UMLS:C0033687 - FACTA Search

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Diabetic nephropathy is the leading cause of end-stage kidney disease in the United States. The majority of these cases are attributed to those with type 2 diabetes. Elevated blood pressure, proteinuria, and increased activity of the renin-angiotensin-aldosterone system (RAAS) play a major role in the development and progression of chronic kidney disease attributed to diabetes mellitus. Moreover, drugs that inhibit angiotensin II synthesis or block the angiotensin II type I receptor lower blood pressure, reduce proteinuria, and improve outcomes in patients with chronic kidney disease caused by diabetes. This article highlights improvements in the current management of diabetic nephropathy afforded by agents that inhibit the RAAS, discusses their limitations, and considers novel strategies to prevent onset and progression of diabetic nephropathy. Current opinions concerning combination drug therapy with agents that block the RAAS at multiple sites, as well as combining calcium channel blockers with either angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, are also discussed.
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PMID:Appropriate drug therapy for improving outcomes in diabetic nephropathy. 1264 62

Diabetic nephropathy is the leading cause of end-stage renal disease in western or westernised countries and the largest contributor to the total cost of diabetes care around the world. In addition to the development of diabetic nephropathy and end-stage renal failure, diabetic patients with evidence of albuminuria have a much higher risk of developing myocardial infarctions, cerebrovascular accidents, severe progressive retinopathy, and peripheral and autonomic neuropathy. A cumulative incidence of diabetic nephropathy has been documented after duration of diabetes of at least 25 years in both type 1 and type 2 diabetic patients, although more recent studies have demonstrated a substantial reduction of its incidence. Before the onset of overt proteinuria, there are several renal functional changes, including renal hyperfiltration, hyperperfusion, and increasing capillary permeability to macromolecules. Basement-membrane thickening and mesangial expansion have long been recognized as pathological hallmark of diabetic nephropathy. It has been postulated that diabetic nephropathy occurs as a result of the interplay of metabolic and haemodynamic factors in the renal microcirculation. Hyperglycaemia plays a pivotal role in the pathogenesis of diabetic renal disease, but genetic factors are also of crucial importance. The accumulation of advanced glycosilation end products (AGEPs), the activation of isoforms of protein kinase C (PKC) and the acceleration of the aldose reductase pathway may explain how hyperglycaemia damages vessels. Growth factors (i.e. TGF-b, IGF-1, VEGF) may also play an important role in the pathogenesis. There is a familial clustering of diabetic kidney disease: a number of gene loci have been investigated to try to explain the genetic susceptibility to this complication. The two main treatment strategies for prevention of diabetic nephropathy are improved glycaemic control and blood pressure lowering, particularly using drugs such angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists. Many potential treatment modalities in preventing and treating diabetic nephropathy are presently being evaluated; some of them will possibly be available in the near future in order to try to modify the natural course of kidney involvement and disease in patients with diabetes.
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PMID:Kidney involvement and disease in patients with diabetes. 1268 18

A 24-year-old Japanese woman with IgA nephropathy was admitted to our hospital due to the development of proteinuria and pretibial edema while on glucocorticoids and an angiotensin-converting-enzyme(ACE) inhibitor. She had been on both medications for more than 2 years. Urinary protein excretion was 2.53 g/day and renal function laboratory data were within the normal range. Plasma aldosterone concentration was high at 248 pg/ml, with normal plasma renin activity. The renal biopsy specimens showed prominent glomerular hypertrophy. Four weeks after the addition of valsartan, an angiotensin II receptor blocker(ARB), urinary protein excretion was remarkably reduced to 0.6 g/day without adversely affecting blood pressure. During the treatment period, proteinuria was maintained at less than 0.6 g/day and renal function remained normal. We propose that glomerular hypertension caused by insufficient suppression of the renin-angiotensin system was an essential factor underlying the increased urinary protein excretion in this patient. Combination therapy of an ARB and an ACE inhibitor appears to have a beneficial effect in patients with IgA nephropathy patients with persistent glomerular hypertension.
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PMID:[Successful treatment of combination therapy using an angiotensin-converting enzyme inhibitor and an angiotensin II receptor blocker in a patient with IgA nephropathy]. 1270 6

Blood pressure reduction and intensive antihypertensive treatment are effective in reducing both microvascular and macrovascular complications in type 2 diabetes. Blood pressure target levels < 130/85 or 130/80 mmHg are now recommended. Antagonism of the renin-angiotensin-aldosterone system seems to be an important goal in the treatment of hypertension and diabetes-related complications. The renoprotective role of angiotensin-converting enzyme (ACE)-inhibitors has been well documented in type 1 diabetes; in type 2 diabetes ACE-inhibitors have been deemed more effective than other traditional drugs in reducing the onset of overt nephropathy in microalbuminuric patients (secondary prevention) but not in reducing renal dysfunction in patients with clinical proteinuria (tertiary prevention). Recently, four large trials performed on type 2 diabetes showed that angiotensin II receptor blockers (ARBs) prevent the development of clinical proteinuria in microalbuminuric patients (IRMA and MARVAL studies) and delay the progression of nephropathy towards end-stage renal failure in patients with overt nephropathy (IDNT and RENAAL studies). Moreover, ARBs have been deemed more effective in reducing hospitalizations for heart failure compared to placebo (IDNT and RENAAL studies) and in reducing cardiovascular morbidity and mortality compared to conventional therapy (LIFE study) in type 2 diabetes. In conclusion, ARBs are effective in preventing and delaying renal damage in type 2 diabetes. Thus, the recent guidelines for the prevention and treatment of diabetic nephropathy state that ACE-inhibitors are the first-choice drugs in type 1 diabetes while ARBs are considered as the first-choice drugs in secondary prevention, the same as ACE-inhibitors, and are the unique first-choice drug in tertiary prevention of end-stage renal failure in type 2 diabetes. Finally, ACE-inhibitors and ARBs are both first-choice drugs in cardiovascular prevention in type 2 diabetes.
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PMID:[The role of angiotensin II AT1-receptor antagonists in renal and cardiac protection in type-2 diabetes mellitus]. 1278 55

The increased activity of the renin-angiotensin-aldosterone system (RAAS) is an important pathogenetic factor in the development of nephropathy in diabetic patients. The damaging factor of this system is the end-product, angiotensin II, and the damaging effects are vasoconstriction, increase of aldosterone secretion, growth, fibrosis, thrombosis, inflammation and oxidation. Theoretically, on this basis, blockade of the RAAS should have a beneficial effect on the development of diabetic nephropathy. The main goal in the treatment of diabetic nephropathy is control of the glycaemic status and aggressive antihypertensive therapy, primarily with RAAS-blocking agents. It was demonstrated recently that angiotensin II receptor blockers (ARBs) have a slowing effect on the progression of diabetic nephropathy (RENAAL and IDNT trials) or on the development of proteinuria (IRMA) in type 2 diabetes. These effects are specific and independent of the decrease in blood pressure. Theoretically, the combination of an angiotensin-converting enzyme inhibitor (ACEI) and an ARB can lead to a more complete blockade of the RAAS. A new study (ONTARGET) has now started to investigate whether treatment with a combination of an ACEI and an ARB has a more potent beneficial effect on the cardiovascular events and the nephropathy in type 2 diabetic patients as compared with separate treatment with the two agents.
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PMID:Treatment of diabetic nephropathy with angiotensin II blockers. 1281 61

Arterial hypertension (AH) per se is, together with diabetes mellitus, the most important cause of renal failure and of dialysis in the western world. AH is also a well known consequence of chronic renal disease, and at the same time one of the main factors which causes diabetic and/or non-diabetic chronic renal failure progression. AH is mostly registered in patients with focal segmental glomerulosclerosis and with membranoproliferative glomerulonephritis. The pathophysiology and the mechanism of AH within primary glomerular diseases are complex, including activation of the sympathetic nervous system, the renin-angiotensin system (RAS), sodium retention, volume expansion and decreased synthesis of vasodilatatory substances. As autoregulation of glomerular pressure in chronic glomerular disease is disturbed, the increment in systemic blood pressure leads to the rise in glomerular pressure. Glomerular hypertension results in glomerular capillary wall stretch, endothelial damage and a rise in protein glomerular filtration. These processes, in turn, cause changes of mesangial and proximal tubular cells, ultimately resulting in the replacement of functional by non-functional connective tissue and the development of fibrosis. One of the most important factors in the progression of chronic renal failure is activation of the RAS. Its effect is not only elevated blood pressure, but also the promotion of cell proliferation, inflammation and matrix accumulation. Many studies, first in experimental animals and later in humans, have shown that the lowering of blood pressure (and proteinuria) is associated with a slower progression of kidney disease. It seems that angiotensin-converting enzyme inhibitors (ACEIs) are more renoprotective than other antihypertensives (the protection beyond the antihypertensive effect), although some studies have also confirmed a comparatively beneficial effect of non-dihydropiridine calcium channel blockers (CCBs) and angiotensin II receptor blockers (ARBs). Moreover, it seems that a combination of antihypertensives (e.g. ACEI + CCB, ACEI + ARB) has a more effective action than either of the drugs alone. However, the effects depend first on the degree of blood pressure reduction. According to comprehensive studies, the achievement of adequate blood pressure (not higher than 130/85 mmHg) is the most important factor. An even lower blood pressure (125/75 mmHg) has been suggested as the limit value in patients with proteinuria of >1 g/24 h and in Blacks.
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PMID:The role of arterial hypertension in the progression of non-diabetic glomerular diseases. 1281 64

The clinical course of a young female patient with focal segmental glomerulosclerosis (FSGS) who failed to respond to any of the recommended therapeutic protocols will represent the background of a discussion of currently available alternative treatments for FSGS. Traditionally, FSGS has been believed to have a poor prognosis, with a low response rate to treatment and a progressive course terminating with end-stage renal disease (ESRD). Some 40% of patients respond to prolonged corticosteroid treatment. Steroid resistance in adults should perhaps be assumed only after failure to respond to a 6-month course of daily steroid therapy. Regarding recent recommendations, the use of cytotoxic therapy (cyclophosphamide, chlorambucil or azathioprine) may be considered as second-line therapy (evidence D). Treatment with cyclosporin A at doses of 4-6 mg/kg/day has been successful in reducing proteinuria. There is little information available on the effects of such treatment on the progression of FSGS. Even fewer data are available on the success rate of the use of tacrolimus in resistant forms of FSGS in adults. Mycophenolate mofetil has been used with impressive success in a few high-risk patients who failed on previous therapeutic regimens. There is preliminary evidence in an uncontrolled series of patients with resistant primary FSGS that the addition of plasmapheresis may provide effective long-term benefits in some patients. The accurate assessment of the role of plasmapheresis and possibly immunoadsorption in the management of patients with FSGS requires further evaluation. Non-immunosuppressive therapy (i.e. angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, lipid-lowering drugs, non-steroidal anti-inflammatory drugs) should be applied to almost all patients with primary FSGS.
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PMID:Therapy-resistant focal and segmental glomerulosclerosis. 1281 66

In previous studies, the synergistic antiproteinuric effect of the combination therapy of ACE inhibitors and angiotensin II receptor antagonists (ATRAs) has been inconsistent in relation to underlying renal diseases. The influence from the blood pressure (BP) - reducing effect in some studies might also contribute to this inconclusiveness. To examine the possibility of the benefit being different according to underlying renal diseases, we undertook a crossover therapeutic trial of the combination therapy in two selected homogenous groups of patients with diabetic and non-diabetic renal diseases. The BP-reducing effect was excluded during the study. Nineteen biopsy-proven IgA nephropathy, as examples of non-diabetic renal diseases, and 24 type 2 diabetic nephropathy patients were selected as the study subjects. The subjects had to meet the follow criteria: a creatinine clearance (Ccr) between 25 - 90 ml/min/1.73 m2, 24-hr urinary protein excretion rate over 1.0 g/day and a BP maintained at less than 130/80 mmHg, with more than six-month therapy of ramipril, (5.7 +/- 0.4 mg/day, 13 +/- 2 month). The baseline data between the two groups showed no significantly differences. After a 12-week stabilization period (control period), 4 mg, once daily, dose of candesartan (combination period) followed by a placebo (placebo period), or vice versa, were administered in addition to the ramipril, for 12 weeks. The combination, with candesartan, did not change the Ccr, BP, serum and urinary electrolytes or the urea. The 24 hour urinary protein excretion rate was significantly reduced by the combination therapy in the patients with IgA nephropathy (3.1 +/- 0.3 g/day in combination, 4.2 +/- 0.3 in control, and 4.3 +/- 0.2 in placebo; p < 0.05). However, the patients with diabetic nephropathy showed no reduction in their proteinuria with the combination therapy (3.8 +/- 0.2 g/day in combination, 3.9 +/- 0.3 in control, and 4.1 +/- 0.3 in placebo; p=NS). The changes in proteinuria showed no relationship with the changes in the BP in IgA nephropathy. In conclusions, the benefit of combination therapy of its antiproteinuric effect was different between IgA and diabetic nephropathy over the 12-week trial. The difference in the pathophysiological role, and the importance of the renin- angiotensin system, between the two diseases might contribute to the discrepancy in the result. We suggest the discrimination of the underlying renal diseases in the study subjects is an important prerequisite for future studies on this issue.
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PMID:Additive antiproteinuric effect of combination therapy with ACE inhibitor and angiotensin II receptor antagonist: differential short-term response between IgA nephropathy and diabetic nephropathy. 1283 84

Outcome studies in diabetic nephropathy have focused on strategies to prevent progression of diabetic nephropathy, the leading cause of ESRD in the United States. Once diabetics develop overt nephropathy, prognosis is poor. Risk factors for diabetic nephropathy are discussed, and include hyperglycemia, hypertension, angiotensin II, proteinuria, dyslipidemia, smoking, and anemia. Major outcomes as well as outcome studies in diabetic nephropathy for patients with microalbuminuria and macroalbuminuria are reviewed. Furthermore, the role of therapy with angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and mineralocorticoid receptor antagonists as well as selected combination therapy are discussed. Recommendations for therapy with ace inhibitors and angiotensin II receptor blockers are made based on this evidence.
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PMID:Outcome studies in diabetic nephropathy. 1283 94

An interaction effect between the angiotensin-converting enzyme insertion/deletion (ACE I/D) and alpha-adducin (ADD1) Gly460Trp polymorphisms (G460W) on blood pressure regulation has recently been suggested, although its significance in the prognosis of renal function in IgA nephropathy (IgAN) has not been fully investigated. Therefore, we evaluated the clinical manifestations and renal prognosis in 276 Japanese patients with histologically proven IgAN with respect to their ACE I/D and ADD1 G460W polymorphisms. The prognosis of renal function was analyzed by Kaplan-Meier survival curves and multivariate Cox proportional-hazards regression models. Baseline data, including blood pressures, proteinuria, renal function, and incidence of hypertension, were similar for the different genotypes of ACE and ADD1. The individual genotypes taken alone were not associated with the progression of renal dysfunction. However, renal survival of patients with the 460WW polymorphism of ADD1 was significantly worse within the group with the II genotype of ACE (Kaplan-Meier, log rank test; chi2=6.062, P=0.0138) but not for those with other ACE genotypes. In the Cox proportional-hazards regression model with adjustment for clinical risk factors, including hypertension, proteinuria, and no administration of an angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, the 460WW variant of ADD1 was a highly significant and independent risk factor only for patients with the ACE II genotype, with a hazard ratio of 3.65 (P=0.0016), but not for those with other ACE genotypes (hazard ratio=0.65, P=0.2902). These findings suggest an interaction between ACE and ADD1 polymorphisms not only on blood pressure regulation but also on the progression of renal dysfunction in patients with IgAN.
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PMID:Interaction between ACE and ADD1 gene polymorphisms in the progression of IgA nephropathy in Japanese patients. 1288 93

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