ramipril and Kidney-Diseases

Increasing attention is being devoted to the use of combination therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in order to achieve maximal blockade of the renin-angiotensin system (RAS) in patients at high risk of cardiovascular events. This approach has been adopted in the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), which compared the effects of the ARB telmisartan and the ACE inhibitor ramipril, alone and in combination, on cardiovascular mortality and morbidity in high-risk patients with vascular disease or diabetes mellitus and end-organ damage. The results showed that telmisartan was as effective as ramipril for the primary cardiovascular outcome during a 56-month follow-up but was better tolerated. However, dual RAS blockade was not associated with any additional benefits, and the incidence of adverse events was greater with the combination. Based on these findings, optimal cardioprotective strategies in high-risk patients are likely to involve the addition of either telmisartan or ramipril on top of the patient's usual care, but not both. The choice of agent to be used in the long term could be based on other considerations, such as compliance and safety. Both cough and angioedema were higher with ramipril than telmisartan during the 56-month follow-up period in ONTARGET.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Diabetes Mellitus; Humans; Kidney Diseases; Ramipril; Risk Factors; Telmisartan

The renin-angiotensin-aldosterone system (RAAS) plays an important role in the pathogenesis of a variety of clinical conditions, including atherosclerosis, hypertension, left ventricular hypertrophy, myocardial infarction, and heart failure. Inhibition of the RAAS with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ARBs) has been shown to be effective in lowering blood pressure and reducing cardiovascular mortality and morbidity in various at-risk patient populations. A number of studies have shown that these 2 classes are effective in reducing the rate of renal disease progression in patients with diabetic nephropathy, although more long-term vascular outcome studies are needed in patients with chronic kidney disease. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) was the first study to show comparable reno- and cardioprotective effects between an ARB (telmisartan) and ramipril in a broad section of at-risk patients, on top of usual standard care. However, telmisartan showed better tolerability than ramipril in ONTARGET, with less cough and angioedema. This difference was obtained despite patients having been selected for tolerability to both drugs at study entry.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Diabetes Mellitus; Drug Therapy, Combination; Humans; Kidney Diseases; Ramipril; Telmisartan

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

The use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, or aldosterone antagonists can have important beneficial effects on the progression of renal disease associated with glomerular and interstitial fibrosis, especially if the adverse side effects (eg, hyperkalemia) can be minimized. Because it appears that chronic renal insufficiency and proteinuria may well be cardiovascular risk factors, it is exciting to note that recent large scale epidemiologic studies (Heart Outcomes and Prevention Evaluation [HOPE]) have shown both cardioprotective and renoprotective effects of ACE inhibition. It appears paradoxic that such renoprotective effects are clearly evident in diabetes mellitus in which the plasma renin activity may be suppressed. Even in this setting, it appears that there is activation of the renal angiotensin system(s), and inhibitions of these intrarenal systems are involved in the renoprotective effects of these agents. Recent studies have identified nearly all of the components needed to generate angiotensin II in the renal luminal compartment, and suggest that there may be a direct effect through AT(1) receptors on NaCl transport in the distal nephron. The possibility that the components of this intraluminal renin-angiotensin system may be acutely regulated by variations in dietary salt intake provides an opportunity to better understand the normal maintenance of salt balance. Whether or not inhibition of these pathways is involved in the renoprotective effects of ACE inhibitors and angiotensin receptor antagonists is an important issue to be addressed.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Humans; Kidney Diseases; Ramipril; Renal Circulation; Renin-Angiotensin System; Sodium, Dietary

Topics: Angiotensin-Converting Enzyme Inhibitors; Cardiovascular Diseases; Drug Therapy, Combination; Hemodynamics; Humans; Kidney Diseases; Kidney Function Tests; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Vitamin E

Initiation of blockade of the renin-angiotensin system may cause an acute decrease in glomerular filtration rate (GFR): the prognostic significance of this is unknown. We did a post hoc analysis of patients with, or at risk for, vascular disease, in two randomized controlled trials: Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and the Telmisartan Randomized AssessmeNt Study in ACE iNtolerant participants with cardiovascular Disease (TRANSCEND), whose median follow-up was 56 months. In 9340 patients new to renin-angiotensin system blockade, who were then randomized to renin-angiotensin system blockade, a fall in GFR of 15% or more at 2 weeks after starting renin-angiotensin system blockade was seen in 1480 participants (16%), with persistence at 8 weeks in 700 (7%). Both acute increases and decreases in GFR after initiation of renin-angiotensin system blockade were associated with tendencies, mostly not statistically significant, to increased risk of cardiovascular outcomes, which occurred in 1280 participants, and of microalbuminuria, which occurred in 864. Analyses of creatinine-based outcomes were suggestive of regression to the mean. In more than 3000 patients randomized in TRANSCEND to telmisartan or placebo, there was no interaction between acute change in GFR and renal or cardiovascular benefit from telmisartan. Thus, both increases and decreases in GFR on initiation of renin-angiotensin system blockade are common, and may be weakly associated with increased risk of cardiovascular and renal outcomes. Changes do not predict increased benefit from therapy.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cardiovascular Diseases; Disease Progression; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Odds Ratio; Ramipril; Renin-Angiotensin System; Risk Factors; Telmisartan; Time Factors; Treatment Outcome

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

In the Ongoing Telmisartan Alone and in Combination with Ramipril Trial (ONTARGET), dual agent renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) did not reduce the risk of renal and cardiovascular outcomes compared with the single use of either agent. Dual therapy however increased the incidence of hyperkalemia. We examined risk factors for hyper- and hyokalemia and hypothesized that both would be associated with worse cardiovascular and renal outcomes.. A post-hoc analysis of the ONTARGET trial comparing dual therapy (ramipril and telmisartan) vs monotherapy (ramipril or telmisartan) was performed. The association between serum potassium at week 6 on cardiovascular and renal outcomes during the 56 months follow-up was assessed by multivariate Cox analysis. The main cardiovascular outcome was the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure. The renal outcome was defined as the composite of a doubling of serum creatinine or chronic dialysis.. Six weeks after randomization, hyperkalemia developed in 210 (2.7%) patients on dual therapy vs. 264 (1.6%) patients on monotherapy (p < 0.001 vs. dual therapy). Hypokalemia developed in 87 (1.1%) patients on dual therapy vs. 200 (1.2%)patients on monotherapy. Serum potassium was nonlinearly associated with cardiovascular and renal events with a nadir between 4.0-5.0 mmol/l for cardiovascular and 4.0-4.5 mmol/l for renal events such that subjects above or below these values exhibited higher risks. This association was independent of age, gender, diabetes, estimated glomerular filtration rate, systolic blood pressure and diuretic use.. With the precautions stipulated by the protocol of the ONTARGET trial, hypokalemia and hyperkalemia were infrequent events. Nevertheless, both high and low serum potassium were associated with an increased risk of cardiovascular and renal disease.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Creatinine; Drug Therapy, Combination; Female; Heart Failure; Hospitalization; Humans; Hyperkalemia; Hypertension; Hypokalemia; Kidney; Kidney Diseases; Logistic Models; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Nonlinear Dynamics; Odds Ratio; Potassium; Proportional Hazards Models; Ramipril; Renal Dialysis; Renin-Angiotensin System; Risk Assessment; Risk Factors; Stroke; Telmisartan; Time Factors; Treatment Outcome

Obesity may increase the risk for progression of CKD, but the effect of established renoprotective treatments in overweight and obese patients with CKD is unknown. In this post hoc analysis of the Ramipril Efficacy In Nephropathy (REIN) trial, we evaluated whether being overweight or obese influences the incidence rate of renal events and affects the response to ramipril. Of the 337 trial participants with known body mass index (BMI), 105 (31.1%) were overweight and 49 (14.5%) were obese. Among placebo-treated patients, the incidence rate of ESRD was substantially higher in obese patients than overweight patients (24 versus 11 events/100 person-years) or than those with normal BMI (10 events/100 person-years); we observed a similar pattern for the combined endpoint of ESRD or doubling of serum creatinine. Ramipril reduced the rate of renal events in all BMI strata, but the effect was higher among the obese (incidence rate reduction of 86% for ESRD and 79% for the combined endpoint) than the overweight (incidence rate reduction of 45 and 48%, respectively) or those with normal BMI (incidence rate reduction of 42 and 45%, respectively). We confirmed this interaction between BMI and the efficacy of ramipril in analyses that adjusted for potential confounders, and we observed a similar effect modification for 24-hour protein excretion. In summary, obesity predicts a higher incidence of renal events, but treatment with ramipril can essentially abolish this risk excess. Furthermore, the reduction in risk conferred by ramipril is larger among obese than nonobese patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Body Mass Index; Chronic Disease; Comorbidity; Creatinine; Disease Progression; Female; Glomerular Filtration Rate; Humans; Incidence; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Obesity; Overweight; Proteinuria; Ramipril; Treatment Outcome

Blood pressure (BP) guidelines that set target BP levels often rely on analyses of achieved BP from hypertension treatment trials. The objective of this article was to compare the results of analyses of achieved BP to intention-to-treat analyses on renal disease progression. Participants (n=1094) in the African-American Study of Kidney Disease and Hypertension Trial were randomly assigned to either usual BP goal defined by a mean arterial pressure goal of 102 to 107 mm Hg or lower BP goal defined by a mean arterial pressure goal of ≤92 mm Hg. Median follow-up was 3.7 years. Primary outcomes were rate of decline in measured glomerular filtration rate and a composite of a decrease in glomerular filtration rate by >50% or >25 mL/min per 1.73 m(2), requirement for dialysis, transplantation, or death. Intention-to-treat analyses showed no evidence of a BP effect on either the rate of decline in glomerular filtration rate or the clinical composite outcome. In contrast, the achieved BP analyses showed that each 10-mm Hg increment in mean follow-up achieved mean arterial pressure was associated with a 0.35 mL/min per 1.73 m(2) (95% CI: 0.08 to 0.62 mL/min per 1.73 m(2); P=0.01) faster mean glomerular filtration rate decline and a 17% (95% CI: 5% to 32%; P=0.006) increased risk of the clinical composite outcome. Analyses based on achieved BP lead to markedly different inferences than traditional intention-to-treat analyses, attributed in part to confounding of achieved BP with comorbidities, disease severity, and adherence. Clinicians and policy makers should exercise caution when making treatment recommendations based on analyses relating outcomes to achieved BP.

Topics: Adult; Aged; Amlodipine; Antihypertensive Agents; Black or African American; Blood Pressure; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Kidney Diseases; Male; Metoprolol; Middle Aged; Proportional Hazards Models; Ramipril; Time Factors; 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 study evaluated the effects of Pycnogenol as an adjunct to angiotensin-converting enzyme (ACE)-inhibitor ramipril treatment of hypertensive patients presenting with early signs of renal function problems. One group of 26 patients was medicated with 10 mg ramipril per day only; a second group of 29 patients took Pycnogenol in addition to the ACE inhibitor over a period of 6 months. At trial end, a lowered systolic and diastolic blood pressure was found in both groups, with a significant further reduction of diastolic pressure in the group given Pycnogenol in addition to ramipril. The major aim of this study was the investigation of kidney-protective effects of Pycnogenol. Urinary albumin decreased from 87 +/- 23 to 64 +/- 16 mg/d with ramipril only. Additional Pycnogenol lowered albumin significantly better from 91 +/- 25 to 39 +/- 13 mg/day (P < .05). In both groups, serum creatinine was lowered; however, only in the combination treatment group did the effect reached statistical significance. In both groups, CRP levels decreased from 2.1 to 1.8 with ramipril and from 2.2 to 1.1 with the ramipril-Pycnogenol combination; the latter reached statistical significance. Kidney cortical flow velocity was investigated by Doppler color duplex ultrasonography. Both systolic and diastolic flow velocities increased significantly after 6 months medication with ramipril. The addition of Pycnogenol to the regimen statistically significantly further enhanced kidney cortical flow velocities, by 8% for diastolic flow and 12% for systolic flow, relative to values found for the group taking ramipril only. The protective effects of Pycnogenol for initial kidney damage found in this study warrant further research with a larger number of patients and over a longer period of time.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Creatinine; Drug Therapy, Combination; Female; Flavonoids; Humans; Hypertension; Kidney; Kidney Diseases; Male; Middle Aged; Plant Extracts; Platelet Aggregation Inhibitors; Ramipril; Treatment Outcome; Ultrasonography

Residual proteinuria is a strong modifiable risk factor for renal failure progression. We previously showed that the antiproteinuric effect of combined half doses of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) is increased by raising diuretic dosage. Methods. We tested whether uptitration of loop diuretics on top of combined half doses of ACEI and ARB would better decrease proteinuria than uptitration to combined full doses of ACEI and ARB in a randomized, crossover, three periods of 6-week controlled study. Eighteen patients with stable proteinuria over 1 g/day with combined ramipril at 5 mg/day and valsartan at 80 mg/day in addition to conventional antihypertensive treatments were randomized to receive combined ramipril at 5 mg/day and valsartan at 80 mg/day, or combined ramipril at 10 mg/day and valsartan at 160 mg/day, or combined ramipril at 5 mg/day, valsartan at 80 mg/day and increased furosemide dosage in random order. The primary end point was the mean urinary protein/creatinine ratio in two 24-hour urine collections at the end of the three treatment periods. Secondary end points included mean 24-hour proteinuria, home systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP) and estimated glomerular filtration rate (eGFR) levels.. The geometric mean urinary protein/creatinine ratio was lower with combined ramipril at 5 mg/day, valsartan at 80 mg/day and increased furosemide dosage compared to combined ramipril at 5 mg/day and valsartan at 80 mg/day, but also to combined ramipril at 10 mg/day and valsartan at 160 mg/day. These differences remained significant after adjustment for SBP, DBP or MAP and 24-hour natriuresis but not after adjustment on eGFR. Diuretic dosage uptitration did not increase the number of home systolic blood pressure measurements below 100 mmHg, but led to a statistically significant increase in the number of symptomatic hypotension episodes.. A cautious uptitration of loop diuretic dosage in addition to combined half doses of ACEI and ARB better decrease proteinuria in patients with CKD and high residual proteinuria than uptitration to full dose of combined ACEI and ARB. This antiproteinuric effect of diuretics was partly explained by an eGFR decrease, suggesting the contribution of haemodynamic modifications, whose safety on the long term still need to be addressed.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Chronic Disease; Diuretics; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Middle Aged; Proteinuria; Ramipril; Tetrazoles; Treatment Outcome; Valine; Valsartan

The African American Study of Kidney Disease and Hypertension was a multicenter trial comparing the effects of 2 levels of blood pressure control (usual or low goal) and initial therapy with metoprolol, ramipril, or amlodipine. We examined effects of treatment-group assignment on health-related quality of life (HRQOL) measures and reported symptoms during 4 years of follow-up.. HRQOL was assessed at baseline and annually by using the Medical Outcomes Study 36-Item Short Form (SF-36) and a symptom checklist. Using a 2-slope model, treatment effects were evaluated for change from baseline to year 1 and for average change during the first 4 years of follow-up.. A total of 1,094 participants were randomly assigned. Average age was 55 years, 61% were men, and the mean of the first glomerular filtration rate in the study was 46 mL/min/1.73 m2 (0.76 mL/s). No significant differences in HRQOL were seen between the low- and usual-blood-pressure groups. Reported side effects also were similar between blood-pressure groups. Mean Physical Health Component (PHC) and Mental Health Component (MHC) scores had a significantly smaller decrease in the ramipril than metoprolol group in both the initial period from baseline to year 1 (PHC, 2.08 +/- 0.56; MHC, 1.89 +/- 0.62) and during the first 4 years of follow-up (PHC, 1.60 +/- 0.44; MHC, 1.48 +/- 0.48). The MHC also had a slightly smaller decrease during the first 4 years in the ramipril group than amlodipine group (1.20 +/- 0.61).. Aggressive blood pressure control is well tolerated in African Americans with hypertensive kidney disease, measured by using the SF-36 and reported symptoms. The clinical significance of smaller decreases in PHC and MHC scores in the ramipril compared with metoprolol group is not clear.

Topics: Adolescent; Adult; Aged; Amlodipine; Antihypertensive Agents; Black or African American; Blood Pressure; Female; Humans; Hypertension; Kidney Diseases; Male; Metoprolol; Middle Aged; Nephrosclerosis; Outcome Assessment, Health Care; Quality of Life; Ramipril

Emerging data suggest that different indices of glycaemia are risk factors for clinical events. The aim of this analysis was to investigate the relationship between fasting plasma glucose or glycated haemoglobin (GHb) levels and incident cardiovascular (CV) outcomes, death, heart failure and overt nephropathy in diabetic and non-diabetic individuals enrolled in the Heart Outcomes Prevention Evaluation (HOPE) study.. The adjusted 4.5-year risk of CV events (myocardial infarction or stroke or CV death), heart failure, death and overt nephropathy was analysed in relation to baseline and updated GHb levels (in 3,529 diabetic HOPE study participants) and baseline fasting plasma glucose levels (in 1,937 non-diabetic and 1,013 diabetic participants).. In diabetic participants, a 1% absolute rise in the updated GHb predicted future CV events (relative risk [RR]=1.07, 95% CI 1.01-1.13; p=0.014), death (RR=1.12, 95% CI 1.05-1.19; p=0.0004), heart failure (RR=1.20, 95% CI 1.08-1.33; p=0.0008) and overt nephropathy (RR=1.26, 95% CI 1.17-1.36; p<0.0001) after adjusting for age, sex, diabetes duration, blood pressure, WHR, hyperlipidaemia and ramipril. Similarly, a 1 mmol/l rise in fasting plasma glucose was related to an increased risk of CV outcomes (RR=1.09, 95% CI 1.05-1.13; p<0.0001), death (RR=1.06, 95% CI 1.01-1.12; p=0.017), heart failure (RR=1.16, 95% CI 1.06-1.13; p=0.0007) and overt nephropathy (RR=1.34, 95% CI 1.23-1.45; p<0.0001) in the group composed of diabetic and non-diabetic individuals. The significant relationship between fasting plasma glucose and CV outcomes persisted after adjustment for diabetes status (RR=1.06, 95% CI 1.00-1.12; p=0.043).. There is an independent progressive relationship between indices of glycaemia and incident CV events, renal disease and death. Clinical trials of glucose lowering to prevent these outcomes in diabetic and non-diabetic individuals are indicated.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Glucose; Cardiovascular Diseases; Diabetes Mellitus; Diabetic Angiopathies; Fasting; Female; Glycated Hemoglobin; Humans; Kidney Diseases; Male; Placebos; Ramipril; Reference Values; Risk Factors; Vitamin E

The HOPE study was a 19 country, prospective randomized trial in which the ACE-inhibitor Ramipril but not Vitamin E significantly reduced the risk of future cardiovascular events in a high-risk population of men and women, including many with diabetes. The benefits were present in all sub-groups, independent of the presence or absence of diabetes, hypertension, evidence of cardiovascular disease, microalbuminuria, blood pressure lowering, the use of aspirin, lipid-lowering or antihypertensive medication. It provided clear evidence that Ramipril should safely and cost-effectively be used in individuals not known to have low ventricular ejection fraction or heart failure but at high-risk of cardiovascular events. It was also beneficial in patients with renal insufficiency, reducing progression of proteinuria and development of new microalbuminuria. It provided micro- and macrovascular benefits in people with diabetes, reduced the development of new cases of diabetes and showed a positive and graded association between the waist-to-hip ratio and the risk of developing diabetes. Sub-studies completed and on-going into the predictive role of natriuretic peptides, infectious and inflammatory markers, provide insight into possible mechanisms of action of Ramipril.

Topics: Angiotensin-Converting Enzyme Inhibitors; Aspirin; Cost-Benefit Analysis; Diabetes Complications; Female; Heart Failure; Humans; Inflammation; Kidney Diseases; Male; Myocardial Infarction; Natriuretic Peptide, Brain; Peptide Fragments; Prospective Studies; Ramipril; Stroke; Ventricular Function, Left; Vitamin E

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

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Humans; Kidney Diseases; Lipids; Ramipril; Risk Factors; Treatment Outcome

The Ramipril Efficacy in Nephropathy (REIN) study found that angiotensin-converting enzyme (ACE) inhibitors effectively decreased proteinuria, glomerular filtration rate (GFR) decline (DeltaGFR), and incidence of end-stage renal disease (ESRD) in patients with proteinuric chronic nephropathies. In this study, we prospectively investigated the main clinical determinants of progression and response to treatment in the 352 patients enrolled into the REIN study. Mean DeltaGFR (0.56 +/- 0.05 [SEM] versus 0.21 +/- 0.05 mL/min/1.73 m(2)/mo; P = 0.0001) and incidence of ESRD (30% and 10%; P = 0.0001) were more than twice that in patients with proteinuria of 2 g/24 h or greater of protein compared with those with protein less than 2 g/24 h (relative risk [RR], 4.07; 95% confidence interval [CI], 2.20 to 7.52), as well as in patients with hypertension compared with normotension (mean DeltaGFR, 0.48 +/- 0. 05 versus 0.22 +/- 0.05 mL/min/1.73 m(2)/mon; P = 0.0006; ESRD, 25% versus 10%; P = 0.004; RR, 3.18; 95% CI, 1.38 to 7.32). Hypertension at study entry (P = 0.038), greater mean blood pressure on follow-up (P = 0.002), and urinary protein excretion rate (P = 0.0001) were independent predictors of faster DeltaGFR. DeltaGFR was approximately twofold faster in patients with type 2 diabetes than in those with primary glomerular disease (P = 0.002; including immunoglobulin A [IgA] nephropathy, P = 0.009); nephrosclerosis (P = 0.03), adult polycystic kidney disease (APKD), or chronic interstitial nephritis (P = 0.006). Diabetes at study entry (P = 0. 02) and greater mean blood pressure (P = 0.0001) and urinary protein excretion rate (P = 0.0001) on follow-up were independent predictors of faster DeltaGFR. After correction for baseline covariates, diabetes was also associated with an increased risk for progression to ESRD (RR, 2.39; 95% CI, 1.01 to 5.68; P < 0.05). At multivariate analyses, ramipril significantly decreased DeltaGFR (regression coefficient,-0.23 +/- 0.11 [SEM]; P = 0.036) and ESRD (RR, 2.08; 95% CI, 1.21 to 3.57; P = 0.008) in patients with baseline proteinuria of 2 g/24 h or greater of protein, and the renoprotective effect increased for increasing levels of proteinuria. Ramipril decreased DeltaGFR to a similar extent in normotensive and hypertensive patients (-0.14 +/- 0.11 versus -0.14 +/- 0.09) and significantly limited ESRD in hypertensive patients (RR, 2.03; 95% CI, 1.26 to 3. 26; P = 0.004). DeltaGFR was decreased by 42% in primary glomerular disea

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Cohort Studies; Confidence Intervals; Diabetic Nephropathies; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Incidence; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Proteinuria; Ramipril; Treatment Outcome

The Ramipril Efficacy in Nephropathy Core and Follow-Up Study found that > or =36 mo of continued ramipril therapy decreased substantially the risk of end-stage renal failure (ESRF) in patients with chronic nephropathies and a urinary protein excretion rate > or =3 g/24 h. This study investigates the time-dependent changes in GFR in these patients and in control subjects who were randomized to conventional therapy during the Core period and switched to ramipril during the Follow-Up study. Analyses included 150 patients (continued ramipril: n = 74; switched to ramipril: n = 76) who had at least three GFR measurements (including baseline) during the whole observation period and a subgroup of 43 patients (continued ramipril: n = 26; switched to ramipril: n = 17) who had at least six GFR measurements, including at least three on the Core and at least three on the Follow-Up study. Ramipril (1.25 to 5 mg/d) and conventional therapy were targeted at achieving a diastolic BP below 90 mm Hg. The main efficacy variables were GFR and ESRF (need for dialysis). Analysis was by intention to treat. Throughout the study, the mean +/- SEM rate of GFR decline (deltaGFR) was significantly lower in patients continued on ramipril compared to those switched to ramipril (0.51+/-0.09 versus 0.76+/-0.10 ml/min per 1.73 m2 per mo, P<0.03). In patients on continued ramipril who had at least six GFR measured--but not in control subjects--deltaGFR progressively improved with time and, in the cohort with the longest follow-up, decreased from (in ml/min per 1.73 m2 per mo): 0.16+/-0.12 (at 18 mo) to 0.10+/-0.05 (at 60 mo). This rate was about 10-fold slower compared to patients on conventional therapy during the REIN Core study. Analyses of the individual slopes found that at the end of the follow-up, 10 of 26 patients on continued ramipril therapy had a positive deltaGFR and another 10 patients had an improvement of deltaGFR while on ramipril therapy. DeltaGFR significantly improved in parallel with a significant reduction in proteinuria. Changes in deltaGFR (P = 0.0001) and proteinuria (P = 0.04) were significantly different in the two groups. Baseline characteristics and changes in systolic and diastolic BP and 24-h urine urea and sodium excretion were comparable. The present results offer evidence that in chronic nephropathies, the tendency of GFR to decline with time can be effectively halted, even in patients with remarkably severe disease.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Cohort Studies; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Ramipril; Remission Induction; Time Factors; Tissue Survival

In diabetic nephropathy, angiotensin-converting-enzyme (ACE) inhibitors have a greater effect than other antihypertensive drugs on proteinuria and the progressive decline in glomerular filtration rate (GFR). Whether this difference applies to progression of nondiabetic proteinuric nephropathies is not clear. The Ramipril Efficacy in Nephropathy study of chronic nondiabetic nephropathies aimed to address whether glomerular protein traffic influences renal-disease progression, and whether an ACE inhibitor was superior to conventional treatment, with the same blood-pressure control, in reducing proteinuria, limiting GFR decline, and preventing endstage renal disease.. In this prospective double-blind trial, 352 patients were classified according to baseline proteinuria (stratum 1: 1-3 g/24 h; stratum 2: > or = 3 g/24 h), and randomly assigned ramipril or placebo plus conventional antihypertensive therapy targeted at achieving diastolic blood pressure under 90 mm Hg. The primary endpoint was the rate of GFR decline. Analysis was by intention to treat.. At the second planned interim analysis, the difference in decline in GFR between the ramipril and placebo groups in stratum 2 was highly significant (p = 0.001). The Independent Adjudicating Panel therefore decided to open the randomisation code and do the final analysis in this stratum (stratum 1 continued in the trial). Data (at least three GFR measurements including baseline) were available for 56 ramipril-assigned patients and 61 placebo-assigned patients. The decline in GFR per month was significantly lower in the ramipril group than the placebo group (0.53 [0.08] vs 0.88 [0.13] mL/min, p = 0.03). Among the ramipril-assigned patients, percentage reduction in proteinuria was inversely correlated with decline in GFR (p = 0.035) and predicted the reduction in risk of doubling of baseline creatinine or endstage renal failure (18 ramipril vs 40 placebo, p = 0.04). The risk of progression was still significantly reduced after adjustment for changes in systolic (p = 0.04) and diastolic (p = 0.04) blood pressure, but not after adjustment for changes in proteinuria. Blood-pressure control and the overall number of cardiovascular events were similar in the two treatment groups.. In chronic nephropathies with proteinuria of 3 g or more per 24 h, ramipril safely reduces proteinuria and the rate of GFR decline to an extent that seems to exceed the reduction expected for the degree of blood-pressure lowering.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria; Ramipril; Risk

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 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

The COL4A3-/- mouse serves as animal model for progressive renal fibrosis. Using this animal model, the present study investigates the nephroprotective effects of Paricalcitol versus Calcitriol alone and on top of ACE-inhibitor therapy.. Eighty six mice were divided into six groups: (PC) with Paricalcitol 0.1 mcg/kg, (CA) Calcitriol 0.03 mcg/kg (dose equipotent), (PLAC) vehicle 0.1 mL i.p. five times per week, (ACE + PC) Paricalcitol plus Ramipril, (ACE + CA) Calcitriol plus Ramipril and (ACE + PLAC) vehicle plus Ramipril 10 mg/kg/day p.o. ACE therapy started pre-emptively in Week 4, PC/CA therapy was initiated in 6-week-old animals with ongoing renal fibrosis and lasted for 8 weeks. Four to six animals were sacrificed after 9.5 weeks and kidneys were further investigated using histological, immunohistological and Western-blot techniques. Survival until end-stage renal failure was determined in the remaining animals.. PC, but not CA, prolonged lifespan until renal failure by 13% compared with untreated controls (P = 0.069). ACE-inhibition prolonged lifespan by >50%. Added on top of ACE inhibition, ACE + PC (but not ACE + CA) even further prolonged lifespan by additional 18.0% (P < 0.01 versus ACE + PLAC) and improved renal function (blood urea nitrogen; P < 0.05 versus ACE + CA). Accumulation of extracellular matrix and renal scarring was decreased in PC and ACE + PC-treated mice.. The present study demonstrated a substantial nephroprotective and antifibrotic effect of the vitamin D-receptor activator Paricalcitol on top of early ACE inhibition in the COL4A3-/- model of progressive kidney fibrosis. The synergistic effect of Paricalcitol on top of RAAS-blockade might as well be valuable in other chronic kidney diseases.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Autoantigens; Bone Density Conservation Agents; Calcitriol; Collagen Type IV; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Ergocalciferols; Extracellular Matrix; Female; Fibrosis; Immunoblotting; Immunoenzyme Techniques; Kidney Diseases; Male; Mice; Mice, Knockout; Ramipril; Receptors, Calcitriol

Peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to ameliorate diabetic nephropathy, but much less are known about their effects in non-diabetic nephropathies. In the present study, metabolic parameters, blood pressure, aortic endothelial function along with molecular and structural markers of glomerular and tubulointerstitial renal damage, were studied in a rat model of normotensive nephropathy induced by adriamycin and treated with PPARγ agonist pioglitazone (12mg/kg, po), angiotensin converting enzyme (ACE) inhibitor ramipril (1mg/kg, po) or their combination. Pioglitazone had no effect on systolic blood pressure, marginally reduced glycemia and improved aortic endothelium-dependent relaxation. In the kidney, pioglitazone prevented the development of proteinuria and focal glomerulosclerosis to the similar extent as blood-pressure lowering ramipril. Renoprotection provided by either treatment was associated with a reduction in the cortical expression of profibrotic plasminogen activator inhibitor-1 and microvascular damage-inducing endothelin-1, and a limitation of interstitial macrophage influx. Treatment with PPARγ agonist, as well as ACE inhibitor comparably affected renal expression of the renin-angiotensin system (RAS) components, normalizing increased renal expression of ACE and enhancing the expression of Mas receptor. Interestingly, combined pioglitazone and ramipril treatment did not provide any additional renoprotection. These results demonstrate that in a nondiabetic renal disease, such as adriamycin-induced nephropathy, PPARγ agonist pioglitazone provides renoprotection to a similar extent as an ACE inhibitor by interfering with the expression of local RAS components and attenuating related profibrotic and inflammatory mechanisms. The combination of the both agents, however, does not lead to any additional renal benefit.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Blood Pressure; Disease Progression; Doxorubicin; Endothelium, Vascular; Gene Expression Regulation; Kidney Diseases; Kidney Glomerulus; Kidney Tubules; Male; Pioglitazone; PPAR gamma; Proteinuria; Ramipril; Rats; Rats, Wistar; Renin-Angiotensin System; Thiazolidinediones

We tested five different angiotensin converting enzyme inhibitors (ACEI) as mitigators of experimental radiation nephropathy at drug doses calibrated to the plasma renin activity (PRA). This was done to determine whether all ACEI had the same efficacy as mitigators of radiation nephropathy when used at drug doses that gave equivalent suppression of the renin angiotensin system.. 10 Gy total body irradiation with bone marrow transplantation was used to cause radiation nephropathy in barrier-maintained rats. Equivalent ACEI doses were determined based on their effect to inhibit angiotensin converting enzyme (ACE) and raise the PRA in unirradiated animals.. PRA-equivalent doses were found for captopril, lisinopril, enalapril, ramipril and fosinopril. These doses overlap the human doses of these drugs on a body surface area basis. All ACE inhibitors, except fosinopril, mitigated radiation nephropathy; captopril was a somewhat better mitigator than lisinopril, enalapril or ramipril.. Most, but not all, ACEI mitigate radiation nephropathy at doses that overlap their clinically-used doses (on a body surface area basis). Fosinopril is known to be an ineffective mitigator of radiation pneumonitis, and it also does not mitigate radiation nephropathy. These pre-clinical data are critical in planning human studies of the mitigation of normal tissue radiation injury.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Biomarkers; Bone Marrow Transplantation; Calibration; Captopril; Enalapril; Fosinopril; Kidney; Kidney Diseases; Lisinopril; Male; Radiation Injuries; Ramipril; Rats; Renin; Renin-Angiotensin System; Whole-Body Irradiation

Topics: Amlodipine; Antihypertensive Agents; Black or African American; Blood Pressure; Glomerular Filtration Rate; Humans; Hypertension; Kidney Diseases; Metoprolol; Ramipril; Treatment Outcome

Topics: Angiotensin-Converting Enzyme Inhibitors; Body Mass Index; Chronic Disease; Comorbidity; Creatinine; Disease Progression; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Failure, Chronic; Obesity; Proteinuria; Ramipril; Treatment Outcome

Type AA amyloidosis is a rare complication of sickle cell anemia. The purpose of this report is to describe the case of a 30-year-old man with heterozygous sickle cell disease who was referred to our unit with nephritic syndrome and microscopic hematuria. Light microscopy on a renal biopsy specimen demonstrated AA amyloidosis. After elimination of other causes, it was concluded that amyloidosis was the result of recurrent acute inflammation secondary to sickle cell disease. To our knowledge, this is the fifth that renal amyloidosis as a complication of sickle cell disease has been described in the literature.

Topics: Adult; Amyloidosis; Anemia, Sickle Cell; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Biopsy; Drug Therapy, Combination; Humans; Kidney Diseases; Male; Ramipril; Rare Diseases; Treatment Outcome

Topics: Benzimidazoles; Benzoates; Blood Pressure; Cardiovascular Diseases; Guidelines as Topic; Humans; Kidney Diseases; Ramipril; Telmisartan

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Chronic Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Kidney Diseases; Ramipril; Telmisartan; Treatment Outcome

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Chronic Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Kidney Diseases; Ramipril; Telmisartan; Treatment Outcome

Renin-angiotensin system (RAS) blockade improves proteinuria and the endothelial functions in diabetic nephropathy. Plasma asymmetric dimethylarginine (ADMA), abundant in the cell than in the plasma, is also improved by RAS blockage. We hypothesized that RAS blockade may reduce ADMA by reducing injurious cell death.. In a hypothesis-generating study, we assessed circulating levels of apoptotic signalling peptides in incident chronic kidney disease (CKD) stage 1 patients (aged >18 years with diabetes mellitus type 2 as the only cause of nephropathy) not previously prescribed statins or RAS blockade. Ninety-three (29 M, 47 ± 5 years) patients with CKD 1 diabetic nephropathy and 38 healthy subjects (20 M, 47 ± 5 years) were enrolled. Ramipril was given (5 mg daily for 12 weeks), and circulating ADMA, soluble Fas (sFas), myostatin and endothelial function [flow-mediated vasodilation (FMD); ultrasound)] were measured.. After the study, ADMA, sFas, myostatin, insulin resistance, high-sensitive C-reactive protein (hsCRP), estimated glomerular filtration rate (eGFR), blood pressure and proteinuria levels were decreased, and FMD and serum albumin levels increased (P < 0.05 for all). ADMA and sFas levels were independently related to FMD levels both before (rho = -0.33; P < 0.005 and rho = -0.26; P < 0.02, respectively) and after (rho = -0.39; P < 0.001 and rho = -0.28; P < 0.002, respectively) ramipril treatment. Changes in sFas and ADMA were related to the change in FMD (-0.32; P > 0.004 and -0.31; P < 0.004, respectively).. A reduction of proteinuria in CKD 1 diabetic kidney disease is accompanied by lower circulating sFas, myostatin and ADMA, suggesting that increased cell death may contribute to ADMA formation and endothelial dysfunction in diabetic CKD.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Arginine; Chronic Disease; Diabetic Nephropathies; fas Receptor; Female; Humans; Kidney Diseases; Male; Middle Aged; Multivariate Analysis; Myostatin; Proteinuria; Ramipril

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Humans; Kidney Diseases; Ramipril; Renin-Angiotensin System; Telmisartan

Clinical Pharmacology is commonly accepted to be a bridging discipline between basic science observations and clinical practice. Today, it should be a major task of the clinical pharmacologist in academia to provide support in the interpretation of preclinical and clinical study data, to develop evidence-based treatment guidelines and to serve as drug expert supporting all disciplines of clinical medicine with specific pharmacological and therapeutic knowledge. The results of the ONTARGET-trial confront both researchers and clinicians with the unexpected truth that AT(1)-receptor-blockade with an angiotensin-receptor-blocker (ARB) does not seem to have superior therapeutic benefit compared with an ACE-inhibitor (ACE-I) at reducing fatal and nonfatal cardiovascular events. The combination of the two drugs was associated with more adverse events without an increase in benefit. Therefore, the crucial question 'ACE-I, ARB, or both?' requires a new and critical appraisal depending on the medical indication for which these renin-angiotensin-system (RAS)-inhibitors are used: In a population of high-risk patients suffering from cardiovascular disease or diabetes mellitus, the evidence to favor an ARB over an ACE-I is still limited after ONTARGET and because of the higher costs for ARBs one can rather support the old therapeutic advice that ARBs are equally effective as ACE-Is and therefore therapeutic alternatives for patients with ACE-I intolerance. With respect to a very moderate additive BP-lowering effect of dual therapy with an ACE-I and an ARB seen in metaanalysis which was not even clearly attributable to dual RAS-inhibition and the increased adverse event rate in the combination treatment group of ONTARGET, this regimen seems not to be recommendable for the treatment of hypertension. Dual-RAS-blockade using an ACE-I-ARB-combination is an effective therapy to treat proteinuria and might be of therapeutic benefit especially in diabetic patients without concomitant diseases. There may be a therapeutic rationale to prefer ARBs over ACE-Is in well-selected patients with congestive heart failure (CHF) because a considerable amount of angiotensin II (Ang II) is produced independent of angiotensin-conversion-enzyme (ACE) in the failing heart and is therapeutically unaffected by ACE-I treatment. The results of the Val-HeFt and the CHARM-added-study revealed additive effects of an ARB on heart failure related morbidity and mortality when added to existing therapy w

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Benzimidazoles; Benzoates; Cardiovascular Diseases; Drug Therapy, Combination; Humans; Kidney Diseases; Ramipril; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Telmisartan

Topics: Adolescent; Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Cataract; Female; Hearing Loss, Sensorineural; Humans; Kidney Diseases; Losartan; Male; Molecular Motor Proteins; Mutation; Myosin Heavy Chains; Proteinuria; Ramipril; Renin-Angiotensin System; Syndrome; Telmisartan; Thrombocytopenia

Scleroderma renal crisis is the most severe renal manifestation of scleroderma and has been reported to recur rarely early after renal transplantation. Angiotensin II blockade is critical in preventing and treating scleroderma renal crisis, but some concern exists as to whether angiotensin II receptor blockers are clinically equivalent to angiotensin-converting enzyme inhibitors. The current case indicates that late recurrences of scleroderma renal crisis are possible in renal transplant recipients and that angiotensin-converting enzyme inhibitors, rather than angiotensin II receptor blockers, may be the superior drugs for such patients.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Arterioles; Basement Membrane; Female; Humans; Hypertension, Renal; Immunosuppression Therapy; Kidney Diseases; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Transplantation; Losartan; Postoperative Complications; Ramipril; Recurrence; Renal Artery; Scleroderma, Diffuse

Angiotensin-converting enzyme inhibitors are the drugs of choice in renal hypertension. The efficacy and safety of ramipril in adults has been proved; however, data on effectiveness of ramipril in children are few. The aim of the present study was to investigate the effect of ramipril on blood pressure (BP) and proteinuria in children with chronic kidney diseases.. A total of 31 children (median age 11.3 years, range 1.9-19.8 years) with various chronic nephropathies and hypertension or proteinuria were prospectively treated with ramipril for 6 months. Blood pressure was evaluated using ambulatory BP monitoring and hypertension was defined as mean BP equal to or greater than the 95th percentile for healthy children. Proteinuria was defined as protein excretion > or =100 mg/m(2)/24 h. The starting dose of ramipril was 1.5 mg/m(2)/24 h once daily. In 27 children it was given as monotherapy.. The median decrease in ambulatory BP was 11 mm Hg for daytime systolic, 10 mm Hg for daytime and nighttime diastolic, and 8 mm Hg for nighttime systolic BP. Hypertension normalized in 55% of the children. Proteinuria decreased in 84% of the children with pathologic proteinuria; the median decrease was 51%. A positive correlation was found between initial proteinuria and change of proteinuria (r = 0.95, P <.001). Glomerular filtration rate and serum potassium level did not change significantly. One child developed a cough that was believed to be related to ramipril.. Ramipril is an effective and safe drug in children with chronic kidney diseases associated with hypertension, proteinuria, or both.

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Child; Child Welfare; Child, Preschool; Chronic Disease; Circadian Rhythm; Diastole; Female; Humans; Hypertension; Infant; Kidney Diseases; Male; Prospective Studies; Proteinuria; Ramipril; Severity of Illness Index; Statistics as Topic; Systole; Treatment Outcome

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Clinical Trials as Topic; Humans; Indapamide; Kidney Diseases; Perindopril; Ramipril; Receptor, Angiotensin, Type 1; Stroke

Mast cells are growth factor-rich, bone marrow-derived cells that infiltrate injured tissue where they have been implicated in the pathogenesis of progressive fibrosis.. Mast cell infiltration and the expression of related chemoattractants was examined following 5/6 nephrectomy, a model of progressive, nonimmune-mediated renal injury. In addition, expression of the profibrotic cytokine, transforming growth factor-beta (TGF-beta) within mast cells and the effects of renoprotective therapy with angiotensin-converting enzyme (ACE) inhibition were also determined.. Renal injury was accompanied by mast cell infiltration, in close proximity to areas of tubulointerstitial fibrosis. Mast cells displayed toluidine blue metachromasia and were immunopositive for TGF-beta1 as well as chymase and tryptase. The expression of several mast cell chemokines, including stem cell factor, interleukin-8 (IL-8), and also TGF-beta1, were increased in 5/6 nephrectomized kidneys. ACE inhibition with ramipril led to a reduction in renal injury in association with attenuation of mast cell infiltration and chemokine expression.. Mast cell infiltration and related chemokine expression are prominent and early features following renal mass reduction and may contribute pathogenetically to progressive renal injury.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Chemokines; Disease Progression; Interleukin-8; Kidney Diseases; Macrophages; Male; Mast Cells; Nephrectomy; Ramipril; Rats; Rats, Sprague-Dawley; Stem Cell Factor; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus; Follow-Up Studies; Humans; Kidney Diseases; Placebos; Prospective Studies; Ramipril; Randomized Controlled Trials as Topic; Risk Factors; Time Factors

We studied the effect of ramipril on proteinuria and mild hypertension in a 21-year-old patient affected by glycogen storage disease type I non-A. After few months of therapy we obtained a decrease in total urine protein excretion that later re-increased in spite of the high dose of ACE inhibitor. Even if ACE inhibitors are the only effective therapy for GSD I nephropathy, further studies are requested.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Glucose-6-Phosphatase; Glycogen Storage Disease Type I; Humans; Hypertension, Renal; Kidney Diseases; Male; Proteinuria; Ramipril

Our objectives were to predict the long-term cost and efficacy of the angiotensin-converting enzyme, ramipril, in patients with nondiabetic chronic nephropathies.. The time to end-stage renal disease (ESRD) was predicted by two different models based on the rate of glomerular filtration rate decline (DeltaGFR) and incidence of ESRD (events) measured during the Ramipril Efficacy in Nephropathy Trial in 117 and 166 patients, respectively, randomized to comparable blood pressure control with ramipril or conventional therapy. Direct medical costs of conservative and renal replacement therapy were estimated by a payer perspective, and cases more and less favorable to ramipril were computed by a sensitivity analysis. The study took place at the Clinical Research Center for Rare Diseases, "Aldo & Cele Daccò," Bergamo, Italy. Patients included those with chronic, nondiabetic nephropathies and persistent urinary protein excretion rate >/=3 g/24 h. Time to ESRD, survival, and direct costs of conservative and renal replacement therapy are discussed.. Both in the DeltaGFR-based or events-based models, ramipril delayed progression to ESRD and prolonged patient survival by 1.5 to 2.2 and 1.2 to 1.4 years, respectively, and saved $16,605 to $23,894 lifetime and $2, 422 to $4203 yearly direct costs per patient. Even in the less favorable hypotheses, ramipril allowed lifetime and yearly cost savings that exceeded 10 to 11 and 20 to 40 times, respectively, the additional costs related to prolonged survival.. In our study population, ramipril prolongs life while saving money because of its beneficial effect on the course of nondiabetic chronic nephropathies.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Cost-Benefit Analysis; Disease Progression; Drug Costs; Female; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria; Ramipril; Sensitivity and Specificity; Survival Analysis; Treatment Outcome

Angiotensin II (Ang II) infusion in rats augments vascular injury in balloon-injured carotid arteries and induces marked vascular and tubulointerstitial injury in kidneys. We examined how the AT1 receptor is modulated and whether blockade of the receptor with losartan could prevent the phenotypic and cellular changes. We also examined the role of the local renin-angiotensin system (RAS) by examining the expression of angiotensin-converting enzyme (ACE) and the effect of treatment with the ACE inhibitor, ramipril. Ang II infusion resulted in systemic hypertension and accelerated intimal and medial thickening in balloon-injured carotid arteries. Renal injury was manifested by proteinuria, glomerular phenotypic changes (mesangial expression of alpha-actin and podocyte expression of desmin), and tubulointerstitial injury with the tubular upregulation of the macrophage-adhesive protein, osteopontin, the interstitial accumulation of macrophages and myofibroblasts, and the deposition of collagen types III and IV. Ang II infusion decreased AT1 receptor number in the renal interstitium but not in glomeruli. Losartan completely blocked the Ang II-mediated hypertension, proteinuria, and injury to both carotid and kidney. Ang II infusion was also associated with an increase in ACE protein in both the proximal tubular brush border as well as at interstitial sites of injury, but despite evidence for activation of the local RAS, treatment with ramipril was without effect. These studies demonstrate that the renal and vascular injury induced by Ang II infusion is mediated by the AT1 receptor despite downregulation of the receptor in the interstitium. In addition, although there is evidence for local RAS activation, the injury appears to be mediated solely by the exogenous Ang II.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Carotid Artery Injuries; Catheterization; Kidney Diseases; Losartan; Male; Peptidyl-Dipeptidase A; Ramipril; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Vasoconstrictor Agents

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Black or African American; Calcium Channel Blockers; Humans; Hypertension; Kidney Diseases; Ramipril

In this post hoc, secondary analysis of the Ramipril Efficacy In Nephropathy (REIN) trial, an angiotensin-converting enzyme (ACE) inhibition risk/benefit profile was assessed in 322 patients with nondiabetic, proteinuric chronic nephropathies and different degrees of renal insufficiency. The rate of GFR decline (Delta GFR) and the incidence of end-stage renal disease (ESRD) during ramipril or non-ACE inhibitor treatment were compared within three tertiles of basal GFR. Delta GFR was comparable in the three tertiles, whereas the incidence of ESRD was higher in the lowest tertile than in the middle and highest tertiles. Ramipril decreased Delta GFR by 22%, 22%, and 35% and the incidence of ESRD by 33% (P < 0.05), 37%, and 100% (P < 0.01) in the lowest, middle, and highest tertiles, respectively. Delta GFR reduction was predicted by basal systolic (P < 0.0001), diastolic (P = 0.02), and mean (P < 0.001) BP and proteinuria (P < 0.0001) but not by basal GFR (P = 0.12). ESRD risk reduction was predicted by basal proteinuria (P < 0.01) and GFR (P < 0.0001) and was strongly dependent on treatment duration (P < 0.0001). Adverse events were comparable among the three tertiles and within each tertile in the two treatment groups. Thus, disease progression and response to ACE inhibition do not depend on severity of renal insufficiency. The risk of ESRD and the absolute number of events saved by ACE inhibition is highest in patients with the lowest GFR. However, renoprotection is maximized when ACE inhibition is started earlier and when long-lasting treatment may result in GFR stabilization and definitive prevention of ESRD.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Drug Administration Schedule; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria; Ramipril; Renal Insufficiency

Topics: Angiotensin-Converting Enzyme Inhibitors; Disease Progression; Humans; Kidney Diseases; Kidney Failure, Chronic; Proteinuria; Ramipril

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Enalapril; Kidney; Kidney Diseases; Losartan; Nephrectomy; Ramipril; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

Random, nontimed blood pressure (BP) measurements in the outpatient clinic may fail to provide reliable information on actual daily BP control in renal patients on chronic antihypertensive therapy.. In a cohort of 163 patients with proteinuric chronic nephropathies followed prospectively with repeated BP and glomerular filtration rate (GFR) measurements, we compared baseline and follow-up pretreatment, morning ("trough," measured by standard procedures, and "0 minutes," measured by an automatic device) and post-treatment (120 minutes) measurements, with BP monitored up to 600 minutes after treatment administration. We then evaluated which BP value most reliably predicted GFR decline (delta GFR) and progression to end-stage renal failure (ESRF) over a median (interquartile range) follow-up of 20 (9 to 25) months.. GFR decline was more reliably predicted by systolic as compared with diastolic BP and by pretreatment as compared to post-treatment BP, regardless of the timing and method of measurement, respectively. In particular, at the 120-minute baseline and follow-up measurements, systolic BP had no predictive value in patients with less severe renal insufficiency and baseline diastolic BP, regardless of the level of renal dysfunction. The BP predictive value was remarkably higher in ramipril than in conventionally treated patients. All follow-up-but no baseline-measurements reliably predicted the risk of ESRF in the entire study group.. In patients with progressive chronic nephropathies, systolic BP and pretreatment morning BP measurements are the most reliable predictors of disease outcome and may serve to guide antihypertensive therapy in routine clinical activities and in prospective controlled trials, particularly in patients on angiotensin-converting enzyme inhibitor therapy. Reliability and relevance of single measurements taken at different times after treatment administration are questionable.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Chronic Disease; Disease Progression; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Failure, Chronic; Male; Middle Aged; Multicenter Studies as Topic; Prognosis; Prospective Studies; Proteinuria; Ramipril; Randomized Controlled Trials as Topic

Topics: Animals; Diuretics; Humans; Kidney Diseases; Ramipril; Sulfonamides

A single oral 10-mg dose of ramipril, a long-acting angiotensin converting enzyme (ACE) inhibitor, was given to 24 hypertensive patients with different degrees of renal function. Creatinine clearance ranged from below 15 ml/min (n = 9) to above 80 ml/min (n = 3). Serial blood samples were taken for the determination of ACE activity, plasma renin activity (PRA), aldosterone (ALDO), angiotensin II (AT II), and serum creatinine (CR). Blood pressure was also monitored before and after medication. After administration of ramipril systolic and diastolic blood pressure (BP) fell; the decreases were unrelated to renal function. Peak BP-lowering effect was seen at 6 h basal, 174 +/- 19.5/102.6 +/- 8.9 to 149.8 +/- 19.7/87.6 +/- 13.3 mm Hg (mean +/- SD; p less than 0.001). ACE inhibition occurred within 2 h, being maximal at 4 h: basal, 82.6 +/- 17.9 to 0.2 +/- 0.6 nmol/ml/min (p less than 0.001). The greater the renal impairment, the longer the ACE inhibition. Angiotensin II was reduced maximally at 10 h after dosing, from 10.4 +/- 5.4 to 6.2 +/- 3.6 pg/ml (p less than 0.01). Aldosterone also fell from 212 +/- 188.4 to 134 +/- 73.3 pg/ml at 6 h (p less than 0.01). Plasma creatinine was unchanged: 401.3 +/- 315.7 to 394.9 +/- 306.1 nmol/L (NS). Ramipril, given as a single oral dose, lowers BP in hypertensives with both normal and impaired renal function, inhibits ACE activity, and causes no change in serum creatinine.

Topics: Adult; Aged; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Creatinine; Female; Heart Rate; Humans; Kidney Diseases; Male; Middle Aged; Peptidyl-Dipeptidase A; Ramipril; Renin; Time Factors

In an open trial, the pharmacokinetics of ramipril and its active metabolite ramiprilat were studied in 25 hypertensive patients with various degrees of renal insufficiency given 5 mg ramipril p.o. for 14 days. Ramipril was rapidly absorbed and reached a peak concentration after 1-2 h. Cmax was greater in patients with severe renal insufficiency, which might indicate a reduced renal elimination rate, although, the rapid decline of the concentration-time curve for ramipril was almost independent of renal function. The mean initial apparent half-lives on Days 1 and 12, respectively, were 2.8 and 3.4 h (Group I: creatinine clearance 5-15 ml/min), 1.8 and 2.3 h (Group II: creatinine clearance 15-40 ml/min), and 1.9 and 1.9 h (Group III: creatinine clearance 40-80 ml/min). No accumulation was observed after multiple dosing. In contrast, the kinetics of its active acid metabolite ramiprilat was significantly influenced by renal function. The mean times to the peak plasma concentration were 5.7 h in Group I, 4.4 h in Group II and 3.8 h in Group III. The initial decline in plasma ramiprilat was dependent upon renal function; the mean initial apparent half-lives (Days 1 and 12, respectively) were 16.0 and 14.8 h (Group I), 10.1 and 9.5 h (Group II) and 10.6 and 8.0 h (Group III). Mean trough concentrations and absolute accumulation also increased with worsening renal function, and the renal clearance of ramiprilat was significantly correlated with the creatinine clearance. The subsequent long terminal phase at low plasma ramiprilat concentrations represented slow dissociation of the ACE-inhibitor complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Creatinine; Female; Humans; Hypertension, Renal; Kidney Diseases; Male; Middle Aged; Pyrroles; Ramipril

Acute, subchronic and chronic toxicity studies of 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S, 3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (ramipril, Hoe 498) were conducted in mice, rats, dogs and monkeys. The acute toxicity in mice, rats, and dogs after oral and intravenous administration is very low. There were no significant differences in LD50 values between male and female animals. Treatment periods up to 6 months in rats and monkeys and up to 12 months in dogs revealed consistent compound-related effects with respect to the kidneys and the hemopoietic system probably due to exaggerated pharmacological activity. Species-specific lesions in the gastric fundal mucosa were noted exclusively in rats. No adverse effects were seen at doses of 0.25 mg/kg/d in rats, 2.5 mg/kg/d in dogs, and 0.5 mg/kg/d in monkeys. It is concluded that ramipril can be safely used in humans.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Dogs; Gastric Mucosa; Kidney Diseases; Lethal Dose 50; Macaca mulatta; Mice; Mice, Inbred ICR; Ramipril; Rats; Rats, Inbred Strains; Time Factors

The acute effects and pharmacokinetic properties of an angiotensin converting enzyme (ACE) inhibitor, ramipril, and its potent active diacid metabolite, ramiprilate, were investigated. Hypertensive patients with impaired renal function (IRF; n = 6) and with normal renal function (NRF; n = 5) were studied. The terminal half-life of ramiprilate in IRF was longer than that in NRF. The peak plasma concentrations of ramipril and ramiprilate in IRF were higher than those in NRF. The area under the plasma level-time curves of ramipril and ramiprilate in IRF were greater than those in NRF. A significant inverse correlation was found between creatinine clearance and area under the plasma level-time curve.

Topics: Angiotensin-Converting Enzyme Inhibitors; Bridged Bicyclo Compounds; Humans; Hypertension; Kidney Diseases; Ramipril

The pharmacokinetics of ramipril (HOE 498) were studied after oral administration of a single 10 mg dose to 24 hypertensive patients with different degrees of renal function. The creatinine clearance ranged between 4.1 and 126 ml/min/1.73 m2 and was below 35 ml/min/1.73 m2 in 16 patients. Angiotensin converting enzyme activity and the concentrations of ramipril and its active diacid metabolite ramiprilat were measured in plasma up to 10 days after drug intake. Urine levels of ramipril, ramiprilat, their glucuronides and 2 major metabolites (a diketopiperazine and a diketopiperazine acid) were measured up to 4 days after medication. The plasma concentration-time curve of ramiprilat was polyphasic with an initial steep decline after the peak level and a subsequent very long terminal phase at low concentrations. Impaired renal function resulted in higher peak levels of ramiprilat, longer times to peak and a markedly slower decline of plasma ramiprilat levels. Hence, the duration of angiotensin converting enzyme inhibition was considerably prolonged in renal failure and depended on the severity of renal impairment. The urinary excretion of ramipril and its metabolites decreased with decreasing renal function and was linearly related to the creatinine clearance, suggesting an alternative pathway of elimination. The pattern of excretion rates of ramipril and its various metabolites was not affected by renal failure. In contrast to the marked changes in the renal elimination, no relevant differences were observed in the absorption of ramipril from the gastrointestinal tract. Systolic and diastolic blood pressure decreased in all groups. The single 10 mg dose of ramipril was well tolerated.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Creatinine; Female; Humans; Kidney; Kidney Diseases; Kinetics; Male; Middle Aged; Peptidyl-Dipeptidase A; Ramipril; Time Factors