistochemistry in both experimental and clinical disease, and we show that treatment with fostamatinib, a small molecule kinase inhibitor selective for SYK, completely prevents the induction of experimental autoimmune GN. In established experimental disease, introduction of fostamatinib treatment led to cessation of autoantibody production, reversal of renal injury, preservation of biochemical renal function, and complete protection from lung hemorrhage. B cell ELISpot and flow cytometric analysis suggest that short-term fostamatinib treatment inhibits the generation and activity of antigen-specific B cells without affecting overall B-cell survival. Additionally, fostamatinib inhibited proinflammatory cytokine production by nephritic glomeruli ex vivo and cultured bone marrow-derived macrophages in vitro, suggesting additional therapeutic effects independent of effects on autoantibody production that are likely related to inhibited Fc receptor signaling within macrophages in diseased glomeruli. Given these encouraging results in an in vivo model that is highly applicable to human disease, we believe clinical studies targeting SYK in GN are now warranted.
Todd SK, Pepper RJ, Draibe J, et al., 2014, Regulatory B cells are numerically but not functionally deficient in anti-neutrophil cytoplasm antibody-associated vasculitis, RHEUMATOLOGY, Vol: 53, Pages: 1693-1703, ISSN: 1462-0324
- Author Web Link
- Cite
- Citations: 48
Walsh M, Faurschou M, Berden A, et al., 2014, Long-Term Follow-Up of Cyclophosphamide Compared with Azathioprine for Initial Maintenance Therapy in ANCA-Associated Vasculitis, CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 9, Pages: 1571-1576, ISSN: 1555-9041
- Author Web Link
- Cite
- Citations: 44
Tarzi RM, Mason JC, Pusey CD, 2014, Issues in trial design for ANCA-associated and large-vessel vasculitis, NATURE REVIEWS RHEUMATOLOGY, Vol: 10, Pages: 502-510, ISSN: 1759-4790
- Author Web Link
- Cite
- Citations: 7
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.