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Hypertension frequently coexists with diabetes mellitus, occurring twice as frequently in diabetic as in nondiabetic persons. It accounts for up to 75% of added cardiovascular disease (CVD) risk in people with diabetes, contributing significantly to the overall morbidity and mortality in this high-risk population. Patients with hypertension are two times more prone to have diabetes than are normotensive persons. Hypertension substantially increases the risk for coronary heart disease (CHD), stroke, retinopathy, and nephropathy. In patients with type 2 diabetes, hypertension usually clusters with the other components of the cardiometabolic syndrome, such as microalbuminuria, central obesity, insulin resistance, dyslipidemia, hypercoagulation, increased inflammation, and left ventricular hypertrophy (LVH). In type 1 diabetes, hypertension often occurs subsequent to the development of diabetic nephropathy. Hypertension in people with diabetes is characterized by volume expansion, increased salt sensitivity, isolated systolic blood pressure (BP) elevation, loss of the nocturnal dipping of BP and pulse, and increased propensity toward orthostatic hypotension and albuminuria. Among the treatment strategies tested in hypertensive diabetic persons, low-density lipoprotein (LDL)-cholesterol lowering to less than 100 mg/dL and aggressive BP control to less than 130/80 mm Hg have proven effective in CVD risk reduction. The combination of two or more drugs is usually necessary to achieve the target BP.
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PMID:Diabetes, hypertension, and cardiovascular derangements: pathophysiology and management. 1512 75

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

Diabetic nephropathy is the leading cause of end-stage renal disease, for which effective therapy to prevent the progression at advanced stages remains to be established. There is also a long debate whether diabetic glomerular injury is reversible or not. Lipoatrophic diabetes, a syndrome caused by paucity of adipose tissue, is characterized by severe insulin resistance, dyslipidemia, and fatty liver. Here, we show that a genetic model of lipoatrophic diabetes (A-ZIP/F-1 mice) manifests a typical renal injury observed in human diabetic nephropathy that is associated with glomerular hypertrophy, diffuse and pronounced mesangial widening, accumulation of extracellular matrix proteins, podocyte damage, and overt proteinuria. By crossing A-ZIP/F-1 mice with transgenic mice overexpressing an adipocyte-derived hormone leptin, we also reveal that leptin completely prevents the development of hyperglycemia and nephropathy in A-ZIP/F-1 mice. Furthermore, continuous leptin administration to A-ZIP/F-1 mice by minipump beginning at 40 weeks of age significantly alleviates the glomerular injury and proteinuria. These findings demonstrate the therapeutic usefulness of leptin at least for a certain type of diabetic nephropathy. The model presented here will serve as a novel tool to analyze the molecular mechanism underlying not only the progression but also the regression of diabetic nephropathy.
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PMID:Prevention and reversal of renal injury by leptin in a new mouse model of diabetic nephropathy. 1549 95

Peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Three PPAR isoforms, designated PPARalpha, -beta/delta, and -gamma, have been identified and attracted enormous attention as a result of the key role that these receptors play in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation, and BP. Growing evidence points to a causative relationship between PPAR activity and the metabolic syndrome, including insulin resistance, glucose intolerance or type 2 diabetes, obesity, dyslipidemia, hypertension, atherosclerosis, and albuminuria. Importantly, both PPAR-alpha activators, such as the fibric acid class of hypolipidemic drugs, and PPAR-gamma agonists, including antidiabetic thiazolidinediones, have been proved to be effective for improving diverse aspects of the metabolic syndrome. All three PPAR isoforms seem to play important roles in the development of diabetic nephropathy in type 2 diabetes. Accumulating data suggesting that PPAR may serve as potential therapeutic targets for treating the metabolic syndrome and its related renal complications have begun to emerge. This article reviews the literature pertaining to the action, ligand selectivity, and physiologic role of PPAR. Particular emphasis is placed on their pathogenic roles in the metabolic syndrome and the therapeutic utility of PPAR modulators in the treatment of diabetic nephropathy.
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PMID:Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome. 1550 33

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 earliest clinical evidence of diabetic nephropathy is microalbuminuria. Progression from microalbuminuria to overt nephropathy occurs in 20-40% within a 10-year period with approximately 20% of these patients progressing to end-stage renal disease. End-stage renal disease develops in 50% of type-1 diabetes patients with overt nephropathy within 10 years and in more than 75% by 20 years in the absence of treatment. In type-2 diabetes, a greater proportion of patients have microalbuminuria and overt nephropathy at or shortly after diagnosis of diabetes. The incidence of diabetes is increasing worldwide, with subsequent increase in the incidence of diabetic nephropathy. The risk factors identified in the development of DN from longitudinal and cross-sectional studies include race, genetic susceptibility, hypertension, hyperglycemia, hyperfiltration, smoking, advanced age, male sex, and high-protein diet. Treatment interventions in diabetic nephropathy include glycemic control, treatment of hypertension, hyperlipidemia, cessation of smoking, protein restriction, and renal replacement therapy. Multifactorial approach includes combined therapy targeting hyperglycemia, hypertension, microalbuminuria, and dyslipidemia.
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PMID:Diabetic nephropathy--a review of the natural history, burden, risk factors and treatment. 1558 48

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

The results of new investigations have demonstrated that the appearance of microalbuminuria (urinary albumin excretion rate, UAER>30 mg/24 h) in patients with diabetes increases constantly in about 30% of them only, leading to development of renal failure. In the majority of patients, the contemporary methods of treatment permit the normalization of UAER or the inhibition of progression to macroalbuminuria (UAER>300 mg/24 h). Therefore the actual diagnostic criterion for diabetic nephropathy consists of demonstration of persistent macroalbuminuria (or proteinuria > 0,5 g/24h) and diabetic retinopathy when other kidney or urinary tract diseases can be excluded. Persistent micro- or macroalbuminuria are contemporary considered as the markers of generalized vascular endothelial damage, reflecting increased vascular wall permeability for albumin, which is early event in development of atherosclerosis. An association of several traditional risk factors for atherogenesis, including elevated blood pressure levels, dyslipidemia, procoagulatory state, chronic inflammation and increased production of vascular endothelial growth factor (VEGF), with micro- and macro-albuminuria, was demonstrated. The presence of multiple risk factors for atherogenesis and micro- or macro-albuminuria in patients with diabetes is associated with increased incidence of cardiovascular complications and mortality when compared to normoalbuminuric patients. The effective intervention against all factors involved in the development of vascular changes in patients with diabetes is the main target for therapeutic intervention.
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PMID:[What is new in the treatment of diabetes?--The importance of nephro- and cardioprotective management]. 1566 3

Patients with diabetic nephropathy are known to be associated with many lipoprotein abnormalities, including higher plasma levels of very low-density lipoprotein, low-density lipoprotein and triglycerides, and lower levels of high-density lipoprotein. Many studies have reported that lipids may induce both glomerular and tubulointerstitial injury through mediators such as cytokines, reactive oxygen species, chemokines, and through hemodynamic changes. Clinical studies in patients with diabetic nephropathy showed that lipid control can be associated with an additional effect of reduction in proteinuria. Experimental studies demonstrated that lipid-lowering agents exerted a certain degree of renoprotection, through both indirect effects from lipid lowering and a direct effect on cell protection. Therefore, lipid control appears to be important in the prevention and treatment of diabetic nephropathy. Diabetic nephropathy has become the leading cause of end-stage renal failure in many countries, including Taiwan. One of the major risk factors for the development and progression of diabetic nephropathy is dyslipidemia. In this paper we will review the role of lipid in mediating renal injury and the beneficial effects of lipid control in diabetic nephropathy.
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PMID:Role of lipid control in diabetic nephropathy. 1575 42


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