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
to

525 results found

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: e2022722118-e2022722118, ISSN: 0027-8424

<jats:p>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 <jats:italic>CFHR5</jats:italic> 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.</jats:p>

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, 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

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

Vallant N, Wolfhagen N, Sandhu B, Hamaoui K, Cook T, Pusey C, Papalois Vet al., 2020, A Comparison of Pulsatile Hypothermic and Normothermic Ex Vivo Machine Perfusion in a Porcine Kidney Model., Transplantation

BACKGROUND: Hypothermic Machine Perfusion (HMP) is a well-established method for deceased donor kidney preservation. Normothermic Machine Perfusion (NMP) might offer similar or greater advantages. We compared the two methods in an ex vivo perfusion model using 34 porcine kidneys. METHODS: Thirty kidneys were stored on ice for 24h before undergoing 4h of HMP (n=15) or NMP (n=15) followed by 2h of normothermic ex vivo reperfusion with whole blood. Four kidneys underwent 28h of cold static storage (CSS) followed by 2h of normothermic ex vivo reperfusion. During the 2 hours of normothermic ex vivo reperfusion perfusate flow rates, urinary output and oxygen consumption rates were compared between all groups. RESULTS: Porcine kidneys after HMP showed significantly higher urinary output- (5.31ml/min±2.06ml/min vs. 2.44ml/min±1.19ml/min, p=0.002), oxygen consumption- (22.71±6.27ml/min vs. 11.83±1.29ml/min, p=0.0016) and perfusate flow rates (46.24±12.49ml/min vs. 26.16±4.57ml/min, p=0.0051) than kidneys after NMP. Tunnel staining of tissue sections showed significantly higher rates of apoptosis in kidneys after NMP (p=0.027). CONCLUSIONS: In our study, the direct comparison of HMP and NMP kidney perfusion in a translational model demonstrated superiority of HMP, however further in vivo studies would be needed to validate those results.

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

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

McAdoo S, Prendecki M, Tanna A, Bhatt T, Bhangal G, McDaid J, masuda E, Cook H, Tam F, Pusey Cet al., 2020, Spleen tyrosine kinase inhibition is an effective treatment for established vasculitis in a pre-clinical model, Kidney International, Vol: 97, Pages: 1196-1207, ISSN: 0085-2538

The anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are a group of life-threatening multi-system diseases characterized by necrotising inflammation of small blood vessels and crescentic glomerulonephritis. ANCA are thought to play a direct pathogenic role. Previous studies have shown that spleen tyrosine kinase (SYK) is phosphorylated during ANCA-induced neutrophil activation in vitro. However, the role of SKY in vivo is unknown. Here, we studied its role in the pathogenesis of experimental autoimmune vasculitis, a pre-clinical model of myeloperoxidase-ANCA-induced pauci-immune systemic vasculitis in the Wistar Kyoto rat. Up-regulation of SYK expression in inflamed renal and pulmonary tissue during early autoimmune vasculitis was confirmed by immunohistochemical and transcript analysis. R406, the active metabolite of fostamatinib, a small molecule kinase inhibitor with high selectivity for SYK, inhibited ANCA-induced pro-inflammatory responses in rat leucocytes in vitro. In an in vivo study, treatment with fostamatinib for 14 days after disease onset resulted in rapid resolution of urinary abnormalities, significantly improved renal and pulmonary pathology, and preserved renal function. Short-term exposure to fostamatinib did not significantly affect circulating myeloperoxidase-ANCA levels, suggesting inhibition of ANCA-induced inflammatory mechanisms in vivo. Finally, SYK expression was demonstrated within inflammatory glomerular lesions in ANCA-associated glomerulonephritis in patients, particularly within CD68+ve monocytes/macrophages. Thus, our data indicate that SYK inhibition warrants clinical investigation in the treatment of AAV.

Journal article

Tan PG, O'Brien J, Griffith M, Condon M, Cairns T, Levy J, Cook T, Pusey C, McAdoo Set al., 2020, VALIDATION OF THE ANCA RENAL RISK SCORE IN A LONDON COHORT: POTENTIAL IMPACT OF TREATMENT ON PREDICTION OUTCOME, 57th ERA-EDTA Congress, Publisher: OXFORD UNIV PRESS, Pages: 662-662, ISSN: 0931-0509

Conference paper

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

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, Clinical Journal of the American Society of Nephrology, Vol: 15, Pages: 209-218, ISSN: 1555-9041

BACKGROUND AND OBJECTIVES: Minimal change disease is an important cause of nephrotic syndrome in adults. Corticosteroids are first-line therapy for minimal change disease, but a prolonged course of treatment is often required and relapse rates are high. Patients with minimal change disease are therefore often exposed to high cumulative corticosteroid doses and are at risk of associated adverse effects. This study investigated whether tacrolimus monotherapy without corticosteroids would be effective for the treatment of de novo minimal change disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a multicenter, prospective, open-label, randomized, controlled trial involving six nephrology units across the United Kingdom. Adult patients with first presentation of minimal change disease and nephrotic syndrome were randomized to treatment with either oral tacrolimus at 0.05 mg/kg twice daily, or prednisolone at 1 mg/kg daily up to 60 mg daily. The primary outcome was complete remission of nephrotic syndrome after 8 weeks of therapy. Secondary outcomes included remission of nephrotic syndrome at 16 and 26 weeks, rates of relapse of nephrotic syndrome, and changes from baseline kidney function. RESULTS: There were no significant differences between the tacrolimus and prednisolone treatment cohorts in the proportion of patients in complete remission at 8 weeks (21 out of 25 [84%] for prednisolone and 17 out of 25 [68%] for tacrolimus cohorts; P=0.32; difference in remission rates was 16%; 95% confidence interval [95% CI], -11% to 40%), 16 weeks (23 out of 25 [92%] for prednisolone and 19 out of 25 [76%] for tacrolimus cohorts; P=0.25; difference in remission rates was 16%; 95% CI, -8% to 38%), or 26 weeks (23 out of 25 [92%] for prednisolone and 22 out of 25 [88%] for tacrolimus cohorts; P=0.99; difference in remission rates was 4%; 95% CI, -17% to 25%). There was no significant difference in relapse rates (17 out of 23 [74%] for prednisolone and 16 out of 22

Journal article

Levine AP, Chan MMY, Sadeghi-Alavijeh O, Wong EKS, Cook HT, Ashford S, Carss K, Christian MT, Hall M, Harris CL, McAlinden P, Marchbank KJ, Marks SD, Maxwell H, Megy K, Penkett CJ, Mozere M, Stirrups KE, Tuna S, Wessels J, Whitehorn D, Johnson SA, Gale DPet al., 2020, Large-scale whole-genome sequencing reveals the genetic architecture of primary membranoproliferative GN and C3 glomerulopathy, Journal of the American Society of Nephrology, Vol: 31, Pages: 1-9, ISSN: 1046-6673

Background Primary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN.Methods We analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource–Rare Diseases Study. We examined copy number, rare, and common variants.Results Our analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) (P=3.29×10−8; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 (P=1.21×10−8; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure.Conclusions We found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases.

Journal article

Hamaoui K, Gowers S, Sandhu B, Cook T, Boutelle M, Casanova-Rituerto D, Papalois Vet al., 2020, Cold ischaemia time: is too long really too bad? studies using a porcine kidney ex-vivo reperfusion model, International Journal of Surgery Open, Vol: 23, Pages: 39-47, ISSN: 2405-8572

IntroductionPost-ischaemic hypothermic machine perfusion (HMP) may be beneficial in recovery of marginal kidney grafts. The full capacity of conventional HMP (with passive oxygenation) to recondition an organ has not been realised. We investigated whether HMP can ameliorate ischemic damage caused by extremely prolonged static cold storage (SCS).MethodsPorcine kidneys underwent 4-h (SCS4,n = 4) or 52-h (SCS52,n = 4) SCS, followed by 10 h of HMP and were then subjected to 2 h of isolated normothermic reperfusion (NRP).ResultsThere was a post-SCS graft weight loss in SCS52 vs SCS4 kidneys. SCS52 kidneys showed viable perfusion dynamics during HMP, with significantly shorter times to reach viable parameters vs SCS4 kidneys (p < 0.027). During NRP SCS52 kidneys demonstrated similar trends in perfusion dynamics, renal function, oxygen consumptions, lactate production, and tubular injury to SCS4 kidneys.ConclusionGraft weight loss after SCS, reducing resistance to perfusion, may facilitate better HMP dynamics and graft reconditioning. Clinicians utilising HMP should be aware of this phenomenon when using HMP in kidneys exposed to extreme periods of SCS. HMP after an extended period of SCS can resuscitate kidneys to a level equitable of viability as those after a short period of SCS. Utilising passive oxygenation however may be limiting such recovery and interventions utilising active oxygenation may provide benefit in such organs.

Journal article

Nikolopoulou A, Huang-Doran I, McAdoo SP, Griffith ME, HT C, Pusey CDet al., 2019, Membranous glomerulonephritis with crescents, Kidney International Reports, Vol: 4, Pages: 1577-1584, ISSN: 2468-0249

BackgroundMembranous glomerulonephritis (MGN) is rarely associated with necrotising and crescentic glomerulonephritis (NCGN).MethodsWe report the clinical and pathological findings in 15 patients with MGN and NCGN associated with ANCA, anti-GBM or anti-PLA2R antibodies.ResultsThe cohort consisted of 15 patients: 7 males and 8 females with a median age of 63 years (range 18-79). In 12/15 patients MGN and NCGN were diagnosed at the time of the biopsy and in 3 cases MGN predated the NCGN. ANCA was positive in 7 cases (6 MPO-ANCA and 1 PR3 –ANCA), anti-GBM antibodies were detected in 5 cases and anti-PLA2R antibodies were found in 2 cases. One case was negative for all antibodies. Microscopic haematuria was present in all but one patient who was anuric and median urinary protein/creatinine ratio (uPCR) was 819.5mg/mmol [range 88-5600]. Pathologic evaluation revealed MGN and NCGN with crescents involving 28% of glomeruli (median, range 5-100%). Follow up was available for all 15 patients; all were treated with steroids; 10 with cyclophosphamide and 6 also received rituximab. At a median follow up of 72 months, 9 had stabilisation or improvement of renal function, 6 patients progressed to ESRD and 4 died during the follow up period.ConclusionsMGN with crescents associated with ANCA or anti-GBM antibodies is a rare dual glomerulopathy. Patients present with heavy proteinuria, microscopic haematuria and acute kidney injury and should be treated for a rapidly progressive glomerulonephritis. Prognosis is variable and 40% of patients progress to ESRD.

Journal article

Medjeral-Thomas NR, Moffitt H, Lomax-Browne HJ, Constantinou N, Cairns T, Cook HT, Pickering MCet al., 2019, Glomerular complement factor H–related protein 5 (FHR5) is highly Prevalent in C3 glomerulopathy and associated with renal impairment, Kidney International Reports, Vol: 4, Pages: 1387-1400, ISSN: 2468-0249

IntroductionTherapeutic agents that target complement are increasingly available for glomerular diseases. However, the mechanisms linking glomerular complement deposition with inflammation and damage are incompletely understood. Complement factor H–related protein 5 (FHR5) interacts with complement C3 and is considered to promote activation. Circulating and glomerular FHR5 associates with IgA nephropathy and abnormal FHR5 associates with familial C3 glomerulopathy (C3G). We characterized glomerular FHR5 staining in C3G and assessed its relationships with histological features of glomerular injury and clinical outcome.MethodsWe developed FHR5 staining protocols for formalin-fixed paraffin-embedded (FFPE) renal tissue and applied them to surplus biopsy sections from a C3G cohort.ResultsGlomerular FHR5 was highly prevalent in native and transplant C3G and correlated with glomerular C3 and C5b-9 staining. Glomerular FHR5 staining correlated negatively with estimated glomerular filtration rate (eGFR) (P = 0.04, difference of medians 19.7 ml/min per 1.73 m2; 95% confidence interval [CI] 1.1–43.0) and positively with a membranoproliferative glomerulonephritis pattern at diagnostic biopsy (odds ratio 18; 95% CI 1.6–201; P = 0.049). Glomerular FHR5 staining intensity positively correlated with glomerular complement C3b/iC3b/C3c (Pearson’s correlation coefficient [R] = 0.59; P = 0.0008), C3dg (R = 0.47; P = 0.02) and C5b9 (R = 0.44, P = 0.02).ConclusionsGlomerular FHR5 is highly prevalent in C3G, interacts with glomerular C3, and is associated with markers of disease severity. Glomerular FHR5 likely exacerbates complement-mediated glomerular damage in C3G and its interaction with glomerular complement might be exploited to target complement therapeutic agents.

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., 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

Toulza F, Dominy K, Galliford J, Cook T, McLean A, Roufosse Cet al., 2019, GENE EXPRESSION ANALYSIS IN RENAL TRANSPLANT BIOPSIES: COMPARISON OF SPLIT SAMPLES AND DIFFERENT TECHNIQUES, American-Society-for-Histocompatibility-and-Immunogenetics (ASHI)/BANFF Joint Scientific Meeting, Publisher: ELSEVIER SCIENCE INC, Pages: 52-52, ISSN: 0198-8859

Conference paper

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

Conference paper

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, Vol: 4, Pages: 1342-1348, 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

Navaratnarajah A, Sambasivan K, Cook TH, Pusey C, Roufosse C, Willicombe Met al., 2019, Predicting long-term renal and patient survival by clinicopathological features in elderly patients undergoing a renal biopsy in a UK cohort, Clinical Kidney Journal, Vol: 12, Pages: 512-520, ISSN: 2048-8505

Background: Several publications have demonstrated the use of renal biopsy in elderly patients in establishing a diagnosis and enabling directed therapy. However, evidence on the long-term outcomes following biopsies is lacking. The aim of this study is to describe the renal and patient outcomes in elderly patients according to indication for biopsy, clinical parameters and the histological diagnosis. Methods: We performed a retrospective cohort study of 463 patients >70 years old who underwent a renal biopsy at our centre between 2006 and 2015. Results: The median age of the patients was 74.8 (range 70.0-89.6) years. The most frequent primary diagnoses were pauci-immune crescentic glomerulonephritis (GN; 12%), acute interstitial nephritis (10.8%) and membranous GN (7.1%). Death-censored renal survival at 1 and 5 years following the index biopsy was 85.2 and 75.9%, respectively, and patient survival at 1 and 5 years was 92.2 and 71.6%, respectively. Patients who progressed to end-stage renal disease (ESRD) were at higher risk of dying compared with patients who did not require dialysis [hazard ratio 2.41 (95% confidence interval 1.58-3.68; P < 0.001]. On multivariate analysis, factors associated with the risk of progression to ESRD were creatinine (P < 0.001), heavy proteinuria (P = 0.002) and a non-chronic kidney disease (CKD) biopsy indication (P = 0.006). A histological diagnosis of primary GN (P = 0.001) or tubulointerstitial nephritis (P = 0.008) was associated with a favourable renal outcome, while patients with vasculitis and paraprotein-related renal disease (PPRD) had the highest risk of requiring dialysis (P = 0.0002 and P = 0.003, respectively). PPRD was also an independent risk factor for death. Conclusions: This study demonstrates that renal biopsies in the elderly not only enable directed therapy, but also provide prognostic i

Journal article

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, Vol: 28, Pages: 1091-1100, 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

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