Effect of simvastatin in apolipoprotein E deficient mice with surgically induced chronic renal failure.

PURPOSE: Patients with a surgically reduced renal mass are at increased risk for progressive renal failure, which often requires renal replacement therapy or kidney transplantation. We investigated the effects of simvastatin supplementation on uremia enhanced atherosclerosis and vascular calcification in apoE(-/-) (apolipoprotein E deficient) mice (Charles Rivers Laboratories, Wilmington, Massachusetts) with or without superimposed chronic kidney disease. MATERIALS AND METHODS: The mice were randomly assigned to 4 groups, including 2 groups with normal renal function (simvastatin vs control in 13 mice) and the other 2 with surgically created chronic kidney disease (simvastatin vs control in 18). Simvastatin (100 mg/kg) was administered by daily oral gavage for 4 weeks. RESULTS: Simvastatin treatment did not prevent uremia accelerated atherosclerosis in chronic kidney disease apoE(-/-) mice, nor did it retard atherosclerosis progression in control nonchronic kidney disease mice. However, aortic plaques in simvastatin treated chronic kidney disease mice showed significantly less calcification than those in controls with chronic kidney disease (p <0.03). In addition, the increase of aortic nitrotyrosine staining in mice with chronic kidney disease was prevented by simvastatin treatment (p <0.02). Serum total cholesterol was increased to a similar extent in the 2 chronic kidney disease groups compared with that in the nonchronic kidney disease groups. The beneficial effect of simvastatin on uremia enhanced vascular calcification in apoE(-/-) mice with chronic kidney disease was observed despite the absence of changes in uremia accelerated atherosclerosis progression, serum total cholesterol levels or osteopontin and alkaline phosphatase expression. CONCLUSIONS: Our observation opens the possibility of a cholesterol independent action of statins on vascular calcification via a decrease in oxidative stress.

[Influence of microinflammation and oxidative stress on atherosclerosis progression and calcifications in cardiovascular system of hemodialyzed patients during two years follow-up]. / Wplyw mikrozapalenia i stresu oksydacyjnego na progresje miazdzycy i zwapnien w ukladzie krazenia u chorych hemodializowanych w okresie dwuletniej obserwacji.

Atherosclerosis and calcifications in the cardio-vascular system are the most frequent causes of increased morbidity and mortality in patients with end-stage renal disease treated with hemodialyses. The aim of this study was to estimate the atherosclerosis progression and presence of calcifications in the circulatory system in patients treated with hemodialyses using, non-invasive imaging diagnostic techniques and to search for the relationships between these changes and microinflammation and oxidative stress during two years. The study was performed in 73 patients (36 female and 37 male), aged 25 to 75 years (mean -49.5), treated with hemodialyses, 3 times/week for 12 to 275 months (mean -73.8). In each patient before starting hemodialysis levels of: ox-LDL, Lp (a), procalcitonin, IL-1beta, IL-6, CRP, TGFbeta, TNFalpha, PDGF, AOPP and MPO were determined. Presence of artery calcifications was detected by Multi-Row Spiral Computed Tomography (MSCT) and expressed as coronary artery calcification score (CACS). Ultrasonography was used to evaluate CCA-IMT. During the study CACS increased significantly after 12 and 24 months (p < 0.00001) as compare with baseline. After 12 months, CACS increase significantly correlated with procalcitonin level (r = 0.30 p = 0.01) and after 24 months with CRP (r = 0.46; p = 0.0002) and IL-6 (r = 0.36; p = 0.005). Independent factor of coronary artery calcification progression after 24 months of observation was only CRP (beta = 0.569). CCA-IMT increased during the study and this increase was statistically significant (p < 0.00001). CCA-IMT increase correlated with CACS growth after 12 (r = 0.36; p = 0.003) and 24 months (r = 0.39; p = 0.002). After 12 months significant relationship was noted with procalcitonin (r = 0.29; p = 0.022). After 24 months CCA-IMT correlated with AOPP (r = -0.30; p = 0.017). The independent factor of CCA-IMT progression after 24 months of observation was only CACS (delta CACS beta = 0.49). From the performed study, we can conclude that exacerbation of atherosclerosis and calcification in the circulatory system of patients treated with maintenance hemodialyses depends on microinflammation and oxidative stress. Reasonable tools for diagnostic algorithm estimation of atherosclerosis advancement in this group of patients are non-invasive, visual diagnostic techniques such as MSCT and ultrasonography.

Factors involved in vascular calcification and atherosclerosis in maintenance haemodialysis patients.

BACKGROUND: Atherosclerosis and vascular calcifications are common causes of morbidity and mortality in maintenance haemodialysis patients. In addition to the well-known traditional risk factors, uraemia-specific factors appear to enhance dramatically the progression of the pathological processes involved. The aim of the present study was to evaluate the degree of atherosclerosis and vascular calcifications in chronic haemodialysis patients using non-invasive imaging methods, and to identify potentially involved factors. METHODS: The study included 73 patients (36 females, 37 males), aged 25-75 years, who were on haemodialysis treatment for 12-275 months (mean dialysis vintage 73.8 months). We assessed the following circulating parameters: calcium (Ca), phosphorus, 'intact' parathyroid hormone (iPTH), 25OH vitamin D, lipids, oxidized LDL (ox-LDL), Lp(a), homocysteine, leptin, IL-1-beta, IL-6, CRP, TGF-beta, TNF-alpha, (PDGF), advanced oxidation protein products (AOPP) and myeloperoxidase activity (MPO). Coronary artery calcification score (CACS) was assessed using multi-row spiral CT (MSCT). Intima-media thickness index of the common carotid artery (CCA-IMT) and presence of cervical artery atherosclerotic plaques were evaluated by ultrasonography. RESULTS: Coronary artery calcifications were observed in 79.5% of the patients, with CACS ranging from 0 to 4987. In univariate analysis, a positive correlation was observed between CACS and age, BMI, iPTH, CRP, IL-6 and CCA-IMT, whereas an inverse correlation existed with 25OH vitamin D, TGF-beta and PDGF. CCA-IMT ranged from 0.4 to 1.1 mm. It was positively correlated, in univariate analysis, with age, CACS, CRP and Il-6, and negatively with 25OH vitamin D, TGF-beta and PDGF. Only CACS remained as independent predictive factor of CCA-IMT in multivariate analysis. Atherosclerotic plaques were found in the carotid arteries of 53 patients (72%). The number of plaques was positively correlated with age, CACS, phosphorus, MPO, CRP and IL-6, and inversely with 25OH vitamin D in univariate analysis. In multivariate regression analysis, only age and CACS remained as independent variables. CONCLUSION: In addition to classic risk factors, the degree of atherosclerosis and vascular calcification in our dialysis patient population were associated with several factors that are frequently abnormal in advanced chronic renal failure, but except age, all of them were interdependent. Notably, as in the general population, CACS was an independent predictor of the degree of atherosclerosis in haemodialysis patients.

Dietary salt restriction accelerates atherosclerosis in apolipoprotein E-deficient mice.

BACKGROUND: Whether a general reduction in salt intake reduces or actually enhances cardiovascular mortality in man remains an issue of controversy. Low sodium diets may lead to adverse side effects by stimulating the renin-angiotensin and sympathetic nervous systems. The present study was designed to investigate the effects of low dietary salt on atherosclerotic lesion progression in apolipoprotein E deficient (apoE(-/-)) mice. METHODS AND RESULTS: We fed 7-week-old apoE(-/-) mice on low (0.036% NaCl; n=28) or regular (0.64% NaCl; n=26) salt diets for 16 weeks. At the age of 23 weeks, the cross-section surface area of atherosclerotic plaques was measured in aortic root and thoracic aorta. Serum total cholesterol, triglycerides, plasma angiotensin levels and urinary protein/creatinine concentrations were assessed. Exposure to low salt caused significant increases in atherosclerotic lesion surface area in thoracic aorta, but did not alter lesion area in aortic root. Low-salt mice also had higher serum total cholesterol and higher plasma angiotensin II (ANG-II) concentrations. Atherosclerotic lesion area was correlated with ANG-II levels in low-salt but not in regular-salt animals, and with total cholesterol concentration in all mice. Mean arterial pressure was comparable in both groups. CONCLUSIONS: Dietary salt restriction accelerated atherosclerotic lesion formation in apoE(-/-) mice through a mechanism that is probably related to ANG-II formation. Whether these findings are relevant to human cardiovascular disease remains to be evaluated.

The antioxidant N-acetylcysteine prevents accelerated atherosclerosis in uremic apolipoprotein E knockout mice.

BACKGROUND: Cardiovascular disease is the most frequent cause of mortality in chronic renal failure (CRF). Therefore, it is important to identify appropriate treatment measures. The antioxidant N-acetylcysteine (NAC) has been shown to reduce cardiovascular events in hemodialysis patients. Here we examine a possible direct effect of NAC supplementation on uremia-enhanced atherosclerosis in apolipoprotein E-deficient (apoE(-/-)) mice. METHODS: Uremia was induced surgically in 8-week-old female apoE(-/-) mice. Two weeks after creation of CRF mice were randomized to receive either NAC (daily oral gavage with 200 mg/kg for 8 weeks) or placebo. They were compared to a control group of sham-operated apoE(-/-) mice receiving placebo. After 8 weeks of treatment, the mice were sacrificed, and the cross-section surface area of atherosclerotic plaques was measured in aortic root and descending aorta. RESULTS: At 10 weeks following surgery, atherosclerotic lesions were significantly larger in uremic apoE(-/-) mice than in nonuremic controls. This accelerated atherosclerosis was associated with an increase in aortic nitrotyrosine expression and collagen plaque content. NAC treatment inhibited the progression of atherosclerotic lesions and plaque collagen content compared with placebo treatment. In addition, plaques from NAC-treated uremic animals showed a significant decrease in nitrotyrosine expression whereas the degree of macrophage infiltration was comparable in both uremic groups. There was no difference in mean arterial blood pressure between the three groups. CONCLUSION: We show for the first time that the antioxidant NAC is capable of reducing atheroma progression, in an animal model of uremia-enhanced atherosclerosis, probably via a decrease in oxidative stress.

Uremia accelerates both atherosclerosis and arterial calcification in apolipoprotein E knockout mice.

Chronic renal failure (CRF) favors the development of atherosclerosis and excessive calcification of atheromatous lesions. CRF was induced in apolipoprotein E knockout (apoE(-/-)) mice to study (1) a possible acceleration of aortic atherosclerosis, (2) the degree and type of vascular calcification, and (3) factors involved in the calcification process. For creating CRF, 8-wk-old apolipoprotein E gene knockout (apoE(-/-)) mice underwent partial kidney ablation. Control animals underwent sham operation. Aortic atherosclerotic plaques and calcification were evaluated using quantitative morphologic image processing. At 6 wk after nephrectomy, CRF mice had significantly higher serum urea, cholesterol, and triglyceride concentrations than non-CRF controls. The serum levels of advanced oxidation protein products were elevated in the uremic group and were correlated with serum urea levels. Atherosclerotic lesions in thoracic aorta were significantly larger in uremic apoE(-/-) mice than in nonuremic controls. The relative proportion of calcified area to total surface area of both atherosclerotic lesions and lesion-free vascular tissue was increased in aortic root of uremic apoE(-/-) mice when compared with controls. The calcium deposits were made of hydroxyapatite and calcite crystals. In addition, plaques from uremic animals showed a significant increase in collagen content, whereas the degree of macrophage infiltration was comparable in both groups. There was no difference in mean arterial BP. These findings demonstrate that CRF aggravates atherosclerosis in apoE(-/-) mice. Moreover, CRF enhances arterial calcification at both atheromatous intimal sites and atheroma-free medial sites. We anticipate that this experimental model will be useful to test treatment strategies aimed at decreasing the accelerated atherosclerosis and arterial calcification in uremia.

Acute renal failure in patients with rhabdomyolysis.

BACKGROUND: Rhabdomyolysis is a relatively rare, not always diagnosed cause of acute renal failure (ARF). This fact motivated us to present the results of ARF treatment in the course of this polyetiological clinical syndrome. MATERIAL/METHODS: The analysis was performed on 84 patients (6 F, 78 M) ranging in age from 18 to 82 years (mean 46.5), in whom rhabdomyolysis was diagnosed based on clinical manifestation and laboratory test results (CPK, GTP, GOT, LDH). RESULTS: The most frequent cause of rhabdomyolysis was alcoholic intoxication (41 patients), often accompanied by hypothermia (15 patients) or trauma (30 patients). Isolated trauma was found in 30 patients, epileptic seizure in 5, and physical exercise in 1 case. In 17 patients, besides alcohol consumption, trauma or epileptic seizure, the use of tranquilizers, anticonvulsants, or narcotic drugs was additionally noted. 78 patients developed ARF requiring dialysis therapy; 49 patients recovered, 5 required maintenance dialysis, and 30 died. CONCLUSIONS: During the initial phase of ARF in the course of rhabdomyolysis dynamic increases in serum urea and creatinine were observed, as well as a tendency to hyperkalemia. The treatment results and mortality rate in our study group were primarily influenced by the patients' general condition at admission, as well as the extent of organ damage caused by the primary etiological factor. Favorable treatment results were obtained especially in those patients who were hospitalized in a nephrological center, while the worst outcomes were noted in those patients dialyzed in intensive care units, most with multiple trauma.

[Evaluation of atherosclerosis progression in patients treated repeatedly with hemodialysis]. / Ocena stopnia rozwoju miazdzycy u chorych leczonych powtarzanymi hemodializami.

The main cause of increased morbidity and mortality in patients on maintenance hemodialysis are cardiovascular complications due to accelerated atherosclerosis. Lipid profile disturbances, increased levels of homocysteine (HC), fibrinogen, iPTH as and Ca-P abnormalities seem to be the important factors in atherosclerosis progression. The aim of the study was to evaluate the advancement of atherosclerosis in patients on maintenance hemodialysis and to assess levels of pro-atherosclerotic factors. The study included 50 patients (30 M, 20 F) aged 21-75 years (mean 48.6 y) hemodialyzed three times a week for 12 to 282 months (mean 114.5 m). The homocysteine, fibrinogen, iPTH, calcium, phosphate and indices of lipid metabolism such as total cholesterol, HDL, LDL, triglicerides, Lp (a) and Apo B were measured before hemodialysis. To evaluate the advancement of atherosclerosis, all patients underwent MSCT using Somatom plus 4 apparatus with calcium scoring (CS) calculation and B-mode ultrasound for IMT using Acuson 128 XP 10 apparatus. The above applied methods helped to evaluate changes in central and peripheral arteries. In CS testing, coronary artery calcifications were present in 36 patients (72%). The CS ranged from 0 to 4345, with the mean CS being 584 (SD = 1012). The CS correlated significantly with age (r = 0.39; p < 0.005), P (r = 0.33; p < 0.05), CaxP product (r = 0.39; p < 0.05), iPTH (r = 0.43; p < 0.001) and with IMT (r = 0.56; p < 0.0001). The IMT ranged from 0.5 to 1.5, with mean of 0.89 (SD = 0.28). The IMT correlated significantly with age (r = 0.54; p < 0.0001), time on dialysis (r = 0.40; p < 0.01), fibrinogen (r = 0.43; p < 0.02), LDL (r = 0.30; p < 0.05), P (r = 0.29; p < 0.05), and CaxP product (r = 0.3; p < 0.05). Based on our study, we conclude that age, time on dialysis, increased levels of homocysteine, LDL cholesterol, fibrinogen, P, and iPTH as well as Ca-P disturbances are strong predictors of atherosclerosis in HD patients.