Publications
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Kang A, Antonelou M, Wong NL, et al., 2018, High Incidence of Arterial and Venous Thrombosis in Antineutrophil Cytoplasmic Antibody-associated Vasculitis., Journal of Rheumatology, Vol: 45, ISSN: 0315-162X
OBJECTIVE: To determine the incidence of arterial thrombotic events (ATE) and venous thromboembolism (VTE) in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). METHODS: This is a retrospective cohort study presenting the incidence of ATE (coronary events or ischemic stroke) and VTE [pulmonary embolism (PE) or deep venous thrombosis (DVT)] in patients diagnosed with AAV between 2005 and 2014. RESULTS: There were 204 patients with AAV who were identified. Median followup for surviving patients was 5.8 (range 1-10) years, accounting for 1088 person-years (PY). The incidence of ATE was 2.67/100 PY (1.56 for coronary events and 1.10 for ischemic stroke) and for VTE was 1.47/100 PY (0.83 for DVT only and 0.64 for PE with/without DVT). On multivariate analysis, prior ischemic heart disease (IHD) and advancing age were the only independent predictors of ATE. Among patients without prior IHD or stroke, the incidence of ATE remained elevated at 2.32/100 PY (1.26 for coronary events and 1.06 for ischemic stroke). ATE, but not VTE, was an independent predictor of all-cause mortality. Event rates for both ATE and VTE were highest in the first year after diagnosis of AAV but remained above the population incidence during the 10-year followup period. In comparison to reported rates for the UK population, the event rates in our AAV patients were 15-times higher for coronary events, 11-times higher for incident stroke, and 20-times higher for VTE. CONCLUSION: Patients with AAV have a high incidence of arterial and venous thrombosis, particularly in the first year after diagnosis.
Gulati K, McAdoo SP, 2018, Anti-Glomerular Basement Membrane Disease, Rheumatic Disease Clinics of North America, Vol: 44, Pages: 651-673, ISSN: 0889-857X
Anti–glomerular basement membrane (GBM) disease often presents with rapidly progressive glomerulonephritis with or without lung hemorrhage. It is rare to present with lung hemorrhage alone.• Antibodies are generally directed at EA or EB epitopes found within the noncollagenous (NC1) domain of the α3 chain of type IV collagen.• Renal and patient survival in untreated anti-GBM is poor, although intensive therapy provides improved outcomes in patients with alveolar hemorrhage or rapidly progressive glomerulonephritis not requiring dialysis at outset.• Relapses are uncommon in patients with anti-GBM disease.• Patients who are double positive for antineutrophil cytoplasm antibody and anti-GBM have more relapsing disease and often need maintenance immunosuppressive therapy.
McAdoo SP, Pusey CD, 2018, Peroxidasin-a Novel Autoantigen in Anti-GBM Disease?, Journal of the American Society of Nephrology, Vol: 29, Pages: 2605-2607, ISSN: 1046-6673
Alexander S, John GT, Korula A, et al., 2018, Protocol and rationale for the first South Asian 5-year prospective longitudinal observational cohort study and biomarker evaluation investigating the clinical course and risk profile of IgA nephropathy: GRACE IgANI cohort [version1; referees: 2 approved], Wellcome Open Research, Vol: 3, ISSN: 2398-502X
Background: IgA nephropathy (IgAN) is the most common primary glomerulonephritis and an important cause of end-stage kidney disease. Unlike the slowly progressive course seen among Caucasian and East Asian subjects (actuarial survival 80-85% over 10 years), in India about 30-40% of patients have nephrotic syndrome and renal dysfunction at presentation and a 10-year renal survival of 35%, as reported from a retrospective registry. These observations cannot be entirely attributed to a lack of uniform screening protocols or late referral and attest to the probability that IgAN may not be the same disease in different parts of the world. Methods: We will prospectively recruit 200 patients with IgAN (the GRACE IgANI- Glomerular Research And Clinical Experiments- Ig ANephropathy in Indians-cohort) and stratify them into low and high risk of progression based on published absolute renal risk scores. We will test the validity of this risk score in an unselected Indian IgAN population over a 5-year follow-up period. In parallel, we will undertake extensive exploratory serum, urine, renal and microbiome biomarker studies, firstly, to determine if the underlying pathogenic pathways are the same in Indian IgAN compared to those reported in Caucasian and East Asian IgAN. Secondly, we will systematically assess the value of measuring selected biomarkers and adding this data to traditional measures of risk in IgAN to predict kidney failure. We ultimately hope to generate a composite IgAN risk score specific for the Indian population. Ethics and data dissemination: Approval was obtained from the Institutional Review Board (Silver, Research and Ethics Committee) of the Christian Medical College, Vellore, India (Ref. No. IRB Min. No. 8962 [Other] dated 23.07.2014 and IRB Min. No. 9481 [Other] dated 24.06.2015). It is anticipated that results of this study will be presented at national and international meetings, with reports being published from late 2018.
Prendecki M, Pusey CD, 2018, Recent advances in understanding of the pathogenesis of ANCA-associated vasculitis [version 1; referees: 2 approved], F1000Research, Vol: 7, ISSN: 2046-1402
Anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are rare systemic autoimmune diseases characterised by inflammation of small blood vessels. Recent developments have been made in our understanding of the pathogenesis of these diseases, including the pathogenic role of ANCA, neutrophils and monocytes as mediators of injury, dysregulation of the complement system, and the role of T and B cells. Current treatment strategies for AAV are based on broad immunosuppression, which may have significant side effects. Advances in understanding of the pathogenesis of disease have led to the identification of new therapeutic targets which may lead to treatment protocols with less-toxic side effects. The aim of this review is to summarise current information and recent advances in understanding of the pathogenesis of AAV.
Kraaij T, Kamerling SWA, van Dam LS, et al., 2018, Excessive neutrophil extracellular trap formation in ANCA-associated vasculitis is independent of ANCA, Kidney International, Vol: 94, Pages: 139-149, ISSN: 0085-2538
Neutrophil extracellular traps (NETs) are auto-antigenic strands of extracellular DNA covered with myeloperoxidase (MPO) and proteinase3 (PR3) that can be a source for the formation of anti-neutrophil cytoplasmic autoantibodies (ANCAs). The presence of NETs was recently demonstrated in renal tissue of patients with ANCA-associated vasculitis (AAV). NET formation was enhanced in AAV, suggesting that MPO-ANCA could trigger NET formation, supporting a vicious circle placing NETs in the center of AAV pathogenesis. Here we investigated NET formation in 99 patients with AAV by a novel highly sensitive and automated assay. There was a significant excess of ex vivo NET formation in both MPO-ANCA- and PR3-ANCA-positive patients with AAV compared to healthy individuals. Excessive NET formation did not correlate with serum ANCA levels. Likewise, immunoglobulin G depletion had no effect on excessive NET formation in patients with AAV, indicating an ANCA-independent process. Next, we explored the relation of excessive NET formation to clinical disease in ten patients with AAV and showed that excessive NET formation was predominantly found during active disease, more so than during remission. Excessive NET formation was found in patients with AAV hospitalized for disease relapse but not during severe infection. Thus, excessive NET formation in AAV is independent of ANCA, and an excess of ex vivo NET formation was related to active clinical disease in patients with AAV and a marker of autoimmunity rather than infection.
Prendecki M, Bhatt T, Dudhiya F, et al., 2018, SPLEEN TYROSINE KINASE EXPRESSION IN HUMAN NEUTROPHILS IN AAV, 55th Congress of the European-Renal-Association (ERA) and European-Dialysis-and-Transplantation-Association (EDTA), Publisher: OXFORD UNIV PRESS, ISSN: 0931-0509
McAdoo SP, Medjeral-Thomas N, Gopaluni S, et al., 2018, Long-term follow-up of a combined rituximab and cyclophosphamide regimen in renal anti-neutrophil cytoplasm antibody-associated vasculitis (vol 33, pg 899, 2018), NEPHROLOGY DIALYSIS TRANSPLANTATION, Vol: 33, Pages: 899-899, ISSN: 0931-0509
Gulati K, McAdoo S, Galliford J, et al., 2018, PLASMAPHERESIS, RITUXIMAB AND LOW-DOSE CYCLOPHOSPHAMIDE FOR REMISSION INDUCTION THERAPY IN SEVERE ANCA-ASSOCIATED VASCULITIS, 55th Congress of the European-Renal-Association (ERA) and European-Dialysis-and-Transplantation-Association (EDTA), Publisher: OXFORD UNIV PRESS, ISSN: 0931-0509
Tam FWK, Poo S, Smith C, et al., 2018, UK Kidney Week 2018, UK Kidney Week 2018
Prendecki M, Martin L, Tanna A, et al., 2018, Increased prevalence of thyroid disease in patients with antineutrophil cytoplasmic antibodies-associated vasculitis, Journal of Rheumatology, Vol: 45, ISSN: 0315-162X
OBJECTIVE: Antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) has been linked with thyroid disease as a result of antithyroid medications. We assessed the prevalence of thyroid disease in our patients with AAV. METHODS: Clinical records of 279 patients with AAV diagnosed between 1991 and 2014 were analyzed. RESULTS: Thyroid disease was identified in 21.5% of patients, but only 2 had previously received propylthiouracil. There was a greater proportion of female patients, patients with antimyeloperoxidase antibodies, and patients with renal disease in the group with thyroid disease. CONCLUSION: Our data show a higher prevalence of thyroid disease in patients with AAV than the general population. This was not attributable to antithyroid drugs.
Hill NR, Cook T, Pusey C, et al., 2018, RIPK3-deficient mice were not protected from nephrotoxic nephritis, BMC Nephrology, Vol: 19, ISSN: 1471-2369
Background/Aims: Necrotizing glomerular lesions are a feature of severe glomerulonephritis. Unlike apoptosis, cellular necrosis has the potential to release damage-associated proteins into the microenvironment, thereby potentiating inflammation. Until recently necrosis was thought to be an unregulated cellular response to injury. However, recent evidence suggests that under certain circumstances receptor mediated necrosis occurs in response to death ligand signalling, one form of which is termed necroptosis. RIPK3, a receptor interacting protein, is a limiting step in the intracellular signalling pathway of necroptosis. A non-redundant role for RIPK3 has been implicated in mouse models of renal ischaemia reperfusion injury and toxic renal injury. The aim of this study was to investigate the role of RIPK3 in nephrotoxic nephritis (NTN), a model of immune complex glomerulonephritis in mice. Methods: We induced NTN in RIPK3-/- and WT mice, comparing histology and renal function in both groups. Results: There was no improvement in urinary albumin creatinine ratio, serum urea, glomerular thrombosis or glomerular macrophage infiltration in the RIPK3-/- mice compared to WT. There was also no difference in number of apoptotic cells in glomeruli as measured by TUNEL staining between the RIPK3-/- and WT mice. Conclusion: The data suggests that RIPK3 is not on a critical pathway in the pathogenesis of nephrotoxic nephritis.
Medjeral-Thomas NR, Troldborg A, Constantinou N, et al., 2018, Progressive IgA Nephropathy Is Associated With Low Circulating Mannan-Binding Lectin-Associated Serine Protease-3 (MASP-3) and Increased Glomerular Factor H-Related Protein-5 (FHR5) Deposition, KIDNEY INTERNATIONAL REPORTS, Vol: 3, Pages: 426-438, ISSN: 2468-0249
IntroductionIgA nephropathy (IgAN) is characterized by glomerular deposition of galactose-deficient IgA1 and complement proteins and leads to renal impairment. Complement deposition through the alternative and lectin activation pathways is associated with renal injury.MethodsTo elucidate the contribution of the lectin pathway to IgAN, we measured the 11 plasma lectin pathway components in a well-characterized cohort of patients with IgAN.ResultsM-ficolin, L-ficolin, mannan-binding lectin (MBL)–associated serine protease (MASP)-1 and MBL-associated protein (MAp) 19 were increased, whereas plasma MASP-3 levels were decreased in patients with IgAN compared with healthy controls. Progressive disease was associated with low plasma MASP-3 levels and increased glomerular staining for C3b/iC3b/C3c, C3d, C4d, C5b-9, and factor H–related protein 5 (FHR5). Glomerular FHR5 deposition positively correlated with glomerular C3b/iC3b/C3c, C3d, and C5b-9 deposition, but not with glomerular C4d. These observations, together with the finding that glomerular factor H (fH) deposition was reduced in progressive disease, are consistent with a role for fH deregulation by FHR5 in renal injury in IgAN.ConclusionOur data indicate that circulating MASP-3 levels could be used as a biomarker of disease severity in IgAN and that glomerular staining for FHR5 could both indicate alternative complement pathway activation and be a tissue marker of disease severity.
Wernig F, Hatfield E, Smith C, et al., 2018, Early Treatment With Rituximab Can Improve Clinical Outcomes In Isolated IgG4- related Hypophysitis, The Endocrine Society Annual Meeting, Publisher: Oxford University Press (OUP), ISSN: 0163-769X
Basu N, Karabayas M, Pusey C, 2018, Prognosis and future developments in vasculitis, Best Practice and Research: Clinical Rheumatology, Vol: 32, Pages: 148-165, ISSN: 1521-6942
The prognosis of ANCA-associated vasculitis has been transformed in recent years. Once it was a set of invariably acute and fatal conditions, but these disorders are currently considered to be chronic diseases. This change is largely attributable to earlier diagnosis and the careful application of immunotherapeutics. However, patients still experience premature mortality, relapse, comorbid ill health and poor quality of life. Mortality rates in large-vessel vasculitis are not comparable; however, morbidity and poor patient outcomes prevail. Toxicity secondary to glucocorticoids represents a common driver of poor outcomes across systemic vasculitis. The main thrust of future treatment strategies is to reduce if not eliminate exposure to these agents.
Tam FWK, Montero R, Herath A, et 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.
van Daalen EE, Jennette JC, McAdoo SP, et al., 2018, Predicting Outcome in Patients with Anti-GBM Glomerulonephritis, 18th International Vasculitis and ANCA Workshop, Publisher: AMER SOC NEPHROLOGY, Pages: 63-72, ISSN: 1555-9041
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McAdoo SP, Medjeral-Thomas N, Gopaluni S, et al., 2017, Long-term Follow-up of a Combined Rituximab and Cyclophosphamide Regimen in Renal ANCA-associated Vasculitis, Nephrology Dialysis Transplantation, ISSN: 0931-0509
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.
van Dam L, Kraaij T, Kamerling S, et al., 2017, Ex Vivo Induced Neutrophil Extracellular Traps Are Intrinsically Different in Anca-Associated Vasculitis and Systemic Lupus Erythematosus, Publisher: WILEY, ISSN: 2326-5191
Theodosopoulou M, Casanova Rituerto D, Dor F, et al., 2017, HEALTH LITERACY: THE ROLE OF PERSONAL EXPERIENCE IN DECEASED ORGAN DONATION, Publisher: WILEY, Pages: 432-432, ISSN: 0934-0874
Sandhu B, Ahnstroem J, Crawley J, et al., 2017, CYTOTOPIC THROMBIN INHIBITION ATTENUATES MICROVASCULAR ENDOTHELIAL ISCHAEMIA-REPERFUSION INJURY, Publisher: WILEY, Pages: 48-48, ISSN: 0934-0874
Vallant N, Sandhu B, Trento C, et al., 2017, INVESTIGATION OF MESENCHYMAL STEM CELLS FOR PRECONDITIONING OF KIDNEY GRAFTS IN AN EX-VIVO PORCINE MODEL OF HYPOTHERMIC MACHINE PERFUSION, Publisher: WILEY, Pages: 501-501, ISSN: 0934-0874
Theodosopoulou M, Casanova D, Dor F, et al., 2017, SPANISH MEDICAL STUDENTS AND DECEASED ORGAN DONATION, Publisher: WILEY, Pages: 184-184, ISSN: 0934-0874
Theodosopoulou M, Dor F, Casanova Rituerto D, et al., 2017, LOOKING AT DECEASED ORGAN DONATION CAMPAIGNS FROM LAY PEOPLE'S EYES, Publisher: WILEY, Pages: 433-433, ISSN: 0934-0874
Sandhu B, Rutter G, Prendecki M, et al., 2017, HYPOXIA INDUCES ENDOPLASMIC RETICULUM STRESS AND UNFOLDED PROTEIN RESPONSES IN ISOLATED HUMAN ISLETS, Publisher: WILEY, Pages: 520-520, ISSN: 0934-0874
Theodosopoulou M, Dor F, Rituerto DC, et al., 2017, VIEWS OF UK RENAL PATIENTS REGARDING DECEASED ORGAN DONATION, Publisher: WILEY, Pages: 433-433, ISSN: 0934-0874
Sandhu B, Bishop H, Lioja D, et al., 2017, A NEW EX VIVO MODEL OF REPERFUSION INJURY IN HUMAN ORGANS, Publisher: WILEY, Pages: 505-505, ISSN: 0934-0874
Theodosopoulou M, Dor F, Rituerto DC, et al., 2017, HEALTH LITERACY PRACTICES AMONG DUTCH HOSPITAL ADMINISTRATIVE PERSONNEL, Publisher: WILEY, Pages: 433-433, ISSN: 0934-0874
Vallant N, Wolfhagen N, Sandhu B, et al., 2017, DIRECT COMPARISON OF HYPOTHERMIC AND NORMOTHERMIC MACHINE PERFUSION IN A PORCINE <i>EX</i>-<i>VIVO</i> KIDNEY MODEL, Publisher: WILEY, Pages: 9-9, ISSN: 0934-0874
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