UMLS:C0242339 - FACTA Search

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Query: UMLS:C0242339 (dyslipidemia)
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The metabolic syndrome (MetS) is defined by a set of metabolic risk factors, including insulin resistance, central obesity, dyslipidemia, hyperglycemia, and hypertension for type 2 diabetes and cardiovascular disease. Although both retrospective and prospective clinical studies have revealed that MetS is associated with chronic renal disease, even with a nondiabetic cause, the cellular and molecular mechanisms in this association remain largely uncharacterized. Recently, increasing evidence suggests that peroxisome proliferator-activated receptors (PPARs), a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors, may play an important role in the pathogenesis of MetS. All three members of the PPAR nuclear receptor subfamily, PPARalpha, -beta/delta, and -gamma, are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, inflammation, and blood pressure. PPARs have also been implicated in many renal pathophysiological conditions, including diabetic nephropathy and glomerulosclerosis. Ligands for PPARs such as hypolipidemic PPARalpha activators, and antidiabetic thiazolidinedione PPARgamma agonists affect not only diverse aspects of MetS but also renal disease progression. Emerging data suggest that PPARs may be potential therapeutic targets for MetS and its related renal complications. This review focuses on current knowledge of the role of PPARs in MetS and discusses the potential therapeutic utility of PPAR modulators in the treatment of kidney diseases associated with MetS.
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PMID:PPARs and the kidney in metabolic syndrome. 1823 57

Diabetic Nephropathy (DN) is a major chronic complication of diabetes mellitus (DM), and one of the main causes of new cases for dialysis, being associated with increasing mortality. The main risk factors for DN are hypertension, hyperglycemia, dyslipidemia, and genetic susceptibility. The renin-angiotensin system (RAS) plays an important role in genesis and progression of DN and there is evidence of an interrelationship between this system and the endothelins. Endothelins are powerful vasoconstrictor peptides and act as modulators of vasomotor tone, cell proliferation, and hormone production. These peptides act through two types of receptors (ET-A and ET-B) and are expressed on endothelial cells and vascular smooth-muscle cells. Activation of this receptor in renal cells leads to a complex signaling cascade resulting in stimulation of mesangial cell hypertrophy, proliferation, contraction, and extracellular matrix accumulation. These hemodynamic renal alterations are associated with the onset and progress of renal disease in DM. Elevated endothelin-1 (ET-1) levels have been reported in patients with DM. There is evidence suggesting that an increase in the production of ET-1 leads to glomerular damage. The use of ET receptor antagonists has been reported as renoprotective, correcting the early hemodynamic abnormalities in experimental DM, reinforcing the importance of this system in DN.
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PMID:[Endothelin system function in diabetic nephropathy]. 1860 70

Statins lower cardiovascular risk in patients with diabetes; however, as these patients are at higher risk than other cardiovascular patients, statins merely decrease coronary event rates to the level seen in untreated nondiabetic individuals at risk for cardiovascular disease, indicating the existence of substantial residual risk. One reasonable explanation resides in the fact that statins have only limited effectiveness on hypertriglyceridemia and low HDL cholesterol, and they do not normalize the LDL size-distribution pattern. Peroxisome proliferator-activated receptor (PPAR)alpha agonists, which include fibrates, normalize this atherogenic lipid profile, as well as several cardiovascular risk markers associated with the metabolic syndrome and type 2 diabetes. In particular, hypertriglyceridemia and the ratio of small dense:large buoyant LDL particles are significantly improved. Outcome trials of PPARalpha agonists have demonstrated reductions in cardiovascular morbidity in patients with diabetes and in those with the metabolic syndrome; plaque progression is diminished, diabetic nephropathy and retinopathy are counteracted and amputation-risk decreased. The combination of fibrates with statins improves overall lipoprotein profile further. PPARalpha agonists seem particularly indicated in patients with diabetes who have residual dyslipidemia (high triglyceride and/or low HDL) despite receiving statin therapy, and patients who are nondiabetic, overweight, insulin-resistant and who have hypertriglyceridemia and/or low HDL cholesterol and chronic inflammation.
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PMID:Fibrates and future PPARalpha agonists in the treatment of cardiovascular disease. 1862 76

Diabetic nephropathy, which represents a major form of chronic kidney disease (CKD), is a leading cause of end-stage renal disease worldwide, and is also a risk factor for cardiovascular disease (CVD). Patients with diabetes and CKD have poorer outcomes after myocardial infarction. The underlying pathogenic mechanism that links diabetic nephropathy to a high risk of CVD remains unclear. In addition to traditional risk factors, including hypertension, hyperglycemia, and dyslipidemia, identification of novel modifiable risk factors is important in preventing CVD in people with diabetes. Inflammation/oxidative stress are known to be associated with an increased risk for CVD in patients with diabetic nephropathy. Moreover, homocysteine, advanced glycation end products, asymmetric dimethylarginine, and anemia may play a role in the development and progression of atherosclerosis in patients with diabetic nephropathy. This review summarizes the epidemiologic evidence, molecular mechanisms responsible for the increased risk for CVD in patients with diabetic nephropathy, and therapeutic intervention for diabetic nephropathy as evidenced by large-scale clinical trials.
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PMID:Cardiovascular disease in patients with diabetic nephropathy. 1878 60

Epidemiological investigations reveal that we must expect a rapid increase in cases of diabetes mellitus in the next few years. As a result, vascular complications in the form of macro- and microangiopathy are also expected to arise more frequently. A classical example of macroangiopathy is coronary arteriosclerosis, microangiopathy is exemplified by diabetic nephropathy. In patients suffering from diabetes, macroangiopathy manifests as atherosclerosis like in nondiabetic patients, characterized by formation of plaques that follows in stages but with an accelerated course due to the different risk factors, especially hyper- and dyslipidemia, with cumulative effects. Thus, atherosclerosis in diabetes begins earlier, is more markedly pronounced and progresses more rapidly. The pathogenetic concept is based on an endothelial lesion that occurs as a result of a diabetes-specific, endothelium-damaging parameters. In case of diabetic microangiopathy histologically characterized by a progressive glomerulosclerosis, arteriolosclerosis and interstitial fibrosis hyperglycemia, along with its consecutive and complex processes that induce matrix increase, is considered to be the primary pathogenetically relevant factor involved. Insulin resistance seems to be the major common denominator at the center of both diabetic macroangiopathy and microangiopathy.
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PMID:Pathogenesis of diabetic macro- and microangiopathy. 1879 42

TREATMENT OF ARTERIAL HYPERTENSION - Blood pressure (BP) should be regularly measured in all patients with CKD (Strength of Recommendation C). - BP control and proteinuria reduction delay progression of CKD (Strength of Recommendation A) and reduce cardiovascular risk (Strength of Recommendation C). Thus, control of both factors should be the treatment objective. - The BP target in patients with CKD should be < 130/80 mmHg, and 125/75 mmHg if proteinuria is > 1 g/24 hours (Strength of Recommendation A). - Lifestyle changes should be made: low-sodium diet (less than 100 mEq/day of sodium or 2.4 g/day of salt); weight reduction if patient is overweight (body mass index 20-25 kg/m2); regular aerobic physical exercise and moderate alcohol intake for BP control and prevention of cardiovascular risk (Strength of Recommendation A). - The choice of the antihypertensive drug in patients with CKD depends on the etiology of CKD, cardiovascular risk, or presence of clinical or subclinical cardiovascular disease (Strength of Recommendation A). - Two or more antihypertensive drugs are usually required to control blood pressure in patients with CKD (Strength of Recommendation B), and will frequently include a diuretic, which in stages 4-5 should be a loop diuretic (Strength of Recommendation B). - Renin-angiotensin-aldosterone system (RAAS) inhibitors are first choice drugs in patients with diabetic nephropathy, patients with non-diabetic nephropathy with a protein/creatinine ratio higher than 200 mg/g, and patients with heart failure (Strength of Recommendation A). The combination of ACEIs and ARBs is indicated for reducing proteinuria that remains high despite treatment with a RAAS inhibitor, provided potassium levels do not exceed 5.5 mEq/L (Strength of Recommendation B). - When RAAS blockers are started or their dose is changed in patients with advanced CKD, kidney function and serum potassium levels should be monitored at least after 1-2 weeks. DIAGNOSIS AND TREATMENT OF DYSLIPIDEMIA - A complete evaluation of the lipid profile including total cholesterol, LDL-C, HDL-C, and triglycerides should be performed in any patient with CKD at baseline and at least annually (Strength of Recommendation B). - In patients with stage 4-5 CKD and LDL-C >or= 100 mg/dL, treatment to decrease levels to < 100 mg/dL should be considered because of their high CV risk. This reduction is recommended in secondary prevention and in primary prevention in diabetic patients. Lipid-lowering treatment is recommended in all other patients, although no evidence showing its benefits is available yet (Strength of Recommendation C). - In patients with stage 4-5 CKD and triglyceride levels >or= 500 mg/dL which are not corrected by treating the underlying cases, treatment with triglyceride-lowering drugs may be considered to reduce the risk of pancreatitis. However, treatment with fibrates should be used with caution, and these drugs should not be associated to statins due to the risk of rhabdomyolysis (Strength of Recommendation C). There is little experience on the efficacy and safety of omega-3 fatty acids for the treatment of hypertriglyceridemia in patients with grade 4-5 CRF, but they may be considered a possibly safer alternative to fibrates (Strength of Recommendation C). SMOKING - Smoking is a cardiovascular risk factor and a risk factor for progression of kidney disease in patients with CRF (Strength of Recommendation B). - Use of active measures to achieve smoking cessation is recommended in patients with CRF (Strength of Recommendation C). HOMOCYSTEINE - Hyperhomocysteinemia has been postulated as a cardiovascular risk factor in the general population and in kidney patients, but the available evidence is not consistent. - There is no evidence that vitamin therapy decreases cardiovascular risk in patients with CRF, and recommendation of routine vitamin measurement and start of vitamin therapy to reduce cardiovascular risk in these patients is therefore questionable (Strength of Recommendation B). LEFT VENTRICULAR HYPERTROPHY - Left ventricular hypertrophy (LVH) is a cardiovascular risk factor in patients with CRF (Strength of Recommendation B). - It is advisable to perform an echocardiogram at baseline and every 12-24 months and to consider treatments allowing for LVH regression (Strength of Recommendation C). The approach to LVH should be early and multifactorial because its reversibility is limited once established (Strength of Recommendation C). - RAAS blockade with ACEIs or ARBs partially reverts LVH in patients with CRF (Strength of Recommendation B). ANTI-PLATELET AGGREGATION - Because of the high cardiovascular risk in patients with CKD, anti-platelet aggregant therapy, especially low-dose aspirin, would be indicated in patients with type 2 diabetes as primary prevention, and in all patients with CKD as secondary prevention. There is however no evidence of the benefits of anti-platelet aggregant therapy in primary prevention in patients with CKD, particularly in stages 4-5; indication for treatment in this situation should therefore be individualised because of its greater risk of bleeding. - Adequate good blood pressure control should previously be achieved to minimise the risk of haemorrhagic stroke (Strength of Recommendation C).
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PMID:[Arterial hypertension and dyslipidemia in patients with chronic kidney disease (CKD). Anti-platelet aggregation. Goal oriented treatment]. 1901 37

The microvascular complications of diabetes mellitus confer substantial morbidity and impair patient quality of life. Dyslipidemia and prolonged hyperglycemia promote an increase in oxidative stress, inflammation, and vascular damage, which together promote endothelial dysfunction and are associated with macrovascular and microvascular complications. Microalbuminuria is an early marker of diabetic nephropathy and an independent risk factor for cardiovascular disease. Diabetic nephropathy is the most common cause of end-stage renal disease in developed countries, and its prevalence is increasing. Preventing or limiting the progression of diabetic nephropathy, as demonstrated in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, may prevent or delay renal complications, as well as convey important cardioprotective benefits in patients with type 2 diabetes.
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PMID:Microvascular complications of diabetes mellitus: renal protection accompanies cardiovascular protection. 1908 84

Diabetic nephropathy is a leading cause of end-stage renal disease, which is increasing in incidence worldwide, despite intensive treatment approaches such as glycemic and blood pressure control in patients with diabetes mellitus. New therapeutic strategies are needed to prevent the onset of diabetic nephropathy. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors that play important roles in lipid and glucose homeostases. These agents might prevent the progression of diabetic nephropathy, since PPAR agonists improve dyslipidemia and insulin resistance. Furthermore, data from murine models suggest that PPAR agonists also have independent renoprotective effects by suppressing inflammation, oxidative stress, lipotoxicity, and activation of the renin-angiotensin system. This review summarizes data from clinical and experimental studies regarding the relationship between PPARs and diabetic nephropathy. The therapeutic potential of PPAR agonists in the treatment of diabetic nephropathy is also discussed.
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PMID:Peroxisome proliferator-activated receptors in diabetic nephropathy. 1927 1

Cardiovascular disease is a frequent complication of renal failure and is the most common cause of death in patients with chronic kidney disease (CKD). Accelerated atherogenesis has been widely documented in CKD and diabetic nephropathy is the leading cause of renal failure worldwide. Furthermore, CKD promotes hypertension and dyslipidemia, which in turn may contribute to the progression of renal failure. All together, hypertension, dyslipidemia and diabetes are considered major risk factors for the development of endothelial dysfunction and progression of atherosclerosis. Elevated inflammatory mediators and activation of the renin-angiotensin system contribute through enhanced production of reactive oxygen species, to atherogenesis in CKD. Vascular calcification is also important. Calcification of arteries occurs in the intima in association with atherosclerosis, where it may contribute to plaque formation, and in the media, where it causes stiffening. Increased serum levels of calcification promoters, such as hyperphosphatemia, and a decrease in circulating and local inhibitors of calcification, favor vascular calcification. On the other hand, transdifferentiation of vascular smooth muscle cells to osteblast-like cells would be the pivotal event in calcification. Bone morphogenetic protein agonists and antagonists are playing a role in this osteogenic differentiation. Accelerated atherosclerosis and media calcification will then lead to increased prevalence of coronary artery disease, heart failure, stroke, and peripheral arterial disease. Prevention and treatment of cardiovascular disease are major considerations in the management of individuals with CKD.
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PMID:[Vascular damage in chronic kidney disease]. 1930 81

To determine the prevalence of concomitant microvascular and macrovascular complications of diabetic nephropathy we retrospectively reviewed the medical records of all 1,952 type 2 diabetic patients followed-up at Security Forces Hospital, Riyadh, Saudi Arabia from January 1989 to December 2004. There were 626 (32.1%) patients (294 (47%) were males) who developed diabetic nephropathy. Their mean age was 66.9 +/- 11.4 years, mean duration of diabetes was 15.4 +/- 7.5 years, mean age at the onset of nephropathy was 61.5 +/- 12.4 years, and mean duration of nephropathy was 3.9 +/- 3.8 years. Concomitant diabetic complications included cataract (38.2%), acute coronary syndrome (36.1%), peripheral neuropathy (24.9%), myocardial infarction (24.1%), background retinopathy (22.4%), stroke (17.6%), proliferative retinopathy (11.7%), foot infection (7.3%), limb amputation (3.7%) and blindness (3%). Hypertension was documented in 577 (92.2%) patients, dyslipidemia in 266 (42.5%) and mortality from all causes in 86 (13.7%). There were 148 (23.6%) patients with one complication, 81 (12.9%) with two, 83 (13.3%) with three, and 61 (9.7%) with four or more. Deterioration of glomerular filtration rate was observed in 464 (74%) patients and doubling of serum creatinine in 250 (39.9%), while 95 (15.2%) developed end-stage renal disease (ESRD) at the end of study and 79 (12.6%) required dialysis. Complications were significantly more prevalent among males with greater number reaching ESRD level than females (P< 0.05). Relative risks of developing complications were significant after the onset of nephropathy; ACS (1.41), MI (1.49), stroke (1.48), diabetic foot (1.6), amputation (1.58) and death (1.93). We conclude that complications of diabetes are aggressive and progressive including high prevalence of diabetic nephropathy. Careful monitoring and proper institution of management protocols should be implemented to identify diabetic patients at high risk for complications and mitigate progression into ESRD.
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PMID:Concomitant macro and microvascular complications in diabetic nephropathy. 1941 42

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