Publications
590 results found
Turner-Stokes T, Wilson HR, Morreale M, et al., 2017, Positive antineutrophil cytoplasmic antibodyserology in patients with lupus nephritis isassociated with distinct histopathologic featureson renal biopsy, Kidney International, Vol: 92, Pages: 1223-1231, ISSN: 1523-1755
Class IV-S lupus nephritis (LN) is often associated with more necrosis and fewer subendothelial immune deposits compared to class IV-G LN, suggestive of the necrotising glomerular inflammation found in ANCA-associated vasculitis. ANCA are present in a significant proportion of patients with LN. The aim of this study was to determine whether ANCA are associated with distinct clinical and histopathological features of LN. 32 ANCA positive biopsies were compared to 222 ANCA negative biopsies from patients with LN. The majority of ANCA positive patients had anti-MPO antibodies (82%). Class IV-S LN and glomerular necrosis were more common (36% vs. 16%, p=0.0253 and 35% vs. 15%, p=0.025 respectively) and isolated Class V LN less common (10% vs. 29%, p=0.0282) in the ANCA positive group. ANCA positive patients had higher dsDNA titres (335u/ml vs. 52u/ml, p=0.00007), lower serum C4 concentration (0.125g/L vs. 0.15g/L, p=0.027) and higher serum creatinine (130µmol/L vs. 84µmol/L, p=0.047) at time of biopsy. Hence ANCA appear to influence the histological pattern of LN and are associated with worse baseline renal function and more active lupus serology. There was no significant difference in outcome between groups when matched for severity of disease and treatment using propensity scoring. Further studies are needed to examine whether ANCA in patients with LN have a pathogenic role and whether they are associated with worse renal outcomes or are simply a marker of more severe disease.
McAdoo SP, Pusey CD, 2017, Anti-glomerular basement membrane disease, Clinical Journal of the American Society of Nephrology, Vol: 12, Pages: 1162-1172, ISSN: 1555-905X
Anti-glomerular basement membrane (GBM) disease is a rare small vessel vasculitis that affects the capillary beds of the kidneys and lungs. It is an archetypical autoimmune disease, caused by the development of directly pathogenic autoantibodies targeting a well-characterised autoantigen expressed in the basement membranes of these organs, although the inciting events that induce the autoimmune response are not fully understood. The recent confirmation of spatial and temporal clustering of cases suggest that environmental factors, including infection, may trigger disease in genetically susceptible individuals. The majority of patients develop widespread glomerular crescent formation, presenting with features of rapidly progressive glomerulonephritis, and 40-60% will have concurrent alveolar haemorrhage. Treatment aims to rapidly remove pathogenic autoantibody, typically with the use of plasma exchange, along with steroids and cytotoxic therapy to prevent ongoing autoantibody production and tissue inflammation. Retrospective cohort studies suggest that when this combination of treatment is started early, the majority of patients will have good renal outcome, though presentation with oligoanuria, a high proportion of glomerular crescents, or kidney failure requiring dialysis augur badly for renal prognosis. Relapse and recurrent disease after kidney transplantation are both uncommon, though de novo anti-GBM disease after transplantation for Alport syndrome is a recognised phenomenon. Co-presentation with other kidney diseases such as ANCA-associated vasculitis and membranous nephropathy seems to occur at a higher frequency than would be expected by chance alone, and in addition atypical presentations of anti-GBM disease are increasingly reported. These observations highlight the need for future work to further delineate the immunopathogenic mechanisms of anti-GBM disease, and how to better refine and improve treatments, particularly for patients presenting with advers
Medjeral-Thomas NR, Lomax-Browne HJ, Beckwith H, et al., 2017, Circulating complement factor H-related proteins 1 and 5 correlate with disease activity in IgA nephropathy, Kidney International, Vol: 92, Pages: 942-952, ISSN: 0085-2538
IgA nephropathy (IgAN) is a common cause of chronic kidney disease and end-stage renal failure, especially in young people. Due to a wide range of clinical outcomes and difficulty in predicting response to immunosuppression, we need to understand why and identify which patients with IgAN will develop progressive renal impairment. A deletion polymorphism affecting the genes encoding the complement factor H-related protein (FHR)-1 and FHR-3 is robustly associated with protection against IgAN. Some FHR proteins, including FHR-1 and FHR-5, antagonize the ability of complement factor H (fH), the major negative regulator of the complement alternative pathway, to inhibit complement activation on surfaces, a process termed fH deregulation. From a large cohort of patients, we demonstrated that plasma FHR-1 and the FHR-1/fH ratio were elevated in IgAN and associated with progressive disease. Plasma FHR-1 negatively correlated with eGFR but remained elevated in patients with IgAN with normal eGFR. Serum FHR5 was slightly elevated in IgAN but did not correlate with eGFR. Neither FHR5 levels nor the FHR-5/fH ratio was associated with progressive disease. However, higher serum FHR-5 levels were associated with a lack of response to immunosuppression, the presence of endocapillary hypercellularity, and histology scores of disease severity (the Oxford Classification MEST score). Thus, FHR-1 and FHR-5 have a role in IgAN disease progression.
Chen T, Rotival M, Behmoaras JV, et al., 2017, Identification of ceruloplasmin as a gene that affects susceptibility to glomerulonephritis through macrophage function, Genetics, Vol: 206, Pages: 1139-1151, ISSN: 1943-2631
Crescentic glomerulonephritis (Crgn) is a complex disorder where macrophage activity and infiltration are significant effector causes. In previous linkage studies using the uniquely susceptible Wistar Kyoto (WKY) rat strain, we have identified multiple crescentic glomerulonephritis QTL (Crgn) and positionally cloned genes underlying Crgn1 and Crgn2, which accounted for 40% of total variance in glomerular inflammation. Here, we have generated a backcross (BC) population (n = 166) where Crgn1 and Crgn2 were genetically fixed and found significant linkage to glomerular crescents on chromosome 2 (Crgn8, LOD = 3.8). Fine mapping analysis by integration with genome-wide expression QTLs (eQTLs) from the same BC population identified ceruloplasmin (Cp) as a positional eQTL in macrophages but not in serum. Liquid chromatography-tandem mass spectrometry confirmed Cp as a protein QTL in rat macrophages. WKY macrophages overexpress Cp and its downregulation by RNA interference decreases markers of glomerular proinflammatory macrophage activation. Similarly, short incubation with Cp results in a strain-dependent macrophage polarization in the rat. These results suggest that genetically determined Cp levels can alter susceptibility to Crgn through macrophage function and propose a new role for Cp in early macrophage activation.
Diaz AIG, Vloumidi E, Sardini A, et al., 2017, Cardiac macrophage infiltration during chronic kidney disease accelerates cardiovascular disease, Annual Conference of the British-Cardiovascular-Society (BCS), Publisher: BMJ PUBLISHING GROUP, Pages: A141-A142, ISSN: 1355-6037
Van Dam LS, Kraaij T, Kamerling SW, et al., 2017, ANCA-ASSOCIATED VASCULITIS- AND SYSTEMIC LUPUS ERYTHEMATOSUS-INDUCED NEUTROPHIL EXTRACELLULAR TRAPS HAVE INTRINSICALLY DIFFERENT FEATURES, Annual European Congress of Rheumatology, Publisher: BMJ PUBLISHING GROUP, Pages: 774-774, ISSN: 0003-4967
McAdoo SP, Tanna A, Hrušková Z, et al., 2017, Patients double-seropositive for ANCA and anti-GBM antibodies have varied renal survival, frequency of relapse, and outcomes compared to single-seropositive patients., Kidney International, Vol: 92, Pages: 693-702, ISSN: 1523-1755
Co-presentation with both ANCA and anti-GBM antibodies is thought to be relatively rare. Current studies of such 'double-positive' cases report small numbers and variable outcomes. To study this further we retrospectively analyzed clinical features and long-term outcomes of a large cohort of 568 contemporary patients with ANCA-associated vasculitis, 41 patients with anti-GBM disease, and 37 double-positive patients with ANCA and anti-GBM disease from four European centers. Double-positive patients shared characteristics of ANCA-associated vasculitis (AAV), such as older age distribution and longer symptom duration before diagnosis, and features of anti-GBM disease, such as severe renal disease and high frequency of lung hemorrhage at presentation. Despite having more evidence of chronic injury on renal biopsy compared to patients with anti-GBM disease, double-positive patients had a greater tendency to recover from being dialysis-dependent after treatment and had intermediate long-term renal survival compared to the single-positive patients. However, overall patient survival was similar in all three groups. Predictors of poor patient survival included advanced age, severe renal failure, and lung hemorrhage at presentation. No single-positive anti-GBM patients experienced disease relapse, whereas approximately half of surviving patients with AAV and double-positive patients had recurrent disease during a median follow-up of 4.8 years. Thus, double-positive patients have a truly hybrid disease phenotype, requiring aggressive early treatment for anti-GBM disease, and careful long-term follow-up and consideration for maintenance immunosuppression for AAV. Since double-positivity appears common, further work is required to define the underlying mechanisms of this association and define optimum treatment strategies.
Vallant N, Sandhu B, Wolfhagen N, et al., 2017, Direct Comparison of Hypothermic and Normothermic Organ Preservation in a Porcine Ex-Vivo Kidney Model, American Transplant Congress, Publisher: WILEY, Pages: 729-729, ISSN: 1600-6135
Sandhu B, Prendecki M, Rutter G, et al., 2017, Hypoxia induces tissue factor upregulation in isolated human islets, American Transplant Congress, Publisher: Wiley, Pages: 461-461, ISSN: 1600-6135
Sandhu B, Bishop H, Loja D, et al., 2017, Human organs allocated for research - maximising use of a precious resource using a new ex vivo model of reperfusion injury, American Transplant Congress, Publisher: Wiley, Pages: 498-498, ISSN: 1600-6135
Sandhu B, Prendecki M, Crawley J, et al., 2017, Cytotopic thrombin inhibition prior to cold ischaemia attenuates microvascular endothelial ischaemia-reperfusion injury, American Transplant Congress, Publisher: Wiley, Pages: 731-731, ISSN: 1600-6135
Webster P, Pusey C, 2017, Crescentic glomerulonephritis: beyond the immune system, NATURE REVIEWS NEPHROLOGY, Vol: 13, Pages: 198-199, ISSN: 1759-5061
T cells mediate injury in glomerulonephritis but mice devoid of T cells and B cells can also develop this disease. A new study shows that expression of the cytokine receptor common subunit γ and IL-15 in podocytes protects against crescentic glomerulonephritis, independent of B cells, T cells and natural killer cells.
Webster P, Pusey C, 2017, Glomerular disease: Crescentic glomerulonephritis: beyond the immune system., Nat Rev Nephrol, Vol: 13, Pages: 198-200
Tanna A, Pusey CD, 2017, The Histopathological Classification of ANCA-associated Glomerulonephritis Comes of Age, JOURNAL OF RHEUMATOLOGY, Vol: 44, Pages: 265-267, ISSN: 0315-162X
McAdoo SP, Pusey CD, 2017, Is There a Role for TNFα Blockade In ANCA-Associated Vasculitis and Glomerulonephritis?, Nephrology Dialysis Transplantation, Vol: 32, Pages: i80-i88, ISSN: 1460-2385
Tumour necrosis factor alpha (TNFα) is a cytokine which is pivotal in the inflammatory response. Blockade of TNFα has been shown to be effective in a number of human autoimmune diseases, including rheumatoid arthritis, raising the question whether this approach may be effective in inflammatory kidney disease, such as ANCA-associated vasculitis (AAV). In AAV, there is considerable evidence for the role of TNFα in the pathophysiology of disease, including increased expression of TNFα mRNA in leucocytes and in renal tissue. Importantly, TNFα can induce leucocyte cell membrane expression of the autoantigens involved in vasculitis (proteinase 3 [PR3] and myeloperoxidase [MPO]), thus priming cells for the effects of ANCA. In rodent models of anti-GBM disease (nephrotoxic nephritis), TNF enhances glomerular injury and TNF blockade using soluble TNFαreceptor or anti-TNFα antibody ameliorates disease. Mice deficient in TNFα are protected from nephrotoxic nephritis and this effect is dependent mainly on intrinsic renal cells. A mouse model of anti-MPO antibody induced glomerulonephritis is enhanced by LPS, and this effect is blocked by anti-TNFα antibody. In a rat model of AAV induced by MPO (experimental autoimmune vasculitis) anti-TNFα antibody improves renal pathology and also reduces leucocyte transmigration, as shown by intravital microscopy. In clinical studies, the Wegener’s Granulomatosis Etanercept Trial (WGET) showed no benefit of additional etanercept versus standard therapy. However, there are several reasons why the results of the WGET study do not rule out the use of anti-TNFα antibody in acute renal AAV, including the study design and the considerable biological differences between the effects of etanercept and anti-TNFα antibody. There are several clinical studies demonstrating a response to anti-TNFα antibody in patients with AAV refractory to conventional treatmen
Beckwith H, Medjeral-Thomas N, Galliford J, et al., 2017, Mycophenolate mofetil therapy in immunoglobulin A nephropathy: histological changes after treatment, Nephrology Dialysis Transplantation, Vol: 32, Pages: i123-i128, ISSN: 0931-0509
BackgroundEndocapillary hypercellularity independently predicts renal outcome in immunoglobulin A nephropathy (IgAN). Mycophenolate mofetil (MMF) treatment is offered to patients presenting to the Imperial College Renal and Transplant Centre with IgAN and histological evidence of endocapillary hypercellularity. Clinical trials of MMF in IgAN have been inconclusive and have been limited by a lack of specific histological inclusion and exclusion criteria when recruiting patients. Evidence of histological improvement following MMF treatment would support its therapeutic use. We therefore reviewed histological changes after MMF therapy in a cohort of IgAN patients.MethodEighteen IgAN patients with native renal biopsies before and after repeated MMF treatment were identified. Patients were excluded if they had received any other immunosuppressive therapy, including corticosteroids. On the basis of the Oxford Classification of IgAN, we reviewed histological changes after MMF treatment.ResultsNine patients (50%) were male. At diagnostic renal biopsy, the median age was 35 years [interquartile range (IQR) 30–41], serum creatinine was 97 µmol/L (IQR 79–153) and urine protein creatinine ratio (UPCR) was 146 mg/mmol (IQR 98–212). The median time between biopsies was 24 months (range 9–41). Following MMF treatment, repeat biopsy demonstrated statistically significant improvement in the mean percentage of glomeruli showing endocapillary hypercellularity and cellular/fibrocellular crescents. There was no change in mesangial hypercellularity, segmental sclerosis or tubular atrophy scores. Mesangial IgA deposition was also significantly reduced. Histopathological improvement persisted after the cessation of MMF therapy, suggesting that 2 years of treatment is adequate for benefit. The median serum creatinine remained stable at 3 years follow-up at 104 µmol/L (IQR 79–147).ConclusionMMF treatment is associated with histopathological improveme
Lomax-Browne HJ, Visconti A, Pusey CD, et al., 2017, IgA1 glycosylation is heritable in healthy twins, Journal of the American Society of Nephrology, Vol: 28, Pages: 64-68, ISSN: 1533-3450
IgA Nephropathy (IgAN) is the most common form of primary glomerulonephritis and an important cause of kidney failure. Characteristically, IgAN patients have increased serum levels of under-galactosylated IgA1 (gd-IgA1). We assessed the degree to which serum gd-IgA1 levels are genetically determined in healthy individuals. Serum IgA and gd-IgA1 level were determined by ELISA in a sample of 148 healthy female twins including 27 monozygotic and 47 dizygotic pairs. Using the classical twin model, the heritability of serum gd-IgA1 and IgA levels were 80% (95% CI: 66-89%) and 46% (95% CI: 15-69%) respectively. These data indicate that serum gd-IgA1 levels are highly heritable. Elucidating the genetic basis of this heritability will be important in understanding the pathogenesis of IgAN.
Prendecki M, Tanna A, Salama AD, et al., 2016, Long-term outcome in biopsy-proven acute interstitial nephritis treated with steroids., Clinical Kidney Journal, Vol: 10, Pages: 233-239, ISSN: 2048-8505
Background: There are no prospective randomized controlled trials describing the outcome of acute interstitial nephritis (AIN) treated with steroids, and retrospective studies are limited. Methods: We identified adult patients with a diagnosis of AIN without glomerular pathology over a 14-year period. Treated patients all received oral prednisolone and three also recieved IV methylprednisolone. Data were collected retrospectively on estimated glomerular filtration rate (eGFR), change in eGFR from time of biopsy, dependence on renal replacement therapy (RRT) and mortality, and outcomes were analysed according to the treatment prescribed. Results: A total of 187 eligible patients with AIN were identified and 158 were treated with steroids. There was no difference in median eGFR or dependence on RRT at the time of biopsy. Steroid-treated patients had significantly higher eGFR at all time points post-biopsy up to 24 months, when median eGFR was 43 mL/min in the steroid-treated group and 24 mL/min in the untreated group (P = 0.01). Fewer patients in the steroid-treated group were dialysis dependent by 6 months (3.2% versus 20.6%, P = 0.0022) and 24 months (5.1% versus 24.1%, P = 0.0019). Conclusions: This large retrospective study suggests a benefit of steroids in treatment of AIN with greater improvement in eGFR and fewer patients progressing to end-stage renal disease.
Goceroglu A, Berden AE, Fiocco M, et al., 2016, ANCA-associated glomerulonephritis: risk factors for renal relapse, PLoS One, Vol: 11, ISSN: 1932-6203
Relapse in ANCA-associated vasculitis (AAV) has been studied previously, but there are few studies on renal relapse in particular. Identifying patients at high risk of renal relapse may aid in optimizing clinical management. We investigated which clinical and histological parameters are risk factors for renal relapse in ANCA-associated glomerulonephritis (AAGN). Patients (n = 174) were newly diagnosed and had mild–moderate or severe renal involvement. Data were derived from two trials of the European Vasculitis Society: MEPEX and CYCAZAREM. The Cox regression model was used to identify parameters increasing the instantaneous risk (= rate) of renal relapse (useful for instant clinical decisions). For identifying predictors of renal relapse during follow-up, we used Fine & Gray’s regression model. Competing events were end-stage renal failure and death. The cumulative incidence of renal relapse at 5 years was 9.5% (95% CI: 4.8–14.3%). In the Cox model, sclerotic class AAGN increased the instantaneous risk of renal relapse. In Fine & Gray’s model, the absence of interstitial infiltrates at diagnosis was predictive for renal relapse. In this study we used two different models to identify possible relationships between clinical and histopathological parameters at time of diagnosis of AAV with the risk of experiencing renal relapse. Sclerotic class AAGN increased the instantaneous risk of renal relapse. This association is most likely due to the high proportion of sclerosed glomeruli reducing the compensatory capacity. The absence of interstitial infiltrates increased the risk of renal relapse which is a warning sign that patients with a relatively benign onset of disease may also be prone to renal relapse. Renal relapses occurring in patients with sclerotic class AAGN and renal relapses occurring in patients without interstitial infiltrates were mutually exclusive, which may indicate that they are essentially different.
Al-Ani B, Fitzpatrick M, Al-Nuaimi H, et al., 2016, Changes in urinary metabolomic profile during relapsing renal vasculitis, Scientific Reports, Vol: 6, ISSN: 2045-2322
Current biomarkers of renal disease in systemic vasculitis lack predictive value and are insensitive to early damage. To identify novel biomarkers of renal vasculitis flare, we analysed the longitudinal urinary metabolomic profile of a rat model of anti-neutrophil cytoplasmic antibody (ANCA) vasculitis. Wistar-Kyoto (WKY) rats were immunised with human myeloperoxidase (MPO). Urine was obtained at regular intervals for 181 days, after which relapse was induced by re-challenge with MPO. Urinary metabolites were assessed in an unbiased fashion using nuclear magnetic resonance (NMR) spectroscopy, and analysed using partial least squares discriminant analysis (PLS-DA) and partial least squares regression (PLS-R). At 56 days post-immunisation, we found that rats with vasculitis had a significantly different urinary metabolite profile than control animals; the observed PLS-DA clusters dissipated between 56 and 181 days, and re-emerged with relapse. The metabolites most altered in rats with active or relapsing vasculitis were trimethylamine N-oxide (TMAO), citrate and 2-oxoglutarate. Myo-inositol was also moderately predictive. The key urine metabolites identified in rats were confirmed in a large cohort of patients using liquid chromatography-mass spectrometry (LC-MS). Hypocitraturia and elevated urinary myo-inositol remained associated with active disease, with the urine myo-inositol:citrate ratio being tightly correlated with active renal vasculitis.
Kraaij T, Kamerling S, Bakker J, et al., 2016, NET-Inducing Capacity Is a Biomarker in ANCA-Associated Vasculitis Independent of ANCA Antibodies, Publisher: WILEY, ISSN: 2326-5191
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Vallant N, Tam FWK, Sandhu B, et al., 2016, DIRECT COMPARISON BETWEEN HYPOTHERMIC AND NORMOTHERMIC EXVIVIONAL ORGAN PRESERVATION BASED ON A PIGMENTING MODEL, Publisher: WILEY-BLACKWELL, Pages: 17-17, ISSN: 0934-0874
Montero RM, Bhangal G, Pusey CD, et al., 2016, CCL18 synergises with high concentrations of glucose in stimulating fibronectin production in human renal tubuloepithelial cells., BMC Nephrology, Vol: 17, ISSN: 1471-2369
Background: Diabetic nephropathy is the leading cause of end stage kidney disease worldwide. The pathogenesis of this disease remains elusive and multiple factors have been implicated. These include the effects of hyperglycaemia, haemodynamic and metabolic factors, and an inflammatory process that stimulates cellular signalling pathways leading to disease progression and severe fibrosis. Fibronectin (Fn) is an important protein of the extracellular matrix that is essential in fibrosis and its presence in increased amounts has been identified in the kidney in diabetic nephropathy. Methods: Proximal tubuloepithelial (HK-2) cells were stimulated with high glucose (30mM D-glucose) or glycated albumin (500μg/mmol) + 4mM D-glucose or their controls, Mannitol (26mM+4mM D-glucose) and 4mM D-glucose, respectively. Following 48 hours of stimulation the supernatant was collected and MTT [3-(4,5-dimethylthiazole-2,5-diphenyltetrazolium bromide] assay performed to assess cell viability. HK-2 cells were also stimulated in the above environments with recombinant CCL18 (rCCL18) or MCP-1 (rMCP-1) for 48 hours with quantification of Fn levels using ELISA.Results: Co-stimulation of HK-2 cells with high concentrations of glucose and rCCL18 significantly increased Fn (p<0.001), in comparison to high concentrations of glucose alone. HK-2 cells stimulated with glycated albumin consistently produced Fn and this did not alter following co-stimulation with rCCL18 or rMCP-1. Conclusion: This study demonstrates how stimulation with a specific chemokine CCL18 in high glucose upregulates the production of Fn from proximal tubuloepithelial cells. This may be relevant to the development of renal fibrosis in diabetic nephropathy
Kang A, Antonelou M, Tanna A, et al., 2016, High Incidence of arterial and Venous Thrombosis in patients with ANCA-Associated Vasculitis, Nephrology, Vol: 21, Pages: 77-77, ISSN: 1320-5358
Brunini F, Page TH, Gallieni M, et al., 2016, The role of monocytes in ANCA-associated vasculitides, Autoimmunity Reviews, Vol: 15, Pages: 1046-1053, ISSN: 1873-0183
The anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) are a heterogeneous group of diseases causing inflammation in small blood vessels and linked by the presence of circulating ANCA specific for proteinase 3 (PR3) or myeloperoxidase (MPO). These antigens are present both in the cytoplasmic granules and on the surface of neutrophils, and the effect of ANCA on neutrophil biology has been extensively studied. In contrast, less attention has been paid to the role of monocytes in AAV. These cells contain PR3 and MPO in lysosomes and can also express them at the cell surface. Monocytes respond to ANCA by producing pro-inflammatory and chemotactic cytokines, reactive-oxygen-species and by up-regulating CD14. Moreover, soluble and cell surface markers of monocyte activation are raised in AAV patients, suggesting an activated phenotype that may persist even during disease remission. The presence of monocyte-derived macrophages and giant cells within damaged renal and vascular tissue in AAV also attests to their role in pathogenesis. In particular, their presence in the tertiary lymphoid organ-like granulomas of AAV patients may generate an environment predisposed to maintaining autoimmunity. Here we discuss the evidence for a pathogenic role of monocytes in AAV, their role in granuloma formation and tissue damage, and their potential to both direct and maintain autoimmunity. ANCA-activation of monocytes may therefore provide an explanation for the relapsing–remitting course of disease and its links with infections. Monocytes may thus represent a promising target for the treatment of this group of life-threatening diseases.
Anders H-J, Rovin B, Jayne D, et al., 2016, ISN Nexus 2016 Symposia: Translational Immunology in Kidney Disease-The Berlin Roadmap, Kidney International Reports, Vol: 1, Pages: 327-339, ISSN: 2468-0249
To date, the treatment of immune-mediated kidney diseases has only marginally benefited from highly specific biological drugs that have demonstrated remarkable effects in many other diseases. What accounts for this disparity? In April 2016, the International Society of Nephrology held a Nexus meeting on Translational Immunology in Nephrology in Berlin, Germany, to identify and discuss hurdles that block the translational flow of target identification, and preclinical and clinical target validation in the domain of immune-mediated kidney disease. A broad panel of experts including basic scientists, translational researchers, clinical trialists, pharmaceutical industry drug developers, and representatives of the American and European regulatory authorities made recommendations on how to overcome such hurdles at all levels of the translational research process. The results of these discussions are presented here, which may serve as a roadmap for how to optimize the process of developing more innovative and effective drugs for patients with immune-mediated kidney diseases.
McAdoo SP, Pusey CD, 2016, Clustering of Anti-GBM Disease: Clues to an Environmental Trigger?, Clinical Journal of the American Society of Nephrology, Vol: 11, Pages: 1324-1326, ISSN: 1555-905X
Vallant N, Behmoaras J, Ko J-H, et al., 2016, Extraction of green fluorescent protein labelled mesenchymal stem cells to investigate their mechanisms of action on ischemia-reperfusion Injury in a rat kidney transplant model, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: S652-S652, ISSN: 0041-1337
McAdoo SP, Bedi R, Tarzi R, et al., 2016, Ofatumumab for B cell depletion therapy in ANCA-associated vasculitis: a single-centre case series, Rheumatology, Vol: 55, Pages: 1437-1442, ISSN: 1462-0332
Objectives: B cell depletion is an effective treatment strategy in ANCA-associated vasculitis (AAV). Ofatumumab is a fully humanised anti-CD20 monoclonal antibody that has shown efficacy in the treatment of haematological malignancy and rheumatoid arthritis. The use of ofatumumab in the treatment of AAV has not previously been reported.Methods: A case series of eight patients who received ofatumumab, in conjunction with low-dose cyclophosphamide and oral steroids, in the treatment of AAV.Results: Eight patients received ofatumumab: seven for remission-induction in active disease (three relapsing; four with new disease) and one for remission-maintenance. B cell depletion was achieved in all patients by one month, and sustained until six months at least. All patients with active disease achieved clinical remission (BVAS of zero, or BVAS≤5 if all scores due to persistent urinary abnormalities in the presence of stable or improving renal function) by three months. This was associated with rapid fall in ANCA titres, reduced inflammatory responses, and improvements in renal function. At 12 months, three patients had repopulated B cells associated with recurrence of circulating ANCA, although no patients experienced major clinical relapse in the first 24 months. No unexpected safety signals were observed.Conclusion: Treatment with ofatumumab resulted in similar serological and clinical responses to previous cohorts treated at our centre with a comparable corticosteroid, cyclophosphamide and rituximab-based regimen. Ofatumumab should be considered an alternative B cell depleting agent in patients who are intolerant of, or unresponsive to, rituximab.
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.
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