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.

Regional variations of low-density lipoprotein oxidizability in hemodialysis patients may explain discrepancies in interventional therapy on oxidative profile.

BACKGROUND/AIMS: This study aimed at evaluating oxidative stress (OS) markers (i) in a cross-sectional study of hemodialysis (HD) patients to investigate potential regional effects of these markers and (ii) in a prospective crossover study to evaluate vitamin E-coated membrane (VE) effects. METHODS: At baseline, OS parameters including low-density lipoprotein (LDL) oxidizability were measured in HD patients from five dialysis facilities. Patients were then randomly assigned to two treatment groups: group I patients (n = 33) switching to VE, and group II patients (n = 29) still using reference polysulfone (PS) membrane. After 3 months, patients were switched from VE to PS and vice versa for 6 months. The same OS parameters were measured after each period. RESULTS: At baseline, the cross-sectional analysis of LDL oxidizability showed a regional effect. By contrast, the crossover study did not show beneficial effects of VE on this parameter. CONCLUSION: Regional variations of LDL oxidizability in HD patients exist and may explain discrepancies in interventional therapy on OS.

Sevelamer prevents uremia-enhanced atherosclerosis progression in apolipoprotein E-deficient mice.

BACKGROUND: The novel phosphate binder sevelamer has been shown to prevent the progression of aortic and coronary calcification in uremic patients. Whether it also decreases the progression of atheromatous plaques is unknown. The aim of our study was to examine the effect of sevelamer administration on the development of atherosclerosis and aortic calcification in the uremic apolipoprotein E-deficient mouse as an established model of accelerated atherosclerosis. METHODS AND RESULTS: Female mice were randomly assigned to 4 groups: 2 groups of nonuremic mice (sevelamer versus control) and 2 groups of uremic mice (sevelamer versus control). Sevelamer was given at 3% with chow. The increases in serum phosphorus concentration and calcium-phosphorus product observed in uremic control mice were prevented by sevelamer. Serum total cholesterol was increased in the 2 uremic mouse groups and remained unchanged in response to sevelamer. After 8 weeks of sevelamer treatment, uremic mice exhibited a significantly lower degree of atherosclerosis (P<0.001) and vascular calcification than uremic control mice. Of interest, sevelamer exerted an effect on both intima and media calcification (P=0.005) in uremic mice. Among possible mechanisms involved, we found no evidence for the modulation by sevelamer of inflammation or selected uremic toxins. In contrast, nitrotyrosine staining as a measure of oxidative damage was significantly decreased in response to sevelamer treatment in control and uremic mice (P<0.005). CONCLUSIONS: Sevelamer delays not only vascular calcification but also atherosclerotic lesion progression in uremic apolipoprotein E-deficient mice. It opens the possibility of a cholesterol-independent action of sevelamer on atheroma formation via effects on mineral metabolism, oxidative stress, or both.

[Continued late referral of patients with chronic kidney disease. Causes, consequences, and approaches to improvement]. / Retard persistant au suivi néphrologique de l'insuffisance rénale chronique. Causes, conséquences et moyens d'amélioration.

OBJECTIVES: Efforts in recent years have aimed at increasing physicians' awareness of the frequent and harmful consequences of late referral to nephrologists of patients with chronic kidney disease (CKD), shown in repeated concordant studies. We sought to determine whether these efforts have led to improved predialysis care of these patients. METHODS: This study included all 1391 consecutive patients who began maintenance dialysis at Necker Hospital between January 1989 and December 2000. We examined baseline data and outcomes and determined for four three-year periods the percentage of patients who received early specialized care (at least 6 months before onset of dialysis). RESULTS: Late referral (<6 months before dialysis) did not change significantly over the four periods, remaining around 30%, even during the most recent period (1998-2000). Clinical condition and laboratory indicators of patients referred early but not those referred late improved in the latest period, compared with the initial period (1989-1991). Overall, prevalence of major cardiovascular events (myocardial or cerebral infarction, peripheral arteriopathy, or heart failure) was more than twice as high in patients who received nephrologic care for less than 6 months and nearly twice as high even in those followed 6-35 months than in patients followed for at least 36 months before beginning dialysis. Subsequent mortality after maintenance dialysis was also significantly higher in patients with late referral than in those followed at least 3 years before dialysis. Multivariate Cox proportional model analysis identified graded duration of predialysis nephrologic care as a significant independent factor predictive of risk of mortality while on dialysis. CONCLUSION: Late referral of CKD patients for specialist care remains frequent, around 30%, although it is most often unjustified. Late referral deprives the patient of early implementation of a reno- and cardioprotective therapeutic strategy that reduces cardiovascular comorbidity and mortality. Better coordinated cooperation between family doctors and nephrologists, through the implementation of regional healthcare networks, now appears as the most effective way to improve the care of CKD 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.

Advanced oxidation protein products as risk factors for atherosclerotic cardiovascular events in nondiabetic predialysis patients.

BACKGROUND: Inflammation and oxidative stress are established risk factors for atherosclerosis, but whether they contribute to the accelerated atherogenesis associated with chronic kidney disease (CKD) remains to be assessed at the predialysis stage. METHODS: We prospectively examined the relationship between plasma levels of C-reactive protein (CRP), fibrinogen, and advanced oxidation protein products (AOPPs), as selected markers of inflammation and oxidative stress, and incident first occlusive atherosclerotic cardiovascular (CV) events (ASCVEs) in a single-center cohort of 80 uremic predialysis patients without diabetes with a creatinine clearance ranging from 20 to 40 mL/min/1.73 m2 . RESULTS: During follow-up (median, 7 years), 21 patients developed coronary, cerebral, or peripheral artery occlusive accidents, an incidence of 44/1,000 patient-years. Except for older age, their conventional risk factors did not differ compared with the 59 patients who remained free of such accidents. Conversely, plasma levels of CRP (4.3 +/- 2.7 versus 2.3 +/- 2 mg/L; P = 0.005), fibrinogen (5.6 +/- 1.4 versus 4.4 +/- 1.2 mg/L; P = 0.0009), and AOPPs (58 +/- 20 versus 42 +/- 14 micromol/L; P = 0.0002) were significantly greater at baseline, although serum creatinine levels did not differ between the 2 groups. By multivariate Cox regression analysis, age and CRP, fibrinogen, and AOPP levels were significant independent predictors of ASCVEs. Risk factor-adjusted hazard ratios were as follows: age, 1.13 (95% confidence interval, 1.04 to 1.22; P = 0.002); CRP level, 1.37 (95% confidence interval, 1.05 to 1.79; P = 0.02); fibrinogen level, 2.23 (95% confidence interval, 1.20 to 4.13; P = 0.011); and AOPP level, 1.68 (95% confidence interval, 1.12 to 2.51; P = 0.011). CONCLUSION: CRP, fibrinogen, and AOPP levels independently predict ASCVEs in patients with CKD in the predialysis phase and might directly contribute to the uremia-associated accelerated atherogenesis.

Specific changes in plasma concentrations of matrix metalloproteinase-2 and -9, TIMP-1 and TGF-beta1 in patients with distinct types of primary glomerulonephritis.

BACKGROUND: Dysregulated renal expression of matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMP) and TGF-beta1 contribute to the development of tubulo-interstitial fibrosis characteristic of progressive forms of primary glomerulonephritis (GN). There is little information on the circulating levels of these proteins in human GNs. Here, we assessed whether different histopathological GN types could be associated with distinct plasma patterns of MMPs and regulatory proteins. METHODS: Protein levels of MMP-2, MMP-9, TGF-beta1 and TIMP-1 were measured by ELISA in plasma from venous blood of 108 untreated patients with various types of primary GN defined by kidney biopsy, namely IgAN (n=63), membranous GN (MN, n=26), minimal change nephrotic syndrome (MCNS, n=12) and focal and segmental glomerular sclerosis (FSGS, n=7), and were compared with levels in 50 healthy subjects. Plasma samples were assayed for gelatinolytic activity (zymography). RESULTS: Zymography detected the proforms of MMP-2 and MMP-9. Compared with controls, IgAN patients exhibited a significant, parallel decrease in plasma levels of MMP-2, MMP-9 and TGF-beta1. In MN patients, decreased MMP-9 level contrasted with a high MMP-2 level and a normal TGF-beta1 level. In the MCNS/FSGS group, increased MMP-2 level contrasted with unchanged MMP-9 and decreased TGF-beta1 levels. Plasma concentration of TIMP-1 was elevated in all GN groups. There was no correlation between baseline MMP-2/MMP-9/TIMP-1/TGF-beta1 levels and the degree of renal dysfunction or with progression toward ESRD. CONCLUSIONS: Plasma concentrations of MMP-2, MMP-9 and TGF-beta1 significantly differed between the various histopathological types of primary GNs, thus suggesting the involvement of different underlying mechanisms in the regulation of glomerular and tubulointerstitial fibrosis in these renal diseases.

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.

Early prediction of IgA nephropathy progression: proteinuria and AOPP are strong prognostic markers.

BACKGROUND: Inflammation and oxidative stress have been incriminated in the pathogenesis of IgA nephropathy (IgAN). The aim of the present study was to assess whether markers reflecting these pathophysiologic processes, namely C-reactive protein (CRP) and advanced oxidation protein products (AOPP), would allow-in conjunction with clinical and histopathologic parameters-to predict disease progression. METHODS: Between 1994 and 1997, 120 adult patients with biopsy-proven IgAN were included in a prospective cohort study, and followed until the end of 2002 or start of dialysis. In every patient, we determined plasma levels of CRP and AOPP. These parameters were included, together with clinical data, in a multivariate Cox proportional hazard regression analysis, with halving of baseline creatinine clearance as the primary renal end point. RESULTS: A total of 51 patients reached the renal end point, including 30 who had to start dialysis. With multivariate analysis, the most potent independent risk factors of poor renal outcome were proteinuria > or =1 g/day [proportional hazard risk (HR) = 23.7, P= 0.0001], hypertension (HR = 8.13, P= 0.008), and AOPP plasma level (HR = 1.09 per 10 micromol/L, P= 0.042), whereas angiotensin II inhibitors were protective (HR = 0.19, P= 0.001). CONCLUSION: Our data support the role of oxidative stress in the pathogenesis of IgAN and suggest that patients with proteinuria > or =1 g/day should be eligible for early implemented antioxidant and/or anti-inflammatory therapeutic strategies, with AOPP plasma level as a surrogate marker to evaluate their effects.