Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We studied the effects of a possible interaction between partial nitric oxide deficiency and thyroid hormone excess on the long-term control of blood pressure (BP) and morphological and renal variables and examined the role of the renin-angiotensin system in the increased BP of this interaction. Eight groups (n=8 each) of male Wistar rats were used: a control group; 3 groups that were treated with thyroxine (50 microg/d), Nw-nitro-L-arginine methyl ester (L-NAME; subpressor dose, 1.5 mg x kg(-1) d(-1)), or thyroxine plus L-NAME; and another 4 similarly treated groups that received losartan (20 mg x kg(-1) x d(-1)) in their drinking fluid. All treatments were maintained for 3 weeks. The time course of tail systolic BP was recorded once a week. At the end of the experimental period, we measured mean arterial pressure in conscious rats and assessed the morphological, metabolic, plasma, and renal variables. Thyroxine produced a mild BP increase from the second week of treatment and an increase in plasma angiotensin II and plasma nitrates/nitrites by the end of the study. Simultaneous administration of thyroxine and a subpressor dose of L-NAME produced a marked BP increase that reached significance from the first week of treatment. Losartan produced normotension in thyroxine-treated rats and attenuated the BP elevation in thyroxine+L-NAME-treated rats. Hyperthyroid rats showed relative renal and ventricular hypertrophy, absence of absolute left ventricular hypertrophy, and proteinuria. These alterations were not changed by losartan. We conclude that an impaired nitric oxide system might have a counterregulatory homeostatic role against the prohypertensive effects of thyroid hormone and that the renin-angiotensin system plays an important role in thyroxine+L-NAME hypertension.
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PMID:Increased pressor sensitivity to chronic nitric oxide deficiency in hyperthyroid rats. 1282 1

The present study evaluates the participation of oxidative stress, tissue angiotensin II (Ang II) and endothelin (ET) in the effects of losartan on blood pressure (BP), ventricular hypertrophy and renal injury in spontaneously hypertensive rats (SHRs), and explores how these effects are modified when spontaneous hypertension is transformed in a low-renin model by the administration of deoxycorticosterone acetate (DOCA). The following groups were used: SHR-control, SHR+DOCA, SHR+losartan and SHR+DOCA+losartan. Tail systolic BP was measured once a week. After 9 weeks of treatment, direct BP and metabolic, morphological, biochemical and renal variables were measured. DOCA administration to SHRs produced an increase in BP, ventricular hypertrophy, renal weight, proteinuria, renal histopathological lesions, urinary excretion of isoprostane F2alpha and ET levels in the renal cortex. Losartan reduced BP, plasma malondialdehyde levels, urinary excretion of isoprostane F2alpha, renal Ang II and renal and urinary levels of ET in the SHR and DOCA-treated SHR groups. Losartan increased plasma nitrite/nitrate in SHRs, but not in low-renin DOCA-treated SHRs. Losartan reduced ventricular hypertrophy and ventricular Ang II in SHRs, but not in DOCA-treated SHRs. Losartan significantly decreased proteinuria and renal injury in DOCA-treated SHRs. We conclude that (i) the DOCA-induced aggravation of hypertension, ventricular hypertrophy and renal injury in SHRs is accompanied by augmented oxidative stress and increased levels of ET in the renal cortex, which could contribute to their development; and (ii) losartan reduced oxidative stress and renal Ang II and ET in SHRs and DOCA-treated SHRs, which might contribute to its antihypertensive and renoprotective effects, regardless of renin status.
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PMID:Protective effects of the angiotensin II type 1 (AT1) receptor blockade in low-renin deoxycorticosterone acetate (DOCA)-treated spontaneously hypertensive rats. 1452 6

This study was designed to investigate the effect of hyperglycemia and angiotensin II (AngII) on renal hypertrophy and proteinuria in the pregnant diabetic rat. Secondary objectives were to evaluate changes in components of the renin-angiotensin axis and the effects of administration of losartan on pregnancy outcome. Fifty-three pregnant rats were allocated to 6 groups (1) nondiabetic controls (n = 12), (2) nondiabetic controls administered losartan (70-80 mg/kg/day; n = 10), (3) rats in which intravenous streptozotocin (STZ) was used to induce diabetes (55 mg/kg on day 10 of pregnancy; n = 10), (4) diabetic rats treated with losartan (n = 7), (5) diabetic rats treated with insulin (4 U/day; n = 7), and (6) diabetic rats treated with insulin and losartan (n = 7). Urinary protein excretion measured 4 days after STZ was 4 times greater in the rats with STZ-induced diabetes and significantly less in diabetic rats given losartan, insulin, or both. Postpartum kidney weight was greater in the rats with STZ-induced diabetes (2.04 +/- 0.21 g) than in the controls (1.37 +/- 0.14 g; P <.05) and reduced in the diabetic rats given losartan, insulin, or both (1.57 +/- 0.22, 1.73 +/- 0.13, and 1.51 +/- 0.14 g, respectively; P <.05). Plasma levels of angiotensin II in rats given losartan were more than 3.5 times greater than those in controls (749 +/- 436, 596 +/- 323, 567 +/- 349, and 159 +/- 28 pg/mL; P <.001). Postpartum activity of angiotensin-converting enzyme was increased in the untreated diabetic rats compared with that in control rats (162 +/- 12 vs 117 +/- 16 nmol/mL/min; P <.05). This increase was abolished by treatment with losartan or insulin. The number of newborns and mean weight of each newborn was similar in all groups. In summary, administration of losartan or insulin prevented, in part, kidney hypertrophy and protein excretion in the diabetic pregnant rat. Losartan did not affect the number or weight of newborns. Because angiotensin II receptor-blockers are contraindicated in pregnancy, good control of diabetes through the use of insulin should be advantageous.
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PMID:Insulin and losartan reduce proteinuria and renal hypertrophy in the pregnant diabetic rat. 1453 4

During the past decade, the incidence of end-stage renal disease (ESRD) has risen dramatically, primarily due to an increase in the incidence of diabetes. In patients with diabetes, both hyperglycemia and hypertension are independent risk factors for renal disease. Hypertension is also a risk factor in nondiabetic renal disease and contributes to renal dysfunction by increasing glomerular pressure, glomerular capillary damage, and proteinuria. The resultant nephron damage increases glomerular pressure and damage within remnant functional nephrons, further contributing to deterioration of renal function. In addition to its role in systemic hypertension, angiotensin II has direct effects on the kidney through elevation of glomerular capillary pressure and upregulation of components of the renal injury response. These direct effects of angiotensin II on the kidney support the inclusion of agents that target the renin-angiotensin system (RAS) into treatment regimens for patients at risk for renal disease. Several clinical trials have established the benefits of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in patients with diabetes. The ACE inhibitors have been shown to delay renal decline in patients with type 1 diabetes, whereas the renoprotective effect of these agents in patients with type 2 diabetes is less clear. The ARBs have been shown to provide significant benefits in patients with type 2 diabetes, both at early (microalbuminuria) and late (proteinuria) stages of renal decline. In the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, ARB therapy significantly reduced the progression of overt nephropathy (composite of doubling of serum creatinine, ESRD, and death), a benefit that has not been shown for ACE inhibitors. Moreover, in RENAAL, losartan significantly reduced the incidence of the individual end point of ESRD. The benefits of ARB therapy in IDNT and RENAAL were associated with significant reductions in proteinuria and were independent of blood pressure reductions. In RENAAL, proteinuria was a strong predictor of both renal and cardiovascular events. These findings underscore the importance of RAS blockade as a strategy for improving clinical outcomes in patients with renal disease.
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PMID:Recommendations for the management of special populations: renal disease in diabetes. 1462 61

Diabetic nephropathy is the leading cause of end stage renal disease (ESRD), and given that treating this condition is a considerable economic burden, the prevention of ESRD is a major public health goal. The renin-angiotensin system (RAS) is aberrantly activated in patients with diabetes. Angiotensin II (AII), a downstream effector of the RAS, has haemodynamic and non-haemodynamic effects that contribute to the development and progression of nephropathy. For patients with type 2 diabetes mellitus (T2DM) and hypertension, an AII receptor blocker (AIIRB) is recommended as the first drug that should be used. This review will focus on the rationale for the use of losartan as a treatment for nephropathy associated with T2DM. In animal models of diabetes, losartan reduced proteinuria and conferred renal protection. In RENAAL (Reduction in Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan), the first major randomised trial that investigated the benefit of losartan in patients with T2DM and nephropathy, losartan significantly reduced the risk of a doubling of serum creatinine and progression to ESRD, significantly lowered the levels of proteinuria and slowed the rate of decline in glomerular filtration rate. This review also discusses other clinical trials of losartan and other AIIRBs in T2DM, and considers alternative mechanisms by which losartan may be exerting its effects. The collective experience in treatment trials highlighted in this review indicate that losartan and other AIIRBs can reduce blood pressure and the progression of proteinuria in diabetic renal disease. However, losartan is thus far the only AIIRB that has been shown to reduce significantly the risk of ESRD and cardiovascular events in patients with T2DM. Its use in hypertensive patients with T2DM and nephropathy may play an important role in reducing the burden of ERSD.
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PMID:Advances in the treatment of diabetic renal disease: focus on losartan. 1502 42

A 12-month, multicenter (57 clinical institutions), randomized, open-labeled trial was undertaken to compare the efficacy of the angiotensin II receptor antagonist losartan and the calcium channel blocker amlodipine in patients with proteinuric chronic kidney disease (CKD) and hypertension. A total of 117 patients (79, chronic glomerulonephritis; 14, diabetic nephropathy; 24, other CKD) were randomly allocated into two treatment groups. Losartan and amlodipine exerted the same efficacy for blood pressure (BP) control; however, losartan significantly reduced the 24-h urinary protein excretion at months 3, 6, and 12, with the reduction of 20.7%, 35.2%, 35.8%, whereas amlodipine did not change the amount of proteinuria over the 12-month study period. When patients were stratified into groups according to the level of BP control at 3 months, the reduction in urinary protein excretion by losartan was evident in the group for which a BP of <140/90 mmHg was achieved, as well as in the group for which the goal BP (<130/85 mmHg) for treatment of CKD was not achieved. When patients were stratified according to baseline urinary protein excretion, those with > or = 2 g/day showed a reduction in proteinuria by losartan of 23.3%, 39.4%, and 47.9% at months 3, 6, and 12, and those with <2 g/day showed a reduction of 18.5% and 31.2% at months 3 and 6, respectively. No fatal adverse events were experienced in either drug group. We conclude that losartan reduced proteinuria in patients with CKD and hypertension. This positive effect may contribute to the renal protective benefit of losartan, and is beyond the magnitude of BP control.
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PMID:Renoprotective effect of losartan in comparison to amlodipine in patients with chronic kidney disease and hypertension--a report of the Japanese Losartan Therapy Intended for the Global Renal Protection in Hypertensive Patients (JLIGHT) study. 1505 52

Diabetic nephropathy has become the single most important cause of end-stage renal disease in the USA, Europe and Japan. The earliest marker of incipient diabetic nephropathy is the transition of normoalbuminuria to microalbuminuria at an albumin excretion rate of 20 microg/min. Human studies in patients both with and without diabetic kidney diseases have shown that the severity of baseline proteinuria is an important predictor of the rate of loss of renal function. Moreover, the reduction in protein excretion rate when patients with nephropathies are being treated with antihypertensive agents predicts the efficacy of subsequent renoprotection. Experimental and clinical observations provide the rationale for targeting the renin-angiotensin system as a renoprotective approach in diabetic and nondiabetic proteinuric nephropathies. Losartan (Cozaar, Merck Sharpe and Dohme) is a potent, orally active and highly specific angiotensin-type 1 receptor blocker. In addition to its antihypertensive efficacy, losartan decreases the left ventricular mass index in patients with hypertension, left ventricular end-diastolic and end-systolic volume in subjects with heart failure and prevents cardiovascular morbidity and death, predominantly stroke, independent of blood pressure reduction. Short-term studies in Type 1 diabetic patients with overt nephropathy have demonstrated that losartan and angiotensin-converting enzyme inhibitors have similar beneficial effects on albumin excretion rate, blood pressure and renal hemodynamics. Losartan also lowered albumin excretion rate in microalbuminuric patients with Type 2 diabetes mellitus. Moreover, the large multicenter Reduction of End points in Noninsulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial has shown that blockade of angiotensin-type 1 receptor with losartan is superior to conventional antihypertensive therapy in slowing the progression of overt Type 2 diabetic nephropathy. Together, data from clinical trials demonstrate the beneficial effect of angiotensin-type 1 receptor blockers, including losartan, in the primary and secondary prevention of renal disease progression in diabetic patients. Nevertheless, it can be expected that the positive results achieved so far with this class of drugs may be further implemented by including angiotensin-type 1 receptor antagonists as a part of the multidrug approach that may hold more promise for the future of renoprotection in diabetic patients with chronic nephropathy.
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PMID:Losartan in diabetic nephropathy. 1522 8

Losartan is an orally active, selective, nonpeptide, angiotensin-II Type I-receptor antagonist, and was the first drug marketed in this class. It has been approved for the treatment of hypertension, and may be used alone or in combination with other antihypertensive agents. Based on the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, losartan has been approved for the reduction of cardiovascular events in patients with hypertension and left ventricular hypertrophy, but there is evidence that this benefit does not apply to black patients. Based on the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study, losartan is also indicated for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria, in patients with Type 2 diabetes. The focus of this review is the LIFE study.
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PMID:Losartan for the treatment of hypertension and left ventricular hypertrophy: the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. 1550 Mar 78

Renin angiotensin system inhibitor therapy is seldom offered to individuals who have diabetes and advanced chronic kidney disease because of safety concerns. In this post hoc, secondary analysis of the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial, angiotensin antagonism risk/benefit profile was assessed in 1513 individuals with type 2 diabetes and overt nephropathy. Incidence of ESRD, hospitalizations for heart failure, withdrawals for adverse events, and proteinuria during losartan or conventional treatment were compared within three tertiles of baseline serum creatinine concentration (highest, 2.1 to 3.6 mg/dl; middle, 1.6 to 2.0 mg/dl; lowest, 0.9 to 1.6 mg/dl). Losartan decreased the risk of ESRD by 24.6, 26.3, and 35.3% in highest, middle, and lowest tertiles, respectively. For every 100 patients with serum creatinine >2.0, 1.6 to 2.0, or <1.6 mg/dl, respectively, 4 yr of losartan therapy was estimated to save 18.9, 8.4, and 2.9 ESRD events and US$1,502,855, US$1,021,770, and US$528,591 costs for renal replacement therapy. Losartan also decreased the hospitalizations for heart failure by 50.2 and 45.1, in the highest and middle tertile, respectively. Withdrawals for adverse events other than heart failure were comparable between tertiles and treatment groups. Proteinuria decreased more on losartan than on placebo in all tertiles (highest, 24 versus -8%; middle, 16 versus -8%; lowest, 15 versus -10%). In proteinuric individuals with type 2 diabetes, losartan therapy reduced ESRD and hospitalizations for heart failure and was well tolerated at all levels of renal function. Angiotensin II antagonism is a suitable and well-tolerated treatment for individuals with type 2 diabetes even with GFR levels approaching renal replacement therapy.
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PMID:Continuum of renoprotection with losartan at all stages of type 2 diabetic nephropathy: a post hoc analysis of the RENAAL trial results. 1557 15

We evaluated 10 patients with primary focal segmental glomerulosclerosis (FSGS) treated with plasmapheresis (PS) following renal transplantation. Three patients lost their first graft due to FSGS recurrence. In seven patients, PS was indicated as treatment for probable recurrence defined as the onset of proteinuria above 1 g/24 hours. In the remaining three patients, treatment was started in the first week posttransplant as prophylaxis against recurrence. The PS protocol was 17 sessions with the exchange of 2.5 L of plasma for 5% albumin over 10 to 12 weeks. Losartan (25 to 100 mg/d) was given to most patients at the end of PS treatment. The mean follow-up time after PS was 10 months. All patients currently have a functioning graft. A full response to treatment, defined as persistently reduced proteinuria to less than 500 mg/24 hours or the lack of recurrence in prophylactic treatment, was achieved in six patients. Three patients showed a partial decrease in proteinuria (to less than 1 g/24 hours). One patient failed to respond and still has nephrotic range proteinuria. No adverse effects of PS were recorded. A prompt start of PS combined with the use of losartan yields good results in the prophylaxis and treatment of recurrent FSGS following renal transplant in terms of quickly reduced proteinuria. Given the natural course of FSGS, a longer follow-up is needed to estimate the impact of PS on graft survival.
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PMID:Plasmapheresis for the prophylaxis and treatment of recurrent focal segmental glomerulosclerosis following renal transplant. 1586 44


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