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This paper incorporates the findings from a multidisciplinary meeting on diabetic nephropathy and its renal and cardiovascular complications into a review article. The epidemic of obesity and the growing elderly population in the United States are primary drivers of a secondary epidemic of incipient type 2 diabetes mellitus and diabetic nephropathy. Current therapies aim to treat blood pressure, particularly with agents that block the renin-angiotensin system, to a target of 130/80 mm Hg. However, even lower blood pressure targets may be optimal. Control of hyperglycemia and dyslipidemia, smoking cessation, exercise, and weight loss all compliment blood pressure control and are achieved most effectively when the patient, provider, and health system are aligned with these goals. Once end-stage renal disease (ESRD) is reached, patients enter the highest cardiovascular risk-state appreciated in human medicine. Because of uniform access to care in the United States, advanced data systems, and circulatory system (intravascular) access in most patients, the ESRD population should be the future sampling frame for newer treatments tested in both prospective cohort and randomized trials. Cardiorenal risk, or the degree of excess cardiovascular risk incurred by patients with chronic kidney disease and ESRD, is a state offering considerable research opportunities for novel cardiovascular risk factors. Future studies should fully consider the possibility that improved outcomes would be achieved at a greater cost; thus, cost-effectiveness studies are essential for understanding the economic aspects of implementation. The goal of an ideal clinical trial would be ESRD prevention; however, pragmatic objectives such as a greater understanding of therapeutic toxicities should also be explored in this population.
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PMID:Slowing the progression of diabetic nephropathy and its cardiovascular consequences. 1530 93

Overweight/obesity represent an underestimated risk factor of renal disease. The incidence of obesity-related glomerulopathy (ORG) tremendously increased within the last decade. The first sign of renal damage in overweight conditions is microalbuminuria or proteinuria, indicating the potential risk of its progression to renal insufficiency and the development of premature cardiovascular events. In the early stage of obesity renal hemodynamics are characterized by a renal hypercirculation and glomerular hyperfiltration, particularly in the presence of hypertension. The hyperfiltration is especially harmful in patients with pre-existing inflammatory and metabolic renal disease, or under the conditions of reduced renal mass. Histopathologically, ORG is characterized by glomerulomegaly with/without signs of focal segmental glomerulosclerosis. Pathogenetically, numerous factors are involved, e.g. enhanced glomerular capillary pressure, adrenergic nerve overactivity, inappropriate activation of the renin-angiotensin-aldosterone system, insulin resistance, hyperinsulinemia and hyperleptinemia, dyslipidemia, enhanced clotting tendency and sodium retention. Diabetic nephropathy is one of the most serious complications of obesity-induced diabetes. In the industrial nations type 2 diabetes is the single most frequent cause of end-stage renal disease. After kidney transplantation, overweight/obesity is associated with a less favourable prognosis for the survival of the graft and the patient. Incidence of renal cell carcinomas is enhanced in overweight/obesity. Obesity-related renal disease may be prevented/postponed by an early weight reduction, by dietary intervention combined with physical exercise. In the advanced stages of renal disease benefits of weight reduction are minimal. Concomitant administration of angiotensin-converting-enzyme inhibitors or angiotensin II receptor 1 blockers exerts antiproteinuric effects and thereby aid in retarding the disease progression. Aimed prevention and treatment of obesity represent a challenge for the healthcare system. The concerted action of physicians, patients and the public health authorities is needed.
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PMID:[Overweight and obesity--risk factors in the development and progression of renal disease]. 1532 63

At least 17 million people in the United States have diabetes mellitus, and another 50 million have hypertension. These chronic diseases increasingly coexist in our aging population. Both diseases are important predisposing factors for the development of cardiovascular disease (CVD) and renal disease, and the coexistence of these risk factors is a very powerful promoter of CVD and renal disease. There is accumulating evidence that the rigorous treatment of hypertension and other risk factors such as dyslipidemia and hyperglycemia considerably lessens the burden of CVD and renal disease in patients with diabetes mellitus. There is considerable evidence that strategies addressing diet and exercise reduce the development of diabetes and are an important component of treatment in persons who have established diabetes. There are also considerable data suggesting that the treatment strategies that interrupt the renin-angiotensin system have special benefits in patients with diabetes and may prevent the development of clinical diabetes in hypertensive patients with impaired glucose tolerance. Data from a recent study indicate that the control of systolic blood pressure, using a diuretic agent as part of antihypertensive therapy, reduces the risk of stroke and other CVD end points. Recent reports indicate that angiotensin receptor-blocking agents decrease the rate of development of proteinuria and diabetic renal disease. These observations will likely have a significant impact on treatment of hypertension in patients with type 2 diabetes mellitus.
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PMID:Treatment of hypertension in patients with diabetes. 1545 59

Non-insulin-dependent diabetes mellitus (NIDDM) and the metabolic syndrome separately and additively increase the risk for atherosclerotic cardiovascular disease. Considering the high cardiovascular risk associated with NIDDM and the metabolic syndrome, aggressive therapy of dyslipidemia with tailored combination therapy should be considered given informed consent and discussion of risks. In addition to statins, niacin, and fibrates, therapies shown to decrease the risk for atherosclerotic cardiovascular disease include omega-3 fatty acids, diet, exercise, and optimal blood pressure control with thiazides and blockers of the renin-angiotensin system. These therapies should also be considered to reduce the high cardiovascular risk associated with NIDDM and the metabolic syndrome.
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PMID:Combination therapy of dyslipidemia in non-insulin-dependent diabetes mellitus and the metabolic syndrome. 1546 96

Cardiovascular disease is the major cause of morbidity and mortality in patients with chronic kidney disease (CKD). The presence of CKD whether manifested by albuminuria or reduction in glomerular filtration rate is an independent risk factor for cardiovascular outcome. This is mainly due to both an overexpression of traditional cardiovascular risk factors, and the onset of new factors which are peculiar of CKD. In this revision the role of arterial hypertension and of dyslipidemia is analyzed in detail. Most interventional trials have demonstrated that a reduction of blood pressure and the normalization of lipid profile are associated with a significant reduction in the incidence of major cardiovascular events and mortality. According to the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) recommendations, patients with CKD, regardless of the stage of disease, should be considered the highest risk group for cardiovascular events. For these patients the NKF-K/DOQI guidelines recommend strict blood pressure control, renin-angiotensin system blockade, and the use of statins with target LDL cholesterol levels < 100 mg/dl.
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PMID:[Hypertension, dyslipidemia and cardiovascular risk in chronic renal disease]. 1547 Nov 48

The number of people with diabetes grows worldwide. The complications resulting from this disease are a significant cause of morbidity and mortality. World Health Organization estimates that, while in the year 2000 the number of people with diabetes was about 177 million, by 2025, this will increase to at least 300 million. The diabetes epidemic, without primary prevention, will continue to grow. Individuals with type 2 diabetes are at a significantly higher risk for coronary heart disease, peripheral vascular disease, and stroke, and they have a greater probability of having hypertension, dyslipidemia, and obesity. A number of clinical trials provide evidences that RAAS inhibition could be helpful at preventing new onset of type 2 diabetes mellitus. Pharmacologic treatment that antagonize the renin-angiotensin system (RAS) provide more benefits, not only in patients after myocardial infarction and in congestive heart failure, but also in persons with hypertension and type 2 diabetes mellitus.
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PMID:Renin-Angiotensin-Aldosterone system inhibition in prevention of diabetes mellitus. 1552 18

Conventional risk factors associated with cardiovascular and renal complications of diabetes include hypertension, dyslipidemia, hyperglycemia, and smoking. Recently, albuminuria has also emerged as an important risk factor, as it is independently associated with increased cardiovascular and renal risk. Inhibition of the renin-angiotensin-aldosterone system (RAAS) reduces both blood pressure (BP) and albuminuria, and induced cardiovascular and renal protection is associated with this albuminuria reduction, independent of BP reduction. Based on these results, optimal therapy for patients at risk for type 2 diabetic nephropathy should include BP reduction to <130/80 mm Hg, with the inclusion of a RAAS blocking agent (ie, an angiotensin II receptor blocker) to provide BP control and control of urinary albumin, which should be reduced to <500 mg/d.
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PMID:Should albuminuria be a therapeutic target in patients with hypertension and diabetes? 1553 5

The major cause of morbidity and mortality in persons with diabetes is cardiovascular disease (CVD), the risk of which is increased three- to four-fold versus persons without diabetes. The biology of diabetes is characterized not only by hyperglycemia but also by hypertension, dyslipidemia, microalbuminuria, inflammation, and abnormal thrombolysis. Hypertension is a common feature of diabetes and is the primary contributor to CVD. Recent investigations have revealed a relationship between vascular derangements, insulin resistance, and visceral obesity and have implicated the renin-angiotensin-aldosterone system (RAAS) as a key mediator of cardiovascular dysfunction in diabetes. Angiotensin II has been shown to have direct effects on endothelial dysfunction, oxidative stress, inflammation, skeletal muscle, and adipocyte function. These pathophysiologic considerations have formed the basis for CVD prevention strategies in diabetes. Clinical trials have demonstrated a reduction in cardiovascular events with aspirin, lipid-lowering agents, and antihypertensive agents. Blood pressure (BP) control (<130/80 mm Hg) is a crucial component of risk reduction, and several studies have demonstrated the need for multiple agents to reach therapeutic goals. Clinical trials also demonstrated the benefit of RAAS blocking agents in reducing BP and cardiovascular and renal risk, and suggest clinical benefits beyond BP reduction.
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PMID:Insights into the biology of diabetic vascular disease: what's new? 1553 7

Type 2 diabetes and hypertension are both insulin-resistant states that impose an excessive risk burden for future major cardiovascular events, including coronary heart disease, stroke, and heart failure. beta-adrenergic receptor antagonists are effective for the treatment of hypertension, but they are underused in diabetic patients because of possible adverse effects on carbohydrate and lipid metabolism, including insulin resistance, glucose intolerance, and dyslipidemia. Traditional beta blockers, both nonselective and selective, are vasoconstrictive due to unopposed alpha1 activity; however, vasodilating beta blockers are not associated with these negative metabolic effects. This review discusses the background of insulin resistance and its link to diabetes and hypertension, emphasizing the role of vascular control by the renin-angiotensin and sympathetic nervous systems on insulin sensitivity and glucose utilization. Clinical evidence is reviewed for the use of vasodilating beta blockers in the treatment of hypertension and in reducing cardiovascular risk in the diabetic population.
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PMID:Metabolic properties of vasodilating beta blockers: management considerations for hypertensive diabetic patients and patients with the metabolic syndrome. 1559 17

Diabetic nephropathy is the leading cause of kidney disease in patients starting renal replacement therapy and affects approximately 40% of type 1 and type 2 diabetic patients. It increases the risk of death, mainly from cardiovascular causes, and is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases. Diabetic nephropathy is categorized into stages: microalbuminuria (UAE >20 microg/min and < or =199 microg/min) and macroalbuminuria (UAE > or =200 microg/min). Hyperglycemia, increased blood pressure levels, and genetic predisposition are the main risk factors for the development of diabetic nephropathy. Elevated serum lipids, smoking habits, and the amount and origin of dietary protein also seem to play a role as risk factors. Screening for microalbuminuria should be performed yearly, starting 5 years after diagnosis in type 1 diabetes or earlier in the presence of puberty or poor metabolic control. In patients with type 2 diabetes, screening should be performed at diagnosis and yearly thereafter. Patients with micro- and macroalbuminuria should undergo an evaluation regarding the presence of comorbid associations, especially retinopathy and macrovascular disease. Achieving the best metabolic control (A1c <7%), treating hypertension (<130/80 mmHg or <125/75 mmHg if proteinuria >1.0 g/24 h and increased serum creatinine), using drugs with blockade effect on the renin-angiotensin-aldosterone system, and treating dyslipidemia (LDL cholesterol <100 mg/dl) are effective strategies for preventing the development of microalbuminuria, in delaying the progression to more advanced stages of nephropathy and in reducing cardiovascular mortality in patients with type 1 and type 2 diabetes.
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PMID:Diabetic nephropathy: diagnosis, prevention, and treatment. 1561 52


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