ramipril and Nephrosclerosis

Hypertension is the second leading attributable cause of end-stage renal disease in the United States today. The African-American Study of Kidney Disease and Hypertension was a randomized, double-blind, controlled trial designed to determine whether strict blood pressure (BP) control, angiotensin-converting enzyme inhibitor (ACEI)-based, or calcium channel blocker (CCB)-based regimens were superior to less strict BP control and beta-blocker (BB)-based regimens, respectively. The study enrolled 1093 African Americans with hypertensive nephrosclerosis and followed them for 4 years with repeated direct measurement of glomerular filtration rate (GFR) and monitoring of end points, including rapid decline in GFR, end-stage kidney disease, and death. From this landmark study, we learned that strict BP control is achievable in this study population, but it did not slow progression of kidney disease, and we learned that an ACEI-based therapy was superior to either a BB- or CCB-based regimen. In addition, we learned that proteinuria is the most important predictor of progression of kidney disease; ACEI and CCB have differential effects on proteinuria; and a CCB-based regimen combined with strict BP control may be the next best choice to an ACEI-based regimen in this population.

Topics: Adrenergic beta-Antagonists; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Black People; Blood Pressure; Calcium Channel Blockers; Double-Blind Method; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Metoprolol; Nephrosclerosis; Ramipril; Randomized Controlled Trials as Topic; Treatment Outcome

We review the evidence linking mild renal insufficiency (MRI) with increased cardiovascular risk. MRI is associated with a number of cardiovascular risk factors, including nighttime hypertension, and increased levels of lipoprotein (a), homocysteine, asymmetric dimethyl-arginine, and inflammation and insulin resistance markers and mediators. Epidemiologic evidence associates coronary artery disease and nephrosclerosis, a frequent cause of early renal insufficiency in the elderly. In a middle-aged general population MRI was found in 8% of women and 9% of men, but was not associated with cardiovascular disease. Nonetheless, in a representative sample of middle-aged British men the risk of stroke was 60% higher for the sub-group with MRI: in people at high cardiovascular risk (mostly coronary disease), the HOPE study found a 2-fold (unadjusted) or 1.4-fold (adjusted) higher incidence of cardiovascular outcomes with MRI. The combined incidence of cardiovascular death, myocardial infarction and stroke increased with the level of serum creatinine. Several studies have examined the cardiovascular risk associated with MRI in hypertension. In HDFP, as in HOPE, cardiovascular mortality increased with serum creatinine (five-fold difference in cardiovascular mortality between the lowest and the highest creatinine strata). The risk associated with renal insufficiency was independent of other classic cardiovascular risk factors. Two trials of hypertensives with low risk (HOT and a small Italian trial) found that cardiovascular outcomes approximately doubled in subjects with MRI. Another study (MRFIT) found that it was not baseline creatinine, but its increase on follow-up that predicted future cardiovascular disease. These observational data suggest that regardless of etiology MRI is a strong predictor of cardiovascular disease and is found in 10% of populations at low cardiovascular risk and in up to 30% of those at high risk. No prospective therapeutic trials aimed at reducing the cardiovascular burden in people with MRI are available. Subgroup analyses of the HOPE study indicate that angiotensin-converting enzyme (ACE) inhibition with ramipril is beneficial and does not increase the risk of such side effects as acute renal failure or hyperkalemia. Thus the frequent practice of withholding ACE inhibitors from patients with mild renal insufficiency is unwarranted, especially since MRI identifies a group at high risk that appears to benefit most from treatment. Moreove

Topics: Age Factors; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Creatinine; Diabetes Complications; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Male; Middle Aged; Nephrosclerosis; Prognosis; Ramipril; Randomized Controlled Trials as Topic; Renal Insufficiency; Risk Factors; Sex Factors; Time Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diagnosis, Differential; Follow-Up Studies; Humans; Hypertension; Nephrosclerosis; Prognosis; Ramipril

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

An interim analysis of the AASK trial at three years demonstrates a renoprotective effect [slower decline in glomerular filtration rate (GFR), delayed onset of significant decrease in GFR, end-stage renal disease (ESRD) or death, and a decrease in urinary protein excretion] of the angiotensin converting enzyme (ACE) inhibitor, ramipril, as compared to the dihydropyridine calcium channel blocker (DHP-CCB), amlodipine, in patients with mild-to-moderate renal insufficiency. The beneficial effect occurred in the presence of similar levels of blood pressure control and was apparent in patients with proteinuric (beyond the threshold of "dipstick positive" proteinuria, 300 mg/day) and non-proteinuric hypertensive nephrosclerosis. At the time of the interim analysis, the effectiveness of the beta-blocker metoprolol was not significantly different from that of the ACE inhibitor. The data suggest that DHP-CCBs should be used with caution in the presence of mild-to-moderate renal insufficiency.

Topics: Adrenergic beta-Antagonists; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Black or African American; Calcium Channel Blockers; Glomerular Filtration Rate; Humans; Hypertension, Renal; Metoprolol; Nephrosclerosis; Ramipril; Renal Insufficiency

Topics: Adolescent; Adult; Aged; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Black People; Calcium Channel Blockers; Female; Humans; Hypertension; Male; Middle Aged; Nephrosclerosis; Prospective Studies; Ramipril; Treatment Outcome

Incidence of end-stage renal disease due to hypertension has increased in recent decades, but the optimal strategy for treatment of hypertension to prevent renal failure is unknown, especially among African Americans.. To compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (ramipril), a dihydropyridine calcium channel blocker (amlodipine), and a beta-blocker (metoprolol) on hypertensive renal disease progression.. Interim analysis of a randomized, double-blind, 3 x 2 factorial trial conducted in 1094 African Americans aged 18 to 70 years with hypertensive renal disease (glomerular filtration rate [GFR] of 20-65 mL/min per 1.73 m(2)) enrolled between February 1995 and September 1998. This report compares the ramipril and amlodipine groups following discontinuation of the amlodipine intervention in September 2000.. Participants were randomly assigned to receive amlodipine, 5 to 10 mg/d (n = 217), ramipril, 2.5 to 10 mg/d (n = 436), or metoprolol, 50 to 200 mg/d (n = 441), with other agents added to achieve 1 of 2 blood pressure goals.. The primary outcome measure was the rate of change in GFR; the main secondary outcome was a composite index of the clinical end points of reduction in GFR of more than 50% or 25 mL/min per 1.73 m(2), end-stage renal disease, or death.. Among participants with a urinary protein to creatinine ratio of >0.22 (corresponding approximately to proteinuria of more than 300 mg/d), the ramipril group had a 36% (2.02 [SE, 0.74] mL/min per 1.73 m(2)/y) slower mean decline in GFR over 3 years (P =.006) and a 48% reduced risk of the clinical end points vs the amlodipine group (95% confidence interval [CI], 20%-66%). In the entire cohort, there was no significant difference in mean GFR decline from baseline to 3 years between treatment groups (P =.38). However, compared with the amlodipine group, after adjustment for baseline covariates the ramipril group had a 38% reduced risk of clinical end points (95% CI, 13%-56%), a 36% slower mean decline in GFR after 3 months (P =.002), and less proteinuria (P<.001).. Ramipril, compared with amlodipine, retards renal disease progression in patients with hypertensive renal disease and proteinuria and may offer benefit to patients without proteinuria.

Topics: Adrenergic beta-Antagonists; Adult; Aged; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Black or African American; Calcium Channel Blockers; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Male; Metoprolol; Middle Aged; Nephrosclerosis; Proportional Hazards Models; Proteinuria; Ramipril

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Creatinine; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Nephrosclerosis; Ramipril

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