Guanidino Compounds as Cause of Cardiovascular Damage in Chronic Kidney Disease: An in vitro Evaluation

Schepers, Eva; Glorieux, Griet; Dou, Laetitia; Cérini, Claire; Gayrard, Nathalie; Louvet, Loı̈c; Maugard, Charlotte; Preus, Pierre; Rodríguez‐Ortiz, María E.; Argilés, Àngel; Brunet, Philippe; Cohen, Gerald; Jankowski, Joachim; Jankowski, Vera; Massy, Ziad A.; Rodríguez, Mariano; Vanholder, Raymond

doi:10.1159/000320765

Cited by 48 publications

(48 citation statements)

References 90 publications

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“…These data thus suggest a causal contribution of SDMA to the chronic inflammatory status characterizing the uremic condition and corroborating the previously observed increase in ROS production induced by SDMA (14,15,30). Moreover, in a holistic in vitro approach evaluating 10 guanidino compounds in several experimental test systems of vascular pathophysiology, SDMA exerted the highest number of proinflammatory and vascular damaging effects (31).…”

Section: Discussionsupporting

confidence: 87%

Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease

Schepers¹,

Barreto²,

Liabeuf³

et al. 2011

Clinical Journal of the American Society of Nephrology

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126

107

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SummaryBackground & objectives Chronic kidney disease (CKD) is characterized by chronic inflammation, considered a nontraditional risk factor for cardiovascular disease, the major cause of death in CKD. Symmetric dimethylarginine (SDMA) was recently demonstrated to induce reactive oxygen species in monocytes. The present study further investigates the inflammatory character of SDMA compared with its structural counterpart asymmetric dimethylarginine (ADMA). Design, setting, participants, & measurementsIn vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-␣ was studied followed by an evaluation of nuclear factor (NF)-B activation. Additionally, an association of SDMA with inflammatory parameters in consecutive stages of CKD was evaluated in vivo.Results Monocytes incubated with SDMA showed increased IL-6 and TNF-␣ expression and a rise in active NF-B. N-acetylcysteine abrogated both these effects. No significant effects were observed with ADMA. In vivo, 142 patients (67 Ϯ 12 years) at different stages of CKD showed an inverse association between serum SDMA and ADMA and renal function. Correlations between SDMA and IL-6, TNF-␣, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-␣ at a high significance for SDMA (P Ͻ 0.0001). In receiver operating characteristic analysis for inflammation, defined as an IL-6 level above 2.97 pg/ml (median), the discriminative power of SDMA (area under the curve [AUC]: 0.69 Ϯ 0.05) directly followed that of C-reactive protein (AUC: 0.82 Ϯ 0.04) and albumin (AUC: 0.72 Ϯ 0.05; for all, P Ͻ 0.0001) and preceded that of ADMA (P ϭ 0.002). ConclusionsThe present study shows that SDMA is involved in the inflammatory process of CKD, activating NF-B and resulting in enhanced expression of IL-6 and TNF-␣, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages.

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Section: Discussionsupporting

confidence: 87%

Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease

Schepers¹,

Barreto²,

Liabeuf³

et al. 2011

Clinical Journal of the American Society of Nephrology

Self Cite

126

107

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“…Furthermore, IL-6 was superior to CRP, albumin, or TNF-α in predicting mortality in this patient cohort [4]. Another group of uremic toxins, the guanadino compounds (particularly symmetric dimethylarginine) induce production of reactive oxygen species (ROS) and pro-inflammatory markers (mainly related to microinflammation and leukocyte activation) leading to chronic inflammation [39]. In addition, the surface expression of CD-14, a marker for monocyte differentiation, was increased by all guanadinos except guanidine.…”

Section: Uremic Toxins and Chronic Inflammationmentioning

confidence: 99%

“…In addition, the surface expression of CD-14, a marker for monocyte differentiation, was increased by all guanadinos except guanidine. Therefore, these compounds contribute to monocyte CD expression that may result in enhanced differentiation and endothelium adhesion capacity of these cells and hence ongoing chronic inflammation [39]. Symmetric dimethylarginine is also associated with activation of NF-κB in addition to increased IL-6 and TNF-α expression.…”

Section: Uremic Toxins and Chronic Inflammationmentioning

confidence: 99%

“…In CKD, endothelial dysfunction can be a result of oxidative stress, chronic inflammation, and production of ROS [1]. Furthermore, several uremic compounds have been shown to inhibit endothelial proliferation, potentially contributing to endothelial cell dysfunction [39]. Moreover, impairment of endothelial cell function among patients with CKD is associated with a pro-coagulant environment at the surface of these cells (as illustrated by increases in plasminogen activator inhibitor-1 and von Willebrand factor and decreases in tissue plasminogen activator), as well as dysregulation of vascular tone due to inhibition of endothelial iNOS.…”

Section: Uremic Toxins and Endothelial Cell Functionmentioning

confidence: 99%

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Cardiovascular Burden Associated with Uremic Toxins in Patients with Chronic Kidney Disease

2013

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Background: Retention of uremic toxins in patients with chronic kidney disease (CKD) negatively affects multiple organ systems, including the cardiovascular system, resulting in significant morbidity and mortality. Alleviation of the adverse effects of uremic toxins is an important priority in the management of CKD. Scope: This review focuses on the evidence for the influence of uremic toxins on cardiovascular morbidity and mortality among patients with CKD and slowly developing uremia. The cardiovascular effects of acute kidney injury and rapidly developing azotemia are beyond the scope of this review and will not be discussed. Data on potential treatment options aimed at ameliorating the toxic effects of uremic toxins are summarized. Findings: Uremic toxins are associated with significant cardiovascular morbidity and mortality in patients with CKD. While a number of preclinical studies have detailed these effects, clinical studies directly evaluating cardiovascular outcomes consequent to the presence of uremic toxins have only recently become available. Conclusion: Uremic toxins play an important role in the progression of cardiovascular disease in patients with CKD. Further studies are needed to better characterize the impact of these compounds on cardiovascular outcomes. Beneficial treatments are currently available that, in preliminary studies, appear to neutralize some of the adverse effects of uremic toxins. Large randomized clinical trials are needed to further determine the utility of these varied therapeutic agents.

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“…The first step is the adhesion of activated leukocytes to endothelium [8] . Leukocyte activation could be stimulated by several guanidine compounds [9,10] , advanced glycation end products (AGE) [11] , and p-cresyl sulfate [12] . The expression of endothelial adhesion molecules is increased in uremia.…”

Section: Atherosclerosismentioning

confidence: 99%

Does Uremia Cause Vascular Dysfunction

Brunet

Gondouin

Duval-Sabatier

et al. 2011

Kidney Blood Press Res

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131

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Vascular dysfunction induced by uremia has 4 main aspects. (1) Atherosclerosis is increased. Intima-media thickness is increased, and animal studies have established that uremia accelerates atherosclerosis. Uremic toxins are involved in several steps of atherosclerosis. Leukocyte activation is stimulated by guanidines, advanced glycation end products (AGE), p-cresyl sulfate, platelet diadenosine polyphosphates, and indoxyl sulfate. Endothelial adhesion molecules are stimulated by indoxyl sulfate. Migration and proliferation of vascular smooth muscle cells (VSMC) are stimulated by local inflammation which could be triggered by indoxyl sulfate and AGE. Uremia is associated with an increase in von Willebrand factor, thrombomodulin, plasminogen activator inhibitor 1, and matrix metalloproteinases. These factors contribute to thrombosis and plaque destabilization. There is also a decrease in nitric oxide (NO) availability, due to asymmetric dimethylarginine (ADMA), AGE, and oxidative stress. Moreover, circulating endothelial microparticles (EMP) are increased in uremia, and inhibit the NO pathway. EMP are induced in vitro by indoxyl sulfate and p-cresyl sulfate. (2) Arterial stiffness occurs due to the loss of compliance of the vascular wall which induces an increase in pulse pressure leading to left ventricular hypertrophy and a decrease in coronary perfusion. Implicated uremic toxins are ADMA, AGE, and oxidative stress. (3) Vascular calcifications are increased in uremia. Their formation involves a transdifferentiation process of VSMC into osteoblast-like cells. Implicated uremic toxins are mainly inorganic phosphate, as well as reactive oxygen species, tumor necrosis factor and leptin. (4) Abnormalities of vascular repair and neointimal hyperplasia are due to VSMC proliferation and lead to severe reduction of vascular lumen. Restenosis after coronary angioplasty is higher in dialysis than in nondialysis patients. Arteriovenous fistula stenosis is the most common cause of thrombosis. Uremic toxins such as indoxyl sulfate and some guanidine compounds inhibit endothelial proliferation and wound repair. Endothelial progenitor cells which contribute to vessel repair are decreased and impaired in uremia, related to high serum levels of β₂-microglobulin and indole-3 acetic acid. Overall, there is a link between kidney function and cardiovascular risk, as emphasized by recent meta-analyses. Moreover, an association has been reported between cardiovascular mortality and uremic toxins such as indoxyl sulfate, p-cresol and p-cresyl sulfate.

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Guanidino Compounds as Cause of Cardiovascular Damage in Chronic Kidney Disease: An in vitro Evaluation

Cited by 48 publications

References 90 publications

Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease

Symmetric Dimethylarginine as a Proinflammatory Agent in Chronic Kidney Disease

Cardiovascular Burden Associated with Uremic Toxins in Patients with Chronic Kidney Disease

Does Uremia Cause Vascular Dysfunction

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