enalapril and Kidney-Failure--Chronic

Renal pathophysiology is elicited by activation of angiotensin II type 1 (AT(1)) receptors at all stages of renovascular disease. Angiotensin receptor blockers (ARBs) that specifically block the AT(1) receptor offer the potential to prevent or delay progression to end-stage renal disease independently of reductions in blood pressure. Proteinuria--an early and sensitive marker for progressive renal dysfunction--is reduced by ARB use in patients with type 2 diabetic nephropathy and microalbuminuria or macroalbuminuria. Retrospective analysis of data available from early trials has confirmed this finding and has shown that albuminuria reduction is associated with lessening of cardiovascular risk. The ARB telmisartan is equivalent to enalapril in preventing glomerular filtration rate decline, and equivalent to valsartan in reducing proteinuria. Telmisartan is more effective than conventional therapy in lowering the risk of transition to overt nephropathy in hypertensive and normotensive patients. An additive effect has been seen in smaller studies when telmisartan has been added to lisinopril therapy, and high-dose telmisartan reduces albuminuria better than low-dose telmisartan. Similar data were obtained with other ARBs such as candesartan, losartan, valsartan, or irbesartan. These data support the proposition that blockade of the renin-angiotensin system beyond that required for maximum blood pressure reduction provides optimum renal protection.

Topics: Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Biomarkers; Cardiovascular Diseases; Diabetic Nephropathies; Drug Therapy, Combination; Enalapril; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Telmisartan; Tetrazoles; Treatment Outcome; Valine; Valsartan

Management of hypertension is the mainstay of prevention and treatment of diabetic renal disease; evidence suggests that tight blood pressure control slows renal disease progression in established diabetic nephropathy. Inhibition of the renin-angiotensin-aldosterone system (RAAS) has renoprotective effects over and above those achieved by lowering systemic blood pressure. To date, however, no long-term study using hard end points has directly compared current mechanisms for RAAS inhibition, angiotensin II receptor blockade (ARB) and angiotensin-converting enzyme (ACE) inhibition. This issue was addressed in the recently published Diabetics Exposed to Telmisartan and Enalapril (DETAIL) study, a head-to-head comparison of telmisartan and enalapril in 250 patients with hypertension and type 2 diabetes mellitus and early-stage nephropathy. After 5 years' treatment, change in glomerular filtration rate (GFR), the primary efficacy end point, was equivalent in the 2 treatment groups, as were all secondary end points. The expected steep decline in GFR in the first year was followed by a lesser decrease in the second year and then almost complete stabilization of renal function at > or =3 years. Over 5 years, no patient went into end-stage renal disease or required dialysis. There were also no increases in albumin excretion rate, nor was there an increase in creatinine beyond 200 mumol/L. Incidence of cardiovascular morbidity and mortality was extremely low in both treatment groups, a remarkable outcome given that almost 50% of patients had evidence of cardiovascular disease at randomization. Inhibition of the RAAS should play a major part in management of patients with type 2 diabetes with nephropathy, for which both telmisartan and enalapril provide long-term renoprotection.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Benzoates; Cardiovascular Agents; Diabetic Nephropathies; Enalapril; Glomerular Filtration Rate; Humans; Kidney; Kidney Failure, Chronic; Proteinuria; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Telmisartan; Time Factors; Treatment Outcome

The evidence from recent clinical outcome trials in arterial hypertension (AH) and the treatment guidelines from national and international authorities have placed a clear emphasis on "tight" blood pressure (BP) control. This has been particularly well illustrated in the treatment of patients with diabetes mellitus and AH where "tight" BP control clearly improves the outcome with reduced numbers of fatal and non-fatal cardiovascular events. Whilst the clinical trials in AH have identified benefits through BP reduction with a range of antihypertensive drugs there is a considerable volume of evidence to suggest that the optimal treatment for diabetic nephropathy and microalbuminuria should be based upon ACE inhibition. It is widely held that inhibition of intra-renal renin angiotensin systems leads to greater benefit than can be achieved by hemodynamic changes alone. Thus, management of AH and nephropathy in both DM and other forms of renal disease revolves around BP reduction through an ACE inhibitor-based treatment regimen. Where there is renal failure it may be prudent to administer a drug such as spirapril which has non-renal elimination mechanisms and which has been shown to have no accumulation problems or increased adverse effects.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetic Nephropathies; Enalapril; Humans; Hypertension; Kidney Failure, Chronic; Prognosis; Renal Circulation

The management of hypertension and nephropathy, in both diabetes and other forms of renal disease, is usually based on blood pressure reduction through an angiotensin-converting enzyme (ACE) inhibitor-based treatment regimen. With particular respect to the choice of ACE inhibitor drug, there are no definitive direct comparisons in the treatment of renal disease. In terms of blood pressure reduction, however, there is evidence that spirapril is at least as effective as the reference ACE inhibitor, enalapril. However, patients with diabetic nephropathy and/or chronic renal failure are at potential risk from drug accumulation if the preferred agent relies predominantly on glomerular filtration for its elimination. In this respect spirapril may have an advantage because it has been shown that there are no clinically relevant increases in the spirapril(at) concentrations (24 h post-dose) even in the setting of advanced renal failure (creatinine clearance <20 ml/min). Thus, there is no requirement to modify the dose and no concerns about drug accumulation or the potential for exaggerated therapeutic or adverse effects. In summary, an ACE inhibitor drug is seen as an integral component of the drug treatment regimen for patients with nephropathy. Where there is renal failure it may be prudent to administer a drug, such as spirapril, which also has alternative elimination mechanisms.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Clinical Trials as Topic; Diabetic Nephropathies; Enalapril; Humans; Kidney Failure, Chronic

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Glomerular Filtration Rate; Humans; Kidney; Kidney Failure, Chronic; Uremia; Ventricular Dysfunction, Left

Locally increased synthesis of angiotensin II (ANG II) in the kidney has been linked to glomerular hypertrophy, glomerulosclerosis and tubulo-interstitial fibrosis observed in chronic renal failure after subtotal nephrectomy. This action of ANG II is thought to be mediated mainly by transforming growth factor-beta (TGF-beta), which stimulates the synthesis and decreases the degradation of extracellular matrix (ECM) components, including various collagen types and fibronectin. Some recent reports indicate that reduced ANG II activity diminishes TGF-beta overexpression, and in consequence renal injury. However, no studies in SNx models concerning the influence of ANG II on gene expression regulated by TGF-beta have so far been performed. Therefore, the present study has been initiated with the following aims: 1. To develop a RT-PCR assay for evaluating gene expression concerning renin (REN), angiotensinogen (ATG) and the following ECM components: transforming growth factor-beta 1 (TGF-beta 1), fibronectin (FN), matrix metalloproteinase-2 (MMP-2) and tissue inhibitor of metalloproteinases-2 (TIMP-2); 2. To assess the influence of renal mass reduction (RMR) caused by subtotal (5/6) or partial (2/6) nephrectomy on gene expression for TGF-beta 1, FN, MMP-2 and TIMP-2; 3. To evaluate the correlation between expression of these genes and activity of the circulatory or renal renin-angiotensin systems; 4. To assess the influence of treatment with enalapril (angiotensin-converting enzyme inhibitor) on renal expression of these genes, renal morphology and function in rats, relative to duration of treatment and RMR. The study consisted of two independent experiments performed in adult male Sprague-Dawley rats. Ten days prior to surgery, the animals were matched for body weight and systolic blood pressure (SBP) values and subsequently were distributed into untreated (control) and enalapril treated groups. Treatment with enalapril (EN) (50 mg/l in drinking water) was started 9 days prior to surgery. The first (short-term) experiment was performed in rats with chronic renal failure caused by subtotal nephrectomy. Remnant kidneys were taken for molecular studies at the day of SNx and 3, 7 and 21 days thereafter. Blood samples collected at the time of sacrifice served to determine plasma renin activity and plasma concentration of angiotensinogen and angiotensin II. The second (long-term) experiment was done in subtotally (5/6) and partially (2/6) nephrectomized rats. Remna

Topics: Angiotensins; Animals; Blood Pressure; Disease Models, Animal; Disease Progression; Enalapril; Fibronectins; Gene Expression; Kidney Failure, Chronic; Nephrectomy; Rats; Renin; RNA, Messenger

Normalization of blood pressure--and use of an ACE inhibitor or AT1-receptor blocker for patients with abnormal albumin or creatinine levels--can prevent or significantly slow the rate of progression toward end-stage renal disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Enalapril; Humans; Hypertension; Kidney Failure, Chronic

One of the major challenges for today's nephrology is to elucidate the mechanism of action of ACE-inhibitors in damaged kidneys. Clarification of the mechanisms involved will not only increase the understanding of the pathomechanisms involved in progression, but also enrich the therapeutic armamentarium available to the nephrologist.

Topics: Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diabetic Nephropathies; Enalapril; Humans; Kidney Diseases; Kidney Failure, Chronic

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Enalapril; Humans; Hypertension, Renal; Hypertension, Renovascular; Kidney Failure, Chronic; Product Surveillance, Postmarketing; Renal Circulation

Enalapril maleate is a prodrug which when administered orally is hydrolysed to release the active converting enzyme inhibitor enalaprilat. Enalapril maleate is 60% absorbed and 40% bioavailable as enalaprilat. Both compounds undergo renal excretion without further metabolism. The functional half-life for accumulation of enalaprilat is 11 h, and this is increased in the presence of a reduction in renal function. Inhibition of converting enzyme inhibition is associated with reductions in plasma angiotensin II and plasma aldosterone, and with increases in plasma renin activity and plasma angiotensin I. Acute and chronic effects have been reviewed. When given with hydrochlorothiazide, enalapril attenuates the secondary aldosteronism and ameliorates the hypokalaemia from diuretics. Both acutely and chronically in patients with essential hypertension, enalapril reduced blood pressure with a rather flat dose-response curve. No evidence of a triphasic response such as seen with captopril has been demonstrated with enalapril, and blood pressure returns smoothly to pretreatment levels when the drug is abruptly discontinued. Once- or twice-daily dosing gives similar results. The antihypertensive effects of enalapril are potentiated by hydrochlorothiazide. Haemodynamically, blood pressure reduction is associated with a reduced peripheral vascular resistance and an increase in cardiac output and stroke volume with little change in heart rate. Renal vascular resistance decreases, and renal blood flow may increase without an increase in glomerular filtration in patients with normal renal function. In patients with essential hypertension and glomerular filtration rates below 80 ml/min/m2, both renal blood flow and glomerular filtration rates may increase.

Topics: Aldosterone; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Bradykinin; Dipeptides; Drug Administration Schedule; Enalapril; Enalaprilat; Heart Failure; Heart Rate; Humans; Hydrochlorothiazide; Hypertension; Kidney; Kidney Failure, Chronic; Norepinephrine; Prostaglandins; Renal Circulation; Renin

The efficacy of folic acid therapy on renal outcomes has not been previously investigated in populations without folic acid fortification.. To test whether treatment with enalapril and folic acid is more effective in slowing renal function decline than enalapril alone across a spectrum of renal function at baseline from normal to moderate chronic kidney disease (CKD) among Chinese adults with hypertension.. In this substudy of eligible China Stroke Primary Prevention Trial (CSPPT), 15 104 participants with an estimated glomerular filtration rate (eGFR) 30 mL/min/1.73 m2 or greater, including 1671 patients with CKD, were recruited from 20 communities in Jiangsu province in China.. Participants were randomized to receive a single tablet daily containing 10 mg enalapril and 0.8 mg folic acid (n = 7545) or 10 mg enalapril alone (n = 7559).. The primary outcome was the progression of CKD, defined as a decrease in eGFR of 30% or more and to a level of less than 60 mL/min/1.73 m2 if the baseline eGFR was 60 mL/min/1.73 m2 or more, or a decrease in eGFR of 50% or more if the baseline eGFR was less than 60 mL/min/1.73 m2; or end-stage renal disease. Secondary outcomes included a composite of the primary outcome and all-cause death, rapid decline in renal function, and rate of eGFR decline.. Overall, 15 104 Chinese adults with a mean (range) age of 60 (45-75) years were recruited; median follow-up was 4.4 years. There were 164 and 132 primary events in the enalapril group and the enalapril-folic acid group, respectively. Compared with the enalapril group, the enalapril-folic acid group had a 21% reduction in the odds of the primary event (odds ratio [OR], 0.79; 95% CI, 0.62-1.00) and a slower rate of eGFR decline (1.28% vs 1.42% per year; P = .02). Among the participants with CKD at baseline, folic acid therapy resulted in a significant reduction in the risks for the primary event (OR, 0.44; 95% CI, 0.26-0.75), rapid decline in renal function (OR, 0.67; 95% CI, 0.47-0.96) and the composite event (OR, 0.62; 95% CI, 0.43-0.90), and a 44% slower decline in renal function (0.96% vs 1.72% per year, P < .001). Among those without CKD at baseline, there was no between-group difference in the primary end point.. Enalapril-folic acid therapy, compared with enalapril alone, can significantly delay the progression of CKD among patients with mild-to-moderate CKD.. clinicaltrials.gov Identifier: NCT00794885.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; China; Disease Progression; Double-Blind Method; Drug Combinations; Enalapril; Female; Folic Acid; Glomerular Filtration Rate; Homocysteine; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Vitamin B Complex

Proteinuria is the main indicator of renal disease progression in many chronic conditions. There is currently little information available on the efficacy, safety, and individual tolerance of patients with post-diarrheal hemolytic uremic syndrome (D+ HUS) nephropathy to therapies involving diet, enalapril, or losartan. A multicenter, double-blind, randomized controlled trail was conducted to evaluate the effect of a normosodic-normoproteic diet (Phase I) and the effect of normosodic-normoproteic diet plus enalapril (0.18-0.27 mg/kg/day) or losartan (0.89-1.34 mg/kg/day) (Phase II) on children with D+ HUS, normal renal function, and persistent, mild (5.1-49.9 mg/kg/day) proteinuria. Dietary intervention reduced the mean protein intake from 3.4 to 2.2 mg/kg/day. Of 137 children, proteinuria normalized in 91 (66.4 %) within 23-45 days; the remaining 46 patients were randomized to diet plus placebo (group 1, n = 16), plus losartan (group 2, n = 16), or enalapril (group 3, n = 14). In groups 1, 2, and 3, proteinuria was reduced by 30.0, 82.0, and 66.3%, respectively, and normalized in six (37.5%), three (81.3%), and 11 (78.6%) patients, respectively (χ(2)= 8.9, p = 0.015). These results suggest that: (1) a normosodic-normoproteic diet can normalize proteinuria in the majority of children with D+ HUS with mild sequelae, (2) the addition of enalapril or losartan to such dietary restrictions of protein further reduces proteinuria, and (3) these therapeutic interventions are safe and well tolerated. Whether these short-term effects can be extended to the long-term remains to be demonstrated.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Child; Child, Preschool; Diarrhea; Diet Therapy; Double-Blind Method; Enalapril; Female; Hemolytic-Uremic Syndrome; Humans; Kidney Failure, Chronic; Losartan; Male; Proteinuria

Blocking the renin-angiotensin system (RAS) with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors protects against renal injury in patients with chronic kidney disease (CKD). The aim of this study was to compare the chronic effects of telmisartan and enalapril on proteinuria, urinary liver-type fatty acid-binding protein (L-FABP) and endothelin (ET)-1 levels in patients with mild CKD.. Thirty CKD patients with mild to moderate renal insufficiency (20 men and 10 women; mean age, 37 years; estimated glomerular filtration rate (eGFR) > 60 mL min(-1) and blood pressure > 130/85 mmHg) were included in the study. Patients were randomly assigned to receive telmisartan at 80 mg day(-1) (n = 15) or enalapril at 10 mg day(-1) (n = 15). We measured blood pressure, serum creatinine, eGFR, urinary protein, L-FABP and ET-1 before the start of treatment and 6 and 12 months after the start of treatment.. The blood pressure reduction rate was similar between the two groups. Urinary protein, L-FABP and ET-1 levels were significantly reduced in both groups 6 and 12 months (P < 0.001) after treatment, but the reduction rates were more pronounced in patients receiving telmisartan than in those receiving enalapril (P < 0.001). Estimated glomerular filtration rate was increased similarly in both groups at 12 months.. The study results suggest that telmisartan results in a greater reduction of urinary markers than does enalapril and that this effect occurs by a mechanism independent of blood pressure reduction. It would be needed to investigate whether the differences may be distinct or not the same when other dosages are used.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Creatinine; Enalapril; Endothelin-1; Fatty Acid-Binding Proteins; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Proteinuria; Telmisartan

Endothelin-1 (ET-1) has been implicated in the pathophysiology of chronic kidney disease (CKD) and ET receptor blockade has shown renoprotective effects in animals. We examined the haemodynamic and renal effects of an ET receptor antagonist, TAK-044, in patients with CKD.. Seven patients with CKD (mean arterial pressure 103 mmHg; mean plasma creatinine 3.5 mg/dl) received three 15 min intravenous infusions, each separated by at least 7 days, of either placebo or TAK-044 (100 or 750 mg) in a randomized, double blind crossover study. Systemic and renal haemodynamics, and plasma immunoreactive ET-1, big ET-1 and C-terminal fragment concentrations, were determined before and after the infusions of placebo and drugs.. Compared with placebo, TAK-044 reduced mean arterial pressure (MAP) (100 mg: 7.4 +/- 1.9 mmHg, 750 mg: 8.4 +/- 2.3 mmHg, P < 0.01) and systemic vascular resistance index (100 mg: 650 +/- 140 dyne.s.cm(-5).m(-2), 750 mg: 829 +/- 141 dyne.s.cm(-5).m(-2), P < 0.01) at both doses. TAK-044 increased cardiac index and heart rate to a similar degree at both doses. With regards to renal haemodynamics, TAK-044 had no significant effect on the glomerular filtration rate at either dose but tended to increase renal plasma flow (100 mg: 9.6 +/- 5.0 ml/min, 750 mg: 25.3 +/- 19.5 ml/min) and decreased the effective filtration fraction (100 mg: 3.6 +/- 1.1%, 750 mg: 4.7 +/- 1.7%, P < 0.01), in a dose-dependent manner. TAK-044 had no significant effect on sodium or lithium clearance, or on fractional excretion of sodium and lithium. Plasma ET-1 concentrations rose more than two-fold after 750 mg TAK-044 while big ET-1 and C-terminal fragment concentrations were unchanged.. These findings suggest an important role for ET-1 in controlling systemic and renal haemodynamics in patients with CKD. The antihypertensive and potentially renoprotective actions of ET receptor antagonists shown in this study may prove useful in slowing the progression of CKD. Clinical trials are now needed to address these key questions for CKD.

Topics: Adult; Blood Pressure; Cross-Over Studies; Double-Blind Method; Doxazosin; Enalapril; Endothelin Receptor Antagonists; Furosemide; Hemodynamics; Humans; Kidney Failure, Chronic; Male; Metoprolol; Middle Aged; Peptides, Cyclic; Prospective Studies

Patients with type 2 diabetes are prone to hypertension and persistent protein leakage from the kidney (microalbuminuria or macroalbuminuria). A progressive decline in renal function can lead to overt diabetic nephropathy and ESRD. The likelihood of cardiovascular disease also is increased. Control of hypertension is paramount to prevent these life-threatening complications. Agents that target the renin-angiotensin system--angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers--have been shown to be renoprotective. The groundbreaking Diabetics Exposed to Telmisartan And enalaprIL (DETAIL) trial was designed to address the absence of comparative data on the long-term effects of an angiotensin II receptor blocker versus an angiotensin-converting enzyme inhibitor on renoprotection and survival in 250 patients with hypertension and early type 2 diabetic nephropathy. The primary purpose of the 5-yr double-blind, double-dummy, randomized study was to establish whether 40 to 80 mg of telmisartan conferred similar (i.e., noninferior) renoprotection to 10 to 20 mg of enalapril as determined by the change from baseline in GFR, measured by the plasma clearance of iohexol. Secondary end points included the emergence of ESRD and all-cause mortality. Telmisartan was not inferior to enalapril in reducing the decline in GFR: Mean annual declines in GFR were 3.7 and 3.3 ml/min per 1.73 m(2) with telmisartan and enalapril, respectively. During the 5-yr study period, no patient developed a serum creatinine >200 micromol/L, and none required dialysis. There were only six deaths in each treatment group during the study, with half being due to cardiovascular events.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Creatinine; Diabetes Complications; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Failure, Chronic; Receptors, Angiotensin; Renin-Angiotensin System; Telmisartan

In chronic renal failure, clearance of enalapril is reduced. Hence, a renoprotective effect may be achieved with lower doses than conventionally used. Since marked inter-patient variation in concentrations of enalaprilat has been shown in patients with renal failure despite equivalent dosage of enalapril, a direct comparison of the effect of high versus low plasma concentrations of enalaprilat on the progression of renal failure was undertaken.. Forty patients with a median glomerular filtration rate (GFR) of 17 (6-35) ml/min/1.73 m2 were studied in an open-label, randomised trial comparing patients with a high (>50 ng/ml) with patients with a low (<10 ng/ml) target trough plasma concentration of enalaprilat. The dose of enalapril was titrated accordingly. The patients were followed for 12 months or until they needed renal replacement therapy. GFR was measured at 3-month intervals by the plasma clearance of 51Cr-EDTA, and the individual rates of progression of renal failure were calculated as the slope of GFR versus time plot.. In the high-concentration group, the median enalaprilat trough concentration was 92.9 ng/ml (21.8-371.0 ng/ml) and in the low-concentration group it was 9.1 ng/ml (2.5-74.8 ng/ml) at 3 months follow-up (P<0.001). The median daily doses of enalapril were 10 mg (2.5-30 mg) and 1.88 mg (1.25-5 mg) in the high and low groups, respectively (P<0.001). In the high-concentration group, the mean+/-SE decline in renal function was 6.1+/-1.5 ml/min/1.73 m2 per year and in the low-concentration group it was 4.3+/-14.4 ml/min/1.73 m2 per year (P=0.48). Five patients in the high-concentration group reached end-stage renal failure whereas none in the low-concentration group did (P=0.04). There were no statistically significant differences in blood pressure level, concomitant antihypertensive therapy or urinary albumin excretion. However, the high-enalaprilat concentration group had an overall higher plasma potassium concentration of 0.42 mmol/l than the low group (P<0.001).. In patients with moderate to severe renal insufficiency, a low concentration of enalaprilat afforded the same degree of renoprotection, blood pressure control and minimisation of proteinuria as a high concentration, during 12 months of follow-up. The high-dosage treatment was associated with a more pronounced tendency to hyperkalaemia. Thus, there seems to be no indication for increasing the daily dose of enalapril beyond what achieves adequate blood pressure control in this group of patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Dose-Response Relationship, Drug; Enalapril; Enalaprilat; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Male; Metabolic Clearance Rate; Middle Aged

Myocardial fibrosis commonly occurs in patients with end-stage renal disease (ESRD) and has proven to be an important predictor for cardiovascular events. In experimental settings, angiotensin II type 1 receptor (AT1-R) antagonists have been shown to have anti-fibrotic effects on the myocardium independent of their antihypertensive effects. In this study, to investigate whether the AT1-R antagonist losartan would have such anti-fibrotic effects in patients, we administered losartan or, for purpose of comparison, the angiotensin-converting enzyme enalapril or Ca2+-antagonist amlodipine to patients with ESRD. Thirty-nine ESRD patients with hypertension were randomly assigned to receive losartan (n=13), enalapril (n=13), or amlodipine (n=13). Ultrasonic integrated backscatter (IBS) and serological markers of collagen type I synthesis and degradation were used to assess the degree of myocardial fibrosis just before and after 6 months of treatment. There were no significant differences in antihypertensive effects among the three agents. In the enalapril- and amlodipine-treated groups, the mean calibrated IBS values increased significantly after 6 months of treatment (enalapril: -31.6 +/- 1.3 to -29.4 +/- 1.2 dB, p=0.011; amlodipine: -30.6 +/- 1.4 to -27.2 +/- 1.2 dB, p=0.012). However, the mean calibrated IBS values in the losartan-treated group did not increase after 6 months of treatment (-31.2 +/- 1.7 to -31.3 +/- 1.4 dB, p=0.88). The ratio of the serum concentration of procollagen type I carboxy-terminal peptide to the serum concentration of collagen type I pyridinoline cross-linked carboxy-terminal telopeptide was significantly reduced in the losartan-treated group (42.6 +/- 4.6 to 34.4 +/- 3.6, p=0.038). The present study indicates that losartan more effectively suppresses myocardial fibrosis in patients with ESRD than does enalapril or amlodipine despite a comparable antihypertensive effect among the three drugs.

Topics: Amlodipine; Angiotensin II Type 1 Receptor Blockers; Collagen; Double-Blind Method; Echocardiography; Enalapril; Female; Fibrosis; Humans; Kidney Failure, Chronic; Losartan; Male; Middle Aged; Myocardium; Peptide Fragments; Procollagen

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) have shown numerous benefits to the cardiovascular system. However, using both drugs is associated with hyperkalemia, especially in end-stage renal disease (ESRD) patients. To the authors' knowledge, there has been no prospective systematic study of the safety and potassium homeostasis of both drugs in continuous ambulatory peritoneal dialysis (CAPD) patients.. Twenty-nine stable, normokalemic CAPD patients without potassium-interference drugs were selected randomly to receive, for 4-week periods, 8 mg candesartan or 10 mg enalapril daily. After completion of the initial drug, both treatment groups were crossed.. Twenty-one patients completed the study. Baseline blood pressure, serum potassium level, plasma aldosterone, adequacy of dialysis, and residual renal function were not different between both groups. For the total group, serum potassium changes were not significantly different between baseline and at 4 weeks after treatment in both groups. The incidence of hyperkalemia (potassium > or =5.5 mEq/L [mmol/L]) was 13% and not different between groups. Nine of 11 events of hyperkalemia were associated with Kt/V urea less than 2, and 8 of 11 had low or low-average peritoneal equilibrium tests.. In ESRD patients on CAPD, the standard dose of ACE inhibitor, enalapril, or ARB, candesartan,has little effect on serum potassium, despite drops of plasma aldosterone observed. Both drugs should be considered in CAPD patients with hypertension or cardiovascular complications. However, use of both drugs requires caution in patients with inadequate dialysis or low solute transporters, and dietary noncompliant patients as well.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Cross-Over Studies; Enalapril; Female; Homeostasis; Humans; Hyperkalemia; Kidney Failure, Chronic; Male; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Potassium; Tetrazoles

The aim of this study was to compare the effects on BP and sympathetic activity of chronic treatment with an angiotensin (Ang)-converting enzyme (ACE) inhibitor and an AngII receptor blocker in hypertensive patients with chronic renal failure (CRF). In ten stable hypertensive CRF patients (creatinine clearance, 46 +/- 17 ml/min per 1.73 m(2)), muscle sympathetic nerve activity (MSNA), plasma renin activity (PRA), baroreceptor sensitivity, and 24-h ambulatory BP were measured in the absence of antihypertensive drugs (except diuretics) after 6 wk of enalapril (10 mg orally) and after 6 wk of losartan (100 mg orally). The order of the three phases was randomized. Normovolemia was controlled with diuretics and confirmed with extracellular fluid volume measurements throughout the study. Both enalapril and losartan reduced MSNA (from 33 +/- 10 to 27 +/- 13 and 27 +/- 13 bursts/min, respectively; P < 0.05) and average 24-h BP (from 141 +/- 8/93 +/- 8 to 124 +/- 9/79 +/- 8 and 127 +/- 8/81 +/- 9 mmHg; P < 0.01). PRA was not different during the treatments. The change in BP and the change in MSNA during the treatments were correlated (r = 0.70 and r = 0.63, respectively; both P < 0.05). Baroreceptor sensitivity was not affected by the treatments. This is the first study to compare the effects of ACE inhibition and AngII blockade on MSNA. In hypertensive CRF patients, enalapril and losartan equally reduced BP and MSNA. Differences in modes of action of the two drugs did not result in differences in effects on MSNA, supporting the view that AngII-mediated mechanisms contribute importantly in the pathogenesis of sympathetic hyperactivity in these patients.

Topics: Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cross-Over Studies; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Losartan; Male; Middle Aged; Muscle, Skeletal; Sympathetic Nervous System

In chronic renal failure, the clearance of most ACE inhibitors including enalapril is reduced. Hence, with conventional dosage, plasma enalaprilat may be markedly elevated. It is unclear whether this excess of drug exposure affords an improved control of blood pressure. The aim of the present study was to evaluate short-term blood pressure response to two different plasma levels of enalaprilat.. As part of an open, randomized, controlled trial of the effect of high and low dosage of enalapril on the progression of renal failure, short-term blood pressure response was evaluated. Data were analysed in all patients completing 3 months of follow-up. The patients were allocated to two trough plasma concentrations of enalaprilat, either above 50 ng ml(-1) (high) (n = 17) or below 10 ng ml(-1) (low) (n = 18), and the daily dose of enalapril titrated accordingly.. Median (range) glomerular filtration rate (GFR) at baseline was 18 (7.9) in the high enalaprilat concentration group and 17 (7.3) ml min(-1) 1.73 m(2) in the low concentration group (NS). Nine patients in each group were on treatment with enalapril at baseline with a median daily dose of 5 mg in both the high (5-10) and low (2.5-20) concentration group. At 3 months' follow-up, the dose was 10 (2.5-30) and 1.9 (1.25-5) mg (P < 0.0001), respectively. After 3 months median trough concentrations of enalaprilat were 82.5 (22-244) ng ml(-1) and 9.1 (2.5-74.8) ng ml(-1) (P < 0.002). At baseline the median systolic blood pressures in the two groups were 140 (110-200) and 133 (110-165), in the high and low enalaprilat concentration groups, respectively, and after 3 months they were 135 (105-170) and 130 (105-170) mmHg (NS). Median diastolic blood pressure was 80 mmHg in each group both at baseline (65-100) and at follow-up (60-95) (NS). There was no difference between the groups in concomitant antihypertensive treatment (number of patients treated, mean daily dose) during the observation period. Proteinuria remained stable during the study period in both groups; patients in the high concentration group had higher plasma potassium concentrations at day 90 and patients in the low group experienced a slight increase in GFR.. In moderate to severe chronic renal insufficiency the same degree of blood pressure control was achieved on low as well as moderate daily doses of enalapril. This was irrespective of concomitant antihypertensive treatment.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Dose-Response Relationship, Drug; Enalapril; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged; Potassium; Proteinuria

To determine whether the angiotensin converting enzyme inhibitor enalapril would lower systemic arterial and glomerular capillary pressure and reduce the magnitude of renal injury in a canine model of renal insufficiency.. 18 adult dogs that had renal mass reduced by partial nephrectomy.. After surgical reduction of renal mass and baseline measurements, dogs in 2 equal groups received either placebo (group 1) or enalapril (0.5 mg/kg, PO, q 12 h; group 2) for 6 months.. Values for systemic mean arterial blood pressure determined by indirect and direct measurement after 3 and 6 months of treatment, respectively, were significantly lower in group 2 than in group 1. During treatment, monthly urine protein-to-creatinine ratios were consistently lower in group 2 than in group 1, although values were significantly different only at 3 months. At 6 months, significant reduction in glomerular capillary pressure in group 2 was detected, compared with group 1, but glomerular filtration rate in group 2 was not compromised. Glomerular hypertrophy, assessed by measurement of planar surface area of glomeruli, was similar in both groups. Glomerular and tubulointerstitial lesions were significantly less in group 2, compared with group 1.. Data suggest that inhibition of angiotensin converting enzyme was effective in modulating progressive renal injury, which was associated with reduction of glomerular and systemic hypertension and proteinuria but not glomerular hypertrophy. Inhibition of angiotensin converting enzyme may be effective for modulating progression of renal disease in dogs.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Dogs; Enalapril; Female; Hypertrophy; Kidney Failure, Chronic; Kidney Glomerulus; Male; Peptidyl-Dipeptidase A; Time Factors

Hypertension is commonly associated with chronic renal disease in cats, and inappropriate activation of the renin-angiotensin-aldosterone system (RAAS) may contribute to the hypertensive state. Angiotensin-converting enzyme (ACE) inhibitors are commonly administered when hypertension is present to decrease plasma concentrations of angiotensin II and aldosterone, which cause vasoconstriction and sodium and water retention, respectively. The study reported here was conducted over a 6-month period to assess the effects of two commonly prescribed ACE inhibitors, enalapril and benazepril, on the activity of the RAAS and blood pressure in 16 spontaneously hypertensive cats with chronic renal disease. Plasma aldosterone and plasma renin activity were not significantly affected by ACE inhibitors in hypertensive cats, and systolic blood pressure did not decrease below 170 mm Hg with ACE inhibitor monotherapy in 14 of 16 cats. These results suggest that continued activation of the RAAS is present in hypertensive cats despite treatment with an ACE inhibitor, and ACE inhibitors should not be used as first-line antihypertensive treatment in hypertensive cats.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Cat Diseases; Cats; Enalapril; Female; Hypertension; Kidney Failure, Chronic; Male; Renin

Fibrosis of left ventricle commonly occurs in end stage renal disease(ESRD) patients and is an independent risk factor of cardiovascular events. Angiotensin II type 1 receptor antagonist may be able to reverse fibrosis of left ventricle in ESRD patients. Ultrasonography-integrated backscatter(IBS) of myocardial walls is directly related to the morphometrically evaluated collagen content in humans. In this study, 30 chronically hemodialyzed patients with hypertension were randomly allocated to receive antihypertensive therapy with either angiotensin II type 1 receptor(AT1-R) antagonist losartan(n = 10), angiotensin-converting enzyme(ACE) inhibitor enalapril(n = 10) or calcium antagonist amlodipine(n = 10). IBS of posterior wall of left ventricule were measured by IBS before and after 6 months treatment. Baseline demographic and clinical characteristics did not differ in three subgroups. Although losartan(34.2 +/- 1.8 to 30.2 +/- 2.4 dB: p = 0.0094) treatment demonstrated significant reduce of IBS values, enalapril(30.3 +/- 1.5 to 31.7 +/- 1.4 dB: p = 0.3268) and amlodipine (31.6 +/- 1.6 to 33.1 +/- 1.9 dB: p = 0.4632) did not changed it significantly before and after 6 months treatment. All three groups reduced left ventricular mass index(Losartan 154.5 +/- 9.9 to 114.6 +/- 5.8 g/m2: p = 0.0002) (enalapril 155.6 +/- 14.3 to 135.3 +/- 10.4 g/m2: p = 0.0275) (amlodipine 156.6 +/- 7.3 to 137.2 +/- 4.1 g/m2: p = 0.0589). Three groups manifested a similar significant decrease in the mean blood pressure. Plasma angiotensin II concentration was markedly increased by 5.0-fold relative to the control levels before treatment in Losartan treatment, in contrast unchanged in enalapril and only 2.0-fold increased in amlodipine treatment. This study indicates that losartan reduce of fibrosis of left ventricule and this effect may be via an anti-AT1-R effect.

Topics: Amlodipine; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Cardiomyopathies; Enalapril; Female; Fibrosis; Humans; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Losartan; Male; Middle Aged; Myocardium; Renal Dialysis

Left ventricular hypertrophy (LVH) commonly occurs in patients with end-stage renal disease (ESRD) and is an independent risk factor for cardiovascular events. Angiotensin II type 1 receptor (AT1-R) antagonists may be able to reverse LVH independent to the hypotensive effect in the ESRD setting. Thirty chronically hemodialyzed uremic patients with hypertension were randomly assigned to receive the AT1-R antagonist losartan (n = 10), the angiotensin-converting enzyme (ACD) inhibitor enalapril (n = 10), or calcium antagonist amlodipine (n = 10). Left ventricular mass (LVM) index was measured by echocardiography before and 6 months after treatment. The baseline demographic and clinical characteristics did not differ between the three groups. The mean baseline LVM index also did not differ in the three groups. After 6 months of treatment, losartan treatment significantly reduced the LVM index (-24.7 +/- 3.2%) than amlodipine (-10.5 +/- 5.2%) or enalapril (-11.2 +/- 4.1%) therapy. All three groups had a similar decrease in the mean blood pressure with treatment. The plasma angiotensin II concentration increased 5-fold with losartan treatment. In contrast, the plasma angiotension II concentration did not change with enalapril and only increased 2-fold with amlodipine. Thus, the present study indicates that losartan more effectively regresses LVH in patients with ESRD than do enalapril and amlodipine despite a comparable depressor effect between the three drugs.

Topics: Adult; Aged; Aged, 80 and over; Amlodipine; Angiotensin II; Angiotensin Receptor Antagonists; Antihypertensive Agents; Echocardiography; Enalapril; Female; Heart Ventricles; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Losartan; Male; Middle Aged; Receptor, Angiotensin, Type 1; Renal Dialysis

Angiotensin-converting enzyme (ACE) inhibitors are the drugs of choice for the treatment of hypertension in patients with non-diabetic nephropathies. However, not every trial has reported better results with ACE inhibitors (ACE-I) than with other drugs. This study investigates whether the acute and chronic effects of ACE inhibition on renal and glomerular haemodynamics are similar in glomerular and interstitial nephropathies.. We studied 20 hypertensive patients, on their usual diet, with mild-to-moderate chronic renal failure secondary to non-diabetic nephropathy. After a three-week wash out period, we determined plasma clearances of para-amino-hippurate and inulin before, and after acute oral administration of either enalapril or ramipril. This same test was carried out after one and two years of treatment with the same drug.. Acute ACE inhibition causes a decrease of renal perfusion, glomerular filtration and pressure with an increase of afferent resistances. Long-term ACE inhibition is associated only with a decrease in renal perfusion, with a non-significant tendency to higher filtration fraction and lower afferent resistances. All the renal haemodynamic modifications mentioned above are present only in patients with glomerular diseases.. Renal and glomerular haemodynamic responses are not similar after acute and chronic ACE inhibition. Only patients with glomerular diseases show acute or long-term responses to ACE inhibition.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Glomerular Filtration Rate; Glomerulonephritis; Humans; Hypertension, Renal; Inulin; Kidney Failure, Chronic; Kidney Function Tests; Kidney Glomerulus; Male; Middle Aged; Nephritis, Interstitial; p-Aminohippuric Acid; Ramipril; Renal Circulation

Treatment of hypertension in patients with chronic renal failure has been shown to postpone the decline in renal function. Treatment with an ACE inhibitor has been shown to be superior to conventional antihypertensive treatment, but it is not known how an ACE inhibitor compares to treatment with a calcium channel blocker or to treatment with a combination of these drugs. The aim of the study was to evaluate the rate of decline in GFR in patients with chronic renal failure and hypertension treated with isradipine and spirapril as monotherapy and in combination.. Sixty patients with chronic renal failure and hypertension were enrolled in the study. After enrollment, patients were followed prospectively for 6 months in the outpatient clinic on their usual antihypertensive medication, and then randomized to a double-blinded comparison of either spirapril 6 mg daily, isradipine 5 mg daily or spirapril 3 mg and isradipine 2.5 mg daily. After randomization, patients were followed for 21 months or until the need for dialysis. Every 3 months before and 3.5 months after randomization the glomerular filtration rate was measured by 51Cr-EDTA clearance and the effective renal plasma flow evaluated using the renal clearance of paraaminohippuric acid.. Blood pressure and the decline in glomerular filtration rate did not differ between the groups before randomization. After randomization, the mean decline in the glomerular filtration rate was -0.32 ml/(min x month x 1.73 m2) in the spirapril group, -0.58 ml/(min x month x 1.73 m2) in the isradipine group and -0.14 ml/(min x month x 1.73 m2) in the combination group (p = 0.38). Twelve patients, 4 in each group, reached end-stage renal failure. No significant difference was found with respect to diastolic (p = 0.10) or systolic blood pressure (p = 0.08) during the treatment period, but a trend towards a better blood pressure control in the combination group was present. During treatment, the rate of decline in renal plasma flow did not differ significantly between the groups (p = 0.09), neither did the changes in filtration fraction (FF) (p = 0.58) nor the mean FF (p = 0.22) during the treatment.. Our study indicated differences between the 3 treatment modalities in favor of combined therapy with respect to both the rate of decline in GFR and blood pressure control, but the differences where insignificant. Thus, the treatments might differ, but we were unable to confirm this because of large variation in GFR and small sample size.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Isradipine; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Renal Plasma Flow, Effective

Most angiotensin-converting enzyme (ACE) inhibitors and their metabolites are excreted renally and doses should hence be reduced in renal insufficiency. We studied whether the dosage of enalapril in daily clinical practice is associated with drug accumulation of enalaprilat in chronic renal failure.. Fifty nine out-patients with plasma creatinine >150 micromol/L and chronic antihypertensive treatment with enalapril were investigated, in a cross-sectional design.. Median glomerular filtration rate (GFR) was 23(range 6-60) ml/minute/1.73 m2. The daily dose of enalapril was 10 (2.5-20) mg and the trough serum concentration of enalaprilat was 31.8 (<2.5-584.7)ng/ml. Ninety percent of the patients had higher serum concentrations of enalaprilat than has been reported in subjects with normal kidney function, and a marked elevation of serum enalaprilat was observed in patients with GFR <30 ml/minute. All but three patients had serum ACE activity below the reference range. The ACE genotype did not influence the results. Additional pharmacokinetic studies were done in nine patients in whom GFR was 23 (10-42)ml/minute/1.73 m2. The median clearance of enalaprilat was 28 (16-68) ml/minute and correlated linearly with GFR (r=0.86, p=0.003). Intra-subject day-to-day variation in trough concentrations was 19.7%.. Patients with chronic renal failure given small or moderately high doses of enalapril may thus have markedly elevated levels of serum enalaprilat. Whether this affords extra renoprotection, or on the contrary may inappropriately impair renal function, is not known, and should be investigated in prospective, controlled studies.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cross-Sectional Studies; Enalapril; Enalaprilat; Female; Genotype; Glomerular Filtration Rate; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic

Topics: Antihypertensive Agents; Enalapril; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Losartan; Male; Polycythemia; Postoperative Complications

In the present study we investigated the effect of a single dose, and 3 months of treatment with spirapril on kidney function, renin-angiotensin system, renal handling of sodium and blood pressure, in patients with reduced kidney function (serum creatinine 1.5-3 mg%) and hypertension. A single dose of 6 mg spirapril given at the beginning of the study did not affect glomerular filtration rate (GFR), renal plasma flow (RPF), angiotensin converting enzyme (ACE) activity, plasma renin activity (PRA) or renal handling of sodium. When the single dose of spirapril was given after 3 months of treatment with this agent, renal hemodynamics and PRA did not change. ACE activity, which was depressed by the previous spirapril treatment, decreased further (from 9.5 +/- 3.1 to 1.4 +/- 1.0 nmol/ml/min), (p < 0.05). Administration of 6 mg spirapril o.d. for 3 months did not have any effect on GFR or RPF. Serum ACE activity decreased from 92.1 +/- 8.0 to 5.1 +/- 2.6 nmol/ml/min (p < 0.05) and PRA increased from 1.4 +/- 1.2 to 4.1 +/- 3.6 ng/ml/min (p < 0.05). Plasma aldosterone did not change. Similar results were obtained when spirapril was combined with 5 mg isradipine in the initial and final single dose, or in the 3 months' treatment (5 mg o.d.). Blood pressure was normalized in 38% of the patients who received spirapril and in 71% of the patients who received spirapril and isradipine. Thus, (a) treatment with spirapril in patients with mild to moderate chronic renal insufficiency was not associated with deleterious effects on kidney function; (b) spirapril in a dose of 6 mg alone or in combination with 5 mg isradipine is effective in reducing blood pressure in hypertensive patients with reduced kidney function.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Enalapril; Female; Humans; Hypertension; Isradipine; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Time Factors

Inhibition of angiotensin-converting enzyme (ACE) reduces the risk of cardiovascular problems in patients with chronic renal failure. This effect may be due in part to a decrease in sympathetic nervous activity, but no direct evidence of such an action is available.. We studied muscle sympathetic-nerve activity in 14 patients with hypertension, chronic renal failure, and increased plasma renin activity before, during, and after administration of the ACE inhibitor enalapril. Ten other patients with similar clinical characteristics were studied before and during treatment with the calcium-channel blocker amlodipine. Normal subjects matched for age and weight were included in both studies.. At base line, mean (+/-SD) muscle sympathetic-nerve activity was higher in the group of patients who received enalapril than in the control subjects (35+/-17 vs. 19+/-9 bursts per minute, P=0.004). The baroreflex curve, which reflects changes in muscle sympathetic-nerve activity caused by manipulations of blood pressure with sodium nitroprusside and phenylephrine, was shifted to the right in the patients, but baroreflex sensitivity was similar to that in the control subjects (-2.1+/-1.9 and -2.7+/-1.3 bursts per minute per mm Hg, respectively; P=0.36). A single dose of the sympatholytic drug clonidine caused a greater fall in blood pressure in the patients than in the control subjects. Treatment with enalapril normalized blood pressure and muscle sympathetic-nerve activity (at 23+/-10 bursts per minute) in the patients and shifted the baroreflex curve to the left, reflecting normal blood-pressure levels, without significantly changing sensitivity (-2.3+/-1.8 bursts per minute per mm Hg, P=0.96). In the patients who received amlodipine, treatment also lowered blood pressure but increased muscle sympathetic-nerve activity, from 41+/-19 to 56+/-14 bursts per minute (P=0.02).. Increased sympathetic activity contributes to hypertension in patients with chronic renal disease. ACE inhibition controls hypertension and decreases sympathetic hyperactivity.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Baroreflex; Calcium Channel Blockers; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Muscles; Reference Values; Renin; Sympathetic Nervous System

It was reported previously that dietary fish oil supplementation retarded the progression of renal disease in patients with IgA nephropathy in a multicenter, placebo-controlled, randomized, 2-yr clinical trial. The aim of this study was to determine the long-term influence of fish oil treatment on renal progression in observations on the study cohort of 106 patients extending beyond the 2-yr trial. Renal function was assessed by serial serum creatinine and 24-h urine protein measurements. Vital, end-stage renal disease (ESRD), and BP status and treatment beyond completion of the 2-yr trial were determined. As in the trial, the primary end point was an increase of 50% or more in the serum creatinine, and the secondary end point was ESRD. After a mean follow-up of 6.4 yr, 46 patients-17 in the fish oil group versus 29 in the placebo group-reached the primary end point (P = 0.002), and 27 patients-eight in the fish oil group versus 19 in the placebo group-developed ESRD (P = 0.009). At the end of the 2-yr trial, 75 patients (45 fish oil, 30 placebo) remained at risk for the primary end point. This is also when the double-blind part of the trial ended, allowing physicians to stop supplements, switch original placebo-assigned patients to fish oil, and continue fish oil in original fish oil-assigned patients. A significantly greater number of nonsupplemented placebo patients developed the primary end point (P = 0.02) and ESRD (P = 0.003) compared with long-term supplemented fish oil patients. Conversely, more fish oil-supplemented patients had stable renal function than nonsupplemented patients (P = 0.02). By intention, BP control, primarily treated with angiotensin-converting enzyme inhibition, was equal in the fish oil and placebo groups. Proteinuria was modestly reduced in both groups. It is concluded that early and prolonged treatment with fish oil slows renal progression for high-risk patients with IgA nephropathy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cohort Studies; Creatinine; Disease Progression; Double-Blind Method; Enalapril; Female; Fish Oils; Glomerulonephritis, IGA; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Longitudinal Studies; Male; Proteinuria; Treatment Outcome

We previously reported chronic treatment with angiotensin-converting enzyme inhibitors (ACEis) increases antioxidant defenses in mice. In the present study, however, we examined various antioxidant defenses in chronic hemodialysis (HD) patients either treated with enalapril (10 mg/d) for at least 6 months (+ACEi; n = 11) or untreated (-ACEi; n = 11). The relationship between antioxidant status and HD was investigated by determining oxidative stress markers and antioxidant defenses in a group of chronic HD patients (n = 33) and a group of age-matched controls (n = 29). The effect of a single HD session on those parameters was also evaluated. Before an HD session (pre-HD), HD patients had significantly lower levels of red blood cell (RBC) glutathione (GSH), selenium-dependent glutathione peroxidase activity (RBC-Se-GPx), plasma ubiquinol-10, and alpha-tocopherol than controls. In a randomly selected group of patients (n = 19), a single HD session caused an additional decrease in RBC-GSH and plasma ubiquinol-10 levels. Plasma thiobarbituric acid reactive substance (TBARS) levels were significantly greater in pre-HD patients than controls. Post-HD plasma TBARS levels were similar to control values. The cohort of +ACEi HD patients had greater pre-HD RBC-GSH content, RBC-Se-GPx activity, and plasma beta-carotene concentrations than -ACEi patients (RBC-GSH: +ACEi, 3.1 +/- 0.9 micromol/mL packed RBCs [PRBCs]; -ACEi, 1.2 +/- 0.3 micromol/mL PRBCs [P < 0.05 v +ACEi]; RBC-Se-GPx: +ACEi, 5.8 +/- 0.7 U/mL PRBCs; -ACEi, 4.3 +/- 0.2 U/mL PRBCs [P < 0.05 v +ACEi]; plasma beta-carotene: +ACEi, 0.54 +/- 0.16 micromol/L plasma; -ACEi, 0.19 +/- 0.05 micromol/L plasma [P < 0.05 v +ACEi]). Results show profound alterations in the circulating antioxidant systems of chronic HD patients and that additional oxidative stress occurs during the HD procedure. In addition, in +ACEi HD patients, the levels of several antioxidant defenses are greater than in those in -ACEi HD patients.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Animals; Antioxidants; Catalase; Enalapril; Erythrocytes; Female; Free Radicals; Glutathione; Glutathione Peroxidase; Humans; Kidney Failure, Chronic; Lipid Peroxidation; Male; Malondialdehyde; Mice; Middle Aged; Reactive Oxygen Species; Renal Dialysis; Ubiquinone; Vitamin E

Although angiotensin-converting enzyme inhibitor therapy reduces mortality rates in patients with congestive heart failure (CHF), it may also cause decreased renal function. Little information is available to predict which patients are at highest risk for this complication.. To quantify specific clinical predictors of reduction in renal function in patients with CHF who are prescribed angiotensin-converting enzyme inhibitor therapy.. We analyzed data from the Studies of Left Ventricular Dysfunction (SOLVD), a randomized, double-blind, placebo-controlled trial of enalapril for the treatment of CHF. There were 3379 patients randomly assigned to enalapril with a median follow-up of 974 days and 3379 patients randomly assigned to placebo with a mean follow-up of 967 days. Decreased renal function was defined as a rise in serum creatinine >/=0.5 mg/dL (44 micromol/L) from baseline. We used time-to-event analysis to identify potential predictors of decrease in renal function including age, baseline ejection fraction, baseline creatinine, low systolic blood pressure (<100 mm Hg), history of hypertension, diabetes, and use of antiplatelet, diuretic, and beta-blocker therapy.. Patients randomly assigned to enalapril had a 33% greater likelihood of decreased renal function than controls (P =.003). By multivariate analysis, in both the placebo and enalapril groups older age, diuretic therapy, and diabetes were associated with decreased renal function, whereas beta-blocker therapy and higher ejection fraction were renoprotective. Older age was associated with a greater risk of developing decreased renal function in both groups, but significantly more so in the enalapril group (enalapril: risk ratio [RR] 1.42 per 10 years, 95% confidence interval [CI] 1.32-1.52 with enalapril; placebo: RR 1.18, 95% CI 1.12-1.25). Diuretic therapy was likewise associated with a greater risk of decreased renal function in the enalapril group (RR 1.89, 95% CI 1.70-2.08) than in the placebo group (RR 1.35, 95% CI 1.09-1.66). Conversely, enalapril had a relative renoprotective effect (RR 1.33, 95% CI 1.13-1.53) compared with placebo (RR 1.96, 95% CI 1.57-2.44) in patients with diabetes. A lower risk of renal impairment was seen in both groups with beta-blocker therapy (RR 0.70, 95% CI 0.57-0.85) and higher baseline ejection fraction (RR 0.93 per 5% increment, 95% CI 0.91-0. 96).. Enalapril use caused a 33% increase in the risk of decreased renal function in patients with CHF. Diuretic use and advanced age increased this risk. Diabetes was associated with an increased risk of renal impairment in all patients with CHF, but this risk was reduced in the enalapril group compared with the placebo group. beta-Blocker therapy and higher ejection fraction were renoprotective in all patients regardless of therapy.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Diuretics; Enalapril; Female; Follow-Up Studies; Heart Failure; Humans; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Prognosis; Risk Factors; Stroke Volume; Ventricular Dysfunction, Left

The effect of enalapril (5-10 mg/day) on the progression of chronic renal failure (CRF) was compared with that of metoprolol (40-120 mg/day) in 28 patients for 24 months in a prospective study. Throughout the study, there was no significant difference between the 2 groups in protein intake and urinary sodium excretion. But there was a significant difference between the 2 groups in diastolic and mean arterial blood pressure at 6 months. In the serum creatinine level, there was a significant difference between the 2 groups at 6, 12, 18, and 24 months. In creatinine clearance, there was a significant difference between the 2 groups at 24 months. In addition, the progression of CRF was significantly faster in the metoprolol group than the enalapril group as estimated from the slope of creatinine clearance (p < 0.05) and the slope of glomerular filtration rate (p < 0.0005). In urinary protein excretion, there was a significant difference between the 2 groups at 6 and 18 months (p < 0.05). These findings indicate that enalapril has a suppressive effect on the progression of CRF and also has an antiproteinuric effect by a mechanism independent of its antihypertensive effect.

Topics: Adult; Aged; Antihypertensive Agents; Blood Pressure; Cholesterol, HDL; Creatinine; Diet, Protein-Restricted; Dietary Proteins; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Metoprolol; Middle Aged; Prospective Studies; Proteinuria; Sodium; Triglycerides

Normal blood pressure is a good marker of graft survival after renal transplantation, and effective antihypertensive treatment reduces the progression of graft damage. We conducted a long-term follow-up study of 88 hypertensive renal transplant recipients, all of whom were taking sustained cyclosporine A (CsA) immunosuppression. The patients were treated for at least three years, and initially received 240 mg/day of verapamil (N = 24, group I), 5 mg/day of enalapril (N = 24, group II) or 1 mg/day of doxazosin (N = 40, group III). Baseline creatinine did not differ in the three groups, but proteinuria was higher in the enalapril group (7 patients had proteinuria > 1.5 g/day). Treatment was withdrawn in 5 patients in the verapamil group, 5 in the enalapril group and 2 in the doxazosin group due to drug-related side effects. Blood pressure (BP) control at three years was equivalent in the three groups (systolic BP, group I 157 +/- 12; group II 149 +/- 19; group III 154 +/- 21; diastolic BP, group I 90 +/- 8.7, group II 84 +/- 9.8, group III 90.5 +/- 16; mean BP, group I 113 +/- 7, group II 106 +/- 10, group III 106 +/- 29). Two patients in group I, 3 in group II and 15 in group III required additional antihypertensive drugs. CsA levels increased in the verapamil-treated patients, allowing for an early decrease in CsA doses (1 year doses, 3.3 +/- 1 mg/kg body wt/day in group I, 4.3 +/- 1.6 in group II, 3.7 +/- 1.6 in group III). Six cardiovascular events occurred, 3 in group I, 1 in group II, and 2 in group III patients. One patient died in the enalapril group and another in the doxazosin group. Eight verapamil-treated patients, 8 enalapril-treated patients and 4 doxazosin-treated patients lost their grafts due to biopsy-proven chronic transplant nephropathy. In conclusion, the three antihypertensive agents are effective in reducing blood pressure, with no clear advantage of one above any other. Verapamil allows the CsA dose to be reduced, thus decreasing the cost of immunosupression. Enalapril can be a more effective antiproteinuric agent, but hyperkalemia or impaired allograft function may occur in patients with non-optimal allograft function. Doxazosin offers an excellent safety and efficacy profile, and when not efficient by itself in controlling blood pressure, is an ideal concomitant agent in hypertensive renal transplant patients.

Topics: Adult; Antihypertensive Agents; Calcium Channel Blockers; Doxazosin; Enalapril; Female; Follow-Up Studies; Graft Survival; Humans; Hypercholesterolemia; Hypertension, Renal; Kidney Failure, Chronic; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Postoperative Complications; Verapamil

To determine plasma renin activity (PRA), angiotensin I (Ang I), and aldosterone (ALDO) values in clinically normal cats and hypertensive cats with renal disease, and the relation of renin-angiotensin-aldosterone activation in response to treatment with beta-blockers or angiotensin-converting enzyme inhibitors.. 5 normotensive healthy control cats and 12 Untreated hypertensive cats with chronic renal disease.. Untreated hypertensive cats received either propanolol (n = 6) or enalapril (n = 6) as initial antihypertensive treatment. PRA and baseline plasma Ang I and ALDO concentrations were measured prior to treatment. The difference in Ang I values at 2 hours (Ang I generated) and at time 0 (baseline Ang I) was divided by 2 to give the PRA value. Values for PRA, Ang I, and ALDO were obtained from 5 clinically normal, normotensive cats, and compared with those of hypertensive cats.. Mean +/- SD PRA and baseline Ang I concentration were not significantly different between normotensive and hypertensive cats. Mean ALDO concentration was significantly (P = 0.0235) higher in hypertensive cats with renal disease (186.18 +/- 145.15 pg/ml), compared with that in normotensive controls (51.1 +/- 16.76 pg/ml). Eight hypertensive cats with ALDO concentration > 2 SD above the mean concentration in control cats had low (n = 3), normal (n = 4), or high (n = 1) PRA, suggesting variable activation of the renin-angiotensin-aldosterone axis in the hypertensive state. Overall, enalapril was effective long-term monotherapy in only 1 of 6 cats, and propranolol was ineffective as long-term monotherapy.. Evaluation of the renin-angiotensin-aldosterone system in cats with hypertension associated with renal disease may lead to greater understanding of the pathophysiologic mechanisms of this disorder. In addition, identification of biochemical markers in hypertensive cats may permit selection of appropriate antihypertensive drugs. Propranolol and enalapril were ineffective antihypertensive agents in most cats of this study.

Topics: Adrenergic beta-Antagonists; Aldosterone; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cat Diseases; Cats; Dose-Response Relationship, Drug; Enalapril; Female; Hypertension, Renal; Kidney Failure, Chronic; Male; Propranolol; Radioimmunoassay; Renin; Renin-Angiotensin System

Left ventricular hypertrophy is frequently noted in patients with moderate to severe chronic renal failure not requiring dialysis. Recently, several studies have shown reversal of myocardial hypertrophy in end-stage renal disease with long-term pharmacological control of blood pressure, but it is unclear whether left ventricular mass regresses or normalizes with antihypertensive treatment of patients with earlier stages of chronic renal failure.. Seventy-two undialysed patients with chronic renal failure, chronic mild-to-moderate hypertension, and left ventricular hypertrophy were randomly assigned in a prospective study to either the captopril (n = 36) or enalapril group (n = 36). Blood pressure measurements, echocardiographic and Doppler parameters were evaluated before treatment and at 6 and 12 months of therapy.. During follow-up, six patients developed side-effects including dry cough, taste disturbances, skin rash and gastric intolerance. In the captopril group there was a decrease in mean left ventricular mass index by 12% after 6 months of treatment, which decreased by 20% after 12 months treatment. For enalapril, the average reduction of myocardial mass after 6 months treatment was 14% and after 12 months treatment, the decrease was 19%. In both treatment groups there was significant improvement of left ventricular filling dynamics. No deterioration of left ventricular systolic function was observed.. Our results confirm that antihypertensive monotherapy with the ACE inhibitors, captopril and enalapril, in patients with chronic renal failure results in regression of left ventricular mass index associated with a significant improvement in the diastolic function of the left ventricle without a demonstrable deterioration in left ventricular systolic performance.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Captopril; Diastole; Drug Tolerance; Enalapril; Female; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Single-Blind Method; Systole; Ventricular Function, Left

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Double-Blind Method; Enalapril; Humans; Kidney Failure, Chronic; Middle Aged

Angiotensin-converting enzyme inhibitors delay progression of renal disease in different animal models of nephropathy. We tested this treatment modality in 70 hypertensive patients with severe renal disease of various etiologies. We report a double-blind study of the effect of 5 mg enalapril once daily compared with placebo in patients with nondiabetic severe chronic renal impairment (plasma creatinine 2.8 to 6.8 mg/dL; mean creatinine clearance 15 mL/min/1.73 m2) followed for up to 2 years. Efficacy parameters were the slopes of 51Cr-EDTA clearance, reciprocal of plasma creatinine, creatinine clearance, and the effect on urinary protein excretion. Thirty-one patients completed 2 years of treatment (12 in the enalapril group and 19 in the placebo group). Two patients died from nonrenal causes (one patient each in the enalapril and placebo groups), 16 patients commenced dialysis (seven in the enalapril group and nine in the placebo group), and eight patients were discontinued due to adverse events (five in the enalapril group and three in the placebo group). Eleven patients were discontinued because they were noncompliant, uncooperative, or moved (nine in the enalapril group and two in the placebo group). Two enalapril-treated patients were dropped from the study due to protocol deviations. Importantly, the statistical approach in this study evaluated all patients, regardless of the duration of treatment. A mixed-effects linear model and intention to treat analysis, taking into account the number of observations per patient, indicated that enalapril significantly reduced the rate of deterioration of renal disease: glomerular filtration rate (P = 0.038), reciprocal of plasma creatinine (P = 0.017), or creatinine clearance (P = 0.031). The renal protective effects of enalapril were shown to be in addition to its antihypertensive effect when blood pressure was held constant. Proteinuria was reduced by enalapril (P = 0.007) and was slightly increased in the placebo-treated patients (P = 0.051). The difference between these two groups was highly significant (P = 0.002). In conclusion, enalapril retarded the progression of chronic renal failure, as assessed by changes in glomerular filtration rate, creatinine clearance, and 1/plasma creatinine, and reduced proteinuria in patients with nondiabetic severe chronic renal insufficiency.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Disease Progression; Double-Blind Method; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Linear Models; Male; Middle Aged; Placebos; Prospective Studies; Statistics, Nonparametric

There are a lack of studies about elderly patients with chronic renal failure (CRF). We studied 22 patients, aged 64 to 74 years, who were diagnosed with hypertensive nephropathy (HN), defined as a diastolic blood pressure (DBP) < 95 mm Hg and a basal creatinine clearance (CCr) of 52 +/- 6 ml/min/1.73 m2. During the minimum two-year follow-up, the progression of renal failure (RF) was analyzed by the plotted slope of CCr versus time. Patients were divided into two groups, each administered one of two different drugs, Ca antagonists (group I) and angiotensin converting enzyme (ACE) inhibitors (group II). The DBP in both groups was lowered by the end of the study. The mean arterial pressure (MAP) was less in group I (97.35 +/- 5.98 mm Hg) than in group II (108.3 +/- 9.95 mm Hg). The decline in renal function was a mean rate of -0.62 +/- 0.36 ml/min/month in group I and -1.03 +/- 0.17 ml/min/month in group II. In conclusion, we show that patients who were on ACE inhibitors exhibited a greater MAP and a greater decline in renal function compared with the patients who were on Ca antagonist therapy. We also found that patients who were younger than 70 years old had better control of their blood pressure rates and less of a rate of decline in renal function than their older counterparts.

Topics: Aged; Aged, 80 and over; Aging; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Creatinine; Disease Progression; Enalapril; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Nifedipine

The influence of angiotensin-converting enzyme (ACE) inhibition on renal tubular function in progressive chronic nephropathy was investigated in 69 patients by the lithium clearance (C(Li)) method. Studies were done repeatedly for up to 2 years during a controlled trial on the effect of enalapril on progression of renal failure. The pattern of proteinuria was followed over the first 9 months. At baseline, the glomerular filtration rate (GFR) was 5 to 68 mL/min. Absolute proximal tubular reabsorption rate of fluid (APR), estimated as the difference between GFR and C(Li), was 1 to 54 mL/min. Calculated fractional proximal reabsorption (FPR) was moderately subnormal. During the study, GFR decreased and sodium clearance was unchanged; fractional excretion of sodium therefore increased. In the group of patients randomized to treatment with enalapril (n = 34), GFR at 1 month was 83% (P < 0.001) and C(Li) was 88% (P < 0.01) of the baseline values, APR and FPR had not changed significantly, and potassium clearance was significantly decreased. Through the rest of the study period, APR remained nearly unchanged and FPR even increased in the enalapril group. In the group of patients randomized to treatment with conventional antihypertensive drugs (n = 35), C(Li) was unchanged until severe reduction in GFR, APR and FPR decreased gradually, and potassium clearance was almost unchanged. These differences in tubular function between the two treatment regimens were significant (P < 0.05). An unchanged or increased APR in either treatment regimen was associated with a long-term slower progression of renal failure. Over 9 months, the 24-hour fractional clearance of albumin decreased in the ACE inhibitor group (P < 0.01), whereas the clearances of immunoglobulin G and retinol-binding protein were unchanged in this group. In the conventional group, the fractional clearances of these three plasma proteins all increased. It is concluded that in progressive chronic nephropathy ACE-inhibitor treatment was associated with different adaptive tubular changes in the handling of sodium, water, and protein compared with conventional antihypertensive therapy. During ACE inhibition, the reabsorptive capacity of the proximal tubule appeared to be better preserved, which might be of importance for the beneficial effect of this treatment in chronic renal disease.

Topics: Absorption; Adult; Aged; Albumins; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Disease Progression; Enalapril; Female; Glomerular Filtration Rate; Humans; Immunoglobulin G; Kidney Failure, Chronic; Kidney Function Tests; Kidney Tubules; Lithium; Male; Middle Aged; Potassium; Retinol-Binding Proteins; Retinol-Binding Proteins, Plasma; Sodium

An earlier controlled trial showed that over an average of 26 months, enalapril slowed the progression of chronic renal failure. Following completion of the trial, the patients continued to receive antihypertensive treatment according to ordinary clinical criteria. All but four patients in the enalapril group remained on that drug, and two patients in the control group were switched to an angiotensin-converting enzyme (ACE) inhibitor. In the present study the fate of the 70 patients 44 months after termination of the trial was investigated, with a total follow-up of around 7 years. In the original enalapril group, 12 of the 35 patients (34%) were alive without renal replacement therapy versus five of the 35 patients (14%) in the control group. This difference of 20% in favour of having been in the enalapril group in the original trial was significant (P = 0.05; 95% confidence limits 0.5-39.5%). The influence of baseline proteinuria on clinical outcome was analysed. In the original control group, baseline renal clearances of albumin (Calb) and immunoglobulin G (CIgG) were significantly lower in patients surviving without renal replacement therapy at follow-up than in patients who ultimately developed end-stage renal failure (ESRF) (P < 0.05). In the original enalapril group, these baseline clearances were equal in the two renal outcome groups. In all patients, baseline Calb and CIgG were negatively correlated with the rate of change in GFR during the controlled trial (r = -0.37, P < 0.01 and r = -0.28, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Lipids; Male; Middle Aged; Proteinuria; Sex Characteristics; Survival Analysis; Treatment Outcome

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Glomerular Filtration Rate; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Ramipril; Renal Circulation; Renal Plasma Flow; Time Factors

26 patients with hypertension while on hemodialysis or continuous ambulatory peritoneal dialysis for end-stage renal diseases were treated first with enalapril and then changed to metoprolol. Both drugs were shown to be similarly effective in controlling blood pressure. There was no difference between the two drugs in their effects on renal function, potassium balance, lipid profile, cardiac function, exercise tolerance, and quality of life. Mild worsening of anemia was observed during treatment with enalapril. No serious side effects were reported. Use of enalapril is safe in the treatment of hypertension in dialysis patients.

Topics: Adult; Anemia; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Cell Count; Blood Pressure; Electrocardiography; Enalapril; Exercise Tolerance; Female; Humans; Hypertension; Kidney Failure, Chronic; Kidney Function Tests; Lipids; Male; Metoprolol; Middle Aged; Nifedipine; Peritoneal Dialysis, Continuous Ambulatory; Potassium; Quality of Life; Renal Dialysis

Renal function in 31 patients with mild to moderate heart failure (NYHA Classes II-III) was studied before and during treatment with ACE-inhibitors. Maximal treatment doses were based on randomization: captopril 3 x 12.5 mg or lisinopril or enalapril, both 1 x 10 mg. Before therapy and at the end of titration phase (after 6 days) glomerular filtration rate and renal blood flow were determined from inulin and PAH clearance (steady-state method). In the total study group the median arterial pressure significantly decreased from 94 mmHg to 84 mmHg (p < 0.01), whereas glomerular filtration rate was only moderately, however, significantly reduced from 103 ml/min to 97 ml/min (median values, p < 0.01). Renal blood flow, however, increased from 372 ml/min to 403 ml/min (p < 0.01). Changes in glomerular filtration rate (GFRd) were significantly dependent on those of renal blood flow (GFRd = 0.07 RPFd - 9.2; p < 0.05). All three ACE-inhibitors showed similar changes in glomerular filtration rate and renal blood flow. Ten of the patients had additionally received cyclooxygenase inhibitors. With respect to severity of heart failure and renal function these patients did not differ from the remaining 21 patients of the group. In both groups, a decrease of glomerular filtration rate was found, however, in those patients who had received acetylsalicylic acid there was no increase of renal blood flow.. A small, however significant decrease of glomerular filtration rate is already seen in patients with mild to moderate heart failure treated with ACE-inhibitors. Increase of renal blood flow counteracts the decrease of glomerular filtration rate. During concomitant application of acetylsalicylic acid the increase of renal blood flow remains absent.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Blood Flow Velocity; Blood Pressure; Captopril; Creatinine; Drug Therapy, Combination; Enalapril; Female; Glomerular Filtration Rate; Heart Failure; Humans; Kidney Failure, Chronic; Kidney Function Tests; Lisinopril; Male; Middle Aged; Renal Circulation

To compare the ability of angiotensin converting enzyme inhibitors and beta blockers to slow the development of end stage renal failure in non-diabetic patients with chronic renal failure.. Open randomised multicentre trial with three year follow up.. Outpatient departments of six French hospitals.. 100 hypertensive patients with chronic renal failure (initial serum creatinine 200-400 mumol/l. 52 randomised to enalapril and 48 to beta blockers (conventional treatment).. Enalapril or beta blocker was combined with frusemide and, if necessary, a calcium blocker or centrally acting drug in patients whose diastolic pressure remained above 90 mm Hg.. 17 patients receiving conventional treatment and 10 receiving enalapril developed end stage renal failure. The cumulative renal survival rate was significantly better in the enalapril group than in the conventional group (P < 0.05). The slope of the reciprocal serum creatinine concentration was steeper in the conventionally treated patients (-6.89 x 10(-5)l/mumol/month) than in the enalapril group (-4.17 x 10(-5)l/mumol/month; P < 0.05). No difference in blood pressure was found between groups.. In hypertensive patients with chronic renal failure enalapril slows progression towards end stage renal failure compared with beta blockers. This effect was probably not mediated through controlling blood pressure.

Topics: Acebutolol; Adolescent; Adult; Aged; Atenolol; Blood Pressure; Body Weight; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Potassium; Proteinuria

Spirapril is a recent ACE inhibitor with a both renal and hepatic elimination pathway. In order to determine its tolerability, primarily the impact on renal function, Spirapril was tested in a single-blind trial with a 2-week placebo run-in phase and a 4-week active treatment period. Forty-nine patients (34 males and 15 females) with varying degrees of renal impairment were included. Their pretreatment diastolic blood pressure (DBP) ranged from 95 to 115 mm Hg. Spirapril was administered in oral doses of 6 mg once daily.. Forty-four patients completed the study. Four patients dropped out due to side effects, 1 patient was withdrawn from the study due to lack of antihypertensive efficacy. 48% of the completers with renal failure achieved a normalized diastolic blood pressure (DBP < or = 90 mm Hg) or a reduction in DBP of > or = 10 mm Hg; the corresponding figure for patients with normal renal function was 31%. Renal function was assessed in the beginning and at the end of the active Spirapril treatment period using Tc-99m-DTPA-clearance (representing glomerular filtration rate), J-131-hippuran-clearance (representing renal plasma flow) and creatinine clearance. Particularly in patients with renal impairment, Spirapril did not deteriorate renal function as given by these parameters. Regression analysis revealed a linear correlation between total plasma clearance of the active metabolite Spiraprilate and creatinine clearance. There was no evidence for drug accumulation.. In patients with renal impairment the pharmacokinetic results indicate a non-renal elimination of the drug. Spirapril 6 mg once daily is concluded to be a well tolerated antihypertensive therapy for patients with mild to moderate hypertension and varying degrees of chronic renal failure.

Topics: Administration, Oral; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Kidney Function Tests; Male; Metabolic Clearance Rate; Middle Aged

In this single-blind trial with a 2-week placebo run-in followed by a 4-week active-treatment period, patients were given 6 mg of spirapril once daily. Forty-nine hypertensive men and women were recruited; all had pretreatment diastolic blood pressures (DBP) of 95-115 mmHg with varying degrees of renal impairment. Regression analysis of pharmacokinetic parameters C(max)ss (the maximum steady-state drug concentration in plasma during a dosing interval), Cl/f (total plasma clearance) and k (elimination rate constant) of spirapril on creatinine clearance (Clcr) showed that the pharmacokinetics of spirapril were not significantly influenced by the degree of renal impairment. C(max)ss values of spiraprilat, however, increased with decreasing Clcr, and AUC(l)ss (area under the concentration-time curve during a dosing interval) values also increased. Regression analysis of the pharmacokinetic parameters C(max)ss, Clm/fm (total plasma clearance) and lambda 1 (rate constant of the first disposition phase) of spiraprilat on Clcr showed that Clm/fm as well as lambda 1 were linearly correlated with Clcr (p < 0.01). However, the results indicate that, even when renal elimination is completely blocked, there is significant elimination of spiraprilat through a non-renal pathway. In conclusion, the risk of drug accumulation after multiple dosing is minimal as the presence of a substantial non-renal spiraprilat elimination was consistently demonstrated.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Enalapril; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Regression Analysis; Single-Blind Method

In a single-blind trial with a 2-week placebo run-in phase and a 4-week active-treatment period, spirapril at 6 mg once daily was administered to 49 consecutive hypertensive patients (34 men and 15 women). All had pretreatment diastolic blood pressures (DBP) of 95-115 mmHg and varying degrees of renal impairment. At the end of the placebo run-in and at the end of active treatment, renal function was assessed using the following procedures: technetium 99m-DTPA clearance [for glomerular filtration rate (GFR)]; radioiodine (131I)-labelled sodium iodohippurate (Hippuran) clearance [for renal plasma flow (RPF)]; creatinine clearance (Clcr). No statistically significant differences were found in GFR or Clcr during spirapril treatment. In renally impaired patients, RPF remained virtually unchanged whereas, in patients with normal Clcr, there was an increase of around 10% during active treatment. At the end of the study, 48% of the patients with renal failure achieved normalization of DBP (< or = 90 mmHg) and/or a DBP reduction of > or = 10 mmHg; the corresponding rate for patients with normal renal function was 31%. In conclusion, in patients with mild-to-moderate essential hypertension and varying degrees of renal impairment, spirapril at 6 mg once daily is an efficacious and well tolerated antihypertensive therapy.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalapril; Female; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Single-Blind Method

Angiotensin-converting enzyme (ACE) inhibitors may cause a further decrease in renal function in patients who already have renal failure. The acute effects of the ACE inhibitor spirapril on renal function were investigated in 10 patients with mild-to-moderate renal failure (serum creatinine of 1.5-2.5 mg/dl). Acute oral administration of spirapril at 6 mg resulted in decreases in inulin clearance (from 53.7 +/- 12.8 to 44.6 +/- 8.8 ml/min; p < 0.02; n = 5) and in PAH clearances (from 215 +/- 141.9 to 184 +/- 37.8 ml/min; p < 0.006; n = 5). However, when the acute administration of 6 mg of spirapril was given concomitantly with isradipine at 5 mg, there were no changes in these renal function parameters.

Topics: Angiotensin-Converting Enzyme Inhibitors; Drug Combinations; Enalapril; Humans; Isradipine; Kidney; Kidney Failure, Chronic; Time Factors

To evaluate the renal protection of enalapril a study was made in 37 patients with chronic renal failure and hypertension. Sixteen patients had diabetic nephropathy with the serum creatinine ranging from 2.0 to 4.0 mg/dl. Twenty-one patients had non-diabetic chronic renal failure with serum creatinine from 2.2 to 6.3 mg/dl. Of 16 patients with diabetic nephropathy, 6 served as control and 10 received enalapril. Nine patients in the non-diabetic chronic renal failure group served as controls, while 12 were given enalapril. The control patients received alpha methyldopa (500 mg/day) for blood pressure control. In the studied patients enalapril was given at the dose of 5-10 mg/day. Over a period of 2 yrs, enalapril attenuated progression of renal failure in patients with diabetic nephropathy at the serum creatinine level from 2 to 2.9 mg/dl (creatinine clearance 21.5-38.4 ml/min) when compared with control patients. At the serum creatinine of 3 to 4 mg/dl progression of renal failure did not differ from control patients. In non-diabetic renal failure progression of renal failure was delayed in patients with serum creatinine level ranging from 2.2 to 5 mg/dl (creatinine clearance 18-42 ml/min); patients with serum creatinine level ranging from 5.5 to 6.3 mg/dl had deterioration of renal function as control patients. Proteinuria was decreased in all patients on enalapril. Thus, for preventing progression of renal failure, enalapril should be given in chronic renal failure with milder degree of renal function impairment; in diabetic nephropathy it should be started earlier at the lower serum creatinine level than in non-diabetic chronic renal failure, yet with comparable creatinine clearance.

Topics: Adult; Diabetic Nephropathies; Enalapril; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged

In order to study the influence of angiotensin converting enzyme (ACE) inhibition on the progression of chronic nephropathy, 70 patients with a median glomerular filtration rate (GFR) of 15 (range, 6 to 54) mL/min/1.73 m2 were randomised in an open study to basic treatment with enalapril or conventional antihypertensive treatment. The patients were followed for at least two years or until they needed dialysis. The therapeutic goal, was a blood pressure of 120 ti 140/80 to 90 mmHg. In the enalapril group, the median decline in GFR was -0.20 (range, +0.18 to -7.11) mL/min/1.73 m2/month, and in the control group, it was -0.31 (+0.01 to -1.97) mL/min/1.73 m2/month (p < 0.05). There was no significant difference in blood pressure between the groups. Thus, the progression of moderate to severe chronic nephropathy was slower on a basic treatment with enalapril as compared to conventional antihypertensive therapy.

Topics: Adolescent; Adult; Aged; Diabetic Nephropathies; Enalapril; Female; Glomerulonephritis; Humans; Kidney Failure, Chronic; Male; Middle Aged; Polycystic Kidney Diseases

The authors investigated whether the reduction of arterial pressure, induced by the oral administration of clonidine (CLO), enalapril (EN), and nifedipine (NIF), has any effect on peritoneal transport rates. The study was performed in nine hypertensive patients undergoing continuous ambulatory peritoneal dialysis (CAPD). The patients were submitted to administration of CLO, EN, and NIF, each in randomized succession for two weeks, after withdrawal of any hypotensive therapy for eight days (washout period). The nine patients underwent a four-hour dwell exchange using a 2.27 g/dL glucose two-liter bag after washout and after each hypotensive period. The following parameters were analyzed: mean arterial pressure (MAP), performed in the sitting position; net ultrafiltration; effluent/initial dialysate glucose ratio (GL D/Do); peritoneal clearance of K, BUN, creatinine (Cr), phosphate, beta-2 microglobulin (beta 2), total proteins, and the ratio between beta 2 and Cr clearance. Moreover, residual renal Cr and beta 2 clearances were analyzed. The three drugs significantly reduced MAP at a similar rate. The peritoneal transport parameters after CLO were similar to the results in the washout period. On the contrary, after EN and NIF therapy, Cr and beta 2 clearances were significantly increased, and GL D/Do decreased in comparison to the washout period. The other peritoneal transport parameters after EN and NIF were similar to the washout period. Residual renal Cr and beta 2 clearances after the three drugs were similar to those in the washout. these data suggest that after two weeks of therapy with EN and NIF, glucose, Cr, and beta 2 peritoneal transports are influenced by these hypotensive drugs irrespective of the effect on the arterial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Biological Transport; Clonidine; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Nifedipine; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum

In order to study the influence of angiotensin converting enzyme (ACE) inhibition on the progression of chronic nephropathy, 70 patients with a median glomerular filtration rate (GFR) of 15 (range, 6 to 54) mL/min/1.73 m2 were randomized in an open study to basic treatment with enalapril or conventional antihypertensive treatment. The patients were followed for at least 2 years or until they needed dialysis. The groups were comparable with respect to age and sex distribution, etiology of renal diseases, initial levels of renal function and arterial blood pressure (BP), and protein intake. The therapeutic goal was a BP of 120 to 140/80 to 90 mm Hg. The GFR, estimated by the plasma clearance of 51Cr-EDTA, was measured every third month, and the individual rate of progression was calculated as the slope of the GFR v time plot. In the enalapril group, the median decline in GFR was -0.20 (range, +0.18 to -7.11) mL/min/1.73 m2/month and in the control group it was -0.31 (+0.01 to -1.97) mL/min/1.73 m2/month (P less than .05). There was no significant difference in blood pressure or plasma lipid levels between the groups. Thus, the progression of moderate to severe chronic nephropathy was slower on a basic treatment with enalapril as compared to conventional antihypertensive therapy.

Topics: Adolescent; Adult; Aged; Albuminuria; Antihypertensive Agents; Bicarbonates; Blood Pressure; Body Weight; Enalapril; Hemoglobins; Humans; Kidney Failure, Chronic; Middle Aged; Potassium; Urea

Angiotensin II has many actions in the kidney, including regulation and distribution of renal circulation and glomerular filtration, as well as effects on mesangial contraction and on the filtration coefficient. The reduction in circulating and intrarenal angiotensin II by angiotensin converting enzyme (ACE) inhibitors in essential hypertension is associated with a significant increase in renal blood flow and a decrease in filtration fraction, without changes in glomerular filtration rate. In addition, administration of ACE inhibitors can reduce proximal sodium reabsorption via changes in peritubular hydrostatic and oncotic forces resulting from the fall in postglomerular capillary resistance. In severe hypertension the state of the renal vasculature does not allow ACE inhibition to induce similar haemodynamic changes and, therefore, it cannot contribute to renal sodium handling that requires the recruitment of alternate mechanisms. In spite of this, ACE inhibitors may exert a protective effect on the renal function of patients with severe hypertension as well as in those with renal impairment, by lowering systemic and, probably, intraglomerular pressure, reducing proteinuria and slowing the progression of renal failure.

Topics: Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cilazapril; Enalapril; Female; Humans; Hypertension; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Pyridazines; Renal Circulation

The long-term effects of converting enzyme inhibitors and calcium channel blockers on proteinuria and the progression of renal disease in patients with hypertension and chronic renal insufficiency are not well established. We have studied the long-term effects of treating hypertension with an angiotensin-converting enzyme inhibitor, enalapril, and a calcium channel blocker, nicardipine, on urinary albumin excretion (UAE) and on renal function in 16 patients with hypertension and chronic renal insufficiency (creatinine clearance ranging between 17 and 62 ml/min). After 1 year of treatment, these agents caused a similar decrease in blood pressure. Only enalapril, however, caused a significant decrease in UAE (from 641 +/- 98 to 292 +/- 47 mg/24 h, p less than 0.01), whereas UAE did not change in the group treated with nicardipine (675 +/- 78 vs. 601 +/- 75 mg/24 h). Creatinine clearance at the beginning of the study was similar in the group treated with enalapril and in the group treated with nicardipine (35 +/- 3.6 vs. 40 +/- 4.1 ml/min). After 1 year of follow-up, creatinine clearance remained unchanged in both groups of patients. These studies demonstrate that both enalapril and nicardipine can effectively reduce blood pressure in patients with hypertension and chronic renal insufficiency. Enalapril but not nicardipine, however, appears to reduce urinary albumin excretion in these patients. Whether the reduction in UAE has any significant impact on the progression of renal disease remains to be established.

Topics: Albuminuria; Enalapril; Female; Follow-Up Studies; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Nicardipine; Time Factors

Protein-induced increases in glomerular filtration rate (GFR), termed renal reserve, is said to be abrogated with the onset of renal disease. However, this notion is inconsistent with the results from animal studies which suggest that alterations in protein intake modulate the glomerular hemodynamics in experimental renal disease. Accordingly, 12 normal subjects and 15 patients with renal disease received a protein meal providing 1 g/kg body weight protein. The subjects were pretreated with either placebo or an angiotensin I converting enzyme inhibitor, enalapril. A significant (P less than 0.05) increase in inulin and para-aminohippurate (PAH) clearance was noted in normal subjects as well as in patients with renal disease. The increase in GFR over basal values in normal subjects (28 +/- 9%), patients with moderate renal failure (20 +/- 13%), and advanced renal failure (21 +/- 14%) was not different. Plasma renin activity was unchanged following protein meal in the placebo studies although it increased following enalapril administration. Enalapril pretreatment did not alter the glomerular vasodilation and hyperfiltration following protein meal. We conclude that protein meal induces glomerular hyperfiltration in renal disease and that this protein-induced hyperfiltration is not mediated by angiotensin II. Because glomerular hyperfiltration is implicated in the progression of renal disease, these data suggest that even in patients who have advanced renal failure, high-protein diets may exert a detrimental effect on the kidney.

Topics: Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Dietary Proteins; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Premedication; Renal Circulation

It has been suggested that angiotensin-converting enzyme (ACE) inhibitors halt the progression of chronic renal failure. During the first months of a controlled trial of this hypothesis a fall in haemoglobin (Hb) was observed in patients treated with the ACE inhibitor enalapril. It was investigated whether this was related to changes in serum erythropoietin (EPO). Data were analysed in 59 consecutive patients during an observation period of 90 days. In enalapril-treated patients (n = 27) Hb fell gradually from a median value of 7.6 to 6.7 mmol/l at 90 days of treatment. In the control group of patients on conventional antihypertensive treatment (n = 32) median Hb was unchanged (7.6 mmol/l) throughout the observation period (p less than 0.001 enalapril vs control). In the enalapril-treated group median EPO concentration fell from 32 to 24 U/l at 90 days of treatment, whereas in conventionally treated patients median EPO was 34 U/l and 35 U/l, respectively (p less than 0.05 enalapril vs control). Neither glomerular filtration rate nor arterial blood pressure differed significantly in the two groups. Furthermore, there were no signs of bone marrow suppression, increased haemolysis or change in plasma volume. In conclusion, a decrease in Hb was found after start of treatment with enalapril in patients with progressive chronic renal failure, possibly caused by a suppression of EPO production.

Topics: Adult; Aged; Blood Pressure; Enalapril; Erythropoietin; Female; Glomerular Filtration Rate; Hemoglobins; Humans; Kidney Failure, Chronic; Male; Middle Aged

The effects of angiotensin converting enzyme (ACE) inhibitors and their combined use with an antiestrogenic steroid on erythropoiesis were investigated in patients on chronic hemodialysis (CHD). Hematocrit was decreased by 10% or more in 6 of 12 patients who received either captopril or enalapril for 2-6 months. Erythropoietin (Epo) and angiotensin II (AII) were significantly reduced in these patients. When treatment with mepitiostane was combined with ACE inhibitor, anemia was significantly improved but without evidence of changes in circulating Epo concentrations or indices of renin-angiotensin activity. The reduction of AII and Epo formation by ACE inhibitors seems to play an important role in the worsening of anemia in patients on CHD; addition of an antiestrogenic steroid should be considered.

Topics: Androstanols; Anemia; Angiotensin-Converting Enzyme Inhibitors; Captopril; Enalapril; Erythropoiesis; Erythropoietin; Estrogen Antagonists; Humans; Kidney Failure, Chronic; Middle Aged; Renal Dialysis; Renin-Angiotensin System

About one third of patients receiving dialysis for end stage renal failure have chronic fluid overload despite advice to restrict their oral fluid intake. To investigate the potential of an angiotensin converting enzyme inhibitor in reducing the urge to drink and consequent gain in weight, a double blind, placebo controlled crossover trial of enalapril was conducted in 25 patients receiving dialysis who had fluid overload. The trial comprised a baseline period of four weeks; two periods of treatment, each of four weeks, during which patients received either placebo or enalapril 5 mg twice each week; and a follow up period of four weeks. Five patients withdrew from the trial, one because of an adverse drug reaction to enalapril. A range of biochemical and behavioural variables was measured during the baseline period, at the completion of periods 1 and 2, and during follow up. These variables included gain in weight between dialysis sessions; blood pressure; plasma concentrations of sodium, angiotensin II, and vasopressin; plasma renin and angiotensin converting enzyme activities; osmolality; and estimations of thirst, intake of fluid, and control of drinking. Enalapril caused a significant reduction in gain in weight between dialysis sessions, thirst, and oral intake of fluid in parallel with significantly increased renin activity, significantly decreased angiotensin converting enzyme activity, and decreased concentrations of angiotensin II. Gain in weight and angiotensin converting enzyme activity returned to baseline values once patients stopped taking enalapril. These results suggest that enalapril may act on the renin-angiotensin system and reduce intake of fluid by inhibiting angiotensin converting enzyme.

Topics: Blood Pressure; Body Weight; Clinical Trials as Topic; Double-Blind Method; Drinking Behavior; Enalapril; Female; Humans; Kidney; Kidney Failure, Chronic; Male; Random Allocation; Renal Dialysis; Thirst

Seven patients with glomerular proteinuria and hypertension (six with biopsy confirmation of glomerulonephritis, one with proteinuria after unilateral nephrectomy) were randomly given, for 14 days each, a calcium antagonist and then a conversion enzyme inhibitor, or vice versa, following a 14-day pause of all medication. Fractional albuminuria rose significantly during administration of calcium antagonists (P less than 0.05), while it decreased significantly during administration of converting enzyme inhibitor (P less than 0.05). The explanation for this finding may be that calcium antagonists raise glomerular capillary pressure by dilating the afferent arterioles, while converting enzyme inhibitors predominantly cause dilatation of the efferent arterioles.

Topics: Adult; Albuminuria; Calcium Channel Blockers; Enalapril; Hemodynamics; Humans; Hypertension, Renal; Kidney Failure, Chronic; Kidney Glomerulus; Male; Middle Aged; Nifedipine

Topics: Adult; Antihypertensive Agents; Blood Pressure; Clinical Trials as Topic; Diuretics; Enalapril; Female; Humans; Kidney; Kidney Failure, Chronic; Loop of Henle; Male; Middle Aged; Posture; Uric Acid

Some angiotensin converting enzyme (ACE) inhibitors are efficiently removed from circulation by hemodialysis ('high dialyzability'), whereas others are not ('low dialyzability'). In patients receiving hemodialysis, this may influence the effectiveness of ACE inhibitors.. Using linked healthcare databases we identified older patients receiving chronic hemodialysis who filled new ACE inhibitor prescriptions. The low dialyzability group (n = 3,369) included fosinopril and ramipril. The high dialyzability group (n = 5,974) included enalapril, lisinopril, and perindopril. The primary outcome was all-cause mortality within 180 days of first ACE inhibitor prescription.. There were 361 deaths among 5,974 patients (6.0%) prescribed with low dialyzability ACE inhibitors and 179 deaths among 3,369 patients (5.3%) prescribed with high dialyzability ACE inhibitors (relative risk 1.1, 95% CI 0.9-1.3, p = 0.6).. In this study of older patients receiving hemodialysis, the dialyzability of ACE inhibitors was not associated with mortality or cardiovascular outcomes.

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Cardiotonic Agents; Cardiovascular Diseases; Enalapril; Female; Fosinopril; Hemorheology; Humans; Kidney Failure, Chronic; Kidneys, Artificial; Lisinopril; Male; Middle Aged; Perindopril; Ramipril; Renal Dialysis; Retrospective Studies; Survival Analysis

Cardiovascular disease is the primary cause of mortality in patients with chronic kidney disease (CKD). Heart remodeling in CKD comprises mainly interstitial fibrosis and capillary loss. Beyond correcting renal anemia, erythropoietin (Epo) has potentially beneficial pleiotropic effects on heart remodeling.. 12-week-old male Sprague-Dawley rats were randomized to 5/6 nephrectomy (NX) or sham operation (sham-op); subsequently, they received murine Epo (2.5 μg/kg/week), enalapril (12 mg/kg/day), Epo + enalapril, Epo + dihydralazine (25 mg/kg/day), or vehicle. Heart function and morphology was assessed after 16 weeks of treatment.. Compared with sham-op (81.2%), left ventricle fractional shortening was reduced in vehicle-treated NX (66.3%) and this was ameliorated by Epo (72.6%) and even prevented by enalapril (80.6%). Capillary length density was lower and the area of fibrosis more marked in vehicle-treated NX compared to sham-op. Capillary rarefaction and heart fibrosis were prevented in NX treated with Epo + enalapril and reduced in NX treated with enalapril and Epo + dihydralazine. Despite higher blood pressure, treatment with Epo reduced heart fibrosis but failed to prevent capillary loss. In parallel, expression of the p47phox NADPH oxidase was higher in untreated NX and was effectively reduced in NX treated with Epo + enalapril. Under basal conditions there was no difference between the groups regarding myocardial hypoxia as reflected by pimonidazole staining.. Epo in combination with enalapril caused additive reduction of cardiac fibrosis and microvessel disease in 5/6 nephrectomized rats presumably by decreasing myocardial oxidative stress.

Topics: Albumins; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Apoptosis; Blood Pressure; Drug Synergism; Echocardiography; Enalapril; Erythropoietin; Fibrosis; Heart; Heart Rate; Hemoglobins; Kidney; Kidney Failure, Chronic; Male; Microcirculation; Myocardium; Nephrectomy; Oxidative Stress; Rats; Rats, Sprague-Dawley; Time Factors

A 12-year-old girl with a history of steroid and cyclosporine (CsA) resistant nephrotic syndrome owing to focal and segmental glomerulosclerosis (FSGS) has progressed to end-stage renal disease (ESRD) for which she underwent hemodialysis for 18 months before she successfully received a fully matched kidney transplant from her sister at the age of nine years. The post transplantation (Tx) period was marked by an early and massive proteinuria indicating recurrent FSGS for which she received 12 sessions of plasmapheresis (PP); unfortunately, she did not appear to have any response to the PP therapy; thereafter, a conservative management comprising essentially enalapril and losartan has been initiated and was also not successful during the first four months, however, a very gradual response has been noticed to occur after five months of conservative therapy and ultimately, the patient attained complete remission after 21 months of treatment. Amazingly, 15 months after discontinuation of enalapril and losartan, she remained in a complete and sustained remission with a good renal allograft function. To the best of our knowledge, this is the first case ever reported in the literature of a "spontaneous" remission of post transplant recurrent FSGS.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Child; Disease Progression; Enalapril; Female; Glomerulosclerosis, Focal Segmental; Humans; Kidney Failure, Chronic; Kidney Transplantation; Losartan; Nephrotic Syndrome; Plasmapheresis; Recurrence; Remission, Spontaneous; Treatment Failure

Renal fibrosis is the final common pathway of chronic kidney disease, and its progression predicts the degree of renal dysfunction. We investigated the renoprotective properties of pirfenidone in a remnant kidney model of chronic renal failure to determine its pharmacological potency compared to enalapril. Five-sixths nephrectomized rats were fed diet containing pirfenidone (approximately 700mg/kg/day) for 8weeks. Pirfenidone steadily inhibited the progression of proteinuria, but not to a significant degree. Pirfenidone prevented the elevation of plasma creatinine and blood urea nitrogen. At the end of the experiment, pirfenidone had reduced systolic blood pressure by means of its renoprotective effect. In a histological study, pirfenidone improved interstitial fibrosis in the renal cortex. These effects were supported by the suppression of the expression of TGF-beta and fibronectin in the mRNA of the kidney. In contrast, pirfenidone had little effect on the expression of alpha-smooth muscle actin, which is one of the proteins responsible for epithelial-mesenchymal transition. This property was confirmed by the TGF-beta-induced transdifferentiation observed in cultured normal rat kidney tubular epithelial NRK52E cells. These results suggest that pirfenidone improves the progression of chronic renal failure via its antifibrotic action, although pirfenidone has less effective TGF-beta-induced epithelial to mesenchymal transdifferentiation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Differentiation; Cell Line; Chronic Disease; Disease Progression; Enalapril; Epithelial Cells; Fibrosis; Kidney; Kidney Failure, Chronic; Male; Mesoderm; Nephrectomy; Proteinuria; Pyridones; Rats; Rats, Wistar; Transforming Growth Factor beta

The prevalence of left ventricular hypertrophy (LVH) is frequent in patients with end-stage renal disease following chronic renal failure (CRF). We investigated the therapeutic efficacy of curcumin, the principal curcuminoid of the Indian curry spice turmeric, in attenuation of LVH and sought to delineate the associated signaling pathways in blunting the hypertrophic response in nephrectomized rats. Adult Sprague-Dawley rats underwent nephrectomy (Nx) by removal of 5/6 of the kidneys. Four groups were studied for 7 wk: 1) control (sham), 2) Nx, 3) Nx + curcumin (150 mg/kg bid), and 4) Nx + enalapril (15 mg/kg bid) as positive control. Subtotal nephrectomy caused renal dysfunction, as evidenced by a gradual increase in proteinuria and elevation in blood urea nitrogen and plasma creatinine. Nx rats showed a significant hypertrophic response and increased diameter of inferior vena cava at inspiration, which was inhibited by treatment with curcumin or enalapril. Moreover, the Nx rats demonstrated changes in the signaling molecules critically involved in the hypertrophic response. These include increased glycogen synthase kinase-3β phosphorylation, β-catenin expression, calcineurin, phosphorylated (p) nuclear factor of activated T cells, pERK, and p-cAMP-dependent kinase. Both curcumin and enalapril variably but effectively deactivated these pathways. Curcumin attenuates cardiac hypertrophy and remodeling in nephrectomized rats through deactivation of multiple hypertrophic signaling pathways. Considering the safety of curcumin, these studies should facilitate future clinical trials in suppressing hypertrophy in patients with CRF.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Blood Urea Nitrogen; Calcineurin; Creatinine; Curcumin; Disease Models, Animal; Enalapril; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Nephrectomy; NFATC Transcription Factors; Rats; Rats, Sprague-Dawley; Ventricular Remodeling

TNF-alpha and NF-kappaB play important roles in the development of inflammation in chronic renal failure (CRF). In hepatic cells, curcumin is shown to antagonize TNF-alpha-elicited NF-kappaB activation. In this study, we hypothesized that if inflammation plays a key role in renal failure then curcumin should be effective in improving CRF. The effectiveness of curcumin was compared with enalapril, a compound known to ameliorate human and experimental CRF. Investigation was conducted in Sprague-Dawley rats where CRF was induced by 5/6 nephrectomy (Nx). The Nx animals were divided into untreated (Nx), curcumin-treated (curcumin), and enalapril-treated (enalapril) groups. Sham-operated animals served as a control. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was significantly reduced by curcumin and enalapril treatment. However, only enalapril significantly improved blood pressure. Compared with the control, the Nx animals had significantly higher plasma and kidney TNF-alpha, which was associated with NF-kappaB activation and macrophage infiltration in the kidney. These changes were effectively antagonized by curcumin and enalapril treatment. The decline in the anti-inflammatory peroxisome proliferator-activated receptor gamma (PPARgamma) seen in Nx animals was also counteracted by curcumin and enalapril. Studies in mesangial cells were carried out to further establish that the anti-inflammatory effect of curcumin in vivo was mediated essentially by antagonizing TNF-alpha. Curcumin dose dependently antagonized the TNF-alpha-mediated decrease in PPARgamma and blocked transactivation of NF-kappaB and repression of PPARgamma, indicating that the anti-inflamatory property of curcumin may be responsible for alleviating CRF in Nx animals.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Blood Urea Nitrogen; Cells, Cultured; Creatinine; Curcumin; Disease Models, Animal; Enalapril; Hypertension, Renal; Kidney Failure, Chronic; Macrophages; Mesangial Cells; Nephrectomy; Nephritis; NF-kappa B; PPAR gamma; Proteinuria; Rats; Rats, Sprague-Dawley; Transfection; Tumor Necrosis Factor-alpha

Lipoprotein glomerulopathy (LPG) is a rare hereditary disease characterized by the accumulation of much thrombi material consisting of lipoproteins at the glomerular capillary lumen. Most patients show nephrotic syndrome; nearly half progress to chronic renal failure. Intensive therapy with lipid-lowering agents reportedly engenders clinical remission with histological resolution. We report the case of a 14-year-old Japanese female patient who had been in a nephrotic condition with hematuria from 4 years old and who had been diagnosed based on pathological and molecular examination at 7 years old. We initially treated the patient with probucol, enalapril (angiotensin-converting enzyme inhibitor: ACEI), and dipyridamole from age 7, but achieved no improvement in her nephrotic status. Subsequently, we replaced probucol with bezafibrate at age 11 and added atorvastatin calcium hydrate and valsartan (angiotensin II receptor blocker: ARB) the following year. The next 3 years' treatment improved her nephrotic status, decreased serum apolipoprotein E, and markedly decreased intraglomerular lipoprotein thrombi. Early and intensive therapy with antilipidemic drugs combined with ACEI and ARB is inferred to be effective for LPG.

Topics: Adolescent; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Apolipoproteins E; Bezafibrate; Child; Child, Preschool; Enalapril; Female; Hematuria; Humans; Hypolipidemic Agents; Kidney Diseases; Kidney Failure, Chronic; Kidney Glomerulus; Nephrotic Syndrome; Probucol; Tetrazoles; Valine; Valsartan

Anaphylactoid reactions from blood contact with AN69 hemodialysis membrane in patients taking ACE inhibitors are well-known. Modified AN69 dialyzers (ST-AN69) were invented to create a membrane combining low thrombogenic properties with safety with ACE inhibitors. We report four patients taking ACE inhibitors that presented anaphylactoid reactions with ST-AN69.

Topics: Aged; Anaphylaxis; Angiotensin-Converting Enzyme Inhibitors; Captopril; Enalapril; Equipment Design; Female; Hemofiltration; Humans; Hypertension; Kidney Failure, Chronic; Male; Membranes, Artificial; Middle Aged; Renal Dialysis

Topics: Angiotensin-Converting Enzyme Inhibitors; Creatinine; Enalapril; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Retrospective Studies; Time Factors; Treatment Outcome

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Electrocardiography; Enalapril; Humans; Hyperkalemia; Hypertension; Kidney Failure, Chronic; Male; Potassium; Renal Dialysis; Sodium Bicarbonate; Sympathomimetics

Topics: Aged; Drug Interactions; Drug Therapy, Combination; Enalapril; Glipizide; Humans; Kidney Failure, Chronic; Male; Pancytopenia

It is suggested that appropriate chronic exercise (EX) may produce improvements of the physical strength in patients with chronic renal failure (CRF). Because acute exercise causes proteinuria and decreases the renal blood flow and glomerular filtration rate, it is necessary to consider the influence of EX on renal function. Therefore, we assessed the renal and peripheral effects of moderate to intense EX as well as the effects of the combination of EX and enalapril (ENA) in a rat model of CRF.. Male 5/6-nephrectomized Wistar-Kyoto rats were divided into six groups according to the following treatment: 1) no exercise (C); 2) ENA (2 mg/kg/day, subcutaneously); 3) moderate exercise with treadmill running (20 m/min for 60 min/day, 5 days/week) (EXm); 4) intense exercise with treadmill running (28 m/min for 60 min/day, 5 days/week) (EXi); 5) EXm+ENA; and 6) sham operation (S). The rats were then treated for 12 weeks.. Both EX and ENA blocked the development of hypertension, blunted increases in proteinuria, reduced serum creatinine and blood urea nitrogen, and improved the index of glomerular sclerosis (IGS) and the relative interstitial volume of the renal cortex (RIV). Moreover, IGS and RIV in the EXm+ENA group were the lowest among all other nephrectomized groups. Furthermore, EXm+ENA enhanced capillarization as well as the proportion of type-I fiber in the soleus muscle.. These results suggest that EX and ENA have renoprotective effects. The findings also suggest that EXm+ENA provided greater renoprotective effects than those of ENA alone, and that EXm+ENA had some additional peripheral effects without any complications in this rat model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Enalapril; Glomerular Filtration Rate; Hypertension; Kidney; Kidney Cortex; Kidney Failure, Chronic; Male; Muscle, Skeletal; Nephrectomy; Physical Conditioning, Animal; Proteinuria; Rats; Rats, Inbred WKY

Pax2 is a transcription factor with important functions during kidney development . Ectopic expression of Pax2 in podocytes has been reported in various glomerular diseases , but the functional relevance remains unknown. We developed an inducible mouse model that allows activation of Pax2 specifically in podocytes. Persistent expression of Pax2 did not interfere with the initial differentiation of podocytes, but mice ectopically expressing PAX2 developed end-stage renal failure soon after birth. Similarly, activation of PAX2 in healthy adult animals resulted in renal disease within 3 weeks after podocyte-specific induction of a deleter Cre. PAX2 activation caused repression of the podocyte key regulator molecule Wt1 and consequently a dramatic reduction of nephrin expression. Recruitment of the groucho-related protein TLE4 may be involved in converting Pax2 into a transcriptional repressor of Wt1. Finally, treatment of mice with an angiotensin-converting enzyme (ACE) inhibitor normalized renal function and induced upregulation of the important structural molecule nephrin via a Wt1-independent pathway. Our data demonstrate the functional significance of PAX2 reexpression in mature podocytes for the development of glomerular diseases and suggest that reactivation of PAX genes in terminally differentiated cells leads to a more dedifferentiated phenotype.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Gene Expression Regulation; Kidney Failure, Chronic; Male; Membrane Proteins; Mice; PAX2 Transcription Factor; Podocytes; Proteinuria; WT1 Proteins

Proteinuria in children with sickle cell anemia (SCA) is an early sign of sickle nephropathy, and portends the development of nephrotic syndrome and chronic renal failure. Enalapril has been shown to reduce proteinuria in adult patients with SCA, but the potential benefits of hydroxyurea in this clinical setting have not been reported. A single institution retrospective analysis was performed. Children with sickle nephropathy were identified, and the laboratory effects of enalapril and hydroxyurea therapy were evaluated in children with substantial proteinuria. Three children developed proteinuria at 8 +/- 1 years of age. Pre-treatment laboratory studies included a low serum albumin (2.8 +/- 0.8 g/dl) and a highly elevated urine protein/creatinine ratio (6.9 +/- 3.7, normal <0.2). Enalapril treatment for 3.0 +/- 1.3 years normalized serum albumin (3.9 +/- 0.3 g/dl) without significant changes in serum potassium, serum creatinine, or systolic blood pressure. However, urine protein/creatinine remained elevated in the nephrotic range (1.6 +/- 0.7). The addition of hydroxyurea therapy for 3.5 +/- 1.2 years increased fetal hemoglobin levels (7.0 +/- 3.6% to 21.0 +/- 3.2%) and was associated with a near-normal urine protein/creatinine ratio (0.5 +/- 0.1). Enalapril therapy for children with sickle nephropathy reduces urinary protein excretion and normalizes serum albumin. Hydroxyurea therapy may further normalize the urine protein/creatinine ratio. Combination therapy should be tested prospectively in children with sickle nephropathy.

Topics: Adolescent; Albuminuria; Anemia, Sickle Cell; Antihypertensive Agents; Antisickling Agents; Child; Creatinine; Drug Evaluation; Drug Therapy, Combination; Enalapril; Female; Fetal Hemoglobin; Humans; Hydroxyurea; Kidney Failure, Chronic; Male; Potassium; Retrospective Studies; Serum Albumin

Angiotensin II plays a central role in the progression of chronic renal failure (CRF), and administration of angiotensin-converting enzyme inhibitor (ACEI) in rats delays the progression of CRF. However, ACEI has little effect on CRF progression in rats with established CRF. We therefore examined whether combination therapy with ACEI and oral adsorbent for uremic toxins in the gastrointestinal tract has the desired effect.. Rats subjected to subtotal nephrectomy were given enalapril at 20 mg/kg (n = 10, group E), AST-120 at 5 g (n = 10, group A), enalapril and AST-120 together at the same doses (n = 10, group EA), or no treatment (n = 10, group C) 8 weeks after the operation. The substances were administered in 100 g rat chow. All animals were pair-fed, and all were killed after 8 weeks of pair-feeding.. Body weight did not differ between groups during the study. Blood pressure at week 8 was significantly lower in groups E and EA than in groups C and A (p < 0.05). Urinary protein excretion level and renal plasma flow rate at week 8 were significantly less in groups E and EA than in group C (p < 0.05, p < 0.01). The glomerular filtration rate at week 8 was significantly higher in group EA than in group C (p < 0.05). The glomerular sclerosis index and interstitial fibrosis area at week 8 were significantly less in group EA than in group C (p < 0.01).. ACEI and AST-120 in combination can delay progression of established CRF in rats by inhibiting the appearance of glomerular sclerosis and interstitial fibrosis.

Topics: Adsorption; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Urea Nitrogen; Carbon; Creatinine; Drug Therapy, Combination; Enalapril; Glomerulosclerosis, Focal Segmental; Kidney Failure, Chronic; Male; Nephritis, Interstitial; Oxides; Rats; Rats, Sprague-Dawley; Sorption Detoxification; Uremia

To study safety and efficacy of ACE inhibitor enalapril in chronic transplantation nephropathy (CTN) as well as nephroprotective efficacy of this drug in various clinical variants of CTN.. A retrospective study covered 220 recipients with CRF. The patients were divided into the study group (n = 103) and the control group (n = 117). The study group was given ACE inhibitor enalapril the efficacy of which was assessed by arterial pressure (systolic, diastolic, mean) dynamics, 24 h proteinuria and the rate of CTN progression. This rate was suggested by probability of plasm creatinin doubling (Kaplan-Meier technique).. Enalapril significantly inhibited CTN progression running with minimal or marked proteinuria, had a pronounced hypotensive effect, promoted stabilization of minimal proteinuria (in CTN with minimal proteinuria) or reduction of protein excretion (in a proteinuric variant of CTN).. Use of enalapril in CTN in a daily dose 10 mg maximum is safe and can be used for inhibition of CTN progression.

Topics: Adolescent; Adult; Antihypertensive Agents; Enalapril; Female; Humans; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Retrospective Studies

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Clinical Trials as Topic; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Long-Term Care; Renal Dialysis; Telmisartan; Treatment Outcome

Antihypertensive drugs may have an important effect on glomerular haemodynamics. In chronic nephropathy patients, we compared the effect on glomerular haemodynamics of two second-generation dihydropyridinic agents, nitrendipine and amlodipine, with a first generation dihydropyridinic agent and an ACE-inhibitor, enalapril. In all, 32 patients (pts), divided into four groups, received the different drugs: ENA (enalapril, eight pts), NIF (nifedipine, eight pts), NIT (nitrendipine, eight pts) AML (amlodipine, eight pts). The study assessed the effect on glomerular haemodynamics of a single administration of the test drug in baseline conditions and in glomerular hyperfiltration experimentally induced by amino-acid infusion. The glomerular filtration rate (GFR, measured by inulin clearance), effective renal plasma flow (ERPF, measured by p-aminohippurate clearance), renal vascular resistances (RVR) and filtration fraction (FF) were assessed. Administration of AML and NIT test dose reduced FF, as did ENA, but not NIF, in both baseline (AML: P=0.005; NIT: P=0.02; ENA: P=0.007) and glomerular hyperfiltration conditions (AML: P=0.0003; NIT: P=0.03; ENA: P=0.00006). In baseline conditions, only ENA resulted in a significant drop in the GFR (P=0.008), while NIF, NIT and AML induced a significant increase (P=0.003, 0.03, 0.0001, respectively). However, in hyperfiltration conditions, NIT (0.08) and AML (0.00003) caused a decrease in the GFR, as did ENA (0.0003) but not NIF. In all the experimental conditions, a RVR reduction and an ERPF increase were observed. Single dose of NIT and AML were effective in attenuating the effect of amino-acid infusion on glomerular filtration, similar to ENA; this effect of NIT and AML on the glomerular filtration rate is not observed under basal conditions.

Topics: Adult; Amlodipine; Enalapril; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nitrendipine; Renal Circulation; Vascular Resistance

To estimate the independent effects of kidney disease, anemia, and the treatment effects of angiotensin-converting enzyme (ACE) inhibitors on hospitalization cost in patients with heart failure, we used data from the prevention and treatment trials of the Studies of Left Ventricular Dysfunction trial and retrospectively estimated the relative effects of decreased kidney function, as measured by estimated glomerular filtration rate (GFR) at enrollment, and anemia, as measured by hematocrit levels at enrollment, on hospital utilization and expense. Independent of the effects of age, gender, New York Heart Association (NYHA) class, ejection fraction, and the presence of diabetes mellitus, GFR was significantly related to hospitalization expense (percent change in hospitalization expense -16.8%, 95% confidence interval [CI] -11.9% to -21.5%) for GFR >/=90 ml/min/1.73 m(2) compared with GFR <60 ml/min/1.73 m(2)). Similarly, hematocrit levels were significantly related to hospitalization expense (percent change in hospitalization expense -19.9%, 95% CI -10.2% to -28.6%) for hematocrit >/=36% compared with hematocrit <33%). The beneficial effect of the ACE inhibitor enalapril was significantly related to hospitalization expense independent of the effects of GFR and hematocrit (percent change in hospitalization expense -6.8%, 95% CI -3.6% to -9.9% for treatment vs the placebo group), and the beneficial effect was preserved when independently estimated for subgroups with decreased kidney function. Adjusted mean expense per patient per month (PPPM) in the enalapril group was $708 versus $792 in the placebo group. Comparing survivors, enalapril generated annual cost savings greater than the average wholesale price of the drug at Studies of Left Ventricular Dysfunction mean dosage levels. Adjusted expected hospitalization expense varied from $636 PPPM for patients in the lowest hematocrit-GFR risk class (hematocrit >/=36%, GFR >/=90 ml/min/1.73 m(2)) to $1,127 PPPM for those in the highest risk class (hematocrit <33%, GFR <60 ml/min/1.73 m(2)). For patients who survived with reduced kidney function and anemia, ACE inhibitor therapy with enalapril reduced hospitalization expense more than the additional expense of the drug therapy. Thus, kidney disease and anemia are independent risk factors for hospitalization cost in patients with heart failure, and the beneficial effect of ACE inhibitors on hospitalization expense appears to be preserved within kidney disease and a

Topics: Aged; Anemia; Angiotensin-Converting Enzyme Inhibitors; Chi-Square Distribution; Enalapril; Female; Glomerular Filtration Rate; Hospital Costs; Hospitalization; Humans; Kidney Failure, Chronic; Male; Middle Aged; Randomized Controlled Trials as Topic; Regression Analysis; Retrospective Studies; Risk Factors; Ventricular Dysfunction, Left

Increased physical activity is followed by a stimulation of the sympathetic nervous system and this effect is probably more pronounced in patients with chronic renal failure and hypertension than in healthy controls. The role of sustained exercise in hypertensive patients with chronic renal failure, with and without antihypertensive therapy, is unclear, as is hormonal regulation of the renal hemodynamics. We hypothesized that prolonged low-intensity bicycle exercise would have a greater effect in patients with chronic renal failure than in controls, and that antihypertensive treatment would ameliorate these effects.. Glomerular filtration rate (GFR), effective renal plasma flow (ERPF), mean arterial blood pressure (MAP), norepinephrine (NE) and atrial natriuretic peptide (ANP) were measured in the upright position before and during low-intensity exercise for 2 h in healthy controls (n = 8) and in hypertensive patients with moderately reduced renal function who were not taking antihypertensives (n = 7) or who were receiving treatment with captopril (n = 10), enalapril (n = 6) or verapamil (n = 9).. GFR tended to decrease and ERPF decreased significantly in healthy individuals when exercise duration was prolonged from 1 to 2 h. An earlier decline in GFR and ERPF was seen in the renal failure patients compared with the controls. Filtration fraction (FF) increased during exercise in all groups except the group taking enalapril. MAP increased in the captopril group during exercise but was unchanged in the other groups. Treatment with captopril produced a more pronounced and earlier fall in exercise-induced GFR than in untreated controls, while verapamil treatment completely blunted the decline in GFR, with a concomitant increase in plasma ANP. No significant changes were seen in plasma NE levels, but urinary NE excretion increased in controls and captopril-treated patients during exercise.. The results suggest that prolonged low-intensity exercise has a substantially greater effect on renal hemodynamics in hypertensive renal failure patients than in healthy controls, with negligible changes in plasma NE levels. Verapamil treatment seems to ameliorate the renal effects of exercise on GFR in these patients, and this may in part be mediated via a stimulatory effect on ANP.

Topics: Adult; Antihypertensive Agents; Atrial Natriuretic Factor; Blood Pressure; Captopril; Enalapril; Exercise; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Norepinephrine; Renal Circulation; Renal Plasma Flow, Effective; Verapamil

Potential determinants of chronic renal disease (CRD) progression were studied in male Munich-Wistar rats subjected to 5/6 nephrectomy and treated with candesartan (Csn; n = 30) or enalapril (Ena; n = 27) from 5 wk postsurgery. Despite control of systolic blood pressure (SBP; 24 wk: Csn = 143 +/- 9; Ena = 148 +/- 8 mmHg), urinary protein excretion rates (U(pr)V) increased over 24 wk (Csn = 92 +/- 10; Ena = 99 +/- 8mg/day). Glomerulosclerosis scores (GS) at 24 wk were similar for Csn (42 +/- 7%) vs. Ena (42 +/- 4%), values close to those of untreated controls at 12 wk (43 +/- 4%). At 24 wk, SBP and UprV correlated strongly with GS, together accounting for 72% of the variance in GS. Renal cortex mRNA levels (determined by competitive RT-PCR) for transforming growth factor (TGF)-beta1 and monocyte chemoattractant protein (MCP)-1 were elevated in Csn and Ena at 12 wk and remained higher at 24 wk vs. sham. Strong correlations were evident among TGF-beta1, MCP-1, and interleukin-1beta and renal injury at 24 wk. Cns and Ena are thus equally effective renoprotective agents in this model. During renin-angiotensin system inhibition, renoprotection is dependent on control of both SBP and UprV. Incomplete suppression of renal cytokine gene expression may also contribute to CRD progression.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Chemokine CCL2; Enalapril; Endothelin-1; Interleukin-1; Kidney Cortex; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Renin-Angiotensin System; RNA, Messenger; Tetrazoles; Transforming Growth Factor beta; Transforming Growth Factor beta1

Angiotensin-converting enzyme (ACE) inhibitors exert a renoprotective effect in both diabetic and nondiabetic renal disease with variable efficacy. Proteinuric patients with nondiabetic renal disease, normotension, and restricted protein and sodium intake were treated with ACE inhibitors without diuretics. Fifty-nine patients were treated with either lisinopril (10 mg/d; 36 patients) or enalapril (5 mg/d; 23 patients) over a period of 37.7 +/- 20.7 months. Urinary protein excretion decreased to less than 50% of pretreatment values after 1 to 37 months (6.9 +/- 8.8 months) of therapy in 33 patients (56%); in 29 patients, it reached less than 0.5 g/d of protein. Urinary protein levels remained low in 19 of the 33 patients (57.5%) throughout the entire posttreatment period (30.8 +/- 17.7 months). However, in the remaining 14 patients, escape from the antiproteinuric effect was detected after 19.2 +/- 13.4 months, evidenced by a decrease in the rate of change in creatinine clearance from 0.052 +/- 0.114 mL/min/mon during the low-proteinuria period to -0.697 +/- 1.101 mL/min/mon after the lapse of antiproteinuric effect (P: < 0.001). Although ACE inhibitors reduce the severity of proteinuria in patients with nondiabetic renal disease, our results show that a proportion of patients escape the antiproteinuric effect and subsequently develop an exacerbation of renal dysfunction.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Dietary Proteins; Disease Progression; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Proteinuria; Sodium, Dietary

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Drug Administration Schedule; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Severity of Illness Index

Regardless of the pattern of renal involvement, increased urinary protein excretion rate is the best independent predictor of progression of chronic nephropathies and short-term reduction in proteinuria has been reported to be renoprotective in the long term. Despite such evidence, however, the therapeutic target in renoprotection is almost exclusively on blood pressure control. We report the clinical course of a patient with chronic nephropathy after the institution of a multidrug treatment titrated against urinary protein excretion to achieve renoprotection. The present findings indicate that adjusting renoprotective therapy according to the decline in protein excretion in a multidrug strategy may stabilize or even reverse renal disease progression. This approach should be formally explored in prospective studies.

Topics: Adult; Algorithms; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diuretics; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Kidney Diseases; Kidney Failure, Chronic; Losartan; Lupus Nephritis; Proteinuria; Sodium Chloride Symporter Inhibitors

There is little information on the significance of angiotensin-converting enzyme (ACE) genotypes and medical treatments in children with primary focal segmental glomerulosclerosis (FSGS).. A multicenter retrospective study was performed on the role of ACE genotypes and medical treatments in 43 Japanese children with FSGS (20 males and 23 females), including 17 children who progressed to end-stage renal failure during the mean observation period of 6.9 +/- (SD) 5.0 years.. The incidence of the D allele of the ACE gene was higher in the whole group of 43 children with FSGS and in a subgroup of 28 steroid-resistant FSGS children (p < 0.05) than in the 130 children of the healthy control group (0.48, 0.48, and 0.33, respectively). ACE genotypes did not affect renal survival in the whole FSGS group nor in the steroid-resistant subgroup. Among the 28 steroid-resistant children, treatment with ciclosporin was effective in delaying the development of end-stage renal failure (p = 0.044), independently of other treatment regimens.. The present study of Japanese children with FSGS showed that the D allele of the ACE gene is associated with the development of FSGS, but not associated with the progression of FSGS which was greatly ameliorated with ciclosporin, irrespective of ACE genotypes.

Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Benzazepines; Captopril; Child; Disease Progression; Drug Resistance; Enalapril; Female; Glomerulosclerosis, Focal Segmental; Humans; Incidence; Japan; Kidney Failure, Chronic; Male; Peptidyl-Dipeptidase A; Prednisolone; Proteinuria; Regression Analysis; Retrospective Studies; Survival Rate

Cyclosporine (CsA) has been successfully used for treatment of children with focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome (NS) for the last decade. Response rates of 50% to 100% have been reported using twice-daily dosing of 5 to 32 mg/kg/d, achieving trough blood levels of 70 to 500 ng/mL. Treatment has been associated with a high incidence of side effects, including nephrotoxicity, hypertension, gingival hyperplasia, and hirsutism. To determine whether once-daily low-dose CsA could minimize side effects and still induce remission, 21 children with biopsy-proven FSGS and NS, each treated with CsA, 4.6 +/- 0.8 mg/kg/d, with no predetermined target trough blood levels, were studied. Eleven of 21 children (52%) attained complete remission and 5 of 21 children (24%) attained partial remission, for a total response rate of 76%. Mean time to response was 2.8 +/- 0.8 months, and mean duration of therapy was 20.6 +/- 13.7 months. CsA dosage was tapered or stopped in 9 responders; 3 of these patients maintained remission at last follow-up 6 to 13 months later, and 6 patients relapsed at 1.5 to 18.7 months (mean, 8.7 months). Five of these 6 patients responded again when CsA therapy was restarted or the dosage was increased. Twelve of 16 responders were still being administered CsA at last follow-up 11 to 60 months (mean, 24.6 months) later. Five of 21 patients (24%) had no response to CsA during 2 to 27 months of therapy; 4 of these 5 patients developed end-stage renal disease after CsA therapy was stopped. Side effects of CsA therapy were minimal: 1 patient each developed new-onset hypertension or gingival hyperplasia, and no patient had hirsutism or nephrotoxicity. Single daily low-dose CsA appears to be effective for long-term treatment of children with FSGS and NS, with fewer side effects than twice-daily dosing.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Child; Child, Preschool; Cyclosporine; Drug Administration Schedule; Enalapril; Female; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Nephrotic Syndrome; Remission Induction

Patients with chronic renal failure are restricted to mild physical activity and tend to a lack of exercise. However, there have been few reports regarding the influence of chronic exercise on the progression of renal disease. Similarly, there are few animal models concerned with the effect of exercise training on improving renal function. Therefore, we assessed the renal effects of moderate chronic treadmill exercise in a remnant kidney model of spontaneously hypertensive rats (SHR) with chronic renal failure. We also assessed the effects of exercise and antihypertensive therapy on renal function.. Eight-week-old SHR were subjected to 5/6 nephrectomy by removal of the left kidney and excision of two-thirds of the right kidney. The rats were divided into four groups: (i) no exercise (Non-EX); (ii) moderate exercise with treadmill running (20 m/min, 0 grade incline for 60 min) (EX); (iii) EX with an angiotensin converting enzyme (ACE) inhibitor, enalapril (2 mg/kg per day, i.p.); and (iv) EX with an angiotensin receptor antagonist, losartan (5 mg/kg per day, i.p.), for 4 weeks.. Chronic EX significantly attenuated the increase in proteinuria (P < 0.01) and significantly protected against increases in the index of glomerular sclerosis (IGS). Both enalapril and losartan with EX significantly decreased blood pressure (P < 0.001), and further decreased the IGS. In the stepwise multiple regression analysis, only antihypertensive drug remained in the model as a significant predictor of IGS (P < 0.0001). In contrast, exercise, antihypertensive drug and mean systolic blood pressure (weeks 1-4) remained in the model as a significant predictors of mean proteinuria (weeks 1-4) (all P < 0.0001).. These results suggest that exercise does not worsen renal function and has renal-protective effects in this model of rats. Moreover, the antihypertensive therapy has additional renal-protective effects in this model of rats.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Enalapril; Hypertension; Kidney; Kidney Failure, Chronic; Losartan; Male; Motor Activity; Proteinuria; Rats; Rats, Inbred SHR; Time Factors

The important contribution of hypertension to the progression of renal failure is well realized. However, it have been less discussed which drugs are suitable for the different stages of progressive renal failure. The present study examined the effects of timing of antihypertensive therapy using calcium channel blocker and angiotensin converting enzyme inhibitor in 5/6 nephrectomized spontaneously hypertensive rats (SHRs). Forty male 6 week old SHRs were divided into 5 groups (n=8 in each group), and they were placed on a high salt diet after 5/6 nephrectomy. Group 1, high salt diet without any drug. Group 2 received 0.2 mg/kg/day of amlodipine and group 3 received 0.2 mg/kg/day of enalapril mixed in the high salt diet from week 6 respectively. Similarly group 4 received the same doses of amlodipine, and group 5 received the same doses of enalapril from week 10. Each drug protected from increasing blood pressure in 4 groups, and no significant difference was observed between the effects of amlodipine and enalapril. Proteinuria was reduced with both drugs. In histopathological evaluation, glomerulosclerosis was controlled only in group 2, and arterio/olosclerosis was significantly suppressed in all treated groups except group 5. From these results, both amlodipine and enalapril are renal protective in early stage of renal failure with hypertension. However, in advanced stage of renal failure, amlodipine is superior in its renal protective effect.

Topics: Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Enalapril; Hypertension, Renal; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Inbred SHR; Sodium, Dietary

Inhibition of the renin-angiotensin system by both angiotensin II type 1 receptor antagonists (AT1As) and angiotensin I-converting enzyme inhibitors (ACEIs) shows renoprotective effects in rats with chronic renal failure when treatment is started in the early phase of renal injury. In this study, we examined the renal protective effects of candesartan cilexetil (TCV-116), an AT1A, and enalapril, an ACEI, in the progressive phase of renal injury in 5/6 nephrectomized rats.. Candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) were orally administered once a day for 4 weeks (the short-term experiment) or 16 weeks (the long-term experiment) to 5/6 nephrectomized rats beginning 15 weeks after the nephrectomy, that is, after they had already showed marked proteinuria.. In vehicle-treated rats, proteinuria, glomerulosclerosis, and interstitial fibrosis developed. Moreover, enhanced expression of transforming growth factor-beta1 (TGF-beta1) in the injured glomeruli was observed. These adverse changes progressed with time, and in the short-term experiment, both drugs inhibited them. In the long-term experiment, the progressive proteinuria and the elevation of blood pressure were similarly attenuated by both drugs. However, candesartan cilexetil significantly inhibited the progression of glomerulosclerosis, the expression of TGF-beta1, and interstitial fibrosis, whereas enalapril did not.. These results indicate that candesartan cilexetil shows potent and long-term preventive effects against the progression of previously developed renal injury.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Blood Urea Nitrogen; Creatinine; Dinoprostone; Disease Models, Animal; Enalapril; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Tetrazoles; Transforming Growth Factor beta

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Enalapril; Kidney Failure, Chronic; Nephrectomy; Oxidative Stress; Rats

We assessed the renal effects of moderate treadmill exercise in the spontaneously hypertensive rats (SHR) remnant kidney model of chronic renal failure (CRF). The effects of chronic administration of a specific endothelin (ET) subtype A (ETA) receptor antagonist, FR139317 (32 mg/kg/day i.p.) and an angiotensin-converting enzyme inhibitor, enalapril (2 mg/kg/day i.p.), in combination with moderate exercise were also investigated. Eight-week-old SHR were subjected to 5/6 nephrectomy. One week after surgery the rats were divided into five groups: (a) no treadmill running; (b) moderate treadmill running, 20 m/min for 60 min (Ex) per day; (c) Ex plus FR139317; (d) Ex plus enalapril; and (e) m-Ex plus enalapril in combination with FR139317, for 4 weeks. In SHR-CRF, Ex significantly attenuated the increase in urinary protein excretion. Enalapril significantly attenuated the increase in systolic blood pressure and urinary protein excretion. FR139317 at this dose did not show any antihypertensive or renal protective effect in this model. These results suggest that moderate exercise may protect renal function in SHR CRF. They also suggest that FR139317 may not have an additional antihypertensive and renal protective effect in this exercise model.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Azepines; Blood Pressure; Body Weight; Enalapril; Endothelin Receptor Antagonists; Indoles; Kidney Failure, Chronic; Nephrectomy; Physical Exertion; Proteinuria; Rats; Rats, Inbred SHR; Receptor, Endothelin A

We performed a retrospective study on 26 patients with moderate renal failure (mean GFR = 51 +/- 21 ml min-1 1.73 m-2), hypertension and atherosclerosis. Apart from three patients who had completely normal renal Doppler ultrasonography, all patients underwent renal angiography. Three groups of kidneys with different atherosclerotic renal artery involvement were identified: Group 1, 24 kidneys with no renal artery stenosis (RAS); Group 2, 18 kidneys with mild (> 25% and < 50% diameter) RAS; and Group 3, 10 kidneys with moderate (> 50% diameter) RAS. We used a two-day protocol with frusemide plus enalapril 99Tcm-MAG3 scintigraphy. The mean parenchymal transit time (MPTT), time to the maximum activity (time to peak) of the renal curve (Tmax), residual activity and split renal uptake were evaluated. The measured parameters did not differ before and after enalapril in Group 1 or in Group 2. In Group 3, MPTT and residual activity differed significantly (P < 0.025) before and after enalapril. The Tmax before and after enalapril, MPTT before and after enalapril and residual activity after enalapril differed significantly (P < 0.05) between Groups 1 and 3 and between Groups 2 and 3. Threshold values were obtained to maximize diagnostic accuracy. The Tmax, MPTT and residual activity after enalapril gave satisfactory results, and MPTT performed best with a 75% positive predictive value and a 98% negative predictive value for the diagnosis of renal artery stenosis. We conclude that MPTT, measured after enalapril administration, is a useful parameter to detect renal artery stenosis in patients with hypertension, atherosclerosis and moderate renal insufficiency.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Arteriosclerosis; Diuretics; Enalapril; Furosemide; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Radionuclide Imaging; Radiopharmaceuticals; Renal Artery Obstruction; Retrospective Studies; Technetium Tc 99m Mertiatide

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Biphenyl Compounds; Enalapril; Humans; Imidazoles; Kidney Failure, Chronic; Losartan; Male; Renal Artery Obstruction; Tetrazoles

This study compared the effects of angiotensin converting enzyme (ACE) inhibitors captopril versus enalapril on left ventricular (LV) muscle mass and LV systolic and diastolic function in 58 patients with primary glomerulonephritis and moderate chronic renal failure. The design was a 6-8 week titration phase and 6-month maintenance phase. Mean myocardial mass calculated by M-mode echocardiography in the captopril group was 153 +/- 26 g/m2 before, and 130 +/- 14 g/m2 after 6 months of treatment, in enalapril group 147 +/- 22 g/m2 before, and 126 +/- 23 g/m2 after 6 months of treatment (p < 0.05). LV ejection fraction, early and late transmitral flow velocities and early to late LV inflow velocities ratio were not significantly affected by both ACE inhibitors.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Captopril; Chronic Disease; Drug Evaluation; Enalapril; Female; Glomerulonephritis; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Middle Aged; Remission Induction; Time Factors

Surgical ablation of renal mass leads to a reduction in kidney function and commonly to the development of hypertension and chronic renal failure (CRF) in rats. The objective of this study was to determine whether endothelin (ET)-1 is involved in the maintenance of the hypertension that accompanies loss of renal mass. First, we demonstrated the antihypertensive efficacy of PD 155080, a selective, orally active ET(A) receptor antagonist, in a group of rats made hypertensive by continuous intravenous infusion of ET-1 (2.5 pmol x kg(-1) x min[-1]) for 7 days. ET-1 produced a sustained hypertension and PD 155080 (56.4 micromol/kg [25mg/kg] BID PO) normalized blood pressure (BP) during the 5 days of drug administration. In a second experiment, Sprague-Dawley rats underwent a 5/6 reduction in renal mass (RRM); 4 weeks later, PD 155080 administered for 7 days resulted in a sustained reduction in BP. Sham-operated rats also showed a slight hypotensive response to PD 155080 administration. Plasma urea nitrogen, plasma creatinine, urinary protein excretion, and creatinine clearance were not altered by PD 155080 administration in RRM or sham rats. In a third experiment, we investigated the contribution of the renin-angiotensin system to BP control in RRM rats given PD 155080. In these rats, PD 155080 reduced BP during 5 treatment days, and this antihypertensive effect was not altered by coadministration of the angiotensin-converting enzyme inhibitor enalapril in the drinking water (508 micromol/L [250 mg/L]). These results demonstrate that (1) ET-1 plays a role in established RRM hypertension through activation of the ET(A) receptor subtype, (2) lowering blood pressure with PD 155080 in RRM rats does not adversely affect renal function, and 3) the antihypertensive effect of ET(A) receptor antagonism is not opposed by the renin-angiotensin system.

Topics: Animals; Blood Pressure; Dioxoles; Enalapril; Endothelin Receptor Antagonists; Endothelin-1; Hypertension; Hypertension, Renal; Infusions, Intravenous; Kidney Failure, Chronic; Male; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Renin-Angiotensin System

The renal protective properties of candesartan cilexetil (TCV-116), an angiotensin II type 1 receptor antagonist (AT1A), and enalapril, an angiotensin I converting enzyme inhibitor (ACEI), were investigated in 5/6 nephrectomized (NX) rats. Candesartan cilexetil (1 mg/kg/day) and enalapril (10 mg/kg/day) were administered orally to 5/6 NX rats for four weeks (during the early phase of disease development) or 16 weeks (through the late phase). In vehicle-treated rats, proteinuria, glomerulosclerosis, interstitial mononuclear cell (MNC) infiltration and interstitial fibrosis developed. Moreover, immunohistological studies showed enhanced expression of transforming growth factor-beta 1 (TGF-beta 1) in the injured glomeruli. Both drugs inhibited these adverse changes in the early phase. In the late phase, the progressive proteinuria, interstitial MNC infiltration were attenuated by both drugs. However, candesartan cilexetil significantly inhibited the progression of glomerulosclerosis, the expression of TGF-beta 1 and the interstitial fibrosis, while enalapril did not. Candesartan cilexetil and enalapril showed comparable hypotensive effects after the 16-week administration. These results indicate that candesartan cilexetil shows a more potent protective effect than enalapril against the progression of renal injury in the late phase. Thus, an AT1A might be more useful than an ACEI for the treatment of patients with chronic renal failure.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Disease Progression; Enalapril; Fibrosis; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Kidney Failure, Chronic; Male; Nephrectomy; Proteinuria; Rats; Rats, Sprague-Dawley; Tetrazoles; Transforming Growth Factor beta

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Enalapril; Humans; Kidney Failure, Chronic

Topics: Adult; Anemia; Angiotensin-Converting Enzyme Inhibitors; Azathioprine; Drug Therapy, Combination; Enalapril; Erythropoietin; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Nephrotic Syndrome; Recombinant Proteins; Reoperation; Tissue Donors

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Captopril; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Enalapril; Erythropoietin; Female; Follow-Up Studies; Fosinopril; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Male; Recombinant Proteins; Renal Dialysis; Retrospective Studies

It is known that hypertension to aggravate the course of chronic renal insufficiency (CRI). It is too know the beneficial effect of the angiotensin-converting enzyme inhibitors (ACEI) and the low-protein diet. In this study, the effect of a low protein diet on the course of CRI was compared with that of administration of enalapril (ENA), an ACEI.. A new model of genetic hypertension, the Prague Hypertensive Rat (PHR) was used. In rats just after weaning, 5/6 of renal parenchyma were removed surgically (5/6NX). The rats were observed for 8 weeks after 5/6NX. The animals were fed either a normal rat chow containing 23% of protein, or a low-protein diet containing only 6% protein. Control groups drank tap water, experimental groups received water containing ENA at a dose of 5 mg/kg BW. The rats on normal diet drinking water had the highest levels of blood pressure (200 +/- 4.3 mm Hg), proteinuria (56.2 +/- 14.6 mg/24 hours) and heaviest kidney remnants i.e. highest compensatory hypertrophy (2352 +/- 239.4 mg). Both ENA and low-protein diet significantly improved these functions to the same extent. However, a combination of low-protein diet with ENA had no further beneficial effect as against any of these manoeuvres alone.. We assume every manoeuvre (low-protein diet and enalapril) exerts a maximal beneficial effect per se: the mechanism of this effect is highly speculative: inhibition of growth factors seems to be the most logical explanation. ACEIs are known to inhibit the production of angiotensin II, low-protein diet should inhibit transforming growth factor beta.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Combined Modality Therapy; Diet, Protein-Restricted; Enalapril; Hypertension; Kidney Failure, Chronic; Male; Rats; Rats, Inbred SHR

The effects of chronic treatment with the specific AT1 angiotensin receptor antagonist, irbesartan, or the angiotensin converting enzyme inhibitor, enalapril, were assessed in uninephrectomized fawn-hooded hypertensive rats (FHH) and compared with vehicle treatment. Three days after uninephrectomy, irbesartan (240 mg/liter), enalapril (80 mg/liter) or vehicle were administered via the drinking water. Systolic blood pressure (SBP) and protein excretion rates (UprotV) were determined monthly. In rats receiving irbesartan (N = 7) and enalapril (N = 6) SBP (132 +/- 3 mm Hg and 133 +/- 6, respectively) was essentially normalized at 12 weeks when compared with vehicle (169 +/- 6 mm Hg (N = 6); all comparisons were P < 0.05 by ANOVA). Similarly, proteinuria was lower in irbesartan (44 +/- 12 mg/day) and enalapril (19 +/- 2) groups versus vehicle (123 +/- 10 mg/day). Treatment with both drugs was associated with marked reduction in glomerulosclerosis at 12 weeks (both < 5% vs. vehicle, 43 +/- 9%) without effect on glomerular volume. In identically prepared rats, glomerular capillary hydraulic pressure (PGC, estimated from stop-flow pressure, Psf) was lower in FHH receiving irbesartan (58 +/- 1 mm Hg, N = 6) or enalapril (54 +/- 2, N = 6) than in vehicle-treated rats, in whom PGC was greatly elevated (68 +/- 2 mm Hg; N = 7). Despite this, GFR and single nephron GFR were well maintained. These data support a critical role for AT1 receptor-mediated, angiotensin-dependent processes in the pathogenesis of hypertension in FHH, and further implicate elevated PGC as a major determinant of glomerular injury in this model.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Biphenyl Compounds; Blood Pressure; Enalapril; Irbesartan; Kidney Failure, Chronic; Kidney Glomerulus; Nephrectomy; Proteinuria; Rats; Rats, Inbred SHR; Tetrazoles

We have previously shown that idiopathic focal segmental glomerulosclerosis (FSGS) is the most common non-proliferative primary glomerulopathy in adult African Americans. In this report we present our experience with treated FSGS in 15 such patients followed over five years. They were all treated with prednisone 60 mg daily for three months, followed by a slow tapering. In addition, two patients later had cyclophosphamide, and five had enalapril. At entry hypertension was present in 73% of the patients, nephrotic syndrome in 87%, and elevated serum creatinine (> or = 1.4 mg/dl) in 40%. Five of the 15 patients (33%) developed end-stage renal failure (ESRF), one of them having a "malignant" course after the advent of pregnancy. Two patients (13%) have chronic renal insufficiency (CRI; serum creatinine > 2.5 mg/dl); three (20%) have mild renal insufficiency (serum creatinine 1.4-2.5 mg/dl), and five patients (33%) have normal renal function. The cumulative renal survival was 93% at five years, but only 26% at eight years. At last follow-up all the ten patients who did not develop ESRF were in partial remission (urinary protein of 1.3 g/day +/- 1.21), but 4 of the 5 patients who did not develop ESRF had no prolonged partial remission of nephrotic syndrome. Neither the initial clinical parameters not the use of enalapril correlated with the renal outcome (univariate analysis). However, 4 of the 5 patients who developed ESRF had elevated serum creatinine at entry, versus only 2 of the 10 not developing ESRF (p = 0.09 by two-sided, and 0.045 by one-sided Fisher's exact test). We conclude that the short-term renal outcome in nephrotic adult African Americans with treated FSGS is comparable to that of the non-African Americans, but their long-term prognosis may be poorer. Patients developing ESRF were more likely to present with elevated serum creatinine. Enalapril did not seem to modify the course of renal disease, but its utility and that of other ACE inhibitors in the treatment of FSGS must await prospective randomized studies.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Black or African American; Cyclophosphamide; Disease Progression; Enalapril; Female; Follow-Up Studies; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Hypertension, Renal; Immunosuppressive Agents; Kidney Failure, Chronic; Male; Prednisone; Prognosis; Time Factors

By a reciprocal of creatininemia the rate of chronic renal failure progression (CRF) was assessed in 14 patients with nephropathy on enalapril treatment. The day dose ranged from 2.5 to 15 mg. In patients with serum creatinin levels from 0.24 to 0.41 mmol/l (group 1) enalapril significantly inhibited CRF progression, as it did in group 2 (serum creatinin levels from 0.47 to 0.68 mmol/l) but 1 patient. In patients with creatinin levels over 0.71 mmol/l, the influence of enalapril on CRF progression rate was insignificant. All the patients exhibited stabilization of arterial hypertension. Proteinuria diminished in groups 1 and 2, while creatinin clearance decreased in groups 1 and 3. It is inferred that enalapril control of renal function in nephropathy patients is efficient only in early CRF.

Topics: Adult; Chronic Disease; Creatinine; Diabetic Nephropathies; Disease Progression; Enalapril; Female; Glomerulonephritis; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Pyelonephritis; Statistics, Nonparametric

The pathogenesis of cardiac hypertrophy in chronic uremia is poorly understood. In the present study, the long-term effects of chronic uremia on cardiac morphology and various cysteine proteinases of the heart were investigated in rats with and without antihypertensive therapy by the angiotensin converting enzyme inhibitor enalapril or by the calcium channel blocker verapamil. 16 weeks after subtotal nephrectomy considerable uremia had developed associated with arterial hypertension, rise in heart weight and heart weight/body weight ratio. Morphologically myocardial cells developed marked hypertrophy. Determination of various cysteine proteinases by fluorometry revealed a significant decline of cathepsin B activity while the activities of cathepsin H and L were unchanged. Antihypertensive treatment with enalapril and verapamil normalized the blood pressure and improved renal function significantly. Myocardial cell hypertrophy and the enhanced heart weight/body weight ratio were normalized under treatment with enalapril but not with verapamil. Simultaneously, the impaired cathepsin B activity returned to the normal range after enalapril treatment. It is concluded that the cardiac hypertrophy in uremia is at least partly caused by an activation of the circulating and/or cardiac renin-angiotensin system. Impaired proteinase activity in the uremic state may be involved in the development of cardiac hypertrophy.

Topics: Animals; Cathepsin B; Cathepsin H; Cathepsin L; Cathepsins; Cysteine Endopeptidases; Enalapril; Endopeptidases; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Male; Myocardium; Rats; Rats, Wistar; Renin-Angiotensin System; Verapamil

Topics: Adrenergic beta-Antagonists; Blood Pressure; Enalapril; Humans; Kidney Failure, Chronic

Topics: Ascites; Enalapril; Female; Humans; Kidney Failure, Chronic; Middle Aged; Renal Dialysis

A 66-year-old hypertensive diabetic patient with latent hypoaldosteronism and mild renal failure was treated by adding enalapril, an angiotensin converting enzyme inhibitor, to the furosemide and nifedipine regimen because of an insufficient antihypertensive response for 1 month. Seven days after enalapril addition, the blood pressure was significantly reduced, but frank hyperkalemia occurred with a marked rise in BUN and a slight increase in serum creatinine. Plasma renin activity (PRA) and plasma aldosterone (PA) values remained low before and during enalapril therapy. Transient treatment with sodium polystyrene sulfate after enalapril withdrawal improved the hyperkalemia and renal function, but PRA and PA levels were low. PA and its precursor steroids also responded poorly to graded angiotensin II infusion and rapid ACTH injection. Latent hypoaldosteronism probably predisposed this patient to frank hyperkalemia with progressive dehydration and slightly reduced renal function during antihypertensive therapy.

Topics: Aged; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Therapy, Combination; Enalapril; Furosemide; Humans; Hyperaldosteronism; Hyperkalemia; Hypertension; Kidney Failure, Chronic; Male; Nifedipine

Angiotensin-converting enzyme inhibitors (ACEIs) have been suggested to reduce interdialytic fluid weight gain, presumably via suppression of the dipsogenic angiotensin II. We retrospectively studied 25 (76% black) chronic hemodialysis patients who received ACEIs for blood pressure control. The mean arterial blood pressure decreased from 115.4 +/- 10.4 mm Hg to 112.7 +/- 9.0 mm Hg (mean +/- SD; P = NS) and there was no change in the interdialytic weight gain (3.74 +/- 1.5 kg v 3.72 +/- 1.5 kg; P = NS). Only 10 (40%) patients had some reduction in their interdialytic weight gain; in four of them the reduction was more than 20% of the pre-ACEI weight gain. When nine patients who had no decline in blood pressure were excluded due to possible noncompliance, the mean arterial blood pressure in the remaining 16 patients (75% black) declined from 119.3 +/- 9.9 mm Hg to 111.6 +/- 9.9 mm Hg (P < 0.0001), but there was no change in the interdialytic fluid weight gain (3.7 +/- 1.4 kg v 3.8 +/- 1.4 kg; P = NS). There was no correlation between age, race, etiology of renal failure, or blood pressure response and change in the interdialytic weight gain after ACEI treatment. Our results do not support the previous report that ACEIs significantly decrease the interdialytic weight gain in chronic hemodialysis patients. The multifactorial nature of excessive fluid intake in the hemodialysis patients and the differences in patient population and study design may account for this discrepancy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Black People; Captopril; Enalapril; Fosinopril; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Renal Dialysis; Retrospective Studies; Weight Gain

The beneficial effect of a low-protein diet on the course of renal failure after ablation nephropathy in the rat is known; also calcium channel antagonists (CaA) and angiotensin I converting enzyme inhibitors (ACEI) have a protective effect. Because even simple energy restriction retards the development of spontaneous or ablation-induced glomerulosclerosis the authors decided to replace the lacking dietary protein in the low protein diet by starch (disaccharide) and by fat (cereal oil) and compare these two low-protein diets as to their effect on the development of chronic renal failure (CRI) caused by surgical removal of 5/6 of renal parenchyma (5/6 NX).. In Wistar rats just after weaning, 5/6 of renal parenchyma were removed surgically. Thereafter, the rats were fed either a "high-protein" (21%) or two types of a "low-protein" (6%) diet, in one of the latter, the lack of protein was substituted by saccharide, in the other by fat making the substitution "isocaloric" in either case. In all three diet groups, subgroups drinking either tap water or water containing either the ACE-inhibitor enalapril (ena) or the calcium antagonist diltiazem (dil) or both (ena+dil) were formed. On the high-protein diet, an increase in the weight of kidney remnants, in proteinuria and in systolic blood pressure (SBP) was seen. This was prevented by feeding either type of the low-protein diet but also by ena and ena+dil. Ena and ena+dil not only prevented the increase in SBP but actually lowered it significantly. Dil alone also had a SBP-lowering action but offered no protection from kidney hypertrophy and it significantly. Dil alone also had a SBP-lowering action but offered no protection from kidney hypertrophy and proteinuria. No additive protective action of ena+dil or ena+low-protein or ena+dil+low-protein was seen suggesting that the lower limit of these protective actions was reached by the low-protein diet alone. There was no substantial difference between either type of low-protein diet except a small and transient decrease in body weight in the first week on a fat-rich diet.. In the described experiments and with the set-up used the low-protein diet had no effect on the plasma creatinine and urea levels nor on creatinine clearance. The weight of the kidney remnants and proteinuria were significantly higher in animals on a high-protein diet who drank water or water with diltiazem. These changes were suppressed by administration of angiotensin converting enzyme inhibitors either alone or combined with diltiazem. A low- protein diet (both types tested) as well as angiotensin converting enzyme inhibitors improve the course of chronic renal failure in ablation nephropathy in the rat; the authors did not prove an additive effect of the combination of this diet with angiotensin converting enzyme inhibitors.

Topics: Animals; Dietary Proteins; Diltiazem; Enalapril; Kidney Failure, Chronic; Male; Nephrectomy; Rats; Rats, Wistar

Angiotensin converting enzyme inhibitors do not have any teratogenic effect in man but their use during pregnancy has led to cases of hypotension and subsequent severe renal failure in the newborn. The authors report two cases, one involving a twin pregnancy which illustrate the variability of the foetal involvement. It is emphasized that the side effects of angiotensin converting enzyme inhibitors are not only reversible but also are not constantly found.

Topics: Adult; Diseases in Twins; Enalapril; Female; Humans; Hypertension; Infant; Infant, Newborn; Kidney; Kidney Failure, Chronic; Male; Maternal-Fetal Exchange; Pregnancy; Respiratory Distress Syndrome, Newborn; Twins

Angiotensin I converting enzyme inhibition (ACEi) has been shown to lower urinary protein excretion in human renal disease. The mechanism of this antiproteinuric effect is hypothesized to be mediated by changes in renal hemodynamics. However, clinical studies suggest that the effect on renal hemodynamics is fully established immediately after the start of treatment, whereas others show the antiproteinuric effect to reach maximum only after several weeks. To clarify this issue we studied the course of renal hemodynamics, blood pressure and proteinuria during 28 days of ACEi (enalapril 10 mg oid) in nine patients with proteinuria due to non-diabetic renal disease. The effect of ACEi on blood pressure and renal hemodynamics was already maximal within few hours after start of treatment, and remained stable thereafter: MAP was lowered with 8.6 +/- 1.9%, 10.6 +/- 2.1%, 12.8 +/- 2.3% and 12.9 +/- 2.5%, while FF fell 23.0 +/- 2.0%, 17.0 +/- 2.6%, 16.8 +/- 2.8% and 15.9 +/- 4.0% on days 1, 7, 14 and 28 of ACEi, respectively. However, the antiproteinuric effect only gradually reached its maximum on day 28. Urinary protein excretion decreased with 10.9 +/- 6.1%, 32.7 +/- 6.2%, 46.3 +/- 2.5% and 54.0 +/- 2.5% on days 1, 7, 14 and 28 of ACEi, respectively. After drug withdrawal all parameters returned towards baseline. We conclude that a dissociation occurs in the course of the ACEi induced effects on hemodynamics and urinary protein excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Pressure; Enalapril; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria; Renal Circulation; Time Factors

Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Enalapril; Hypertension; Kidney; Kidney Failure, Chronic; Male; Nephrectomy; Rats; Rats, Inbred SHR

This study was undertaken to determine the role of angiotensin II (AII) in the development of glomerulosclerosis, using an AII receptor antagonist in an animal model of hyperlipidemia. Hyperlipidemic Imai rats were employed because they spontaneously develop glomerulosclerosis; this is especially true in males. Group 1 (n = 5) received no specific therapy. Group 2 (n = 5) was treated with enalapril at a dosage of 50 mg/l in drinking water starting at 6 weeks of age. Group 3 (n = 5) and group 4 (n = 6) were treated with the AII receptor antagonist DuP 753 at a respective dosage of 15 mg/l (low-dose DuP) and 150 mg/l (high-dose DuP) in drinking water. Body weight, blood pressure, urinary protein, serum albumin, cholesterol, BUN and serum creatinine were measured and compared among the groups from 12 to 24 weeks of age. Enalapril and high-dose DuP were almost equally effective in controlling systemic hypertension. Each treatment significantly reduced proteinuria (172 +/- 112 and 152 +/- 72 mg/kg/day at 24 weeks) as compared with that in the controls (421 +/- 147 mg/kg/day; p < 0.05 and p < 0.01, respectively). Hypercholesterolemia also decreased (82 +/- 4 and 89 +/- 6 mg/dl) as compared with that of the controls (141 +/- 48 mg/dl; both p < 0.05). Glomerulosclerosis index (SI) was significantly higher in the untreated control rats (55 +/- 26) than in the enalapril-treated rats (2 +/- 3; p < 0.005) and the high-dose-DuP-treated rats (6 +/- 6, p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin Receptor Antagonists; Animals; Biphenyl Compounds; Blood Pressure; Blood Urea Nitrogen; Cholesterol; Disease Models, Animal; Enalapril; Glomerulonephritis; Hyperlipidemias; Imidazoles; Kidney; Kidney Failure, Chronic; Losartan; Male; Organ Size; Proteinuria; Rats; Renin-Angiotensin System; Serum Albumin; Tetrazoles

Hyperlipidemic Imai rats spontaneously develop hypercholesterolemia, proteinuria and glomerulosclerosis. The aim of the present study was to clarify whether two different antihypertensive regimens (enalapril and a combination of reserpine, hydralazine and hydrochlorothiazide) would offer similar degrees of protection against glomerular injury in male hyperlipidemic Imai rats. Group 1 (n = 4) received no specific therapy. Group 2 (n = 4) was treated with enalapril at a dose of 50 mg/l in drinking water starting at 6 weeks of age. Group 3 (n = 5) was treated with the triple drug regimen (reserpine 5 mg/l, hydralazine 80 mg/l and hydrochlorothiazide 25 mg/l in drinking water). Body weight, blood pressure, urinary protein, serum albumin, cholesterol, BUN and serum creatinine were checked and compared among groups. Although enalapril and triple drug therapy were almost equally effective in controlling systemic hypertension, there were striking differences between the two treated groups in proteinuria, hypercholesterolemia and glomerular injury. Enalapril treatment significantly reduced proteinuria (731 +/- 23 vs. 256 +/- 144 mg/kg/day at 36 week; p < 0.005) and hypercholesterolemia (264 +/- 17 vs. 104 +/- 17 mg/dl at 38 weeks; p < 0.001). Triple drug therapy failed to prevent the development of proteinuria (909 +/- 75 mg/kg/day at 38 weeks) and hypercholesterolemia (330 +/- 61 mg/dl at 38 weeks). The glomerulosclerosis index was significantly higher in untreated control rats (229 +/- 65) and in triple drug-treated rats (218 +/- 59) than in the enalapril-treated group (24 +/- 12; p < 0.05, and p < 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Antihypertensive Agents; Cholesterol; Drug Therapy, Combination; Enalapril; Hydralazine; Hydrochlorothiazide; Hyperlipidemias; Hypertension; Kidney; Kidney Failure, Chronic; Kidney Glomerulus; Male; Proteinuria; Rats; Reserpine; Time Factors

Both glomerular hypertension and hypertrophy have been associated with the development of glomerular injury in models of hypertension and reduced renal mass. The purpose of this study was to examine the effects of antihypertensive therapy on these parameters in the remnant kidney model of progressive glomerular sclerosis. Rats underwent 5/6 nephrectomy and were randomly assigned to receive either no therapy, the calcium entry blocker (CEB), nifedipine, or the angiotensin converting enzyme inhibitor (CEI), enalapril. Administration of either drug was associated with a reduction in systemic blood pressure and in the severity of glomerular injury assessed eight weeks after renal ablation. Micropuncture studies four weeks after ablation revealed that systemic and glomerular capillary pressure were high in untreated remnant kidney rats and reduced by enalapril. Administration of nifedipine was associated with a decline in systemic pressure, however, plasma renin levels increased, causing efferent arteriolar vasoconstriction and persistence of glomerular hypertension. Morphometric analysis showed that kidney weight, glomerular volume and glomerular capillary radius were lower in nifedipine treated rats than in the other two groups, indicating that the CEB, but not enalapril, inhibited the hypertrophic response to ablation of renal mass. Therefore, both CEIs and CEBs reduce glomerular injury in rats with remnant kidneys but they may act by different mechanisms. CEI reduce glomerular capillary pressure while CEBs inhibit compensatory kidney growth.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channel Blockers; Enalapril; Glomerulosclerosis, Focal Segmental; Hypertension, Renal; Hypertrophy; Kidney; Kidney Failure, Chronic; Male; Nifedipine; Proteinuria; Rats; Rats, Wistar

The hypothesis that converting enzyme inhibition and a protein-restricted diet could have additive antiproteinuric effects has been tested. A group of 17 patients with proteinuria in excess of 3 g/24 h per 1.73 m2 of body surface area were submitted to a 3-wk period of study, after a 4-wk wash-out period during which protein intake was 1.0 g/kg per day and in the absence of any medication. During the first and second weeks of the study, protein intake was lowered to 0.3 g/kg per day, and in the third week, it returned to 1.0 g/kg per day. Enalapril (20 mg daily) was administered during the second and third weeks of the study. Initially and at the end of each week thereafter, we determined blood pressure, GFR (inulin clearance), RPF (para-aminohippurate clearance), plasma sodium and potassium, PRA and aldosterone, and the 24-h urine excretion of sodium potassium, protein, and urea. The low protein intake during the first week induced a significant fall of proteinuria (P < 0.01), GFR (P < 0.01), and RPF (P < 0.01) in the absence of changes in filtration fraction. The addition of enalapril induced a further decrease of proteinuria (P < 0.01) and a fall in filtration fraction (P < 0.05), whereas plasma potassium, PRA, GFR, and RPF values increased (P < 0.01). The rise in protein intake during the last week of the study induced a significant rise in proteinuria, GFR, and RPF (P < 0.01), although the first of these parameters attained values significantly lower (P < 0.05) than those observed initially.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Combined Modality Therapy; Dietary Proteins; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Middle Aged; Proteinuria; Renal Circulation

Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Creatinine; Enalapril; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Middle Aged

The phosphinyl ester prodrug fosinopril, a new angiotensin converting enzyme (ACE) inhibitor, is fully hydrolysed after oral administration to the pharmacologically active diacid, fosinoprilat. This metabolite is cleared by both hepatic and renal routes, while most other ACE inhibitors are cleared exclusively by the kidney. In the present study, after administration of multiple fixed oral doses the accumulation of the active moieties of fosinopril, enalapril and lisinopril was compared in patients with renal insufficiency. 29 patients with creatinine clearances (CLCR) less than 30 ml/min received either fosinopril 10mg (n = 9), enalapril 2.5mg (n = 10) or lisinopril 5mg (n = 10) once daily for 10 days in a nonblind (open-label) parallel study. Pharmacokinetic parameters including area under the serum concentration-time curve (AUC), peak serum concentration (Cmax) and time to peak concentration (tmax), as well as renal function, blood pressure, and plasma renin activity (PRA) and aldosterone levels, were determined on the first and last days of the study. The percentage (+/- SEM) increases in AUC from day 1 to day 10 for fosinoprilat, enalaprilat and lisinopril were 26.8 +/- 9.9 (nonsignificant), 76.6 +/- 16.6 (p less than 0.001) and 161.7 +/- 31.8% (p less than 0.001), respectively. These results indicate that there was significantly less accumulation of fosinoprilat, based on accumulation indices, relative to either enalaprilat (p less than 0.05) or lisinopril (p less than 0.001) during the study. The Cmax of fosinopril increased significantly less than that of lisinopril (21.1 vs 123.6%; p less than 0.01). Renal function was not altered in any group, and blood pressure changed modestly.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Fosinopril; Humans; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Proline

Topics: Aldosterone; Anemia; Blood Pressure; Enalapril; Erythropoietin; Hematocrit; Humans; Hypertension; Kidney Failure, Chronic; Kidney Neoplasms; Male; Middle Aged; Polycystic Kidney Diseases; Renal Dialysis; Renin-Angiotensin System

Topics: Adult; Captopril; Chronic Disease; Enalapril; Female; Humans; Kidney Failure, Chronic; Male; Nigeria; Proteinuria

Forty-eight hypertensive patients affected by various levels of renal failure entered this open, non controlled study, lasting 12 weeks. Patients were divided into two groups according to baseline creatinine clearance: Group I (29 patients): creatinine clearance greater than or equal to 25 ml/min but less than 45 ml/min; Group II (19 patients): creatinine clearance greater than or equal to 10 ml/min but less than 25 ml/min. Patients in Group I started with enalapril 5 mg q.d. and patients in Group II with enalapril 2.5 mg q.d. Enalapril could be titrated up to 20 mg/day. At the end of the study in both groups of patients blood pressure normalization was reached in a high percentage of patients without any significant change in renal function parameters. Plasma potassium showed a significant increase during the study but no patient discontinued treatment due to hyperkaliemia. In conclusion this study shows antihypertensive therapy with enalapril during chronic renal insufficiency to be effective at low dosage (5-10 mg) in lowering blood pressure and to have a good safety profile.

Topics: Adult; Aged; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged

Glomerular filtration rate (GFR) and renal uptake of dimercaptosuccinic acid (DMSA) were measured in 31 patients with progressive chronic nephropathy before and immediately after the start of treatment with angiotensin converting enzyme (ACE) inhibitor in order to control adverse effects on kidney function. Scintigrams of the kidneys showed an unaltered distribution of DMSA during treatment. GFR estimated by 51Cr-EDTA plasma clearance fell by 14% (P less than 0.01), but renal uptake of 99mTc-DMSA increased by 10% (P less than 0.01). It is concluded that DMSA in chronic renal failure is mainly taken up by the tubular cells from the peritubular capillaries since the uptake was unaffected by the acute decrease in GFR.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Organotechnetium Compounds; Radionuclide Imaging; Succimer; Sulfhydryl Compounds; Technetium Tc 99m Dimercaptosuccinic Acid

1. In order to examine the potential role of atrial natriuretic factor in modulating the increased sodium excretion per nephron in chronic renal failure, we studied 12 uraemic patients on the last day of two successive 7 day periods during which their sodium intake was 100 and 20 mmol of sodium/day, respectively. 2. There was a parallel decrease from 6.31 +/- 0.75 to 2.17 +/- 0.32% in the fractional excretion of filtered sodium and from 234.4 +/- 74.9 to 80.6 +/- 20.3 pg/ml (supine position) or 140.1 +/- 43.6 to 60.7 +/- 14.6 pg/ml (upright position) in plasma atrial natriuretic factor. Both parameters were significantly correlated during the two periods of different sodium intake (P less than 0.05). The ratio of plasma guanosine 3':5'-cyclic monophosphate to plasma creatinine changed proportionally to plasma atrial natriuretic factor. Plasma aldosterone and plasma renin activity increased during the sodium-depleted period but only plasma renin activity was significantly correlated with fractional excretion of filtered sodium. 3. The predominant role of atrial natriuretic factor compared with that of aldosterone in the renal response to varying sodium intake is suggested both by regression analysis and by the effect of 5 day's treatment with a converting enzyme inhibitor (enalapril) in six other uraemic patients on a normal (100 mmol/day) sodium intake. Such treatment, although resulting in a significant increase in plasma renin activity and a significant decrease in plasma aldosterone, at least in the supine position, did not modify the fractional excretion of sodium and plasma atrial natriuretic factor.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aldosterone; Atrial Natriuretic Factor; Creatine; Cyclic GMP; Enalapril; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Renin; Sodium; Sodium, Dietary

Topics: Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Middle Aged; Scleroderma, Systemic

14 patients (8 male, 6 female), aged 35 to 64 years, with glomerulopathies consisting of membranoproliferative glomerulonephritis (GN) [n = 6], membranous GN (n = 3), focal and diffuse glomerulosclerosis (n = 4), and post-streptococcal GN (n = 1) were studied. Diagnosis was established by renal biopsy in 12 of the 14 patients. All 14 patients had impaired renal function (creatinine clearance = 25 to 55 ml/min) and proteinuria (1.0 to 10.4 g/day). Five normotensive patients received enalapril 20 mg/day, whereas 9 patients with hypertension received 20 to 40 mg/day to control blood pressure. Diuretics were administered concomitantly to 8 patients. Patients attended the clinic every 14 days for 30 months and their diets were closely monitored, with sodium intake limited to between 50 and 100 mEq/day and protein to between 1.0 and 1.2 g/kg/day. Blood pressure was significantly controlled in the patients with hypertension. Serum creatinine, blood urea nitrogen, creatinine clearance and 24-hour urinary protein excretion all significantly improved during the 30-month study. No adverse clinical events were noted. Thus, over a period of time, enalapril therapy may improve the prognosis of patients with glomerulonephritis by maintaining glomerular filtration rates and decreasing proteinuria and blood pressure.

Topics: Adult; Enalapril; Female; Glomerulonephritis; Humans; Hypertension, Renal; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Proteinuria

Ten patients (6 men, 4 women, age range 35-64 years) with glomerulopathies were studied. Diagnoses were membranoproliferative glomerulonephritis (GN; n = 4), membranous GN (n = 3), focal and diffuse glomerulosclerosis (n = 2), and poststreptococcal GN (n = 1). These were confirmed by renal biopsy in 8 of the 10 patients. All patients had reduced function (creatinine clearance 15-55 ml/min); proteinuria ranged from 1.0 to 10.4 g/day. Three normotensive patients received enalapril 10 mg once daily. Seven hypertensives received enalapril 10-40 mg once daily to control blood pressure (BP). Concomitant diuretic therapy (furosemide/bumetanide) was administered to 6 patients. There were visits every 14 days for a mean of 15.9 months (range 9-26 months). Diet was monitored, and BP was significantly controlled in the hypertensive patients but not altered in the normotensives. Serum creatinine, blood urea nitrogen, creatinine clearance, and 24-hour urinary protein improved and did not deteriorate progressively. Serum potassium did not change significantly. No adverse clinical events were noted. Enalapril therapy may improve the prognosis for GN over time by maintaining glomerular filtration rate and decreasing proteinuria.

Topics: Adult; Chronic Disease; Creatinine; Enalapril; Female; Glomerulonephritis; Glomerulonephritis, Membranoproliferative; Glomerulonephritis, Membranous; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Male; Middle Aged; Prospective Studies; Proteinuria; Time Factors

1. We have investigated the effects of the non-renin-mediated actions of angiotensin converting enzyme inhibitors on the progression of chronic renal failure accelerated by hypertension. For this purpose, we studied the effects of captopril (a thiol-containing angiotensin converting enzyme inhibitor), enalapril (an angiotensin converting enzyme inhibitor without a thiol group) and cysteine (a thiol-containing amino acid which has no angiotensin converting enzyme-inhibitory action) in adriamycin-treated rats with deoxycorticosterone acetate-salt hypertension, in which the renin-angiotensin system was suppressed. 2. There were no significant differences in blood pressure between these groups and the control group [adriamycin-treated group with deoxycorticosterone acetate-salt loading, 206 +/- 7 mmHg (27.4 +/- 0.9 kPa) at week 10]. 3. Massive proteinuria occurred in all groups. At the end of the experiment (at week 10), urinary protein excretion was significantly reduced in the captopril and cysteine groups compared with the control group. No manifest improvements appeared in the enalapril group. 4. Levels of serum creatinine and blood urea nitrogen increased progressively. At week 10, the increases in the serum levels of creatinine were less in the captopril (87 +/- 16 mmol/l) and cysteine (80 +/- 19 mmol/l) groups than in the control group (124 +/- 27 mmol/l) (P less than 0.01). No marked differences were found between the control and enalapril groups. 5. Captopril and cysteine caused more than a three-fold reduction in the focal glomerulosclerosis score when compared with that in the control group, but enalapril did not decrease the score. The extent of tubulointerstitial change was parallel with the focal glomerulosclerosis score. 6. We conclude that the thiol group is possibly involved in the mechanism of the beneficial effects of some angiotensin converting enzyme inhibitors on the progression of chronic renal failure exacerbated by hypertension.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Cysteine; Enalapril; Kidney Failure, Chronic; Male; Rats; Rats, Inbred Strains; Sulfhydryl Compounds

Topics: Diabetic Nephropathies; Enalapril; Humans; Hypertension; Kidney Failure, Chronic

We studied the effects of mid-term enalapril administration on protein-load-induced renal responses in 10 patients with early chronic renal failure (serum creatinine 2.70 +/- 1.0 mg/dl). The oral protein load was performed twice, before and after a 10-day therapy with enalapril. Glomerular filtration rate (125I-iothalamate clearance) rose from 22.5 +/- 10.6 to 60.1 +/- 32.8 ml/min after the protein load before enalapril; it did not change after the protein load during enalapril therapy. Percent fractional excretion of sodium, urinary osmolality and free water clearance were significantly affected only by the protein load before enalapril. Enalapril blunts the protein-load-induced changes in glomerular filtration rate and in tubular function; these effects might be mediated by angiotensin II blockade.

Topics: Adult; Angiotensin II; Blood Pressure; Body Weight; Creatinine; Dietary Proteins; Enalapril; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Male; Urea

A case of irreversible renal failure during treatment with enalapril in bilateral renal artery stenosis is described. In the use of converting enzyme inhibitors, caution and monitoring of renal function during treatment is advised.

Topics: Adult; Enalapril; Humans; Hypertension; Kidney Failure, Chronic; Male; Middle Aged; Renal Artery Obstruction

Ten hypertensive, non-nephrotic patients with immunoglobulin (IgA) nephropathy treated with conventional therapy (vasodilators, beta-blockers, diuretics) were observed for 21.4 +/- 9 months. Treatment was then changed to an angiotensin converting enzyme (ACE) inhibitor alone for an additional 22.6 +/- 9 months. The ACE inhibitor therapy was associated with a lower diastolic blood pressure and a slowing in the rate of decline in renal function, but no change in proteinuria.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Diuretics; Drug Therapy, Combination; Enalapril; Glomerulonephritis, IGA; Humans; Hypertension; Kidney Failure, Chronic; Time Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Lisinopril

In order to establish if pharmacological treatment of systemic hypertension modifies the course of progressive renal failure, we studied the effects of an angiotensin converting enzyme inhibitor and a calcium antagonist, on the renal structure and function in the remnant kidney model of chronic renal failure in the rat. Progressive renal failure was induced in adult female Sprague Dawley rats (SDR) by surgical removal of the right kidney, and segmental infarction of seven-eighths of the left kidney. Following subtotal nephrectomy, plasma creatinine rose from 65 +/- 16 mumol/l to 173 +/- 19 mumol/l (P less than 0.001) over a period of 6 weeks, systolic blood pressure (SBP) rose from 121 +/- 2 mmHg to 176 +/- 7 mmHg (P less than 0.001) and urinary protein excretion from 0.6 +/- 0.2 to 84 +/- 22 mg/24 h (P less than 0.001). Glomerular mesangial expansion was present after 2 weeks, then progressed, in association with the development of glomerular sclerosis, which became prominent after 6 weeks. Rats were treated with enalapril (5 mg/kg per day) or felodipine (30 mg/kg per day) from 1 week after subtotal nephrectomy, and their course compared with that of untreated rats. Systemic SBP decreased to a similar degree by both drug treatments. Six weeks after surgery, plasma creatinine concentration was lower in the enalapril-treated group (110 +/- 8 mumol/l, P less than 0.05) than in the felodipine-treated group (153 +/- 23 mumol/l). The latter group showed similar plasma creatinine concentrations to those of the untreated rats (173 +/- 19 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Calcium Channel Blockers; Enalapril; Felodipine; Female; Hypertension, Renovascular; Kidney Failure, Chronic; Nitrendipine; Rats; Rats, Inbred Strains

Topics: Enalapril; Humans; Hypertension; Kidney; Kidney Failure, Chronic

The antihypertensive efficacy and renal effects of enalapril maleate therapy were evaluated in 13 hypertensive patients with chronic renal failure. Enalapril was administered as follows: alone; added to furosemide, clonidine hydrochloride, or atenolol; or in combination with any of the aforementioned drugs. Three patients did not complete the study; uncontrolled hypertension was the cause in two of these patients. In the remaining ten patients, short-term (mean +/- SD, 63 +/- 9 days) enalapril maleate therapy decreased the patient's seated blood pressure from 161/98 +/- 19/8 to 130/80 +/- 13/7 mm Hg. Furosemide was administered to eight patients; the dose of concomitant sympatholytic therapy was decreased in five of five patients. Serum potassium concentration increased from 4.1 +/- 0.3 to 4.5 +/- 0.3 mmol/L. Levels of urinary total protein excretion decreased from 2.23 +/- 2.05 to 1.08 +/- 1.45 g/d. Renal function (creatinine clearance, 0.58 +/- 0.21 mL/s) did not change from baseline. During long-term therapy, the rate of progression of renal insufficiency seemed to slacken in three of four patients with diabetic nephropathy. Thus enalapril can reduce blood pressure and proteinuria in hypertensive patients with chronic renal insufficiency. The possibility that enalapril can slow the progression of diabetic nephropathy remains to be confirmed by future studies.

Topics: Adult; Aged; Blood Pressure; Creatinine; Enalapril; Female; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Kidney Function Tests; Male; Middle Aged; Proteinuria

1. Lisinopril, a new orally active angiotensin converting enzyme inhibitor, was given to eight patients with stable chronic renal failure, in a dose of 5 mg 24 h-1 for 1 week. Creatinine clearance of the subjects ranged from 0.22 to 1.11 ml s-1. Lisinopril pharmacokinetics were studied over 8 days. 2. There was a close correlation between creatinine clearance and total 'area under the curve' over the 8 days of study (r = -0.88, P less than 0.05), and plateau lisinopril concentration and creatinine clearance (r = -0.77, P less than 0.05). 3. Serum angiotensin converting enzyme activity was inhibited in proportion to log serum lisinopril concentration (r = -0.99, P less than 0.001). Calculated IC50 was 47 ng lisinopril ml-1. from pooled data, with individual patients IC50 ranging from 20 to 70 ng lisinopril ml-1. 4. Creatinine clearance was unaltered by treatment. Serum potassium rose to over 5 mmol 1-1 in four patients, without adverse clinical effect.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatine; Enalapril; Female; Humans; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Peptidyl-Dipeptidase A; Proteinuria; Pulse

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Enalapril; Kidney Failure, Chronic; Kidney Glomerulus; Male; Nephrectomy; Proteinuria; Rats; Rats, Inbred Strains; Reference Values; Thromboxane-A Synthase

1. Lisinopril and enalapril were administered as 2.5 mg single doses and as eight single daily 2.5 mg doses to separate groups of six patients with chronic renal failure. Patients were receiving regular haemodialysis. 2. In the absence of haemodialysis, the decline in plasma concentrations of lisinopril and enalaprilat was extremely slow and plasma concentrations were generally high. 3. Haemodialysis had large effects on plasma concentrations of lisinopril and enalaprilat. A 4 h period reduced plasma concentrations of both drugs by around one-half and often by significantly more than this. Even 1 or 2 h of haemodialysis had significant effects. 4. Haemodialysis plasma clearance was similar for both drugs with mean values of the order of 40 ml min-1. Clearance did not markedly differ when measured after 1, 2 or 4 h of haemodialysis or after single or multiple doses of lisinopril or enalapril. 5. The design of dosage regimens of both lisinopril and enalapril for patients with severe renal impairment or chronic renal failure should take into consideration the use and effects of haemodialysis.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Enalapril; Enalaprilat; Female; Humans; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Renal Dialysis

1. Nephrotoxic serum nephritis was induced immunologically in uninephrectomized Sprague-Dawley rats (n = 24). One-half were assigned randomly to treatment with enalapril (5 mg/kg per 24 h). 2. Untreated rats (n = 12) developed a progressive fall in creatinine clearance, a progressive rise in systolic blood pressure and marked proteinuria over a 6 week period. The mortality rate was 42% at 5 weeks and 66% at 6 weeks. 3. Enalapril-treated rats (n = 12) had no significant reduction in systolic blood pressure, and a similar reduction in creatinine clearance to that in untreated rats. Mortality was 50% at 5 weeks, and 92% at 6 weeks. 4. Proteinuria but not the blood pressure rise was significantly reduced by enalapril treatment. 5. Converting enzyme inhibitors may have a specific role in the treatment of nephritic diseases.

Topics: Animals; Blood Pressure; Creatinine; Enalapril; Female; Glomerular Filtration Rate; Kidney Failure, Chronic; Nephritis; Proteinuria; Rats; Rats, Inbred Strains

Sprague-Dawley rats subjected to subtotal (1 7/8) nephrectomy or streptozotocin diabetes were treated with an angiotensin converting enzyme inhibitor or a calcium channel blocker and their course compared with untreated control animals. Subtotal nephrectomy led to hypertension, proteinuria, reduced creatinine clearance, and glomerulosclerosis over 6 weeks. Enalapril treatment (5 mg/kg/day, n = 11) or felodipine (30 mg/kg/day, n = 11) reduced systolic blood pressure to a comparable degree. Plasma creatinine (mumol/l) was lower after enalapril treatment (110 +/- 8, p less than 0.05) than with felodipine treatment (153 +/- 27) or no treatment (173 +/- 19, n = 18). Proteinuria (mg/24 h) was lower with enalapril treatment (15 +/- 3, p less than 0.001) than with no treatment (85 +/- 22) and increased with felodipine (221 +/- 35). Glomerulosclerosis was reduced with enalapril but not felodipine treatment. Diabetic rats were treated with enalapril (5 mg/kg/day, n = 17), verapamil (5 mg/kg/day, n = 17), or untreated. Diabetic rats had increased creatinine clearance (ml/min) compared with nondiabetic controls (1.52 +/- 0.06 vs. 1.15 +/- 0.05, n = 11, p less than 0.01). Enalapril and verapamil treatment reduced blood pressure equally. Enalapril but not verapamil reduced the elevated creatinine clearance of diabetic rats (enalapril, 1.37 +/- 0.04 ml/min, p less than 0.01; verapamil, 1.49 +/- 0.5 ml/min). Proteinuria (mg/24 h) was lower (p less than 0.05) with enalapril treatment (36 +/- 3) but not with verapamil treatment (58 +/- 10) in comparison to that in untreated diabetes (71 +/- 18).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Enalapril; Felodipine; Hypertension; Kidney Failure, Chronic; Nephrectomy; Nitrendipine; Proteinuria; Rats; Rats, Inbred Strains; Verapamil

Lisinopril (L), a novel angiotensin converting enzyme inhibitor, was studied as sole drug in the management of hypertensive, dialysis-treated, end-stage renal failure patients to assess its efficiency, tolerance, and removal by dialysis. High blood pressure (BP) was defined as sitting diastolic (D) BP greater than or equal to 95 mm Hg. Ten patients, two females and eight males, were treated for 12 weeks. Their features were age 49 +/- 14 years; dialysis duration 43 +/- 25 months; body weight 61 +/- 10 kg; and body mass index 21.7 +/- 3 (mean +/- SD). Serum L concentrations were measured regularly by radioimmunoassay, both before and after dialysis, which was performed with Cuprophane membranes three times per week. L, 2.5 mg orally, was given every 24 h initially; in six patients, dosage was decreased to an alternate or once-a-week schedule, because of a hypotensive effect during dialysis. At 12 weeks, BP--as compared to prestudy BP--was decreased in eight of nine patients (one patient had been withdrawn after kidney transplantation), and not changed in one patient (mean +/- SD): sitting DBP from 107 +/- 7 to 87 +/- 10 mm Hg, p less than 0.001; erect DBP from 105 +/- 5 to 86 +/- 10 mm Hg, p less than 0.001. L serum concentration was decreased by dialysis, the mean ratio of post-/predialysis serum L concentrations was 0.47 +/- 0.07 (n = 67). No side effects were disclosed, except for three patients, in whom hemoglobin decreased, while two of them also received quinine for a febrile illness of viral origin.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged

Topics: Enalapril; Glomerular Filtration Rate; Heart Failure; Humans; Kidney Failure, Chronic

Topics: Aged; Captopril; Enalapril; Humans; Kidney; Kidney Failure, Chronic

Lisinopril (MK521), a lysine analogue of enalaprilic acid, the bioactive metabolite of enalapril, has a longer half-life than enalaprilic acid, and is excreted unchanged in the urine. Its kinetic profile and antihypertensive and hormonal effects have been investigated in an open study in 3 groups each of 6 hypertensive patients, with normal, moderate and severe impairment of renal function. Serum drug level, blood pressure, converting enzyme activity (CEA), plasma renin activity (PRA), aldosterone concentration (PAC), and serum potassium and creatinine were measured during 1 week following a single oral dose and subsequently following 8 daily doses of 5 mg lisinopril. Accumulation of lisinopril was found in the severe renal failure group. CEA was suppressed to less than 10% of its initial value from 4 to 24 h after the initial dose in all three groups, and the suppression was more marked and lasted longer in patients with severe renal failure. An inverse correlation was found in all patients between log serum lisinopril concentration and log CEA. Lisinopril lowered blood pressure in all three groups over 24 h. PRA rose and PAC fell similarly in the groups. Serum potassium increased in the renal failure groups and creatinine remained unchanged in all groups. Thus, when lisinopril 5 mg is given daily to patients with severe renal failure it may accumulate. The high serum lisinopril concentration does not cause an excessive antihypertensive effect. In patients with severe renal failure, adjustment of the dose or the dosing frequency to the degree of renal failure is recommended to avoid administration of doses in excess of those required to achieve adequate inhibition of converting enzyme.

Topics: Adult; Aged; Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Enalapril; Female; Humans; Hypertension; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Peptidyl-Dipeptidase A; Potassium; Renin; Time Factors

The remnant kidney model of chronic renal failure was established in rats subject to subtotal (1 7/8) nephrectomy and the evolution of renal injury studied over a period of 6 wk. One wk after subtotal nephrectomy, rats had a mean conscious systolic blood pressure of 158 +/- 5 mm Hg and serum creatinine of 128 +/- 9 mumol/l. Both systolic blood pressure and serum creatinine rose over the next 5 wk in concert with progressive glomerulosclerosis and proteinuria. Enalapril, an angiotensin converting enzyme inhibitor, was administered (5 mg/kg/day) to rats (n = 11) from 1 wk after subtotal nephrectomy. Enalapril lowered systolic blood pressure over the treatment period. Systolic blood pressure was 122 +/- 5 mm Hg compared with 176 +/- 7 mm Hg in untreated rats (p less than 0.001) at 6 wk. Serum creatinine 6 wk after subtotal nephrectomy was 110 +/- 9 mumol/l with enalapril treatment, compared with 159 +/- 21 mumol/l (p less than 0.025) in control animals. Enalapril treated rats had lower urinary protein excretion than controls (15 +/- 3 mg/24 hr vs 85 +/- 22 mg/24 hr, p less than 0.0001) at 6 weeks. Glomerulosclerosis, assessed by blinded histological score, was also reduced in the enalapril treated group (1.79 +/- 0.08 vs 2.36 +/- 0.16, p less than 0.01). Enalapril treatment was associated with a reduction in filtration fraction (51Cr-EDTA/125I-hippurate clearance). At 6 wk, filtration fraction was 0.30 +/- 0.03 in enalapril treated and 0.48 +/- 0.03 in control rats (p less than 0.001). Enalapril treatment in the subtotal nephrectomy model of renal failure preserved renal structure and function.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Enalapril; Female; Hemodynamics; Kidney; Kidney Failure, Chronic; Nephrectomy; Rats; Rats, Inbred Strains; Renal Circulation

Micropuncture and morphological studies were performed in three protocols assessing the renal hemodynamic and structural effects of angiotensin I-converting enzyme inhibitors (CEIs) in the progression of glomerular injury. In protocol I, rats were subjected to 5/6 renal ablation and received no therapy, enalapril (CEI), or triple-drug therapy (TRX) for 12 weeks. Control of systemic and glomerular hypertension with CEI resulted in prevention of glomerular capillary hypertension and protection against glomerular injury. Despite equivalent control of systemic BP, failure of TRX to control glomerular hypertension was associated with no protection against eventual proteinuria and glomerular sclerosis, values for these indexes being as abnormal as in rats receiving no therapy. In protocol II, rats were again subjected to 5/6 renal ablation and followed for 18 weeks. Early institution of CEI soon after ablation again prevented systemic and glomerular hypertension and largely limited glomerular injury. In a third group, enalapril therapy was delayed for 8 weeks after ablation until hypertension and proteinuria were established. Late institution of CEI resulted in prompt reduction in systemic and glomerular capillary hypertension and stabilization of glomerular disease. In protocol III, CEI was administered to normotensive, moderately hyperglycemic diabetic rats. A modest, 20-mm Hg reduction in systemic arterial pressure was associated with the normalization of glomerular capillary pressure and a striking reduction in the development of albuminuria and glomerular injury. These studies suggest that CEI effectively prevent glomerular capillary hypertension and thereby afford protection against glomerular injury in diverse models of progressive renal disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Diabetes Mellitus, Experimental; Enalapril; Hypertension, Renal; Kidney Failure, Chronic; Kidney Glomerulus; Male; Rats; Renal Circulation; Renin-Angiotensin System

Angiotensin converting enzyme (ACE) and the ACE inhibitor lisinopril were measured in patients with renal impairment, by both radioinhibitor 125I MK351A binding studies, and by radioimmunoassay. Plasma concentration of lisinopril estimated by radioinhibitor binding displacement correlated closely with that measured by radioimmunoassay. Plateau lisinopril concentration in 8 patients with varying degrees of renal failure treated with 5 mg lisinopril per day for 1 week, was inversely related to renal function. Plasma lisinopril concentrations of 30-70 ng/ml were required for 50% inhibition of plasma ACE activity in vivo. Acute studies in the rat showed inhibition of ACE in different tissues had different time courses. These observations suggest that 125I MK351A binding studies in tissues will be useful in establishing the pharmacokinetic and pharmacodynamic profiles of newer ACE inhibitors, and may help delineate the contribution of ACE in different tissues to cardiovascular homeostasis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Dipeptides; Enalapril; Humans; Kidney Failure, Chronic; Kidney Function Tests; Kinetics; Lisinopril; Peptidyl-Dipeptidase A; Protein Binding; Rats

Topics: Enalapril; Humans; Hyperkalemia; Hypertension, Renal; Kidney Failure, Chronic

Topics: Adult; Enalapril; Female; Humans; Hypertension, Renal; Kidney Failure, Chronic; Male; Middle Aged; Renal Dialysis

The effects of a single oral dose of enalapril (20 mg) on blood pressure (BP), heart rate (HR) plasma renin activity (PRA) aldosterone (PA), converting enzyme inhibition (CEI) and enalaprilat (E, active metabolite) were investigated during 96 h in 3 groups of 5 hypertensive patients with (1) normal renal function (creatinine clearance: Clcr greater than 80 ml.min-1); (2) moderate chronic renal failure: 80 greater than or equal to Clcr greater than 30 ml.min-1; (3) severe chronic renal failure: 30 greater than or equal to Clcr greater than 10 ml.min-1. Results are as follows (mean +/- SEM): (Table: see text) CEmax: maximal plasma concentration; TEmax: delay corresponding to CEmax; TE 1/2: plasma elimination half-life; AUCE: area under plasma level versus time curve. a: p less than 0.01; b: p less than 0.001; versus (1). In the 3 groups, CEI reached 87-94% as early as the 3rd h; however, at 96 h, CE1 was higher in (3) than in (1) and (2): 77.6 +/- 3.3% versus 6.0 +/- 1.6 and 17.7 +/- 4.8 (p less than 0.001 respectively). In (3). PRA increased at the 1st h and remained elevated: at 96 h, delta PRA was + 3.0 +/- 2.9 ng.ml-1 -.h-1 in (3) versus + 0.10 +/- 0.06 and + 0.25 +/- 0.17 ng.ml-1.h-1 .n (1) and (2) [(3) versus (1): p less than 0.01]; delta PA was lower in (3): -4.56 +/- 2.01 ng. 100 ml-1 versus -0.54 +/- 0.31 and -2.50 +/- 0.38 ng. 100 ml-1 [(3) versus (1): p less than 0.05].(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalapril; Heart Rate; Humans; Hypertension; Kidney Failure, Chronic; Renin

Enalaprilate, an antihypertensive agent that inhibits angiotensin-converting enzyme activity, is not directly absorbable. It is therefore administered as an inactive precursor, an énalaprilate ester which is hydrolysed in vivo with an ultimate bioavailability of 30-40 p. 100. Enalaprilate is entirely excreted through the kidney. With repeated administrations steady state is rapidly reached, and the drug does not accumulate. The effective half-life is 10 hours. Kinetics are linear and depend on renal function. These data, obtained in healthy volunteers with 10 mg doses, also apply to hypertensive patients receiving 20 mg. Following a 20 mg per day dose a more than 50 p. 100 inhibition of the angiotensin-converting enzyme is maintained for 24 hours. In patients with moderate renal impairment or in elderly people (creatinine clearance greater than 30 ml/min), plasma concentrations are slightly increased and there is no need for dosage adjustment. In patients with severe renal impairment (creatinine clearance less than or equal to 30 ml/min) plasma concentrations are considerably increased with a risk of strong accumulation, and dosage must be reduced to 5 or 2.5 mg per day.

Topics: Angiotensin-Converting Enzyme Inhibitors; Enalapril; Humans; Kidney; Kidney Failure, Chronic; Kinetics

Sustained increases in glomerular capillary pressure and flow accompany systemic hypertension in rats that have undergone extensive ablation of the renal mass. These intrarenal hemodynamic changes are, in turn, associated with the progressive development of proteinuria and glomerular sclerosis, leading ultimately to failure of remnant nephron units. The efficacy of antihypertensive therapy with enalapril was evaluated in this animal model of chronic renal insufficiency. A dose of enalapril sufficient to prevent systemic hypertension normalized the glomerular capillary pressure without reducing the glomerular filtration rate in the remnant kidney. Maintenance of normal capillary pressure markedly reduced the development of proteinuria and sclerotic lesions in remnant glomeruli. These results suggest that antihypertensive therapy directed at reducing the glomerular capillary pressure could retard the progressive loss of renal function in patients whose functional renal mass has been reduced by disease.

Topics: Animals; Enalapril; Glomerulosclerosis, Focal Segmental; Hypertension; Kidney Failure, Chronic; Kidney Glomerulus; Male; Oligopeptides; Proteinuria; Rats; Rats, Inbred Strains; Teprotide

Topics: Adult; Aged; Enalapril; Humans; Hypertension; Kidney Failure, Chronic; Kinetics; Middle Aged