Reduction In Urinary Albumin Excretion Research Articles

Aliskiren enhances protective effects of valsartan against type 2 diabetic nephropathy in mice

Addition of aliskiren, a direct renin inhibitor, to losartan provides additive reduction of urinary albumin excretion in type 2 diabetic patients. However, the detailed effect of aliskiren on type 2 diabetic nephropathy is still unknown. This study was undertaken to examine the efficacy of aliskiren and the combination of aliskiren with valsartan on type 2 diabetic nephropathy. db/db mice were treated with aliskiren (3 mg/kg per day), valsartan (5 or 10 mg/kg per day), combined aliskiren (3 mg/kg per day) and valsartan (5 mg/kg per day), and hydralazine (80 mg/kg per day), for 6 weeks, and the protective effects against diabetic nephropathy were compared among each group. Aliskiren significantly attenuated albuminuria and glomerular mesangial matrix expansion in db/db mice, which was associated with the improvement of the increased glomerular transforming growth factor-beta and type IV collagen expressions, the increased macrophage infiltration, and the decreased glomerular nephrin expression of db/db mice. These protective effects of aliskiren in db/db mice were attributed to the attenuation of p22(phox)-related nicotinamide adenine dinucleotide phosphate oxidase-induced superoxide. Addition of aliskiren to valsartan treatment provided more beneficial effects on all the above-mentioned parameters than valsartan monotherapy. Aliskiren protected against type 2 diabetic nephropathy, through pleiotropic effects, and significantly enhanced the protective effects of valsartan against diabetic nephropathy in db/db mice.

Manidipine treatment in patients with albuminuria not sufficiently reduced with renin–angiotensin system blockers

Microalbuminuria is an issue of great concern in hypertensive patients owing to its close relation with cardiovascular morbidity and mortality. Treatment should aim to reduce microalbuminuria to the normal range. Drugs that block the renin–angiotensin system have specific antiproteinuric properties, but more than one drug is needed to achieve blood pressure control in most cases. The aim of this study was to compare the effects of adding manidipine to the treatment of patients with essential hypertension and persistent albuminuria, despite full-dose treatment with a renin–angiotensin system blocker on urinary albumin excretion (UAE) after 24 weeks of therapy. Patients with diabetes and renal insufficiency were excluded. At baseline, blood pressure and UAE were 155.1 ± 12/87.76 ± 11 mmHg and 293.19 ± 285 mg/g, respectively. At study end, blood pressure was 137.1 ± 13.1/77.24 ± 10.4 mmHg (p < 0.001 vs baseline). UAE was reduced by 45% to 161.52 ± 163 mg/g (p < 0.001 vs baseline). No correlations were found between systolic blood pressure reduction and UAE reduction (Pearson’s R = -0.034; p = not significant) nor between estimated glomerular filtration rate and UAE reduction (Pearson’s R = -0.0056; p = not significant). No patient withdrew from the study owing to side effects. In conclusion, treatment with manidipine resulted in a large reduction in UAE rates, and this reduction appeared to be independent of the degree of blood pressure reduction or changes in estimated glomerular filtration rate. Our data supports the added value of manidipine in the treatment of patients with hypertension and microalbuminuria.

Antihypertensive effects of double the maximum dose of valsartan in African–American patients with type 2 diabetes mellitus and albuminuria

The blood pressure (BP)-lowering response to renin-angiotensin-aldosterone system blockade in hypertensive African-Americans is typically less than in whites. To determine whether higher than conventional doses of renin-angiotensin-aldosterone system blockade can improve BP reduction in African-American patients. Hypertensive patients with type 2 diabetes and albuminuria were enrolled: 110 African-Americans (BP = 150/87 mmHg, aged 57.5 +/- 11 years) and 281 non-African-Americans (BP = 151/89 mmHg, aged 57.7 +/- 11 years). All patients received valsartan 160 mg once daily in the morning for 4 weeks, following which patients were randomized to receive one of three valsartan doses: 160, 320 or 640 mg/day (2x, maximal recommended dose) for 26 weeks. If at week 6, target BP (<130/80 mmHg) was not achieved, then other add-on antihypertensives were allowed. The predominant BP (DeltaSBP/DeltaDBP) reduction was observed within 4 weeks and was lesser in African-Americans (7.8 +/- 15/4.5 +/- 9 mmHg) than non-African-Americans (8.9 +/- 14/6.6 +/- 1 mmHg, P < 0.05). Greater reduction in urinary albumin excretion was observed with higher doses (320 or 640 mg); however, the responses were similar between African-Americans and non-African-Americans. Use of add-on antihypertensives was higher in African-American (56%) vs. non-African-American patients (36%) with a similar rate across the three valsartan doses. From week 4-26, reduction in BP was lesser (P < 0.05) for African-American than non-African-American patients at the160-mg dose but not with 320 and 640-mg doses. In African-American patients, a lower BP reduction response was observed to conventional doses of valsartan than non-African-American patients, but at 640 mg, a higher response was observed in African-American patients than in non-African-American patients.

Abstract 5264: Recombinant Human Angiotensin Converting Enzyme 2 Normalizes Blood Pressure and Reduces the Progression of Diabetic Nephropathy

Background: Diabetes nephropathy is one of the most common causes of end-stage renal failure. Inhibition of ACE2 function exacerbates diabetic kidney injury while renal ACE2 is downregulated in diabetic nephropathy. We hypothesize that recombinant human ACE2 (rhACE2) will slow the progression of diabetic kidney injury. Methods and Results: Male 12-week old diabetic Akita mice ( Ins2 WT/C96Y ) and controls ( Ins2 WT/WT ) were injected daily with rhACE2 (2 mg/kg, i.p.) or placebo for four consecutive weeks. In Akita Ins2 WT/C96Y mice injected with hrACE2, plasma ACE2 activity showed a marked increase resulting in significant reduction in urinary albumin excretion (118±21 vs 224±16 μ g/24 hrs; n=6~8; p&lt;0.05). Treatment with rhACE2 decreased renal cortical angiotensin (Ang) II (12.1±1.9 vs 22.4±3.2 pg/mg; p&lt;0.05) and increased Ang (1–7) (14.2±2.1 vs 8.8±1.9 pg/mg; p&lt;0.05) levels, respectively, independent of changes in the expression of Ace and Ace2 while NADPH oxidase activity in renal cortical tissue from Akita mice was reduced by treatment with rhACE2 (364±45 vs 1720±277 RLU/sec/mg protein; n=6, p&lt;0.05). These effects resulted in normalization of the increased extracellular matrix gene expression ( α -smooth muscle actin, collagen III and fibronectin), reduction in glomerular volume and basement membrane thickness in the diabetic Akita mice. Activation of protein kinase C (PKC)á and PKCâ was reduced by 60 –70% in Akita diabetic mice treated with rhACE2. Ang II and high glucose-induced reactive oxygen species generation was evaluated using lucigenin-based NADPH oxidase activity and DHE fluorescence in cultured rat mesangial cells was suppressed by 25 and 250 ng/ml of rhACE2 in a dose-dependent manner. The mild hypertension in Akita Ins2 WT/C96Y mice was normalized by treatment with rhACE2 (122.3±2.1 vs 108.4±1.9 mmHg; n=6, p&lt;0.05) while the beneficial effects seen with rhACE2 occurred in the absence of hyperkalemia or acute renal failure and without a differential impact on hyperglycemia in the Akita diabetic model. Conclusions: We conclude that biologic antagonism of the RAS using rhACE2 can slow the progression of diabetic kidney injury and ACE2 may prove to be a useful adjunctive therapy for diabetic kidney disease.

Effects of Benidipine, a Long-Acting T-Type Calcium Channel Blocker, on Home Blood Pressure and Renal Function in Patients with Essential Hypertension

Calcium channel antagonists (calcium channel blockers [CCBs]) are often used in the treatment of patients with hypertension to achieve strict blood pressure (BP) targets. In the present study, we compared the antihypertensive effects (determined by home BP [HBP] measurements) and the effects on renal function of benidipine (hydrochloride) and amlodipine (mesylate), a commonly used CCB. Changes in HBP and urinary albumin excretion (UAE) were investigated in 47 benidipine and 37 amlodipine recipients with essential hypertension and albuminuria between January 2007 and December 2007. Both benidipine and amlodipine significantly reduced morning and evening HBP over a 12-month period. Both medications also significantly reduced UAE compared with pretreatment values; however, the reduction in UAE observed in the benidipine group occurred independent of the drug's antihypertensive effects, whereas a positive correlation was shown between the reduction in morning systolic BP and UAE in the amlodipine group. These results demonstrate that benidipine favourably affects renal function in patients with essential hypertension compared with amlodipine, suggesting that the clinical benefits of benidipine as an antihypertensive drug include a renoprotective effect.

Antiproteinuric effects of antihypertensive agents in non-diabetic hypertensive population

Abstract Arterial hypertension and proteinuria are important factors associated with the progression of both diabetic and nondiabetic chronic kidney disease. The objective of the present study was to determine the influence of different antihypertensive drug groups on urinary albumin excretion (UAE) as related to blood pressure in non-diabetic population. Subjects (n=39) with chronic renal disease accompanied by mild to moderate hypertension and varying degrees of proteinuria were divided into 3 groups based on UAE values and placed on nonpharmacological and/or treatment with an antihypertensive drug regimen (consisting of one or more antihypertensive drugs [beta blocker, ACE inhibitor or calcium-channel blocker]) to achieve a target blood pressure ≤ 130/85 mmHg. Periodic UAE measurements were performed. A reduction was observed over time in most patients, however, it reached statistical significance only in the microalbuminuric group (P&lt;0.01). Patients were further stratified into 5 groups depending on assigned therapy: 0, nonpharmacological treatment; 1-drug group 1; 12-drug groups 1 and 2; 13-drug groups 1 and 3; 123-all 3 drug groups (1-ACE inhibitors, 2-beta blockers, 3-calcium channel blockers). A statistically significant change in mean UAE values at the start and end of the study period in patients assigned to drug groups 12, 13, and 123 was achieved (P &lt; 0.05). Also, there was a statistically significant difference in the average reduction of proteinuria under varying antihypertensive drug regimens (P &lt; 0.05). In conclusion, in patients with hypertension, changes in UAE depend on initial UAE values and administered antihypertensive treatment. ACE inhibitors combined with calcium channel blockers resulted in a higher UAE reduction than other drug groups.

Microalbuminuria and urinary albumin excretion: French guidelines

Measurement of urinary albumin excretion (UAE) may be done on a morning urinary sample or on a 24 hour-urine sample. Values defining microalbuminuria are: - 24-hour urine sample: 30-300 mg/24 hours - Morning urine sample: 20-200 mg/mL or 30-300 mg/g creatinine or 2.5-25 mg/mmol creatinine (men) or 3.5-35 mg/mol (women). - Timed urine sample: 20-200 mug/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been shown in humans. In diabetic subjects, microalbuminuria is a marker of increased risk of cardiovascular (CV) and renal morbidity and mortality in type 1 and type 2 diabetic subjects. The increase in UAE during follow-up is also a marker of CV and renal risk in type 1 and type 2 diabetic subjects; its decrease during follow-up is associated with lower risks. In non-diabetic subjects, microalbuminuria is a marker of increased risk for diabetes mellitus, deterioration of the renal function, CV morbidity and all-cause mortality. It is a marker of increased risk for the development of hypertension in normotensive subjects, and is associated with unfavorable outcome in patients with cancer and lymphoma. Persistence or elevation of UAE overtime is associated with deleterious outcome in some hypertensive subjects. Measurement of UAE may be recommended in hypertensive subjects with 1 or 2 CV risk factors in whom CV risk remains difficult to assess, and in those with refractory hypertension: microalbuminuria indicates a high CV risk and must lead to strict control of arterial pressure. Studies focused on microalbuminuria in non-diabetic, non-hypertensive subjects are limited; most of them suggest that microalbuminuria predicts CV complications and deleterious outcome as it is in diabetic or hypertensive subjects. Subjects with a history of CV or cerebrovascular disease have an even greater CV risk if microalbuminuria is present than if it is not; however, in all cases, therapeutic intervention must be aggressive regardless of whether microalbuminuria is present or not. It is not recommended to measure UAE in non-diabetic non-hypertensive subjects in the absence of history of renal disease. Monitoring of renal function (UAE, serum creatinine and estimation of GFR) is annually recommended in all subjects with microalbuminuria. in patients with microalbuminuria, weight reduction, sodium restriction (< 6 g/day), smoking cessation, strict glucose control in diabetic subjects, strict arterial pressure control are necessary; in diabetic subjects: use of maximal doses of ACEI or ARB are recommended; ACEI/ARB and thiazides have synergistic actions on arterial pressure and reduction of UAE; in non-diabetic subjects, any of the five classes of anti-hypertensive medications (ACEI, ARB, thiazides, calcium channel blockers or beta-blockers) can be used.

Specificity of MMP-9 assays

In this journal van de Wal et al. recently reported that an effective reduction of urinary albumin excretion with the angiotensin-converting enzyme (ACE)-inhibitor fosinopril was not related to plasma matrix metalloproteinase-9 (MMP-9) levels. The authors indicated that the Elisa they used for MMP-9 analysis (Amersham, Buckinghamshire, UK), detects both MMP-9, proMMP-9 and the proMMP-9/TIMP-1 complex. However, according to the manufacturer (Amersham, Buckinghamshire, England), this Elisa mainly detects enzymatically inactive proMMP-9; active MMP-9 enzyme shows only 3% cross-reactivity relative to pro-MMP-9 in this Elisa (Instructions for use, Elisa code RPN 2614, Amersham).

Lowering the Threshold for Defining Microalbuminuria: Effects of a Lifestyle-metformin Intervention in Obese "Normoalbuminuric" Non-diabetic Subjects

We investigated whether levels of albuminuria (urinary albumin excretion (UAE)) below those conventionally accepted as microalbuminuria (<30 mg/day) are sensitive to correction of obesity and obesity-related risk factors. The effects of a 12-month lifestyle modification-metformin program were evaluated in otherwise healthy overweight/obese "normoalbuminuric" subjects: group I with UAE of <10 mg/day (n = 23) and group II with UAE of 10-29 mg/day (n = 18). The subjects of group II were older and heavier, and had higher blood pressure (BP) and lower high-density lipoprotein (HDL) levels, than those of group I. Creatinine clearances were also higher in group II (148 +/- 14 ml/min) than in group I (108 +/- 9 ml/min). Although the intervention induced comparable reductions in obesity, BP, lipids and insulin levels in both groups, UAE was significantly reduced in group II (9.1 +/- 1.8 mg/24 h; 60% reduction; P < 0.001), and non-significantly in group I (0.75 +/- 0.5 mg/day; 12% reduction; P > 0.1). Additionally, greater reduction in creatinine clearance was observed in subjects with higher UAE rates. After the intervention, both groups achieved similar UAE rates (5.7 +/- 0.9 and 5.2 +/- 1.0 mg/day; P > 0.10). Basal UAE was related to the subjects' creatinine clearance (r = 0.38; P = 0.04). For both groups together, intervention-induced changes in UAE rates were not significantly related to BP, age, or body weight. However, for group II subjects, BP and UAE reduction were positively associated (r = 0.44; P = 0.03). UAE of 10-29 mg/day (hyperalbuminuria), below the conventionally used limit to define microalbuminuria, is already associated with a more adverse cardiovascular risk profile, and is exquisitely sensitive to interventions that reduce obesity, BP, and insulin resistance.

Plasma matrix metalloproteinase-9 and ACE-inhibitor-induced improvement of urinary albumin excretion in non-diabetic, microalbuminuric subjects

Elevated plasma matrix metalloproteinase-9 (MMP-9) levels have been suggested to precede the development of microalbuminuria. As angiotensin-converting enzyme (ACE) inhibitors effectively reduce urinary albumin excretion (UAE), in the present study we have investigated the potential association of plasma MMP-9 levels with UAE and treatment effects of ACE-inhibition. In a placebo-controlled randomised trial we determined plasma MMP-9 levels at baseline and after three months of randomisation to either placebo (n=202) or fosinopril (20 mg/day, n=204) treatment. Baseline plasma MMP-9 levels were not related to baseline UAE (r=-0.008, p=0.871). Three months of fosinopril treatment effectively reduced UAE compared to placebo treatment (-10.4+/-2.4 vs. 1.8+/-1.3 mg/24 hours, p<0.001, respectively). However, fosinopril treatment failed to significantly change plasma MMP-9 levels compared to placebo (-0.47+/-7.68 vs. 0.06+/-9.20, p=0.646, respectively). In addition, the change in UAE was not related with change in MMP-9 levels. The effective reduction of UAE with fosinopril was not related to plasma MMP-9 levels.

Abstract 3781: A Reduction in Urinary Albumin Excretion is Associated with a Decrease in 10-year Cardiovascular Mortality in Hypertensive Type 2 Diabetic Patients

Urinary albumin excretion (UAE) is one of the strongest predictors of both adverse renal and cardiovascular outcomes in patients with type 2 diabetes. Although measurement of UAE is widely recommended, there is little available data to suggest that reducing UAE translates into a reduction in cardiovascular mortality. We assessed whether an early reduction in UAE is associated with improved long-term cardiovascular mortality in hypertensive type 2 diabetic patients with normo, micro, or overt albuminuria at baseline. The study is a 10-year longitudinal analysis of a prospective, randomized study- the Appropriate Blood Pressure Control in Diabetes (ABCD) trial including 393 type 2 diabetic patients with hypertension. We evaluated the association between the change in UAE from baseline to 1-year with the incidence of all cause and cardiovascular mortality over a ten year period. Our results revealed that a reduction in log UAE achieved at one-year was one of the strongest predictors of reduced cardiovascular mortality in a multivariable model that adjusted for multiple cardiovascular risk factors (HR1.42, 95% CI 1.06 – 1.92). This association was at all levels of UAE, normo, micro and overt albuminuria. In conclusion, an early reduction in UAE even at the normoalbuminuria level is associated with improvements in long-term cardiovascular mortality. Our data support current guideline recommendations to screen for UAE in all type 2 diabetic patients, but also suggest that serial UAE measurements after initiation of therapy may have clinical value. Prospective studies addressing this approach to care are needed prior to widespread adoption in practice.

Microalbuminuria and urinary albumin excretion: French clinical practice guidelines

Urinary albumin excretion (UAE) may be assayed on a morning urinary sample or a 24 h-urine sample. Values defining microalbuminuria are: 1) 24-h urine sample: 30–300 mg/24 h; 2) morning urine sample: 20–200 mg/ml or 30–300 mg/g creatinine or 2.5–25 mg/mmol creatinine (men) or 3.5–35 mg/mmol (women); 3) timed urine sample: 20–200 μg/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been obtained in humans. In diabetic subjects Microalbuminuria is a marker of increased risk of cardiovascular (CV) and renal morbidity and mortality in type 1 and type 2 diabetic subjects. The increase in UAE during follow-up is associated with greater CV and renal risks in type 1 and type 2 diabetic subjects; its decrease during follow-up is associated with lower risks. In non-diabetic subjects Microalbuminuria is a marker of increased risk for diabetes mellitus, deterioration of renal function, CV morbidity and all-cause mortality. It is a marker of increased risk for the development of hypertension in normotensive subjects, and is associated with unfavorable outcome in patients with cancer and lymphoma. Persistence of elevated UAE during follow-up is associated with poor outcome in some hypertensive subjects. Measurement of UAE may be recommended in hypertensive medium-risk subjects with 1 or 2 CV risk factors in whom CV risk remains difficult to assess, and in those with refractory hypertension: microalbuminuria indicates a high CV risk and must lead to strict control of arterial pressure. Studies focused on microalbuminuria in non-diabetic non-hypertensive subjects are limited; most of them suggest that microalbuminuria predicts CV complications and deleterious outcome. Subjects with a history of CV or cerebrovascular disease have an even greater CV risk if microalbuminuria is present than if it is not; however, in all cases, therapeutic intervention must be aggressive regardless of whether microalbuminuria is present or not. It is not recommended to measure UAE in non-diabetic non-hypertensive subjects in the absence of history of renal disease. Monitoring of renal function (UAE, serum creatinine and estimation of GFR) is recommended annually in all subjects with microalbuminuria. Management In patients with microalbuminuria, weight reduction, sodium restriction (< 6 g per day), smoking cessation, strict glucose control in diabetic subjects, strict arterial pressure control are necessary; in diabetic subjects: use of maximal doses of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) are recommended; ACEI/ARB and thiazides have synergistic actions on arterial pressure and reduction of UAE; in non-diabetic subjects, any of the five classes of anti-hypertensive medications (ACEI, ARB, thiazides, calcium channel blockers or beta-blockers) can be used.

Microalbuminurie et excrétion urinaire d'albumine : recommandations pour la pratique clinique

Measurement of urinary albumin excretion (UAE) may be done on a morning urinary sample or on a 24 hours-urine sample. Values defining microalbuminuria are: 24 hour-urine sample: 30–300 mg/24 hours; morning urine sample: 20–200 mg/ml or 30–300 mg/g creatinine or 2.5–25 mg/mmol creatinine (men) or 3.5–35 mg/mol (women). Timed urine sample: 20–200 μg/min. The optimal use of semi-quantitative urine test-strip is not clearly defined. It is generally believed that microalbuminuria reflects a generalized impairment of the endothelium; however, no definite proof has been shown in humans. In diabetic subjects Microalbuminuria is a marker of increased risk of cardiovascular (CV) and renal morbidity and mortality in type 1 and type 2 diabetic subjects. The increase in UAE during follow-up is also a marker of CV and renal risk in type 1 and type 2 diabetic subjects; its decrease during follow-up is associated with lower risks. In no diabetic subjects Microalbuminuria is a marker of increased risk for diabetes mellitus, deterioration of the renal function, CV morbidity and all-cause mortality. It is a marker of increased risk for the development of hypertension in normotensive subjects, and is associated with unfavorable outcome in patients with cancer and lymphoma. Persistence or elevation of UAE overtime is associated with deleterious outcome in some hypertensive subjects. Measurement of UAE may be recommended in hypertensive subjects with one or two CV risk factors in whom CV risk remains difficult to assess, and in those with refractory hypertension: microalbuminuria indicates a high CV risk and must lead to strict control of arterial pressure. Studies focused on microalbuminuria in non-diabetic non-hypertensive subjects are limited; most of them suggest that microalbuminuria predicts CV complications and deleterious outcome as it is in diabetic or hypertensive subjects. Subjects with a history of CV or cerebrovascular disease have an even greater CV risk if microalbuminuria is present than if it is not; however, in all cases, therapeutic intervention must be aggressive regardless of whether microalbuminuria is present or not. It is not recommended to measure UAE in non-diabetic non-hypertensive subjects in the absence of history of renal disease. Monitoring of renal function (UAE, serum creatinine and estimation of GFR) is annually recommended in all subjects with microalbuminuria. Management In patients with microalbuminuria, weight reduction, sodium restriction (< 6 g/day), smoking cessation, strict glucose control in diabetic subjects, strict arterial pressure control are necessary; in diabetic subjects: use of maximal doses of ACEI or ARB are recommended; ACEI/ARB and thiazides have synergistic actions on arterial pressure and reduction of UAE; in non diabetic subjects, any of the five classes of antihypertensive medications (ACEI, ARB, thiazides, calcium channel blockers or betablockers) can be used.

Chronotherapy in hypertensive patients: administration–time dependent effects of treatment on blood pressure regulation

Ambulatory blood pressure measurements (ABPM) correlate more closely with target organ damage and cardiovascular events than clinical cuff measurements. ABPM reveals the significant circadian variation in BP, which in most individuals presents a morning increase, small post-prandial decline, and more extensive lowering during nocturnal rest. However, under certain pathophysiological conditions, the nocturnal BP decline may be reduced (nondipper pattern) or even reversed (riser pattern). This is clinically relevant since the nondipper and riser circadian BP patterns constitute a risk factor for left ventricular hypertrophy, microalbuminuria, cerebrovascular disease, congestive heart failure, vascular dementia and myocardial infarction. Hence, there is growing interest in how to best tailor and individualize the treatment of hypertension according to the circadian BP pattern of each patient. Significant administration-time differences in the kinetics and in the beneficial and adverse effects of antihypertensive medications are well known. Thus, bedtime dosing with nifedipine gastrointestinal therapeutic system (GITS) is more effective than morning dosing, while also significantly reducing adverse effects. The therapeutic coverage and efficacy of doxazosin GITS are dependent on the circadian time of drug administration. Moreover, valsartan administration at bedtime, as opposed to upon wakening, results in an improved diurnal/nocturnal BP ratio, increased percentage of controlled patients, and significant reduction in urinary albumin excretion in hypertensive patients. Chronotherapy provides a means of individualizing the treatment of hypertension according to the circadian BP profile of each patient, and constitutes a new option to optimize BP control and reduce the risk of cardiovascular disease.

Anti-albuminuric effect of losartan versus amlodipine in hypertensive Japanese patients with type 2 diabetes mellitus: A prospective, open-label, randomized, comparative study

Abstract. The antiproteinuric effect of the angiotensin II receptor-antagonist losartan has been observed in patients with type 2 diabetes mellitus (T2DM). Proteinuria is considered to be a predictor of the progression of kidney disease. The aims of the present study were to compare and examine the ability of losartan and amlodipine to ameliorate albuminuria in hypertensive Japanese patients (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) with T2DM and whether the change in albuminuria was associated with a change in glomerular filtration rate (GFR). This prospective, open-label, randomized, comparative study was conducted over 3 months at the Kinki University School of Medicine, Osaka-Sayama, Japan. Hypertensive patients with T2DM were enrolled and randomly assigned to 1 of 2 study groups receiving either losartan (25-100 mg/d) or the calcium channel-blocker amlodipine (2.5-5 mg/d). Urinary albumin excretion (UAE), creatinine clearance, and GFR were recorded at study initiation (baseline) and study end (month 3). The GFR was measured from the fractional renal accumulation of (99m)Tc-diethylenetriaminepentaacetic acid. Adverse events (AEs) were monitored by a clinical research nurse during the examination. Fifty patients were asked to enroll and 38 returned the informed written consent. Thirty-five Japanese patients were included in the final study analysis. Seventeen patients were assigned to the losartan group (male sex, 10 [58.8%]; mean [SD] age, 58.1 [8.2] years) and 18 were assigned to the amlodipine group (male sex, 10 [55.6%]; mean [SD] age, 57.4 [8.9] years); no significant between-group difference in demographics was observed. A significant decrease from baseline to month 3 of mean (SD) UAE was observed in the losartan group (352.5 [556.6] mg/d vs 275.7 [466.1] mg/d; P = 0.048). No significant difference in mean (SD) UAE was observed in the amlodipine group for the same time period (298.2 [416.6] mg/d vs 322.7 [415.4] mg/d). There was a statistically significant difference found in the mean (SD) percent change of UAE from baseline to month 3 in the losartan group compared with the amlodipine group (-23.52 [28.42] vs +27.90 [63.51]; P = 0.004). Neither group was associated with a significant change in GFR during the course of the study. No patient discontinued the study due to AEs that were considered, by the investigator, to be possibly or probably associated with study treatment. Treatment with losartan, but not amlodipine, was associated with a reduction in albuminuria in these hypertensive Japanese patients with T2DM within a period as short as 3 months. Neither drug was associated with a significant change in GFR. Therefore, the reduction of UAE was independent of a change in the GFR.

Optimal timing for antihypertensive dosing: focus on valsartan.

Some specific features of the 24 h blood pressure (BP) pattern are linked to the progressive injury of target tissues and the triggering of cardiac and cerebrovascular events. In particular, many studies show the extent of the nocturnal BP decline relative to the diurnal BP mean (the diurnal/nocturnal ratio, an index of BP dipping) is deterministic of cardiovascular injury and risk. Normalization of the circadian BP pattern is considered to be an important clinical goal of pharmacotherapy because it may slow the advance of renal injury and avert end-stage renal failure. The chronotherapy of hypertension takes into account the epidemiology of the BP pattern, plus potential administration-time determinants of the pharmacokinetics and dynamics of antihypertensive medications, as a means of enhancing beneficial outcomes and/or attenuating or averting adverse effects. Thus, bedtime dosing with nifedipine gastrointestinal therapeutic system (GITS) is more effective than morning dosing, while also reducing significantly secondary effects. The dose-response curve, therapeutic coverage, and efficacy of doxazosin GITS are all markedly dependent on the circadian time of drug administration. Moreover, valsartan administration at bedtime as opposed to upon wakening results in improved diurnal/nocturnal ratio, a significant increase in the percentage of patients with controlled BP after treatment, and significant reductions in urinary albumin excretion and plasma fibrinogen. Chronotherapy provides a means of individualizing treatment of hypertension according to the circadian BP profile of each patient, and constitutes a new option to optimize BP control and reduce risk.

Urinary albumin excretion and the renin–angiotensin system in cardiovascular risk management

Microalbuminuria has been shown to be a strong predictor of cardiovascular morbidity and mortality in diabetic and hypertensive patients, but also in the general population. Moreover, several reports suggest that reduction of urinary albumin excretion (UAE) is associated with improvement of cardiovascular prognosis. Reduction of UAE can be achieved by lowering arterial blood pressure, but blockers of the renin–angiotensin system (RAS) with their specific renal actions have demonstrated to be able to reduce UAE more than might be expected from reduction of blood pressure alone. Consequently, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may also provide superior cardiovascular protection, especially in subjects with higher levels of albuminuria, but evidence is still scarce. The ability of both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers to reduce UAE and provide cardiovascular protection suggests that the RAS may play a central role. New developments in this area include the use of aldosterone antagonists in albuminuric/proteinuric subjects, and the development of oral renin inhibitors. Combinations of the aforementioned drugs may have the ability to fully block the RAS, potentially avoiding all detrimental effects of this hormonal cascade. However, combination therapy is expected to also increase the incidence of side effects, such as hyperkalaemia and acute renal insufficiency. The current knowledge of microalbuminuria represents the proverbial tip of the iceberg, and future studies should focus on the underlying pathophysiological mechanism of urinary albumin excretion in relation to cardiovascular protection. Only then can a better understanding of the problem be achieved and the optimal pharmacological approach be ascertained.

Determinants of urinary albumin excretion reduction in essential hypertension: a long-term follow-up study

The objective of the present study was to assess factors related to long-term changes in urinary albumin excretion (UAE) of nondiabetic microalbuminuric (n = 252) or proteinuric hypertensive individuals (n = 58) in a prospective follow-up. After enrollment, patients were placed on usual care including nonpharmacological treatment and/or treatment with an antihypertensive drug regime to achieve blood pressure < 135/85 mmHg. Periodic UAE measurements were performed until regression or significant reduction (defined when UAE dropped > 50% from the initial values, plus reduction of UAE to < 30 mg/24 h for microalbuminuric patients and < 300 mg/24 h for proteinuric patients). Among the microalbuminuric patients, 113 (44.8%) significantly reduced UAE after a mean follow-up of 18 months (range 12-69 months), 20.3/100 patients per year. Among the proteinuric patients, 29 (50%) significantly reduced UAE after a mean follow-up of 25 months (range 12-51 months), 20.2/100 patients per year. The baseline glomerular filtration rate, diastolic blood pressure and fasting glucose during follow-up were independent factors related to the regression or significant reduction in a Cox proportional hazard model. Regression of UAE was independently related to initial estimated glomerular filtration rate < or = 60 ml/min per 1.73 m (hazard ratio, 0.57; 95% confidence interval, 0.38-0.86; P = 0.001) and DBP > or = 90 mmHg achieved during the follow-up (hazard ratio, 0.57; 95% confidence interval, 0.38-0.86; P = 0.001), even when adjusted for age, gender, body mass index, fasting glucose, presence of treatment at the beginning of the study and treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers during the follow-up. The reduction of urinary albumin excretion was linked to the preserved glomerular filtration rate and to adequate blood pressure control.

Renal protection in diabetic patients: benefits of a first-line combination of perindopril–indapamide (Preterax®)

Type 2 diabetes mellitus (T2DM) is often accompanied by high blood pressure (BP) and the clustering of several cardiovascular risk factors, and is the most frequent cause of end-stage renal disease. The stages of development of overt nephropathy in T2DM patients range from an initial alteration in renal function with an increased GFR, followed by the development of microalbuminuria and macroalbuminuria or proteinuria, featuring an established diabetic nephropathy, which eventually progresses to end-stage renal disease. Early intervention is needed to prevent the development of diabetic nephropathy and requires effective control of the different risk factors, and in particular high BP. In the initial stages of the disease, strict BP control is crucial to prevent the development of initial renal and vascular damage. Adequate BP control is particularly difficult in T2DM patients and in most cases requires the use of combination therapy. Preterax, a fixed-dose combination of perindopril 2 mg and indapamide 0.625 mg, allows BP to be significantly reduced compared with conventional strategies; this combination can be uptitrated to BiPreterax when further BP control is needed. In the PREMIER study performed in T2DM over 12 months, the perindopril/indapamide combination brought about, in addition to excellent BP control, a significant reduction in urinary albumin excretion, compared with monotherapy with enalapril. In more advanced degrees of renal damage, higher doses of the fixed combination have to be considered. The pharmacological basis of the renoprotective effect of perindopril/indapamide is the demonstration that this combination prevented nephropathy as well as proteinuria in obese Zucker rats, independently of BP control. Strict BP control from the initial stages of nephropathy together with inhibition of the renin-angiotensin system is mandatory to prevent albuminuria. The fixed combination of perindopril/indapamide can greatly help clinicians in achieving the above goals, using Preterax in the early and BiPreterax in the late stages of nephropathy.

The angiotensin II receptor antagonist telmisartan reduces urinary albumin excretion in patients with isolated systolic hypertension: results of a randomized, double-blind, placebo-controlled trial

To examine the effect of telmisartan or hydrochlorothiazide on the control of urinary albumin excretion (UAE) in patients with isolated systolic hypertension (ISH) unselected for albuminuria in a pre-planned substudy of a large, multicentre, double-blind, placebo-controlled, randomized study. The Angiotensin II Receptor Antagonist Micardis in Isolated Systolic hypertension (ARAMIS) study compared the antihypertensive efficacy after 6 weeks of once-daily fixed doses of telmisartan 20, 40 or 80 mg versus hydrochlorothiazide 12.5 mg or placebo in patients (n = 1039, aged 35-84 years) with ISH (seated blood pressure 150-179/< 90 mmHg). The prospective substudy analysed UAE using spot morning samples. Urinary albumin (> 2.2-901.6 mg/l) was detected at baseline in 614 out of 918 patients who were included in the substudy analysis. In the telmisartan group (n = 354, all doses combined), a median reduction in UAE from a baseline of 14.1% [95% confidence interval (CI) 7.3, 21.8] was observed versus 1.1% (95% CI -13.5 to 16.0) and 2.7% (95% CI -0.9 to 19.9) in the hydrochlorothiazide (n = 140) and placebo (n = 120) groups, respectively. The difference between telmisartan and hydrochlorothiazide was significant (P = 0.017). Reductions in UAE with telmisartan were observed in patients with baseline normoalbuminuria, microalbuminuria or macroalbuminuria. Telmisartan and hydrochlorothiazide produced comparable reductions in systolic blood pressure in these patients. In patients with ISH unselected for baseline albuminuria, telmisartan 20-80 mg after 6 weeks' treatment afforded significantly greater lowering of UAE than hydrochlorothiazide 12.5 mg, irrespective of the baseline UAE, and despite comparable reductions in systolic blood pressure with both drugs.