Imperial College London

ProfessorFrederickTam

Faculty of MedicineDepartment of Immunology and Inflammation

Ken and Mary Minton Chair of Renal Medicine
 
 
 
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Contact

 

+44 (0)20 3313 2354f.tam

 
 
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Location

 

9N, 15C, Commonwealth BuildingHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

135 results found

Tam F, Tempest-Roe S, Prendecki M, McAdoo S, Tanna A, Turner-Stokes T, Masuda E, Willicombe M, Cook T, Roufosse C, Taube D, Pusey Cet al., 2021, Inhibition of Spleen Tyrosine Kinase Decreases Donor Specific Antibody Levels in a Rat Model of Sensitization, Scientific Reports, ISSN: 2045-2322

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, Vol: 255, Pages: 107-119, ISSN: 0022-3417

Experimental autoimmune vasculitis (EAV) is a model of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) induced by immunisation of susceptible rat strains with myeloperoxidase (MPO). Animals develop circulating MPO-ANCA, pulmonary haemorrhage and glomerulonephritis, although renal injury is mild and recovers spontaneously without treatment. In this study we aimed to augment the severity of glomerulonephritis. Following induction of EAV on day 0, a sub-nephritogenic dose of nephrotoxic serum (NTS) containing heterologous antibodies to glomerular basement membrane was administered on day 14. This resulted in a significant increase in disease severity at day 28 compared to MPO immunisation alone - with more urinary abnormalities, infiltrating glomerular leucocytes, and crescent formation that progressed to glomerular and tubulointerstitial scarring by day 56, recapitulating important features of human disease. Importantly, the glomerulonephritis remained pauci-immune, and was strictly dependent on the presence of autoimmunity to MPO, as there was no evidence of renal disease following administration of sub-nephritogenic NTS alone or after immunisation with a control protein in place of MPO. Detailed phenotyping of glomerular leucocytes identified an early infiltrate of non-classical monocytes following NTS administration that, in the presence of autoimmunity to MPO, may initiate the subsequent influx of classical monocytes which augment glomerular injury. We also showed that this model can be used to test novel therapeutics by using a small molecule kinase inhibitor (fostamatinib) that rapidly attenuated both glomerular and pulmonary injury over a four-day treatment period. We believe that this enhanced model of MPO-AAV will prove useful for the study of glomerular leucocyte behaviour and novel therapeutics in AAV in the future. This article is protected by copyright. All rights reserved.

Journal article

Gulati K, Edwards H, Prendecki M, Cairns TD, Condon M, Galliford J, Griffith M, Levy JB, Tam FWK, Tanna A, Pusey CD, McAdoo SPet al., 2021, Combination treatment with rituximab, low-dose cyclophosphamide and plasma exchange for severe antineutrophil cytoplasmic antibody-associated vasculitis, Kidney International, ISSN: 0085-2538

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis can present with life-threatening lung-kidney syndromes. However, many controlled treatment trials excluded patients with diffuse alveolar hemorrhage or severely impaired glomerular filtration rates, and so the optimum treatment in these cases is unclear. In this retrospective cohort study, we report the outcomes of 64 patients with life-threatening disease treated with a combination regimen of rituximab, low-dose intravenous cyclophosphamide, oral glucocorticoids, and plasma exchange. At entry, the median estimated glomerular filtration rate was 9 mL/min, 47% of patients required dialysis, and 52% had diffuse alveolar hemorrhage. All patients received a minimum of seven plasma exchanges, and the median cumulative doses of rituximab, cyclophosphamide, and glucocorticoid were 2, 3, and 2.6 g, respectively, at six months. A total of 94% of patients had achieved disease remission (version 3 Birmingham Vasculitis Activity Score of 0) at this time point, and 67% of patients who required dialysis recovered independent kidney function. During long-term follow-up (median duration 46 months), overall patient survival was 85%, and 69% of patients remained free from end-stage kidney disease, which compares favorably to a historic cohort with severe disease treated with a conventional induction regimen. Combination treatment was associated with prolonged B cell depletion and low rates of relapse; 87% of patients were in continuous remission at month 36. The serious infection rate during total follow-up was 0.28 infections/patient/year, suggesting that combination treatment is not associated with an enduring risk of infection. Thus, we suggest that combination immunosuppressive therapy may permit glucocorticoid avoidance and provide rapid and prolonged disease control in patients with severe ANCA-associated vasculitis.

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

Chen C-H, Chen C-Y, Yu M-C, Fu J-F, Hou Y-C, Wang I-K, Chih Y-H, Weng C-H, Huang W-H, Hsu C-W, Tam FWK, Yen T-Het al., 2021, Impact of kidney size on mortality in diabetic patients receiving peritoneal dialysis., Scientific Reports, Vol: 11, Pages: 1-9, ISSN: 2045-2322

Although patients with diabetes mellitus mostly present with enlarged or normal-sized kidneys throughout their life, a small proportion of patients have small kidneys. This longitudinal study enrolled 83 diabetic patients treated with peritoneal dialysis (PD) between 2015 and 2019. Patients were stratified into two groups, those with enlarged or normal (n = 67) or small (n = 16) kidneys, based on their kidney sizes before dialysis. Patients with small kidney size were not only older (76.63 ± 10.63 vs. 68.03 ± 11.26 years, P = 0.007), suffered longer duration of diabetes mellitus (272.09 ± 305.09 vs. 151.44 ± 85.31 month, P = 0.006) and predominantly female (75.0 vs. 41.8%, P = 0.017), but also had lower serum levels of creatinine (9.63 ± 2.82 vs. 11.74 ± 3.32 mg/dL, P = 0.022) and albumin (3.23 ± 0.67 vs. 3.60 ± 0.47 g/dL, P = 0.010) than patients with enlarged or normal kidney size. At the end of analysis, 14 (16.9%) patients died. Patients with small kidney size demonstrated higher all-cause (50.0 vs. 9.0%, P < 0.001) and infection-related (43.8 vs. 7.5%, P < 0.001) mortality than patients with enlarged or normal kidney size. In a multivariate-logistic-regression model, small kidney size was a powerful predictor of mortality (odds ratio 6.452, 95% confidence interval 1.220-34.482, P = 0.028). Diabetic patients with small kidney size at the beginning of PD carry a substantial risk for mortality.

Journal article

Falcone S, Nicol T, Blease A, Randles MJ, Angus E, Page A, Tam FWK, Pusey CD, Lennon R, Potter PKet al., 2021, A novel model of nephrotic syndrome results from a point mutation in Lama5 and is modified by genetic background, Publisher: WILEY, Pages: 127-128, ISSN: 0959-9673

Conference paper

Mason J, Dattani R, Barwick T, Wardany G, Gibbons N, Morgan P, Pusey C, Tam F, Tomlinson Jet al., 2020, An international patient centred study of Retroperitoneal Fibrosis, QJM: an international journal of medicine, Vol: hcaa327, ISSN: 1460-2393

BackgroundThe impact that rare chronic disorders, such as retroperitoneal fibrosis (RPF), can have on the physical and psychological aspects of a patient’s health is poorly understood. Patient-related outcome measures and experiences provide a unique opportunity to understand the impact rare chronic disorders have on a patient’s life as well as allowing healthcare providers to compare and improve performance.AimTo understand the physical and psychosocial impact that RPF has upon peoples’ lives.DesignAn international online questionnaire was therefore created to gain insights into how patients with RPF, a rare fibro-inflammatory condition, viewed their health and experiences.MethodsAn international online questionnaire comprising 62 questions/free text options, was designed in collaboration with two patient advocates and the multi-disciplinary Renal Association Rare Disease Registry (RaDaR) RPF Group the questionnaire was anonymous and freely accessible on a GOOGLE Form online platform for 6 months.ResultsA total of 229 patients from 30 countries across 5 continents responded. Four key issues were identified; (i) pain; (ii) therapy-related side effects; (iii) lack of informed doctors/information about their condition and its management; and (iv) psychological burden. Variations in diagnosis and management are highlighted with 55% undergoing a biopsy to reach a diagnosis of RPF; 75% of patients underwent a further interventional procedure with 60% concurrently treated medically.ConclusionThis study will guide further development of clinical and academic multi-disciplinary activity and shows the importance of trying to understand the impact of rare chronic disorders on the physical and psychological aspects of a patient’s health.

Journal article

Kost-Alimova M, Sidhom E-H, Satyam A, Chamberlain BT, Dvela-Levitt M, Melanson M, Alper SL, Santos J, Gutierrez J, Subramanian A, Byrne PJ, Grinkevich E, Bricio ER, Kim C, Clark A, Watts A, Thompson R, Marshall J, Pablo JL, Coraor J, Roignot J, Vernon KA, Keller K, Campbell A, Emani M, Racette M, Bazua-Valenti S, Padovano V, Weins A, McAdoo SP, Tam FWK, Ronco L, Wagner F, Tsokos GC, Shaw JL, Greka Aet al., 2020, A high content screen for mucin-1-reducing compounds identifies fostamatinib as a candidate for rapid repurposing for acute lung injury, Cell Reports Medicine, Vol: 1, Pages: 1-15, ISSN: 2666-3791

Drug repurposing has the advantage of identifying potential treatments on a shortened timescale. In response to the pandemic spread of SARS-CoV-2, we took advantage of a high-content screen of 3,713 compounds at different stages of clinical development to identify FDA-approved compounds that reduce mucin-1 (MUC1) protein abundance. Elevated MUC1 levels predict the development of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) and correlate with poor clinical outcomes. Our screen identifies fostamatinib (R788), an inhibitor of spleen tyrosine kinase (SYK) approved for the treatment of chronic immune thrombocytopenia, as a repurposing candidate for the treatment of ALI. In vivo, fostamatinib reduces MUC1 abundance in lung epithelial cells in a mouse model of ALI. In vitro, SYK inhibition by the active metabolite R406 promotes MUC1 removal from the cell surface. Our work suggests fostamatinib as a repurposing drug candidate for ALI.

Journal article

Tam F, Magayr TA, Song X, Streets AJ, Vergoz L, Chang L, Valluru MK, Yap HL, Lannoy M, Haghighi A, Simms RJ, Pei Y, Ong ACMet al., 2020, Global microRNA profiling in human urinary exosomes reveals novel disease biomarkers and cellular pathways for Autosomal Dominant Polycystic Kidney Disease, Kidney International, Vol: 98, Pages: 420-435, ISSN: 0085-2538

MicroRNAs (miRNAs) play an important role in regulating gene expression in health and disease but their role in modifying disease expression in Autosomal Dominant Polycystic Kidney Disease (ADPKD) remains uncertain. Here, we profiled human urinary exosome miRNA by global small RNA-sequencing in an initial discovery cohort of seven patients with ADPKD with early disease (eGFR over 60ml/min/1.73m2), nine with late disease (eGFR under 60ml/min/1.73m2), and compared their differential expression with six age and sex matched healthy controls. Two kidney-enriched candidate miRNA families were identified (miR-192/miR-194-2 and miR-30) and selected for confirmatory testing in a 60 patient validation cohort by quantitative polymerase chain reaction. We confirmed that miR-192-5p, miR-194- 5p, miR-30a-5p, miR-30d-5p and miR-30e-5p were significantly downregulated in patient urine exosomes, in murine Pkd1 cystic kidneys and in human PKD1 cystic kidney tissue. All five miRNAs showed significant correlations with baseline eGFR and ultrasound-determined mean kidney length and improved the diagnostic performance (area under the curve) of mean kidney length for the rate of disease progression. Finally, inverse correlations of these two miRNA families with increased expression in their predicted target genes in patient PKD1 cystic tissue identified dysregulated pathways and transcriptional networks including novel interactions between miR-194-5p and two potentially relevant candidate genes, PIK3R1 and ANO1. Thus, our results identify a subset of urinary exosomal miRNAs that could serve as novel biomarkers of disease progression and suggest new therapeutic targets in ADPKD.

Journal article

McAdoo S, Prendecki M, Tanna A, Bhatt T, Bhangal G, McDaid J, masuda E, Cook H, Tam F, Pusey Cet al., 2020, Spleen tyrosine kinase inhibition is an effective treatment for established vasculitis in a pre-clinical model, Kidney International, Vol: 97, Pages: 1196-1207, ISSN: 0085-2538

The anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are a group of life-threatening multi-system diseases characterized by necrotising inflammation of small blood vessels and crescentic glomerulonephritis. ANCA are thought to play a direct pathogenic role. Previous studies have shown that spleen tyrosine kinase (SYK) is phosphorylated during ANCA-induced neutrophil activation in vitro. However, the role of SKY in vivo is unknown. Here, we studied its role in the pathogenesis of experimental autoimmune vasculitis, a pre-clinical model of myeloperoxidase-ANCA-induced pauci-immune systemic vasculitis in the Wistar Kyoto rat. Up-regulation of SYK expression in inflamed renal and pulmonary tissue during early autoimmune vasculitis was confirmed by immunohistochemical and transcript analysis. R406, the active metabolite of fostamatinib, a small molecule kinase inhibitor with high selectivity for SYK, inhibited ANCA-induced pro-inflammatory responses in rat leucocytes in vitro. In an in vivo study, treatment with fostamatinib for 14 days after disease onset resulted in rapid resolution of urinary abnormalities, significantly improved renal and pulmonary pathology, and preserved renal function. Short-term exposure to fostamatinib did not significantly affect circulating myeloperoxidase-ANCA levels, suggesting inhibition of ANCA-induced inflammatory mechanisms in vivo. Finally, SYK expression was demonstrated within inflammatory glomerular lesions in ANCA-associated glomerulonephritis in patients, particularly within CD68+ve monocytes/macrophages. Thus, our data indicate that SYK inhibition warrants clinical investigation in the treatment of AAV.

Journal article

Tam FWK, Ong ACM, 2020, Renal monocyte chemoattractant protein-1: An emerging universal biomarker and therapeutic target for kidney diseases?, Nephrology Dialysis Transplantation, Vol: 35, Pages: 198-203, ISSN: 0931-0509

Journal article

Falcone S, Wisby L, Nicol T, Blease A, Starbuck B, Parker A, Sanderson J, Brown SDM, Scudamore CL, Pusey C, Tam F, Potter PKet al., 2019, Modification of an aggressive model of Alport Syndrome reveals early differences in disease pathogenesis due to genetic background, Scientific Reports, Vol: 9, ISSN: 2045-2322

The link between mutations in collagen genes and the development of Alport Syndromehas been clearly established and a number of animal models, including knock-out mouselines, have been developed that mirror disease observed in patients. However, it is clearfrom both patients and animal models that the progression of disease can vary greatlyand can be modified genetically. We have identified a point mutation in Col4a4 in micewhere disease is modified by strain background, providing further evidence of thegenetic modification of disease symptoms. Our results indicate that C57BL/6J is aprotective background and postpones end stage renal failure from 7 weeks, as seen on aC3H background, to several months. We have identified early differences in diseaseprogression, including expression of podocyte-specific genes and podocyte morphology.In C57BL/6J mice podocyte effacement is delayed, prolonging normal renal function.The slower disease progression has allowed us to begin dissecting the pathogenesis ofmurine Alport Syndrome in detail. We find that there is evidence of differential geneexpression during disease on the two genetic backgrounds, and that disease diverges by4 weeks of age. We also show that an inflammatory response with increasing MCP-1 andKIM-1 levels precedes loss of renal function.

Journal article

Luz HL, Reichel M, Unwin RJ, Mutig K, Najenson AC, Tonner LM, Eckardt K-U, Tam FWK, Knauf Fet al., 2019, P2X7 receptor stimulation is not required for oxalate crystal-induced kidney injury, Scientific Reports, Vol: 9, ISSN: 2045-2322

Oxalate crystal-induced renal inflammation is associated with progressive kidney failure due to activation of the NLRP3/CASP-1 inflammasome. It has been suggested previously that purinergic P2X7 receptor signaling is critical for crystal-induced inflammasome activation and renal injury. Therefore, we investigated the role of the P2X7 receptor in response to crystal-induced cytokine release, inflammation, and kidney failure using in vitro and in vivo models. Dendritic cells and macrophages derived from murine bone marrow and human peripheral blood mononucleated cells stimulated with calcium-oxalate crystals, monosodium urate crystals, or ATP lead to the robust release of interleukin-1beta (IL-1ß). Treatment with the P2X7 inhibitor A740003 or the depletion of ATP by apyrase selectively abrogated ATP-induced, but not oxalate and urate crystal-induced IL-1ß release. In line with this finding, dendritic cells derived from bone marrow (BMDCs) from P2X7-/- mice released reduced amounts of IL-1ß following stimulation with ATP, while oxalate and urate crystal-induced IL-1ß release was unaffected. In sharp contrast, BMDCs from Casp1-/- mice exhibited reduced IL-1ß release following either of the three stimulants. In addition, P2X7-/- mice demonstrated similar degrees of crystal deposition, tubular damage and inflammation when compared with WT mice. In line with these findings, increases in plasma creatinine were no different between WT and P2X7-/- mice. In contrast to previous reports, our results indicate that P2X7 receptor is not required for crystal-induced CKD and it is unlikely to be a suitable therapeutic target for crystal-induced progressive kidney disease.

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

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

Kang A, Antonelou M, Wong NL, Tanna A, Arulkumaran N, Tam FWK, Pusey CDet al., 2019, Dr. Kang, et al, reply., J Rheumatol, ISSN: 0315-162X

We were surprised to read the letter by Berti and colleagues1, commenting on our recent article on the incidence of arterial and venous thrombosis in antineutrophil cytoplasmic antibody-associated vasculitis (AAV)2 They make the unjustified comment that "the incidence estimates for [arterial (ATE) and venous thrombosis events (VTE)] may be inflated" when we give clear and accurate incidence rates.

Journal article

Kang A, Antonelou M, Wong NL, Tanna A, Arulkumaran N, Tam FWK, Pusey CDet al., 2019, Dr. Kang, et al reply., J Rheumatol, Vol: 46, Pages: 866-867, ISSN: 0315-162X

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

Dooley D, van Timmeren MM, O'Reilly VP, Brady G, O'Brien EC, Fazekas B, Hickey FB, Leacy E, Pusey CD, Tam FWK, Mehrling T, Heeringa P, Little MAet al., 2018, Alkylating histone deacetylase inhibitors may have therapeutic value in experimental myeloperoxidase-ANCA vasculitis, Kidney International, Vol: 94, Pages: 926-936, ISSN: 0085-2538

Current therapies for treating antineutrophil cytoplasm autoantibody (ANCA)–associated vasculitis include cyclophosphamide and corticosteroids. Unfortunately, these agents are associated with severe adverse effects, despite inducing remission in most patients. Histone deacetylase inhibitors are effective in rodent models of inflammation and act synergistically with many pharmacological agents, including alkylating agents like cyclophosphamide. EDO-S101 is an alkylating fusion histone deacetylase inhibitor molecule combining the DNA alkylating effect of Bendamustine with a pan-histone deacetylase inhibitor, Vorinostat. Here we studied the effects of EDO-S101 in two established rodent models of ANCA-associated vasculitis: a passive mouse model of anti-myeloperoxidase IgG-induced glomerulonephritis and an active rat model of myeloperoxidase-ANCA microscopic polyangiitis. Although pretreatment with EDO-S101 reduced circulating leukocytes, it did not prevent the development of passive IgG-induced glomerulonephritis in mice. On the other hand, treatment in rats significantly reduced glomerulonephritis and lung hemorrhage. EDO-S101 also significantly depleted rat B and T cells, and induced DNA damage and apoptosis in proliferating human B cells, suggesting a selective effect on the adaptive immune response. Thus, EDO-S101 may have a role in treatment of ANCA-associated vasculitis, operating primarily through its effects on the adaptive immune response to the autoantigen myeloperoxidase.

Journal article

Tam FWK, McAdoo S, 2018, The role of the spleen tyrosine kinase pathway in driving inflammation in IgA nephropathy, Seminars in Nephrology, Vol: 38, Pages: 496-503, ISSN: 0270-9295

IgA nephropathy is the most common type of primary glomerulonephritis worldwide. At least 25% of patients may progress to kidney failure requiring dialysis or transplantation. Treatment of IgA nephropathy using generalised immunosuppression is controversial, with concerns regarding the balance of safety and efficacy in a non-specific approach. The aim of this review is to describe the recent scientific evidence, and a current clinical trial, investigating whether spleen tyrosine kinase (SYK) may be a novel and selective therapeutic target for IgA nephropathy. SYK, a cytoplasmic tyrosine kinase, has a pivotal role as an early intermediate in intracellular signal transduction cascades for the B cell receptor and the immunoglobulin Fc receptor, and thus is critical for B cell proliferation, differentiation and activation, and for mediating pro-inflammatory responses following Fc receptor engagement in various cell types. In renal biopsies of patients with IgA nephropathy, increased expression and phosphorylation of SYK were detected, and this correlated with the histological features of mesangial and endocapillary proliferation. In cell culture studies, patient-derived IgA1 stimulated mesangial cell SYK activation, cell proliferation and cytokine production, and these responses were attenuated by pharmacological or molecular inhibition of SYK. A global randomised, double-blind, placebo-controlled trial investigating the safety and efficacy of fostamatinib (an oral pro-drug SYK inhibitor) in the treatment of patients with IgA nephropathy is ongoing, which may provide important evidence of the safety and efficacy of targeting this pathway in clinical disease.

Journal article

Nguyen C, König K, Tam F, Hopfer H, Molyneux K, Binet F-I, Jeong Kim Met al., 2018, Higher serum galactose-deficient immunoglobulin A1 concentration is associated with stronger mesangial cellular inflammatory response and more severe histologic findings in immunoglobulin A nephropathy, Clinical Kidney Journal, Vol: 12, Pages: 232-238, ISSN: 2048-8505

BackgroundGalactose-deficient immunoglobulin A1 (Gd-IgA1) is known to play a key role in the pathogenesis of IgA nephropathy (IgAN). We aimed to evaluate whether serum Gd-IgA1 is associated with in vitro activation of mesangial cells in individual patients and how this affects the clinical and histologic parameters.MethodsSerum samples and clinical and histologic data were collected in the University Hospital Basel and Hammersmith Hospital, London. Serum levels of IgA1 and Gd-IgA1 were measured by enzyme-linked immunosorbent assay (ELISA) and lectin-binding assay using lectin Helix aspersa (HA). Primary human mesangial cells were stimulated with IgA1 isolated from serum from individual patients and the concentrations of monocyte chemoattractant protein-1 and interleukin-6 were measured in cell culture supernatant by ELISA.ResultsThirty-three patients were enrolled. A significant correlation was observed between serum Gd-IgA1 levels and the concentration of MCP-1 in the culture supernatant in individual patients (Spearman r = 0.5969, P = 0.0002). There was no significant correlation between serum Gd-IgA1 levels and proteinuria or estimated glomerular filtration rate at diagnosis. However, the serum Gd-IgA1 level was significantly higher in patients with segmental glomerulosclerosis (S0 versus S1, P = 0.0245) and tubular atrophy/interstitial fibrosis (T0 versus T1 and T2, P = 0.0336; T0 versus T2, P = 0.0225).ConclusionsHigher serum Gd-IgA1 concentration is associated with stronger mesangial cell inflammatory response with production of a greater amount of MCP-1 in vitro. This in turn is associated with severe histologic changes. The disease progression with worse renal outcome in patients with higher serum Gd-IgA1 may be therefore mediated by more pronounced mesangial cell inflammatory response leading to more severe histologic changes.

Journal article

Tam FWK, Penfold RS, Prendecki M, McAdoo Set al., 2018, Primary IgA nephropathy: current challenges and future prospects, International Journal of Nephrology and Renovascular Disease, ISSN: 1178-7058

Journal article

Penfold R, Prendecki M, McAdoo S, Tam FWKet al., 2018, Primary IgA nephropathy: current challenges and future prospects, International Journal of Nephrology and Renovascular Disease, Vol: 11, Pages: 137-148, ISSN: 1178-7058

IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, exhibiting a variable clinical and pathological course and significantly contributing to the global burden of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Current standards of care focus on optimization of anti-hypertensive and anti-proteinuric therapies (typically renin-angiotensin system blockade) to reduce disease progression. Much recent attention has focused on whether additional immunosuppression confers better outcomes than supportive management alone and indeed several trials have demonstrated renoprotective effects following use of oral corticosteroids. However, results have been inconsistent and perceived benefits must be balanced against risks and adverse effects associated with generalized immunosuppression, as highlighted by the high-profile STOP-IgAN and TESTING clinical trials. Recent translational research in vitro and animal models of IgAN have generated greater insight into potential therapeutic targets for this complex autoimmune disease. Deeper understanding of the roles of the mucosal immune barrier, complement activation and deposition, T-cell dependent and independent mechanisms of B cell activation, and of the deposition and downstream inflammatory signalling pathways of nephritogenic polymeric IgA1 complexes (eg. signaling of immune receptors via Syk) have formed the rationale for the development of novel agents and clinical trials of more targeted therapies. However, translating findings into clinical practice is challenging, with many immunopathological features of IgAN specific to humans. Recent comprehensive reviews outline current understanding of mechanisms of IgAN as well as ongoing and future clinical trials; it is not our aim to replicate this here. Instead, we take a mechanistic approach to current treatment strategies, outlining advantages and limitations of each before exploring ongoing research with potential translation i

Journal article

Tam FWK, Poo S, Smith C, Hamdulay S, Jacyna M, Tomlinson J, Wernig F, Pusey Cet al., 2018, UK Kidney Week 2018, UK Kidney Week 2018

Conference paper

Tam FWK, Arulkumaran N, Sixma M, Ceravola E, Jentho E, Prendecki M, Bass P, unwin RJ, Singer Met al., 2018, P2X7 receptor antagonism ameliorates renal dysfunction in a rat model of sepsis, Physiological Reports, Vol: 6, Pages: e13622-e13622, ISSN: 2051-817X

Sepsis is a major clinical problem associated with significant organ dysfunction and high mortality. The ATP‐sensitive P2X7 receptor activates the NLRP3 inflammasome and is a key component of the innate immune system. We used a fluid‐resuscitated rat model of fecal peritonitis and acute kidney injury (AKI) to investigate the contribution of this purinergic receptor to renal dysfunction in sepsis. Six and 24 h time‐points were chosen to represent early and established sepsis, respectively. A selective P2X7 receptor antagonist (A‐438079) dissolved in dimethyl sulfoxide (DMSO) was infused 2 h following induction of sepsis. Compared with sham‐operated animals, septic animals had significant increases in heart rate (−1(−4 to 8)% vs. 21(12–26)%; P = 0.003), fever (37.4(37.2–37.6)°C vs. 38.6(38.2–39.0)°C; P = 0.0009), and falls in serum albumin (29(27–30)g/L vs. 26(24–28); P = 0.0242). Serum IL‐1β (0(0–10)(pg/mL) vs. 1671(1445–33778)(pg/mL); P < 0.001) and renal IL‐1β (86(50–102)pg/mg protein vs. 200 (147–248)pg/mg protein; P = 0.0031) were significantly elevated in septic compared with sham‐operated animals at 6 h. Serum creatinine was elevated in septic animals compared with sham‐operated animals at 24 h (23(22–25) μmol/L vs. 28 (25–30)μmol/L; P = 0.0321). Renal IL‐1β levels were significantly lower in A‐438079‐treated animals compared with untreated animals at 6 h (70(55–128)pg/mg protein vs. 200(147–248)pg/mg protein; P = 0.021). At 24 h, compared with untreated animals, A‐438079‐treated animals had more rapid resolution of tachycardia (22(13–36)% vs. −1(−6 to 7)%; P = 0.019) and fever (39.0(38.6–39.1)°C vs. 38.2(37.6–38.7)°C; P < 0.024), higher serum albumin (23(21–25)g/L vs. (27(25–28)g/L); P = 0.006), lower arterial lactate (3.2(2.5–4.3)mmol/L vs. 1.4(0.9–1.8)mmol/L; P = 0.037), and

Journal article

Tam FWK, Montero R, Herath A, Qureshi A, Esfandiari E, Pusey C, Frankel Aet al., 2018, Defining Phenotypes in Diabetic Nephropathy: a novel approach using a cross-sectional analysis of a single centre cohort., Scientific Reports, Vol: 8, ISSN: 2045-2322

The global increase in Diabetes Mellitus (DM) has led to an increase in DM-Chronic Kidney Disease (DM-CKD). In this cross-sectional observational study we aimed to define phenotypes for patients with DM-CKD that in future may be used to individualise treatment We report 4 DM-CKD phenotypes in 220 patients recruited from Imperial College NHS Trust clinics from 2004–2012. A robust principal component analysis (PCA) was used to statistically determine clusters with phenotypically different patients. 163 patients with complete data sets were analysed: 77 with CKD and 86 with DM-CKD. Four different clusters were identified. Phenotypes 1 and 2 are entirely composed of patients with DM-CKD and phenotypes 3 and 4 are predominantly CKD (non-DM-CKD). Phenotype 1 depicts a cardiovascular phenotype; phenotype 2: microvascular complications with advanced DM-CKD; phenotype 3: advanced CKD with less anaemia, lower weight and HbA1c; phenotype 4: hypercholesteraemic, younger, less severe CKD. We are the first group to describe different phenotypes in DM-CKD using a PCA approach. Identification of phenotypic groups illustrates the differences and similarities that occur under the umbrella term of DM-CKD providing an opportunity to study phenotypes within these groups thereby facilitating development of precision/personalised targeted medicine.

Journal article

Arulkumaran N, Pollen S, Greco E, Courtneidge H, Hall A, Duchen M, Tam FWK, Unwin R, Singer Met al., 2018, Renal tubular cell mitochondrial dysfunction occurs despite preserved renal oxygen delivery in experimental septic acute kidney injury, Critical Care Medicine, Vol: 46, Pages: e318-e325, ISSN: 0090-3493

Objective: To explain the paradigm of significant renal functionalimpairment despite preserved hemodynamics and histology insepsis-induced acute kidney injury.Design: Prospective observational animal study.Setting: University research laboratory.Subjects: Male Wistar rats.Intervention: Using a fluid-resuscitated sublethal rat model offecal peritonitis, changes in renal function were characterized inrelation to global and renal hemodynamics, and histology at 6 and24 hours (n = 6–10). Sham-operated animals were used as comparison(n = 8). Tubular cell mitochondrial function was assessedusing multiphoton confocal imaging of live kidney slices incubatedin septic serum.Measurements and Main Results: By 24 hours, serum creatininewas significantly elevated with a concurrent decrease in renal lactateclearance in septic animals compared with sham-operatedand 6-hour septic animals. Renal uncoupling protein-2 was elevatedin septic animals at 24 hours although tubular cell injury wasminimal and mitochondrial ultrastructure in renal proximal tubularcells preserved. There was no significant change in global or renalhemodynamics and oxygen delivery/consumption between shamoperatedand septic animals at both 6- and 24-hour timepoints. Inthe live kidney slice model, mitochondrial dysfunction was seen inproximal tubular epithelial cells incubated with septic serum withincreased production of reactive oxygen species, and decreasesin nicotinamide adenine dinucleotide and mitochondrial membranepotential. These effects were prevented by coincubation with thereactive oxygen species scavenger, 4-hydroxy-2,2,6,6-tetramethyl-piperidin-1-oxyl. Conclusions: Renal dysfunction in sepsis occurs independentlyof hemodynamic instability or structural damage. Mitochondrialdysfunction mediated by circulating mediators that induce localoxidative stress may represent an important pathophysiologicmechanism.

Journal article

Tam FWK, Höllriegl W, Bauer A, Baumgartner B, Dietrich B, Douillard P, Kerschbaumer R, Höbarth G, McKee J, Schinagl A, Thiele M, Weber A, Wolfsegger M, Turecek M, Muchitsch E-M, Scheiflinger F, Glantschnig Het al., 2017, Pharmacokinetics, disease-modifying activity, and safety of an experimental therapeutic targeting an immunological isoform of macrophage migration inhibitory factor, in rat glomerulonephritis, European Journal of Pharmacology, Vol: 820, Pages: 206-216, ISSN: 0014-2999

New therapeutic agents are needed to overcome the toxicity and suboptimal efficacy observed in current treatment of glomerulonephritis (GN). BaxB01 is a fully human monoclonal antibody targeting a disease-related immunologically distinct isoform of Macrophage migration Inhibitory Factor (MIF), designated oxidized MIF (oxMIF) and locally expressed in inflammatory conditions. We report the pharmacokinetic profile of BaxB01, and its dose and exposure-related disease-modifying activity in experimentally induced rat GN.BaxB01 bound to rat oxMIF with high affinity and reduced rat macrophage migration in vitro. After intravenous administration in rats, BaxB01 demonstrated favorable pharmacokinetics, with a half-life of up to nine days. Disease modification was dose-related (≥10 mg/kg) as demonstrated by significantly reduced proteinuria and diminished histopathological glomerular crescent formation. Importantly, a single dose was sufficient to establish an exposure-related, anti-inflammatory milieu via amelioration of glomerular cellular inflammation. Pharmacodynamic modeling corroborated these findings, consistently predicting plasma exposures that were effective in attenuating both anti-inflammatory activity and reducing loss of kidney function. This pharmacologic benefit on glomerular function and structure was sustained during established disease, while correlation analyses confirmed a link between the antibody's anti-inflammatory activity and reduced crescent formation in individual rats. Finally, safety assessment in rats showed that the experimental therapeutic was well tolerated without signs of systemic toxicity or negative impact on kidney function.These data define therapeutically relevant exposures correlated with mechanism-based activity in GN, while toxicological evaluation suggests a large therapeutic index and provides evidence for achieving safe and effective exposure to a MIF isoform-directed therapeutic in nephritis-associated disease.

Journal article

Tam FWK, Pusey CD, 2017, TESTING corticosteroids in IgA nephropathy: a continuing challenge, Clinical Journal of the American Society of Nephrology, Vol: 13, Pages: 158-160, ISSN: 1555-9041

IgA nephropathy (IgAN) is the commonest type of glomerulonephritis worldwide, although the prevalence in some countries may be underestimated depending on the local policy for kidney biopsy. Patients with IgAN have a wide range of prognosis, from microscopic haematuria with stable kidney function through to kidney failure. Long term data show that 20-40% of patients progress to end stage kidney disease within 10-20 years of diagnosis. Recurrence of IgA deposition in the transplanted kidney is common, despite patients being on immunosuppression, and is an important cause of graft failure (1). Clinical features, including hypertension and proteinuria, have been shown to be useful in assessing prognosis. Recently, a combination of histopathological score with clinical data has improved prediction of the risk of progression to kidney failure(2). However, the main role of histology in recent trials has been confirmation of the diagnosis of IgAN, and exclusion of patients with other types of glomerulonephritis or severely scarred kidneys.

Journal article

Tam FWK, Yap HL, frankel A, 2017, MCP-1: A potential target for diabetic microvascular complications?, Urology and Nephology Open Access Journal, Vol: 5, ISSN: 2378-3176

MCP-1 is a potent chemokine with the ability to mobilize and stimulate leucocytes, especially monocytes and macrophages. It is increasingly recognized as an important player in the inflammatory process that is diabetic nephropathy. In this article, we describe its role in inducing renal injury by outlining key studies in animal models and clinical studies of diabetic nephropathy, its association with diabetic retinopathy, as well as its potential use as a prognostic biomarker and as a therapeutic target in the clinical setting.

Journal article

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