Basic and Translational Concepts of Immune-Mediated Glomerular Diseases

Couser, William G.

doi:10.1681/asn.2011030304

Cited by 179 publications

(180 citation statements)

References 284 publications

(424 reference statements)

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“…Contrary to HIVAN, in which many HIV-1 transgenic models exhibit the clinical and pathologic features of HIVAN, none of these animal models exhibit features of HIVICK (28,29). This observation suggests that viral replication or immune responses to viral proteins may be essential to trigger HIVICK (30). The role of hypertension and diabetes in the development of immune complex disease is less clear.…”

Section: Discussionmentioning

confidence: 94%

Comparison of Risk Factors and Outcomes in HIV Immune Complex Kidney Disease and HIV-Associated Nephropathy

Foy

Estrella²,

Lucas³

et al. 2013

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives HIV-associated nephropathy (HIVAN) is well described, but the clinical features of a group of renal pathologies characterized by Ig or immune complex depositions referred to as HIV-associated immune complex kidney disease (HIVICK) have not been well established. The objective of this study is to assess risk factors for HIVICK compared with contemporaneous control participants.Design, setting, participants, & measurements A nested case-control study of 751 HIV-infected patients followed from January 1996 to June 2010 was conducted. Groups were compared using the chi-squared test or ranksum analysis. Conditional logistic regression was used to estimate odds ratios (ORs) for HIVICK. Incidences of overall ESRD and with/without combined antiretroviral therapy (cART) exposure were calculated.Results HIVICK patients were predominantly African American (92%). Compared with matched controls, patients with HIVICK were more likely to have HIV RNA .400 copies/ml (OR, 2.5; 95% confidence interval [95% CI], 1.2 to 5.2), diabetes (OR, 2.8; 95% CI, 1.1 to 6.8), and hypertension (OR, 2.3; 95% CI, 1.2 to 4.5). Compared with HIVAN, patients with HIVICK had more antiretroviral therapy exposure, lower HIV viral loads, and higher CD4 and estimated GFR. ESRD was less common in the HIVICK versus the HIVAN group (30% versus 82%; P,0.001), and the use of cART was not associated with ESRD in HIVICK patients (25% versus 26; P=0.39).Conclusions HIVICK was predominantly observed in African-American patients and associated with advanced HIV disease. ESRD incidence is lower in HIVICK patients compared with those with HIVAN. Unlike HIVAN, cART use was not associated with the incidence of ESRD in HIVICK.

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Section: Discussionmentioning

confidence: 94%

Comparison of Risk Factors and Outcomes in HIV Immune Complex Kidney Disease and HIV-Associated Nephropathy

Foy

Estrella²,

Lucas³

et al. 2013

Clinical Journal of the American Society of Nephrology

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“…IgA nephropathy, characterized by recurrent bouts of GN, focal mesangial cell expansion, and IgA deposition, is likely mediated by MBLdependent and/or alternative pathway-dependent, antibody-initiated complement activation (62). Deposits of C3 and C5b-9 are detectable in the diseased glomeruli and correlate with disease severity and prognosis.…”

Section: Complement and Kidney Diseasementioning

confidence: 99%

Molecules Great and Small

Mathern

Heeger

2015

Clinical Journal of the American Society of Nephrology

242

192

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The 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 kidney transplant 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.

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“…2 Imatinib inhibits T cell development, activation, and proliferation through its inhibition of c-kit, c-abl, and lck. Signaling of c-kit is required for T cell lymphopoiesis, as illustrated by the adult c-kit null mice, which have a marked reduction in thymic T cell progenitor cells.…”

Section: B Cellsmentioning

confidence: 99%

“…1 In these inflammatory diseases, B cell-mediated antibody production, T cell proinflammatory cytokine production, macrophages, and dendritic cells all play a role in the pathogenesis of renal injury. 2,3 Inflammation plays an important physiologic role in response to injury, but prolonged infiltration of lymphocytes, macrophages, and dendritic cells also leads to fibrosis through increased generation of reactive oxygen species and production of profibrotic cytokines and growth factors. Many of the drugs currently used to treat autoimmune diseases of the kidney were originally developed as antineoplastic agents; they have suboptimal efficacy, and toxic adverse effects limit their use.…”

mentioning

confidence: 99%

Imatinib

Wallace

Gewin

2013

Journal of the American Society of Nephrology

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The treatments for many autoimmune diseases are limited in efficacy, and long-term use is associated with severe adverse events. The tyrosine kinase inhibitors have proven to be well tolerated for long treatment periods, with minimal adverse events, in the oncology population. These agents have recently been used to treat autoimmune diseases. We review the potential mechanisms whereby tyrosine kinase inhibitors may modulate the immune response and inhibit fibrogenesis and discuss the current evidence for their use in the treatment of autoimmune diseases of the kidney.

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Basic and Translational Concepts of Immune-Mediated Glomerular Diseases

Cited by 179 publications

References 284 publications

Comparison of Risk Factors and Outcomes in HIV Immune Complex Kidney Disease and HIV-Associated Nephropathy

Comparison of Risk Factors and Outcomes in HIV Immune Complex Kidney Disease and HIV-Associated Nephropathy

Molecules Great and Small

Imatinib

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