Imperial College London

PROFESSOR H. TERENCE COOK

Faculty of MedicineDepartment of Immunology and Inflammation

Emeritus Professor
 
 
 
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Contact

 

+44 (0)20 3313 2009t.h.cook

 
 
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Assistant

 

Miss Claudia Rocchi +44 (0)20 3313 2315

 
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Location

 

9N9Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

539 results found

Wong EKS, Marchbank KJ, Lomax-Browne H, Pappworth IY, Denton H, Cooke K, Ward S, McLoughlin A-C, Richardson G, Wilson V, Harris CL, Morgan BP, Hakobyan S, McAlinden P, Gale DP, Maxwell H, Christian M, Malcomson R, Goodship THJ, Marks SD, Pickering MC, Kavanagh D, Cook HT, Johnson SA, MPGNDDDC3 Glomerulopathy Rare Disease Group and National Study of MPGNDDDC3 Glomerulopathy Investigatorset al., 2021, C3 Glomerulopathy and Related Disorders in Children: Etiology-Phenotype Correlation and Outcomes., Clin J Am Soc Nephrol, Vol: 16, Pages: 1639-1651

BACKGROUND AND OBJECTIVES: Membranoproliferative GN and C3 glomerulopathy are rare and overlapping disorders associated with dysregulation of the alternative complement pathway. Specific etiologic data for pediatric membranoproliferative GN/C3 glomerulopathy are lacking, and outcome data are based on retrospective studies without etiologic data. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A total of 80 prevalent pediatric patients with membranoproliferative GN/C3 glomerulopathy underwent detailed phenotyping and long-term follow-up within the National Registry of Rare Kidney Diseases (RaDaR). Risk factors for kidney survival were determined using a Cox proportional hazards model. Kidney and transplant graft survival was determined using the Kaplan-Meier method. RESULTS: Central histology review determined 39 patients with C3 glomerulopathy, 31 with immune-complex membranoproliferative GN, and ten with immune-complex GN. Patients were aged 2-15 (median, 9; interquartile range, 7-11) years. Median complement C3 and C4 levels were 0.31 g/L and 0.14 g/L, respectively; acquired (anticomplement autoantibodies) or genetic alternative pathway abnormalities were detected in 46% and 9% of patients, respectively, across all groups, including those with immune-complex GN. Median follow-up was 5.18 (interquartile range, 2.13-8.08) years. Eleven patients (14%) progressed to kidney failure, with nine transplants performed in eight patients, two of which failed due to recurrent disease. Presence of >50% crescents on the initial biopsy specimen was the sole variable associated with kidney failure in multivariable analysis (hazard ratio, 6.2; 95% confidence interval, 1.05 to 36.6; P<0.05). Three distinct C3 glomerulopathy prognostic groups were identified according to presenting eGFR and >50% crescents on the initial biopsy specimen. CONCLUSIONS: Crescentic disease was a key risk factor associated with kidney failure in a national cohort of pediatric patients with mem

Journal article

Rovin BH, Adler SG, Barratt J, Bridoux F, Burdge KA, Chan TM, Cook HT, Fervenza FC, Gibson KL, Glassock RJ, Jayne DRW, Jha V, Liew A, Liu Z-H, Mejia-Vilet JM, Nester CM, Radhakrishnan J, Rave EM, Reich HN, Ronco P, Sanders J-SF, Sethi S, Suzuki Y, Tang SCW, Tesar V, Vivarelli M, Wetzels JFM, Lytvyn L, Craig JC, Tunnicliffe DJ, Howell M, Tonelli MA, Cheung M, Earley A, Floege Jet al., 2021, Executive summary of the KDIGO 2021 Guideline for the Management of Glomerular Diseases, KIDNEY INTERNATIONAL, Vol: 100, Pages: 753-779, ISSN: 0085-2538

Journal article

Dixon BP, Fakhouri F, Pickering MC, Cook T, Kavanagh D, Remuzzi G, Walker P, Licht C, Appel G, Vivarelli M, Zhang Z, Kocinsky Het al., 2021, PHASE 3, RANDOMIZED, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF PEGCETACOPLAN IN TREATMENT OF C3G OR IC-MPGN, Publisher: SPRINGER, Pages: 3399-3400, ISSN: 0931-041X

Conference paper

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

Kidney Disease Improving Global Outcomes KDIGO Glomerular Diseases Work Group, 2021, KDIGO 2021 clinical practice Guideline for the management of glomerular diseases., Kidney International, Vol: 100, Pages: S1-S276, ISSN: 0085-2538

This guideline is published as a supplement supported by KDIGO. The development and publication of this guideline are strictly funded by KDIGO, and neither KDIGO nor its guideline Work Group members sought or received monies or fees from corporate or commercial entities in connection with this work. The opinions or views expressed in this professional education supplement are those of the authors and do not necessarily reflect the opinions or recommendations of the International Society of Nephrology or Elsevier. Dosages, indications, and methods of use for products that are referred to in the supplement by the authors may reflect their clinical experience or may be derived from the professional literature or other clinical sources. Because of the differences between in vitro and in vivo systems and between laboratory animal models and clinical data in humans, in vitro and animal data may not necessarily correlate with clinical results.

Journal article

Dotz V, Visconti A, Lomax-Browne HJ, Clerc F, Hipgrave Ederveen AL, Medjeral-Thomas NR, Cook HT, Pickering MC, Wuhrer M, Falchi Met al., 2021, O- and N-glycosylation of serum immunoglobulin A is associated with IgA nephropathy and glomerular function., Journal of the American Society of Nephrology, Vol: 32, Pages: 1-12, ISSN: 1046-6673

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 N-glycans as post-translational modification, only IgA1 features extensive hinge-region O-glycosylation. IgA1 galactose deficiency on the O-glycans is commonly detected by a lectin-based method. To date, limited detail is known about IgA O- and N-glycosylation in IgAN. METHODS: To gain insights into the complex O- and N-glycosylation of serum IgA1 and IgA2 in IgAN, we used liquid chromatography-mass spectrometry (LC-MS) for the analysis of tryptic glycopeptides of serum IgA from 83 patients with IgAN and 244 age- and sex-matched healthy controls. RESULTS: Multiple structural features of N-glycosylation of IgA1 and IgA2 were associated with IgAN and glomerular function in our cross-sectional study. These features included differences in galactosylation, sialylation, bisection, fucosylation, and N-glycan complexity. Moreover, IgA1 O-glycan sialylation was associated with both the disease and glomerular function. Finally, glycopeptides were a better predictor of IgAN and glomerular function than galactose-deficient IgA1 levels measured by lectin-based ELISA. CONCLUSIONS: Our high-resolution data suggest that IgA O- and N-glycopeptides are promising targets for future investigations on the pathophysiology of IgAN and as potential noninvasive biomarkers for disease prediction and deteriorating kidney function.

Journal article

Singh S, Roufosse C, Smith A, Cook HT, Moran Let al., 2021, An Audit of Electron Microscopic Evaluation of Native Renal Biopsies, Publisher: WILEY, Pages: S47-S47, ISSN: 0022-3417

Conference paper

Medjeral-Thomas NR, Cook HT, Pickering MC, 2021, Complement activation in IgA nephropathy, Springer Seminars in Immunopathology, Vol: 43, Pages: 679-690, ISSN: 1863-2297

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.

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

Vallant N, Wolfhagen N, Sandhu B, Hamaoui K, Cook T, Pusey C, Papalois Vet al., 2021, A Comparison of Pulsatile Hypothermic and Normothermic Ex Vivo Machine Perfusion in a Porcine Kidney Model, TRANSPLANTATION, Vol: 105, Pages: 1760-1770, ISSN: 0041-1337

Journal article

Toulza F, Dominy K, Beadle J, Willicombe M, Cook T, Mclean A, Szydlo R, Roufosse Cet al., 2021, GENE EXPRESSION ANALYSIS USING QRT-PCR IN THE DIAGNOSIS OF ANTIBODY-MEDIATED REJECTION IN RENAL TRANSPLANT BIOPSIES, Publisher: WILEY, Pages: 290-290, ISSN: 0934-0874

Conference paper

Garcia E, Lightley J, Kumar S, Kalita R, Gorlitz F, Alexandrov Y, Cook T, Dunsby C, Neil M, Roufosse C, French Pet al., 2021, Application of direct stochastic optical reconstruction microscopy (dSTORM) to the histological analysis of human glomerular disease, Publisher: SPRINGER, Pages: S142-S142, ISSN: 0945-6317

Conference paper

Roufosse C, Cook H, Dominy K, Willicombe M, Beadle J, Szydlo R, McLean A, Toulza Fet al., 2021, Diagnostic application of transcripts associated with antibody-mediated rejection in kidney transplant biopsies, Nephrology Dialysis Transplantation, ISSN: 0931-0509

BackgroundThe diagnosis of antibody-mediated rejection (AMR) is reached using the Banff Classification for Allograft Pathology, which now includes gene expression analysis. In this study, we investigate the application of “Increased Expression Of Thoroughly Validated Gene Transcripts/Classifiers Strongly Associated With AMR” as a diagnostic criteria.MethodWe used qRT-PCR for 10 genes associated with AMR in a retrospective cohort of 297 transplant biopsies, including biopsies that met the full diagnostic criteria for AMR, even without molecular data (AMR, n = 27); biopsies that showed features of AMR, but that would only meet criteria for AMR with increased transcripts (AMRsusp, n = 49) and biopsies that would never meet criteria for AMR (No-AMR, n = 221).ResultsA 10-gene AMR score trained by a receiver-operating characteristic to identify AMR found 16 cases with a high score amongst the AMRsusp cases (AMRsusp-high) that had significantly worse graft survival than those with a low score (AMRsusp-low) (n = 33). In both univariate and multivariate Cox regression analysis, the AMR 10-gene score was significantly associated with an increased hazard ratio for graft loss in the AMRsusp group (HR 1.109, p = 0.004 and HR 1.138, p = 0.012), but not in the whole cohort. Net reclassification index and integrated discrimination improvement analyses demonstrated improved risk classification and superior discrimination respectively for graft loss when considering the gene score in addition to histological and serological data, but only in the AMRsusp group, not the whole cohort.ConclusionsThis study provides evidence that a gene score strongly associated with AMR helps identify cases at higher risk of graft loss in biopsies that are suspicious for AMR but don’t meet full criteria.

Journal article

Garcia E, Lightley J, Kumar S, Kalita R, Gorlitz F, Alexandrov Y, Cook T, Dunsby C, Neil MAA, Roufosse CA, French PMWet al., 2021, Application of direct stochastic optical reconstruction microscopy (dSTORM) to the histological analysis of human glomerular disease, JOURNAL OF PATHOLOGY CLINICAL RESEARCH, Vol: 7, Pages: 438-445

Journal article

Medjeral-Thomas NR, Pickering MC, Cook HT, 2021, Complement and kidney disease, new insights., Curr Opin Nephrol Hypertens, Vol: 30, Pages: 310-316

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.

Journal article

Malik TH, Gitterman DP, Lavin DP, Lomax-Browne HJ, Hiemeyer EC, Moran LB, Boroviak K, Cook HT, Gilmore AC, Mandwie M, Ahmad A, Alexander IE, Logan GJ, Marchbank KJ, Bradley A, Pickering MCet al., 2021, Gain-of-function factor H–related 5 protein impairs glomerular complement regulation resulting in kidney damage, Proceedings of the National Academy of Sciences, Vol: 118, Pages: 1-9, ISSN: 0027-8424

Genetic variation within the factor H–related (FHR) genes is associated with the complement-mediated kidney disease, C3 glomerulopathy (C3G). There is no definitive treatment for C3G, and a significant proportion of patients develop end-stage renal disease. The prototypical example is CFHR5 nephropathy, through which an internal duplication within a single CFHR5 gene generates a mutant FHR5 protein (FHR5mut) that leads to accumulation of complement C3 within glomeruli. To elucidate how abnormal FHR proteins cause C3G, we modeled CFHR5 nephropathy in mice. Animals lacking the murine factor H (FH) and FHR proteins, but coexpressing human FH and FHR5mut (hFH-FHR5mut), developed glomerular C3 deposition, whereas mice coexpressing human FH with the normal FHR5 protein (hFH-FHR5) did not. Like in patients, the FHR5mut had a dominant gain-of-function effect, and when administered in hFH-FHR5 mice, it triggered C3 deposition. Importantly, adeno-associated virus vector-delivered homodimeric mini-FH, a molecule with superior surface C3 binding compared to FH, reduced glomerular C3 deposition in the presence of the FHR5mut. Our data demonstrate that FHR5mut causes C3G by disrupting the homeostatic regulation of complement within the kidney and is directly pathogenic in C3G. These results support the use of FH-derived molecules with enhanced C3 binding for treating C3G associated with abnormal FHR proteins. They also suggest that targeting FHR5 represents a way to treat complement-mediated kidney injury.

Journal article

Nikolopoulou A, Teixeira C, Cook H, Roufosse C, Cairns THD, Levy JB, Pusey C, Griffith MEet al., 2021, Membranous nephropathy associated with viral infection, Clinical Kidney Journal, Vol: 14, Pages: 876-883, ISSN: 2048-8505

BackgroundMembranous nephropathy (MN) can be associated with hepatitis infection and less commonly with human immunodeficiency virus (HIV) infection. The significance of anti-phospholipase A2 receptor (PLA2R) and anti-thrombospondin type 1 domain-containing 7A (THSD7A) antibodies in this setting is unclear.MethodsWe describe the clinical, histopathological and outcome data of 19 patients with MN and hepatitis B virus (HBV), hepatitis C virus (HCV) or HIV infection identified through our renal biopsy database and the association with anti-PLA2R antibodies and anti-THSD7A antibodies.ResultsThe cohort consisted of 19 patients, 8 male and 11 female, with a median age of 42 years (range 23–74). HBV infection was found in six cases, HCV in four and HIV in nine (two HIV patients had HBV co-infection and one HCV co-infection). PLA2R staining on biopsy was positive in 10/19 patients: 4 with HBV-MN, 3 with HCV-MN and 3 with HIV-MN and circulating anti-PLA2R antibodies were detected in 7/10 cases. THSD7A staining on biopsy was positive in three PLA2R-negative cases, one with HBV-MN and two with HIV-MN. Mean proteinuria was higher in the PLA2R-positive group and the median urinary protein:creatinine ratio (uPCR) was 963 mg/mmol (range 22–2406) compared with the PLA2R-negative group [median uPCR 548 mg/mmol (range 65–1898); P = 0.18 Mann–Whitney]. Spontaneous remission occurred in 6/19 patients and after-treatment remission occurred in 7/11 patients. Renal function was preserved in all but two patients who required haemodialysis 2 and 11 years from diagnosis.ConclusionsWe describe a cohort of patients with MN associated with viral infection, including rare cases of HIV-MN with PLA2R and THSD7A positivity. The mechanism of coincidental or viral-related MN needs to be investigated further.

Journal article

Gilmore AC, Zhang Y, Cook HT, Lavin DP, Katti S, Wang Y, Johnson KK, Kim S, Pickering MCet al., 2021, Complement activity is regulated in C3 glomerulopathy by IgG-factor H fusion proteins with and without properdin targeting domains, Kidney International, Vol: 99, Pages: 396-404, ISSN: 0085-2538

C3 glomerulopathy is characterized by accumulation of complement C3 within glomeruli. Causes include, but are not limited to, abnormalities in factor H, the major negative regulator of the complement alternative pathway. Factor H-deficient (Cfh-/-) mice develop C3 glomerulopathy together with a reduction in plasma C3 levels. Using this model, we assessed the efficacy of two fusion proteins containing the factor H alternative pathway regulatory domains (FH1-5) linked to either a non-targeting mouse immunoglobulin (IgG-FH1-5) or to an anti-mouse properdin antibody (Anti-P-FH1-5). Both proteins increased plasma C3 and reduced glomerular C3 deposition to an equivalent extent, suggesting that properdin-targeting was not required for FH1-5 to alter C3 activation in either plasma or glomeruli. Following IgG-FH1-5 administration, plasma C3 levels temporally correlated with changes in factor B levels whereas plasma C5 levels correlated with changes in plasma properdin levels. Notably, the increases in plasma C5 and properdin levels persisted for longer than the increases in C3 and factor B. In Cfh-/- mice IgG-FH1-5 reduced kidney injury during accelerated serum nephrotoxic nephritis. Thus, our data demonstrate that IgG-FH1-5 restored circulating alternative pathway activity and reduced glomerular C3 deposition in Cfh-/- mice and that plasma properdin levels are a sensitive marker of C5 convertase activity in factor H deficiency. The immunoglobulin conjugated FH1-5 protein, through its comparatively long plasma half-life, may be a potential therapy for C3 glomerulopathy.

Journal article

Canney M, Barbour SJ, Zheng Y, Coppo R, Zhang H, Liu Z-H, Matsuzaki K, Suzuki Y, Katafuchi R, Reich HN, Cattran D, International IgA Nephropathy Network, International IgA Nephropathy Network Investigatorset al., 2021, Quantifying Duration of Proteinuria Remission and Association with Clinical Outcome in IgA Nephropathy., J Am Soc Nephrol, Vol: 32, Pages: 436-447

BACKGROUND: On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. METHODS: In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to <1 g/d. The exposure of interest was the total duration of first remission, treated as a time-varying covariate using longitudinal proteinuria measurements. We used time-dependent Cox proportional hazards regression models to quantify the association between the duration of remission and the primary outcome (ESKD or a 50% reduction in eGFR). RESULTS: During a median follow-up of 3.9 years, 274 of 1864 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and outcome was nonlinear. Each 3 months in sustained remission up to approximately 4 years was associated with an additional 9% reduction in the risk of disease progression (hazard ratio [HR], 0.91; 95% confidence interval [95% CI], 0.89 to 0.93). Thereafter, each additional 3 months in remission was associated with a smaller, nonsignificant risk reduction (HR, 0.99; 95% CI, 0.96 to 1.03). These findings were robust to multivariable adjustment and consistent across clinical and histologic subgroups. CONCLUSIONS: Our findings support the use of proteinuria as a surrogate outcome in IgA nephropathy, but additionally demonstrate the value of quantifying the duration of proteinuria remission when estimating the risk of hard clinical endpoints.

Journal article

Rovin BH, Caster DJ, Cattran DC, Gibson KL, Hogan JJ, Moeller MJ, Roccatello D, Cheung M, Wheeler DC, Winkelmayer WC, Floege J, Adler SG, Alpers CE, Ayoub I, Bagga A, Barbour SJ, Barratt J, Chan DTM, Chang A, Choo JCJ, Cook HT, Coppo R, Fervenza FC, Fogo AB, Fox JG, Glassock RJ, Harris D, Hodson EM, Hogan JJ, Hoxha E, Iseki K, Jennette JC, Jha V, Johnson DW, Kaname S, Katafuchi R, Kitching AR, Lafayette RA, Li PKT, Liew A, Lv J, Malvar A, Maruyama S, Mejía-Vilet JM, Mok CC, Nachman PH, Nester CM, Noiri E, O'Shaughnessy MM, Özen S, Parikh SM, Park HC, Peh CA, Pendergraft WF, Pickering MC, Pillebout E, Radhakrishnan J, Rathi M, Ronco P, Smoyer WE, Tang SCW, Tesar V, Thurman JM, Trimarchi H, Vivarelli M, Walters GD, Wang AYM, Wenderfer SE, Wetzels JFMet al., 2021, Management and treatment of glomerular diseases (part 2): Conclusions from a kidney disease: Improving global outcomes (kdigo) controversies conference, Nephrology (Saint-Petersburg), Vol: 25, Pages: 96-119, ISSN: 1561-6274

In November 2017, the Kidney Disease: Improving Global Outcomes (KDIGO) initiative brought a diverse panel of experts in glomerular diseases together to discuss the 2012 KDIGO glomerulonephritis guideline in the context of new developments and insights that had occurred over the years since its publication. During this KDIGO Controversies Conference on Glomerular Diseases, the group examined data on disease pathogenesis, biomarkers, and treatments to identify areas of consensus and areas of controversy. This report summarizes the discussions on primary podocytopathies, lupus nephritis, anti-neutrophil cytoplasmic antibody-associated nephritis, complement mediated kidney diseases, and monoclonal gammopathies of renal significance.

Journal article

Dattani R, Corbett RW, Galliford J, Hill P, Cairns T, Cook HT, Roufosse C, Ashby DRet al., 2020, The Effect of Kidney Biopsy on Glomerular Filtration Rate: A Frequent Patient Concern, AMERICAN JOURNAL OF NEPHROLOGY, Vol: 51, Pages: 903-906, ISSN: 0250-8095

Journal article

Toulza F, Dominy K, Cook H, Galliford J, Beadle J, McLean A, Roufosse Cet al., 2020, Technical considerations when designing a gene expression panel for renal transplant diagnosis, Scientific Reports, Vol: 10, ISSN: 2045-2322

Gene expression analysis is emerging as a new diagnostic tool in transplant pathology, in particular for the diagnosis of antibody-mediated rejection. Diagnostic gene expression panels are defined on the basis of their pathophysiological relevance, but also need to be tested for their robustness across different preservatives and analysis platforms. The aim of this study is the investigate the effect of tissue sampling and preservation on candidate genes included in a renal transplant diagnostic panel. Using the NanoString platform, we compared the expression of 219 genes in 51 samples, split for formalin-fixation and paraffin-embedding (FFPE) and RNAlater preservation (RNAlater). We found that overall, gene expression significantly correlated between FFPE and RNAlater samples. However, at the individual gene level, 46 of the 219 genes did not correlate across the 51 matched FFPE and RNAlater samples. Comparing gene expression results using NanoString and qRT-PCR for 18 genes in the same pool of RNA (RNAlater), we found a significant correlation in 17/18 genes. Our study indicates that, in samples from the same routine diagnostic renal transplant biopsy procedure split for FFPE and RNAlater, 21% of 219 genes of potential biological significance do not correlate in expression. Whether this is due to fixatives or tissue sampling, selection of gene panels for routine diagnosis should take this information into consideration.

Journal article

Barbour SJ, Canney M, Coppo R, Zhang H, Liu Z-H, Suzuki Y, Matsuzaki K, Katafuchi R, Induruwage D, Er L, Reich HN, Feehally J, Barratt J, Cattran DC, International IgA Nephropathy Networket al., 2020, Improving treatment decisions using personalized risk assessment from the International IgA Nephropathy Prediction Tool., Kidney Int, Vol: 98, Pages: 1009-1019

Immunosuppression in IgA nephropathy (IgAN) should be reserved for patients at high-risk of disease progression, which KDIGO guidelines determine based solely on proteinuria 1g or more/day. To investigate if treatment decisions can be more accurately accomplished using individualized risk from the International IgAN Prediction Tool, we simulated allocation of a hypothetical immunosuppression therapy in an international cohort of adults with IgAN. Two decision rules for treatment were applied based on proteinuria of 1g or more/day or predicted risk from the Prediction Tool above a threshold probability. An appropriate decision was defined as immunosuppression allocated to patients experiencing the primary outcome (50% decline in eGFR or ESKD) and withheld otherwise. The net benefit and net reduction in treatment are the proportion of patients appropriately allocated to receive or withhold immunosuppression, adjusted for the harm from inappropriate decisions, calculated for all threshold probabilities from 0-100%. Of 3299 patients followed for 5.1 years, 522 (15.8%) experienced the primary outcome. Treatment allocation based solely on proteinuria of 1g or more/day had a negative net benefit (was harmful) because immunosuppression was increasingly allocated to patients without progressive disease. Compared to using proteinuria, treatment allocation using the Prediction Tool had a larger net benefit up to 23.4% (95% confidence interval 21.5-25.2%) and a larger net reduction in treatment up to 35.1% (32.3-37.8%). Thus, allocation of immunosuppression to high-risk patients with IgAN can be substantially improved using the Prediction Tool compared to using proteinuria.

Journal article

Turner-Stokes T, Garcia Diaz A, Pinheiro D, Prendecki M, McAdoo SP, Roufosse C, Cook HT, Pusey CD, Woollard KJet al., 2020, Live imaging of monocyte subsets in immune complex-mediated glomerulonephritis reveals distinct phenotypes and effector functions., Journal of the American Society of Nephrology, Vol: 31, Pages: 1-1, ISSN: 1046-6673

BACKGROUND: Immune complexes within glomerular capillary walls cause crescentic GN (CrGN). Monocytes and macrophages are important in mediating CrGN, but little work has been done to phenotype the subpopulations involved and determine their respective contributions to glomerular inflammation. METHODS: Live glomerular imaging using confocal microscopy monitored intravascular monocyte subset behavior during nephrotoxic nephritis (NTN) in a novel WKY-hCD68-GFP monocyte/macrophage reporter rat strain. Flow cytometry and qPCR further analyzed ex vivo the glomerular leukocyte infiltrate during NTN. RESULTS: Non-classical monocytes surveyed the glomerular endothelium via lymphocyte function-associated antigen 1 (LFA-1) in the steady state. During NTN, non-classical monocytes were recruited first, but subsequent recruitment and retention of classical monocytes was associated with glomerular damage. Monocytes recruited to the glomerular vasculature did not undergo transendothelial migration. This finding suggests that inflammation in immune complex-mediated CrGN is predominantly intravascular, driven by dynamic interactions between intravascular blood monocytes and the endothelium. Glomerular endothelium and non-classical monocytes overexpressed a distinct chemokine axis, which may orchestrate inflammatory myeloid cell recruitment and expression of damage mediators. Reduced classical monocyte recruitment in Lewis rats during NTN confirmed a role for CD16 in mediating glomerular damage. CONCLUSIONS: Monocyte subsets with distinct phenotypes and effector functions may be important in driving inflammation in experimental CrGN resulting from immune complexes formed within the glomerular capillary wall. LFA-1-dependent endothelial surveillance by non-classical monocytes may detect immune complexes through CD16, orchestrating the inflammatory response through intravascular retention of classical monocytes, which results in glomerular damage and proteinuria.

Journal article

Roufosse C, Curtis E, Moran L, Hollinshead M, Cook T, Hanley B, Horsfield C, Neil Det al., 2020, Electron microscopic investigations in COVID-19: not all crowns are coronas, Kidney International, Vol: 98, Pages: 505-506, ISSN: 0085-2538

Journal article

Nayagam JS, McGrath S, Montasser M, Delaney M, Cairns TD, Marchbank KJ, Sacks SH, Cook HT, Shah S, Heaton N, Pickering MC, Suddle Aet al., 2020, Successful simultaneous liver-kidney transplantation for renal failure associated with hereditary complement C3 deficiency., American Journal of Transplantation, Vol: 20, Pages: 2260-2263, ISSN: 1600-6135

Hereditary complement C3 deficiency is associated with recurrent bacterial infections and proliferative glomerulonephritis. We describe a case of an adult with complete deficiency of complement C3 due to homozygous mutations in C3 gene: c.1811delT (Val604Glyfs*2), recurrent bacterial infections, crescentic glomerulonephritis and end-stage renal failure. Following isolated kidney transplantation he would remain C3 deficient with a similar, or increased, risk of infections and glomerulonephritis. As C3 is predominantly synthesised in the liver, with a small proportion of C3 monocyte-derived and kidney-derived, he proceeded to simultaneous liver-kidney transplantation. The procedure has been successful with restoration of his circulating C3 levels, normal liver and kidney function at 26 months of follow up. Simultaneous liver-kidney transplant is a viable option to be considered in this rare setting.

Journal article

Medjeral-Thomas NR, Lawrence C, Condon M, Sood B, Warwicker P, Brown H, Pattison J, Bhandari S, Barratt J, Turner N, Cook HT, Levy JB, Lightstone L, Pusey C, Galliford J, Cairns TD, Griffith Met al., 2020, Randomized, controlled trial of tacrolimus and prednisolone monotherapy for adults with de novo minimal change disease: a multicenter, randomized, controlled trial (vol 15, pg 209, 2020), Clinical Journal of the American Society of Nephrology, Vol: 15, Pages: 1027-1027, ISSN: 1555-9041

Journal article

Prendecki M, Clarke C, Cairns T, Cook T, Roufosse C, Thomas D, Willicombe M, Pusey CD, McAdoo SPet al., 2020, Anti-glomerular basement membrane disease during the COVID-19 pandemic, Kidney International, ISSN: 0085-2538

Journal article

Gilmore AC, Wilson HR, Cairns T, Botto M, Lightstone L, Bruce IN, Cook T, Pickering Met al., 2020, WHOLE KIDNEY TRANSCRIPTOMIC ANALYSIS OF FORMALIN-FIXED PARAFFIN-EMBEDDED LUPUS NEPHRITIS KIDNEY BIOPSY TISSUE USING THE NANOSTRING NCOUNTER PLATFORM, Annual European Congress of Rheumatology (EULAR), Publisher: BMJ PUBLISHING GROUP, Pages: 29-29, ISSN: 0003-4967

Conference paper

Coppo R, D'Arrigo G, Tripepi G, Russo ML, Roberts ISD, Bellur S, Cattran D, Cook TH, Feehally J, Tesar V, Maixnerova D, Peruzzi L, Amore A, Lundberg S, Di Palma AM, Gesualdo L, Emma F, Rollino C, Praga M, Biancone L, Pani A, Feriozzi S, Polci R, Barratt J, Del Vecchio L, Locatelli F, Pierucci A, Caliskan Y, Perkowska-Ptasinska A, Durlik M, Moggia E, Ballarin JC, Wetzels JFM, Goumenos D, Papasotiriou M, Galesic K, Toric L, Papagianni A, Stangou M, Benozzi L, Cusinato S, Berg U, Topaloglu R, Maggio M, Ots-Rosenberg M, D'Amico M, Geddes C, Balafa O, Quaglia M, Cravero R, Lino Cirami C, Fellstrom B, Floege J, Egido J, Mallamaci F, Zoccali C, ERA-EDTA Immunonephrology Working Groupet al., 2020, Is there long-term value of pathology scoring in immunoglobulin A nephropathy? A validation study of the Oxford Classification for IgA Nephropathy (VALIGA) update., Nephrol Dial Transplant, Vol: 35, Pages: 1002-1009

BACKGROUND: It is unknown whether renal pathology lesions in immunoglobulin A nephropathy (IgAN) correlate with renal outcomes over decades of follow-up. METHODS: In 1130 patients of the original Validation Study of the Oxford Classification for IgA Nephropathy (VALIGA) cohort, we studied the relationship between the MEST score (mesangial hypercellularity, M; endocapillary hypercellularity, E; segmental glomerulosclerosis, S; tubular atrophy/interstitial fibrosis, T), crescents (C) and other histological lesions with both a combined renal endpoint [50% estimated glomerular filtration rate (eGFR) loss or kidney failure] and the rate of eGFR decline over a follow-up period extending to 35 years [median 7 years (interquartile range 4.1-10.8)]. RESULTS: In this extended analysis, M1, S1 and T1-T2 lesions as well as the whole MEST score were independently related with the combined endpoint (P < 0.01), and there was no effect modification by age for these associations, suggesting that they may be valid in children and in adults as well. Only T lesions were associated with the rate of eGFR loss in the whole cohort, whereas C showed this association only in patients not treated with immunosuppression. In separate prognostic analyses, the whole set of pathology lesions provided a gain in discrimination power over the clinical variables alone, which was similar at 5 years (+2.0%) and for the whole follow-up (+1.8%). A similar benefit was observed for risk reclassification analyses (+2.7% and +2.4%). CONCLUSION: Long-term follow-up analyses of the VALIGA cohort showed that the independent relationship between kidney biopsy findings and the risk of progression towards kidney failure in IgAN remains unchanged across all age groups and decades after the renal biopsy.

Journal article

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