Publications
562 results found
Dominy KM, Roufosse C, de Kort H, et al., 2015, Use of quantitative real time polymerase chain reaction to assess gene transcripts associated with antibody-mediated rejection of kidney transplants, Transplantation, Vol: 99, Pages: 1981-1988, ISSN: 0041-1337
Introduction Microarray studies have shown elevated transcript levels of endothelial and natural killer (NK) cell–associated genes during antibody-mediated rejection (AMR) of the renal allograft. This study aimed to assess the use of quantitative real-time polymerase chain reaction as an alternative to microarray analysis on a subset of these elevated genes.Methods Thirty-nine renal transplant biopsies from patients with de novo donor-specific antibodies and eighteen 1-year surveillance biopsies with no histological evidence of rejection were analyzed for expression of 11 genes previously identified as elevated in AMR.Results Expression levels of natural killer markers were correlated to microcirculation inflammation and graft outcomes to a greater extent than endothelial markers. Creating a predictive model reduced the number of gene transcripts to be assessed to 2, SH2D1b and MYBL1, resulting in 66.7% sensitivity and 89.7% specificity for graft loss.Discussion This work demonstrates that elevated gene expression levels, proposed to be associated with AMR, can be detected by established quantitative real-time polymerase chain reaction technology, making transition to the clinical setting feasible. Transcript analysis provides additional diagnostic information to the classification schema for AMR diagnosis but it remains to be determined whether significant numbers of centres will validate transcript analysis in their laboratories and put such analysis into clinical use.
Tesar V, Troyanov S, Bellur S, et al., 2015, Corticosteroids in IgA nephropathy: a retrospective analysis from the VALIGA study, Journal of the American Society of Nephrology, Vol: 26, Pages: 2248-2258, ISSN: 1046-6673
Current guidelines suggest treatment with corticosteroids (CS) in IgA nephropathy (IgAN) when proteinuria is persistently ≥1 g/d despite 3–6 months of supportive care and when eGFR is >50 ml/min per 1.73 m2. Whether the benefits of this treatment extend to patients with an eGFR≤50 ml/min per 1.73 m2, other levels of proteinuria, or different renal pathologic lesions remains unknown. We retrospectively studied 1147 patients with IgAN from the European Validation Study of the Oxford Classification of IgAN (VALIGA) cohort classified according to the Oxford-MEST classification and medication used, with details of duration but not dosing. Overall, 46% of patients received immunosuppression, of which 98% received CS. Treated individuals presented with greater clinical and pathologic risk factors of progression. They also received more antihypertensive medication, and a greater proportion received renin angiotensin system blockade (RASB) compared with individuals without immunosuppressive therapy. Immunosuppression was associated with a significant reduction in proteinuria, a slower rate of renal function decline, and greater renal survival. Using a propensity score, we matched 184 subjects who received CS and RASB to 184 patients with a similar risk profile of progression who received only RASB. Within this group, CS reduced proteinuria and the rate of renal function decline and increased renal survival. These benefits extended to those with an eGFR≤50 ml/min per 1.73 m2, and the benefits increased proportionally with the level of proteinuria. Thus, CS reduced the risk of progression regardless of initial eGFR and in direct proportion to the extent of proteinuria in this cohort.
Shiu KY, McLaughlin L, Rebollo-Mesa I, et al., 2015, B-lymphocytes support and regulate indirect T-cell alloreactivity in individual patients with chronic antibody-mediated rejection, KIDNEY INTERNATIONAL, Vol: 88, Pages: 560-568, ISSN: 0085-2538
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- Citations: 36
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.
Pickering MC, Ismajli M, Condon MB, et al., 2015, Eculizumab as rescue therapy in severe resistant lupus nephritis., Rheumatology, Vol: 54, Pages: 2286-2288, ISSN: 1462-0332
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.
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
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- 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
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- Citations: 11
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
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
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- Citations: 31
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
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- Citations: 11
McLean A, Dominy K, Sosinsky A, et al., 2015, Use of RNA Sequencing for Discovery of Markers of Accommodation in Surveillance Biopsies from Recipients of an ABO-Incompatible Renal Transplant, American Transplant Congress, Publisher: WILEY-BLACKWELL, ISSN: 1600-6135
Koutroutsos K, Charif R, Goodall D, et al., 2015, Recurrent IgA Nephropathy in Kidney Transplant Recipients Receiving a Steroid Sparing Immunosuppression Protocol, American Transplant Congress, Publisher: WILEY-BLACKWELL, ISSN: 1600-6135
Porter A, Condon MB, Doyle AF, et al., 2015, PROSPECTIVE LONG TERM FOLLOW UP OF THE RITUXILUP STEROID SPARING REGIMEN IN LUPUS NEPHRITIS, 52nd Congress of the European-Renal-Association-European-Dialysis-and-Transplant-Assocation, Publisher: OXFORD UNIV PRESS, ISSN: 0931-0509
Wong EKS, Marchbank K, Pappworth I, et al., 2015, THE NATIONAL STUDY OF MEMBRANOPROLIFERATIVE GLOMERULONEPHRTIS AND C3 GLOMERULOPATHY - CHARACTERISATION OF THE PAEDIATRIC COHORT, 52nd Congress of the European-Renal-Association-European-Dialysis-and-Transplant-Assocation, Publisher: OXFORD UNIV PRESS, ISSN: 0931-0509
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- Citations: 1
Yen T-H, Alison MR, Goodlad RA, et al., 2015, Epidermal growth factor attenuates tubular necrosis following mercuric chloride damage by regeneration of indigenous, not bone marrow-derived cells, Journal of Cellular and Molecular Medicine, Vol: 19, Pages: 463-473, ISSN: 1582-4934
To assess effects of epidermal growth factor (EGF) and pegylated granulocyte colony-stimulating factor (P-GCSF; pegfilgrastim) administration on the cellular origin of renal tubular epithelium regenerating after acute kidney injury initiated by mercuric chloride (HgCl2). Female mice were irradiated and male whole bone marrow (BM) was transplanted into them. Six weeks later recipient mice were assigned to one of eight groups: control, P-GCSF+, EGF+, P-GCSF+EGF+, HgCl2, HgCl2+P-GCSF+, HgCl2+EGF+ and HgCl2+P-GCSF+EGF+. Following HgCl2, injection tubular injury scores increased and serum urea nitrogen levels reached uraemia after 3 days, but EGF-treated groups were resistant to this acute kidney injury. A four-in-one analytical technique for identification of cellular origin, tubular phenotype, basement membrane and S-phase status revealed that BM contributed 1% of proximal tubular epithelium in undamaged kidneys and 3% after HgCl2 damage, with no effects of exogenous EGF or P-GCSF. Only 0.5% proximal tubular cells were seen in S-phase in the undamaged group kidneys; this increased to 7–8% after HgCl2 damage and to 15% after addition of EGF. Most of the regenerating tubular epithelium originated from the indigenous pool. BM contributed up to 6.6% of the proximal tubular cells in S-phase after HgCl2 damage, but only to 3.3% after additional EGF. EGF administration attenuated tubular necrosis following HgCl2 damage, and the major cause of this protective effect was division of indigenous cells, whereas BM-derived cells were less responsive. P-GCSF did not influence damage or regeneration.
Wilhelmus S, Cook HT, Noel L-H, et al., 2015, Interobserver Agreement on Histopathological Lesions in Class III or IV Lupus Nephritis, CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 10, Pages: 47-53, ISSN: 1555-9041
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- Citations: 35
Cook HT, Pickering MC, 2015, Histopathology of MPGN and C3 glomerulopathies, NATURE REVIEWS NEPHROLOGY, Vol: 11, Pages: 14-22, ISSN: 1759-5061
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- Citations: 65
Lai P-C, Chiu L-Y, Srivastava P, et al., 2014, Unique Regulatory Properties of Mesangial Cells Are Genetically Determined in the Rat, PLOS One, Vol: 9, ISSN: 1932-6203
Mesangial cells are glomerular cells of stromal origin. During immune complex mediated crescentic glomerulonephritis (Crgn), infiltrating and proliferating pro-inflammatory macrophages lead to crescent formation. Here we have hypothesised that mesangial cells, given their mesenchymal stromal origin, show similar immunomodulatory properties as mesenchymal stem cells (MSCs), by regulating macrophage function associated with glomerular crescent formation. We show that rat mesangial cells suppress conA-stimulated splenocyte proliferation in vitro, as previously shown for MSCs. We then investigated mesangial cell-macrophage interaction by using mesangial cells isolated from nephrotoxic nephritis (NTN)-susceptible Wistar Kyoto (WKY) and NTN-resistant Lewis (LEW) rats. We first determined the mesangial cell transcriptome in WKY and LEW rats and showed that this is under marked genetic control. Supernatant transfer results show that WKY mesangial cells shift bone marrow derived macrophage (BMDM) phenotype to M1 or M2 according to the genetic background (WKY or LEW) of the BMDMs. Interestingly, these effects were different when compared to those of MSCs suggesting that mesangial cells can have unique immunomodulatory effects in the kidney. These results demonstrate the importance of the genetic background in the immunosuppressive effects of cells of stromal origin and specifically of mesangial cell-macrophage interactions in the pathophysiology of crescentic glomerulonephritis.
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.
Kang H, Kerloc'h A, Rotival M, et al., 2014, Kcnn4 is a regulator of macrophage multinucleation in bone homeostasis and inflammatory disease, Cell Reports, Vol: 8, Pages: 1210-1224, ISSN: 2211-1247
Macrophages can fuse to form osteoclasts in boneor multinucleate giant cells (MGCs) as part of theimmune response. We use a systems geneticsapproach in rat macrophages to unravel their geneticdeterminants of multinucleation and investigate theirrole in both bone homeostasis and inflammatory disease.We identify a trans-regulated gene networkassociated with macrophage multinucleation andKcnn4 as being the most significantly trans-regulatedgene in the network and induced at the onsetof fusion. Kcnn4 is required for osteoclast andMGC formation in rodents and humans. Geneticdeletion of Kcnn4 reduces macrophage multinucleationthrough modulation of Ca2+ signaling, increasesbone mass, and improves clinical outcomein arthritis. Pharmacological blockade of Kcnn4reduces experimental glomerulonephritis. Our dataimplicate Kcnn4 in macrophage multinucleation,identifying it as a potential therapeutic target for inhibitionof bone resorption and chronic inflammation.
Owen-Casey MP, Sim R, Cook HT, et al., 2014, Value of antibodies to free light chains in immunoperoxidase studies of renal biopsies, Journal of Clinical Pathology, Vol: 67, Pages: 661-666, ISSN: 1472-4146
Aims Because immunoglobulin abnormalities may affect the kidney, investigation of renal biopsies requires immunohistological study of light chains. A problem is that most antibodies to light chains react with whole immunoglobulins as well as free light chains, and there are generally many more whole immunoglobulins than free light chains. The usefulness of antibodies that only detected free light chains was investigated.Methods Antibodies to free light chains were used in an immunoperoxidase method on paraffin sections of 198 renal biopsies, and compared with conventional antibodies against light chains examined by immunofluorescence on 13 frozen sections and by immunoperoxidase on 46 paraffin sections.Results Immunofluorescence and immunoperoxidase were concordant on 10 of 13 biopsies. Immunofluorescence detected slight deposition of light chains in three biopsies not shown by immunoperoxidase, of undetermined clinical significance. Using immunoperoxidase, the free light chain antibodies were more sensitive than conventional antibodies, giving much cleaner staining and better detection of deposits in AL amyloid, light chain deposition disease and cryoglobulinaemic glomerulonephritis. The free light chain antibodies showed discordance or ambiguity between immunohistological and clinical findings in seven (4%) of 185 patients with known immunoglobulin status. These included two of 28 cases of AL amyloid that showed no light chain deposition. The method was not designed for detection of light chain restriction in neoplastic plasma or lymphoplasmacytic cells.Conclusions Polyclonal antibodies to free light chains are an improvement on conventional antibodies in immunoperoxidase study of paraffin sections of renal biopsies and are useful in everyday practice.
McLean A, Chan K, Roufosse C, et al., 2014, 5-Year Outcomes of a Randomized Prospective Trial of Tacrolimus Maintenance Monotherapy After Alemtuzumab Induction and Early Steroid Withdrawal in Kidney Transplantation: Rejection, HLA Antibody Formation, and Recurrent Disease., World Transplant Congress, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 114-114, ISSN: 0041-1337
McLean A, Brookes P, Charif R, et al., 2014, One Agent-Once a Day: 2 Year Outcomes of a Prospective Randomized Trial of Once Daily (Extended Release) Tacrolimus Maintenance Monotherapy vs Twice Daily (Standard Release) Tacrolimus After Alemtuzumab Induction & Early Steroid Cessation (TAESR Trial). Rejection and Variation in Tacrolimus Levels., World Transplant Congress, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 536-536, ISSN: 0041-1337
Willicombe M, Roufosse C, Moran L, et al., 2014, Significance of Tubuloreticular Inclusions in Renal Allografts, World Transplant Congress, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 529-529, ISSN: 0041-1337
Clarke C, Lawrence C, Willicombe M, et al., 2014, IgG Donor Specific Antibodies [DSAs] in Patients With Transplant Glomerulopathy [TG] Are Associated With Inferior Allograft Survival, World Transplant Congress, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 440-440, ISSN: 0041-1337
Smith J, Syed A, Bhangal G, et al., 2014, Treatment With a Spleen Tyrosine Kinase Inhibitor Reduced Inflammation and Protected Kidney Function in Experimental Renal Allograft Rejection, World Transplant Congress, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 27-27, ISSN: 0041-1337
McAdoo S, Bhangal G, Smith J, et al., 2014, Spleen Tyrosine Kinase (SYK) Expression in Antibody-Mediated Renal Allograft Rejection, World Transplant Congress, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 513-514, ISSN: 0041-1337
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