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1.
Beneficial long-term effect of aldosterone antagonist added to a traditional blockade of the renin-angiotensin-aldosterone system among patients with obesity and proteinuria.
Morales, E, Gutiérrez, E, Caro, J, Sevillano, A, Rojas-Rivera, J, Praga, M
Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia. 2015;(6):554-61
Abstract
INTRODUCTION Over the past decade, obesity has become a risk factor for developing chronic kidney disease. Proteinuria is known to be an independent determinant of the progression of chronic kidney disease, and adipose tissue is a recognized source of components of the renin-angiotensin-aldosterone system (RAAS). Recent studies have shown that plasma aldosterone levels are disproportionately higher in patients with obesity. Drugs that block the RAAS are unable to inhibit aldosterone in the long term. The aim of our study was to analyze the renoprotective effect of an aldosterone antagonist in combination with RAAS blockers in patients with obesity and proteinuric nephropathy. MATERIAL AND METHODS This study is a substudy of previously published study on the renoprotective effect of mineralocorticoid receptor blockers in patients with proteinuric nephropathies. Patients with proteinuria levels >1g/24h who were taking spironolactone and were being treated with other RAAS blockers were divided according to body mass index (BMI) into an obesity group (BMI ≥30kg/m2) and a control group. RESULTS Seventy-one patients were included in the study, with a mean age of 56.7±15.1 years. More than 50% of the patients in both groups had diabetes. Thirty-two patients were included in the obesity group and 39 were included in the control group. There were no significant differences in renal function, proteinuria, blood pressure, serum potassium levels and the percentage of RAAS blockers in both groups. After a follow-up of 28.9 (14-84) months, there was a 59.4% reduction in proteinuria in the obesity group (2.8±2.1 vs. 1.3±1.6g/24h, p<.05). The reduction in proteinuria was greater than 50% in 22 (68.8%) cases, and the mean blood pressure showed a significant decrease (from 100.6±9 to 92.1±7.4mm Hg, p<.05). The control group showed a 69.6% reduction in proteinuria (1.9±1.4 to 0.8±0.5, p<0.05). The reduction of proteinuria was higher than 50% in 22 (68.8%) cases in obese patients and in 33 (84.6%) cases in non-obese group. Renal function remained stable in both groups during the follow-up. Nine patients (28.1%) in the obesity group experienced gynecomastia. The incidence of hyperkalemia was similar for the 2 groups (6.3%). CONCLUSION Aldosterone antagonist treatment in obese patients with proteinuric nephropathies induces a drastic and sustained reduction in proteinuria but not more than the non-obese group. There was a trend toward slowing progression of renal failure with few adverse events.
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2.
Effect of acute and chronic vitamin D administration on systemic renin angiotensin system in essential hypertensives and controls.
Bernini, G, Carrara, D, Bacca, A, Carli, V, Virdis, A, Rugani, I, Duranti, E, Ghiadoni, L, Bernini, M, Taddei, S
Journal of endocrinological investigation. 2013;(4):216-20
Abstract
AIM: To investigate the systemic renin-angiotensin system (RAS) in essential hypertensives (EH) and controls (C) after short- and long-term vitamin D receptor activation. DESIGN Ten consecutive EH (under controlled low-salt diet) and 10 C underwent calcitriol administration (0.25 μg bid) for 1 week (Group A). Eighteen consecutive EH under angiotensin II receptor antagonist therapy received a single oral dose of 300,000 IU of cholecalciferol and were followed up for 8 weeks (Group B). METHODS In basal conditions and at the end of the study (1 week in Group A and 8 weeks in Group B), plasma renin activity (PRA), plasma active renin, aldosterone, and angiotensin II were evaluated, as well as blood pressure, plasma 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D], and PTH. RESULTS In Group A, plasma 25(OH)D levels in EH and C were below the normal range, although lower levels were found in the former. No association between basal plasma 25(OH)D or 1,25(OH)2D levels and blood pressure values or RAS components was observed either in the whole group or in the two subgroups. Calcitriol administration did not affect any RAS parameter either in EH or in C. In Group B, cholecalciferol significantly increased 25(OH)D and 1,25(OH)2D levels without interfering with the angiotensin II receptor antagonist-induced increase in RAS components. No correlation was found between plasma 25(OH)D or 1,25(OH)2D levels and blood pressure values or RAS parameters before and after cholecalciferol administration. CONCLUSIONS The present data suggest that, in our experimental conditions, vitamin D receptor activation is unable to influence systemic RAS activity.
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3.
Effect of renin-angiotensin-aldosterone system (RAAS) blockade on visfatin levels in diabetic nephropathy.
Eyileten, T, Sonmez, A, Saglam, M, Cakir, E, Caglar, K, Oguz, Y, Vural, A, Yenicesu, M, Yilmaz, MI
Nephrology (Carlton, Vic.). 2010;(2):225-9
Abstract
AIM: Plasma visfatin levels are elevated in diabetic nephropathy in parallel to the severity of proteinuria and glomerular filtration rate. The aim of this study was to find out whether the renin-angiotensin-aldosterone system (RAAS) blockage has any effect on the plasma visfatin levels. METHODS Thirty-two patients with diabetic proteinuria (>500 mg/day) with a normal glomerular filtration rate (GFR) and 33 healthy subjects were enrolled. Patients were treated with ramipril 5 mg daily for 2 months. Proteinuria, GFR, high-sensitivity C-reactive protein (hsCRP), visfatin, flow-mediated dilatation (FMD) and homeostasis model assessment of insulin resistance (HOMA-IR) index measurements were performed both before and after the treatment. RESULTS The plasma visfatin, and hsCRP levels of the patients were significantly higher and the FMD was significantly lower (P < 0.001 for all). The visfatin levels were significantly correlated to FMD, systolic and diastolic blood pressures, proteinuria, eGFR, HOMA-IR and hsCRP. Ramipril treatment resulted in a significant decrease in plasma visfatin, proteinuria, hsCRP, HOMA-IR and increase in FMD (P < 0.001) in patients (P < 0.001 for all). CONCLUSION The present study suggests that plasma visfatin levels are related to the endothelial functions, inflammation and the severity of proteinuria in diabetic nephropathy. Treatment with ramipril causes a significant decrease in visfatin levels along with the improvement of proteinuria, endothelial dysfunction and inflammatory state in diabetic nephropathy.
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Proteinuria-lowering effect of heparin therapy in diabetic nephropathy without affecting the renin-angiotensin-aldosterone system.
Benck, U, Haeckel, S, Clorius, JH, van der Woude, FJ
Clinical journal of the American Society of Nephrology : CJASN. 2007;(1):58-67
Abstract
Angiotensin-converting enzyme inhibitors and angiotensin II (AngII) type 1 receptor blockers lower proteinuria and preserve renal function in diabetic nephropathy (DN). The antiproteinuric effects are greater than their blood pressure reduction, involving the sieving properties of the glomerular filter. In DN, glomerular staining for heparan sulfate proteoglycans is decreased. AngII inhibits heparan sulfate synthesis. Also, heparins modulate AngII signaling in glomerular cells, inhibiting aldosterone synthesis and lowering proteinuria in DN. Is the antiproteinuric effect of heparins due to its interference with the renin-angiotensin-aldosterone system? Ten volunteers each with DN and glomerulonephritis and control subjects were examined before and after low-dosage enoxaparin. Renal hemodynamics were determined with (99m)Tc-DTPA and (131)I-hippurate clearance. Glomerular filtration rate (GFR), effective renal plasma flow, mean arterial pressure, and heart rate were measured at baseline and during AngII infusion before and after enoxaparin while on normal salt and salt restriction. Enoxaparin did not lower aldosterone levels. GFR remained stable in all groups. AngII caused a significant decrease in effective renal plasma flow, whereas mean arterial pressure and heart rate increased significantly. Enoxaparin did not influence the AngII-induced changes of renal hemodynamics during normal salt intake or salt restriction. All groups showed identical responses to AngII before and after enoxaparin. In patients with diabetes, enoxaparin caused a significant decrease in proteinuria. It is concluded that the antiproteinuric effect of heparins in DN cannot be explained via interaction with the renin-angiotensin-aldosterone system. The absence of hemodynamic changes combined with reduced proteinuria point to intrinsic alterations in the glomerular filter. The effects were seen only in DN, not in glomerulonephritis.
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Blockade of renin-angiotensin system reduces QT dispersion and improves intracellular Ca/Mg status in hemodialysis patients.
Averbukh, Z, Berman, S, Efrati, S, Manevits, E, Rosenberg, R, Malcev, E, Galperin, E, Weissgarten, J
Nephron. Clinical practice. 2006;(4):c176-84
Abstract
BACKGROUND Electrolyte impairments are common in hemodialysis (HD) patients. Consequently, QT dispersion (QTd) is prolonged, correlating with high intracellular magnesium. In patients with cardiac disorders, renin-angiotensin system (RAS) inhibition reduces QTd. AIM: To compare the effects of ACE inhibition or AT-1 blockade on QTd duration and intracellular magnesium (Mg)/calcium (Ca) in peripheral blood mononuclear cells (PBMC) from chronic HD patients. METHODS 24 HD patients received cilazapril for 8 weeks and, following a 2-week withdrawal, were switched to valsartan for additional 8 weeks. QTd measurements and PBMC isolation were performed at the beginning and the end of each period. Total intracellular Ca and Mg were assessed by atomic spectrometer, and cytosolic free Ca2+ by fluorocytometer. RESULTS Both treatments significantly decreased QTd, demonstrating similar reduction magnitudes. In both groups, PBMC exhibited basally low cytosolic Ca2+ and undisturbed high transmembrane Ca2+ influx following phytohemagglutinin stimulation. Total intracellular Ca was increased, while Mg was reduced, following either treatment. The total intracellular Ca/Mg ratio inversely correlated with QTd duration. CONCLUSIONS (1) RAS inhibition reduces prolonged QTd in HD patients. (2) In PBMC from ordinarily Ca-depleted HD patients, RAS suppression brings about elevation of total intracellular Ca. (3) RAS blockade decreases high intracellular Mg in PBMC from HD patients. Consequently, the Ca/Mg ratio increases, inversely correlating with QTd reduction.
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Partial angiotensin-converting enzyme inhibition during acute orthostatic stress in persons with tetraplegia.
Wecht, JM, Radulovic, M, Weir, JP, Lessey, J, Spungen, AM, Bauman, WA
The journal of spinal cord medicine. 2005;(2):103-8
Abstract
INTRODUCTION Individuals with tetraplegia rely on the renin-angiotensin system for orthostatic blood pressure control. OBJECTIVES To determine the effect of partial angiotensin-converting enzyme (ACE) inhibition on heart rate (HR), active plasma renin (PR), and mean arterial blood pressure (MAP) during acute orthostasis in subjects with tetraplegia (n = 7) and nondisabled persons (n = 8). METHODS Subjects were instructed to avoid caffeine and alcohol for 24 hours before testing and to report to the laboratory between 10 AM and 1 PM. Progressive head-up tilt (15 degrees, 25 degrees, 35 degrees, and 45 degrees) was performed on 2 separate days; Day 1: without ACE inhibition; Day 2: after intravenous (IV) infusion of enalaprilat (0.625 mg). RESULTS HR was reduced during orthostasis in the tetraplegia compared with the nondisabled group (P < 0.0001), and was unaffected by ACE inhibition in either group. PR was not increased with orthostasis in either group, but was increased after ACE inhibition in both groups (P < 0.001). MAP was not affected by orthostasis in either group, but was reduced with ACE inhibition in both groups (P < 0.01). In the tetraplegia group, MAP was initially reduced after ACE inhibition, but was maintained thereafter with increasing angles of tilt, and no subject complained of symptomatic orthostatic hypotension. CONCLUSION Subjects with tetraplegia were tolerant of an acute bout of orthostatic stress after partial ACE inhibition. This may have clinical relevance because of the increased prevalence of type 2 diabetes mellitus in this population and the use of ACE inhibitors for the treatment of progressive renal and cardiovascular disease.
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7.
Sodium status and angiotensin-converting enzyme inhibition: effects on plasma angiotensin-(1-7) in healthy man.
Kocks, MJ, Lely, AT, Boomsma, F, de Jong, PE, Navis, G
Journal of hypertension. 2005;(3):597-602
Abstract
OBJECTIVE Angiotensin-converting enzyme (ACE) inhibitors provide effective intervention for cardiovascular and renal disease. Changes in angiotensin-(1-7) have been proposed to be involved in the mechanism of action of ACE inhibition (ACEi). In particular, an altered balance between angiotensin II and angiotensin-(1-7) might be involved. A shift in sodium status modifies the activity of the renin-angiotensin-aldosterone system and the effects of ACEi, but its effects on angiotensin-(1-7) are unknown. We therefore studied the effect of a shift in sodium intake on angiotensin-(1-7), during placebo and ACEi. METHODS A double-blind, placebo-controlled study was conducted in 17 healthy men. The subjects were studied for two 2-week periods: 20 mg/day enalapril and placebo. The first week of each period they used a 50 mmol Na+ diet [low sodium (LS)], the second week a 200 mmol Na+ diet. Angiotensin levels and blood pressure were measured at the end of each week. RESULTS During placebo, LS intake elicited a three-fold rise in ang-(1-7) that paralleled the rise in other components of the renin-angiotensin system. During ACEi LS did not affect angiotensin II, but did induce a clear-cut rise in angiotensin-(1-7)--to the extent that angiotensin-(1-7) was highest during combination of ACEi and LS. Consequently, during ACEi LS shifted the balance between angiotensin-(1-7) and angiotensin II towards angiotensin-(1-7). CONCLUSION The sodium status modifies levels of angiotensin-(1-7). During ACEi angiotensin-(1-7) is still subject to stimulation by sodium restriction, and provides opportunity for therapeutic manipulation. Exploration of this opportunity in patient populations may lead to strategies to improve therapeutic benefits of ACEi.
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Aldosterone escape during blockade of the renin-angiotensin-aldosterone system in diabetic nephropathy is associated with enhanced decline in glomerular filtration rate.
Schjoedt, KJ, Andersen, S, Rossing, P, Tarnow, L, Parving, HH
Diabetologia. 2004;(11):1936-9
Abstract
AIMS/HYPOTHESIS It has been suggested that aldosterone plays a role in the initiation and progression of renal disease independently of arterial blood pressure and plasma angiotensin II levels. We evaluated the influence of plasma aldosterone levels on progression of diabetic nephropathy during long-term blockade of the renin-angiotensin-aldosterone system. METHODS A total of 63 hypertensive patients with type 1 diabetes and diabetic nephropathy were treated with losartan, 100 mg once daily, for a mean follow-up period of 35 months. Plasma aldosterone, GFR, albuminuria and 24-h blood pressure were determined at baseline and at regular intervals during the study. RESULTS Patients were divided according to their increasing or decreasing levels of plasma aldosterone during long-term losartan treatment in an escape group (n=26) and a non-escape group (n=37). In the escape group, aldosterone levels increased from (geometric mean [95% CI]) 57 pg/ml (43-76 pg/ml) at 2 months, to 102 pg/ml (78-134 pg/ml) at the end of the study (p<0.01). The corresponding levels in the non-escape group were 83 pg/ml (69-102 pg/ml) and 49 pg/ml (40-60 pg/ml; p<0.01). The median rate of decline in GFR was 5.0 ml.min(-1).year(-1) (range 0.4-15.9 ml.min(-1).year(-1)) in the escape group, compared with 2.4 ml.min(-1).year(-1) (-1.6 to 11.0 ml.min(-1).year(-1)) in the non-escape group (p<0.005). The increase in plasma aldosterone correlated with the rate of decline in GFR (r(2)=0.19, p<0.001), corresponding to a decline in GFR of 1.5 ml.min(-1).year(-1) for every two-fold increase in plasma aldosterone. Pre-treatment and treatment values of plasma aldosterone were not related to albuminuria or to changes in albuminuria during the study. CONCLUSIONS/INTERPRETATION Our data suggest that aldosterone escape during long-term blockade of the renin-angiotensin-aldosterone system is associated with an enhanced decline in GFR in patients with type 1 diabetes and diabetic nephropathy.