The Determinants of Endothelial Dysfunction in CKD: Oxidative Stress and Asymmetric Dimethylarginine

Yılmaz, Mahmut İlker; Sağlam, Mutlu; Çağlar, Kayser; Çakır, Erdinç; Sönmez, Alper; Özgürtaş, Taner; Aydın, Ahmet; Eyıleten, Tayfun; Özcan, Ömer; Açıkel, Cengizhan; Taşar, Mustafa; Gençtoy, Gültekin; Erbil, Kemal; Vural, Abdülgaffar; Zoccali, Carmine

doi:10.1053/j.ajkd.2005.09.029

Cited by 299 publications

(279 citation statements)

References 42 publications

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“…Furthermore, endothelial dysfunction was recently reported to be associated with the decline of renal function in hypertensive patients (5). ADMA was reported to be one of the main determinants of endothelial dysfunction in patients with CKD (25), and elevated plasma ADMA levels have been observed in patients with ESRD and mild to moderate CKD (17,26). Short-term elimination of circulating ADMA by hemodialysis was associated with improved endothelial function in ESRD patients (27).…”

Section: Discussionmentioning

confidence: 99%

Asymmetric Dimethylarginine and Clinical Outcomes in Chronic Kidney Disease

Chung²,

Lin

et al. 2011

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Elevated plasma level of asymmetric dimethylarginine (ADMA) have been reported to be associated with endothelial dysfunction and atherosclerosis risk factors, and may predict cardiovascular events in patients with ESRD. In this study, we aimed to assess the association between plasma ADMA and long-term outcome in a cohort of patients with stage 3 to 4 chronic kidney disease (CKD).Design, setting, participants, & measurements From July 2006 to June 2009, 298 consecutive patients with stage 3 to 4 CKD scheduled to undergo coronary angiography were recruited. Plasma ADMA levels were determined using HPLC. ResultsThe mean age was 73 Ϯ 10 years. Approximately half of the patients had diabetes and 88 patients had proteinuria. The baseline estimated GFR (eGFR) was 44 Ϯ 13 ml/min per 1.73 m 2 . The plasma ADMA levels of the patients with proteinuria were significantly higher than those without. The plasma ADMA levels correlated significantly with eGFR. During the median follow-up period of 2.7 years, we observed 26 all-cause deaths, 12 nonfatal myocardial infarctions, and 2 strokes. Multivariate Cox analysis revealed that an increase of 0.1 mol/L in plasma ADMA level was associated with a 37% increased risk of the composite outcomes of all-cause deaths, nonfatal myocardial infarctions, and strokes. ConclusionsIn this elder and high-risk population with stage 3 to 4 CKD, high plasma ADMA level was associated with low eGFR and macroalbuminuria. Furthermore, high plasma ADMA level appeared to be an independent predictor of long-term outcome.

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Section: Discussionmentioning

confidence: 99%

Asymmetric Dimethylarginine and Clinical Outcomes in Chronic Kidney Disease

Chung²,

Lin

et al. 2011

Clinical Journal of the American Society of Nephrology

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“…Our findings also could reflect differences in response to oxidative stress in cats as a species compared to humans. For example, humans with advanced CKD show lower plasma activities of glutathione peroxidase (GPx), lower concentrations of its cofactor selenium, and lower reduced‐to‐oxidized glutathione (GSH:GSSG) ratios 6, 8, 35, 36. In contrast, cats with stage 4 CKD show a modest but significant increase in plasma GPx activities, with no decreases in serum selenium concentrations, and higher GSH:GSSG ratios 26, 37.…”

Section: Discussionmentioning

confidence: 99%

Urinary F₂‐Isoprostanes in Cats with International Renal Interest Society Stage 1–4 Chronic Kidney Disease

Whitehouse

Quimby

Wan

et al. 2017

Veterinary Internal Medicne

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BackgroundF2‐isoprostanes, a biomarker of oxidant injury, increase with advancing chronic kidney disease (CKD) in humans. In cats, the relationship between CKD and oxidative stress is poorly understood.ObjectivesTo determine whether cats with advancing CKD have increasing urinary F2‐isoprostanes.AnimalsControl cats without evidence of CKD (≥6 years old; n = 11), and cats with IRIS stage 1 (n = 8), 2 (n = 38), 3 (n = 21), and 4 (n = 10) CKD.MethodsThis was a prospective observational study. Urinary F2‐isoprostanes (specifically free 15‐F2t‐isoprostanes) normalized to urine creatinine (IsoPs) were compared among groups and tested for correlations with blood pressure, proteinuria, serum creatinine concentration, and urine specific gravity. The IsoPs also were compared between cats with and without hypertension or proteinuria, and in cats fed predominantly standard versus renal diets.ResultsUrinary IsoPs were increased, but not significantly, in cats with stage 1 CKD (median 263 pg/mg creatinine; range, 211–380) compared to controls (182 pg/mg; range, 80–348) and decreased significantly from stage 1 through advancing CKD (stage 2, 144 pg/mg; range, 49–608; stage 3, 102 pg/mg; range, 25–158; stage 4, 67 pg/mg; range, 26–117; P < .01). Urinary IsoPs were inversely correlated with serum creatinine (r = −0.66, P < .0001).Conclusion and Clinical ImportanceUrinary IsoPs are significantly higher in early CKD (stage 1) compared to cats with more advanced CKD. Additional studies are warranted to characterize oxidative stress in cats with stage 1 CKD and determine whether early antioxidant treatments have a protective effect on CKD progression.

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“…Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase and a modulator of cardiovascular 16 and renal 17 function, has been reported to be a risk factor for endothelial dysfunction 18 and atherosclerosis 19 associated with progression of CKD in several cohort studies. [20][21][22][23] Experimental data show that ADMA administration in uninephrectomized mice induced glomerular and vascular fibrosis, with elevated deposits of collagen I, III, and fibronectin, as well as reduced peritubular capillaries.…”

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confidence: 99%

Competitive Interaction Between Fibroblast Growth Factor 23 And Asymmetric Dimethylarginine in Patients With CKD

Tripepi

Kollerits

Leonardis

et al. 2015

Journal of the American Society of Nephrology

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Both fibroblast growth factor 23 (FGF-23) and asymmetric dimethylarginine (ADMA) are associated with progression of CKD. We tested the hypothesis that ADMA and FGF23 are interactive factors for CKD progression in a cohort of 758 patients with CKD in Southern Europe (mean eGFR6SD, 36613 ml/min per 1.73 m 2 ) and in a central European cohort of 173 patients with CKD (MMKD study, mean eGFR, 64639 ml/min per 1.73 m 2 ). In the first cohort, 214 patients had renal events (decrease in eGFR of .30%, dialysis, or kidney transplantation) during a 3-year follow-up. Both intact FGF-23 and ADMA predicted the incidence rate of renal events in unadjusted and adjusted analyses (P,0.001). There was a strong competitive interaction between FGF-23 and ADMA in the risk of renal events (P,0.01 in adjusted analyses); the risk associated with raised ADMA levels was highest in patients with low FGF-23 levels. These results were confirmed in the MMKD cohort, in which FGF-23 level was again an effect modifier of the relationship between plasma ADMA level and renal events (doubling of baseline serum creatinine, dialysis, or kidney transplantation) in the adjusted analyses (P,0.01). Furthermore, in the MMKD cohort there was a parallel, independent competitive interaction between symmetric dimethylarginine level and c-terminal FGF-23 level for the risk for renal events (P=0.001). These findings indicate that the association of ADMA level with the risk of CKD progression is modified by FGF-23 level and provide further evidence that dysregulation of the nitric oxide system is involved in CKD progression.

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The Determinants of Endothelial Dysfunction in CKD: Oxidative Stress and Asymmetric Dimethylarginine

Cited by 299 publications

References 42 publications

Asymmetric Dimethylarginine and Clinical Outcomes in Chronic Kidney Disease

Asymmetric Dimethylarginine and Clinical Outcomes in Chronic Kidney Disease

Urinary F₂‐Isoprostanes in Cats with International Renal Interest Society Stage 1–4 Chronic Kidney Disease

Competitive Interaction Between Fibroblast Growth Factor 23 And Asymmetric Dimethylarginine in Patients With CKD

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The Determinants of Endothelial Dysfunction in CKD: Oxidative Stress and Asymmetric Dimethylarginine

Cited by 299 publications

References 42 publications

Asymmetric Dimethylarginine and Clinical Outcomes in Chronic Kidney Disease

Asymmetric Dimethylarginine and Clinical Outcomes in Chronic Kidney Disease

Urinary F2‐Isoprostanes in Cats with International Renal Interest Society Stage 1–4 Chronic Kidney Disease

Competitive Interaction Between Fibroblast Growth Factor 23 And Asymmetric Dimethylarginine in Patients With CKD

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Urinary F₂‐Isoprostanes in Cats with International Renal Interest Society Stage 1–4 Chronic Kidney Disease