Imperial College London

PROFESSOR H. TERENCE COOK

Faculty of MedicineDepartment of Immunology and Inflammation

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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495 results found

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., 2019, 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, Vol: 34, Pages: 1681-1690, 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

Nikolopoulou A, Condon M, Turner-Stokes T, Cook HT, Duncan N, Galliford J, Levy J, Lightstone L, Pusey C, Roufosse C, Cairns T, Griffith Met al., 2019, Mycophenolate mofetil and tacrolimus versus tacrolimus alone for the treatment of idiopathic membranous glomerulonephritis: A randomised controlled trial., BMC Nephrology, Vol: 20, Pages: 1-9, ISSN: 1471-2369

Background: Tacrolimus (TAC) is effective in treating membranous nephropathy (MN);however relapses are frequent after treatment cessation. We conducted a randomisedcontrolled trial to examine whether the addition of mycophenolate mofetil (MMF) to TACwould reduce relapse rate.Methods: 40 patients with biopsy proven idiopathic MN and nephrotic syndrome wererandomly assigned to receive either TAC monotherapy (n=20) or TAC combined with MMF(n=20) for 12 months. When patients had been in remission for 1 year on treatment the MMFwas stopped and the TAC gradually withdrawn in both groups over 6 months. Patients alsoreceived supportive treatment with angiotensin blockade, statins, diuretics andanticoagulation as needed. Primary endpoint was relapse rate following treatmentwithdrawal. Secondary outcomes were remission rate, time to remission and change in renalfunction.Results: 16/20 (80%) of patients in the TAC group achieved remission compared to 19/20(95%) in the TAC/MMF group (p=0.34). The median time to remission in the TAC groupwas 54 weeks compared to 40 weeks in the TAC/MMF group (p=0.46). There was nodifference in the relapse rate between the groups: 8/16 (50%) patients in the TAC grouprelapsed compared to 8/19 (42%) in the TAC/MMF group (p=0.7). The addition of MMF toTAC did not adversely affect the safety of the treatment.Conclusions: Addition of MMF to TAC does not alter the relapse rate of nephrotic syndromein patients with MN.

Journal article

Tennekoon H, Cook T, Palmer A, Roufosse Cet al., 2019, Congophilic fibrillary glomerulonephritis, Publisher: SPRINGER, Pages: S373-S373, ISSN: 0945-6317

Conference paper

Foschi V, Bortolotti D, Doyle AF, Stratigou V, Stephens L, Trivedi P, Rinaldi R, Padovan M, Bortoluzzi A, Lightstone L, Cairns TD, Botto M, Cook TH, Rizzo R, Govoni M, Pickering MCet al., 2019, Analysis of HLA-G expression in renal tissue in lupus nephritis: a pilot study, Lupus, ISSN: 1477-0962

BACKGROUND: The study aimed to investigate whether HLA-G antigen is expressed in the kidneys of patients affected by lupus nephritis (LN) and whether its detection in renal biopsies could be adopted as a marker of treatment response and prognosis. METHODS: Thirty renal biopsies from patients with LN were selected and analyzed through immunohistochemistry. Laboratory and clinical data were retrospectively collected at baseline, 6 and 12 months and at the latest clinical appointment. A number of patients (63.3%) were treated with rituximab (RTX) +/- methylprednisolone in the induction phase. The expression of HLA-G in glomeruli, tubules and infiltrating cells was examined and compared between lupus patients who achieved either complete or partial renal response and those who did not respond to treatment. RESULTS: HLA-G staining was observed in the glomeruli of 20 of 30 samples from patients with LN. The expression of the antigen was detected in podocytes, along glomerular capillary walls, on parietal glomerular epithelial cells and within the juxtaglomerular apparatus. Seventy per cent of patients whose glomeruli expressed HLA-G achieved partial or complete response at 6 months and 75% at the latest available follow up compared with 30% and 40%, respectively, of those who did not show any expression. The pattern of staining in tubules and infiltrating cells was highly variable precluding any clinical correlation. CONCLUSION: This study demonstrates that HLA-G is expressed in renal tissue in LN. Our retrospective data suggest that its expression could correlate with response to treatment.

Journal article

Pereira M, Chen T-D, Buang N, Olona A, Ko J-H, Prendecki M, Costa ASH, Nikitopoulou E, Tronci L, Pusey CD, Cook HT, McAdoo SP, Frezza C, Behmoaras Jet al., 2019, Acute iron deprivation reprograms human macrophage metabolism and reduces inflammation in vivo, Cell Reports, Vol: 28, Pages: 498-511.e5, ISSN: 2211-1247

Iron is an essential metal for fine-tuning the innate immune response through macrophage function. An integrative view of transcriptional and metabolic responses generated from iron perturbation in macrophages is lacking. Here we induced acute iron chelation in primary human macrophages and measured their transcriptional and metabolic responses by integrating RNA-sequencing and stable isotope tracing. We show that acute iron deprivation causes an anti-proliferative Warburg transcriptome characterized by an ATF4-dependent signature. Metabolically, iron-deprived human macrophages show an inhibition of oxidative phosphorylation and a concomitant increase in glycolysis, a large increase in glucosederived citrate pools associated with lipid droplet accumulation and modest levels of itaconate production. LPS polarization increases itaconate/succinate ratio and decreases pro-inflammatory cytokine production in iron-deprived macrophages. Acute iron deprivation reduces the severity of macrophage-dependent crescentic glomerulonephritis by limiting glomerular cell proliferation and inducing lipid accumulation in the renal cortex, phenocopying partly the iron-driven metabolic and transcriptional responses. These results suggest that acute iron deprivation has in vivo protective effects, by causing an antiinflammatory immuno-metabolic switch in macrophages.

Journal article

Barbour SJ, Coppo R, Zhang H, Liu Z-H, Suzuki Y, Matsuzaki K, Katafuchi R, Er L, Espino-Hernandez G, Kim SJ, Reich HN, Feehally J, Cattran DC, Russo ML, Troyanov S, Cook HT, Roberts I, Tesar V, Maixnerova D, Lundberg S, Gesualdo L, Emma F, Fuiano L, Beltrame G, Rollino C, Amore A, Camilla R, Peruzzi L, Praga M, Feriozzi S, Polci R, Segoloni G, Colla L, Pani A, Piras D, Angioi A, Cancarini G, Ravera S, Durlik M, Moggia E, Ballarin J, Di Giulio S, Pugliese F, Serriello I, Caliskan Y, Sever M, Kilicaslan I, Locatelli F, Del Vecchio L, Wetzels JFM, Peters H, Berg U, Carvalho F, da Costa Ferreira AC, Maggio M, Wiecek A, Ots-Rosenberg M, Magistroni R, Topaloglu R, Bilginer Y, D'Amico M, Stangou M, Giacchino F, Goumenos D, Kalliakmani P, Gerolymos M, Galesic K, Geddes C, Siamopoulos K, Balafa O, Galliani M, Stratta P, Quaglia M, Bergia R, Cravero R, Salvadori M, Cirami L, Fellstrorn B, Smerud HK, Ferrario F, Stellato T, Egido J, Martin C, Floege J, Eitner F, Lupo A, Bernich P, Mene R, Morosetti M, van Kooten C, Rabelink T, Reinders MEJ, Boria Grinyo JM, Cusinato S, Benozzi L, Savoldi S, Licata C, Mizerska-Wasiak M, Martina G, Messuerotti A, Dal Canton A, Esposito C, Migotto C, Triolo G, Mariano F, Pozzi C, Boero R, Bellur S, Mazzucco G, Giannakakis C, Honsova E, Sundelin B, Di Palma AM, Ferrario F, Gutierrez E, Asunis AM, Barratt J, Tardanico R, Perkowska-Ptasinska A, Arce Terroba J, Fortunato M, Pantzaki A, Ozluk Y, Steenbergen E, Soderberg M, Riispere Z, Furci L, Orhan D, Kipgen D, Casartelli D, Ljubanovic DG, Gakiopoulou H, Bertoni E, Cannata Ortiz P, Karkoszka H, Groene HJ, Stoppacciaro A, Bajema I, Bruijn J, Fulladosa Oliveras X, Maldyk J, Loachim E, Bavbek N, Cook T, Troyanov S, Alpers C, Amore A, Barratt J, Berthoux F, Bonsib S, Bruijn J, D'Agati V, D'Amico G, Emancipator S, Emmal F, Ferrario F, Fervenza F, Florquin S, Fogo A, Geddes C, Groene H, Haas M, Hill P, Hogg R, Hsu S, Hunley T, Hladunewich, Jennette C, Joh K, Julian B, Kawamura T, Lai F, Leung C, Li L, Liet al., 2019, Evaluating a New International Risk-Prediction Tool in IgA Nephropathy, ISN World Congress of Nephrology, Publisher: AMER MEDICAL ASSOC, Pages: 942-952, ISSN: 2168-6106

Conference paper

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

Kousios A, Duncan N, Charif R, Tam FWK, Levy J, Cook HT, Pusey CD, Roufosse C, Chaidos Aet al., 2019, Autologous stem cell transplant for the treatment of type I crystal cryoglobulinaemic glomerulonephritis caused by monoclonal gammopathy of renal significance (MGRS), Kidney International Reports, ISSN: 2468-0249

Cryoglobulins (CGs) are immunoglobulins that precipitate at temperatures below 37°C and dissolve again after rewarming. Cryoglobulinemia may be asymptomatic or cause end-organ damage by CG precipitation in small- to medium-sized blood vessels.1 In their seminal work, Brouet et al.2 classify cryoglobulinemias into 3 subgroups according to CG composition and clonality. In type II cryoglobulinemia there is a mixture of monoclonal IgM with rheumatoid factor activity and polyclonal IgG. In type III, CGs consist of polyclonal IgM and IgG.1 Type II and III cryoglobulinemias are also referred to as mixed cryoglobulinemias and are often caused by chronic hepatitis C infection and less frequently by autoimmune diseases or other viral infections (hepatitis B infection, HIV).3CGs in type I cryoglobulinemia are monoclonal Igs (MIg), also known as paraproteins, commonly IgG, IgM subtypes, or free light chains. The underlying pathological process is a plasma cell or B-cell lymphoproliferative disease, such as multiple myeloma (MM), Waldenström macroglobulinemia, chronic lymphocytic leukemia, or other B-cell non-Hodgkin lymphoma. However, in approximately 40% of symptomatic cases, the plasma cell or B-cell clone is too small to fulfill the diagnostic criteria of MM or overt lymphoma. The term monoclonal gammopathy of undetermined significance (MGUS) used for these cases is a misnomer, as the MIg causes disease regardless of the size and tumor burden.4 For cases with renal involvement, the International Kidney and Monoclonal Gammopathy Research Group introduced the term monoclonal gammopathies of renal significance (MGRS).5 The updated MGRS definition includes monoclonal gammopathies that cause renal disease but have low tumor burden and thus treatment from the hematological standpoint is not imminently indicated.6 These patients may have fewer than 10% plasma cells in bone marrow biopsy, smoldering myeloma, or low-grade lymphomas.7 MGRSs are not of undetermined significanc

Journal article

Kousios A, Storey R, Troy-Barnes E, Hamady M, Salisbury E, Duncan N, Charif R, Tam F, Cook T, Crane J, Chaidos A, Roufosse C, Flora Ret al., 2019, Plasmacytoma-like post-transplant lymphoproliferative disease in a disused arterio-venous fistula: the importance of histopathology., Kidney International Reports, Vol: 4, Pages: 749-755, ISSN: 2468-0249

Common causes of swelling in arteriovenous fistulae (AVFs) include thrombosis, infection, aneurysm, and superior vena cava (SVC) obstruction secondary to previous dialysis vascular catheter use. Malignancies confined in AVFs are rare and have been described in case series and case reports, mostly in immunosuppressed patients.1 Patients who undergo transplantation frequently have functioning or nonfunctioning AVFs. The risk of malignancy is increased in this patient group and thus should be considered in patients presenting with symptomatic AVF. The most common histopathological diagnosis is angiosarcoma.1, 2 Plasmacytoma-like posttransplant lymphoproliferative disease (PTLD) confined in an AVF has not been previously described.

Journal article

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

Wong N, Kang A, Mcadoo S, Cook T, Pusey Cet al., 2019, MEST-C SCORE IN ADULT HENOCH-SCHONLEIN PURPURA NEPHRITIS, 19th International Vasculitis and ANCA Workshop, Publisher: OXFORD UNIV PRESS, Pages: 51-51, ISSN: 1462-0324

Conference paper

Mcadoo S, Prendecki M, Turner-Stokes T, Bhangal G, Cook T, Tam F, Pusey Cet al., 2019, FOSTAMATINIB TREATMENT OF A NEW MODEL OF MPO-ANCA VASCULITIS IN WKY RATS INDUCED BY ADMINISTRATION OF A SUBNEPHRITOGENIC DOSE OF NEPHROTOXIC SERUM AFTER IMMUNIZATION WITH HUMAN MYELOPEROXIDASE, 19th International Vasculitis and ANCA Workshop, Publisher: OXFORD UNIV PRESS, Pages: 92-92, ISSN: 1462-0324

Conference paper

Prendecki M, Mcadoo S, Turner-Stokes T, Bhangal G, Woollard K, Behmoaras J, Aitman T, Cook T, Unwin R, Pusey C, Tam Fet al., 2019, THE EFFECT OF P2X7 ANTAGONISM ON NEPHROTOXIC NEPHRITIS, 19th International Vasculitis and ANCA Workshop, Publisher: OXFORD UNIV PRESS, Pages: 93-94, ISSN: 1462-0324

Conference paper

Prendecki M, Mcadoo S, Turner-Stokes T, Garcia-Diaz A, Woollard K, Behmoaras J, Cook T, Unwin R, Aitman T, Pusey C, Tam Fet al., 2019, A NOVEL P2X7 KNOCKOUT RAT IS NOT PROTECTED FROM EXPERIMENTAL GLOMERULONEPHRITIS OR VASCULITIS, 19th International Vasculitis and ANCA Workshop, Publisher: OXFORD UNIV PRESS, ISSN: 1462-0324

Conference paper

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, Vol: 129, Pages: 1061-1075, 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

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, 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

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

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

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