ramipril and Albuminuria

Blockade of the renin-angiotensin-aldosterone system (RAAS) prevents the development and progression of diabetic kidney disease (DKD). It is controversial whether the simultaneous use of two RAAS inhibitors (ie, dual RAAS blockade) further improves renal outcomes. This review examines the scientific rationale and current clinical evidence addressing the use of dual RAAS blockade to prevent and treat DKD. It is concluded that dual RAAS blockade should not be routinely applied to patients with low or moderate risk of progressive kidney disease (normoalbuminuria or microalbuminuria with preserved glomerular filtration rate). For patients with high risk of progressive kidney disease (substantial albuminuria or impaired glomerular filtration rate), clinicians should carefully weigh the potential risks and benefits of dual RAAS blockade on an individual basis until ongoing clinical trials provide further insight.

Topics: Albuminuria; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Benzimidazoles; Benzoates; Diabetic Nephropathies; Humans; Hyperkalemia; Models, Biological; Ramipril; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Telmisartan

Advanced glycation endproducts (AGEs) have been postulated to play a role in the development of both nephropathy and large vessel disease in diabetes. However, it is still not clear which AGE subtypes play a pathogenetic role and which of several AGE receptors mediate AGE effects on cells. This review summarises the renoprotective effect of inhibitors of AGE formation, including aminoguanidine, and of cross-link breakers, including ALT-711, on experimental diabetic nephropathy and on mesenteric vascular hypertrophy. It also demonstrates similar effects of aminoguanidine and ramipril (an angiotensin converting enzyme inhibitor) on fluorescent and immunoassayable AGE levels, renal protein kinase C activity, nitrotyrosine expression, lysosomal function, and protein handling in experimental diabetes. These findings indicate that inhibition of the renin angiotensin system blocks both upstream and downstream pathways leading to tissue injury. We postulate that the chemical pathways leading to advanced glycation endproduct formation and the renin angiotensin systems may interact through the generation of free radicals, induced both by glucose and angiotensin II. There is also evidence to suggest that AGE-dependent pathways may play a role in the development of tubulointerstitial fibrosis in the diabetic kidney. This effect is mediated through RAGE and is TGF-beta and CTGF-dependent.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Enzyme Inhibitors; Forecasting; Glycation End Products, Advanced; Guanidines; Humans; Protein Kinase C; Ramipril; Renin-Angiotensin System; Thiazoles

Diabetes has long been recognized as a risk factor for heart disease. Recent evidence has brought to light complex interactions that seem to influence both the renal and the vascular complications of diabetes. The use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been shown to ameliorate renal and cardiac risks in both type 1 and type 2 diabetes to a degree that is disproportionate to blood pressure-lowering effects. The judicious use of these agents can materially improve the prognosis for patients with diabetes.

Topics: Albuminuria; Amlodipine; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Calcium Channel Blockers; Captopril; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Diabetic Nephropathies; Humans; Irbesartan; Kidney Diseases; Losartan; Prognosis; Ramipril; Tetrazoles

In a randomized, double-blind, placebo-controlled study, we investigated in normotensive type 2 diabetics with microalbuminuria the effect of ramipril, an ACE inhibitor, on urine albumin excretion and serum lipids. A total of 1,882 patients were screened for urine microalbumin consecutively by dipstick test, Rapi Tex-Albumin test and RIA. The final 28 normotensive and microalbuminuric patients were assigned to receive either ramipril (1.25 mg/d, n = 16) or placebo (n = 12) for 12 weeks. Throughout the study, both groups had no changes in blood pressure, fasting plasma glucose, HbA1C, serum creatinine and electrolytes and no difference in creatinine clearance. At week 12 only the placebo group showed the significant increment of urine albumin excretion and triacylglycerol (30.6 +/- 38.3 to 39.0 +/- 19.7 and 167 +/- 64 to 208 +/- 77 mg/dl, respectively) but the decrement of HDL-cholesterol (46 +/- 16 to 35 +/- 6 mg/dl). During a 3 month period, increased urine albumin excretion was observed in normotensive type 2 diabetes with microalbuminuria who received only placebo. We conclude that ramipril may arrest the progression of albumin excretion and had favorable effects on serum lipids. Ramipril was safe and well-tolerated without untoward side effects during the study period.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Hyperlipidemias; Ramipril

Gross et al. present results of the EARLY PRO-TECT trial, a randomized controlled trial of ramipril versus placebo in children with early-stage Alport syndrome. Although under-enrolled and not a positive trial in the traditional sense, EARLY PRO-TECT does provide strong supportive evidence for both long-term safety and a clinical benefit of early treatment with angiotensin-converting enzyme inhibitors in slowing the progression of both albuminuria and estimated glomerular filtration rate decline in children with Alport syndrome.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Child; Glomerular Filtration Rate; Humans; Nephritis, Hereditary; Ramipril

The combination of weight excess and hypertension significantly contributes to cardiovascular risk and progressive kidney damage. An unfavorable renal hemodynamic profile is thought to contribute to this increased risk and may be ameliorated by direct renin inhibition (DRI). The aim of this trial was to assess the effect of DRI on renal and systemic hemodynamics and on RAAS activity, in men with weight excess and hypertension.. A randomized, double-blind, cross-over clinical trial to determine the effect of DRI (aliskiren 300 mg/day), with angiotensin converting enzyme inhibition (ACEi; ramipril 10 mg/day) as a positive control, on renal and systemic hemodynamics, and on RAAS activity (n = 15).. Mean (SEM) Glomerular filtration rate (101 (5) mL/min/1.73m2) remained unaffected by DRI or ACEi. Effective renal plasma flow (ERPF; 301 (14) mL/min/1.73m2) was increased in response to DRI (320 (14) mL/min/1.73m2, P = 0.012) and ACEi (317 (15) mL/min/1.73m2, P = 0.045). Filtration fraction (FF; 34 (0.8)%) was reduced by DRI only (32 (0.7)%, P = 0.044). Mean arterial pressure (109 (2) mmHg) was reduced by DRI (101 (2) mmHg, P = 0.008) and ACEi (103 (3) mmHg, P = 0.037). RAAS activity was reduced by DRI and ACEi. Albuminuria (20 [9-42] mg/d) was reduced by DRI only (12 [5-28] mg/d, P = 0.030).. In men with weight excess and hypertension, DRI and ACEi improved renal and systemic hemodynamics. Both DRI and ACEi reduced RAAS activity. Thus, DRI provides effective treatment in weight excess and hypertension.. Dutch trial register, registration number: 2532 www.trialregister.nl.

Topics: Albuminuria; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure Monitoring, Ambulatory; Cross-Over Studies; Double-Blind Method; Fumarates; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Kidney Diseases; Male; Middle Aged; Overweight; Ramipril; Renal Circulation; Renin; Renin-Angiotensin System

The aim of this study was to assess the antihypertensive efficacy and safety of aliskiren versus ramipril or losartan in hypertensive patients with type 2 diabetes mellitus, microalbuminuria and uncontrolled hypertension, despite the use of optimal conventional antihypertensive therapy.. In this open-label active comparator study, 126 patients were randomly assigned to receive 24 weeks of additional therapy with aliskiren (Group A) or either losartan or ramipril (Group B), according to whether a patient was already treated with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, respectively.. After 24 weeks, both treatment groups experienced a significant reduction of systolic blood pressure (-11.37% and -8.47%, respectively; both p <0.001 vs. baseline) and diastolic blood pressure levels (-10.67% and -9.28%, respectively; both p <0.001 vs. baseline), with a greater reduction of mean systolic values in Group A compared with Group B (p <0.001). Furthermore, after six months microalbuminuria was significantly decreased in both treatment groups (-67.62% and -49.1%, respectively; both p <0.001), with a reduction rate in Group A significantly higher than in Group B (p<0.001).. The addition of aliskiren to optimal conventional therapy provided a higher reduction of blood pressure and urinary albumin excretion when compared with the addition of losartan or ramipril.

Topics: Aged; Albuminuria; Amides; Blood Pressure; Creatinine; Diabetes Mellitus, Type 2; Diastole; Drug Therapy, Combination; Female; Fumarates; Humans; Hypertension; Losartan; Male; Potassium; Ramipril; Systole

The aim was to compare the antiproteinuric effect of aliskiren and ramipril in hypertensive patients with type 2 diabetes and microalbuminuria.. A total of 138 patients were treated with aliskiren 300 mg/day or ramipril 10 mg/day for 12 weeks and checked after 1, 2, 4, 8 and 12 weeks and 2 and 4 weeks after treatment withdrawal.. Clinic and ambulatory BP, urinary albumin excretion rate (UAER) and plasma aldosterone were measured.. Both aliskiren and ramipril induced a similar lowering in clinic and ambulatory BP (p < 0.001 vs baseline). However, such a lowering persisted longer after stopping aliskiren than after stopping ramipril regimen. Both treatments reduced UAER, but the decrease in UAER associated with aliskiren was more pronounced, the difference vs ramipril being maximal at week 12 (-42 vs -15%, p < 0.01). Two weeks after stopping therapy, UAER remained below baseline values with aliskiren, but not in the ramipril group. Plasma aldosterone decreased in the aliskiren group, whereas in the ramipril group it decreased until week 8 and thereafter increased toward baseline values.. Aliskiren has a greater and more prolonged antiproteinuric effect than R; it might partly be related to a higher degree of intrarenal renin-angiotensin-aldosterone system blockade.

Topics: Adult; Aged; Albumins; Albuminuria; Aldosterone; Amides; Antihypertensive Agents; Arterial Pressure; Biomarkers; Blood Pressure Monitoring, Ambulatory; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Ramipril; Renin; Single-Blind Method; Treatment Outcome

Aim of this study was to compare the antiproteinuric effect of imidapril (I) and ramipril (R) in diabetic hypertensive patients with microalbuminuria.. One hundred and seventy-six patients were randomised to I 10 - 20 mg once daily (od) (n = 88) or R 5 - 10 mg od (n = 88) for 24 weeks. Clinic, ambulatory, central blood pressure (BP), urinary albumin excretion (UAE), plasma Angiotensin II (Ang II), bradykinin and brain natriuretic peptide (BNP) were assessed at baseline and after 6, 12 and 24 weeks.. Both I and R produced a similar decrease in clinic, ambulatory and central BP (p < 0.001 vs baseline). Both treatments significantly reduced UAE throughout the study, but the decrease in UAE associated with I was more pronounced, being evident at week 6 (p = 0.05) and maximal at week 24 end-point (-42 vs -29%, p < 0.01). BNP and Ang II levels were similarly reduced by I and R, while bradykinin increased more with R (+132 vs +86%, p < 0.05).. These findings showed that in diabetic hypertensive patients with microalbuminuria, despite equivalent BP-lowering effect, I produced a greater antiproteinuric effect than R, which might be due to different intrinsic molecular properties of the two drugs.

Topics: Adult; Aged; Albumins; Albuminuria; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bradykinin; Diabetes Mellitus, Type 2; Female; Humans; Hypertension; Imidazolidines; Male; Middle Aged; Natriuretic Peptide, Brain; Prospective Studies; Ramipril; Treatment Outcome

The microvascular circulation plays an important role in bone health. This study examines whether albuminuria, a marker of renal microvascular disease, is associated with incident hip and pelvic fractures.. This study reanalyzed data from the Ongoing Telmisartan Alone and in combination with Ramipril Global End Point Trial/Telmisartan Randomized Assessment Study in Angiotensin-Converting Enzyme Intolerant Subjects with Cardiovascular Disease trials, which examined the impact of renin angiotensin system blockade on cardiovascular outcomes (n=28,601). Albuminuria was defined as an albumin-to-creatinine ratio≥30 mg/g (n=4597). Cox proportional hazards models were used to determine the association of albuminuria with fracture risk adjusted for known risk factors for fractures, estimated GFR, and rapid decline in estimated GFR (≥5%/yr).. There were 276 hip and pelvic fractures during a mean of 4.6 years of follow-up. Participants with baseline albuminuria had a significantly increased risk of fracture compared with participants without albuminuria (unadjusted hazard ratio=1.62 [1.22, 2.15], P<0.001; adjusted hazard ratio=1.36 [1.01, 1.84], P=0.05). A dose-dependent relationship was observed, with macroalbuminuria having a large fracture risk (unadjusted hazard ratio=2.01 [1.21, 3.35], P=0.007; adjusted hazard ratio=1.71 [1.007, 2.91], P=0.05) and microalbuminuria associating with borderline or no statistical significance (unadjusted hazard ratio=1.52 [1.10, 2.09], P=0.01; adjusted hazard ratio=1.28 [0.92, 1.78], P=0.15). Estimated GFR was not a predictor of fracture in any model, but rapid loss of estimated GFR over the first 2 years of follow-up predicted subsequent fracture (adjusted hazard ratio=1.47 [1.05, 2.04], P=0.02).. Albuminuria, especially macroalbuminuria, and rapid decline of estimated GFR predict hip and pelvic fractures. These findings support a theoretical model of a relationship between underlying causes of microalbuminuria and bone disease.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Fractures, Bone; Glomerular Filtration Rate; Hip Fractures; Humans; Pelvic Bones; Prospective Studies; Ramipril; Risk Factors; Telmisartan; Time Factors

In the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET), dual therapy did not reduce cardiovascular or renal outcomes compared with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers alone. Previous controlled trials with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers have demonstrated greater cardiovascular and renal benefit in people with renal risk. We hypothesized that dual therapy would be more effective than monotherapy in patients with low glomerular filtration rate and elevated albuminuria.. Post hoc analysis was performed of renal subgroups of dual therapy versus monotherapy for the ONTARGET study and angiotensin receptor blocker versus placebo for the Telmisartan Randomized Assessment Study in ACE Intolerant Subjects With Cardiovascular Disease (TRANSCEND). The studies featured hazard ratios by subgroups and Cox regression models with factors for treatment, subgroup, and interactions. The main cardiovascular outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure, and the main renal outcome was the composite of chronic dialysis or doubling of creatinine. In ONTARGET, there was no cardiovascular or renal benefit from dual over monotherapy in any subgroup, even with low glomerular filtration rate and/or elevated albuminuria. In TRANSCEND, in the comparison of angiotensin receptor blocker with placebo, there was a significant interaction for the main renal outcome (P = 0.01) in the direction of harm for patients with normoalbuminuria (0.37 versus 0.16 events per 100 patient-years; hazard ratio, 2.35; confidence interval, 1.33 to 4.15) but a trend to benefit with microalbuminuria (0.52 versus 0.89 events per 100 patient-years; hazard ratio, 0.60; confidence interval, 0.25 to 1.46) and macroalbuminuria (1.57 versus 2.60 events per 100 patient-years; hazard ratio, 0.71; confidence interval, 0.21 to 2.44).. This post hoc analysis does not support dual therapy over monotherapy in high-vascular risk patients with low glomerular filtration rate or albuminuria. This observation is a post hoc comparison and should be interpreted appropriately.. URL: http://clinicaltrials.gov Identifier: NCT00153101.

Topics: Aged; Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Creatinine; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Heart Failure; Heart Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Myocardial Infarction; Ramipril; Stroke; Telmisartan; Treatment Outcome

Hypertension treatment guidelines recommend that blood pressure (BP) be lowered to <140/90 mm Hg, but that a reduction to <130/80 mm Hg be adopted in patients at high cardiovascular (CV) risk. We investigated the CV and renal benefits associated with these BP targets in the high-CV-risk population of the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial (ONTARGET).. Patients were divided into 4 groups according to the proportion of in-treatment visits before the occurrence of an event (<25%->75%) in which BP was reduced to <140/90 or <130/80 mm Hg. After adjustment for demographic and clinical variables, a progressive increase in the proportion of visits in which BP was reduced to <140/90 or <130/80 mm Hg was associated with a progressive reduction in the risk of stroke, new onset of microalbuminuria or macroalbuminuria, and return to normoalbuminuria in albuminuric patients. An increased frequency of BP control to either target did not have any consistent effect on the adjusted risk of myocardial infarction and heart failure. The adjusted risk of CV events was reduced by increasing the frequency of BP control to <140/90 mm Hg, but not to <130/80 mm Hg. Similar findings were obtained for the achievement of the BP target in the visit preceding a CV event.. The more frequent achievement of the BP targets recommended by guidelines led to cerebrovascular and renal protection, but did not increase cardiac protection. Overall, CV protection was favorably affected by the less tight but not by the tighter BP target. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00153101.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Cardiovascular Diseases; Dose-Response Relationship, Drug; Drug Therapy, Combination; Guidelines as Topic; Humans; Incidence; Kidney Diseases; Middle Aged; Ramipril; Risk; Stroke; Telmisartan

This subgroup analysis assessed the effects of treatment based on the direct renin inhibitor, aliskiren, or the angiotensin-converting enzyme inhibitor, ramipril, on plasma renin activity (PRA), plasma renin concentration (PRC) and other biomarkers in a 26-week randomised, double-blind trial. Changes in PRA and PRC after stopping treatment were also assessed.. After placebo run-in, 842 patients (mean sitting diastolic blood pressure (BP) 95-109 mmHg) were randomised to aliskiren 150 mg or ramipril 5 mg. Dose titration and hydrochlorothiazide addition were allowed after Week 6 and 12, respectively, for inadequate BP control. Patients completing active treatment were re-randomised to current regimen or placebo during a 4-week posttreatment phase.. BP reductions were independent of baseline PRA at Week 12, were greater with aliskiren- than ramipril-based therapy at Week 26 (17.9/13.3 vs. 15.2/12.0 mmHg, p<0.05) and persisted for longer after stopping aliskiren. Aliskiren-based therapy reduced geometric mean PRA (-63%, p<0.05; n=103), while ramipril-based therapy increased PRA (+143%, p<0.05; n=100) at Week 26; PRC increased in both groups (aliskiren: +224% [n=33], ramipril: +145% [n=39], both p<0.05). Four weeks after stopping aliskiren-based therapy, PRA remained 52% below pre-treatment baseline; PRA returned to baseline 2 weeks after stopping ramipril-based therapy.. Aliskiren-based therapy produced sustained BP and PRA reductions over 26 weeks; ramipril-based therapy lowered BP and increased PRA. PRA reductions persisted 4 weeks after stopping aliskiren, suggesting an inhibitory effect beyond the elimination half-life of the drug.

Topics: Albuminuria; Amides; Antihypertensive Agents; Biomarkers; Blood Pressure; Creatinine; Demography; Diastole; Female; Fumarates; Humans; Hypertension; Male; Middle Aged; Ramipril; Renin; Renin-Angiotensin System; Systole; Time Factors

Micro-albuminuria is a marker for declining kidney function and predicts increasing cardiovascular risk especially in diabetic hypertensives. Angiotensin receptor blockers and angiotensin-converting enzyme inhibitors may slow the progression of proteinuric kidney disease and thus would be valuable in these high risk patients. The present study was undertaken to assess the efficacy and tolerability of a fixed dose combination (FDC) of telmisartan and ramipril in adult Indian patients with sustained stage 2 hypertension, comorbidities and micro-albuminuria. A total 382 patients were enrolled in this multicentric, prospective open, non-comparative phase IV postmarketing surveillance study by 40 physicians in India and treated with FDC of telmisartan 40 mg+ ramipril 5 mg once daily for 12 weeks. A total 370 patients completed the study but 12 patients were lost to follow-up and considered as drop-outs. There was a significant (p<0.05) reduction in the systolic blood pressure (SBP) from 170.89 at baseline to 132. 77 mm Hg at week 12 and diastolic blood pressure (DBP) from 104.47 to 83.30 mm Hg at the end of 12 weeks therapy as well as urine albumin levels from 186.25 mg/24-hour to 62.42 mg/24-hour (66.49%) at the end of 12 weeks. Overall assessment of treatment was rated as good to excellent in 87.3% and fair in 11.4% patients. The most common adverse event reported was cough (5.2%). Results of the present study indicate that the FDC of telmisartan+ramipril brings about significant reductions in the systolic and diastolic blood pressure as well as urine albumin excretion.

Topics: Adult; Aged; Aged, 80 and over; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Biomarkers; Female; Humans; Hypertension; Male; Middle Aged; Product Surveillance, Postmarketing; Prospective Studies; Ramipril; Telmisartan

Microalbuminuria independently predicts increased cardiovascular risk in hypertensive patients, especially in those with concomitant diabetes or established cardiovascular disease. Drugs that target the renin-angiotensin-aldosterone system reduce microalbuminuria regardless of diabetic status. The Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events was a multicenter, randomized, double-blind, placebo-controlled paralleled group study in which hypertensive patients with microalbuminuria and increased cardiovascular risk were randomized to 20 weeks treatment with ramipril plus irbesartan or to ramipril plus placebo. Patients discontinued or tapered previous antihypertensive therapy during a 14-day placebo lead-in period. Change in albumin excretion rate from baseline to week 20 was the primary end point. Adjusted week 20 baseline geometric ratios for ramipril plus irbesartan and ramipril plus placebo were not significantly different. Although differences in blood pressure reductions were observed between the two treatments, these changes did not affect microalbuminuria. More patients on dual therapy achieved target blood pressure goals at week 20 than with monotherapy. The incidence of adverse effects and treatment-related adverse effects was similar in both groups. Our results suggest that patients with cardiovascular risk and relatively low albumin excretion rates in early-stage disease may only require monotherapy with renin-angiotensin-aldosterone blocking agents.

Topics: Aged; Aged, 80 and over; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Cardiovascular Diseases; Female; Humans; Hypertension; Irbesartan; Male; Middle Aged; Ramipril; Tetrazoles; Treatment Outcome

To evaluate the impact of microalbuminuria (MAU) or tubular proteinuria (TPU) on cardiovascular and cerebrovascular events and all-cause mortality, and to assess whether a normalization of MAU and/or TPU induced by angiotensin-converting enzyme-inhibitor-based antihypertensive treatment with ramipril improves cerebrovascular prognosis in essential hypertensive patients without diabetes mellitus.. A prospective, controlled, multicenter study was performed involving 3529 hypertensive participants (average follow-up 42.5 months). Ramipril was the basic antihypertensive medication. Proteinuria analysis (albumin, alpha 1-microglobulin, SDS electrophoresis) was performed by quantitative measurement every year. Ambulatory blood pressure monitoring was performed once yearly. The main outcome determined was cardiovascular and cerebrovascular events and all-cause mortality.. In patients with TPU and/or MAU, the risk for endpoints increased significantly compared with normal (TPU, 30.0%; MAU, 54.7%; MAU + TPU, 64.0%; macroproteinuria, 74.4%). A change of protein excretion either from pathologic to normal or from normal to pathologic showed a clear trend to correlate with cerebrovascular endpoints (P = 0.056 and P = 0.055). Normal protein excretion at baseline and during follow-up indicated a significantly better prognosis than pathologic proteinuria at baseline and during follow-up. (P < 0.0001). TPU normalized in 31.9%, MAU in 30.6%, MAU + TPU in 29.3%, and macroproteinuria in 10.2% of patients. A total of 445 (25.4%) patients with normal protein excretion developed pathologic proteinuria during follow-up.. In non-diabetic hypertensive patients, MAU as well as TPU increases the incidence of cardiovascular events. Normalization of MAU, TPU or macroproteinuria during angiotensin-converting enzyme-inhibitor-based treatment correlates with a reduction of cardiovascular events. Beyond blood pressure control, normalization of MAU and TPU should be considered as a further therapeutic goal. There is a need for further studies to optimize treatment if proteinuria is unresponsive to angiotensin-converting enzyme inhibitors.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Blood Pressure; Cardiovascular Diseases; Female; Humans; Hypertension; Male; Middle Aged; Prospective Studies; Proteinuria; Ramipril; Stroke

To investigate whether a low dose of the angiotensin converting enzyme (ACE) inhibitor ramipril lowers cardiovascular and renal events in patients with type 2 diabetes who have microalbuminuria or proteinuria.. Randomised, double blind, parallel group trial comparing ramipril (1.25 mg/day) with placebo (on top of usual treatment) for cardiovascular and renal outcomes for at least three years.. Multicentre, primary care study conducted mostly by general practitioners in 16 European and north African countries.. 4912 patients with type 2 diabetes aged >50 years who use oral antidiabetic drugs and have persistent microalbuminuria or proteinuria (urinary albumin excretion > or = 20 mg/l in two consecutive samples), and serum creatinine < or = 150 micromol/l.. The primary outcome measure was the combined incidence of cardiovascular death, non-fatal myocardial infarction, stroke, heart failure leading to hospital admission, and end stage renal failure.. Participants were followed for 3 to 6 (median 4) years. There were 362 primary events among the 2443 participants taking ramipril (37.8 per 1000 patient years) and 377 events among the 2469 participants taking placebo (38.8 per 1000 patient years; hazard ratio 1.03 (95% confidence interval 0.89 to 1.20, P = 0.65)). None of the components of the primary outcome was reduced. Ramipril lowered systolic and diastolic blood pressures (by 2.43 and 1.06 mm Hg respectively after two years) and favoured regression from microalbuminuria (20-200 mg/l) or proteinuria (> 200mg/l) to normal level (< 20 mg/l) or microalbuminuria (P < 0.07) in 1868 participants who completed the study.. Low dose (1.25 mg) ramipril once daily has no effect on cardiovascular and renal outcomes of patients with type 2 diabetes and albuminuria, despite a slight decrease in blood pressure and urinary albumin. The cardiovascular benefits of a daily higher dose (10 mg) ramipril observed elsewhere are not found with an eightfold lower daily dose.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Double-Blind Method; Female; Humans; Male; Middle Aged; Ramipril; Risk Factors; Treatment Outcome

The study was conducted to evaluate efficacy and tolerability of fixed dose combination (FDC) of Losartan and Ramipril in the management of mild to moderate hypertensive Native Asian Indian patients with associated diabetes mellitus. The secondary objective was to evaluate the efficacy of the combination in reducing microalbuminuria.. The study was an open, non-comparative, multicentric clinical trial conducted in seven Indian centres in 315 eligible patients. All the patients were treated with Losartan 50 mg + Ramipril 2.5 mg or Losartan 50 mg + Ramipril 5 mg once a day in 12 weeks and consisted of a total of eight visits.. The mean age of patients was 52.93 years (range 45 - 60 years). Of the total patients, 62.86% were males and 37.14% were females. The mean prestudy systolic blood pressure was 160.56 +/- 14.44 which was significantly reduced to 126.85 +/- 9.78 at the end of 12 weeks (P < 0.001). Similarly the mean diastolic blood pressure was 98.91 +/- 8.33 at baseline (stage I) which was significantly reduced to 79.82 +/- 5.42 at the end of 12 weeks (P < 0.001). A mean fall of 33.72 mmHg in systolic blood pressure and the mean fall of 19.10 mmHg was observed in systolic and diastolic blood pressure respectively at the end of the treatment which was statistically highly significant (P < 0.001). The JNC-VII goal of blood pressure < 130/80 was achieved in 79.05% patients after the treatment which losartan and ramipril combination only. Microalbuminuria (urinary albumin excretion > 30 but < 300 mg/day) was seen in 83/250 (33.2%) patients and 135 (54%) patients had clinical proteinuria (albuminuria) at baseline. At the end of the therapy 20.8% patients achieved normoalbuminuria. Good to excellent efficacy response was reported in 98.09% patients and 98.41% patients reported good to excellent tolerability to the treatment.. The fixed dose combination of Losartan and Ramipril showed good to excellent efficacy response in 98.10% patients and achieved a target blood pressure of 130/80 mmHg in 79.05% patients in 12 weeks. The combination reduced the urinary albumin excretion in majority of the patients with microalbuminuria and proteinuria (the major marker of nephropathy).

Topics: Albuminuria; Antihypertensive Agents; Blood Pressure; Comorbidity; Diabetic Angiopathies; Drug Combinations; Female; Humans; Hypertension; Losartan; Male; Middle Aged; Ramipril; Treatment Outcome

Microalbuminuria and hypertension are risk factors for diabetic nephropathy in Type 2 diabetic patients. Recent data suggest that blockade of the renin-angiotensin system slows the progression of diabetic nephropathy; in contrast, the results on the renoprotective effect of calcium channel antagonists are conflicting. We evaluated the effectiveness of lercanidipine, in comparison with ramipril, on the reduction in albumin excretion rate (AER) and blood pressure in mild-to-moderate hypertensive patients with Type 2 diabetes and persistent microalbuminuria. A total of 277 patients were enrolled in a multicentric, randomized, double-blind, active-controlled, parallel-group trial; 180 were randomized to receive 10-20 mg/day of lercanidipine or 5-10 mg/day of ramipril and followed up for 9-12 months. The primary outcome was the change in AER from baseline. After 9-12 months of follow-up, a reduction in AER of -17.4+/-65 microg/min (p<0.05) and -19.7+/-52.5 (p<0.05) in the lercanidipine and ramipril group, respectively, was observed, without differences between the groups. A significant reduction in systolic and diastolic blood pressure was observed in both the lercanidipine and ramipril-based treatment groups (p<0.0001 for both). This study demonstrated that treatment with lercanidipine 10-20 mg/day does not worsen albuminuria in microalbuminuric Type 2 diabetic patients with hypertension. Indeed, both lercanidipine and ramipril treatments resulted in a significant reduction in AER without a statistically significant difference between the two groups.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Dihydropyridines; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Ramipril; Treatment Outcome

In people with diabetes, renal disease tends to progress from microalbuminuria to clinical proteinuria to renal insufficiency. Little evidence has been published for the nondiabetic population. This study retrospectively analyzed changes of proteinuria over 4.5 yr in the HOPE (Heart Outcomes and Prevention Evaluation) study, which compared ramipril's effects to placebo in 9297 participants, including 3577 with diabetes and 1956 with microalbuminuria. This report is restricted to 7674 participants with albuminuria data at baseline and at follow-up. Inclusion criteria were known vascular disease or diabetes plus one other cardiovascular risk factor, exclusion criteria included heart failure or known impaired left ventricular function, dipstick-positive proteinuria (>1+), and serum creatinine >2.3 mg/dl (200 microM). Baseline microalbuminuria predicted subsequent clinical proteinuria for the study participants overall (adjusted odds ratio [OR], 17.5; 95% confidence interval [CI], 12.6 to 24.4), in participants without diabetes (OR, 16.7; 95% CI, 8.6 to 32.4), and in participants with diabetes (OR, 18.2; 95% CI, 12.4 to 26.7). Any progression of albuminuria (defined as new microalbuminuria or new clinical proteinuria) occurred in 1859 participants; 1542 developed new microalbuminuria, and 317 participants developed clinical proteinuria. Ramipril reduced the risk for any progression (OR, 0.87; 95% CI, 0.78 to 0.97; P = 0.0146). People without and with diabetes who are at high risk for cardiovascular disease are also at risk for a progressive rise in albuminuria. Microalbuminuria itself predicts clinical proteinuria in nondiabetic and in diabetic people. Ramipril prevents or delays the progression of albuminuria.

Topics: Aged; Albuminuria; Antihypertensive Agents; Cardiovascular Diseases; Diabetic Nephropathies; Disease Progression; Female; Follow-Up Studies; Humans; Male; Middle Aged; Predictive Value of Tests; Ramipril; Renal Insufficiency; Risk Factors

The DIABHYCAR (type 2 DIABetes, Hypertension, CArdiovascular Events and Ramipril) study allowed investigators to analyze factors leading to the development of congestive heart failure (CHF) in type 2 diabetic patients with abnormal urinary albumin concentration.. Type 2 diabetic subjects of both sexes aged >or=50 years who had a urinary albumin concentration >or=20 mg/l were randomly allocated to 1.25 mg/day ramipril or placebo in addition to their usual treatment and treated for 3-6 years in a double-blind fashion. Major outcomes including hospitalization for CHF were recorded during the follow-up.. Of the 4912 included patients, 187 developed CHF during the study. There was no significant difference in the incidence of CHF between the two treatment groups. Using a multivariate analysis, independent risk factors for the occurrence of CHF were age, history of cardiovascular disease, baseline urinary albumin concentration, baseline HbA(1c), and smoking habits. A total of 68 of the 187 patients (36.4%) died during the 12 +/- 11-month period after the first hospitalization for CHF, whereas the annual mortality rate of the population who did not develop CHF was 3.2%.. Presence of atherosclerotic disease, baseline urinary albumin concentration, and HbA(1c) level were indicators for further development of CHF. Occurrence of CHF is a major prognostic turn in a diabetic patient's life.

Topics: Aged; Albuminuria; Antihypertensive Agents; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Female; Heart Failure; Humans; Hypertension, Renal; Incidence; Male; Middle Aged; Patient Selection; Predictive Value of Tests; Prognosis; Ramipril; Risk Factors

The aim of this work was to ascertain, in nonmodulating essential hypertension, whether the abnormality in the renal blood supply is extended to the extremities and showed a similar response to ACE inhibition and whether these abnormalities could be identified in normotensive offspring of hypertensives, as non-modulation is a familial process with genetic underpinnings. We measured forearm vascular blood flow (FBF) and forearm vascular resistance (FVR) by plethysmography and urinary albumin excretion in 20 normotensive without family story of hypertension (NT: 25+/-9 years), 10 modulating offspring of hypertensive parents (MHO: 25+/-6 years), 10 nonmodulating offspring of hypertensive parents (NMHO: 26+/-5 years), 12 modulating essential hypertensives (MHT: 34+/-5 years), and 11 nonmodulating essential hypertensives (NMHT: 32+/-4 years). Measurements were repeated in hypertensives after 3-month treatment with ramipril (5 mg daily). Nonmodulating individuals showed lower maximum FBF (NMHT: 41.96+/-3.3 mL/100 g per minute and NMHO: 35.6+/-9.0 mL/100 g per minute) than modulating subjects (MHT: 57.5+/-10.0 mL/100 g per minute and MHO: 51.8+/-7.0 mL/100 g per minute; P<0.003). Likewise, all nonmodulating subjects showed higher minimum FVR (NMHT: 2.5+/-0.2 AU; NMO: 2.8+/-0.5 AU) than modulating individuals (MHT: 1.9+/-0.5 AU; MHO, 1.8+/-0.3AU; P<0.025). Urinary albumin excretion was higher in NMHT and NMHO than MHT, MHO, and NT (P<0.05). Ramipril increased maximum FBF to 53.8+/-8.0 mL/100 g per minute and reduced minimum FVR to 1.9+/-0.5 AU in NMHT (P<0.01). Likewise, ramipril increased effective renal plasma flow and reduced renal vascular resistance and urinary albumin excretion only in NMHT (P<0.05). These results have shown an early involvement of the peripheral circulation in association with increased urinary albumin excretion not only in essential hypertensives but also in NMHO. The effectiveness of ramipril in reducing minimum FVR and urinary albumin excretion in NMHT also suggests a common mechanism.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Family Health; Female; Forearm; Glomerular Filtration Rate; Humans; Hypertension; Male; Plethysmography; Ramipril; Regional Blood Flow; Renal Circulation; Sodium; Vascular Resistance

In patients with type 2 diabetes with overt nephropathy, the risk for progressive renal failure is high. This risk is less well established for those with type 2 diabetes and microalbuminuria or normalbuminuria. We studied changes in serum creatinine levels during 3.5 to 5.5 years in a large cohort of people with diabetes at high cardiovascular risk with microalbuminuria or normalbuminuria.. Retrospective analysis of serum creatinine levels at baseline and yearly thereafter was performed in the Microalbuminuria and Renal Outcomes in the Heart Outcomes and Prevention Evaluation study comparing ramipril's effects with placebo during 4.5 years in 3,577 participants with diabetes, including 1,139 participants with microalbuminuria and 333 participants with renal insufficiency. Participants with dipstick-positive proteinuria (>1+) or serum creatinine levels greater than 2.3 mg/dL (200 micromol/L) were excluded.. Serum creatinine levels did not increase significantly during the study if all participants with diabetes are considered or for subgroups with microalbuminuria and/or renal insufficiency at baseline. However, slopes of serum creatinine over time showed a significant trend for increasing values. There were no differences between the placebo and ramipril-treated groups. A serum creatinine level of 1.4 mg/dL (125 micromol/L) or greater newly developed in 474 of 3,238 people (243 patients, placebo; 231 patients, ramipril; P = 0.5033). A doubling of baseline serum creatinine level or end-stage renal disease developed in 8 of 333 participants with renal insufficiency at baseline.. In people with type 2 diabetes, but without overt nephropathy, who are at high risk for cardiovascular disease, progression of renal insufficiency is slow on the basis of changes in creatinine levels. On the basis of reaching threshold levels of renal function, progression rates are clinically meaningful, especially considering population life expectancy.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biomarkers; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Double-Blind Method; Female; Humans; Male; Middle Aged; Ramipril; Renal Insufficiency; Retrospective Studies; Risk Factors; Statistics as Topic

Albuminuria has been shown to identify patients with an increased cardiovascular risk, and in clinical studies ACE inhibitors reduce the urinary protein excretion. It was the primary aim of this intensified monitoring project to determine whether these results can be reproduced in a clinical practice setting. Micro- (2.7-22.6 mg albumin/mmol creatinine) or macroalbuminuria (>22.6 mg/mmol) was confirmed by a central laboratory in 598 out of 773 patients with hypertension who had albuminuria >50 mg/l on a Micral Test II performed by 147 general practitioners. Coronary heart disease (prevalence rates 15% in patients with normalbuminuria, 33% in patients with microalbuminuria, and 40% in patients with macroalbuminuria), heart failure (prevalence rates 19, 29, and 32%, respectively), left ventricular hypertrophy (prevalence rates 30, 42, and 38%, respectively), and peripheral vascular disease (prevalence rates 7, 15, and 20%, respectively) were significantly more common in patients with elevated urinary albumin excretion. 230 patients with microalbuminuria and 202 subjects with macroalbuminuria were treated with the angiotensin-converting enzyme inhibitor ramipril for 6 months. The treatment significantly lowered mean arterial blood pressure (from a median value of 120 mm Hg, quartiles 113-125 mm Hg, to 103 mm Hg, quartiles 100-109 mm Hg) as well as urinary albumin excretion (from a median value of 18 mg/mmol creatinine, quartiles 7.2-54.6 mg/mmol creatinine, to 6.5 mg/mmol creatinine, quartiles 1.6-23.1 mg/mmol creatinine). The treatment efficacy was unaffected by age, body mass index, and smoking status. Patients with diabetes mellitus type II and heart failure also had a significant, although less pronounced reduction of albuminuria. In summary, we conclude that ramipril is able to reduce the urinary albumin excretion in a clinical practice setting, as has been shown in clinical studies. However, the treatment response is not completely uniform, as special patient populations seem to be more resistant to therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Austria; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Creatinine; Female; Glycated Hemoglobin; Humans; Lipids; Male; Middle Aged; Monitoring, Physiologic; Proteinuria; Ramipril; Risk Factors

To study whether administration of 1.25 and 5.0 mg ramipril daily, compared with placebo treatment, reduces the urinary albumin excretion rate (UAER) in normotensive patients with type 1 diabetes.. Ramipril was administered double blind at two different doses (1.25 [n = 19] and 5.0 mg [n = 18]), and compared with placebo (n = 18) after a single-blind placebo period of 1-4 weeks. The patients (total, n = 55; women, n = 14) were followed for 2 years. To document an effect on the renin-angiotensin system, ACE activity and plasma-renin activity (PRA) were measured. In addition, 24-h ambulatory blood pressure (BP) was recorded at baseline and repeated after 1 and 2 years using a Spacelab 90207 ambulatory BP recording device (Spacelab, Redmont, CA).. Both doses of ramipril were sufficient to reduce ACE activity and to increase PRA significantly as compared with placebo (P < 0.05 for both). On the other hand, neither ambulatory nor clinic BP was affected by either dose of ramipril compared with the placebo group. There was no progression of UAER in the placebo group during the 2 years of the study. Analysis of covariance showed no differences in UAER between the three treatment groups at year 1 (P = 0.94) or year 2 (P = 0.97), after adjusting for baseline. Furthermore, there were no statistically significant changes from baseline UAER within any of the three treatment groups.. Treatment with ramipril did not affect microalbuminuria or clinic or ambulatory BP in this study. On the basis of the present study, we question the clinical use of ACE inhibitors in stably normotensive patients with type 1 diabetes and microalbuminuria in whom a concomitant reduction in BP is not demonstrated.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Male; Peptidyl-Dipeptidase A; Placebos; Ramipril; Renin; Single-Blind Method; Time Factors

The renoprotective effect of ACE inhibition in chronic renal disease is well established but the studies on effects of calcium antagonists on progression of renal disease and on proteinuria have given varying results.. We conducted an open long-term randomized prospective multi-centre study comparing the combination of ramipril and felodipine ER (F) with either drug alone in non-diabetic renal disease. Included were patients with uncontrolled hypertension (diastolic blood pressure (DBP)) > or =95 mmHg on treatment with a diuretic and a beta-blocker. Fifty-one patients received the combination of R and F, 54 patients R, and 53 patients F. The treatment goal was a DBP <90 mmHg and a similar BP reduction in the three groups. Mean doses at the last visit were 5+5, 10 and 9 mg, respectively, after a mean treatment time of nearly 2 years. The progression of renal impairment was studied by serial measurements of serum creatinine, iohexol clearance, and albuminuria.. The reduction in supine systolic (S) BP and DBP expressed as median values were -19.0/-14.5,-14.3/-15.0 and -13.5/-13.3 mmHg in the R+F, R, and F groups, respectively. There was no significant difference between the groups. When correction for the acute drug effect was performed the R+F group had a slower progression rate of the renal disease (loss of glomerular filtration rate (GFR) ml/min/year) compared with the F group (P<0.05) but not to the R group (P>0.20). There was a rise in albuminuria after 2 years in the F group (P<0.05), but no significant change was found in the other groups.. In patients with non-diabetic renal disease the combination of an ACE inhibitor and a calcium antagonist in reduced doses used in addition to baseline therapy with beta-blockers and diuretics, tended to cause a better BP reduction as each drug per se. The R+F treatment also caused a slower progression of the renal disease compared with F alone. The combination treatment seems to afford better BP control and appears to be a favourable therapeutic option in patients with renal disease and hypertension.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Disease Progression; Drug Combinations; Felodipine; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies; Ramipril

The Heart Outcomes Prevention Evaluation (HOPE) study found that the ACE inhibitor ramipril can lower the risk of atherosclerotic disease events and death in patients without heart failure but with known atherosclerosis or with diabetes plus at least one cardiovascular risk factor. This benefit was independent of ramipril's effect on blood pressure. Additional benefits were a reduced risk of diabetic nephropathy in diabetic patients, and a lower likelihood of newly diagnosed diabetes. On the other hand, vitamin E in the doses and duration studied (400 IU/day for 4.5 years) did not lower risk significantly.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Double-Blind Method; Female; Humans; Hypertension; Male; Middle Aged; Ramipril; Risk Factors; Treatment Outcome; Vitamin E

Whether ACE inhibition is useful for type 2 diabetic patients with micro- and macroalbuminuria remains unknown. The Non-Insulin-Dependent Diabetes, Hypertension, Microalbuminuria, Cardiovascular Events and Ramipril (DIABHYCAR) Study was set up to address this issue through a multicenter double-blind parallel placebo-controlled > or = 3-year trial in Europe and North Africa. In this article, we report the characteristics of the randomized patients.. The main selection criteria were as follows: men or women aged > or = 50 years with type 2 diabetes treated with oral antidiabetic drugs, with or without hypertension, with a plasma creatinine level < 150 mumol/l, and with persistent micro- or macroalbuminuria, as assessed centrally by two successive urine samples containing a urinary albumin concentration > or = 20 mg/l. Patient characteristics were studied by comparing patients who were randomized to those who were not, taking their geographical origin into account.. There were 25,455 patients screened for urinary albumin (20,296 from France, 918 from Germany, 1,019 from Northwest Europe, 969 from Central Europe, 959 from Mediterranean Europe, and 1,294 from North Africa). Of these patients, 4,937 were randomized. Compared with the nonrandomized patients, the randomized patients were older, more often men, more obese, had higher systolic/diastolic blood pressure and plasma glucose, smoked more tobacco, drank more alcohol, and had complications more frequently. Using a logistic regression analysis, all the above-mentioned items appeared as independent determinants for randomization into the study, with the exception of alcohol intake. The contribution of each item varied slightly from one geographical origin to another.. The physical, biological, and behavioral characteristics create a poor renal and cardiovascular prognosis for the type 2 diabetic patients randomized to the DIABHYCAR Study because of micro- and macroalbuminuria. Testing the usefulness of ACE inhibition for the type 2 diabetic patients with microalbuminuria seems feasible through the DIABHYCAR Study.

Topics: Africa, Northern; Albuminuria; Alcohol Drinking; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Complications; Diabetes Mellitus, Type 2; Double-Blind Method; Europe; Female; Humans; Male; Middle Aged; Obesity; Placebos; Ramipril; Smoking

The non-insulin-dependent DIABetes, HYpertension, microalbuminuria or proteinuria, CARdiovascular events, and Ramipril (DIABHYCAR) study is a randomized, prospective, double-blind, placebo-controlled, multicenter international trial of the ACE inhibitor ramipril (1.25 mg/day) in patients with type II diabetes and micro- or macroalbuminuria. The main outcome of the study is the time to first occurrence of either death from a cardiovascular origin, including sudden death, nonfatal myocardial infarction, stroke, or congestive heart failure, or requirement of hemodialysis or renal transplantation. The study was launched in France in early 1995 with the participation of general practitioners only, but had to be extended to 15 other countries in 1997 due to difficulties in recruitment. Since 2.5 years after the beginning of the trial the observed event rate was much less than anticipated, it was decided to increase recruitment and follow-up duration and to include congestive heart failure in the definition of the main outcome to keep the study power at a satisfactory level. Recruitment ended on April 1, 1998 with 4937 randomized patients. Following the early discontinuation for efficacy of another study of ramipril in high cardiovascular risk patients, the Heart Outcomes Prevention Evaluation study (HOPE), the second interim analysis of DIABHYCAR was performed early (when 406 instead of 500 patients presented a main outcome) and the Data Safety and Monitoring Board recommended that the study continue. Follow-up is planned to end on March 31, 2001.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Clinical Trials as Topic; Data Interpretation, Statistical; Diabetes Mellitus, Type 2; Europe; Female; France; Humans; Male; Multicenter Studies as Topic; Patient Selection; Ramipril; Randomized Controlled Trials as Topic; Research Design; Sample Size

Inhibition of the angiotensin-converting enzyme (ACE) exerts a renoprotective effect in adult patients with chronic kidney disease. We evaluated prospectively changes in blood pressure (BP), protein excretion and renal function after administration of the long-acting ACE inhibitor ramipril as monotherapy during 6 months in 14 moderately hypertensive children aged 5-18 years with various nephropathies. Four patients initially had a decreased glomerular filtration rate (GFR below 60 ml/min/1.73 m2). BP was evaluated by ambulatory 24-h monitoring. After 2 weeks of treatment by oral ramipril (1.5 mg/m2 once daily), mean values of systolic and diastolic 24-h ambulatory BP fell by more than 5 mmHg in nine patients. In eight patients the dose was doubled. At the end of the study systolic BP was below the 95th percentile in 9 and diastolic BP in 13 patients. The initially reduced nocturnal dip increased significantly. Of 11 patients with an increased albumin excretion (median 1.3 g/g creatinine), 6 responded to ramipril by a median reduction of 78% (range 24-83%), whilst in 5 albuminuria increased (median +19%). GFR was well preserved and no other adverse effects from the drug were noted. The study demonstrates that ramipril is an efficacious antihypertensive agent in children with renal hypertension. It is well tolerated, even in mild renal insufficiency. In addition, the drug has a persistent antiproteinuric action in about half of the patients contributing to conserve renal function.

Topics: Adolescent; Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Child; Child, Preschool; Diastole; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Male; Ramipril; Systole

To assess if low (1.25 mg) and/or standard (5 mg) doses of the ACE inhibitor ramipril could prevent progression of microalbuminuria (incipient diabetic nephropathy) in normotensive type 1 diabetic patients.. This study, using a multicenter randomized placebo-controlled double-blind parallel group, was conducted over 2 years in 28 outpatient diabetic clinics in the U.K. and Ireland. We screened 334 type 1 diabetic patients with suspected microalbuminuria and normal blood pressure; of these, 140 patients 18-65 years of age with a diagnosis of type 1 diabetes and persistent microalbuminuria, defined as urinary albumin excretion rate (AER) of 20-200 microg/min, were enrolled in the study.. The proportion of patients progressing to macroalbuminuria was reduced in the ramipril groups but did not reach statistical significance over 2 years. AER was significantly lower at year 2 in the combined ramipril-treated patients versus placebo (P = 0.013). More patients on ramipril regressed to normoalbuminuria (<20 microg/min), with 11% for 1.25 mg ramipril, 20% for 5 mg ramipril, and 4% for placebo (P = 0.053). Blood pressure was significantly reduced to a similar extent with both 1.25 and 5 mg ramipril. Supine systolic blood pressure increased from 130 to 134 mmHg in the placebo group and fell in the 1.25 mg ramipril group (from 132 to 129 mmHg) and in the 5 mg ramipril group (from 134 to 130 mmHg) (P = 0.003, compared with placebo). No statistically significant changes were observed in glomerular filtration rate (GFR) between the placebo- and ramipril-treated groups during the 2-year period.. Microalbuminuria is reduced significantly by ramipril treatment in type 1 diabetic patients without hypertension. Although the magnitude of the response was greater, there is no significant difference between responses to 1.25 or 5 mg ramipril. Small but highly significant reductions in systolic and mean arterial pressures occur in ramipril-treated patients. GFR is stable at this stage of the evolution of diabetic nephropathy and is unaffected by ramipril treatment for 2 years.

Topics: Adolescent; Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Humans; Ireland; Male; Middle Aged; Placebos; Ramipril; United Kingdom

The aim of this study was to compare the effects of ramipril and nitrendipine chronic treatment on urinary albumin excretion (UAE) in hypertensive patients with type II non-insulin-dependent diabetes mellitus (NIDDM) and impaired renal function. A 2-year, prospective, randomised study was conducted on 51 men with a diastolic blood pressure (DBP) > or =95 and < or =105 mm Hg, stable NIDDM, serum creatinine between 1.6 and 3.0 mg/dl and persistent UAE >300 and <2000 mg/24 h. After a 3-month preliminary observation period, during which patients began a low-protein, low-sodium diet, and a subsequent 4-week run-in period on placebo, patients were randomly treated with ramipril 5 mg or nitrendipine 20 mg for 2 years. Both drugs similarly reduced BP without affecting glucose homeostasis. In the ramipril group UAE significantly decreased after only 3 months of treatment, whereas in the nitrendipine group a significant although lesser reduction in UAE was observed only after 1 year. During the second year the UAE% change was not statistically different between the two treatments. Serum creatinine and creatinine clearance showed no significant change with both drugs. The progression of renal insufficiency as assessed by the rate of reduction of creatinine clearance over the 2 years of the study was similar in the ramipril and the nitrendipine groups. In conclusion both ramipril and nitrendipine were associated with a decrease in UAE although such a reduction was earlier and more marked with ramipril. The decline of renal function did not differ significantly between the two treatments.

Topics: Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Creatinine; Diabetes Mellitus, Type 2; Humans; Hypertension; Kidney; Longitudinal Studies; Male; Middle Aged; Nitrendipine; Prospective Studies; Ramipril

To evaluate the effect of the ACE inhibitor ramipril as compared with placebo on left ventricular mass index (LVMI) in normotensive, nonalbuminuric NIDDM patients with left ventricular hypertrophy (LVH). Patients with NIDDM are characterized by excessive cardiovascular morbidity and mortality, and LVH, an independent risk factor for cardiac events, is often present in NIDDM patients.. A total of 38 normotensive, nonalbuminuric (albuminuria < 100 mg/24 h) NIDDM patients with LVH (LVMI > 131 g/m2 in men and > 100 g/m2 in women) were enrolled in a 6-month randomized, double-blind parallel group study to compare the effects of ramipril (5 mg/day) with placebo on LVMI (echocardiography, Vingmed CFM725, Diasonics Sonotron), QTc dispersion determined as the interlead variation in QTc interval on standard electrocardiogram (ECG), and 24-h ambulatory blood pressure (A&D TM2420, Tokyo, Japan). A total of 16 ramipril (10 men, 60 +/- 9 years [mean +/- SD]) and 15 placebo-treated (8 men, 55 +/- 10 years) patients completed the study, and their data are presented.. Ambulatory blood pressure was almost identical at baseline (132/76 +/- 3/1 vs. 133/74 +/- 5/2 mmHg [mean +/- SEM]) and remained stable during follow-up (134/76 +/- 3/1 vs. 136/74 +/- 6/2 mmHg) in the ramipril and placebo group, respectively. LVMI was comparable at baseline (137.1 +/- 7.0 vs. 129.6 +/- 3.7 g/m2) in the ramipril and placebo group, respectively, and decreased significantly more in the ramipril group as compared with the placebo group (17.6 +/- 3.0 vs. 5.7 +/- 4.6 g/m2, respectively, 11.9 [0.7-23.1] g/m2, mean difference [95% CI]; P = 0.037). QTc dispersion was comparable at baseline (60.2 [5.5] vs. 64.1 [6.5] ms) and did not change significantly during follow-up: -2.5 [7.0] vs. -12.2 [9.5] ms; mean difference 9.8 (-14.2 to 33.8 ms) in the ramipril and placebo group, respectively.. Ramipril induces regression of LVH in normotensive, nonalbuminuric NIDDM patients, independent of reduction in systemic blood pressure.

Topics: Aged; Albuminuria; Antihypertensive Agents; Biomarkers; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Electrocardiography; Female; Heart Ventricles; Humans; Hypertrophy, Left Ventricular; Male; Middle Aged; Ramipril; Reference Values; Treatment Outcome

In a randomized, double-blind, placebo-controlled study, we investigated in normotensive type 2 diabetics with microalbuminuria the effect of ramipril, an ACE inhibitor, on urine albumin excretion and serum lipids. A total of 1,882 patients were screened for urine microalbumin consecutively by dipstick test, Rapi Tex-Albumin test and RIA. The final 28 normotensive and microalbuminuric patients were assigned to receive either ramipril (1.25 mg/d, n = 16) or placebo (n = 12) for 12 weeks. Throughout the study, both groups had no changes in blood pressure, fasting plasma glucose, HbA1C, serum creatinine and electrolytes and no difference in creatinine clearance. At week 12 only the placebo group showed the significant increment of urine albumin excretion and triacylglycerol (30.6 +/- 38.3 to 39.0 +/- 19.7 and 167 +/- 64 to 208 +/- 77 mg/dl, respectively) but the decrement of HDL-cholesterol (46 +/- 16 to 35 +/- 6 mg/dl). During a 3 month period, increased urine albumin excretion was observed in normotensive type 2 diabetes with microalbuminuria who received only placebo. We conclude that ramipril may arrest the progression of albumin excretion and had favorable effects on serum lipids. Ramipril was safe and well-tolerated without untoward side effects during the study period.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Hyperlipidemias; Ramipril

The effects of an ACE-inhibitor (ramipril), a calcium antagonist (felodipine) and placebo on glomerular filtration rate (GFR), urinary albumin/creatinine ratio, blood pressure (BP) and vasoactive hormones were investigated in a randomized, prospective, double-blind, placebo-controlled study of patients with chronic glomerulonephritis and hypertension, with measurements at entrance and after 12 and 24 months. In total, 33 patients were included: 21 completed the study with 7 patients in each group. GFR was measured as 51Cr-EDTA clearance and the vasoactive hormones with radioimmunoassays. The reduction in GFR was significantly more pronounced in the felodipine group (-7 ml/min) than in the ramipril group (0 ml/min) but the same as in the placebo group (-6 ml/min). The urinary albumin/creatinine ratio was significantly more reduced in the ramipril group (-74 mg/mmol) than in the placebo group (-11 mg/mmol), which did not deviate from the felodipine group (-10 mg/mmol). BP was significantly reduced by ramipril and felodipine, but not by placebo. Angiotensin II and aldosterone in plasma increased or tended to increase in the felodipine and placebo groups, but were unchanged in the ramipril group. Endothelin increased only in the placebo group, and vasopressin, atrial natriuretic peptide, and brain natriuretic peptide were not significantly changed in any of the groups. It is concluded that ramipril seems to be superior to felodipine in chronic glomerulonephritis owing to better preservation of GFR.

Topics: Adolescent; Adult; Aged; Albuminuria; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Double-Blind Method; Endothelins; Felodipine; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Male; Middle Aged; Placebos; Prospective Studies; Ramipril

To describe the rationale and design of a large international study (microalbuminuria, cardiovascular, and renal outcomes [MICRO] in the HOPE [Heart Outcomes Prevention Evaluation] study) of an ACE inhibitor and vitamin E for the prevention of diabetic nephropathy (DN) and cardiovascular disease (CVD) in patients with diabetes and microalbuminuria (MA).. A total of 3,657 diabetic subjects, including 1,129 with MA, are randomly allocated to receive the ACE inhibitor ramipril (or placebo) and vitamin E (or placebo) for 4 years in a two-by-two factorial design. Diabetic subjects are a subset of the 9,541 subjects enrolled in the HOPE study.. The development of DN in microalbuminuric diabetic subjects and the development of MA in normoalbuminuric subjects, as well as cardiovascular death, myocardial infarction, and storke, are the main outcomes. The correlation of changes in albuminuria with changes in carotid atherosclerosis documented in a subset of subjects will also be analyzed.. The effect of both an ACE inhibitor and vitamin E on the progression of renal and CVD in patients with diabetes is being assessed in the MICRO-HOPE study.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Factor Analysis, Statistical; Humans; Middle Aged; Placebos; Ramipril; Research Design; Risk Factors; Time Factors; Vitamin E

Angiotensin-converting enzyme inhibitors reduce proteinuria in both normotensive and hypertensive patients with proteinuric renal disease. However, the mechanism of the antiproteinuric effect has not been clarified. We performed a prospective, double-blind, placebo-controlled, randomized crossover trial to test the hypothesis that the antiproteinuric effect of ramipril was due to an improvement in glomerular permselectivity independent of blood pressure and glomerular filtration rate. The effect of low-dose (1.25 mg/d) and high-dose (5 mg/d) ramipril was assessed in 15 normotensive nondiabetic patients with proteinuria (> 150 mg/d). The study was divided into four 12-week periods: placebo, high- or low-dose ramipril, crossover to low- or high-dose ramipril, and placebo. Blood pressure, glomerular filtration rate, renal plasma flow rate, urinary protein excretion rate, and plasma angiotensin II levels were measured at the end of each period. Mean arterial pressure, urine protein to creatinine ratio, and albumin excretion rate decreased significantly during low- and high-dose ramipril. Glomerular filtration rate and renal plasma flow rate were not changed significantly. Plasma angiotensin II levels decreased with both low- and high-dose ramipril. There were no episodes of hypotension and only one subject developed cough during ramipril that did not require discontinuation of the study drug. In conclusion, administration of ramipril in both low and high doses lowered blood pressure and reduced proteinuria in this cohort of normotensive patients with a variety of proteinuric renal diseases. The antiproteinuric effect of ramipril is probably mediated by a reduction in glomerular capillary pressure.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Albuminuria; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Cross-Over Studies; Diabetes Mellitus; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies; Proteinuria; Ramipril; Renal Plasma Flow

The clinical importance of selection of different antihypertensive drugs for the treatment of diabetic patients is still unclear. Thus we performed a randomised, controlled study in 105 hypertensive non-insulin-dependent diabetic (NIDDM) patients with microalbuminuria over 1 year. Patients received either the angiotensin converting enzyme (ACE) inhibitor ramipril (2.5-5.0 mg/day; in addition 24% of patients also received felodipine) or the beta blocking agent atenolol (50-100 mg/day; in addition 24% of patients also received hydrochlorothiazide). Blood pressure, metabolic control, lipid levels and albumin excretion rate were studied during the follow-up. After 1 year an almost identical fall (p < 0.001) in blood pressure was observed with ramipril (170/100 vs 150/ 85 mmHg, median) and atenolol (180/100 vs 150/ 80 mmHg, median). With ramipril a reduction of total cholesterol (6.3 vs 5.9 mmol/l), of LDL cholesterol (3.8 vs 3.6 mmol/l) and HDL cholesterol (1.3 vs 1.2 mmol/l) was found, whereas triglycerides slightly increased (1.8 vs 2.0 mmol/l). With atenolol a similar reduction of total cholesterol (6.3 vs 5.9 mmol/l), LDL cholesterol (3.8 vs 3.7 mmol/l) and HDL cholesterol (1.4 vs 1.2 mmol/l) and an increase of triglycerides (1.4 vs 1.7 mmol/l) was noted. Metabolic control of the patients was maintained with both ramipril and atenolol treatment. With ramipril treatment urinary albumin creatinine ratio (14.4 vs 13.8 mg/mmol) and creatinine clearance (82 vs 84 ml/min) were constant, but with atenolol an increase of albumin creatinine ratio (13.9 vs 19 mg/mmol, p < 0.001) and a slight decrease of creatinine clearance (80 vs 66 ml/min, p < 0.05, not significant after Bonferroni correction) was observed.. 1-year treatment of NIDDM patients with ramipril or atenolol does not influence metabolic control, the changes in serum lipids were similar. Despite almost identical blood pressure reduction in both groups the albumin creatinine ratio was constant under ramipril, but increased under atenolol treatment.

Topics: Adrenergic beta-Antagonists; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Atenolol; Blood Pressure; Cohort Studies; Creatinine; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Felodipine; Female; Humans; Kidney; Male; Middle Aged; Prospective Studies; Ramipril; Vasodilator Agents

Microalbuminuria and proteinuria are strong independent predictors for increased cardiovascular mortality in non-insulin-dependent diabetic (NIDDM) patients. In such patients, angiotensin converting enzyme (ACE) inhibition improves the evolution of diabetic nephropathy; however, no data are currently available on the effects of such intervention on cardiovascular morbidity and mortality. The aim of the Diab-Hycar study is to test the hypothesis that ACE inhibition with a low daily dose of 1.25 mg ramipril, which has no significant effect on blood pressure, may reduce cardiovascular morbidity and/or mortality in normotensive or hypertensive NIDDM patients with persistent albuminuria. Selected and followed by general practitioners, 4000 patients will receive their usual oral antidiabetic treatment and if necessary antihypertensive treatment (ACE inhibitors excluded). In addition in a randomized, double-blind trial they will be given either a placebo or 1.25 mg ramipril daily. The follow-up is currently scheduled to last 3 years. The efficacy of ACE-inhibition will be assessed by the following major end-points: cardiovascular death, sudden death, myocardial infarction, stroke, renal replacement therapy. The Diab-Hycar study started on 3 February 1995. By 1 September 1995, 11,000 urine samples were tested. The prevalence of persistent albuminuria was 23%, 964 patients were initially included in the study, with 619 eligible patients included soon after. Different strategies have been developed to record cardiovascular events correctly and to minimize the number of patients lost to follow-up.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Clinical Protocols; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Female; Follow-Up Studies; Humans; Hypertension; Male; Middle Aged; Patient Selection; Proteinuria; Ramipril

The purpose of this study was to compare the effects of ramipril and nitrendipine on urinary albumin excretion (UAE) in hypertensive patients with non-insulin-dependent diabetes mellitus (NIDDM) and impaired renal function. Forty patients with mild hypertension with NIDDM and persistent albuminuria (> 300 mg/24h) were studied. After a 3-week run-in period on placebo, patients were randomly treated with ramipril 5 mg once daily or nitrendipine 20 mg once daily for 6 months, according to a double-blind design. Blood pressure (BP), UAE, creatinine clearance and glycosilated haemoglobin were evaluated at the end of the placebo period and after 1,3 and 6 months of active treatment. Both ramipril and nitrendipine significantly lowered BP values without affecting glucose homeostasis and renal function. Despite equivalent BP control, only ramipril afforded a significant reduction in UAE, thus suggesting that the antiproteinuric effect of ramipril is at least partially independent of its anti-hypertensive effect.

Topics: Aged; Albuminuria; Analysis of Variance; Confidence Intervals; Creatinine; Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Humans; Hypertension; Kidney Function Tests; Male; Middle Aged; Nitrendipine; Ramipril; Renal Insufficiency

The effect of intensified blood pressure (BP) control with a reduction of the diastolic BP to < or = 85 mm Hg on renal function and urinary albumin excretion (UAE) was studied in 28 men with primary hypertension (aged 62 to 72 years) treated for 13 +/- 5 years with beta-blockade, diuretics, or hydralazine. They were compared with 25 normotensive (NT) men of similar age. At baseline (BL), glomerular filtration rate (GFR), renal plasma flow (RPF) (clearance of inulin and para-aminohippurate), and the UAE were studied. Thereafter, all antihypertensive drugs except beta-blockers were withdrawn and either felodipine (5 to 20 mg; n = 13) or ramipril (2.5 to 10 mg; n = 15) was added in a double blind, randomized fashion. Hydrochlorothiazide was added if necessary. The investigations were repeated after 6 weeks and 1 year of double-blind treatment. At BL, the BP and the renal vascular resistance (RVR) were significantly higher and GFR and RPF were significantly lower in both hypertensive groups than in NT. After 1 year, the BP treatment goal was reached by all patients in the felodipine group but only by two-thirds in the ramipril group in spite of addition of diuretics to 60% of the latter group. In the felodipine group, the BP, GFR, and RVR after 1 year no longer differed significantly from normal. The UAE and the fractional albumin clearance increased significantly after 1 year's treatment in the felodipine group but did not change in the ramipril group. The fractional albumin clearance, however, did not differ significantly from normal either at BL or after 1 year's treatment in any of the hypertensive groups. It is therefore possible to reduce BP and improve renal function in primary hypertension to levels not significantly different from normal after treatment with felodipine in combination with beta-blockade. Although this regimen increased the low UAE slightly, the fractional albumin clearance changed less and did not differ significantly from normal. The ramipril/beta-blocker combination reduced BP less and did not change the slightly reduced renal function or the UAE.

Topics: Adrenergic beta-Antagonists; Aged; Albuminuria; Blood Pressure; Drug Therapy, Combination; Felodipine; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Middle Aged; Ramipril

Microalbuminuria predicts early mortality and renal disease in non-insulin-dependent diabetic patients. In insulin-dependent diabetic patients, angiotensin converting enzyme inhibition decreases microalbuminuria and retards the progression of renal disease. The aim of this study was to evaluate the effect of low dose ramipril on albumin excretion rate (AER) and blood pressure in non-insulin-dependent diabetic patients with persistent microalbuminuria (AER > 20 < 200 micrograms/min) and normal blood pressure or mild hypertension. The study was a randomized, double-blind, placebo-controlled clinical trial of 6 months duration at 14 hospital-based diabetes centers in northeastern Italy. Blood pressure, plasma glucose, and body weight were determined every month; AER, serum creatinine, glycosylated hemoglobin, and plasma lipids at baseline, after 1 month, and at the end of the study. Of 122 non-insulin-dependent diabetic patients randomly allocated in blocks of four to receive either ramipril (1.25 mg/day) or placebo, 108 (54 in the ramipril group and 54 in the placebo group) completed the study. At baseline, age, duration of diabetes, body mass index, and glycosylated hemoglobin were similar in the two groups and remained unchanged throughout the study. In the placebo group, AER rose from a baseline median of 65 micrograms/min (range 53 to 76, 95% confidence Interval) to 72 micrograms/min (57 to 87) and to 83 micrograms/min (62 to 104) after 1 and 6 months, respectively, but fell from 62 micrograms/min (48 to 76) to 45 micrograms/min (33 to 57) and to 53 micrograms/min (38 to 69), respectively, in the ramipril group, a significant difference between the groups (P < .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Albuminuria; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Humans; Hypertension; Lipids; Male; Middle Aged; Ramipril

The mechanism of action of angiotensin-converting enzyme (ACE) inhibitors on urinary albumin excretion (UAE) in diabetic patients remains controversial. Sixteen type 1, insulin-dependent diabetics with incipient nephropathy received ramipril, a long-acting ACE inhibitor, at hypotensive doses (treatment A: 5 mg/day, n = 8) or at nonhypotensive doses (treatment B: 1.25 mg/day, n = 8) during a 6-week, double-blind, parallel study to establish whether its antihypertensive effects could be dissociated from its local renal effects. Blood pressure, UAE, glomerular filtration rate (GFR), effective renal plasma flow (ERPF, constant [125I]iodothalamate + [131I]hippurate infusion), and ACE activity were measured before and after treatment. Blood pressure was lowered with treatment A but not with treatment B. UAE and ACE activity were reduced with both treatments. Baseline GFR and ERPF were not altered by either treatment. In the patient population as a whole, ACE inhibition correlated with a rise in ERPF and with a reduction in filtration fraction (GFR/ERPF), but not with the changes in blood pressure. Changes in UAE correlated with the changes in filtration fraction. It is concluded that renal hemodynamics may be modified by ramipril independently of blood pressure changes.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Blood Pressure; Bridged Bicyclo Compounds; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Double-Blind Method; Female; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Potassium; Ramipril; Sodium; Urea

The mechanism of action of angiotensin converting enzyme (ACE) inhibitors on urinary albumin excretion (UAE) in diabetics is controversial. In order to dissociate the hypotensive and intrarenal effects, 16 insulin-dependant diabetics with permanent microalbuminuria (30-300 mg/24 h) without hypertension were given Ramipril, a long acting ACE inhibitor, at hypotensive (treatment A 5 mg/day; N = 8) and at sub-hypotensive doses (treatment B, 1.25 mg/day; N = 8) over a 6 week period in parallel double-blind study. Blood pressure, UAE, glomerular filtration renal blood flow (continuous 125I-Iodothalamate + 131I-Hippurate infusion) and converting enzyme activity (Liebermann's method), before and after treatment. In treatment group A, the blood pressure fell from 133 +/- 5/79 +/- 4 (mean +/- SE) to 125 +/- 4/77 +/- 2 mmHg (p less than 0.05 for systolic blood pressure) whereas it remained stable in treatment group B (132 +/- 7/79 +/- 4 to 128 +/- 5/80 +/- 4 mmHg). The UAE decreased in both groups: group A from an average of 74 (40-198) to 47 (5-202) mg/24 h (p = 0.07; group B, from an average of 77 (50-136) to 19 (15-120) mg/24 h (p less than 0.005), as did ACE activity: group A from 332 +/- 44 to 163 +/- 33 iu/l (p less than 0.004), group B from 423 +/- 39 to 191 +/- 28 iu/l (p less than 10-4).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bridged Bicyclo Compounds; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney; Male; Middle Aged; Ramipril; Regional Blood Flow

The objective of the present study was to investigate the effects of single and combined administration of ramipril and losartan on renal structure and function in spontaneously hypertensive rats (SHRs). Thirty-two 9-week-old SHRs and eight Wistar-Kyoto (WKY) rats were randomly divided into five groups: the WKY control group, the SHR control group, the SHR-ramipril group, the SHR-losartan group, and the SHR-combined mediation group. The rat body weight, SBP, heart rate, and urinary albumin excretion rate (UAER) were measured. (1) The SBP was reduced to the normal level in all groups of rats except for the SHR control group. Combined administration of ramipril and losartan can be reduced to the normal level earlier than single (P < 0.01). (2) The SHR-ramipril group and the SHR-losartan group still experienced a higher UAER than that in the WKY control group (P < 0.01). (3) The renal mass/BW ratio was decreased in the SHR-ramipril group, SHR-losartan group, and SHR-combined medication group compared to that in the SHR control group (P < 0.01). (4) Compared with the SHR control group, the SHR-ramipril group, the SHR-losartan group, and the SHR-combined medication group had a lower percentage of the IOD of glomerular collagen relative to the glomerular area (P < 0.01). (5) The reduction in tubulointerstitial injury score was more significant in the SHR-combined medication group than in the SHR-ramipril group and the SHR-losartan group (P < 0.01). The combination of ramipril and losartan is superior to either single drug in reducing the UAER, resisting glomerular collagen deposition, and protecting renal tubular structure.

Topics: Albuminuria; Animals; Antihypertensive Agents; Collagen; Drug Therapy, Combination; Female; Hypertension; Kidney Glomerulus; Kidney Tubules; Losartan; Male; Microscopy; Organ Size; Ramipril; Random Allocation; Rats; Rats, Inbred SHR; Rats, Inbred WKY

The renin-angiotensin-aldosterone system (RAAS) plays pivotal roles in the pathogenesis of chronic kidney disease (CKD) progression. Aliskiren, a direct renin inhibitor, inhibits the rate-limiting step of the RAAS without any alternative pathway. It is proven to reduce albuminuria in CKD patients treated with angiotensin blockade. However, there are few reports which evaluate the advantage of aliskiren as the first-line drug against CKD progression in RAAS-activated hypertensive patients.. Tsukuba hypertensive mice (THM), double transgenic mice carrying both the human renin and human angiotensinogen genes, were fed a high-salt diet and treated with hydraladine, ramipril and aliskiren for 10 weeks. Blood pressure and urinary albumin excretion were measured every 2 weeks during the experimental period. We evaluated renal histological changes and gene expression. Plasma angiotensin concentration was measured to evaluate the RAAS inhibitory effect.. High-salt-loaded THM showed severe hypertension and renal injury. All antihypertensive drugs suppressed blood pressure and prevented renal disease progression. RAAS blockade showed a higher renoprotective effect than hydraladine despite an equivalent blood pressure lowering effect. Aliskiren exhibited even stronger renoprotection than ramipril. Plasma angiotensin concentration was increased in THM fed both normal salt and high salt. Hydraladine did not alter the plasma angiotensin concentration. Ramipril significantly decreased angiotensin II concentration. Aliskiren treatment almost completely suppressed angiotensin I and resulted in lower angiotensin II concentration than ramipril treatment.. Aliskiren prevents renal disease progression by suppressing both angiotensin I and II in RAAS-activated pathology. Our data suggest the application of a renin inhibitor for preventing kidney disease progression in CKD patients.

Topics: Albuminuria; Amides; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Antihypertensive Agents; Blood Pressure; Cytoprotection; Disease Models, Animal; Disease Progression; Down-Regulation; Fumarates; Humans; Hydralazine; Hypertension; Kidney; Kidney Diseases; Mice; Mice, Transgenic; Ramipril; Renin; Renin-Angiotensin System; Sodium Chloride, Dietary; Time Factors

Rho-family GTPases like RhoA and Rac-1 are potent regulators of cellular signaling that control gene expression, migration and inflammation. Activation of Rho-GTPases has been linked to podocyte dysfunction, a feature of chronic kidney diseases (CKD). We investigated the effect of Rac-1 and Rho kinase (ROCK) inhibition on progressive renal failure in mice and studied the underlying mechanisms in podocytes. SV129 mice were subjected to 5/6-nephrectomy which resulted in arterial hypertension and albuminuria. Subgroups of animals were treated with the Rac-1 inhibitor EHT1846, the ROCK inhibitor SAR407899 and the ACE inhibitor Ramipril. Only Ramipril reduced hypertension. In contrast, all inhibitors markedly attenuated albumin excretion as well as glomerular and tubulo-interstitial damage. The combination of SAR407899 and Ramipril was more effective in preventing albuminuria than Ramipril alone. To study the involved mechanisms, podocytes were cultured from SV129 mice and exposed to static stretch in the Flexcell device. This activated RhoA and Rac-1 and led via TGFβ to apoptosis and a switch of the cells into a more mesenchymal phenotype, as evident from loss of WT-1 and nephrin and induction of α-SMA and fibronectin expression. Rac-1 and ROCK inhibition as well as blockade of TGFβ dramatically attenuated all these responses. This suggests that Rac-1 and RhoA are mediators of podocyte dysfunction in CKD. Inhibition of Rho-GTPases may be a novel approach for the treatment of CKD.

Topics: Albuminuria; Animals; Isoquinolines; Male; Mice; Piperidines; Podocytes; Pyrones; Quinolines; rac1 GTP-Binding Protein; Ramipril; Renal Insufficiency, Chronic; rhoA GTP-Binding Protein

Diabetic nephropathy is the main cause of end-stage renal disease. N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), a physiological tetrapeptide hydrolyzed by the angiotensin-converting enzyme (ACE), has antifibrotic effects in the cardiovascular system and in the kidney in experimental models of hypertension, heart failure and renal disease. The aim of the study was to evaluate the effect of Ac-SDKP in diabetic nephropathy and the potential additive effect of Ac-SDKP, when compared to ACE inhibitors alone, on the development of renal fibrosis.. Diabetes was induced in 28 Sprague-Dawley rats by a single intraperitoneal injection of streptozotocin. Control rats (n = 10) received only buffer solution. An ACE inhibitor (ramipril, 3 mg/kg/day) was administered to 11 diabetic rats. After 2 months, Ac-SDKP (1 mg/kg/day) was administered by osmotic minipumps for 8 weeks to 7 diabetic rats and to 6 diabetic rats treated with ramipril. Osmotic minipumps delivered saline solution in the corresponding sham-treated rats (diabetic rats, n = 10, and ramipril-treated diabetic rats, n = 5).. Diabetic rats showed a significant increase in blood glucose level, urinary albumin excretion and renal fibrosis, and a reduction of glomerular nephrin expression with respect to control rats. Ac-SDKP administration significantly reduced renal fibrosis in diabetic rats, without significantly reducing urinary albumin excretion. Ramipril treatment caused a significant decrease in albuminuria and renal fibrosis and restored glomerular nephrin expression. Administration of Ac-SDKP, in addition to ramipril, further reduced renal fibrosis with respect to ramipril alone, while it did not improve the antiproteinuric effect of ramipril.. Ac-SDKP administration reduces renal fibrosis in diabetic nephropathy. Addition of Ac-SDKP to ACE inhibition therapy improves the reduction of renal fibrosis with respect to ACE inhibition alone, suggesting a beneficial effect of this pharmacological association in diabetic nephropathy.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetic Nephropathies; Drug Evaluation, Preclinical; Glomerular Filtration Rate; Growth Inhibitors; Kidney Glomerulus; Male; Membrane Proteins; Nephrosclerosis; Oligopeptides; Ramipril; Rats; Rats, Sprague-Dawley

Angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) have been used to normalize the blood pressure and the dipping pattern in patients with type 1 diabetes mellitus (T1DM) and nephropathy. However, there are no data on the effect of the dual blockade on the dipping pattern in these subjects. We therefore, carried out this study to evaluate the effect of administrating an ACEI followed by ARB in the optimum doses in T1DM patients with nephropathy on 24 h blood pressure (BP) profile and nocturnal dipping pattern.. An open label interventional pilot study was done during a one year period involving 30 consecutive patients who were treated with telmisartan 80 mg (0800-1000 h) for eight weeks followed by addition of ramipril 10 mg (1200-1400 h) for the next eight weeks. Ambulatory BP, dipping pattern and albumin excretion rate were studied after each phase. Twenty patients were hypertensive and 10 patients had macro- and 20 patients had microalbuminuria.. Telmisartan produced a fall in the clinic BP by 4/1.3 mm Hg (P<0.05 and P<0.362, respectively), 2/1.9 mm Hg in the mean 24 h BP, 1.4/1.1 mm Hg in the day BP and 3.7/3 mm Hg in the trough BP. Addition of ramipril to telmisartan produced a further reduction of 6.3/5.9 mm Hg in the clinic BP (P<0.001 for both), 4.3/4.2 mm Hg in the mean 24 h BP (P<0.01 and P<0.0001, respectively), 5.8/3.9 mm Hg in the day BP (P<0.01 for both), 4.2/2.5 mm Hg in the trough BP, with a reduction of clinic SBP and DBP of 10.3/7.2 mm Hg from the baseline. Telmisartan restored normal systolic dipping pattern in 33.3 per cent of the nondippers (P<0.01) but addition of ramipril was not complimentary. Hyperkalamia (>5.5 mmol/l) was observed only in 2 patients towards the end of the study.. The dual blockade with telmisartan and ramipril had complimentary effect on lowering of the BP, however, similar beneficial effect on the nocturnal dipping was not observed. Further studies with large number of subjects with longer duration of follow-up are required to validate these observations.

Topics: Adult; Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pilot Projects; Ramipril; Telmisartan

Antihypertensive therapies such as angiotensin-converting enzyme-1 inhibitors (ACEi) slow the decline in renal function seen with diabetic nephropathy, although there is still progression ultimately to end-stage renal disease. The aim of this study was to determine if there were added renoprotective benefits seen by combining ACEi with blockade of NADPH oxidase.. Sprague-Dawley diabetic and non-diabetic rats were randomized to receive intervention therapy with apocynin (15 mg/kg/day, weeks 16-32), apocynin + the ACEi ramipril (1 mg/kg/day, weeks 16-32), or ramipril alone (1 mg/kg).. All three treatments retarded the development of albuminuria in the diabetic rats. Apocynin conferred its benefit either as a monotherapy or in combination with ramipril without affecting blood pressure per se. Renal morphological injury was attenuated by all three treatment strategies. Diabetes was associated with increasing renal fibronectin and type IV collagen protein expression, with the combination regimen resulting in the highest decrease in extracellular matrix accumulation. All three treatments prevented the diabetes-associated increases in renal cytosolic superoxide generation as well as urinary isoprostanes. While renal TGF-beta1 activation was reduced by ramipril treatment but not by apocynin as a monotherapy, kidney cortical membranous VEGF was reduced by apocynin as monotherapy and dual therapy but not by ramipril alone.. Combination of NADPH oxidase blockade with ACE inhibitors is a promising regimen which warrants further investigation as a way to confer additional renoprotection in diabetes.

Topics: Acetophenones; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Drug Therapy, Combination; Enzyme Inhibitors; Extracellular Matrix; Glomerular Filtration Rate; Kidney; Male; NADPH Oxidases; Oxidative Stress; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Sprague-Dawley

The efficacy of the combination of angiotensin receptor blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors in patients of type 1 diabetes mellitus (DM) with nephropathy is debatable. The antialbuminuric efficacy of dual blockade in patients of type 1 DM with micro- or macroabuminuria were evaluated.. In this open label observational study 30 patients (20 male 10 female) with type 1 DM were included who were initially treated with telmisartan 80 mg for eight weeks followed by addition of ramipril 10 mg for a further eight weeks. Albuminuria reduction was studied at the end of each phase.. Therapy with telmisartan for 8 wk resulted in a 39 per cent (P<0.01) reduction in albumin excretion rate (AER). Combination therapy with telmisartan and ramipril produced a further reduction in AER of 33.4 per cent (P<0.01), amounting to a total AER reduction of 59 per cent (P<0.001). Dual blockade was more effective in the group of macroalbuminuric as compared to microalbuminuric subjects (P<0.05). Telmisartan produced a significant reduction in SBP (P<0.05). The addition of ramipril produced a further reduction in BP, the total reduction being 10.3 in SBP and 7.2 mmHg in DBP (P<0.001 for both). There was an increase in mean serum potassium of 0.39 mmol/l (P<0.01) from baseline at the end of the study period and two patients had hyperkalemia>5.5 mmol/l with dual blockade.. Dual blockade with ramipril enhanced the antialbuminuric efficacy of telmisartan and further reduced blood pressure. The effect of dual blockade was more pronounced in the macroalbuminuric subjects and it was well tolerated. However, careful monitoring of serum potassium is required.

Topics: Albumins; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Drug Combinations; Female; Humans; Male; Potassium; Ramipril; Statistics, Nonparametric; Telmisartan

Recent studies suggest that expression of the transforming growth factor-beta (TGF-beta)-inducible gene-h3 (betaig-h3) and its anti-lysosomal activity may be responsible for the development of albuminuria and cardiovascular disease associated with hypertension.. We evaluated the proposed linkage using the spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat models. The kidney and left ventricular weight/body weight ratios were measured and cardiac collagen deposition was analyzed by Masson's trichrome stain. Renal and cardiac TGF-beta(1) and betaig-h3 expression were determined by real-time reverse transcription-polymerase chain reaction, and renal and cardiac cathepsin B and L activities were measured as an indicator of lysosomal proteolytic activity.. SHR exhibited increased levels of intact urinary albumin without significant change in total albumin (intact plus albumin-derived material) excretion. This was accompanied by renal hypertrophy, increased renal betaig-h3 expression, and reduced renal cathepsin B and L activities. At the same time, increased cardiac TGF-beta(1) and betaig-h3 expression and reduced cardiac cathepsin B activity was identified in SHR in addition to cardiac hypertrophy and increased collagen deposition. All these changes could be ameliorated with ramipril treatment.. These findings implicate for the first time betaig-h3 expression and lysosomal activity as a key factor in the induction of albuminuria and cardiovascular disease associated with hypertension.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cardiomegaly; Cathepsins; Extracellular Matrix Proteins; Fibrosis; Hypertension; Kidney; Lysosomes; Male; Myocardium; Ramipril; Random Allocation; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1; Up-Regulation

Topics: Albuminuria; Antihypertensive Agents; Cardiovascular Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; DNA Transposable Elements; Humans; Hypertension; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Prognosis; Ramipril; Sequence Deletion

Diabetes in spontaneously hypertensive rats is associated with cortical renal GLUT1 and GLUT2 overexpression. Our objective was to evaluate the effect of the angiotensin-converting enzyme blockade on cortical renal GLUT1 and GLUT2 expression, urinary albumin and urinary TGF-beta1. Streptozotocin, 50 mg/kg, or citrate buffer (N = 16) was administered as a single injection into the tail vein in adult spontaneously hypertensive rats (approximately 260 g). Thirty days later, these diabetic spontaneously hypertensive rats received ramipril by gavage: 0.01 mg x kg(-1) x day(-1) (D0.01, N = 14), 1 mg x kg(-1) x day(-1) (D1, N = 9) or water (D, N = 11) for 15 days. Albumin and TGF-beta1 (24-h urine), direct arterial pressure, renal tissue angiotensin-converting enzyme activity (fluorometric assay), and GLUT1 and GLUT2 protein levels (Western blot, renal cortex) were determined. Glycemia and glycosuria were higher (P < 0.05) in the diabetic rats compared with controls, but similar between the diabetic groups. Diabetes in spontaneously hypertensive rats lowered renal tissue angiotensin-converting enzyme activity (40%), which was reduced further when higher ramipril doses were used. Diabetes associated with hypertension raised GLUT1 by 28% (P < 0.0001) and GLUT2 by 76% (P = 0.01), and both doses of ramipril equally reduced cortical GLUT1 (D vs D1 and vs D0.01, P < or = 0.001). GLUT2 levels were reduced in D0.01 (P < 0.05 vs D). Diabetes increased urinary albumin and TGF-beta1 urinary excretion, but the 15-day ramipril treatment (with either dose) did not reduce them. In conclusion, ramipril is effective in lowering renal tissue angiotensin-converting enzyme activity, as well as blocking cortical GLUT1 overexpression, which may be beneficial in arresting the development of diabetic nephropathy.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Experimental; Glucose; Glucose Transporter Type 1; Glucose Transporter Type 2; Kidney Cortex; Male; Ramipril; Rats; Rats, Inbred SHR; Transforming Growth Factor beta1

Diabetic nephropathy (DN) can be delayed by the use of angiotensin-converting enzyme inhibitors (ACEi). The mechanisms of ACEi renal protection are not univocal. To investigate the impact of bradykinin B(2) receptor (B2R) activation during ACE inhibition, type II diabetic mice (C57BLKS db/db) received for 20 wk: 1) ACEi (ramipril) alone, 2) ACEi + HOE-140 (a specific B2R antagonist), 3) HOE-140 alone, or 4) no treatment. The development of DN, defined by an increase in albuminuria and glomerulosclerosis, was largely prevented by ACEi treatment (albuminuria: 980 +/- 130 vs. 2,160 +/- 330 mg/g creatinine; mesangial area: 22.5 +/- 0.5 vs. 27.6 +/- 0.3%). The protective effect of ramipril was markedly attenuated by B2R blockade (albuminuria: 2,790 +/- 680 mg/g creatinine; mesangial area: 30.4 +/- 1.1%), whereas HOE-140 alone significantly increased albuminuria. Despite such benefits, glomerular filtration rate remained unchanged, probably because of the combination of the hypotensive effect of diabetes in this model and the renal hemodynamic action of ramipril. Finally, the renal protective effect of ACEi was associated with a marked decrease in glomerular overexpression of insulin-like growth factor-1 (IGF-1) and transforming growth factor-beta pathways, but also in advanced glycation end product receptors and lipid peroxidation assessed by 4-hydroxy-2-nonenal (4-HNE) adducts. Concomitant blockade of B2R partly restored glomerular overexpression of IGF-1 receptor beta and 4-HNE complexes. These results support the critical role of B2R activation in the mediation of ACEi renal protection against DN and provide the rationale to examine the benefit of B2R activation by itself as a new therapeutic approach for DN.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blotting, Western; Bradykinin; Bradykinin B2 Receptor Antagonists; Diabetic Neuropathies; Glomerular Filtration Rate; Kidney; Kidney Function Tests; Kidney Glomerulus; Mice; Mice, Inbred C57BL; Mice, Obese; Protective Agents; Ramipril; Signal Transduction

Increased urinary excretion of albumin or total protein has become firmly established as a risk predictor for progression of chronic kidney disease. Observational analyses have raised a strong hypothesis that albuminuria reduction should be a clinical treatment target. Bakris et al. report further exploration of albuminuria-lowering capabilities of intensified renin-angiotensin system inhibition in a randomized clinical trial that included patients at high cardiovascular risk, most of whom appeared to have diabetic kidney disease.

Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biomarkers; Biphenyl Compounds; Humans; Irbesartan; Ramipril; Tetrazoles

Vasopeptidase inhibition has been shown to be an effective antihypertensive principle but its long-term effects on hypertensive target organ damage are not known. We investigated the myocardial, vascular and renal effects of chronic vasopeptidase inhibition in arterial hypertension.. One hundred and thirty-nine male spontaneously hypertensive rats aged 15 months were treated chronically with either the pure angiotensin-converting enzyme (ACE) inhibitor, ramipril (1 mg/kg/d in drinking water, n=46), or the vasopeptidase inhibitor AVE7688 (30 mg/kg/d in chow, n=46), or placebo (n=47) and followed up until they died. After six months, both ramipril and AVE7688 had markedly reduced plasma ACE activity, normalised blood pressure (BP), reduced left ventricular mass and improved systolic function to similar extents. Acetylcholine mediated relaxation of aortic rings was improved by both ramipril and AVE7688. There was substantial albuminuria in the placebo group (albumin-to-creatinine ratio 107+/-54 microg/mg), which was significantly reduced by ramipril to 57+/-34 microg/mg, and practically abolished in the AVE7688 group (22+/-12 microg/mg, p<0.05 vs. placebo and ramipril). Tubulo-interstitial damage (semi-quantitative score) was significantly reduced by AVE7688 and ramipril. Overall mortality was markedly reduced in the ramipril and AVE7688 groups (13% and 16% at six months, respectively), both p<0.05 vs. placebo (71%).. Vasopeptidase inhibition effectively controls BP and reduces myocardial, vascular and renal target organ damage, resulting in a markedly prolonged survival. At similar degrees of plasma ACE inhibition, AVE7688 compared to ramipril offers superior protection against hypertensive kidney damage.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Endothelium, Vascular; Fibrosis; Heterocyclic Compounds, 3-Ring; Hypertension; Hypertension, Renal; Kidney; Male; Myocardium; Peptide Hydrolases; Peptidyl-Dipeptidase A; Placebos; Protease Inhibitors; Ramipril; Rats; Rats, Inbred SHR; Ventricular Function, Left

ACE inhibition protects kidney function, but ACE insertion/deletion (I/D) polymorphism affects renal prognosis in type 1 diabetic patients. ACE genotype may influence the renal benefits of ACE inhibition. We studied the impact of ACE I/D polymorphism on the renal hemodynamic changes induced by ACE inhibition in type 1 diabetes. We studied renal hemodynamics (glomerular filtration rate [GFR], effective renal plasma flow [ERPF], filtration fraction [GFR/ERPF], mean arterial pressure [MAP], and total renal resistances [MAP/ERPF]) repeatedly during normoglycemia and then hyperglycemia in 12 normotensive, normoalbuminuric type 1 diabetes and the II genotype (associated with nephroprotection) versus 22 age- and sex-matched subjects with the ACE D allele after three randomly allocated 2- to 6-week periods on placebo, 1.25 mg/day ramipril, and 5 mg/day ramipril in a double-blind, cross-over study. During normoglycemia, the hemodynamic changes induced by ramipril were similar in both genotypes. During hyperglycemia, the changes induced by ramipril were accentuated in the II genotype group and attenuated dose dependently in the D allele group (treatment-genotype interaction P values for ERPF, 0.018; MAP, 0.018; and total renal resistances, 0.055). These results provide a basis to different renal responses to ACE inhibition according to ACE genotype in type 1 diabetes.

Topics: Adult; Albuminuria; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetes Mellitus, Type 1; Female; Gene Deletion; Genotype; Glomerular Filtration Rate; Hemodynamics; Humans; Hyperglycemia; Kidney; Male; Mutagenesis, Insertional; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Ramipril; Renin

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Axilla; Blood Pressure; Diarrhea; Diuretics; Germany; Hidradenitis Suppurativa; Humans; Male; Middle Aged; Nephrotic Syndrome; Ramipril; Treatment Outcome; White People

Albumin excretion is modulated post-filtration by lysosomal processing that produces a spectrum of albumin-derived material in urine, much of which is not detected by conventional immunoassays. This study aimed to determine the efficacy of ramipril treatment (+ RAM) after 24 weeks on total albumin excretion (intact plus albumin-derived peptides) in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with (d) and without (c) diabetes.. Intact albumin excretion was analysed by radioimmunoassay and total albumin excretion was analysed by measuring radioactivity derived from circulating [ C]albumin. Renal lysosomal activity was determined by urinary [ H]dextran sulphate desulphation. Renal transforming growth factor-beta 1 (TGF-beta 1), TGF-beta inducible gene-h3 (beta ig-h3) and angiotensinogen mRNA production were analysed by real time reverse transcriptase-polymerase chain reaction.. Hypertension (SHR-c and SHR-d) resulted in a significant increase in intact albumin excretion, which was significantly reduced by ramipril treatment (P < 0.05 for SHR-c + RAM and 0.001 for SHR-d + RAM compared to non-treated). This was accompanied by a significant decrease in blood pressure (P < 0.001 for SHR-c + RAM and SHR-d + RAM), renal beta ig-h3 mRNA production (P < 0.05 for SHR-c + RAM and SHR-d + RAM), and an increase in lysosomal activity. Diabetes (WKY-d and SHR-d) primarily caused a significant increase in total albumin excretion, predominantly in the form of albumin-derived fragments in the WKY-d group and intact albumin in the SHR-d group. Ramipril treatment reduced total albumin excretion in the WKY-d + RAM group (P < 0.001).. Ramipril prevents increases in both intact albumin and total albumin excretion in hypertensive and diabetic states, respectively.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Blood Pressure; Diabetes Mellitus; Extracellular Matrix Proteins; Hypertension; Lysosomes; Male; Ramipril; Rats; Rats, Inbred SHR; Rats, Inbred WKY; RNA, Messenger; Transforming Growth Factor beta; Transforming Growth Factor beta1

Blocking the renin-angiotensin system is an established therapeutic principle in diabetic nephropathy. We investigated whether inhibition of both neutral endopeptidase and ACE (vasopeptidase inhibition) can prevent functional and morphological features of nephropathy in the Zucker diabetic fatty (ZDF) rat, an animal model of type II diabetes.. Homozygous (fa/fa) ZDF rats (each n=15) aged 10 weeks were treated with placebo, ramipril (1 mg/kg/day in drinking water), or the vasopeptidase inhibitor AVE7688 (45 mg/kg/day in chow). Metabolic parameters and renal function (metabolic cages) were assessed at baseline (age 10 weeks), and at age 17, 27, and 37 weeks. Twenty heterozygous animals (fa/-) served as lean, nondiabetic controls. At age 37 weeks, the animals were sacrificed and the kidneys analyzed histopathologically.. Overt diabetes mellitus (blood glucose >20 mmol/l) was established at age 17 weeks in all homozygous ZDF rats. In the placebo group, urinary protein excretion increased progressively from 8+/-1 (baseline) to 342+/-56 mg/kg/day (week 37) whereas diabetes and proteinuria were absent in the lean control group. Ramipril tended to reduce albuminuria and morphological damage (p=ns) but AVE7688 virtually prevented albuminuria (33+/-12 mg/kg/day, p<0.05 vs. ZDF placebo) and drastically reduced the incidence and severity of glomerulosclerosis and tubulointerstitial damage.. In ZDF rats, development of diabetes mellitus is accompanied by functional and morphological kidney damage that resembles human diabetic nephropathy. Diabetic nephropathy can be prevented by chronic vasopeptidase inhibition.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Area Under Curve; Benzazepines; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enzyme Inhibitors; Half-Life; Heterocyclic Compounds, 3-Ring; Kidney; Male; Peptidyl-Dipeptidase A; Prodrugs; Protease Inhibitors; Pyridines; Ramipril; Rats; Rats, Zucker

Diabetic nephropathy is a glomerular disease, which causes most of premature mortality observed in diabetic patients. The risk of diabetic nephropathy is not entirely accounted for by diabetes duration and control. Diagnosis has been improved by sensitive assays for urinary albumin (microalbuminuria). Treatment relies up on early and liberal use of several antihypertensive agents. Among them, angiotensin I converting enzyme inhibitors rank first, because of their efficacy.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Cardiovascular Diseases; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Diuretics; Female; Glomerular Filtration Rate; Humans; Hypertension; Male; Primary Prevention; Prognosis; Prospective Studies; Proteinuria; Ramipril; Renin-Angiotensin System; Risk Factors; Time Factors

This study examined whether the prevention of diabetes-related albuminuria by aminoguanidine (AG) or ramipril (RAM) may be mediated by a common post-glomerular basement membrane renal intracellular mechanism involving protein kinase C (PKC). The renal handling of albumin was examined over 24 weeks in control and streptozotocin (STZ)-induced diabetic rats. A radioimmunoassay (RIA) that measures intact albumin, and intravenously injected tritium-labeled rat serum albumin, was used to assess the proportion of intact albumin and albumin fragments in urine. Diabetes was induced in male Sprague-Dawley rats by the intravenous administration of STZ at a dose of 50 mg/kg. Age-matched control rats received buffer alone. Diabetes was characterized by an increase in blood glucose (>15 mmol/l), an increase in GHb (means at 24 weeks 29.3+/-1.1%; control 6.1+/-0.1%, P<0.005), an increase in glomerular filtration rate (GFR) (4.13+/-0.15 ml/min; control 3.54+/-0.19 ml/min, P<0.005), an increase in intact albumin excretion rate (expressed as geometric mean 11.64 times/divided by 2.11 mg/24 h; control 0.74 times/divided by 1.57 mg/24 h, P<0.005) as measured by RIA, and an increase in glomerular PKC activity (26.83+/-2.38 pmol x mg(-1) x min(-1); control 14.6+/-2.99 pmol x mg(-1) x min(-1), P<0.005). Treatment of diabetic rats with either AG or RAM prevented the rise in intact albuminuria and glomerular PKC activity. Renal lysosomal cathepsin activity decreased in diabetic rats and this was not prevented by AG or RAM. Neither drug affected glycemic control or GFR, but RAM reduced systolic blood pressure (BP), whereas AG did not. These data indicate that urinary excretion of intact albumin and albumin-derived fragments in diabetes may be modulated independently of glycemic control (AG and RAM) and systolic BP (RAM). While both drugs are known for their different mechanisms of action, the fact that both prevent diabetes-related increases in glomerular PKC activity and albuminuria supports the hypothesis that PKC plays a central role in the development of diabetic nephropathy.

Topics: Albuminuria; Animals; Antihypertensive Agents; Cathepsins; Diabetes Mellitus, Experimental; Enzyme Inhibitors; Guanidines; Hemodynamics; Kidney; Kidney Glomerulus; Lysosomes; Male; Protein Kinase C; Ramipril; Rats; Rats, Sprague-Dawley; Reference Values

Fifty patients with stable slight and moderate uncomplicated essential hypertension, treated by ramipril, atenolol, or isradipine, were examined. Total protein and urinary excretion of individual proteins were studied before and after treatment. Urinary concentrations of apolipoproteins A1 and B1, alpha 1-acid glycoprotein, alpha 1-antitrypsin, prealbumin, albumin, beta 2-microglobulin, transferrin, haptoglobin, IgG and IgA, and C3 and C4 complement components were measured. Index of proteinuria selectiveness was calculated for each portion of urine. All three drugs exerted a nephroprotective effect, atenolol being the most active of them. Apolipoproteins, IgG, and complement components were the most valuable for diagnosis. Their excretion correlated with the severity of arterial hypertension and efficiency of treatment. Use of protein markers helps reliably assess the renal function and monitor the treatment efficiency.

Topics: Adult; Aged; Albuminuria; Antihypertensive Agents; Apolipoproteins; Atenolol; Biomarkers; Complement C3; Complement C4; Female; Haptoglobins; Humans; Hypertension; Immunoglobulin G; Immunoglobulins; Isradipine; Kidney; Male; Middle Aged; Models, Theoretical; Monitoring, Physiologic; Prealbumin; Proteinuria; Ramipril; Transferrin

In diabetic patients endothelial dysfunction is reflected by an increased urinary albumine excretion, which can be reduced by ACE-inhibitors. No data are available showing a endothelial-protective effect by determining a marker reflecting endothelial cell-damage.. The effect of angiotensin converting enzyme inhibitor (ACEI) (ramipril) treatment on the progression of endothelial cell damage,--assessed by measurement of plasma-thrombomodulin (TM),--was investigated in an open, non randomized, prospective pilot study over a period of 18 months in diabetic patients. 87 patients with an urinary albumin concentration (UAC) below 100 mg/l at baseline were included. 46 patients were treated without ACEI and served as a control group, 41 patients were treated with ACEI. Participation in this study did not affect intensity in the treatment of blood glucose, blood pressure or diet. At study entry both groups were comparable with respect to duration of diabetes, diabetic complications, vascular risk factors, body mass index, medications used to treat diabetes, presence of hypertension, glycemic control, tryglycerides, HDL cholesterol, creatinine, UAC and plasma-TM. Age, blood pressure, and total cholesterol were significantly higher in the ACEI group, compared with the control group.. After a follow up of 18 months a significant increase in UAC (delta UAC = 10.48 mg/l, p = 0.03) and plasma-TM (delta TM = 3.06 ng/l, p = 0.009) was observed in the control group, while in the ACEI treated group a decrease in albuminuria (delta UAC = -7.44 mg/l, p = 0.01) and plasma-TM (delta TM = -4.78 ng/l, p = 0.001) was seen. Despite a similar approach in hypertension and diabetes control in both groups, UAC and plasma-TM decreased after 18 months only in the ACEI treated group. Treatment with ACEI was the strongest predictor (p = 0.0001) indicating decrease of UAC and plasma-TM (multi regression analysis).. Plasma-thrombomodulin might be a useful marker for assessing the efficacy of drugs potentially protecting the vessel wall. While the present study was a open, non randomized study, further investigation is necessary to proof the hypothesis in a randomized, placebo-controlled, double-blind study.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Monitoring; Endothelium, Vascular; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pilot Projects; Prospective Studies; Ramipril; Thrombomodulin

To assess the effect of ramipril on indicators of glucose metabolism, incl. insulin resistance, on renal function with microalbuminuria, changes of some echocardiographic signs of hypertrophy and compliance of the left ventricle in patients with hypertension and type II diabetes mellitus.. The authors examined 32 patients with hypertension grade I and II and with diabetes type II, who had ramipril, 2.5-10 mg/day, for a period of six months. The examination before and after long-term treatment comprised basic biochemical sampling incl. concentrations of immunoreactive insulin, C-peptide and glycated haemoglobin and also complete functional examination of the kidneys, incl. microalbuminuria. Echocardiographic examination was focused on assessment of signs of hypertrophy and compliance of the left ventricle. Treatment of diabetes was not changed in the course of 6 months.. In addition to the anticipated drop of blood pressure a declining trend of insulin resistance was recorded, there was a significant decline of microalbuminuria and a rise of natriuresis, the left ventricle mass declined and its compliance improved.. Ramipril one of the inhibitors of angiotensin converting enzyme is an effective and useful medication for type II diabetics suffering from hypertension.

Topics: Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Glucose; Diabetes Mellitus, Type 2; Female; Heart; Humans; Hypertension; Insulin Resistance; Kidney; Male; Middle Aged; Natriuresis; Ramipril; Ventricular Function, Left

The objective of the present-study was to determine whether acute inhibition of angiotensin converting enzyme (ACE), normalizes intrarenal sodium handling, renal haemodynamics and renal dopamine output in response to an i.v. NaCl infusion in type 1 diabetic patients with early nephropathy. Nine diabetic patients (aged 28 +/- 3 years) with elevated urinary albumin excretion (173 +/- 39 mg.min-1) were studied. The effects of a 2-hour NaCl infusion (12.5 ml.kg-1-h-1) on para-amino hippuric acid (PAH), insulin, lithium and sodium clearances as well as the urinary dopamine excretion were studied before and after 2 days of acute ACE inhibition. Fifteen healthy subjects (aged 34 +/- 1 years) served as controls. The results showed that 2 days of ACE inhibition improved the natriuretic response significantly (P < 0.05) within the first 2 h following an i.v. NaCl load due to a normalization of the proximal tubular sodium handling. In control subjects urinary dopamine output increased by 14% (P < 0.01) following i.v. NaCl infusion, whereas a blunted increase was seen in the diabetic patients, which tended to normalize following inhibition of ACE. In conclusion, this study demonstrates that patients with type 1 diabetes and early nephropathy display abnormalities in renal haemodynamics, natriuresis and urinary dopamine mobilization in response to a sodium load, which can be reversed by short-term inhibition of ACE.

Topics: Adult; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Dopamine; Glomerular Filtration Rate; Hemodynamics; Humans; Infusions, Intravenous; Inulin; Lithium; Male; Metabolic Clearance Rate; Middle Aged; p-Aminohippuric Acid; Ramipril; Reference Values; Renal Circulation; Renin; Sodium; Sodium Chloride

We explored the relative roles of the suppression of angiotensin II and the prevention of bradykinin degradation in mediating the renoprotective effects of ACE inhibitors in experimental diabetic nephropathy. Over a 24-week period, we studied male Sprague-Dawley diabetic and control rats and Sprague-Dawley diabetic rats treated with the ACE inhibitor ramipril, the angiotensin II-AT1 receptor antagonist valsartan, the bradykinin-B2 receptor antagonist HOE 140 (icatibant), and a combination of ramipril and icatibant. Serial measurements of urinary albumin excretion, blood pressure, and glycated hemoglobin were performed monthly. After 6 months, the animals were killed for the measurement of kidney weight and the assessment of glomerular ultrastructure. Over 24 weeks, urinary albumin excretion showed a continuous rise in the untreated diabetic rats. Both ramipril and valsartan, which were equihypotensive, prevented the increase in urinary albumin excretion over the whole study period. Icatibant therapy did not attenuate the antialbuminuric effect of the ACE inhibitor, nor did it have any effect as the sole therapy. Diabetes was associated with increased glomerular basement membrane thickness, glomerular volume, and total mesangial volume. Both ACE inhibition and angiotensin II receptor antagonism attenuated the glomerular ultrastructural changes to a similar degree. Icatibant did not attenuate the effects of ramipril on glomerular morphology. ACE inhibitors and angiotensin II-AT1 receptor blockers appear to confer similar benefits in experimental diabetic nephropathy, and bradykinin-B2 receptor blockers do not influence this effect. These findings suggest that the blockade of angiotensin II is the major pathway responsible for renoprotection afforded by ACE inhibition in experimental diabetic nephropathy.

Topics: Albuminuria; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bradykinin; Bradykinin Receptor Antagonists; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Kidney; Kidney Glomerulus; Male; Organ Size; Ramipril; Rats; Rats, Sprague-Dawley; Tetrazoles; Valine; Valsartan

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Glomerular Filtration Rate; Humans; Hypertension; Lisinopril; Ramipril

Converting enzyme inhibition (CEI) ameliorates progressive loss of function in non-immune-mediated renal diseases and experimental hypertension. Little, however, is known on the potential role of CEI in established experimental chronic glomerular immune injury. We therefore studied the effect of the CEI ramipril on renal function and morphology in a model of immune mediated glomerular injury.. The immune complex glomerulonephritis was induced in uninephrectomized rats by intrarenal perfusion with the cationized antigen followed by an intravenous application of the antibody. This disease is characterized by the development of progressive albuminuria and a nephrotic syndrome (albuminuria: immune complex glomerulonephritis 342 +/- 58, control 76 +/- 18 mg/24h; P < 0.001). The CEI by ramipril, dissolved in the drinking water, was given 28 weeks after induction of the disease and treatment was continued for 12 weeks.. In these experiments ramipril significantly reduced albumin excretion (immune complex glomerulonephritis + CEI 109 +/- 16 mg/24h; P < 0.01) when compared with untreated nephritic rats. Ramipril, however, did not significantly change inulin clearances (immune complex glomerulonephritis 224 +/- 67, immune complex glomerulonephritis + CEI 278 +/- 48 microliters/min/100 g bw). Glomerular structural damage expressed as glomerular damage index was significantly greater in rats with immune complex glomerulonephritis when compared with controls (immune complex glomerulonephritis 0.91 +/- 0.13; control 0.60 +/- 0.08; P < 0.05), but was uneffected by the treatment with the CEI (immune complex) glomerulonephritis + CEI 1.02 +/- 0.26; control + CEI 0.63 +/- 0.11).. These data demonstrate that ramipril reduced albuminuria in a model of immune complex glomerulonephritis; however, it failed to alter GFR and glomerular damage index. The study suggests that ramipril ameliorates proteinuria independently of obvious glomerular histological changes. The reduction of proteinuria is, however, associated with a significant decrease in filtration fraction and therefore is at least partially haemodynamically mediated.

Topics: Albuminuria; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Animals; Glomerulonephritis; Kidney; Kidney Function Tests; Lipids; Male; Organ Size; Ramipril; Rats; Rats, Wistar; Renin; Serum Albumin

Topics: Albuminuria; Antihypertensive Agents; Diabetes Mellitus, Type 2; Humans; Hypertension; Nitrendipine; Ramipril

Ramipril was administered to 13 patients, aged 49-80 years, weighing 53.5-90.3 kg, with congestive heart failure (CHF) for 2 weeks in an open trial. One patient dropped out after day 1 and another accidentally received another angiotensin-converting enzyme (ACE) inhibitor, so that 11 patients remained for analysis. Each patient received 5 mg of ramipril daily for 2 weeks, followed by a 1-week washout period. Urine was collected in 4-h fractions for 12 h followed by a 12-h fraction on days 1, 8, and 15. Creatinine clearance, as well as the excretion of albumin and the urinary brush border enzymes gamma-glutamyl transferase (GGT), alanine aminopeptidase (AAP), N-acetyl-beta-D-glucosaminidase (NAG), and lactate dehydrogenase (LDH) were determined. The values for albumin excretion, creatinine clearance, GGT, AAP, NAG, and LDH obtained for the various days during the time course before and during multiple dosing were subjected to an analysis of variance followed by Scheffe's test for means. Daily albumin excretion decreased during treatment with ramipril from 23.8 +/- 27.4 mg/24 h (baseline) to 12.9 +/- 15.1 (day 1), 10.8 +/- 15.6 (day 8), and 12.4 +/- 12.7 mg/24 h (day 15). The differences were significant (alpha = 0.05) when compared to pretreatment albumin excretion. Creatinine clearance increased from 78.8 +/- 38.3 ml/min (baseline) to 82.4 +/- 34.6 (day 1), 85.1 +/- 28.5 (day 8), and 91.7 +/- 36.4 ml/min (day 15). The change on day 15 was significant (alpha = 0.05) when compared to pretreatment values.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acetylglucosamine; Aged; Aged, 80 and over; Albuminuria; Aminopeptidases; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Bridged Bicyclo Compounds; CD13 Antigens; Chronic Disease; Creatinine; gamma-Glutamyltransferase; Heart Failure; Humans; Kidney; Kidney Function Tests; L-Lactate Dehydrogenase; Middle Aged; Ramipril

1. Streptozotocin diabetes was induced in Wistar-Kyoto rats fed a 50% protein diet. Animals were randomized to receive either the ACE inhibitor ramipril, 1 mg/L in drinking water (n = 7), or no treatment (n = 7) and were studied for 6 months. Blood glucose, body weight and glomerular filtration rate (GFR) were measured at 0, 1, 4, 8 and 16 weeks of diabetes and urinary albumin excretion was measured every 8 weeks. 2. In both groups, GFR increased significantly within 1 week of induction of diabetes (P less than 0.001) and thereafter remained stable. There was no difference in GFR between the treated and untreated groups. 3. Urinary albumin excretion increased progressively in both groups throughout the study. Ramipril treatment reduced albuminuria by approximately 50% at weeks 16 and 24 (P less than 0.01). 4. The amelioration of diabetic albuminuria by ACE inhibition, in the setting of high dietary protein intake, may have important implications for the treatment of human diabetic nephropathy.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Blood Pressure; Body Weight; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Diabetes Mellitus, Experimental; Diet; Dietary Proteins; Glomerular Filtration Rate; Male; Ramipril; Rats; Rats, Inbred WKY; Time Factors