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Article ; Online: Can Urinary Complement Proteins Stratify Patients to Therapeutic Complement Inhibitors?

Medjeral-Thomas, Nicholas R

Kidney international reports

2022 Volume 7, Issue 5, Page(s) 939–941

Language	English
Publishing date	2022-03-28
Publishing country	United States
Document type	Editorial
ISSN	2468-0249
ISSN (online)	2468-0249
DOI	10.1016/j.ekir.2022.03.024
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Article ; Online: New Insights into Epidemiology and Outcome of Bacterial Infection-Related Glomerulonephritis.

Medjeral-Thomas, Nicholas R / Pusey, Charles D

Clinical journal of the American Society of Nephrology : CJASN

2021 Volume 16, Issue 8, Page(s) 1149–1151

MeSH term(s)	Bacterial Infections ; Glomerulonephritis/diagnosis ; Glomerulonephritis/epidemiology ; Humans
Language	English
Publishing date	2021-08-03
Publishing country	United States
Document type	Editorial ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2226665-3
ISSN	1555-905X ; 1555-9041
ISSN (online)	1555-905X
ISSN	1555-9041
DOI	10.2215/CJN.07910621
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Zs.A 6584: Show issues

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Article ; Online: Complement in IgA Nephropathy: The Role of Complement in the Pathogenesis, Diagnosis, and Future Management of IgA Nephropathy.

Medjeral-Thomas, Nicholas R / O'Shaughnessy, Michelle M

Advances in chronic kidney disease

2020 Volume 27, Issue 2, Page(s) 111–119

Abstract: Immunoglobulin A (IgA) nephropathy (IgAN) is an important cause of chronic and end-stage kidney disease. IgAN pathogenesis is incompletely understood. In particular, we cannot adequately explain the heterogeneity in clinical and histologic features and ... ...

Abstract	Immunoglobulin A (IgA) nephropathy (IgAN) is an important cause of chronic and end-stage kidney disease. IgAN pathogenesis is incompletely understood. In particular, we cannot adequately explain the heterogeneity in clinical and histologic features and severities that characterizes IgAN. This limits patient stratification to appropriate and effective treatments and the development of disease-targeted therapies. Studies of the role of the alternative, lectin, and terminal complement pathways in IgAN have enhanced our understanding of disease pathogenesis and inform the development of novel diagnostic and therapeutic strategies. For example, recent genetic, serologic, and immunohistologic evidence suggests that imbalances between the main alternative complement pathway regulator protein (factor H) and competitor proteins that deregulate complement activity (factor H-related proteins 1 and 5, FHR1, and FHR5) associate with IgAN severity: a relative abundance of FHR1 and FHR5 amplifies complement-dependent inflammation and exacerbates kidney injury. Ongoing characterization of the mechanisms by which complement activity contributes to IgAN pathogenesis will facilitate the development of complement-based diagnostic techniques, biomarkers of disease activity and severity, and novel targeted therapies.
Language	English
Publishing date	2020-06-19
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1548-5609 ; 1548-5595
ISSN (online)	1548-5609
ISSN	1548-5595
DOI	10.1053/j.ackd.2019.12.004
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Zs.A 4627: Show issues

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Article ; Online: Complement activation in IgA nephropathy.

Medjeral-Thomas, Nicholas R / Cook, H Terence / Pickering, Matthew C

Seminars in immunopathology

2021 Volume 43, Issue 5, Page(s) 679–690

Abstract: IgA nephropathy pathogenesis is incompletely understood, and this limits the development of disease-specific biomarkers and effective therapies. Evidence of complement activity in IgA nephropathy is well established. However, a growing body of research ... ...

Abstract	IgA nephropathy pathogenesis is incompletely understood, and this limits the development of disease-specific biomarkers and effective therapies. Evidence of complement activity in IgA nephropathy is well established. However, a growing body of research indicates complement activity is an important contributor to IgA nephropathy pathology. In particular, multiple associations have been identified between complement alternative, lectin and terminal pathway proteins and IgA nephropathy severity. Recently, we have also gained insight into possible mechanisms that could link glomerular IgA deposition, complement activity, glomerular inflammation and disease severity. Ongoing clinical trials of therapeutic complement inhibitors will provide insight into the importance of complement activity to IgA nephropathy pathogenesis. Further research into mechanisms of complement activity is essential to improving our understanding and management of patients with IgA nephropathy.
MeSH term(s)	Complement Activation ; Complement System Proteins/metabolism ; Glomerulonephritis, IGA/diagnosis ; Glomerulonephritis, IGA/etiology ; Glomerulonephritis, IGA/metabolism ; Humans ; Immunoglobulin A/metabolism ; Kidney Glomerulus/metabolism
Chemical Substances	Immunoglobulin A ; Complement System Proteins (9007-36-7)
Language	English
Publishing date	2021-08-11
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2316828-6
ISSN	1863-2300 ; 1863-2297
ISSN (online)	1863-2300
ISSN	1863-2297
DOI	10.1007/s00281-021-00882-9
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Zs.A 1425: Show issues

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Article ; Online: Complement and kidney disease, new insights.

Medjeral-Thomas, Nicholas R / Pickering, Matthew C / Cook, H Terence

Current opinion in nephrology and hypertension

2021 Volume 30, Issue 3, Page(s) 310–316

Abstract: Purpose of review: In this review, we discuss recent studies showing the importance of the complement pathway in kidney disease.: Recent findings: Recent findings in C3 glomerulopathy (C3G) include: acute postinfectious glomerulonephritis is ... ...

Abstract	Purpose of review: In this review, we discuss recent studies showing the importance of the complement pathway in kidney disease. Recent findings: Recent findings in C3 glomerulopathy (C3G) include: acute postinfectious glomerulonephritis is characterised by the presence of antifactor B antibodies; human leukocyte antigen type, but not rare complement gene variation, is associated with primary immunoglobulin-associated membranoproliferative GN and C3G. Immunohistochemistry in C3G shows that factor H related protein 5 (FHR5) is the most prevalent complement protein and correlates with kidney function. A multicentre study supported the use of mycophenolate mofetil (MMF) in C3G even after a propensity matching analysis. In immunoglobulin A nephropathy (IgAN) several studies have emphasised the importance of complement. Imbalances of circulating FH and FHR1 and FHR5, which interfere with the regulatory functions of FH, associate with IgAN. Immunohistochemistry has shown associations between glomerular FHR5 deposition and C3 activation; glomerular FHR5 associated with clinical markers of IgAN severity. Data also suggest the lectin complement pathway contributes to IgAN severity. We also discuss complement activation in thrombotic microangiopathy and other kidney diseases. Summary: Complement activity can be detected in a wide range of kidney diseases and this provides pathogenic insight and potential for therapy with the ongoing development of several drugs directed at complement activation.
MeSH term(s)	Complement Activation ; Complement System Proteins ; Humans ; Kidney Diseases/immunology ; Multicenter Studies as Topic
Chemical Substances	CFHR5 protein, human ; Complement System Proteins (9007-36-7)
Language	English
Publishing date	2021-10-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1151092-4
ISSN	1473-6543 ; 1535-3842 ; 1062-4813 ; 1062-4821
ISSN (online)	1473-6543 ; 1535-3842
ISSN	1062-4813 ; 1062-4821
DOI	10.1097/MNH.0000000000000705
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Zs.A 3686: Show issues

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Article ; Online: Cohort Study of Outpatient Hemodialysis Management Strategies for COVID-19 in North-West London.

Medjeral-Thomas, Nicholas R / Thomson, Tina / Ashby, Damien / Muthusamy, Anand / Nevin, Margaret / Duncan, Neill / Loucaidou, Marina

Kidney international reports

2020 Volume 5, Issue 11, Page(s) 2055–2065

Abstract: Background: Dialysis patients are at risk of severe coronavirus disease 2019 (COVID-19). We managed COVID-19 hemodialysis outpatients in dedicated satellite dialysis units. This provided rare opportunity to study early disease progress in community- ... ...

Abstract	Background: Dialysis patients are at risk of severe coronavirus disease 2019 (COVID-19). We managed COVID-19 hemodialysis outpatients in dedicated satellite dialysis units. This provided rare opportunity to study early disease progress in community-based patients. We aimed to (i) understand COVID-19 progression, (ii) identify markers of future clinical severity, and (iii) assess associations between dialysis management strategies and COVID-19 clinical outcomes. Methods: We conducted a cohort study of all outpatients managed at a COVID-19 hemodialysis unit. We analyzed data recorded as part of providing COVID-19 clinical care. We analyzed associations between features at diagnosis and the first 3 consecutive hemodialysis sessions in patients who required future hospital admission, and those who had died at 28 days. Results: Isolated outpatient hemodialysis was provided to 106 patients over 8 weeks. No patients received antiviral medication or hydroxychloroquine. Twenty-one patients (20%) were admitted at COVID-19 diagnosis; 29 of 85 patients (34%) were admitted after initial outpatient management; 16 patients (15%) died. By multivariate analysis, nonactive transplant list status, use of institutional transport, and increased white cell count associated with future hospitalization and increased age associated with death. Oxygen saturations progressively decreased over the first 3 dialysis sessions in the cohorts that progressed to future hospital admission or death. Mean ultrafiltration volume of the first 3 hemodialysis sessions was reduced in the same cohorts. Conclusions: Outpatient hemodialysis in patients with COVID-19 is safe for patients and staff. Features at the first 3 dialysis sessions can identify individuals at risk of future hospitalization and death from COVID-19.
Keywords	covid19
Language	English
Publishing date	2020-08-25
Publishing country	United States
Document type	Journal Article
ISSN	2468-0249
ISSN (online)	2468-0249
DOI	10.1016/j.ekir.2020.08.022
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Article ; Online: Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy.

Kidney international reports

2023 Volume 8, Issue 12, Page(s) 2754–2764

Abstract: Introduction: Complement 3 glomerulopathy (C3G) is a rare inflammatory kidney disease mediated by dysregulation of the alternative complement pathway. No targeted therapy exists for this aggressive glomerulonephritis. Efficacy, safety, tolerability, ... ...

Abstract	Introduction: Complement 3 glomerulopathy (C3G) is a rare inflammatory kidney disease mediated by dysregulation of the alternative complement pathway. No targeted therapy exists for this aggressive glomerulonephritis. Efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) (measured by complement biomarkers) of iptacopan were assessed in patients with C3G. Methods: In this phase 2, multicenter, open-label, single-arm, nonrandomized study, adults with biopsy-proven, native kidney C3G (native cohort) and kidney transplant recipients with C3G recurrence (recurrent kidney transplant [KT] cohort) received iptacopan twice daily (bid) for 84 days (days 1-21: 10-100 mg; days 22-84: 200 mg). The primary end point was the urine protein-to-creatinine ratio (UPCR; native cohort) and the change in the C3 deposit score of kidney biopsy (recurrent KT cohort). The complement pathway measures included Wieslab assay, soluble C5b9, and serum C3 levels. Results: A total of 27 patients (16 native cohort and 11 recurrent KT cohort) were enrolled and all completed the study. In the native cohort, UPCR levels decreased by 45% from baseline to week 12 ( Conclusion: Iptacopan resulted in statistically significant and clinically important reductions in UPCR and normalization of serum C3 levels in the native cohort and reduced C3 deposit scores in the recurrent KT cohort with favorable safety and tolerability. (ClinicalTrials.gov identifier: NCT03832114).
Language	English
Publishing date	2023-09-22
Publishing country	United States
Document type	Journal Article
ISSN	2468-0249
ISSN (online)	2468-0249
DOI	10.1016/j.ekir.2023.09.017
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Article ; Online: Glomerular Complement Factor H-Related Protein 5 (FHR5) Is Highly Prevalent in C3 Glomerulopathy and Associated With Renal Impairment.

Medjeral-Thomas, Nicholas R / Moffitt, Hilary / Lomax-Browne, Hannah J / Constantinou, Nicholas / Cairns, Tom / Cook, H Terence / Pickering, Matthew C

Kidney international reports

2019 Volume 4, Issue 10, Page(s) 1387–1400

Abstract: Introduction: Therapeutic agents that target complement are increasingly available for glomerular diseases. However, the mechanisms linking glomerular complement deposition with inflammation and damage are incompletely understood. Complement factor H- ... ...

Abstract	Introduction: Therapeutic agents that target complement are increasingly available for glomerular diseases. However, the mechanisms linking glomerular complement deposition with inflammation and damage are incompletely understood. Complement factor H-related protein 5 (FHR5) interacts with complement C3 and is considered to promote activation. Circulating and glomerular FHR5 associates with IgA nephropathy and abnormal FHR5 associates with familial C3 glomerulopathy (C3G). We characterized glomerular FHR5 staining in C3G and assessed its relationships with histological features of glomerular injury and clinical outcome. Methods: We developed FHR5 staining protocols for formalin-fixed paraffin-embedded (FFPE) renal tissue and applied them to surplus biopsy sections from a C3G cohort. Results: Glomerular FHR5 was highly prevalent in native and transplant C3G and correlated with glomerular C3 and C5b-9 staining. Glomerular FHR5 staining correlated negatively with estimated glomerular filtration rate (eGFR) ( Conclusions: Glomerular FHR5 is highly prevalent in C3G, interacts with glomerular C3, and is associated with markers of disease severity. Glomerular FHR5 likely exacerbates complement-mediated glomerular damage in C3G and its interaction with glomerular complement might be exploited to target complement therapeutic agents.
Language	English
Publishing date	2019-06-19
Publishing country	United States
Document type	Journal Article
ISSN	2468-0249
ISSN (online)	2468-0249
DOI	10.1016/j.ekir.2019.06.008
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Article ; Online: Protease inhibitor plasma concentrations associate with COVID-19 infection.

Medjeral-Thomas, Nicholas R / Troldborg, Anne / Hansen, Annette G / Pihl, Rasmus / Clarke, Candice L / Peters, James E / Thomas, David C / Willicombe, Michelle / Palarasah, Yaseelan / Botto, Marina / Pickering, Matthew C / Thiel, Steffen

Oxford open immunology

2021 Volume 2, Issue 1, Page(s) iqab014

Abstract: Protease inhibitors influence a range of innate immunity and inflammatory pathways. We quantified plasma concentrations of key anti-inflammatory protease inhibitors in chronic haemodialysis patients with coronavirus disease 2019 (COVID-19). The samples ... ...

Abstract	Protease inhibitors influence a range of innate immunity and inflammatory pathways. We quantified plasma concentrations of key anti-inflammatory protease inhibitors in chronic haemodialysis patients with coronavirus disease 2019 (COVID-19). The samples were collected early in the disease course to determine whether plasma protease inhibitor levels associated with the presence and severity of COVID-19. We used antibody-based immunoassays to measure plasma concentrations of C1 esterase inhibitor, alpha2-macroglobulin, antithrombin and inter-alpha-inhibitor heavy chain 4 (ITIH4) in 100 serial samples from 27 haemodialysis patients with COVID-19. ITIH4 was tested in two assays, one measuring intact ITIH4 and another also detecting any fragmented ITIH4 (total ITIH4). Control cohorts were 32 haemodialysis patients without COVID-19 and 32 healthy controls. We compared protease inhibitor concentration based on current and future COVID-19 severity and with C-reactive protein. Results were adjusted for repeated measures and multiple comparisons. Analysis of all available samples demonstrated lower plasma C1 esterase inhibitor and α2M and higher total ITIH4 in COVID-19 compared with dialysis controls. These differences were also seen in the first sample collected after COVID-19 diagnosis, a median of 4 days from diagnostic swab. Plasma ITIH4 levels were higher in severe than the non-severe COVID-19. Serum C-reactive protein correlated positively with plasma levels of antithrombin, intact ITIH4 and total ITIH4. In conclusion, plasma protease inhibitor concentrations are altered in COVID-19.
Language	English
Publishing date	2021-07-07
Publishing country	England
Document type	Journal Article
ISSN	2633-6960
ISSN (online)	2633-6960
DOI	10.1093/oxfimm/iqab014
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Article ; Online: O

Dotz, Viktoria / Visconti, Alessia / Lomax-Browne, Hannah J / Clerc, Florent / Hipgrave Ederveen, Agnes L / Medjeral-Thomas, Nicholas R / Cook, H Terence / Pickering, Matthew C / Wuhrer, Manfred / Falchi, Mario

Journal of the American Society of Nephrology : JASN

2021 Volume 32, Issue 10, Page(s) 2455–2465

Abstract: Background: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is a leading cause of renal failure. The disease mechanisms are not completely understood, but a higher abundance of galactose-deficient IgA is recognized to ... ...

Abstract	Background: IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide and is a leading cause of renal failure. The disease mechanisms are not completely understood, but a higher abundance of galactose-deficient IgA is recognized to play a crucial role in IgAN pathogenesis. Although both types of human IgA (IgA1 and IgA2) have several Methods: To gain insights into the complex Results: Multiple structural features of Conclusions: Our high-resolution data suggest that IgA
MeSH term(s)	Adult ; Case-Control Studies ; Chromatography, Liquid ; Cross-Sectional Studies ; Female ; Galactose/chemistry ; Galactose/metabolism ; Glomerular Filtration Rate ; Glomerulonephritis, IGA/blood ; Glomerulonephritis, IGA/physiopathology ; Glycopeptides/analysis ; Glycosylation ; Humans ; Immunoglobulin A/chemistry ; Immunoglobulin A/metabolism ; Male ; Mass Spectrometry ; Middle Aged ; N-Acetylneuraminic Acid/metabolism ; Polysaccharides/chemistry
Chemical Substances	Glycopeptides ; Immunoglobulin A ; Polysaccharides ; N-Acetylneuraminic Acid (GZP2782OP0) ; Galactose (X2RN3Q8DNE)
Language	English
Publishing date	2021-06-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2020081208
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