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Complement and New Therapies

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18 papers 0 to 25 followers
By P O Pediatrics, Nephrology
Richard J H Smith, Gerald B Appel, Anna M Blom, H Terence Cook, Vivette D D'Agati, Fadi Fakhouri, Véronique Fremeaux-Bacchi, Mihály Józsi, David Kavanagh, John D Lambris, Marina Noris, Matthew C Pickering, Giuseppe Remuzzi, Santiago Rodriguez de Córdoba, Sanjeev Sethi, Johan Van der Vlag, Peter F Zipfel, Carla M Nester
The C3 glomerulopathies are a group of rare kidney diseases characterized by complement dysregulation occurring in the fluid phase and in the glomerular microenvironment, which results in prominent complement C3 deposition in kidney biopsy samples. The two major subgroups of C3 glomerulopathy - dense deposit disease (DDD) and C3 glomerulonephritis (C3GN) - have overlapping clinical and pathological features suggestive of a disease continuum. Dysregulation of the complement alternative pathway is fundamental to the manifestations of C3 glomerulopathy, although terminal pathway dysregulation is also common...
January 28, 2019: Nature Reviews. Nephrology
Hidemi Toyoda, Hideo Wada, Toshiyuki Miyata, Keishiro Amano, Kentaro Kihira, Shotaro Iwamoto, Masahiro Hirayama, Yoshihiro Komada
Eculizumab, terminal complement inhibitor, has become the frontline treatment for atypical hemolytic uremic syndrome (aHUS). However, the optimal treatment schedule has not yet been established. We describe here an aHUS patient with a mutation of C3 I1157T who achieved remission with eculizumab and suffered a recurrence after eculizumab discontinuation, a clinical situation that has not been previously described in patients with C3 mutation. A 9-year-old male experienced an onset of aHUS after viral gastroenteritis and was treated with hemodialysis...
April 2016: Journal of Pediatric Hematology/oncology
Aadil Kakajiwala, Tricia Bhatti, Bernard S Kaplan, Rebecca L Ruebner, Lawrence Copelovitch
A 7-year-old male with poststreptococcal glomerulonephritis (PSGN) developed hemolytic uremic syndrome (HUS) and achieved remission. He was treated with eculizumab for 1 year. The eculizumab was discontinued and the patient remained in remission. This is the 10th reported case of PSGN associated with HUS. The histopathological feature observed at the 1-year follow-up was indistinguishable from the expected findings in an individual with healed PSGN without associated HUS. The relatively good prognosis in most prior cases and the absence of any reported recurrences strongly suggest that this form of atypical HUS does not warrant long-term eculizumab therapy...
February 2016: Clinical Kidney Journal
Sandra Habbig, Carsten Bergmann, Lutz T Weber
No abstract text is available yet for this article.
March 2016: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
Jorge Rojas-Rivera, Gema Fernández-Juárez, Manuel Praga
A rapidly progressive and crescentic IgA nephropathy (IgAN) is uncommon, but it has a high risk of progression to end-stage renal disease and variable response to immunosuppression. The importance of a positive anti-neutrophil cytoplasmic antibody (ANCA) serology in this group of patients is not fully understood but may have prognostic significance. On the other hand, there is growing evidence of the role of complement in the pathogenesis of IgAN, especially in cases of crescentic IgAN. Therapies directed against the complement system are a potential and rational therapeutic approach...
October 2015: Clinical Kidney Journal
Troels Ring, Birgitte Bang Pedersen, Giedrius Salkus, Timothy H J Goodship
IgA nephropathy (IgAN) is characterized by a variable clinical course and multifaceted pathophysiology. There is substantial evidence to suggest that complement activation plays a pivotal role in the pathogenesis of the disease. Therefore, complement inhibition using the humanized anti-C5 monoclonal antibody eculizumab could be a rational treatment. We report here a 16-year-old male with the vasculitic form of IgAN who failed to respond to aggressive conventional therapy including high-dose steroids, cyclophosphamide and plasma exchange and who was treated with four weekly doses of 900 mg eculizumab followed by a single dose of 1200 mg...
October 2015: Clinical Kidney Journal
Carmine Pecoraro, Alfonso Vincenzo Salvatore Ferretti, Erica Rurali, Miriam Galbusera, Marina Noris, Giuseppe Remuzzi
A 12-year-old boy was hospitalized for hemolytic anemia, thrombocytopenia, acute kidney injury, and generalized seizures. The childhood onset, severely decreased kidney function, absence of prodromal diarrhea, negative test results for Shiga-like toxin-producing Escherichia coli, elevated plasma levels of the terminal complement complex sC5b-9, and ex vivo testing in endothelial cells showing serum-induced complement activation were all consistent with a diagnosis of complement-mediated atypical hemolytic uremic syndrome...
December 2015: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
Hosseini Soudabeh, Kalantar Ebrahim, Hooman Nakisa, Dorgalaleh Akbar, Hosseini Shamsabadi Rozita, Taregh Bamedi
BACKGROUND: Atypical hemolytic uremic syndrome (aHUS), a rare disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure, is associated with mutations and polymorphisms in various components and regulators of the complement alternative pathway (AP), including factor H, factor I, membrane cofactor protein (MCP or CD46) and factor B. This impaired regulation of the alternative pathway leads to a procoagulant state with microthrombi formation in the renal vasculature, which influences disease onset and progression...
2014: Central-European Journal of Immunology
Melissa Inman, Ginnie Prater, Huma Fatima, Eric Wallace
C3 glomerulopathy (C3G) is characterized by C3 deposits with minimal immunoglobulin deposition caused by alternative complement pathway dysregulation. Unfortunately, no therapeutic intervention has consistently improved outcomes for patients with C3G. Eculizumab, a monoclonal antibody to C5, is currently the only approved complement-specific agent with some efficacy in the treatment of C3 glomerulonephritis (C3GN). Here, we describe a patient with acute crescentic C3GN with no identified complement mutation or family history of renal disease who required dialysis for 6 months...
August 2015: Clinical Kidney Journal
Laura Rodriguez-Osorio, Alberto Ortiz
Eculizumab is an anti-C5 antibody that inhibits C5 cleavage and prevents the generation of the terminal complement complex C5b-9. Eculizumab is licensed to treat paroxysmal nocturnal haemoglobinuria or atypical haemolytic uraemic syndrome (aHUS). Clinical trials are ongoing for C3 glomerulopathy. Given the unfamiliarity of physicians with these rare diseases and the variability of clinical presentation, a delayed initiation of eculizumab therapy is common. Thus, the question arises as to what extent improvement of kidney function may be expected when patients have been dialysis dependent for weeks or months already when eculizumab is initiated...
August 2015: Clinical Kidney Journal
Marieta M Ruseva, Tao Peng, Melissa A Lasaro, Keith Bouchard, Susan Liu-Chen, Fang Sun, Zhao-Xue Yu, Andre Marozsan, Yi Wang, Matthew C Pickering
C3 glomerulopathy refers to renal disorders characterized by abnormal accumulation of C3 within the kidney, commonly along the glomerular basement membrane (GBM). C3 glomerulopathy is associated with complement alternative pathway dysregulation, which includes functional defects in complement regulator factor H (FH). There is no effective treatment for C3 glomerulopathy. We investigated the efficacy of a recombinant mouse protein composed of domains from complement receptor 2 (CR2) and FH (CR2-FH) in two models of C3 glomerulopathy with either preexisting or triggered C3 deposition along the GBM...
February 2016: Journal of the American Society of Nephrology: JASN
Thomas Sajan, Srinivasa Vinay, Nigam Sonu, Parnham Alan
A 24-year-old man with diarrhea found to have acute renal failure with microangiopathic hemolytic anemia (MAHA). A diagnosis of hemolytic uraemic syndrome (HUS) was made. He was initiated on plasma exchange and hemodialysis. On day 6, he was started on eculizumab. His renal functions progressively improved. His main complication during eculizumab therapy was hypertension-related posterior reversible encephalopathy syndrome.
April 2014: Clinical Case Reports
Edwin K S Wong, Holly E Anderson, Andrew P Herbert, Rachel C Challis, Paul Brown, Geisilaine S Reis, James O Tellez, Lisa Strain, Nicholas Fluck, Ann Humphrey, Alison Macleod, Anna Richards, Daniel Ahlert, Mauro Santibanez-Koref, Paul N Barlow, Kevin J Marchbank, Claire L Harris, Timothy H J Goodship, David Kavanagh
Complement C3 activation is a characteristic finding in membranoproliferative GN (MPGN). This activation can be caused by immune complex deposition or an acquired or inherited defect in complement regulation. Deficiency of complement factor H has long been associated with MPGN. More recently, heterozygous genetic variants have been reported in sporadic cases of MPGN, although their functional significance has not been assessed. We describe a family with MPGN and acquired partial lipodystrophy. Although C3 nephritic factor was shown in family members with acquired partial lipodystrophy, it did not segregate with the renal phenotype...
November 2014: Journal of the American Society of Nephrology: JASN
Li Zhu, Ya-Ling Zhai, Feng-Mei Wang, Ping Hou, Ji-Cheng Lv, Da-Min Xu, Su-Fang Shi, Li-Jun Liu, Feng Yu, Ming-Hui Zhao, Jan Novak, Ali G Gharavi, Hong Zhang
Complement activation is common in patients with IgA nephropathy (IgAN) and associated with disease severity. Our recent genome-wide association study of IgAN identified susceptibility loci on 1q32 containing the complement regulatory protein-encoding genes CFH and CFHR1-5, with rs6677604 in CFH as the top single-nucleotide polymorphism and CFHR3-1 deletion (CFHR3-1∆) as the top signal for copy number variation. In this study, to explore the clinical effects of variation in CFH, CFHR3, and CFHR1 on IgAN susceptibility and progression, we enrolled two populations...
May 2015: Journal of the American Society of Nephrology: JASN
Sally Ann Johnson, Edwin K S Wong, C Mark Taylor
Over recent years, complement has emerged as a major player in the development of a number of glomerular diseases, including atypical haemolytic uraemic syndrome, membranoproliferative glomerulonephritis and the recently described C3 glomerulonephritis. Some patients and pedigrees show overlapping features of these conditions. Intriguingly, a few complement gene mutations are common to different disease phenotypes. In this review, we explore the evidence for complement dysregulation in these diseases and the clinical interface between them, and present a hypothesis to explain the variable phenotype associated with dysregulation of the alternative complement pathway...
October 2014: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Katell Michaux, Justine Bacchetta, Etienne Javouhey, Pierre Cochat, Véronique Frémaux-Bacchi, Anne-Laure Sellier-Leclerc
BACKGROUND: Neonatal atypical hemolytic uremic syndrome (aHUS) is a rare but severe disease that is mainly due to methylmalonic aciduria or genetic complement abnormalities. Traditional management of aHUS includes plasma infusion/exchange, but in small or unstable infants, plasma exchange can be challenging because of high extracorporeal volume and difficulty to obtain an adequate venous access. The C5 complement blocker eculizumab has become a cornerstone of first-line management of aHUS due to complement deregulation in older patients...
December 2014: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Rosanna Coppo, Licia Peruzzi, Alessandro Amore, Silvana Martino, Luca Vergano, Inna Lastauka, Arrigo Schieppati, Marina Noris, Pier Angelo Tovo, Giuseppe Remuzzi
BACKGROUND: Treatment of systemic lupus erythematosus (SLE) with severe diffuse proliferative nephritis is often challenging, particularly in small children in whom a genetic conditioning is likely to play a role. The effectiveness of standard therapy based on glucocorticoid and immunosuppressive drugs is often unsatisfactory. CASE: A 4 year-old girl, whose parents were first-grade cousins of Moroccan ancestry, developed SLE that progressed to severe renal involvement despite standard therapy...
January 2015: Pediatric Nephrology: Journal of the International Pediatric Nephrology Association
Julia A Sharp, Pamela H Whitley, Kenji M Cunnion, Neel K Krishna
The classical pathway of complement plays multiple physiological roles including modulating immunological effectors initiated by adaptive immune responses and an essential homeostatic role in the clearance of damaged self-antigens. However, dysregulated classical pathway activation is associated with antibody-initiated, inflammatory diseases processes like cold agglutinin disease, acute intravascular hemolytic transfusion reaction (AIHTR), and acute/hyperacute transplantation rejection. To date, only one putative classical pathway inhibitor, C1 esterase inhibitor (C1-INH), is currently commercially available and its only approved indication is for replacement treatment in hereditary angioedema, which is predominantly a kinin pathway disease...
2014: Frontiers in Immunology
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