Imperial College London

PROFESSOR H. TERENCE COOK

Faculty of MedicineDepartment of Medicine

Professor of Renal Pathology
 
 
 
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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
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484 results found

Wei W, Tuna S, Keogh MJ, Smith KR, Aitman TJ, Beales PL, Bennett DL, Gale DP, Bitner-Glindzicz MAK, Black GC, Brennan P, Elliott P, Flinter FA, Floto RA, Houlden H, Irving M, Koziell A, Maher ER, Markus HS, Morrell NW, Newman WG, Roberts I, Sayer JA, Smith KGC, Taylor JC, Watkins H, Webster AR, Wilkie AOM, Williamson C, Attwood A, Brown M, Brod NC, Crisp-Hihn A, Davis J, Deevi SVV, Dewhurst EF, Edwards K, Erwood M, Fox J, Frary AJ, Hu F, Jolley J, Kingston N, Linger R, Mapeta R, Martin J, Meacham S, Papadia S, Rayner-Matthews PJ, Samarghitean C, Shamardina O, Simeoni I, Staines S, Staples E, Stark H, Stephens J, Titterton C, Tuna S, von Ziegenweidt J, Watt C, Whitehorn D, Wood Y, Yates K, Yu P, James R, Ashford S, Penkett CJ, Stirrups KE, Bariana T, Lentaigne C, Sivapalaratnam S, Westbury SK, Allsup DJ, Bakchoul T, Biss T, Boyce S, Collins J, Collins PW, Curry NS, Downes K, Dutt T, Erber WN, Evans G, Everington T, Favier R, Gomez K, Greene D, Gresele P, Hart D, Kazmi R, Kelly AM, Lambert M, Madan B, Mangles S, Mathias M, Millar C, Obaji S, Peerlinck K, Roughley C, Schulman S, Scully M, Shapiro SE, Sibson K, Simeoni I, Sims MC, Tait RC, Talks K, Thys C, Toh C-H, Van Geet C, Westwood J-P, Papadia S, Mumford AD, Ouwehand WH, Freson K, Laffan MA, Tan RYY, Harkness K, Mehta S, Muir KW, Hassan A, Traylor M, Drazyk AM, Markus HS, Parry D, Ahmed M, Kazkaz H, Vandersteen AM, Aitman TJ, Ormondroyd E, Thomson K, Dent T, Brennan P, Buchan RJ, Bueser T, Carr-White G, Cook S, Daniels MJ, Harper AR, Ware JS, Watkins H, Dixon PH, Chambers J, Cheng F, Estiu MC, Hague WM, Marschall H-U, Vazquez-Lopez M, Williamson C, Arno G, Dewhurst EF, Erwood M, French CE, Michaelides M, Moore AT, Sanchis-Juan A, Carss K, Webster AR, Raymond FL, Chinnery PF, Griffiths P, Horvath R, Hudson G, Jurkute N, Pyle A, Wei W, Yu-Wai-Man P, Whitworth J, Adlard J, Ahmed M, Armstrong R, Brewer C, Casey R, Cole TRP, Evans DG, Greenhalgh L, Hanson HL, Hoffman J, Izatt L, Kumar A, Lalloo F, Ong KR, Park S-M, Searet al., 2019, Germline selection shapes human mitochondrial DNA diversity, Science, Vol: 364, ISSN: 0036-8075

INTRODUCTIONOnly 2.4% of the 16.5-kb mitochondrial DNA (mtDNA) genome shows homoplasmic variation at >1% frequency in humans. Migration patterns have contributed to geographic differences in the frequency of common genetic variants, but population genetic evidence indicates that selection shapes the evolving mtDNA phylogeny. The mechanism and timing of this process are not clear.Unlike the nuclear genome, mtDNA is maternally transmitted and there are many copies in each cell. Initially, a new genetic variant affects only a proportion of the mtDNA (heteroplasmy). During female germ cell development, a reduction in the amount of mtDNA per cell causes a “genetic bottleneck,” which leads to rapid segregation of mtDNA molecules and different levels of heteroplasmy between siblings. Although heteroplasmy is primarily governed by random genetic drift, there is evidence of selection occurring during this process in animals. Yet it has been difficult to demonstrate this convincingly in humans.RATIONALETo determine whether there is selection for or against heteroplasmic mtDNA variants during transmission, we studied 12,975 whole-genome sequences, including 1526 mother–offspring pairs of which 45.1% had heteroplasmy affecting >1% of mtDNA molecules. Harnessing both the mtDNA and nuclear genome sequences, we then determined whether the nuclear genetic background influenced mtDNA heteroplasmy, validating our findings in another 40,325 individuals.RESULTSPreviously unknown mtDNA variants were less likely to be inherited than known variants, in which the level of heteroplasmy tended to increase on transmission. Variants in the ribosomal RNA genes were less likely to be transmitted, whereas variants in the noncoding displacement (D)–loop were more likely to be transmitted. MtDNA variants predicted to affect the protein sequence tended to have lower heteroplasmy levels than synonymous variants. In 12,975 individuals, we identified a correlation between

Journal article

Smith RJH, Appel GB, Blom AM, Cook HT, D'Agati VD, Fakhouri F, Fremeaux-Bacchi V, Jozsi M, Kavanagh D, Lambris JD, Noris M, Pickering MC, Remuzzi G, Rodriguez de Cordoba S, Sethi S, Van der Vlag J, Zipfel PF, Nester CMet al., 2019, C3 glomerulopathy - understanding a rare complement-driven renal disease, NATURE REVIEWS NEPHROLOGY, Vol: 15, Pages: 129-143, ISSN: 1759-5061

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, 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

Smith-Jackson K, Yang Y, Denton H, Pappworth IY, Cooke K, Barlow PN, Atkinson JP, Liszewski MK, Pickering MC, Kavanagh D, Cook HT, Marchbank KJet al., 2019, Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice, Journal of Clinical Investigation, ISSN: 0021-9738

Atypical hemolytic uremic syndrome (aHUS) is frequently associated in humans with loss-of-function mutations in complement-regulating proteins or gain-of-function mutations in complement-activating proteins. Thus, aHUS provides an archetypal complement-mediated disease with which to model new therapeutic strategies and treatments. Herein, we show that, when transferred to mice, an aHUS-associated gain-of-function change (D1115N) to the complement-activation protein C3 results in aHUS. Homozygous C3 p.D1115N (C3KI) mice developed spontaneous chronic thrombotic microangiopathy together with hematuria, thrombocytopenia, elevated creatinine, and evidence of hemolysis. Mice with active disease had reduced plasma C3 with C3 fragment and C9 deposition within the kidney. Therapeutic blockade or genetic deletion of C5, a protein downstream of C3 in the complement cascade, protected homozygous C3KI mice from thrombotic microangiopathy and aHUS. Thus, our data provide in vivo modeling evidence that gain-of-function changes in complement C3 drive aHUS. They also show that long-term C5 deficiency is not accompanied by development of other renal complications (such as C3 glomerulopathy) despite sustained dysregulation of C3. Our results suggest that this preclinical model will allow testing of novel complement inhibitors with the aim of developing precisely targeted therapeutics that could have application in many complement-mediated diseases.

Journal article

Kousios A, Duncan N, Tam FWK, Chaidos A, Cook HT, Roufosse C, Charif Ret al., 2019, Proliferative glomerulonephritis with monoclonal Ig deposits (PGNMID): diagnostic and treatment challenges for the nephrologist!, Kidney International, Vol: 95, Pages: 467-468, ISSN: 0085-2538

Journal article

Koutroutsos K, Charif R, Moran L, Moss J, Cook T, Roufosse C, Pusey C, Taube D, Loucaidou Met al., 2019, Successful management of post-transplant focal segmental glomerulosclerosis with therapeutic plasma exchange and rituximab, Clinical and Experimental Nephrology, ISSN: 1342-1751

BACKGROUND: Post-transplant focal segmental glomerulosclerosis (FSGS) is associated with renal allograft loss. Currently, optimal treatment remains controversial. METHODS: The aim of our study was to examine the efficacy and safety of therapeutic plasma exchange (TPE), and rituximab (RTX), in the management of post-transplant FSGS. The treatment protocol consisted of RTX and monthly cycles of 5 plasma exchanges for 6 months. We treated 10 transplant recipients with biopsy-proven post-transplant FSGS. Lastly, we compared the studied group to a historic control group of nine patients with post-transplant FSGS. RESULTS: 9 out of 10 patients achieved remission after the conclusion of treatment (4 complete and 5 partial), while 1 patient did not respond to treatment. During the follow-up period, there was one graft loss and one patient died while in remission from unrelated complications. There was a significant reduction in mean uPCR between diagnosis (517.4 ± 524.2 mg/mmol) and last follow-up (87 ± 121.6 mg/mmol) in the patients with sustained remission (p = 0.026). There was no significant decline in eGFR in the eight relapse-free responders at the end of follow-up. (54.4 ± 16.7 from 49.8 ± 20.4 ml/min) (p = 0.6) An increased response rate to the combined TPE and RTX treatment was demonstrated, when compared to a historic control group of nine patients with post-transplant FSGS, as only five out of nine patients achieved remission (two complete and three partial) in that group. CONCLUSIONS: In this study, treatment with TPE and RTX appears to be safe, well tolerated and effective in the management of patients with post-transplant FSGS.

Journal article

Wilson HR, Medjeral-Thomas NR, Gilmore AC, Trivedi P, Seyb K, Farzaneh-Far R, Gunnarsson I, Zickert A, Cairns TD, Lightstone L, Cook HT, Pickering MCet al., 2019, Glomerular membrane attack complex is not a reliable marker of ongoing C5 activation in lupus nephritis, Kidney International, Vol: 95, Pages: 655-665, ISSN: 0085-2538

Complement plays an important role in the pathogenesis of lupus nephritis (LN). With the emergence of therapeutic complement inhibition, there is a need to identify patients in whom complement-driven inflammation is a major cause of kidney injury in LN. Clinical and histopathological data were obtained retrospectively from 57 biopsies with class III, IV, and V LN. Biopsies were stained for complement components C9, C5b-9, C3c, and C3d and for the macrophage marker CD68. C9 and C5b-9 staining were highly correlated (r = 0.92 in the capillary wall). C5b-9 staining was detected in the mesangium and/or capillary wall of both active and chronic proliferative LN in all but one biopsy and in the capillary wall of class V LN in all biopsies. C5b-9 staining intensity in the tubular basement membrane correlated with markers of tubulointerstitial damage, and more intense capillary wall C5b-9 staining was significantly associated with nonresponse to conventional treatment. Glomerular C5b-9 staining intensity did not differ between active and chronic disease; in contrast, C3c and CD68 staining were associated with active disease. Evaluation of serial biopsies and comparison of staining in active and chronic LN demonstrated that C5b-9 staining persisted for months to years. These results suggest that C5b-9 staining is almost always present in LN, resolves slowly, and is not a reliable marker of ongoing glomerular C5 activation. This limits the utility of C5b-9 staining to identify patients who are most likely to benefit from C5 inhibition.

Journal article

Dominy KM, Willicombe M, Al Johani T, Beckwith H, Goodall D, Brookes P, Cook HT, McLean A, Roufosse CAet al., 2019, Molecular assessment of C4d positive renal transplant biopsies without evidence of rejection, Kidney International Reports, Vol: 4, Pages: 148-158, ISSN: 2468-0249

IntroductionImmunohistochemical staining for C4d in peritubular capillaries has been part of antibody-mediated rejection (AbMR) definition in the Banff Classification for Allograft Pathology since 2003. However, it has limited sensitivity and specificity, therefore the clinical significance of C4d-positive biopsies without evidence of rejection (C4d+ WER) is unknown. We investigated the transcript levels of genes associated with AbMR in C4d+ WER biopsies from both ABO-compatible and incompatible renal transplant patients.MethodsRNA was extracted from formalin-fixed paraffin-embedded renal transplant biopsies (n = 125) and gene expression analysis of 35 AbMR-associated transcripts carried out using the NanoString nCounter system.ResultsAbMR-associated transcripts were significantly increased in samples with AbMR or suspicious AbMR. A subgroup of 17 of 35 transcripts that best distinguished AbMR from C4d-negative biopsies without evidence of rejection was used to study C4d+ WER samples. There was no differential expression between C4d-negative and C4d+ WER from both ABO-incompatible and -compatible transplants. The geometric mean of 17 differentially expressed genes was used to assign the C4d+ WER biopsies a high- or low-AbMR transcript score. Follow-up biopsies showed AbMR within 1 year of initial biopsy in 5 of 7 high-AbMR transcript patients but only 2 of 46 low-AbMR transcript patients. In multivariate logistic regression analysis, elevated transcript levels in a C4d+ WER biopsy were associated with increased odds for biopsy-proven AbMR on follow-up (P = 0.032, odds ratio 16.318), whereas factors including donor-specific antibody (DSA) status and time since transplantation were not.ConclusionGene expression analysis in C4d+ WER samples has the potential to identify patients at higher risk of developing AbMR.

Journal article

Bellur S, Roberts ISD, Troyanov S, Royal V, Coppo R, Cook HT, Cattran D, Terroba YA, Asunis AM, Bajema I, Bertoni E, Bruijn JA, Cannata-Ortiz P, Casartelli D, Di Palma AM, Ferrario F, Fortunato M, Furci L, Gakiopoulou H, Ljubanovic DG, Giannakakis K, Gomà M, Gröne H-J, Gutiérrez E, Haider SA, Honsova E, Ioachim E, Karkoszka H, Kipgen D, Maldyk J, Mazzucco G, Orhan D, Ozluk Y, Pantzaki A, Perkowska-Ptasinska A, Riispere Z, Soderberg M, Steenbergen E, Stoppacciaro A, Sundelin B, Tardanico Ret al., Reproducibility of the Oxford Classification of IgA nephropathy, impact of biopsy scoring on treatment allocation and clinical relevance of disagreements: evidence from the VALIGA study cohort, Nephrology Dialysis Transplantation, ISSN: 0931-0509

Objective & Methods: The VALIGA study investigated the utility of the Oxford Classification of IgA nephropathy (IgAN) in 1147 patients from 13 European countries. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive treatments (CS/IS), and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present-central absent, local absent-central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS.Results: All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy whilst the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity), and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. By contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes compared to central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent l

Journal article

Smith-Jackson K, Yang Y, Denton H, Pickering MC, Pappworth IY, Cook HT, Marchbank KJet al., 2018, CS deficiency protects ageing C3 gain-of-function mice from renal injury despite significant C3 deposition in the kidney, 27th International Complement Workshop (ICW), Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 187-187, ISSN: 0161-5890

Conference paper

Sadeghi-Alavijeh O, Henderson S, Bass P, Cook T, DeGroot K, Salama ADet al., 2018, Crescentic glomerulonephritis with anti-GBM antibody but no glomerular deposition, BMC Nephrology, Vol: 19, ISSN: 1471-2369

BackgroundAnti-glomerular basement membrane (GBM) antibodies are highly specific for Goodpasture’s or anti-GBM disease, in which they are generally directed against the non-collagenous (NC1) domain of the alpha 3 chain of type IV collagen(α3(IV)), and less commonly, toward the α 4(IV) or α 5(IV) chains, which form a triple helical structure in GBM and alveolar basement membrane (ABM). Alterations in the hexameric structure of the NC1 (α3 (IV)), allows novel epitopes to be exposed and an immune response to develop, with subsequent linear antibody deposition along the GBM, leading to a crescentic glomerulonephritis. Positive anti-GBM antibodies are assumed to be pathogenic and capable of binding GBM in vivo, especially in the context of rapidly progressive glomerulonephritis.We have investigated patients with circulating anti-GBM antibodies, reactive to α3 (IV) and human GBM by immunoassays and Western blotting respectively, with focal necrotising crescentic glomerulonephritis but no linear GBM antibody deposition on immunohistochemistry. Three out of four were also ANCA positive. Despite not binding native GBM, patients’ sera showed linear binding to primate glomeruli by indirect immunofluorescence, in the 2 cases tested. Following treatment, significant improvements in kidney function were found in 3/4 patients.Case presentationWe present four patients with crescentic glomerulonephritis and circulating anti-GBM antibodies, but no glomerular binding.ConclusionsThese novel findings, demonstrate that in some patients anti-GBM antibodies may not bind their own GBM. This has important implications for clinical diagnosis, suggesting that histological confirmation of kidney injury by anti-GBM antibodies should be obtained, as non-binding GBM antibodies may be associated with significant renal recovery.

Journal article

Roufosse CA, Webster P, Moss J, Moran L, Loucaidou M, Cook HTet al., 2018, Familial Fibrillary Glomerulonephritis with Positive Immunohistochemistry for DNAJB9, 11th Joint Meeting of the British-Division of the International-Academy-of-Pathology and the Pathological-Society-of-Great-Britain-and-Ireland, Publisher: WILEY, Pages: S38-S38, ISSN: 0022-3417

Conference paper

Roufosse CA, Willicombe M, Galliford J, Cook HT, McLean A, Dominy Ket al., 2018, C4d Positive Renal Transplant Biopsies With No other Evidence of Rejection: Transcriptional Investigation of Biological Significance Using Nanostring nCounter Technology, 11th Joint Meeting of the British-Division of the International-Academy-of-Pathology and the Pathological-Society-of-Great-Britain-and-Ireland, Publisher: WILEY, Pages: S18-S18, ISSN: 0022-3417

Conference paper

Roufosse C, Willicombe M, Al Johani T, Galliford J, McLean A, Cook T, Dominy Ket al., 2018, Molecular assessment of C4d positive renal transplant biopsies without evidence of rejection, Publisher: SPRINGER, Pages: S15-S16, ISSN: 0945-6317

Conference paper

Kousios A, Brah T, Troy-Barnes E, Duncan N, Naresh K, Chaidos A, Charif R, Cook T, Roufosse Cet al., 2018, The Histopathological Spectrum of Monoclonal Gammopathies of Renal Significance: A Single Centre Experience, 11th Joint Meeting of the British-Division of the International-Academy-of-Pathology and the Pathological-Society-of-Great-Britain-and-Ireland, Publisher: WILEY, Pages: S19-S19, ISSN: 0022-3417

Conference paper

Roufosse C, Brah T, Troy-Barnes E, Duncan N, Naresh K, Chaidos A, Charif R, Cook HT, Kousios Aet al., 2018, The histopathological spectrum of monoclonal gammopathies of renal significance: a single centre experience, Publisher: SPRINGER, Pages: S81-S81, ISSN: 0945-6317

Conference paper

Alexander S, John GT, Korula A, Vijayakumar TS, David VG, Mohapatra A, Valson AT, Jacob S, Koshy PM, Rajan G, John EE, Matthai SM, Jeyaseelan L, Ponnusamy B, Cook T, Pusey C, Daha MR, Feehally J, Barratt J, Varughese Set 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.

Journal article

Koskinen AR, Cheng Z-Z, Pickering MC, Kairemo K, Meri T, Cook HT, Meri S, Jokiranta TSet al., 2018, Distribution of exogenous complement factor H in mice invivo, Scandinavian Journal of Immunology, Vol: 88, ISSN: 0300-9475

Factor H is an important regulator of complement activation in plasma and on cell surfaces in both humans and mice. If FH function is compromised, inappropriate complement activation on self‐surfaces can have disastrous effects as seen in the kidney diseases atypical haemolytic uremic syndrome (aHUS) and C3 glomerulopathy. As FH constructs have been proposed to be used in treatment for these diseases, we studied the distribution of exogenous FH fragments in mice. Full‐length mFH, mFH1‐5 and mFH18‐20 fragments were radiolabelled, and their distribution was examined in WT, FH−/− and FH−/−C3−/− mice in vivo. Whole body scintigraphy revealed accumulation of radioactivity in the abdominal part of the mice, but also to the thyroid gland and urinary bladder. At organ level in WT mice, some full‐length FH accumulated in internal organs, but most of it remained in the circulation. Both of the mFH fragments accumulated in the kidneys and were excreted in urine. For mFH1‐5, urinary secretion is the likely cause for the accumulation. Concentration of mFH18‐20 to kidneys was slower, and at tissue level, mFH18‐20 was localized at the proximal tubuli in WT and FH−/−C3−/− mice. No C3‐independent binding to glomeruli was detected. In conclusion, these results show that glomerular glycosaminoglycans and sialic acids alone do not collect FH in kidneys. Deposition of C3 fragments is also needed, which implies that in aHUS, the problem is in simultaneous recognition of C3 fragments and glycosaminoglycans or sialic acids by FH, not just the inability of FH to recognize glomerular endothelium as such.

Journal article

Saja M, Cook HT, Ruseva M, Szajna M, Pickering MC, Woollard KJ, Botto Met al., 2018, A triglyceride-rich lipoprotein environment exacerbates renal injury in the accelerated nephrotoxic nephritis model, Clinical and Experimental Immunology, Vol: 192, Pages: 337-347, ISSN: 1365-2249

Hyperlipidaemia accompanies chronic renal disease either as a consequence of the renal dysfunction or as part of generalized metabolic derangements. Under both situations, the lipid profile is characterized by accumulation of triglyceride‐rich lipoproteins (TGRLs). This lipid profile is recognized as a risk factor for cardiovascular complications. Whether it may pose a risk for renal injury as well remains unclear. A hyper‐TGRL state was generated in C57BL/6 mice using poloxamer‐407 (P‐407) and immune complex‐mediated renal injury was triggered using the accelerated nephrotoxic nephritis (ANTN) model. The hyper‐TGRL animals were hypersensitive to ANTN demonstrated by greater haematuria and glomerular cellularity. These changes were accompanied by increased glomerular accumulation of CD68+ macrophages. The hypersensitive response to ANTN was not seen in low‐density lipoprotein receptor knock‐out mice fed with a high fat diet, where triglyceride levels were lower but cholesterol levels comparable to those obtained using P‐407. These data indicate that a hyper‐TGRL state might be more detrimental to the kidneys than low‐density lipoprotein‐driven hypercholesterolaemia during immune complex‐mediated nephritis. We speculate that the hyper‐TGRL environment primes the kidney to exacerbated renal damage following an inflammatory insult with increased accumulation of macrophages that may play a key role in mediating the injurious effects.

Journal article

Kocinsky H, Kelleher C, Apelian D, Bulawski A, Geffner M, Huang M, Price J, Yang J, Yang W, Zhao Y, van de Kar N, Wetzels J, Bouman K, Cook T, Barbour Tet al., 2018, FACTOR D INHIBITION WITH ACH-4471 TO REDUCE COMPLEMENT ALTERNATIVE PATHWAY HYPERACTIVITY AND PROTEINURIA IN C3 GLOMERULOPATHY: PRELIMINARY PROOF OF CONCEPT DATA, 55th Congress of the European-Renal-Association (ERA) and European-Dialysis-and-Transplantation-Association (EDTA), Publisher: OXFORD UNIV PRESS, Pages: 322-322, ISSN: 0931-0509

Conference paper

Cook HT, 2018, Evolving complexity of complement-related diseases: C3 glomerulopathy and atypical haemolytic uremic syndrome, Current Opinion in Nephrology and Hypertension, Vol: 27, Pages: 165-170, ISSN: 1535-3842

PURPOSE OF REVIEW: The current review will discuss recent advances in our understanding of the pathology of C3 glomerulopathy and atypical haemolytic uremic syndrome (aHUS). RECENT FINDINGS: C3 glomerulopathy and aHUS are associated with abnormalities of control of the alternative pathway of complement. Recent articles have provided new insights into the classification of C3 glomerulopathy and its relationship to idiopathic immune complex-mediated glomerulonephritis. They suggest that there may be considerable overlap in pathogenesis between these entities and have indicated novel ways in which classification may be improved. There is increasing evidence that monoclonal gammopathy may cause C3 glomerulopathy or aHUS in older patients and emerging evidence that treatment of the underlying plasma cell clone may ameliorate the kidney disease. SUMMARY: Recent work has provided new insights into the causes of C3 glomerulopathy and aHUS, and the mechanism by which complement is dysregulated. This is of particular importance with the advent of new therapeutic agents which can specifically target different parts of the complement cascade.

Journal article

Wilson H, Turner-Stokes T, Griffith M, Levy J, Beckwith H, Cairns T, Cook HT, Lightstone Let al., 2018, Twenty years of lupus nephritis management - evaluation of a multi ethnic patient cohort to identify factors affecting outcome, 55th Congress of the European-Renal-Association (ERA) and European-Dialysis-and-Transplantation-Association (EDTA), Publisher: Oxford University Press (OUP), ISSN: 0931-0509

Conference paper

Bajema IM, Wilhelmus S, Alpers CE, Bruijn JA, Colvin RB, Cook HT, D'Agati VD, Ferrario F, Haas M, Jennette JC, Joh K, Nast CC, Noël L-H, Rijnink EC, Roberts ISD, Seshan SV, Sethi S, Fogo ABet al., 2018, Revision of the International Society of Nephrology/Renal Pathology Society classification for lupus nephritis: clarification of definitions, and modified National Institutes of Health activity and chronicity indices, Kidney International, Vol: 93, Pages: 789-796, ISSN: 0085-2538

We present a consensus report pertaining to the improved clarity of definitions and classification of glomerular lesions in lupus nephritis that derived from a meeting of 18 members of an international nephropathology working group in Leiden, Netherlands, in 2016. Here we report detailed recommendations on issues for which we can propose adjustments based on existing evidence and current consensus opinion (phase 1). New definitions are provided for mesangial hypercellularity and for cellular, fibrocellular, and fibrous crescents. The term "endocapillary proliferation" is eliminated and the definition of endocapillary hypercellularity considered in some detail. We also eliminate the class IV-S and IV-G subdivisions of class IV lupus nephritis. The active and chronic designations for class III/IV lesions are replaced by a proposal for activity and chronicity indices that should be applied to all classes. In the activity index, we include fibrinoid necrosis as a specific descriptor. We also make recommendations on issues for which there are limited data at present and that can best be addressed in future studies (phase 2). We propose to proceed to these investigations, with clinicopathologic studies and tests of interobserver reproducibility to evaluate the applications of the proposed definitions and to classify lupus nephritis lesions.

Journal article

Hill NR, Cook T, Pusey C, Tarzi Ret 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.

Journal article

Medjeral-Thomas NR, Troldborg A, Constantinou N, Lomax-Browne HJ, Hansen AG, Willicombe M, Pusey CD, Cook HT, Thiel S, Pickering MCet 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.

Journal article

Hamaoui K, Gowers S, Sandhu B, Vallant N, Cook T, Boutelle M, Casanova D, Papalois Vet al., 2018, Development of pancreatic machine perfusion: translational steps from porcine to human models, JOURNAL OF SURGICAL RESEARCH, Vol: 223, Pages: 263-274, ISSN: 0022-4804

Journal article

Cook HT, Pickering MC, 2017, Clusters not classifications: making sense of complement-mediated kidney injury, Journal of the American Society of Nephrology, Vol: 29, Pages: 9-12, ISSN: 1046-6673

Journal article

Medjeral-Thomas NR, Troldborg A, Lomax-Browne H, Willicombe M, Cook HT, Thiel S, Pickering MCet al., 2017, Plasma levels of lectin pathway components in IgA nephropathy, 16th European Meeting on Complement in Human Disease (EMCHD), Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 178-178, ISSN: 0161-5890

Conference paper

Lomax HJ, Medjeral-Thomas NR, Cook HT, Pickering MCet al., 2017, Natural history study of C3 glomerulopathy, 16th European Meeting on Complement in Human Disease (EMCHD), Publisher: PERGAMON-ELSEVIER SCIENCE LTD, Pages: 176-176, ISSN: 0161-5890

Conference paper

Turner S, Yeung KT, Moser S, Cook T, Roufosse C, Charif R, Mclean A, Taube D, Tait P, Muthusamy Aet al., 2017, ULTRASOUND-GUIDED ALLOGRAFT PANCREAS BIOPSY: SAFETY AND DIAGNOSTIC USE, Publisher: WILEY, Pages: 141-141, ISSN: 0934-0874

Conference paper

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