We investigated an effect of uraemia on structural and functional features of human resistance vasculature. Arteries (≈ 200 μm) isolated from subcutaneous fat biopsies obtained from 35 ESRD (end-stage renal disease) patients starting peritoneal dialysis and 30 matched controls were studied using isolated small artery bioassays. Flow-mediated dilatation was attenuated in ESRD patients compared with controls. NO (nitric oxide) contribution to flow was lacking in ESRD patients, but present in the controls. ADMA (asymmetrical dimethyl L-arginine) levels were higher in the ESRD group compared with the control group. Dilatation in response to acetylcholine was reduced in ESRD patients compared with controls, but response to NO donor was similar. Expression of nitrotyrosine and heat shock proteins 70 and 27, but not 90, was increased in arteries from ESRD patients compared with controls. Arterial remodelling was absent in ESRD patients. There was no difference between the groups in myogenic tone, vascular reactivity or sensitivity to several vasoconstrictors. Arterial distensibility, reflecting passive properties of the vascular wall, was reduced in ESRD patients compared with controls. Exclusion of ESRD patients with diabetes and/or cardiovascular disease from analyses had no influence on the main findings. Thus we propose that uraemia has a strong impact on endothelial function and passive properties of the arterial wall of human peripheral resistance vasculature. The reduced contribution of NO to flow stimulus via enhanced nitrosative stress and higher plasma concentrations of ADMA may suggest potential mechanisms behind endothelial dysfunction in the resistance peripheral circulation in ESRD.
"We also show independent and strong associations between PTX3 mRNA expression and ADMA levels. Recent studies by our group suggest that raised ADMA plasma levels are indicative of endothelial dysfunction in CKD patients, linked to atherosclerosis progression and enhanced vascular resistance , . Our finding corroborates previously reported associations between elevated PTX3 and surrogate markers of endothelial dysfunction. "
[Show abstract][Hide abstract] ABSTRACT: Elevated systemic pentraxin 3 (PTX3) levels appear to be a powerful marker of inflammatory status and a superior outcome predictor in patients with chronic kidney disease (CKD). As previous data imply that PTX3 is involved in vascular pathology and that adipose tissue mass may influence circulating PTX3 levels, we aimed to study the importance of adipose tissue expression of PTX3 in the uremic milieu and its relation to endothelial dysfunction parameters. Plasma PTX3 and abdominal subcutaneous adipose tissue (SAT) PTX3 mRNA levels were quantified in 56 stage 5 CKD patients (median age 57 [range 25-75] years, 30 males) and 40 age and gender matched controls (median age 58 [range 20-79] years, 27 males). Associations between PTX3 measures and an extensive panel of clinical parameters, including surrogate markers of endothelial function, were assessed. Functional ex vivo studies on endothelial status and immunohistochemical staining for PTX3 were conducted in resistance subcutaneous arteries isolated from SAT. SAT PTX3 mRNA expression correlated with plasma PTX3 concentrations (rho = 0.54, p = 0.0001) and was increased (3.7 [0.4-70.3] vs. 1.2 [0.2-49.3] RQ, p = 0.02) in CKD patients with cardiovascular disease (CVD), but was not significantly different between patients and controls. The association to CVD was lost after adjustments. SAT PTX3 mRNA levels were independently correlated to asymmetric dimethylarginine and basal resistance artery tone developed after inhibition with nitric oxide synthase and cyclooxygenase (rho = -0.58, p = 0.002). Apparent positive PTX3 immunoreactivity was observed in both patient and control arteries. In conclusion, fat PTX3 mRNA levels are associated with measures of endothelial cell function in patients with CKD. PTX3 may be involved in adipose tissue-orchestrated mechanisms that are restricted to the uremic milieu and modify inflammation and vascular complications in CKD patients.
PLoS ONE 05/2013; 8(5):e63493. DOI:10.1371/journal.pone.0063493 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite technological innovations in renal replacement therapy, mortality is still high in patients with end-stage renal disease. This increase in mortality is not only limited to dialysis patients, but also includes all stages of chronic kidney disease (CKD) and is mainly because of cardiovascular disease. Protein-energy wasting becomes clinically manifest at an advanced CKD stage, early before or during the dialytic stage, and increases the morbidity and mortality in this patients' population. The purpose of this article is to review the recent observations on alterations of amino acid and protein metabolism which cause wasting and increase cardiovascular risk.
Recent studies have consistently increased our understanding of mechanisms causing wasting and vascular disease in CKD patients. These include changes in amino acid and lipoprotein metabolism potentially leading to alterations of biology and function of the vascular wall, anorexia and endocrine dysfunction, altered muscle intracellular signaling through the insulin receptor substrate/phosphatidylinositol 3-kinase/Akt pathway, and defective myocyte regeneration. These mechanisms may trigger wasting through an increase in protein degradation and/or acceleration of apoptotic processes in skeletal muscle and may be accelerated by hemodialysis, leading to progression of vascular disease and wasting.
The new understanding holds promise for new treatments which can prevent/treat vascular diseases and wasting in CKD patients.
[Show abstract][Hide abstract] ABSTRACT: Chronic kidney disease (CKD) is strongly associated with cardiovascular disease (CVD); a graded inverse relationship between estimated glomerular filtration rate (eGFR) and cardiovascular event rates has emerged from large-scale observational studies. Chronic kidney disease is also associated with endothelial dysfunction (ED) although the precise relationship with GFR and the "threshold" at which ED begins are contentious. Abnormal endothelial function is certainly present in late-stage CKD but data in early-stage CKD appear confounded by disease states such as diabetes and hypertension which themselves promote ED. Thus, the direct effect of a reduction in GFR on endothelial function and, therefore, cardiovascular (CV) risk is far from completely established. In human studies, the precise duration of kidney impairment is seldom known and the onset of CVD often insidious, making it difficult to determine exactly when CVD first appears in the context of CKD. Kidney donors provide a near-ideal experimental model of CKD; subjects undergo an acute change from normal to modestly impaired renal function at the time of nephrectomy and lack the confounding co-morbidity that has made observational studies of CKD patients so challenging to interpret. By examining changes in endothelial function in living kidney donors before and after nephrectomy, useful insight might be gained into the pathophysiology of CVD in CKD and help determine whether targeting ED or the renal disease itself has the potential to reduce CV risk.
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