Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II receptor antagonists (AAIIs) are the most specific inhibitors of the renin-angiotensin-aldosterone system. There are two types of angiotensin II (Ang II) receptors, the AT(1) receptor, which is responsible for all the classical physiological properties of Ang II, and the AT(2) receptor, whose function in humans remains unclear. The different AAIIs used in clinical practice vary depending on their pharmacodynamic and pharmacokinetic properties, and, for some of them, depending on their metabolism in vivo into an active metabolite. AAIIs are relatively well tolerated, and, unlike angiotensin-converting enzyme inhibitors (ACEIs), do not induce cough. AAIIs are indicated in mild, moderate and severe essential hypertension, where their efficacy has been proven in many studies. The maximal antihypertensive effect is obtained in a few days or weeks, and is somewhat retarded when compared with ACEIs. Their effect is independent of age and sex, but does depend to a certain extent on ethnic origin, since Afro-American patients are less sensitive to AAIIs than Caucasians. In general, the antihypertensive and haemodynamic response to blockers of the renin-angiotensin system is potentiated in presence of a negative salt balance and attenuated in case of a positive salt balance. This means that AAII efficiency is improved by salt depletion induced by a salt-free diet or thiazide diuretics. AAIIs induce short-term improvement of haemodynamic parameters in cardiac insufficiency. Several ongoing clinical trials have been designed to compare their efficacy in cardiac insufficiency and myocardial infarction with those of reference treatments. Valsartan has been recently shown to improve morbimortality in patients with cardiac insufficiency and receiving a conventional treatment including an ACEI. It has been convincingly shown that blockade of the renin-aldosterone system by ACEIs decreases proteinuria and slows down the progression of renal insufficiency, especially in type 2 diabetic nephropathy. Recent trials have shown that AAIIs share the same properties as ACEIs in these indications. It appears that the beneficial effect of AAIIs and ACEIs is not entirely explained by the blood pressure lowering effect of these drugs. AAII administration increases renin release and Ang II production, which may overcome Ang II blockade. On this basis, the combination of an AAII and an ACEI has been proposed to achieve a maximal renin-angiotensin system blockade. Several experimental studies in animals and preliminary clinical studies all indicate that the combination of the two drugs may be more beneficial than either drug used alone in hypertension, cardiac insufficiency and post-myocardial infarction. Clinical trials are necessary to further document the putative advantages of such a combined therapy. The future of AAIIs depends on the following: progress made in the understanding of the molecular and cellular activities of angiotensin (angiotensin receptor signalling, receptor dimerisation, presence of other angiotensin receptor subtypes, role of AT(2) receptor, etc.);a comprehensive view of the role of the local renin system in various organs (local generation and effect of Ang II on cellular proliferation, fibrosis, inflammation, angiogenesis, etc.);predictability of the response to AAII treatment (genetic predisposition to AAII treatment, in conjunction with environmental factors); andresults of the ongoing clinical trials designed to assess the long-term effects of AAIIs in cardiovascular mortality and morbidity, in comparison with reference treatments.
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PMID:[Angiotensin II receptor blockers: current status and future prospects]. 1203 89

Microalbuminuria (MA) i.e. slightly elevated albumin excretion in the urine, is now considered to be an atherosclerotic risk factor. MA predicts future cardiovascular disease risk in diabetic patients, in elderly patients, as well as in the general population. It has been implicated as an independent risk factor for cardiovascular disease and premature cardiovascular mortality for patients with type 1 and type 2 diabetes mellitus, as well as for patients with essential hypertension. Although microalbuminuria is associated with a certain degree of sub-clinical artherosclerotic damage, it is not known how early in the atherosclerotic process microalbuminuria appears. Epidemiological studies have shown an association between MA and insulin resistance, obesity, salt sensitivity and dyslipidaemia in patients with essential hypertension and diabetes. Patients with microalbuminuria are also characterised by an increased prevalence of left ventricular hypertrophy and retinal microvascular lesions. Microalbuminuria, is associated with an excess of other cardiovascular risk factors. The mechanisms linking microalbuminuria and risk for cardiovascular disease are not fully understood, but in subjects at risk it may be related to increased transvascular leakiness of albumin in systemic as well as renal vessels. A recent concept is that microalbuminuria is a marker of extensive endothelial dysfunction or generalised vasculopathy, which may lead to heightened atherogenic states. One possible explanation is that endothelial dysfunction might promote increased penetration of atherogenic lipoprotein particles in the arterial wall, but glycaemic status, insulin resistance, procoagulant state and adhesion molecules have all been implicated in the pathogenesis. Current evidence suggests that tight blood pressure control may reduce the risk of microalbuminuria in diabetic patients with hypertension and that inhibitors of the rennin-angiotensin system (RAS) can prevent or delay the progression of microalbuminuria to overt nephropathy in normotensive persons. ACE inhibitors are currently recognised as first-line antihypertensive therapy in diabetic patients with proteinuria, and these agents afford unique benefits in modifying the progression and severity of cardiovascular disease (CVD) as well as of diabetic nephropathy. Whether albuminuria is a risk factor or just a marker for CV disease, it identifies the high-risk diabetic patient who should be targeted for early, aggressive intervention against proven risk factors. If persistent microalbuminuria is confirmed, strict blood pressure control with added RAS inhibition should be pursued in an attempt to stabilise or even reduce microalbuminuria, preserve kidney function and possibly improve cardiovascular risk.
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PMID:The link between microalbuminuria, endothelial dysfunction and cardiovascular disease in diabetes. 1238 63

Experimental studies have demonstrated that proteins filtered by the glomerulus induce a proliferation of proximal tubular cells accompanied by an increased synthesis of many vasoactive and proinflammatory substances. The appearance of interstitial cellular infiltrates, a well-known finding in proteinuric diseases, precedes progressive tubulointerstitial fibrosis. Activation of the transcription factor kappaB (NF-kappaB) plays a pivotal role in the renal damage induced by proteinuria. In this scenario, any therapeutic intervention that reduces proteinuria should be beneficial for the kidney. Drugs that block the renin-angiotensin system [angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (ARA)] have repeatedly shown striking antiproteinuric and renoprotective properties, both in experimental and clinical studies. Studies in patients with type 1 and type 2 diabetic nephropathy as well as in non-diabetic nephropathies have confirmed that the renoprotection obtained with ACEI/ARA is closely related with their antiproteinuric effect and is largely independent of blood pressure changes. However, resistance to the antiproteinuric effect of ACEI/ARA is a common clinical observation. Several therapeutic measures (that is, adequate blood pressure control, early introduction of ACEI/ARA, dietary protein restriction, low salt diets, weight loss in overweight patients, addition of a diuretic, increasing ACEI/ARA dose titrated against proteinuria levels, combined therapy ACEI plus ARA, addition of drugs with antiproteinuric effect such as non-dihydropiridine calcium channel blockers or NSAIDs) may increase the proteinuria reduction induced by ACEI and ARA.
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PMID:Renal damage associated with proteinuria. 1241 Aug 54

Diabetes mellitus contributes greatly to morbidity, mortality, and overall health care costs. In major part, these outcomes derive from the high incidence of progressive kidney dysfunction in patients with diabetes making diabetic nephropathy a leading cause of end-stage renal disease. A better understanding of the early dysfunctions observed in the diabetic kidney may permit the development of new strategies to prevent diabetic nephropathy. This review proposes a "tubulo-centric" view of glomerular function in early type I diabetes mellitus. The following are particularly discussed (1) the primary role of an increase in reabsorption by the proximal tubule in early glomerular hyperfiltration, (2) the role of sodium-glucose cotransport and tubular growth under these conditions, and (3) the primary role of reabsorption by the proximal tubule for the paradoxical relationship between dietary salt and glomerular filtration rate. Finally, an outline is presented of potential therapeutic implications for the prevention of diabetic kidney disease.
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PMID:Glomerular hyperfiltration and the salt paradox in early [corrected] type 1 diabetes mellitus: a tubulo-centric view. 1253 55

It appears to be confirmed by international studies that the development of end-stage nephropathy, cardiovascular mortality and morbidity can be reduced to a large extent by achieving a target blood pressure of 130/85 mmHg in diabetes hypertension and 125/75 mmHg in diabetic nephropathy. Diuretics, beta-blockers, ACE inhibitors and calcium antagonists are all recommended agents with evidence "A" according to both international and national recommendations. The most efficient nephroprotection and simultaneous intensive and efficient blood pressure reduction can be achieved by ACE inhibitors and AT1 receptor blockers as basic agents. It is often required to use combination treatment to achieve the target blood pressure. In the predialysis stage, tight blood pressure control should be completed with balanced glucose metabolism, restricted protein intake, controlled salt and water metabolism, early treatment of metabolic acidosis and preparation for kidney substitution treatment. The patient and the treating physicians should work together in a coordinated way during the complex nephrology, diabetes, cardiology care to slow down the progress of the disease.
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PMID:[Therapy of diabetic nephropathy]. 1262 14

The renin-angiotensin-aldosterone system (RAAS) exerts a principal influence in maintaining vascular tone, optimal salt and water homeostasis, and forward cardiac output in human beings. Overactivity of the RAAS can lead to pathologic consequences in states of diabetic nephropathy, hypertension, renal artery stenosis, left ventricular hypertrophy, coronary atherosclerosis, myocardial infarction, and congestive heart failure. In addition to fluid and hemodynamic effects, the RAAS may have a critical role in the activation of the sympathetic nervous system, the progression of atherosclerosis, the dysregulation of endothelial function, and the inhibition of the fibrinolytic system. Accumulated basic and clinical evidence supports the use of inhibitors of the RAAS, including aldosterone antagonists, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, in treating hypertension, improving diabetic nephropathy, preventing or ameliorating congestive heart failure, and optimizing the prognosis after myocardial infarction.
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PMID:Renin-angiotensin-aldosterone system: fundamental aspects and clinical implications in renal and cardiovascular disorders. 1267 84

Prevalence of diabetic nephropathy is increasing. Understanding of pathogenesis and clinical picture helps to manage this disease. Recent data of the research of this disease support that the renin-angiotensin system plays a pivotal role in the pathogenesis. Hyperglycaemia activates the renin-angiotensin system and induces transforming growth factor-beta expression. These both lead to glomerulosclerosis and tubulointerstitial fibrosis. Diabetic nephropathy develops earlier and progress faster in patients with DD or ID genotypes of angiotensin-I-converting-enzyme gene. Angiotensinogen and type 1 angiotensin-II-receptor gene mutations may be also predisposing factors for diabetic nephropathy. All these factors can be responsible for the hyperfiltration, albuminuria, salt sensitivity, and hypertension, which are characteristic features of diabetic nephropathy. According to these, one can suppose that inhibitors of the renin-angiotensin system are effective in the prevention and treatment of this disease. Evidence of clinical studies suggests that angiotensin-I-converting-enzyme inhibitors in type 1 diabetes can prevent overt nephropathy, decrease proteinuria, inhibit the loss of the glomerular filtration and decelerate progression. Angiotensin-II-receptor blockers exert the same effect in type 2 diabetic patients, and presumably angiotensin-I-converting-enzyme inhibitors have similar activity in this group of patients. That is why, in the case of intolerance of one class of drugs, the other should be substituted. Combination therapy of angiotensin-I-converting-enzyme inhibitors with angiotensin-II-receptor blockers can be the choice of treatment in the future.
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PMID:[Role of the renin-angiotensin system in the pathogenesis, clinical picture and treatment of diabetic nephropathy]. 1272 86

The renin-angiotensin-aldosterone system (RAAS) plays an integral role in maintaining vascular tone, optimal salt and water homeostasis, and cardiac function in humans. However, it has been recognized in recent years that pathologic consequences may also result from overactivity of the RAAS. Clinical disease states such as renal artery stenosis, hypertension, diabetic and nondiabetic nephropathies, left ventricular hypertrophy, coronary atherosclerosis, myocardial infarction, and congestive heart failure (CHF) are examples. Part of the adverse cardiorenal effects of the RAAS may be related to the prominent role that this system plays in the activation of the sympathetic nervous system, the dysregulation of endothelial function and progression of atherosclerosis, as well as inhibition of the fibrinolytic system. Also, direct profibrotic actions of angiotensin II and aldosterone in the kidney and heart promote end organ injury. Current basic science and clinical research supports the use of inhibitors of the RAAS, including angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists in treating hypertension, improving diabetic nephropathy and other forms of chronic kidney disease, preventing or ameliorating CHF, and optimizing prognosis after myocardial infarction.
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PMID:The renin-angiotensin-aldosterone system: cardiorenal effects and implications for renal and cardiovascular disease states. 1286 Nov 21

There is a unique relationship between the kidney and blood pressure. The importance of the kidney on the pathogenesis of hypertension was clearly demonstrated in renal transplantation studies both in genetic hypertensive rats and humans with hypertension. Also, hypertension accelerates loss of function of the diseased kidney and the antihypertensive treatment attenuates the progression of various renal diseases. A lot of mechanisms to explain this relationship are considered: salt retention, abnormalities of renal hemodynamics, inappropriate activation of the renin-angiotensin system etc. This review is an attempt to highlight a renal role on the development of hypertension, especially in diabetic nephropathy.
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PMID:[Kidney and hypertension]. 1287 73

The International Diabetes Federation (Europe) has updated these guidelines on hypertension management specifically in Type 2 diabetes in the light of recent results of the first prospective, randomized controlled studies to investigate clinical outcomes in people with diabetes and hypertension. The guidelines are knowledge based, i.e. based not only on evidence originating from clinical trials, but also from epidemiological and pathophysiological studies. A successful management strategy requires the following components: 1. Regular surveillance to detect developing hypertension and other cardiovascular (CV) risk factors. 2. Considering more frequent monitoring and review of CV risk factors if any single blood pressure (BP) measurement > 140/85 mmHg (or 130/75 if microalbuminuria); when appropriate, using ambulatory or home monitoring to establish the baseline BP. 3. Considering other CV risk factors, such as a raised albumin excretion rate, in setting the intervention threshold. 4. Individualizing the target BP in accordance with other CV risk factors. 5. Agreeing lifestyle and therapeutic interventions with the patient, with education and empowerment as required. 6. Implementing lifestyle modifications, including controlling calorie, salt and alcohol intake, increased physical activity, weight control and smoking cessation. 7. Therapeutic strategy: the primary goal of therapy is to reduce BP markedly. Combination therapy is often necessary, e.g. an angiotensin converting enzyme (ACE) inhibitor and a diuretic. Some classes are particularly useful for certain patients, notably longer-acting ACE inhibitors, angiotensin 2 receptor antagonists (A2RAs) and calcium antagonists in those at risk of diabetic nephropathy, loop diuretics and thiazides in those at risk of hyperkalaemia, beta-blockers and calcium antagonists (except short-acting dihydropyridines) in patients with angina, beta-blockers and ACE inhibitors after a myocardial infarction or in those with left ventricular dysfunction, and thiazide diuretics and long-acting dihydropyridine calcium antagonists for isolated systolic hypertension. A2RAs should be particularly considered when ACE inhibitors are not tolerated. alpha 1-Blockers should not be considered first line in the absence of outcome data. Cost of drugs will modify these strategies in developing countries. 8. Monitoring response to therapies and, if target levels are not achieved, either intensifying drug therapy if the CV risk justifies it, or reassessing the target. 9. Maintaining a quality assurance strategy. This strategy is summarized in a simple, practical management algorithm.
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PMID:Hypertension in people with Type 2 diabetes: knowledge-based diabetes-specific guidelines. 1463 98


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