UMLS:C0033687 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
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Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can decrease hemoglobin, causing anemia and this may be an independent risk factor for chronic kidney disease progression. We studied the relationship between a decline in hemoglobin and outcome in 1513 patients with type 2 diabetes and kidney disease by a post hoc analysis of the RENAAL Study (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) with an average follow-up of 3.4 years. The relationship between baseline and year-1 hemoglobin and treatment on end-stage renal disease (ESRD) and ESRD or death was evaluated using multivariate Cox models (covariates: baseline hemoglobin, proteinuria, serum albumin, serum creatinine, and year-1 hemoglobin). Compared with placebo, losartan treatment was associated with a significant decrease of hemoglobin, with the largest between-group difference at 1 year. After adjustment, there were significant relative risk reductions for losartan compared with placebo for ESRD and for ESRD or death regardless of the baseline hemoglobin even in those patients with a baseline hemoglobin below 120 g l(-1). Hence, the renoprotective properties of losartan were maintained despite a significant lowering of the hemoglobin concentration.
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PMID:The effect of losartan on hemoglobin concentration and renal outcome in diabetic nephropathy of type 2 diabetes. 1809 75

Losartan treatment reduced renal outcomes in proteinuric patients with type 2 diabetes in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. It is unknown whether an insertion (I)/deletion (D) polymorphism in the angiotensin I-converting enzyme (ACE) gene predicts renal outcomes and death and influences the effect of losartan in these patients. Pharmacogenetic analyses were performed comparing losartan with placebo administered with conventional blood pressure-lowering therapy in 1435 (95%) of the 1513 RENAAL study patients. The primary endpoint was the composite of doubling of baseline serum creatinine concentration, end-stage renal disease (ESRD) or death. Cox regression models were stratified on baseline proteinuria and included treatment, geographic region, ACE/ID genotype, and treatment x genotype interaction. Within the placebo group, subjects with the ID or DD genotype were more likely than those with the II genotype to reach the composite endpoint (by 17.5% and 38.1%, respectively, P = 0.029) or its individual components. Within the losartan group, genotype did not correlate with reaching the composite endpoint. Compared with placebo, however, losartan reduced the risk of reaching the composite endpoint by 5.8% (95% confidence interval, -23.3, 28.0), 17.6% (3.8, 29.4), and 27.9% (7.0, 44.1) among those with the II, ID, and DD genotypes, respectively. Similar trends were demonstrated for the individual endpoints. In conclusion, proteinuric type 2 diabetic patients with the D allele of the ACE gene have an unfavorable renal prognosis, which can be mitigated and even improved by losartan.
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PMID:ACE gene polymorphism and losartan treatment in type 2 diabetic patients with nephropathy. 1819 98

Microalbuminuria is the earliest detectable clinical abnormality in diabetic glomerulopathy. On a molecular level, metabolic pathways activated by hyperglycemia, glycated proteins, hemodynamic factors, and oxidative stress are key players in the genesis of diabetic kidney disease. A variety of growth factors and cytokines are then induced through complex signal transduction pathways. Transforming growth factor-beta 1 (TGF-beta1) has emerged as an important downstream mediator for the development of renal hypertrophy and the accumulation of mesangial extracellular matrix components, but there is limited evidence to support its role in the development of albuminuria. The loss of proteoglycans in the glomerular basement membrane (GBM) has been recently questioned as causative of the albuminuria, and current research has focused on the podocyte as a central target for the effects of the metabolic milieu in the development and progression of diabetic albuminuria. Podocyte-derived vascular endothelial growth factor (VEGF), a permeability and angiogenic factor whose expression is increased in diabetic kidney disease, is perhaps a major mediator of the increased protein filtration. Decreased podocyte number and/or density as a result of apoptosis or detachment, GBM thickening with altered matrix composition, and a reduction in nephrin protein in the slit diaphragm with podocyte foot process effacement, all comprise the principal features of diabetic podocytopathy that clinically manifests as albuminuria and proteinuria. Many of these events are mediated by angiotensin II whose local concentration is stimulated by high glucose, mechanical stretch, and proteinuria itself. Angiotensin II in turn stimulates podocyte-derived VEGF, suppresses nephrin expression, and induces TGF-beta1 leading to podocyte apoptosis and fostering the development of glomerulosclerosis. Proteinuria can then induce in tubular cells a genetic program leading to tubulointerstitial inflammation, fibrosis and tubular atrophy. Besides direct effects of albuminuria on tubular cells, pathophysiological changes in the ultrafiltration barrier lead to an increased tubular filtration of various growth factors (TGF-beta1, insulin-like growth factor I) that may further alter the function of tubular cells. Moreover, angiotensin II also stimulates uptake of ultrafiltered proteins into tubular cells and enhances the production of proinflammatory and profibrotic cytokines within the cells. Migration of macrophages and other inflammatory cells into the tubulointerstitium occurs. Increased synthesis and decreased turnover of extracellular matrix proteins in tubular cells and interstitial fibroblasts contribute to interstitial fibrosis. In addition, under locally high concentrations of angiotensin II and TGF-beta1, tubular cells may change their phenotype and become fibroblasts by a process called epithelial to mesenchymal transition (EMT) which contributes to interstitial fibrosis and tubular atrophy because of vanishing epithelia cells. An alternative explanation for the development of albuminuria in diabetic nephropathy that involves primarily an abnormality in tubular handling of ultrafiltered proteins has also been suggested, but these changes are not necessarily exclusive of the altered properties of glomerular ultrafiltration barrier.
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PMID:Pathogenesis of the podocytopathy and proteinuria in diabetic glomerulopathy. 1822 Jun 94

The Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH) study is a nationwide, prospective, multicentered, observational study that was designed to enroll 30,000 hypertensive Japanese patients from more than 3,000 private practitioners. It is the first large-scale observational study to assess the efficacy and safety of losartan, an angiotensin II receptor antagonist, in Japan. Patients were enrolled between June 2000 and May 2002, and followed up to June 2005. The data from 29,850 patients were used for the analysis of safety and efficacy. These patients were treated with losartan mostly at a daily dose of 25-50 mg. The mean follow-up period was 2.9 years. The patients were aged 62.4+/-12.1 years (mean+/-SD) and their mean systolic/diastolic blood pressure was 165.3+/-17.2/94.3+/-11.7 mmHg (mean+/-SD). Mean blood pressure in patients who were evaluated for efficacy decreased from 165.8/94.8 mmHg (n=26,512) at baseline to 145.5/84.4 mmHg after 3 months (n=21,269) and 138.6/80.0 mmHg after 36 months of treatment (n=13,879). Blood pressure was well controlled during the study period by losartan alone or losartan-based combination therapy. In nearly half of the patients, blood pressure was reduced to less than 140/90 mmHg during the study period. In addition to its antihypertensive effect, losartan reduced the uric acid level in patients whose baseline uric acid level was > or =7 mg/dL. Losartan also prevented acceleration of proteinuria. Adverse drug reactions occurred in 1,081 of the 29,850 patients. Long-term losartan therapy was effective and well tolerated in Japanese clinical practice.
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PMID:Efficacy and safety of long-term losartan therapy demonstrated by a prospective observational study in Japanese patients with hypertension: The Japan Hypertension Evaluation with Angiotensin II Antagonist Losartan Therapy (J-HEALTH) study. 1836 50

Angiotensin II type 1 (AT(1)) receptor antagonists (blockers) [ARBs] are highly selective for the AT(1) receptor and block the diverse effects of angiotensin II. When high BP is not controlled by low-dose ARB monotherapy, physicians need to employ another strategy, either high-dose ARB monotherapy or combination therapy with calcium channel antagonists (blockers) [CCBs], diuretics, or other agents. High-dose ARB monotherapy is more effective for decreasing proteinuria than low-dose ARB monotherapy or CCBs. Although the ARB valsartan has been shown to prevent coronary restenosis in a clinical study (Val-PREST [Valsartan for prevention of restenosis after stenting of type B2/C lesions]), it is still unclear whether ARBs help to prevent restenosis. The results reported by Peters in this issue highlight the relative efficacies of low- (80 mg/day) and high-dose valsartan (160-320 mg/day) for the prevention of in-stent restenosis after the implantation of bare-metal stents, and suggest that high-dose valsartan can reduce the in-stent restenosis rate, target lesion revascularization and target vessel revascularization rates, late lumen loss, and major adverse cardiac events rate more effectively than low-dose valsartan. A better understanding of the differences in the efficacies of high- and low-dose ARBs could be useful in the treatment of patients with cardiovascular disease and may resolve the issue of whether ARBs prevent coronary restenosis. Clinical benefits may be induced by complete blockade of the renin-angiotensin system using high-dose ARB monotherapy. Therefore, physicians need to select a strategy carefully; i.e. either high-dose ARB monotherapy or combination therapy.
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PMID:Which strategy is more effective for the treatment of cardiovascular disease: high-dose angiotensin II type 1 receptor antagonist monotherapy or combination therapy? 1842 91

The metabolic syndrome is a risk factor for the development of chronic kidney disease. Angiotensin II type 1 receptor blockers (ARBs) and thiazolidinediones (TZDs) provide renovascular protection, probably in the metabolic syndrome. However, the effect of both agents administered together in patients with metabolic syndrome remains to be determined. The aim of this study was to assess the effects of ARB plus TZD combination therapy in Zucker obese rats fed a high-protein diet, an animal model of metabolic syndrome and renal injury. Zucker obese rats were fed a high-protein diet (OHP; n=6), a high-protein diet containing candesartan, an ARB (OHP+C; n=6), or a high-protein diet containing both candesartan and pioglitazone (OHP+CP; n=6) for 12 weeks. Systolic blood pressure and urinary protein excretion were measured throughout the study, and renal histology and immunohistochemistry were assessed at 12 weeks. OHP rats developed hypertension (157+/-4 mmHg) and proteinuria (178+/-44 mg/d), and these conditions were significantly ameliorated by candesartan (to 143+/-3 mmHg and 84+/-25 mg/d, respectively). Pioglitazone enhanced the antihypertensive and anti-proteinuric effects of candesartan (121+/-3 mmHg, 16+/-8 mg/d, respectively). Histologically, candesartan ameliorated glomerulosclerosis, podocyte injury, interstitial fibrosis and monocyte/macrophage infiltration into the tubulointerstitium in the kidneys of OHP rats. Pioglitazone abrogated residual interstitial fibrosis in the kidneys of OHP+C rats. Our results suggested that pioglitazone augmented the antihypertensive, anti-proteinuric and possibly renal anti-fibrotic actions of candesartan in Zucker obese rats fed a high-protein diet. The combination therapy of ARB and TZD may protect against renal injury in patients with metabolic syndrome.
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PMID:Pioglitazone enhances the antihypertensive and renoprotective effects of candesartan in Zucker obese rats fed a high-protein diet. 1863 87

An insertion (I)/deletion (D) polymorphism of the angiotensin-converting-enzyme (ACE) gene influences the circulating and renal activity of the renin-angiotensin-aldosterone system. This Practice Point commentary discusses a 2008 paper by Parving et al. that analyzed the interaction between losartan and the I/D polymorphism in patients in the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study. The investigators found that patients with type 2 diabetes and proteinuria who have the D allele have an unfavorable renal prognosis, which is improved by losartan treatment (vs placebo) when given together with conventional antihypertensive treatment. No significant improvement in outcomes was observed in losartan-treated patients with the II genotype. Previous observational studies had suggested a decreased beneficial effect of ACE inhibitors in patients with type 1 diabetic nephropathy who have the DD genotype. Prospective studies in this area are needed before I/D genotype characterization can be used to guide the choice of therapy in patients with diabetes and proteinuria.
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PMID:ACE gene polymorphism and the prognosis and treatment of overt diabetic nephropathy. 880 48

Angiotensin II blockade delays progression of chronic kidney disease by modifying intrarenal hemodynamics, but the effects on metabolic adaptations are unknown. Using the remnant kidney model of chronic kidney disease in rats, we measured the effects of combined angiotensin II blockade with captopril and losartan on renal oxygen consumption (QO(2)) and factors influencing QO(2). Remnant kidneys had proteinuria and reductions in the glomerular filtration rate (GFR), renal blood flow (RBF) and nitric oxide synthase-1 protein expression while QO(2), factored by sodium reabsorption (QO(2)/TNa), was markedly increased. Combined blockade treatment normalized these parameters while increasing sodium reabsorption but, since QO(2) was unchanged, QO(2)/TNa also normalized. Triple antihypertensive therapy, to control blood pressure, and treatment with lysine, to increase GFR and RBF, did not normalize QO(2)/TNa, suggesting a specific effect of angiotensin II in elevating QO(2)/TNa. Inhibition of nitric oxide synthase increased QO(2) in the kidney of sham-operated rats but not in the remnant kidney of untreated rats. Our study shows that combined captopril and losartan treatment normalized QO(2)/TNa and functional nitric oxide activity in the remnant kidney independent of blood pressure and GFR effects, suggesting that other mechanisms in addition to hemodynamics underlie the benefits of angiotensin II blockade.
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PMID:Regulation of oxygen utilization by angiotensin II in chronic kidney disease. 1881 81

We determined the relationship between the progression of immunoglobulin A nephropathy (IgAN) and the A1818T polymorphism in intron 2 of Angiotensin II type 2 receptor (AT2R) gene, which might play protective roles in the pathogenesis of IgAN. Patients with biopsy-proven IgAN were recruited from the registry of the Progressive REnal disease and Medical Informatics and gEnomics Research (PREMIER) which was sponsored by the Korean Society of Nephrology. A1818T polymorphism of AT2R gene was analyzed with PCR-RFLP method and the association with the progression of IgAN, which was defined as over 50% increase in baseline serum creatinine level, was analyzed with survival analysis. Among the 480 patients followed for more than 10 months, the group without T allele had significantly higher rates of progression of IgAN than the group with T allele (11.4% vs. 3.9%, p=0.024), although there were no significant differences in the baseline variables such as initial serum creatinine level, the degree of proteinuria, and blood pressure. In the Cox's proportional hazard model, the hazard ratio of disease progression in the patients with T allele was 0.221 (95% confidence interval for Exp(B): 0.052-0.940, p=0.041) compared to that of without T allele. In conclusion, A1818T polymorphism of AT2R gene was associated with the progression of IgAN.
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PMID:Association of angiotensin II type 2 receptor gene A1818T polymorphism with progression of immunoglobulin A nephropathy in Korean patients. 1919 60

The incidence of chronic kidney disease, such as diabetic nephropathy, is increasing throughout the world. Many biologically active peptides play important roles in the kidney. The classical example is the renin-angiotensin system (RAS). Angiotensin II plays critical roles in the progression of chronic kidney disease through its vasoconstrictor action, stimulatory action on cell proliferation, and reactive oxygen-generating activity. A renin inhibitor, aliskiren, has recently been shown to be a clinically effective drug to reduce proteinuria in patients with diabetic nephropathy. (Pro)renin receptor, a specific receptor for renin and prorenin, was newly identified as a member of the RAS. When bound to prorenin, (pro)renin receptor activates the angiotensin I-generating activity of prorenin in the absence of cleavage of the prosegment, and directly stimulates the pathway of mitogen-activated protein kinase independently from the RAS. The kidney peptides that antagonize the intrarenal RAS may have renoprotective actions. Adrenomedullins, potent vasodilator peptides, have been shown to have renoprotective actions. On the other hand, urotensin II, a potent vasoconstrictor peptide, may promote the renal dysfunction in chronic kidney disease together with the renal RAS. Thus, in addition to the renin inhibitor and (pro)renin receptor, adrenomedullins and urotensin II may be novel targets to develop therapeutic strategies against chronic kidney disease.
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PMID:The renin-angiotensin system, adrenomedullins and urotensin II in the kidney: possible renoprotection via the kidney peptide systems. 1947 9

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