Publications
562 results found
Giacomassi C, Buang N, Ling GS, et al., 2016, Complement C3 exacerbates imiquimod-induced skin inflammation and psoriasiform dermatitis, Journal of Investigative Dermatology, Vol: 137, Pages: 760-763, ISSN: 1523-1747
The complement system is pivotal in protection against pathogens, but also plays important roles in bridging innate and adaptive immune responses (Scott and Botto, 2015) and in modulating local and systemic inflammation (Markiewski and Lambris, 2007). Activation of complement occurs through three different pathways (classical, alternative and lectin), converges at C3 cleavage and culminates in the formation of the membrane attack complex. The anaphylotoxic fragments, C3a and C5a, generated during the proteolytic cascade, recruit immune cells that can promote the removal of debris and pathogens, but can also cause tissue damage (Markiewski and Lambris, 2007).
Bellur SS, Lepeytre F, Vorobyeva O, et al., 2016, Clinical Value of Subclassification of Focal Segmental Glomerulosclerosis in IgA Nephropathy, 9th Joint Meeting of the British-Division of the International-Academy-of-Pathology and the Pathological-Society-of-Great-Britain-and-Ireland, Publisher: WILEY-BLACKWELL, Pages: 23-23, ISSN: 0022-3417
Coppo R, Lofaro D, Camilla RR, et al., 2016, Erratum to: Risk factors for progression in children and young adults with IgA nephropathy: an analysis of 261 cases from the VALIGA European cohort., Pediatric Nephrology, Vol: 32, Pages: 193-194, ISSN: 1432-198X
Bellur S, Lepeytre F, Vorobyeva O, et al., 2016, Subclassification of focal segmental glomerulosclerosis in IgA nephropathy: is it of clinical value? Evidence from the Oxford Classification cohort., Kidney International, ISSN: 1523-1755
Hamaoui K, Aftab A, Gowers S, et al., 2016, An ex vivo comparison of adenosine and lidocaine solution and University of Wisconsin solution for hypothermic machine perfusion of porcine kidneys: potential for development, JOURNAL OF SURGICAL RESEARCH, Vol: 208, Pages: 219-229, ISSN: 0022-4804
Moran L, Dominy K, Moss J, et al., 2016, A correlation of ultrastructuralmicrovascular features with endothelial cell transcripts in renal transplant biopsies, Publisher: SPRINGER, Pages: S11-S11, ISSN: 0945-6317
Moran L, Moss J, Willicombe M, et al., 2016, A comparison of ultrastructural glomerular features in biopsies from patients with de novo donor specific antibodies with surveillance biopsies, Publisher: SPRINGER, Pages: S24-S24, ISSN: 0945-6317
Moran L, Dominy K, Moss J, et al., 2016, A correlation of ultrastructural microvascular features with endothelial cell transcripts in renal transplant biopsies, Publisher: SPRINGER, Pages: S11-S11, ISSN: 0945-6317
Moran L, Moss J, Willicombe M, et al., 2016, A comparison of ultrastructural glomerular features in biopsies from patients with de novo donor specific antibodies with surveillance biopsies, Publisher: SPRINGER, Pages: S24-S24, ISSN: 0945-6317
Coppo R, Lofaro DD, Camilla RR, et al., 2016, Risk factors for progression in children and young adults with IgA nephropathy: an analysis of 261 cases from the VALIGA European cohort, Pediatric Nephrology, Vol: 32, Pages: 139-150, ISSN: 1432-198X
BACKGROUND: There is a need for early identification of children with immunoglobulin A nephropathy (IgAN) at risk of progression of kidney disease. METHODS: Data on 261 young patients [age <23 years; mean follow-up of 4.9 (range 2.5-8.1) years] enrolled in VALIGA, a study designed to validate the Oxford Classification of IgAN, were assessed. Renal biopsies were scored for the presence of mesangial hypercellularity (M1), endocapillary hypercellularity (E1), segmental glomerulosclerosis (S1), tubular atrophy/interstitial fibrosis (T1-2) (MEST score) and crescents (C1). Progression was assessed as end stage renal disease and/or a 50 % loss of estimated glomerular filtration rate (eGFR) (combined endpoint) as well as the rate of renal function decline (slope of eGFR). Cox regression and tree classification binary models were used and compared. RESULTS: In this cohort of 261 subjects aged <23 years, Cox analysis validated the MEST M, S and T scores for predicting survival to the combined endpoint but failed to prove that these scores had predictive value in the sub-group of 174 children aged <18 years. The regression tree classification indicated that patients with M1 were at risk of developing higher time-averaged proteinuria (p < 0.0001) and the combined endpoint (p < 0.001). An initial proteinuria of ≥0.4 g/day/1.73 m(2) and an eGFR of <90 ml/min/1.73 m(2) were determined to be risk factors in subjects with M0. Children aged <16 years with M0 and well-preserved eGFR (>90 ml/min/1.73 m(2)) at presentation had a significantly high probability of proteinuria remission during follow-up and a higher remission rate following treatment with corticosteroid and/or immunosuppressive therapy. CONCLUSION: This new statistical approach has identified clinical and histological risk factors associated with outcome in children and young adults with IgAN.
Willicombe M, Moss J, Moran L, et al., 2016, Tubuloreticular inclusions in renal allografts associate with viral infections and donor-specific antibodies, Journal of the American Society of Nephrology, Vol: 27, Pages: 2188-2195, ISSN: 1046-6673
The presence of tubuloreticular inclusions (TRIs) in native glomerular endothelial cells associates with viral infections and lupus nephritis. However, the associations of TRIs in renal transplant biopsy specimens are not known. We analyzed data from 316 patients who had a transplant biopsy with electron microscopy examination; 41 of 316 (13.0%) patients had TRIs. Patients with TRIs had significantly lower allograft survival rates (50.9%) than patients without TRIs (74.3%; P=0.03). Transplant glomerulopathy–free survival was also inferior in the TRI-positive group (57.5%) compared with the TRI-negative group (87.3%; P=0.002). Serologically, hepatitis C associated with the presence of TRIs (P=0.04) along with donor-specific antibodies (P=0.01). Furthermore, patients who were TRI positive were more likely than patients who were TRI negative to have had a previous rejection episode (P=0.02). On multivariate analysis, TRIs associated with prior rejection, viral infections, and class 1 HLA donor–specific antibodies. These results show that the presence of TRIs in renal allograft biopsy specimens associates with poor allograft outcomes and serologic evidence of viral infections and alloimmunity. The association with alloimmunity is a novel finding that warrants additional investigation.
McGuire E, Roufosse C, Cook T, et al., 2016, Biopsies for Delayed Graft Function After Alemtuzumab Induction in Kidney Transplantation: The Incidence of Early Rejection After Alemtuzumab Is Very Low but Not Negligible., American Transplant Congress, Publisher: WILEY-BLACKWELL, Pages: 453-453, ISSN: 1600-6135
Koutroutsos K, Kousios A, Leighton L, et al., 2016, The Effect of Immunosuppression Regimen on Iga Nephropathy Recurrence Post Kidney Transplantation, American Transplant Congress, Publisher: WILEY-BLACKWELL, Pages: 686-686, ISSN: 1600-6135
Koutroutsos K, Moss J, Moran L, et al., 2016, Treatment of Post-Transplant Focal Glomerulosclerosis: The Effect on Histopathology Lesions and Podocyte Foot Process Effacement., American Transplant Congress, Publisher: WILEY-BLACKWELL, Pages: 775-775, ISSN: 1600-6135
Koutroutsos K, Charif R, Moran L, et al., 2016, Insights into the Treatment of Post-Transplant Focal Glomerulosclerosis: Experience Gained from a Concise Diagnostic and Management Protocol., American Transplant Congress, Publisher: WILEY-BLACKWELL, Pages: 343-343, ISSN: 1600-6135
Vernon KA, Ruseva MM, Cook HT, et al., 2016, Partial complement factor H deficiency associates with C3 glomerulopathy and thrombotic microangiopathy, Journal of the American Society of Nephrology, Vol: 27, Pages: 1334-1342, ISSN: 1046-6673
The complement–mediated renal diseases C3 glomerulopathy (C3G) and atypical hemolytic uremic syndrome (aHUS) strongly associate with inherited and acquired abnormalities in the regulation of the complement alternative pathway (AP). The major negative regulator of the AP is the plasma protein complement factor H (FH). Abnormalities in FH result in uncontrolled activation of C3 through the AP and associate with susceptibility to both C3G and aHUS. Although previously developed FH–deficient animal models have provided important insights into the mechanisms underlying susceptibility to these unique phenotypes, these models do not entirely reproduce the clinical observations. FH is predominantly synthesized in the liver. We generated mice with hepatocyte–specific FH deficiency and showed that these animals have reduced plasma FH levels with secondary reduction in plasma C3. Unlike mice with complete FH deficiency, hepatocyte–specific FH–deficient animals developed neither plasma C5 depletion nor accumulation of C3 along the glomerular basement membrane. In contrast, subtotal FH deficiency associated with mesangial C3 accumulation consistent with C3G. Although there was no evidence of spontaneous thrombotic microangiopathy, the hepatocyte–specific FH–deficient animals developed severe C5–dependent thrombotic microangiopathy after induction of complement activation within the kidney by accelerated serum nephrotoxic nephritis. Taken together, our data indicate that subtotal FH deficiency can give rise to either spontaneous C3G or aHUS after a complement-activating trigger within the kidney and that the latter is C5 dependent.
Connor TM, Aiello V, Griffith M, et al., 2016, The natural history of immunoglobulin M nephropathy in adults, Nephrology Dialysis Transplantation, Vol: 32, Pages: 823-829, ISSN: 1460-2385
BACKGROUND: Immunoglobulin M (IgM) nephropathy is an idiopathic glomerulonephritis characterized by diffuse mesangial deposition of IgM. IgM nephropathy has been a controversial diagnosis since it was first reported, and there are few data identifying specific pathological features that predict the risk of progression of renal disease. METHODS: We identified 57 cases of IgM nephropathy among 3220 adults undergoing renal biopsy at our institution. Biopsies had to satisfy the following three criteria to meet the definition of IgM nephropathy in this study: (i) dominant mesangial staining for IgM, (ii) mesangial deposits on electron microscopy (EM) and (iii) exclusion of systemic disease. RESULTS: The median age was 42 years and 24 patients were male. Thirty-nine per cent of patients presented with the nephrotic syndrome, 49% presented with non-nephrotic proteinuria and 39% had eGFR <60 mL/min. The median post-biopsy follow-up was 40 months and serum creatinine had doubled in 31% by 5 years. Of histological parameters, glomerular sclerosis and tubular atrophy, but not mesangial proliferation, were risk factors for renal insufficiency. Thirty-nine per cent of nephrotic patients achieved complete remission, and outcome was significantly worse in those who did not respond to treatment. Focal segmental glomerulosclerosis was diagnosed in 80% of those undergoing repeat renal biopsy, despite ongoing mesangial IgM deposition. CONCLUSIONS: We propose criteria for a consensus definition of IgM nephropathy.
de Kort H, Willicombe M, Brookes P, et al., 2016, Peritubular Capillary Basement Membrane Multilayering in Renal Allograft Biopsies of Patients With De Novo Donor-Specific Antibodies, Transplantation, Vol: 100, Pages: 889-897, ISSN: 1534-6080
Background. Severe peritubular capillary basement membrane multilayering (PTCBML) is part of the Banff definition of chronicantibody-mediated rejection. We retrospectively investigated whether assessment of the mean number of layers of basementmembrane (BM) around peritubular capillaries (PTC) can be used in a cohort of patients with de novo donor-specific antibodies(dnDSA) as an early marker to predict long-term antibody-mediated injury. Methods. This is a retrospective cohort study with151 electron microscopy samples from 54 patients with dnDSA, assessed at around 1 year after transplantation, for a mean numberof BM layers around PTC and in serial biopsies. Graft survival and time to transplant glomerulopathy (TG) development wereestimated in survival analyses. Results. We found that a mean PTCBML count greater than 2.5 layers assessed in a sample of 25PTCs around 1 year after transplantation is indicative of the development of TG in patients with dnDSA (P = 0.001). In addition, inpatients with serial biopsies available for electron microscopy analysis, we could distinguish 2 groups: patients with a meanPTCBML count of 2.5 or less on all biopsies, and patients who developed greater than 2.5 layers at any time after transplantation.The latter group reflected dnDSA patients at risk for TG development (P < 0.001). In patients with dnDSA, PTCBML score addedsignificantly to the sensitivity and specificity of prediction of TG compared with microcirculation injury score alone. Conclusions.Our results highlight the potential value of assessing the mean number of BM in PTC for early prediction of progression to chronicantibody-mediated injury
Progatzky F, Cook HT, Lamb JR, et al., 2016, Mucosal inflammation at the respiratory interface: a zebrafish model, AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, Vol: 310, Pages: L551-L561, ISSN: 1040-0605
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- Citations: 21
Moschidou D, Corcelli M, Hau K-L, et al., 2016, Human Chorionic Stem Cells: Podocyte Differentiation and Potential for the Treatment of Alport Syndrome, STEM CELLS AND DEVELOPMENT, Vol: 25, Pages: 395-404, ISSN: 1547-3287
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- Citations: 12
Pusey CD, Connor TM, Aiello V, et al., 2016, The natural history of IgM nephropathy in adults, Nephrology Dialysis Transplantation, ISSN: 1460-2385
Background: Immunoglobulin M (IgM) nephropathy is an idiopathic glomerulonephritis characterised by diffuse mesangial deposition of IgM. IgM nephropathy has been a controversial diagnosis since it was first reported, and there are few data identifying specific pathological features that predict risk of progression of renal disease.Methods: We identified 57 cases of IgM nephropathy among 3220 adults undergoing renal biopsy at our institution. Biopsies had to satisfy the following three criteria to meet the definition of IgM nephropathy in this study: (1) dominant mesangial staining for IgM, (2) mesangial deposits on EM, (3) exclusion of systemic disease.Results: The median age was 42 years and 24 patients were male. 39% of patients presented with the nephrotic syndrome, 49% patients presented with non-nephrotic proteinuria, and 39% had eGFR <60 ml/min. Median post-biopsy follow-up was 40 months and serum creatinine had doubled in 31% by 5 years. Of histological parameters, glomerular sclerosis and tubular atrophy, but not mesangial proliferation, were risk factors for renal insufficiency. 39% of nephrotic patients achieved complete remission, and outcome was significantly worse in those who did not respond to treatment. FSGS was diagnosed in 80% of those undergoing repeat renal biopsy, despite ongoing mesangial IgM deposition. Conclusions: We propose criteria for a consensus definition of IgM nephropathy.
Dubrey SW, Patel K, Lachmann H, et al., 2016, Non-Hodgkin's lymphoma causing light-chain (AL) amyloidosis, BRITISH JOURNAL OF HOSPITAL MEDICINE, Vol: 77, Pages: 188-189, ISSN: 1750-8460
Barbour TD, Ling GS, Ruseva MM, et al., 2016, Complement receptor 3 mediates renal protection in experimental C3 glomerulopathy, Kidney International, Vol: 89, Pages: 823-832, ISSN: 1523-1755
C3 glomerulopathy is a complement-mediated renal disease that is frequently associated with abnormalities in regulation of the complement alternative pathway. Mice with deficiency of factor H (Cfh–/–), a negative alternative pathway regulator, are an established experimental model of C3 glomerulopathy in which complement C3 fragments including iC3b accumulate along the glomerular basement membrane. Here we show that deficiency of complement receptor 3 (CR3), the main receptor for iC3b, enhances the severity of spontaneous renal disease in Cfh–/– mice. This effect was found to be dependent on CR3 expression on bone marrow–derived cells. CR3 also mediated renal protection outside the setting of factor H deficiency, as shown by the development of enhanced renal injury in CR3-deficient mice during accelerated nephrotoxic nephritis. The iC3b–CR3 interaction downregulated the proinflammatory cytokine response of both murine and human macrophages to lipopolysaccharide stimulation in vitro, suggesting that the protective effect of CR3 on glomerular injury was mediated via modulation of macrophage-derived proinflammatory cytokines. Thus, CR3 has a protective role in glomerulonephritis and suggests that pharmacologic potentiation of the macrophage CR3 interaction with iC3b could be therapeutically beneficial.
Feehally J, Coppo R, Troyanov S, et al., 2016, Tonsillectomy in a European Cohort of 1,147 Patients with IgA Nephropathy, Nephron, Vol: 132, Pages: 15-24, ISSN: 1423-0186
Background: Tonsillectomy has been considered a treatment for IgA nephropathy (IgAN). It is aimed at removing a source of pathogens, reducing mucosa-associated lymphoid tissue and decreasing polymeric IgA synthesis. However, its beneficial effect is still controversial. In Asia, favorable outcomes have been claimed mostly in association with corticosteroids. In Europe, small, single-center uncontrolled studies have failed to show benefits. Methods: The European validation study of the Oxford classification of IgAN (VALIGA) collected data from 1,147 patients with IgAN over a follow-up of 4.7 years. We investigated the outcome of progression to end-stage renal disease (ESRD) and/or 50% loss of estimated glomerular filtration rate (eGFR) and the annual loss of eGFR in 61 patients who had had tonsillectomy. Results: Using the propensity score, which is a logistic regression model, we paired 41 patients with tonsillectomy and 41 without tonsillectomy with similar risk of progression (gender, age, race, mean blood pressure, proteinuria, eGFR at renal biopsy, previous treatments and Oxford MEST scores). No significant difference was found in the outcome. Moreover, we performed an additional propensity score pairing 17 patients who underwent tonsillectomy after the diagnosis of IgAN and 51 without tonsillectomy with similar risk of progression at renal biopsy and subsequent treatments. No significant difference was found in changes in proteinuria, or in the renal end point of 50% reduction in GFR and/or ESRD, or in the annual loss of eGFR. Conclusion: In the large VALIGA cohort of European subjects with IgAN, no significant correlation was found between tonsillectomy and renal function decline.
Carlucci F, Botto M, Ishaque A, et al., 2016, C1q modulates the response to TLR7 stimulation by pristane-primed macrophages: implications for pristane-induced lupus, Journal of Immunology, Vol: 196, Pages: 1488-1494, ISSN: 1550-6606
The complement component C1q is known to play a controversial role in thepathogenesis of systemic lupus erythematosus (SLE), but the underlying mechanismsremain poorly understood. Intraperitoneal injection of pristane induces a lupus-likesyndrome whose pathogenesis implicates the secretion of type I IFN by CD11b+Ly6Chigh inflammatory monocytes in a TLR7-dependent fashion. C1q has also beenshown to influence the secretion of IFN-α. Herein we explored whether C1qdeficiency could affect pristane-induced lupus (PIL). Surprisingly, C1qa-/- micedeveloped lower titres of circulating antibodies and milder arthritis compared to thecontrols. In keeping with the clinical scores, two weeks after pristane injection theperitoneal recruitment of CD11b+ Ly6Chigh inflammatory monocytes in the C1qa-/-mice was impaired. Furthermore, C1q-deficient pristane-primed resident peritonealmacrophages secreted significantly less CCL3, CCL2, CXCL1 and IL-6 whenstimulated in vitro with TLR7 ligand. Replenishing C1q in vivo during the pristanepriming phase rectified this defect. Conversely, pristane-primed macrophages fromC3-deficient mice did not show any impaired cytokine production. These findingsdemonstrate that C1q deficiency impairs the TLR7-dependent chemokine productionby pristane-primed peritoneal macrophages and suggest that C1q, and not C3, isinvolved in the handling of pristane by phagocytic cells which is required to triggerdisease in this model.
Barbour SJ, Espino-Hernandez G, Reich HN, et al., 2016, The MEST score provides earlier risk prediction in lgA nephropathy., Kidney Int, Vol: 89, Pages: 167-175
The Oxford Classification of IgA nephropathy (IgAN) includes the following four histologic components: mesangial (M) and endocapillary (E) hypercellularity, segmental sclerosis (S) and interstitial fibrosis/tubular atrophy (T). These combine to form the MEST score and are independently associated with renal outcome. Current prediction and risk stratification in IgAN requires clinical data over 2 years of follow-up. Using modern prediction tools, we examined whether combining MEST with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than current best methods that use 2 years of follow-up data. We used a cohort of 901 adults with IgAN from the Oxford derivation and North American validation studies and the VALIGA study followed for a median of 5.6 years to analyze the primary outcome (50% decrease in eGFR or ESRD) using Cox regression models. Covariates of clinical data at biopsy (eGFR, proteinuria, MAP) with or without MEST, and then 2-year clinical data alone (2-year average of proteinuria/MAP, eGFR at biopsy) were considered. There was significant improvement in prediction by adding MEST to clinical data at biopsy. The combination predicted the outcome as well as the 2-year clinical data alone, with comparable calibration curves. This effect did not change in subgroups treated or not with RAS blockade or immunosuppression. Thus, combining the MEST score with cross-sectional clinical data at biopsy provides earlier risk prediction in IgAN than our current best methods.
Henderson SR, Shah A, Copley SJ, et al., 2015, Occam's razor or Hickam's dictum? Allergic bronchopulmonary aspergillosis and eosinophilic granulomatosis with polyangiitis, Thorax, Vol: 71, Pages: 193-195, ISSN: 1468-3296
Wilhelmus S, Alpers CE, Cook HT, et al., 2015, The Revisited Classification of GN in SLE at 10 Years: Time to Re-Evaluate Histopathologic Lesions, JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 26, Pages: 2938-2946, ISSN: 1046-6673
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Cook HT, 2015, C4d Staining in the Diagnosis of C3 Glomerulopathy, JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, Vol: 26, Pages: 2609-2611, ISSN: 1046-6673
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Saja MF, Baudino L, Jackson WD, et al., 2015, Triglyceride-Rich Lipoproteins Modulate the Distribution and Extravasation of Ly6C/Gr1<SUP>low</SUP> Monocytes, CELL REPORTS, Vol: 12, Pages: 1802-1815, ISSN: 2211-1247
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- Citations: 29
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