|
|
|
|
||
Re: OMER does not need a secondary at all In my research career, I spent some time working on the complement system (over 185 peer-reviewed publications and over 15 granted US patents) The textbook review that you provided, inflamman is certainly useful as a general overview of this complex system, but does not deal so much with the role of complement in kidney pathology. Thus, I want to provide some starting points for further readings and insight into kidney diseases. In addition to OMER, I have investments in other complement companies and OMER is not my largest investment. The full publications are generally available via the PubMed links provided. Curr Opin Nephrol Hypertens. 2013 May;22(3):295-301. doi: 10.1097/MNH.0b013e32835ff9cb. Complement and kidney disease.Cook HT1. AbstractPURPOSE OF REVIEW:This review summarizes recent key findings relating to the role of the complement system in renal pathology. RECENT FINDINGS:There is increasing association of genetic variations in complement and complement control proteins with renal disease. Genome-wide association studies have shown that polymorphisms at the complement factor H-related gene locus are associated with susceptibility to IgA nephropathy and systemic lupus erythematosus (SLE). Rare mutations in these genes are associated with familial forms of C3 glomerulopathy. Mutations in other complement genes have been associated with C3 glomerulopathy and hemolytic uremic syndrome. There are now several reports of the use of anti-C5 antibody therapy in renal disease. Preclinical studies have shown the utility of targeted inhibition of C3 activation in models of lupus glomerulonephritis and ischemia reperfusion injury. SUMMARY:Complement activation or dysregulation is important in a range of renal pathology and new therapeutic strategies are being developed which may allow rational therapy for these diseases. Clin J Am Soc Nephrol. 2015 Sep 4;10(9):1636-50. doi: 10.2215/CJN.06230614. Epub 2015 Jan 7. Molecules Great and Small: The Complement System.AbstractThe complement cascade, traditionally considered an effector arm of innate immunity required for host defense against pathogens, is now recognized as a crucial pathogenic mediator of various kidney diseases. Complement components produced by the liver and circulating in the plasma undergo activation through the classical and/or mannose-binding lectin pathways to mediate anti-HLA antibody-initiated kidneytransplant rejection and autoantibody-initiated GN, the latter including membranous glomerulopathy, antiglomerular basement membrane disease, and lupus nephritis. Inherited and/or acquired abnormalities of complement regulators, which requisitely limit restraint on alternative pathway complement activation, contribute to the pathogenesis of the C3 nephropathies and atypical hemolytic uremic syndrome. Increasing evidence links complement produced by endothelial cells and/or tubular cells to the pathogenesis of kidney ischemia-reperfusion injury and progressive kidney fibrosis. Data emerging since the mid-2000s additionally show that immune cells, including T cells and antigen-presenting cells, produce alternative pathway complement components during cognate interactions. The subsequent local complement activation yields production of the anaphylatoxins C3a and C5a, which bind to their respective receptors (C3aR and C5aR) on both partners to augment effector T-cell proliferation and survival, while simultaneously inhibiting regulatory T-cell induction and function. This immune cell-derived complement enhances pathogenic alloreactive T-cell immunity that results in transplant rejection and likely contributes to the pathogenesis of other T cell-mediated kidney diseases. C5a/C5aR ligations on neutrophils have additionally been shown to contribute to vascular inflammation in models of ANCA-mediated renal vasculitis. New translational immunology efforts along with the development of pharmacologic agents that block human complement components and receptors now permit testing of the intriguing concept that targeting complement in patients with an assortment of kidney diseases has the potential to abrogate disease progression and improve patient health. Am J Kidney Dis. 2015 Aug; 66(2): 359–375. PMCID: PMC4528072 PMID: 26032627 Glomerular Diseases Dependent on Complement Activation, Including Atypical Hemolytic Uremic Syndrome, Membranoproliferative Glomerulonephritis, and C3 Glomerulopathy: Core Curriculum 2015Complement is part of the innate immune system and plays a fundamental role in the clearance of immune complexes and cell debris. The main effector mechanisms of complement activation are induction of inflammatory response and phagocytosis and cell lysis. However, complement activation is a double-edged sword and has the potential to damage self-tissues. In order to avoid self-damage, there is an absolute need for strict control by fluid-phase and membrane-bound regulatory proteins. Thus, an underperforming regulatory system (due to either genetic or acquired abnormalities) can shift the balance between regulation and activation toward the latter and lead to tissue injury in response to otherwise innocuous stimuli. Deposition of both actived complement fragments from plasma in glomeruli and complement locally produced and activated in the kidney may contribute to many kidney disorders, including lupus nephritis, postinfectious glomerulonephritis, membranous nephropathy, antineutrophil cytoplasmic antibody vasculitis, and anti–glomerular basement membrane (anti-GBM) glomerulonephritis. Interest in the complement system has been boosted in the past 15 years by the discovery that rare devastating kidney diseases, including atypical hemolytic uremic syndrome (aHUS) and membranoproliferative glomerulonephritis (MPGN), are disorders of complement regulation. Additional Readings
Semin Nephrol. 2013 Nov;33(6):543-56. doi: 10.1016/j.semnephrol.2013.08.005. The role of the complement system in acute kidney injury.AbstractAcute kidney injury is a common and severe clinical problem. Patients who develop acute kidney injury are at increased risk of death despite supportive measures such as hemodialysis. Research in recent years has shown that tissue inflammation is central to the pathogenesis of renal injury, even after nonimmune insults such as ischemia/reperfusion and toxins. Examination of clinical samples and preclinical models has shown that activation of the complement system is a critical cause of acute kidney injury. Furthermore, complement activation within the injured kidney is a proximal trigger of many downstream inflammatory events within the renal parenchyma that exacerbate injury to the kidney. Complement activation also may account for the systemic inflammatory events that contribute to remote organ injury and patient mortality. Complement inhibitory drugs have now entered clinical use and may provide an important new therapeutic approach for patients suffering from, or at high risk of developing, acute kidney injury. Int J Nephrol Renovasc Dis. 2018 Apr 12;11:137-148. doi: 10.2147/IJNRD.S129227. eCollection 2018. Primary IgA nephropathy: current challenges and future prospects.AbstractIgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, exhibiting a variable clinical and pathological course and significantly contributing to the global burden of chronic kidney disease and end-stage renal disease. Current standards of care focus on optimization of antihypertensive and antiproteinuric therapies (typically renin- angiotensin system blockade) to reduce disease progression. Much recent attention has focused on whether additional immunosuppression confers better outcomes than supportive management alone, and indeed, several trials have demonstrated renoprotective effects following the use of oral corticosteroids. However, results have been inconsistent, and perceived benefits must be balanced against risks and adverse effects associated with generalized immunosuppression, as highlighted by the high-profile STOP-IgAN and TESTING clinical trials. Recent translational research in vitro and animal models of IgAN have generated greater insight into potential therapeutic targets for this complex autoimmune disease. Deeper understanding of the roles of the mucosal immune barrier, complement activation and deposition, T-cell dependent and independent mechanisms of B cell activation, and of the deposition and downstream inflammatory signaling pathways of nephritogenic polymeric IgA1 complexes (e.g., signaling of immune receptors via spleen tyrosine kinase) has formed the rationale for the development of novel agents and clinical trials of more targeted therapies. However, translating findings into clinical practice is challenging, with many immunopathological features of IgAN specific to humans. Recent comprehensive reviews outline current understanding of mechanisms of IgAN as well as ongoing and future clinical trials; it is not our aim to replicate this here. Instead, we take a mechanistic approach to current treatment strategies, outlining advantages and limitations of each before exploring ongoing research with potential translation into future targeted therapies for this complex disease. |
return to message board, top of board |
Msg # | Subject | Author | Recs | Date Posted |
1468 | OT Re: OMER does not need a secondary at all | inflamman | 3 | 8/13/2018 9:14:42 AM |
1469 | Re: OMER ... secondary and things | Biotech_Jim | 4 | 8/13/2018 9:51:19 AM |
1471 | Re: OMER does not need a secondary at all | brokeman2 | 0 | 8/13/2018 8:10:25 PM |