Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Vascular calcifications are more frequent in dialysis patients than in the general population or in patients with cardiovascular disease (CVD) and normal renal function. The reasons for this high incidence are multiple; they include traditional factors such as hypertension, diabetes, dyslipidemia, and specific factors such as sodium overload, hyperomocysteinemia, chronic inflammation and oxidative stress, as well as mineral metabolism disturbances. Specifically, hyperphosphatemia and the elevated calcium (Ca) x phosphate product have been associated with an increased risk for the development of vascular calcification and death. Treatment with Ca salts can induce hypercalcemia, increased Ca x phosphate product and Ca overload. Sevelamer substitution for Ca salts has been documented to attenuate the progression of coronary artery and aortic calcification. A possible mechanism explaining this observation could be ongoing Ca loading related to oral Ca ingestion. Treatment with Ca salts could induce Ca overload, particularly in patients dialyzed against a high dialysate Ca (>1.5 mmol/L) solution, which is known to determine a positive dialysis balance. Conversely, an overall negative Ca balance can result from low Ca dialysate use (1.25 mmol/L) when the patients do not receive Ca supplements or vitamin D metabolites. Maintaining normal Ca and phosphate balances remains a primary goal in the management of dialysis patients. Control of hyperphopshataemia should be achieved either using Ca and aluminum-free phosphate binders, such as sevelamer, or Ca salts, alone or in combination, provided that a daily oral elemental Ca intake of 1.5 g is not exceeded.
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PMID:[Control of calcium and phosphate metabolism and prevention of vascular calcifications in uremic patients]. 1578 2

Cardiovascular risk is dramatically increased in patients with end-stage renal disease (ESRD). However, even minor dys-functions such as microalbuminuria or a mild increase in serum creatinine (Cr) have a major impact on cardiovascular risk. Increased cardiovascular risk is present in multiple populations, including general populations, patients with moderate risk such as hypertensives, and high-risk patients including patients with heart failure and myocardial necrosis. There are many mechanisms underpinning the increased cardiovascular risk. Regarding atherosclerosis, the kidney can be victim or villain. On the one hand, both kidney disease per se and renal insufficiency can induce vascular damage, thereby increasing cardiovascular risk. Kidney disease without renal insufficiency can cause an increased prevalence in hypertension, dyslipidemia (nephrotic syndrome), sympathetic system hyperactivity, and in renin angiotensin system hyperactivity. A moderate-severe renal insufficiency can induce an increase in many vasculotoxic substances such as ADMA, lipoprotein(a), homocysteine, disturbances in calcium and phosphate metabolism, anemia and left ventricular hypertrophy. A more severe renal insufficiency can induce the ominous malnutrition-inflammation-atherosclerosis (MIA) syndrome. On the other hand, the kidney can be the victim of atherosclerosis. Ischemic nephropathy, caused by atherosclerotic renal artery disease and atheroembolism from abdominal aorta are two examples. Finally, it is important to consider that the kidney, being an organ with a wide vasculature, could be a sophisticated sensor of subclinical cardiovascular damage.
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PMID:[Hypertension, atherosclerosis and kidney]. 1578 9

Vitamin D3 is modified by vitamin D3-25-hydroxylase in the liver, and 25-hydroxyvitamin D3-1alpha-hydroxylase in the kidney, to form the active metabolite, 1,25-dihydroxyvitamin D3. Chronic kidney disease (CKD) is characterized by reduced synthesis of 1,25-dibydroxyvitamin D3, inadequate renal phosphate clearance and calcium imbalance, secondary hyperparathyroidism (SHPT) and bone disease. CKD patients encounter a much higher risk of cardiovascular disease (CVD) than the general public. The cardiovascular risk factors for CKD patients include conventional factors such as age, gender, hypertension, diabetes, dyslipidemia and smoking, and non-conventional factors, such as anemia, uremia, reduced vascular compliance, inflammation and various hormonal factors. Several vitamin D analogs are currently available for the treatment of SHPT, and recent clinical data show that these analogs provide survival benefit for CKD patients in the order of paricalcitol > calcitriol > no vitamin D analog, independent of parathyroid hormone and calcium. Moreover, the survival benefit seems to be associated with cardiovascular causes. The observations made from these clinical studies raised intriguing questions about the involvement of the vitamin D receptor locus (VDR) in the cardiovascular system. This review discusses recent data regarding the role of vitamin D and its analogs in the CVD associated with CKD.
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PMID:Cardiovascular disease in chronic kidney failure: is there a role for vitamin D analogs? 1581

Dyslipidemia and progression of cardiovascular calcification (CVC) in patients with end-stage renal disease (ESRD). Cardiovascular calcification (CVC) is commonly encountered both in the general population as well as in patients with end-stage renal disease (ESRD). The etiology of CVC in patients with ESRD is multifactorial. Despite that, current debate remains narrowly focused on the role of calcium loading from calcium-based phosphate binders (CBPB) in the pathogenesis and progression of CVC. Yet, the alleged link between these binders and CVC has not been substantiated in well-designed controlled trials. In contrast, the purported role of sevelamer, a non-calcium-based phosphate binder, in slowing the progression of CVC in dialysis patients has attracted widespread attention. The beneficial effect of sevelamer on progression of calcification was thought to be due to lower calcium loading during its use. However, an alternative and possibly more likely mechanism involves sevelamer-induced lowering of LDL cholesterol. In this context, previous studies in individuals with normal renal function have documented amelioration of coronary artery calcification (CAC) with reduction of LDL-cholesterol by treatment with HMG-CoA reductase inhibitors (statins). Given that CAC is a well-accepted marker of atherosclerosis, and that high plasma cholesterol concentration is one of the main risk factors for atherosclerosis, then it is not unreasonable to suspect that CAC may be halted or even reversed by lowering of LDL cholesterol level with statin therapy. Unfortunately, the effect of lowering the LDL-cholesterol level on CAC has not been studied in patients with ESRD. Therefore, conclusions about this important topic should await the results of well-designed clinical studies that control for all factors potentially implicated in the CVC burden of patients with ESRD. In this review, I will discuss the role of various potential mechanisms involved in the pathogenesis of CVC in patients with ESRD, and emphasize the role of dyslipidemia and its treatment in this important clinical entity.
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PMID:Dyslipidemia and progression of cardiovascular calcification (CVC) in patients with end-stage renal disease (ESRD). 1588 13

We have shown that renal injury and chronic kidney disease (CKD) directly inhibit skeletal anabolism, and that stimulation of bone formation decreases the serum phosphate. Most recently, these observations were rediscovered in low-density lipoprotein receptor null mice fed high-fat/cholesterol diets, a model of the metabolic syndrome (hypertension, obesity, dyslipidemia, and insulin resistance). We had demonstrated that these mice have vascular calcification (VC) of both the intimal atherosclerotic type and medial type. We have shown that VC is worsened by CKD and ameliorated by bone morphogenetic protein -7 (BMP-7). The finding that high-fat-fed low-density lipoprotein receptor null animals without CKD have hyperphosphatemia led us to examine the skeletons of these mice. We found significant reductions in bone formation rates, associated with increased VC and superimposing CKD results in the adynamic bone disorder (ABD), while VC was worsened and hyperphosphatemia persisted. A pathological link between abnormal bone mineralization and VC through the serum phosphorus was demonstrated by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. BMP-7 treatment corrected the ABD and corrected hyperphosphatemia, compatible with BMP-7-driven stimulation of skeletal phosphate deposition reducing plasma phosphate and thereby removing a major stimulus to VC. Thus, in the metabolic syndrome with CKD, a reduction in bone-forming potential of osteogenic cells leads to ABD producing hyperphosphatemia and VC, processes ameliorated by the skeletal anabolic agent BMP-7, in part through increased bone formation and skeletal deposition of phosphate, and in part through direct actions on vascular smooth muscle cells. We have demonstrated that the processes leading to vascular calcification begin with even mild levels of renal injury before demonstrable hyperphosphatemia, and they are preventable and treatable. Therefore, early intervention in CKD is warranted and may affect mortality of the disease.
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PMID:Connections between vascular calcification and progression of chronic kidney disease: therapeutic alternatives. 1633 68

The current implementation into nephrology clinical practice of guidelines on treatment of cardiovascular (CV) risk factors in chronic kidney disease (CKD) is unknown. We designed a cross-sectional analysis to evaluate the prevalence and treatment of eight modifiable CV risk factors in 1058 predialysis CKD patients (stage 3: n=486; stage 4: n=430, stage 5: n=142) followed for at least 1 year in 26 Italian renal clinics. The median nephrology follow-up was 37 months (range: 12-391 months). From stages 3 to 5, hypertension was the main complication (89, 87, and 87%), whereas smoking, high calcium-phosphate product and malnutrition were uncommon. The prevalence of proteinuria (25, 38, and 58%), anemia (16, 32, and 51%) and left ventricular hypertrophy (51, 55, and 64%) significantly increased, while hypercholesterolemia was less frequent in stage 5 (49%) than in stages 4 and 3 (59%). The vast majority of patients received multidrug antihypertensive therapy including inhibitors of renin-angiotensin system; conversely, diuretic treatment was consistently inadequate for both frequency and dose despite scarce implementation of low salt diet (19%). Statins were not prescribed in most hypercholesterolemics (78%), and epoietin treatment was largely overlooked in anemics (78%). The adjusted risk for having a higher number of uncontrolled risk factors rose in the presence of diabetes (odds ratio 1.29, 95% confidence interval 1.00-1.66), history of CV disease (odds ratio 1.48, 95% confidence interval 1.15-1.90) and CKD stages 4 and 5 (odds ratio 1.75, 95% confidence interval 1.37-2.22 and odds ratio 2.85, 95% confidence interval 2.01-4.04, respectively). In the tertiary care of CKD, treatment of hypertension is largely inadequate, whereas therapy of anemia and dyslipidemia is frequently omitted. The risk of not achieving therapeutic targets is higher in patients with diabetes, CV disease and more advanced CKD.
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PMID:Global approach to cardiovascular risk in chronic kidney disease: reality and opportunities for intervention. 1639 61

In two independent and separate studies, we have shown that renal injury and chronic kidney disease (CKD) directly inhibit skeletal anabolism, and that stimulation of bone formation decreased the serum phosphate. In the first study, the serum Ca PO(4), parathyroid hormone (PTH), and calcitriol were maintained normal after renal ablation in mice, and even mild renal injury equivalent to stage 3 CKD decreased bone formation rates. More recently, these observations were rediscovered in low-density lipoprotein receptor null (LDLR-/-) mice fed high-fat/cholesterol diets, a model of the metabolic syndrome (hypertension, obesity, dyslipidemia and insulin resistance). We demonstrated that these mice have vascular calcification (VC) of both the intimal atherosclerotic type and medial calcification. We have also shown that VC is made worse by CKD and ameliorated by bone morphogenetic protein-7 (BMP-7). The finding that high-fat fed LDLR-/- animals with CKD had hyperphosphatemia which was prevented in BMP-7-treated animals lead us to examine the skeletons of these mice. It was found that significant reductions in bone formation rates were associated with high-fat feeding, and superimposing CKD resulted in the adynamic bone disorder (ABD), while VC was made worse. The effect of CKD to decrease skeletal anabolism (decreased bone formation rates and reduced number of bone modelling units) occurred despite secondary hyperparathyroidism. The BMP-7 treatment corrected the ABD and hyperphosphatemia, owing to BMP-7-driven stimulation of skeletal phosphate deposition reducing plasma phosphate and thereby removing a major stimulus to VC. A pathological link between abnormal bone mineralization and VC through the serum phosphorus was demonstrated by the partial effectiveness of directly reducing the serum phosphate by a phosphate binder that had no skeletal action. Thus, in the metabolic syndrome with CKD, a reduction in bone forming potential of osteogenic cells leads to the ABD producing hyperphosphatemia and VC, processes ameliorated by BMP-7, in part through increased bone formation and skeletal deposition of phosphate and in part through direct actions on vascular smooth muscle cells. We have demonstrated that the processes leading to vascular calcification begin with even mild levels of renal injury affecting the skeleton before demonstrable hyperphosphatemia and that they are preventable and treatable. Therefore, early intervention in the skeletal disorder associated with CKD is warranted and may affect mortality of the disease.
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PMID:Function and effect of bone morphogenetic protein-7 in kidney bone and the bone-vascular links in chronic kidney disease. 1688 97

Increased aortic stiffness, as measured by pulse wave velocity (PWV) and augmentation index (Aix), and vascular calcification have been associated with an unfavourable cardiovascular outcome in hemodialysis patients. However, the majority of data have been published in white patients and epidemiological data are discordant on the fate of patients of different races. In this cross sectional study we measured PWV and Aix by applanation tonometry and coronary artery and thoracic aorta calcium score (CAC and AoC) by electron beam tomography (EBT) in 81 Blacks and 61 Whites on maintenance hemodialysis. Vascular stiffness measurements and EBT scans were performed within a week of each other. There was no difference between races in age, systolic blood pressure or gender distribution. Blacks had a more frequent history of hypertension (100% versus 89%; P=0.002), lower prevalence of dyslipidemia (30% versus 66%; P<0.001), higher PTH levels (geometric mean 607 pg/ml versus 245 pg/ml; P=0.039), received calcium based phosphate binders less frequently (37% versus 60%, P=0.007) and calcium antagonists more frequently than Whites (54% versus 28%; P=0.003). Nonetheless, the unadjusted and risk adjusted PWV and Aix, as well as CAC and AoC were not statistically different between races. In this dialysis cohort there was no difference in markers of vasculopathy between black and white patients despite differences in baseline clinical characteristics. Epidemiological data from the general population indicate that Blacks have lower calcium scores and stiffer vessels than Whites. Some studies in the renal populations suggest a better and others a similar survival of Blacks and Whites on hemodialysis. Our findings raise the important question of the prognostic significance of markers of vasculopathy in patients of different races and with different risk profiles.
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PMID:Markers of vascular disease do not differ in black and white hemodialysis patients despite a different risk profile. 1752 8

Obstructive sleep apnea (OSA), a condition leading to intermittent hypoxia (IH) during sleep, has been associated with dyslipidemia, atherosclerosis, and increased cardiovascular mortality. We previously showed in C57BL/6J mice that IH causes hypercholesterolemia and upregulation of sterol regulatory element binding protein (SREBP)-1, a transcription factor of lipid biosynthesis in the liver. The goal of the present study was to provide mechanistic evidence that IH causes hypercholesterolemia via the SREBP-1 pathway. We utilized mice with a conditional knockout of SREBP cleavage-activating protein (SCAP) in the liver (L-Scap- mice), which exhibit low levels of an active nuclear isoform of SREBP-1 (nSREBP-1). We exposed L-Scap- mice and wild-type (WT) littermates to IH or intermittent air control for 5 days. IH was induced during the 12-h light phase by decreasing Fi(O(2)) from 20.9% to 5% for a period of 30 s with rapid reoxygenation to 20.9% through the subsequent 30 s. In WT mice, IH increased fasting levels of serum total and HDL cholesterol, serum triglycerides, serum and liver phospholipids, mRNA levels of SREBP-1 and mitochondrial glycerol-3-phosphate acyltransferase (mtGPAT), and protein levels of SCAP, nSREBP-1, and mtGPAT in the liver. In L-Scap- mice, IH did not have any effect on serum and liver lipids, and expression of lipid metabolic genes was not altered. We conclude that hyperlipidemia in response to IH is mediated via the SREBP-1 pathway. Our data suggest that the SREBP-1 pathway could be used as a therapeutic target in patients with both OSA and hyperlipidemia.
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PMID:Effect of deficiency in SREBP cleavage-activating protein on lipid metabolism during intermittent hypoxia. 1766 24

Accelerated formation of advanced glycation/lipoxidation and endproducts (AGEs/ALEs) has been implicated in the pathogenesis of various diabetic complications. Several natural and synthetic compounds have been proposed and tested as inhibitors of AGE/ALE formation. We have previously reported the therapeutic effects of several new AGE/ALE inhibitors on the prevention of nephropathy and dyslipidemia in streptozotocin (STZ)-induced diabetic rats. In this study, we investigated the effects of various concentrations of a compound, LR-90, on the progression of renal disease and its effects on AGE and receptor for AGE (RAGE) protein expression on the kidneys of diabetic STZ-rats. Diabetic male Sprague-Dawley rats were treated with or without LR-90 (0, 5, 20, 25, and 50 mg/l of drinking water). After 32 weeks, body weight, glycemic status, renal function, and plasma lipids were measured. Kidney histopathology and AGE/ALE accumulation and RAGE protein expression in tissues were also determined. In vitro studies were also performed to determine the possible mechanism of action of LR-90 in inhibiting AGE formation and AGE-protein cross-linking. LR-90 protected the diabetic kidneys by inhibiting the increase in urinary albumin-to-creatinine ratio and ameliorated hyperlipidemia in diabetic rats in a concentration-dependent fashion without any effects on hyperglycemia. LR-90 treatment also reduced kidney AGE/ALE accumulation and RAGE protein expression in a concentration-dependent manner. In vitro, LR-90 exhibited general antioxidant properties by inhibiting metal-catalyzed reactions and reactive oxygen species (OH radical) and reactive carbonyl species (methlyglyoxal, glyoxal) generations without any effect on pyridoxal 5' phosphate. The compound also prevents AGE-protein cross-linking reactions. These findings demonstrate the bioefficacy of LR-90 in treating nephropathy and hyperlipidemia in diabetic animals by inhibiting AGE accumulation, RAGE protein expression, and protein oxidation in the diabetic kidney. Additionally, our study suggests that LR-90 may be useful also to delay the onset and progression of diabetic atherosclerosis as the compound can inhibit the expression of RAGE and inflammation-related pathology, as well as prevent lipid peroxidation reactions.
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PMID:Novel inhibitors of glycation and AGE formation. 1770 84


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