lisinopril and Kidney-Failure--Chronic

Sickle cell disease (SCD), one of the commonest severe monogenic disorders, is caused by the inheritance of two abnormal haemoglobin (beta-globin) genes. SCD can cause severe pain, significant end-organ damage, pulmonary complications, and premature death. Kidney disease is a frequent and potentially severe complication in people with SCD. Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function present for more than three months. Sickle cell nephropathy refers to the spectrum of kidney complications in SCD. Glomerular damage is a cause of microalbuminuria and can develop at an early age in children with SCD, with increased prevalence in adulthood. In people with sickle cell nephropathy, outcomes are poor as a result of the progression to proteinuria and chronic kidney insufficiency. Up to 12% of people who develop sickle cell nephropathy will develop end-stage renal disease. This is an update of a review first published in 2017.. To assess the effectiveness of any intervention for preventing or reducing kidney complications or chronic kidney disease in people with sickle cell disease. Possible interventions include red blood cell transfusions, hydroxyurea, and angiotensin-converting enzyme inhibitors (ACEIs), either alone or in combination.. We searched for relevant trials in the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register, CENTRAL, MEDLINE, Embase, seven other databases, and two other trials registers.. Randomised controlled trials (RCTs) comparing interventions to prevent or reduce kidney complications or CKD in people with SCD. We applied no restrictions related to outcomes examined, language, or publication status.. Two review authors independently assessed trial eligibility, extracted data, assessed the risk of bias, and assessed the certainty of the evidence (GRADE).. We are unsure if hydroxyurea improves glomerular filtration rate or reduces hyperfiltration in children aged nine to 18 months, but it may improve their ability to concentrate urine and may make little or no difference to the incidence of acute chest syndrome, painful crises, and hospitalisations. We are unsure if ACEI compared to placebo has any effect on preventing or reducing kidney complications in adults with normal blood pressure and microalbuminuria. We are unsure if ACEI compared to vitamin C has any effect on preventing or reducing kidney complications in children with normal blood pressure and microalbuminuria. No RCTs assessed red blood cell transfusions or any combined interventions to prevent or reduce kidney complications. Due to lack of evidence, we cannot comment on the management of children aged over 18 months or adults with any known genotype of SCD. We have identified a lack of adequately designed and powered studies, although we found four ongoing trials since the last version of this review. Only one ongoing trial addresses renal function as a primary outcome in the short term, but such interventions have long-term effects. Trials of hydroxyurea, ACEIs or red blood cell transfusion in older children and adults are urgently needed to determine any effect on prevention or reduction of kidney complications in people with SCD.

Topics: Acute Chest Syndrome; Adolescent; Adult; Anemia, Sickle Cell; Angiotensin-Converting Enzyme Inhibitors; Antisickling Agents; Ascorbic Acid; Captopril; Child; Creatinine; Humans; Hydroxyurea; Kidney Failure, Chronic; Lisinopril; Proteinuria

Renin inhibitors (RIs) reduce blood pressure more than placebo, with the magnitude of this effect thought to be similar to that for angiotensin converting enzyme (ACE) inhibitors. However, a drug's efficacy in lowering blood pressure cannot be considered as a definitive indicator of its effectiveness in reducing mortality and morbidity. The effectiveness and safety of RIs compared to ACE inhibitors in treating hypertension is unknown.. To evaluate the benefits and harms of renin inhibitors compared to ACE inhibitors in people with primary hypertension.. The Cochrane Hypertension Group Information Specialist searched the following databases for randomized controlled trials up to August 2020: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We also contacted authors of relevant papers about further published and unpublished work. The searches had no language restrictions.. We included randomized, active-controlled, double-blinded studies (RCTs) with at least four weeks follow-up in people with primary hypertension, which compared renin inhibitors with ACE inhibitors and reported morbidity, mortality, adverse events or blood pressure outcomes. We excluded people with proven secondary hypertension.. Two review authors independently selected the included trials, evaluated the risks of bias and entered the data for analysis.. We include 11 RCTs involving 13,627 participants, with a mean baseline age from 51.5 to 74.2 years. Follow-up duration ranged from four weeks to 36.6 months. There was no difference between RIs and ACE inhibitors for the outcomes: all-cause mortality: risk ratio (RR) 1.05, 95% confidence interval (CI) 0.93 to 1.18; 5 RCTs, 5962 participants; low-certainty evidence; total myocardial infarction: RR 0.86, 95% CI 0.22 to 3.39; 2 RCTs, 957 participants; very low-certainty evidence; adverse events: RR 0.98, 95% CI 0.93 to 1.03; 10 RTCs, 6007 participants;  moderate-certainty evidence; serious adverse events: RR 1.21, 95% CI 0.89 to 1.64; 10 RTCs, 6007 participants; low-certainty evidence; and withdrawal due to adverse effects: RR 0.85, 95% CI 0.68 to 1.06; 10 RTCs, 6008 participants; low-certainty evidence. No data were available for total cardiovascular events, heart failure, stroke, end-stage renal disease or change in heart rate. Low-certainty evidence suggested that RIs reduced systolic blood pressure: mean difference (MD) -1.72, 95% CI -2.47 to -0.97; 9 RCTs, 5001 participants;  and diastolic blood pressure: MD -1.18, 95% CI -1.65 to -0.72; 9 RCTs, 5001 participants,  to a greater extent than ACE inhibitors, but we judged this to be more likely due to bias than a true effect.  AUTHORS' CONCLUSIONS: For the treatment of hypertension, we have low certainty that renin inhibitors (RI) and angiotensin converting enzyme (ACE) inhibitors do not differ for all-cause mortality and myocardial infarction. We have low to moderate certainty that they do not differ for adverse events. Small reductions in blood pressure with renin inhibitors compared to ACE inhibitors are of low certainty.  More independent, large, long-term trials are needed to compare RIs with ACE inhibitors, particularly assessing morbidity and mortality outcomes, but also on blood pressure-lowering effect.

Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cardiovascular Diseases; Cause of Death; Female; Fumarates; Heart Rate; Humans; Irbesartan; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Myocardial Infarction; Patient Dropouts; Ramipril; Randomized Controlled Trials as Topic; Renin

Hypertension among patients on hemodialysis is predominantly systolic (either isolated or combined with diastolic hypertension), whereas the scenario of isolated diastolic hypertension is rare and more common in younger patients. Uncontrolled hypertension that persists despite aggressive antihypertensive drug therapy is a reflection of the volume overload that is a prominent mediator of systolic and diastolic BP elevation. Clinical-trial evidence supports the notion that dry-weight probing is an effective strategy to improve BP control, even when overt clinical signs and symptoms of volume overload are not present. Accelerated arterial stiffness influences the patterns and rhythms of interdialytic ambulatory BP and is a major determinant of isolated systolic hypertension in hemodialysis. Posthoc analyses of the Hypertension in Hemodialysis patients treated with Atenolol or Lisinopril (HDPAL) trial, however, suggest that arterial stiffness does not make hypertension more resistant to therapy and is unable to predict the treatment-induced improvement in left ventricular hypertrophy. A combined strategy of sodium restriction, dry-weight adjustment, and antihypertensive medication use was effective in improving ambulatory BP control regardless of the severity of underlying arteriosclerosis in HDPAL. Other nonvolume-dependent mechanisms, such as erythropoietin use, appear to be also important contributors and should be taken into consideration, particularly in younger hemodialysis patients with diastolic hypertension. In this article, we explore the role of volume overload, arterial stiffness, and erythropoietin use as causes of systolic vs diastolic hypertension in patients on hemodialysis. We conclude with clinical practice recommendations and with a call for a "volume-first" approach when managing hemodialysis hypertension.

Topics: Atenolol; Diastole; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Kidney Failure, Chronic; Lisinopril; Male; Renal Dialysis; Risk Assessment; Systole; Vascular Stiffness; Water-Electrolyte Imbalance

Pulse pressure, especially in central arteries, is an independent predictor of adverse cardiovascular events in patients with increased elastic artery stiffness (or elastance). The central arterial pressure wave is composed of a forward traveling wave generated by left ventricular ejection and a later arriving reflected wave from the periphery. Increased stiffness of elastic arteries is the primary cause of increased pulse pressure in subjects with degeneration and hyperplasia of the arterial wall. As stiffness increases, transmission velocity of both forward and reflected waves increase, which causes the reflected wave to arrive earlier in the central aorta and augments pressure in late systole [ie, augmentation index = (augmented pressure/pulse pressure) increases]. These changes in wave reflection properties are associated with vascular disease and aging and cause an increase in left ventricular afterload, myocardial mass, and oxygen consumption. Vasoactive drugs have little direct effect on large elastic arteries but can markedly change wave reflection amplitude and augmentation index by altering stiffness of the muscular arteries and modifying transmission velocity of the reflected wave from the periphery to the heart. This change in amplitude and timing of the reflected wave causes a generalized change in central arterial systolic and pulse pressure that is not detected by cuff pressure measurements in the brachial artery.

Topics: Antihypertensive Agents; Arteries; Blood Pressure; Elasticity; Endothelium, Vascular; Female; Humans; Hypercholesterolemia; Kidney Failure, Chronic; Lisinopril; Male; Peripheral Vascular Diseases; Radial Artery; Sex Characteristics; Vasodilation

Among hemodialysis patients, probing dry weight is an effective strategy for improving control of hypertension. Whether controlling hypertension improves or worsens symptoms among such patients remains unclear. The purpose of the study was to develop a tool to evaluate symptoms and examine the relationship of the change in these symptoms with blood pressure (BP) control.. Among patients participating in the Hemodialysis Patients Treated with Atenolol or Lisinopril (HDPAL) randomized controlled trial, a confirmatory factor analysis (CFA) was performed to establish the relationship between symptoms and organ systems. Next, the change in symptom scores pertaining to organ systems was analyzed using a mixed model. Finally, the independent effect of lowering home BP on change in symptoms was evaluated.. Among 133 participants where symptoms were available at baseline, CFA revealed four level 1 domains: gastrointestinal symptoms, dialysis-related symptoms, cardiovascular symptoms and general symptoms. All except dialysis-related symptoms were ascribed to uremia (level 2 domain). Uremic symptoms improved over 6 months and then increased. Dialysis-related symptoms (fatigue, cramps and orthostatic dizziness) did not worsen despite lowering home BP. Probing dry weight was independently associated with an improvement in cardiovascular symptoms such as shortness of breath.. Reducing BP through the use of a strategy that includes volume control and medication improves symptoms seemingly unrelated to volume excess. In long-term hemodialysis patients, treating hypertension using home BP measurements may improve well-being.

Topics: Antihypertensive Agents; Atenolol; Blood Pressure; Blood Volume; Body Weight; Female; Humans; Hypertension; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Renal Dialysis; Treatment Outcome

Arterial stiffness is associated with elevated blood pressure (BP), but it is unclear whether it also makes hypertension more resistant to treatment. Among hypertensive dialysis patients, this study investigated whether aortic stiffness determines ambulatory BP and predicts its improvement with therapy.. Post hoc analysis of the Hypertension in Hemodialysis Patients Treated With Atenolol or Lisinopril (HDPAL) trial.. 179 hypertensive hemodialysis patients with echocardiographic left ventricular hypertrophy.. Baseline aortic pulse wave velocity (PWV).. Baseline and treatment-induced change in 44-hour ambulatory BP at 3, 6, and 12 months.. Aortic PWV was assessed with an echocardiographic-Doppler technique (ACUSON Cypress, Siemens Medical), and 44-hour interdialytic ambulatory BP monitoring was performed with a Spacelabs 90207 monitor.. Mean baseline aortic PWV was 7.6±2.7 (SD) m/s. Overall treatment-induced changes in ambulatory systolic BP (SBP) were -15.6±20.4, -18.9±22.5, and -20.0±19.7 mmHg at 3, 6, and 12 months. Changes in SBP were no different among tertiles of baseline PWV. Aortic PWV was associated directly with baseline ambulatory SBP and pulse pressure (PP) and inversely with diastolic BP (DBP). After adjustment for several cardiovascular risk factors, each 1-m/s higher PWV was associated with 1.34-mm Hg higher baseline SBP (β=1.34±0.46; P=0.004) and 1.02-mm Hg higher PP (β=1.02±0.33; P=0.002), whereas the association with DBP was no longer significant. Baseline PWV did not predict treatment-induced changes in SBP (Wald test, P=0.3) and DBP (Wald test, P=0.7), but was a predictor of an overall improvement in PP during follow-up (Wald test, P=0.03).. Observational design; predominantly black patients were studied.. Because aortic PWV is not a predictor of treatment-induced change in ambulatory BP among hypertensive dialysis patients, it indicates that among these patients, hypertension can be controlled successfully regardless of aortic stiffness.

Topics: Adult; Aged; Antihypertensive Agents; Aorta; Atenolol; Blood Pressure Monitoring, Ambulatory; Early Termination of Clinical Trials; Echocardiography, Doppler; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Pulse Wave Analysis; Renal Dialysis; Treatment Outcome; Vascular Stiffness

Proteinuric diabetic kidney disease frequently progresses to ESRD. Control of BP delays progression, but the optimal BP to improve outcomes remains unclear. The objective of this analysis was to evaluate the relationship between BP and renal outcomes in proteinuric diabetic kidney disease.. BP data from all 1448 randomized participants in the Veterans Affairs Nephropathy in Diabetes Trial were included in a post hoc analysis. The associations of mean on-treatment BP with the primary end point (decline in eGFR, ESRD, or death), renal end point (decline in eGFR or ESRD), rate of eGFR decline, and mortality were measured.. The median (25th, 75th percentile) follow-up time was 2.2 (1.2, 3.0) years. There were 284 primary end points. In univariate analyses, both mean systolic and mean diastolic BPs were strongly associated (P<0.001) with the primary end point. After multivariate adjustment, the hazard of developing the primary end point became progressively higher as mean systolic BP rose from <120 to ≥ 150 mmHg (P=0.02), with a significantly higher hazard ratio for 140-149 versus 120-129 mmHg (1.51 [1.06, 2.15]; P=0.02). There was also a significant association of mean diastolic BP with the hazard of developing the primary end point (P<0.01), with a significantly higher hazard ratio when mean diastolic BP was 80-89 versus 70-79 mmHg (1.54 [1.05, 2.25]; P=0.03); there was also a strong trend when mean diastolic BP was <60 mmHg. Associations between BP and both renal end point and rate of eGFR decline were similar to those with the primary end point. No association of BP with mortality was observed, possibly because of the limited number of mortality events.. In patients with proteinuric diabetic kidney disease, mean systolic BP ≥ 140 mmHg and mean diastolic BP ≥ 80 mmHg were associated with worse renal outcomes.

Topics: Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Diabetic Nephropathies; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Lisinopril; Losartan; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Proteinuria; Risk Factors; Time Factors; Treatment Outcome; United States; United States Department of Veterans Affairs

to study the opportunities for cardio and nephroprotection by 6-month combined antihypertensive therapy with lisinopril and amlodipine in hypertensive patients with diabetes mellitus (DM) type 2.. 30 patients with arterial hypertension (AH) stage II-III, chronic kidney disease (CKD) stages 2-3 and type 2 DM were included in to research. We evaluated the results of the physical examination, blood pressure monitoring (ABPM), structural and functional state of the heart and kidneys. Combined analysis the risk of progression of CKD and cardiovascular complications (CVC) depending on the glomerular filtration rate (GFR) and albuminuria (AU) was performed. We also studied carbohydrate and lipid metabolism and estimated the severity of insulin resistance (IR).. Against the background of long-term therapy by Equator 100% of patients had achieved target BP values. The circadian BP profile was significantly improved. There was a significant decrease in the index of left ventricular mass by 8.0%, a decline of PU by 58% and AU by 43.6%, respectively. There was the redistribution of patients to assess the combined risk of CKD progression and CVC: 50% of patients in the group crossed a moderate risk by reducing the percentage of patients at high and very high risk of 36.7% and 13.4%, respectively (p < 0.001), as well as significant improvement in metabolic parameters and reduction in IR. A statistically significant correlation between IR and condition of the heart and kidney was determined.. Long-term combined therapy with lisinopril and amlodipine fully meets the modern requirements for antihypertensive therapy--it leads to a significant reduction in the risk of progression of CKD and development of the CVC and is metabolically neutral. The decrease in the combined risk of CKD progression and development CVC was associated with cardio and nephroprotective action of the Equator, as well as with a reduction in the negative impact of IR in patients with AH and type 2 DM.

Topics: Adult; Aged; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Prospective Studies; Treatment Outcome

The purpose of this study was to determine among maintenance hemodialysis patients with echocardiographic left ventricular hypertrophy and hypertension whether in comparison with a β-blocker-based antihypertensive therapy, an angiotensin converting enzyme-inhibitor-based antihypertensive therapy causes a greater regression of left ventricular hypertrophy.. Subjects were randomly assigned to either open-label lisinopril (n = 100) or atenolol (n = 100) each administered three times per week after dialysis. Monthly monitored home blood pressure (BP) was controlled to <140/90 mmHg with medications, dry weight adjustment and sodium restriction. The primary outcome was the change in left ventricular mass index (LVMI) from baseline to 12 months.. At baseline, 44-h ambulatory BP was similar in the atenolol (151.5/87.1 mmHg) and lisinopril groups, and improved similarly over time in both groups. However, monthly measured home BP was consistently higher in the lisinopril group despite the need for both a greater number of antihypertensive agents and a greater reduction in dry weight. An independent data safety monitoring board recommended termination because of cardiovascular safety. Serious cardiovascular events in the atenolol group occurred in 16 subjects, who had 20 events, and in the lisinopril group in 28 subjects, who had 43 events {incidence rate ratio (IRR) 2.36 [95% confidence interval (95% CI) 1.36-4.23, P = 0.001]}. Combined serious adverse events of myocardial infarction, stroke and hospitalization for heart failure or cardiovascular death in the atenolol group occurred in 10 subjects, who had 11 events and in the lisinopril group in 17 subjects, who had 23 events (IRR 2.29, P = 0.021). Hospitalizations for heart failure were worse in the lisinopril group (IRR 3.13, P = 0.021). All-cause hospitalizations were higher in the lisinopril group [IRR 1.61 (95% CI 1.18-2.19, P = 0.002)]. LVMI improved with time; no difference between drugs was noted.. Among maintenance dialysis patients with hypertension and left ventricular hypertrophy, atenolol-based antihypertensive therapy may be superior to lisinopril-based therapy in preventing cardiovascular morbidity and all-cause hospitalizations. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases; ClinicalTrials.gov number: NCT00582114).

Topics: Adult; Aged; Antihypertensive Agents; Atenolol; Double-Blind Method; Early Termination of Clinical Trials; Female; Humans; Hypertension; Hypertrophy, Left Ventricular; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Myocardial Infarction; Renal Dialysis; Treatment Failure

Hypertension develops early in patients with autosomal dominant polycystic kidney disease (ADPKD) and is associated with disease progression. The renin-angiotensin-aldosterone system (RAAS) is implicated in the pathogenesis of hypertension in patients with ADPKD. Dual blockade of the RAAS may circumvent compensatory mechanisms that limit the efficacy of monotherapy with an angiotensin-converting-enzyme (ACE) inhibitor or angiotensin II-receptor blocker (ARB).. In this double-blind, placebo-controlled trial, we randomly assigned 486 patients, 18 to 64 years of age, with ADPKD (estimated glomerular filtration rate [GFR], 25 to 60 ml per minute per 1.73 m(2) of body-surface area) to receive an ACE inhibitor (lisinopril) and placebo or lisinopril and an ARB (telmisartan), with the doses adjusted to achieve a blood pressure of 110/70 to 130/80 mm Hg. The composite primary outcome was the time to death, end-stage renal disease, or a 50% reduction from the baseline estimated GFR. Secondary outcomes included the rates of change in urinary aldosterone and albumin excretion, frequency of hospitalizations for any cause and for cardiovascular causes, incidence of pain, frequency of ADPKD-related symptoms, quality of life, and adverse study-medication effects. Patients were followed for 5 to 8 years.. There was no significant difference between the study groups in the incidence of the composite primary outcome (hazard ratio with lisinopril-telmisartan, 1.08; 95% confidence interval, 0.82 to 1.42). The two treatments controlled blood pressure and lowered urinary aldosterone excretion similarly. The rates of decline in the estimated GFR, urinary albumin excretion, and other secondary outcomes and adverse events, including hyperkalemia and acute kidney injury, were also similar in the two groups.. Monotherapy with an ACE inhibitor was associated with blood-pressure control in most patients with ADPKD and stage 3 chronic kidney disease. The addition of an ARB did not alter the decline in the estimated GFR. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; HALT-PKD [Study B] ClinicalTrials.gov number, NCT01885559.).

Topics: Adolescent; Adult; Albuminuria; Aldosterone; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Benzoates; Blood Pressure; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Polycystic Kidney, Autosomal Dominant; Renal Insufficiency, Chronic; Telmisartan; Young Adult

Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Double-Blind Method; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Kaplan-Meier Estimate; Kidney Failure, Chronic; Lisinopril; Losartan; Male; Middle Aged

CKD is common among older patients. This article assesses long-term renal and cardiovascular outcomes in older high-risk hypertensive patients, stratified by baseline estimated GFR (eGFR), and long-term outcome efficacy of 5-year first-step treatment with amlodipine or lisinopril, each compared with chlorthalidone.. This was a long-term post-trial follow-up of hypertensive participants (n=31,350), aged ≥55 years, randomized to receive chlorthalidone, amlodipine, or lisinopril for 4-8 years at 593 centers. Participants were stratified by baseline eGFR (ml/min per 1.73 m(2)) as follows: normal/increased (≥90; n=8027), mild reduction (60-89; n=17,778), and moderate/severe reduction (<60; n=5545). Outcomes were cardiovascular mortality (primary outcome), total mortality, coronary heart disease, cardiovascular disease, stroke, heart failure, and ESRD.. After an average 8.8-year follow-up, total mortality was significantly higher in participants with moderate/severe eGFR reduction compared with those with normal and mildly reduced eGFR (P<0.001). In participants with an eGFR <60, there was no significant difference in cardiovascular mortality between chlorthalidone and amlodipine (P=0.64), or chlorthalidone and lisinopril (P=0.56). Likewise, no significant differences were observed for total mortality, coronary heart disease, cardiovascular disease, stroke, or ESRD.. CKD is associated with significantly higher long-term risk of cardiovascular events and mortality in older hypertensive patients. By eGFR stratum, 5-year treatment with amlodipine or lisinopril was not superior to chlorthalidone in preventing cardiovascular events, mortality, or ESRD during 9-year follow-up. Because data on proteinuria were not available, these findings may not be extrapolated to proteinuric CKD.

Topics: Amlodipine; Antihypertensive Agents; Canada; Chlorthalidone; Chronic Disease; Coronary Disease; Double-Blind Method; Female; Glomerular Filtration Rate; Heart Failure; Humans; Hypertension; Hypolipidemic Agents; Incidence; Kaplan-Meier Estimate; Kidney; Kidney Diseases; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Proportional Hazards Models; Puerto Rico; Risk Assessment; Risk Factors; Severity of Illness Index; Stroke; Time Factors; Treatment Outcome; United States; United States Virgin Islands

Both angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can slow the progression of diabetic nephropathy. Even with ACEI or ARB treatment, the proportion of patients who progress to end-stage renal disease (ESRD) remains high. Interventions that achieve more complete blockade of the renin-angiotensin system, such as combination ACEI and ARB, might be beneficial. This approach may decrease progression of nondiabetic kidney disease. In diabetic nephropathy, combination therapy decreases proteinuria, but its effect in slowing progression is unknown. In addition, the potential for hyperkalemia may limit the utility of combined therapy in this population. VA NEPHRON-D is a randomized, double-blind, multicenter clinical trial to assess the effect of combination losartan and lisinopril, compared with losartan alone, on the progression of kidney disease in 1850 patients with diabetes and overt proteinuria. The primary endpoints are time to (1) reduction in estimated GFR (eGFR) of > 50% (if baseline < 60 ml/min/1.73 m(2)); (2) reduction in eGFR of 30 ml/min/1.73 m(2) (if baseline > or = 60 ml/min/1.73 m(2)); (3) progression to ESRD (need for dialysis, renal transplant, or eGFR < 15 ml/min/1.73 m(2)); or (4) death. The secondary endpoint is time to change in eGFR or ESRD. Tertiary endpoints are cardiovascular events, slope of change in eGFR, and change in albuminuria at 1 yr. Specific safety endpoints are serious hyperkalemia (potassium > 6 mEq/L, requiring admission, emergency room visit, or dialysis), all-cause mortality, and other serious adverse events. This paper discusses the design and key methodological issues that arose during the planning of the study.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Hyperkalemia; Kidney Failure, Chronic; Kidney Transplantation; Lisinopril; Losartan; Prospective Studies; Proteinuria; Renal Dialysis; Research Design; Time Factors; Treatment Outcome; United States; United States Department of Veterans Affairs

The FGB gene codes for fibrinogen-beta, a polypeptide of the coagulation factor fibrinogen, which is positively associated with cardiovascular diseases. Studies show that angiotensin-converting enzyme (ACE) inhibitors lower plasma fibrinogen concentrations, whereas diuretics and calcium-channel blockers do not. As carriers of the FGB-455 minor 'A' allele have higher levels of fibrinogen while ACE inhibitors lower it, we hypothesize that 'A' allele carriers benefit more from antihypertensive treatment with ACE inhibitors than calcium-channel blockers or diuretics, relative to 'GG' genotype individuals.. The Genetics of Hypertension Associated Treatment (GenHAT) study [ancillary to Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)] genotyped hypertensive participants for several hypertension-related candidate genes, making this a post-hoc analysis of a randomized trial. In total, 90.1% of the ALLHAT population was successfully genotyped for FGB-455. We included participants (n=30 076) randomized to one of three antihypertensive medications (lisinopril, amlodipine, chlorthalidone), with two treatment comparisons: lisinopril versus chlorthalidone and lisinopril versus amlodipine. The primary outcome of ALLHAT/GenHAT was coronary heart disease, defined as fatal coronary heart disease or non-fatal myocardial infarction, and secondary outcomes included stroke, heart failure, all-cause mortality, and end-stage renal disease (ESRD) with mean follow-up time of 4.9 years. Genotype-by-treatment interactions (pharmacogenetic effects) were tested with the Cox regression.. Stroke: common 'GG' homozygotes had higher risk on lisinopril versus amlodipine [hazard ratio (HR)=1.38, P<0.001], whereas minor 'A' allele carriers had slightly lower risk (HR=0.96, P=0.76; P value for interaction=0.03). Mortality: 'GG' homozygotes had higher risk on lisinopril versus amlodipine (HR=1.12, P=0.02) or chlorthalidone (1.05, P=0.23), whereas 'A' allele carriers had slightly lower risk (HR=0.92, P=0.33 for lisinopril versus amlodipine; HR=0.88, P=0.08 for lisinopril versus chlorthalidone; P value for interactions 0.04 and 0.03, respectively). ESRD: 'GG' homozygotes had higher risk on lisinopril versus chlorthalidone (HR=1.27, P=0.08), whereas 'A' allele carriers had lower risk (HR=0.64, P=0.12; P value for interaction=0.03).. There was evidence of pharmacogenetic effects of FGB-455 on stroke, ESRD, and mortality, suggesting that relative to those homozygous for the common allele, variant allele carriers of the FGB gene at position -455 have a better outcome if randomized to lisinopril than chlorthalidone (for mortality and ESRD) or amlodipine (for mortality and stroke). For the models in which a pharmacogenetic effect was observed, the outcome rates among 'GG' homozygotes were higher in those randomized to lisinopril versus amlodipine or chlorthalidone, whereas minor 'A' allele carriers had lower event rates when randomized to lisinopril versus the other medications.

Topics: Aged; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Calcium Channel Blockers; Chlorthalidone; Coronary Disease; Diuretics; Fibrinogen; Genetic Variation; Genotype; Humans; Hypertension; Kidney Failure, Chronic; Lisinopril; Middle Aged; Stroke; Treatment Outcome

Chronic kidney disease is common in older patients with hypertension.. To compare rates of coronary heart disease (CHD) and end-stage renal disease (ESRD) events; to determine whether glomerular filtration rate (GFR) independently predicts risk for CHD; and to report the efficacy of first-step treatment with a calcium-channel blocker (amlodipine) or an angiotensin-converting enzyme inhibitor (lisinopril), each compared with a diuretic (chlorthalidone), in modifying cardiovascular disease (CVD) outcomes in high-risk patients with hypertension stratified by GFR.. Post hoc subgroup analysis.. Multicenter randomized, double-blind, controlled trial.. Persons with hypertension who were 55 years of age or older with 1 or more risk factors for CHD and who were stratified into 3 baseline GFR groups: normal or increased (> or = 90 mL/min per 1.73 m2; n = 8126 patients), mild reduction (60 to 89 mL/min per 1.73 m2; n = 18,109 patients), and moderate or severe reduction (< 60 mL/min per 1.73 m2; n = 5662 patients).. Random assignment to chlorthalidone, amlodipine, or lisinopril.. Rates of ESRD, CHD, stroke, and combined CVD (CHD, coronary revascularization, angina, stroke, heart failure, and peripheral arterial disease).. In participants with a moderate to severe reduction in GFR, 6-year rates were higher for CHD than for ESRD (15.4% vs. 6.0%, respectively). A baseline GFR of less than 53 mL/min per 1.73 m2 (compared with >104 mL/min per 1.73 m2) was independently associated with a 32% higher risk for CHD. Amlodipine was similar to chlorthalidone in reducing CHD (16.0% vs. 15.2%, respectively; hazard ratio, 1.06 [95% CI, 0.89 to 1.27]), stroke, and combined CVD (CHD, coronary revascularization, angina, stroke, heart failure, and peripheral arterial disease), but less effective in preventing heart failure. Lisinopril was similar to chlorthalidone in preventing CHD (15.1% vs. 15.2%, respectively; hazard ratio, 1.00 [CI, 0.84 to 1.20]), but was less effective in reducing stroke, combined CVD events, and heart failure.. Proteinuria data were not available, and combination therapies were not tested.. Older high-risk patients with hypertension and reduced GFR are more likely to develop CHD than to develop ESRD. A low GFR independently predicts increased risk for CHD. Neither amlodipine nor lisinopril is superior to chlorthalidone in preventing CHD, stroke, or combined CVD, and chlorthalidone is superior to both for preventing heart failure, independent of level of renal function.

Topics: Aged; Amlodipine; Antihypertensive Agents; Cardiovascular Diseases; Chlorthalidone; Chronic Disease; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Risk Factors

This study was performed to determine whether, in high-risk hypertensive patients with a reduced glomerular filtration rate (GFR), treatment with a calcium channel blocker or an angiotensin-converting enzyme inhibitor lowers the incidence of renal disease outcomes compared with treatment with a diuretic.. We conducted post hoc analyses of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Hypertensive participants 55 years or older with at least 1 other coronary heart disease risk factor were randomized to receive chlorthalidone, amlodipine, or lisinopril for a mean of 4.9 years. Renal outcomes were incidence of end-stage renal disease (ESRD) and/or a decrement in GFR of 50% or more from baseline. Baseline GFR, estimated by the simplified Modification of Diet in Renal Disease equation, was stratified into normal or increased (> or =90 mL /min per 1.73 m(2), n = 8126), mild reduction (60-89 mL /min per 1.73 m(2), n = 18 109), or moderate-severe reduction (<60 mL /min per 1.73 m(2), n = 5662) in GFR. Each stratum was analyzed for effects of the treatments on outcomes.. In 448 participants, ESRD developed. Compared with patients taking chlorthalidone, no significant differences occurred in the incidence of ESRD in patients taking amlodipine in the mild (relative risk [RR], 1.47; 95% confidence interval [CI], 0.97-2.23) or moderate-severe (RR, 0.92; 95% CI, 0.68-1.24) reduction in GFR groups. Compared with patients taking chlorthalidone, no significant differences occurred in the incidence of ESRD in patients taking lisinopril in the mild (RR, 1.34; 95% CI, 0.87-2.06) or moderate-severe (RR, 0.98; 95% CI, 0.73-1.31) reduction in GFR groups. In patients with mild and moderate-severe reduction in GFR, the incidence of ESRD or 50% or greater decrement in GFR was not significantly different in patients treated with chlorthalidone compared with those treated with amlodipine (odds ratios, 0.96 [P = .74] and 0.85 [P = .23], respectively) and lisinopril (odds ratios, 1.13 [P = .31] and 1.00 [P = .98], respectively). No difference in treatment effects occurred for either end point for patients taking amlodipine or lisinopril compared with those taking chlorthalidone across the 3 GFR subgroups, either for the total group or for participants with diabetes at baseline. At 4 years of follow-up, estimated GFR was 3 to 6 mL /min per 1.73 m(2) higher in patients assigned to receive amlodipine compared with chlorthalidone, depending on baseline GFR stratum.. In hypertensive patients with reduced GFR, neither amlodipine nor lisinopril was superior to chlorthalidone in reducing the rate of development of ESRD or a 50% or greater decrement in GFR. Participants assigned to receive amlodipine had a higher GFR than those assigned to receive chlorthalidone, but rates of development of ESRD were not different between the groups.

Topics: Aged; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Chlorthalidone; Coronary Disease; Diuretics; Double-Blind Method; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Hypertension; Incidence; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Patient Compliance; Risk Factors; Treatment Outcome

Hyperkalemia is a known side effect during treatment with Angiotensin Converting Enzyme Inhibitors (ACEIs). The purpose of this study was to compare the effect of an ACEI (Lisinopril) to an Angiotensin II Receptor Blocker (Losartan) on serum potassium (K) level in patients with known history of high normal serum K (mean = 4.8) while on treatment with ACEIs or Angiotensin II Receptor Blockers (ARBs).

Topics: Adult; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Cross-Over Studies; Female; Humans; Hyperkalemia; Kidney Failure, Chronic; Lisinopril; Losartan; Male; Middle Aged

Progression of renal failure, despite renoprotection with angiotensin-converting enzyme (ACE) inhibitors in patients with proteinuric nephropathies, may be caused by persistent renal production of transforming growth factor-beta1 (TGF-beta1) through the angiotensin II subtype 1 (AT1) receptors. We tested the hypothesis that AT1-receptor blocker therapy added to a background of chronic maximal ACE inhibitor therapy will result in a reduction in urinary TGF-beta1 levels in such patients. Sixteen patients completed a two-period, crossover, randomized, controlled trial, details of which have been previously reported. All patients were administered lisinopril, 40 mg/d, with either losartan, 50 mg/d, or placebo. Blood pressure (BP) was measured using a 24-hour ambulatory BP monitor. Overnight specimens of urine were analyzed for urine TGF-beta1, protein, and creatinine concentrations. Mean age of the study population was 53 +/- 9 (SD) years; body mass index, 38 +/- 5.7 kg/m2; seated BP, 156 +/- 18/88 +/- 12 mm Hg; and urine protein excretion, 3.6 +/- 0.71 g/g of creatinine. Twelve patients had diabetic nephropathy, and the remainder had chronic glomerulonephritis. At baseline, urinary TGF-beta1 levels were significantly increased in the study population compared with healthy controls (13.2 +/- 1.2 versus 1.7 +/- 1.1 ng/g creatinine; P < 0.001). There was a strong correlation between baseline urine protein excretion and urinary TGF-beta1 level (r2 = 0.53; P = 0.001), as well as systolic BP and urinary TGF-beta1 level (r2 = 0.57; P < 0.001). After 4 weeks of add-on losartan therapy, there was a 38% (95% confidence interval [CI], 16% to 55%) decline in urinary TGF-beta1 levels (13.3 [95% CI, 11.4 to 15.5] to 8.2 pg/mg creatinine [95% CI, 6.2 to 10.7]). The reduction in urinary TGF-beta1 levels occurred independent of changes in mean urinary protein excretion or BP. Thus, proteinuric patients with renal failure, despite maximal ACE inhibition, had increased urinary levels of TGF-beta1 that improved over 1 month of add-on therapy with losartan. We speculate that dual blockade with losartan and an ACE inhibitor may provide additional renoprotection by decreasing renal production of TGF-beta1.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Cross-Over Studies; Drug Therapy, Combination; Female; Humans; Hypertension; Kidney Failure, Chronic; Lisinopril; Losartan; Male; Middle Aged; Proteinuria; Transforming Growth Factor beta

The aim of the study was to determine whether Lisinopril, an ACE-inhibitor (ACEi), was more effective than other antihypertensive agents in slowing the progression of non-diabetic chronic renal diseases in patients with baseline proteinuria < or =1.0 g/day.. In an open, multicentre study all eligible patients entered a 3 months run-in phase during which antihypertensive therapy (with exclusion of ACEi) was adjusted in order to obtain a supine diastolic blood pressure < or =90 mmHg and urinary protein excretion and renal function stability were verified. One hundred and thirty-one patients with chronic renal insufficiency (Clcr between 20-50 ml/min) because of primary renoparenchymal diseases and proteinuria < or =1.0 g/day, were randomized to Lisinopril (L=66) or alternative antihypertensive therapy (C=65). Changes in renal function were assessed by inulin (Clin) clearance.. During the follow-up period of 22.5+/-5.6 months, Clin did not change significantly in group L (-1.31+/-0.6 ml/min/1.73 m(2)) differing significantly from group C in which it declined markedly (-6.71+/-3.6 ml/min/1.73 m(2)) (P<0.04). Seven patients experienced adverse events that prompted discontinuation of treatment: four in group L and three in group C; in addition seven patients showed severe deterioration in renal function requiring dialysis: two in group L and five in group C. The overall risk of the combined end-points: need for dialysis or halving of GFR was significantly higher in group C versus group L. During the study the mean value for systolic blood pressure was 137.8+/-14.6 SD mmHg in group L and 140.8+/-14.1 SD mmHg in group C; the mean difference between groups, during and at the end of the study, was 2 mmHg (NS). The mean diastolic blood pressure during the study was 83.8+/-8.6 SD mmHg in group L and 84.3+/-7.56 SD mmHg in group C; during and at the end of the study the mean diastolic difference between groups was 1 mmHG:. This study, employing a sensitive measurement of renal function and with similar blood pressure in both groups, provides support to the hypothesis that ACEi have a specific renoprotective effect, in addition to blood pressure control, also in patients with mild proteinuria.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Antineoplastic Agents; Blood Pressure; Chronic Disease; Diastole; Disease Progression; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Prospective Studies; Protective Agents; Proteinuria

Prolonged angiotensin-converting enzyme (ACE) inhibitor therapy leads to angiotensin I (Ang I) accumulation, which may "escape" ACE inhibition, generate Ang II, stimulate the Ang II subtype 1 (AT1) receptor, and exert deleterious renal effects in patients with chronic renal diseases. We tested the hypothesis that losartan therapy added to a background of chronic (>3 months) maximal ACE inhibitor therapy (lisinopril 40 mg q.d.) will result in additional Ang II antagonism in patients with proteinuric chronic renal failure with hypertension.. Sixteen patients with proteinuric moderately advanced chronic renal failure completed a two-period, crossover, randomized controlled trial. Each period was one month with a two-week washout between periods. In one period, patients received lisinopril 40 mg q.d. along with other antihypertensive therapy, and in the other, losartan 50 mg q.d. was added to the previously mentioned regimen. Hemodynamic measurements included ambulatory blood pressure monitoring (ABP; Spacelabs 90207), glomerular filtration rate (GFR) with iothalamate clearances and cardiac outputs by acetylene helium rebreathing technique. Supine plasma renin activity and plasma aldosterone and 24-hour urine protein were measured in all patients.. Twelve patients had diabetic nephropathy, and four had chronic glomerulonephritis. The mean age (+/- SD) was 53 +/- 9 years. The body mass index was 38 +/- 5.7 kg/m(2), and all except two patients were males. Seated cuff blood pressure was 156 +/- 18/88 +/- 12 mm Hg. The pulse rate was 77 +/- 11 per min, and the cardiac index was 2.9 +/- 0.5 L/min/m(2). Mean log 24-hour protein excretion/g creatinine or overall ABPs did not change. Mean placebo subtracted, losartan-attributable change in protein excretion was +1% (95% CI, -20% to 28%, P = 0.89). Similarly, the change in systolic ambulatory blood pressure (ABP) was 4.6 mm Hg (-5.7 to 14.9, P = 0.95), and diastolic ABP was 1.5 mm Hg (-4.5 to 7.6, P = 0.59). No change was seen in cardiac output. However, there was a mean 14% increase (95% CI, 3 to 26%, P = 0.017) in GFR attributable to losartan therapy. A concomitant fall in plasma renin activity by 32% was seen (95% CI, -15%, - 45%, P = 0.002). No hyperkalemia, hypotension, or acute renal failure occurred in the trial. These results were not attributable to sequence or carryover effects.. Add-on losartan therapy did not improve proteinuria or ABP over one month of add on therapy. Improvement of GFR and fall in plasma renin activity suggest that renal hemodynamic and endocrine changes are more sensitive measures of AT1 receptor blockade. Whether add-on AT1 receptor blockade causes antiproteinuric effects or long-term renal protection requires larger and longer prospective, randomized controlled trials.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aldosterone; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Cardiac Output; Cross-Over Studies; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Lisinopril; Losartan; Male; Middle Aged; Proteinuria; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renal Circulation; Renin; Urine

To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril.. Patients with congestive heart failure (CHF, NYHA Class II-IV) and chronic renal insufficiency (creatinine clearance

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalaprilat; Female; Fosinopril; Heart Failure; Humans; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Peptidyl-Dipeptidase A; Time Factors

Angiotensin-converting enzyme (ACE) inhibitors may exacerbate anemia in patients with chronic renal failure, as well as in dialysis patients. To better answer this question, a prospective, crossover study was conducted to evaluate the effect of ACE inhibitors on recombinant human erythropoietin (rHuEPO) requirements in hemodialysis patients. Patients administered an ACE inhibitor when entering the study remained on this drug for the initial 4 months and were then switched to another antihypertensive agent for 4 more months. Patients not initially administered an ACE inhibitor were switched to lisinopril at 4 months. rHuEPO doses were adjusted using a sliding scale based on weekly laboratory hematocrit values. The inclusion criteria were met by 51 patients undergoing dialysis. Demographics were as follows: 61% were women, 64% were black, 46% had diabetes, average age was 53.2 +/- 13.3 years, and time on hemodialysis was 38.0 +/- 44.5 months. Thirty-three patients completed the study. Hematocrit averaged 32.7% +/- 1.9% while on ACE inhibitor therapy and 33.1% +/- 2.1% off ACE inhibitor therapy (P = 0.217). There was no difference in rHuEPO dose per treatment during each period (3,500 +/- 1,549 U on ACE inhibitor therapy versus 3,312 +/- 1,492 U off ACE inhibitor therapy; P = 0.300). No significant differences were found in degree of blood pressure control or various clinical and laboratory parameters that might be associated with rHuEPO resistance between the two periods. Similarly, no differences were found in hospitalization days, duration of infections, or transfusion requirements. These findings suggest that ACE inhibitors do not contribute to rHuEPO resistance in hemodialysis patients.

Topics: Anemia; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Blood Transfusion; Cross-Over Studies; Diabetes Complications; Drug Resistance; Epoetin Alfa; Erythropoietin; Female; Follow-Up Studies; Hematinics; Hematocrit; Hospitalization; Humans; Infections; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Prospective Studies; Recombinant Proteins; Renal Dialysis; Time Factors

This study was undertaken to compare the effects of chronic angiotensin-converting enzyme (ACE) inhibition on blood pressure (BP) and renal hemodynamics in older black and nonblack hypertensive patients with chronic renal insufficiency. A multicenter, placebo lead-in double-blind, parallel group study was performed to compare the antihypertensive efficacy and renal hemodynamic response to the once-daily ACE inhibitor fosinopril (n = 14) and lisinopril (n = 13) over a 22-week period. The study goal was to lower diastolic blood pressure (DBP) to 90 mm Hg or less. Furosemide was added after 6 weeks if blood pressure goal was not achieved. At outpatient clinics at university medical centers, 27 older hypertensive patients (> or = 45 years; 12 blacks, 15 nonblacks; 19 male, eight female) with DBP of 95 mm Hg or higher and 4-hour creatinine clearance 20 to 70 mL/min/1.73 m2 were studied. Changes (delta) from baseline in BP, glomerular filtration rate (GFR), and renal plasma flow (RPF) were measured. Mean systolic blood pressure (SBP) and DBP decreased significantly and to a similar extent in randomized groups: fosinopril (mean +/- SEM) delta DBP at 6 weeks was -13 +/- 2 (P < 0.0001; 95% CI, -16 to -9) and at 22 weeks was -12 +/- 2 (P < 0.0001; 95% CI, -16 to -9); lisinopril delta DBP at 6 weeks was -14 +/- 6 (P < 0.0001; 95% CI, -10 to -18) and at 22 weeks was -16 +/- 2 (P < 0.0001; 95% CI, -12 to -21). GFR and RPF did not change significantly in either group. BP was significantly reduced and to a similar extent in blacks and nonblacks: for blacks, delta DBP at 6 weeks was -11 +/- 3 (P < 0.05; 95% CI, -0.01 to -9) and at 22 weeks was -16 +/- 2 (P < 0.0001; 95% CI, -11 to -20); for nonblacks, delta DBP at 6 weeks was -14 +/- 1 (P < 0.0001; 95% CI, -12 to -17) and at 22 weeks was -12 +/- 2 (P < 0.0001; 95% CI, -16 to -8). Eight patients (five blacks and three nonblacks) required an addition of furosemide after 6 weeks to reach the DBP goal of < or = 90 mm Hg at 22 weeks. GFR was not significantly altered for either racial group at 6 weeks; however, at 22 weeks; however, at 22 weeks, GFR decreased significantly in blacks (delta GFR, -16 +/- 5; P < 0.006; 95% CI, -26 to -5) and tended to increase in nonblacks (delta GFR, 7 +/- 6; P > 0.25). delta GFR correlated directly with the delta RPF (delta GFR = 0.0611* delta RPF -2.35 +; r = 0.68; P < 0.003). There was no correlation between delta MAP and delta GFR or delta RPF in blacks or nonblacks. We conclude that chroni

Topics: Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Black People; Double-Blind Method; Female; Fosinopril; Glomerular Filtration Rate; Humans; Hypertension; Infant, Newborn; Kidney; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Prospective Studies

Calcium channel blockers facilitate the renal excretion of sodium and this effect is maintained during chronic administration of these drugs. However, it is unknown whether this natriuretic effect remains despite the presence of a decreased renal function.. To compare the natriuretic capacity of nifedipine gastrointestinal therapeutic system (GITS) and lisinopril in patients with mild-to-moderate chronic renal failure.. An open-label, randomized, comparative study was conducted to compare the natriuretic capacity of nifedipine GITS and lisinopril in the presence of mild-to-moderate renal failure (creatinine clearance 30-80 ml/min). After a wash-out period of 4 weeks an intravenous saline infusion (30 ml/kg of body weight of isotonic saline in 4 h) was performed and repeated after 4 weeks of active therapy. Two sex- and age-matched groups of hypertensive patients (n = 25) were included in the study. Renal failure was diagnosed as secondary to nephrosclerosis in all the patients.. A significant increase in the renal capacity to excrete the sodium load was observed in patients receiving nifedipine GITS (n = 11) but not in those taking lisinopril (n = 13). Both drugs controlled blood pressure to a similar extent. No changes were observed in body weight, glomerular filtration rate and renal plasma flow (measured as inulin and paraaminohippurate clearances). A significant drop was observed in urinary albumin excretion after lisinopril, but not after nifedipine. Heart rate was higher in nifedipine group.. The natriuretic capacity of nifedipine GITS remains despite the presence of mild-to-moderate chronic renal failure. Such an effect takes place in the absence of changes in renal hemodynamics, suggesting that it is caused by a direct tubular effect.

Topics: Administration, Oral; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Natriuresis; Nifedipine; Prospective Studies; Sodium; Treatment Outcome

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

Topics: Adult; Basement Membrane; Captopril; Double-Blind Method; Female; Glomerulonephritis; Humans; Hypertension, Renal; Kidney Failure, Chronic; Kidney Glomerulus; Lisinopril; Male; Middle Aged; Prospective Studies; Proteinuria; Renal Circulation

The incidence of end stage kidney disease (ESKD) is increasing in Ghana as with the rest of the world. This study compared the sociodemographic, diagnostic characteristics (clinical, biochemical and imaging) and clinical outcomes of ESKD patients who chose either renal replacement therapy (RRT) or conservative therapy as well as the factors that influenced their choice.. We retrospectively reviewed the records of 382 ESKD patient from 2006 to 2018. The data was collected from the Nephrology Clinic at the Komfo Anokye Teaching Hospital (KATH). Sociodemographic, diagnostic (clinical, biochemical and imaging) and therapeutic data were obtained, organized and analyzed with Statistical Package for the Social Sciences (SPSS).. Of the 382 patients, 321 had conservative therapy whiles 61 had renal replacement therapy. The mean age of participants was 47.71 ± 16.10 years. Bipedal swelling (16.8%), fatigue (10.4%) and facial swelling (9.2%) were the major clinical features. Chronic glomerulonephritis (31.4%), hypertension (30.3%) and diabetes mellitus nephropathy (28.2%) were the most frequent predisposing conditions. Nifedipine (82.0%), bisoprolol (32.8%), aspirin (19.7%), ranitidine (26.2%), metformin (13.1%) and lasix (78.7%) were commonly used by the RRT patients than their conservative therapy counterparts. Compared to their RRT counterparts, patients on conservative therapy were more on irbesartan/lisinopril (57.9%) and sodium hydro carbonate (NaHCO. Patients on conservative therapy have worse clinical outcomes than their RRT counterparts. Early referrals to nephrologist as well as subsidized RRT should be targeted.

Topics: Adult; Aspirin; Bisoprolol; Conservative Treatment; Furosemide; Ghana; Humans; Irbesartan; Kidney Failure, Chronic; Lisinopril; Metformin; Middle Aged; Nifedipine; Ranitidine; Renal Replacement Therapy; Retrospective Studies; Sodium

Increased visit-to-visit variability of BP is associated with cardiovascular disease risk. We examined the association of visit-to-visit variability of BP with renal outcomes among 21,245 participants in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.. We measured mean BP and visit-to-visit variability of BP, defined as SD, across five to seven visits occurring 6-28 months after participants were randomized to chlorthalidone, amlodipine, or lisinopril. The composite outcome included incident ESRD after assessment of SD of systolic BP or ≥50% decline in eGFR between 24 months and 48 or 72 months after randomization. We repeated the analyses using average real variability and peak value of systolic BP and for visit-to-visit variability of diastolic BP.. Over a mean follow-up of 3.5 years, 297 outcomes occurred. After multivariable adjustment, including baseline eGFR and mean systolic BP, the hazard ratios for the composite end point were 1.29 (95% confidence interval [95% CI], 0.75 to 2.22), 1.76 (95% CI, 1.06 to 2.91), 1.46 (95% CI, 0.88 to 2.45), and 2.05 (95% CI, 1.25 to 3.36) for the second through fifth (SD of systolic BP =6.63-8.82, 8.83-11.14, 11.15-14.56, and >14.56 mmHg, respectively) versus the first (SD of systolic BP <6.63 mmHg) quintile of SD of systolic BP, respectively (P trend =0.004). The association was similar when ESRD and a 50% decline in eGFR were analyzed separately, for other measures of visit-to-visit variability of systolic BP, and for visit-to-visit variability of diastolic BP.. Higher visit-to-visit variability of BP is associated with higher risk of renal outcomes independent of mean BP.

Topics: Aged; Amlodipine; Antihyperkalemic Agents; Blood Pressure; Blood Pressure Determination; Chlorthalidone; Disease Progression; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Proportional Hazards Models; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Risk Factors; Time Factors; Treatment Outcome

The benefit of dual blockade of the renin-angiotensin system is limited by adverse effects. We performed a secondary analysis of the Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) Study to describe the effect of increased intensity of renin-angiotensin system blockade on the incidence, risk factors, and outcomes of AKI.. The incidence of AKI was 12.2 (95% confidence interval, 10.5 to 14.0) versus 6.7 (95% confidence interval, 5.6 to 8.2) per 100 patient-years in the combination arm versus monotherapy arms (P<0.001). Individuals with AKI were more likely to develop the primary study end point of death, ESRD, or decline in kidney function (hazard ratio, 1.78; 95% confidence interval, 1.34 to 2.26; P<0.001). Patients with AKI in the combination arm had greater recovery of kidney function (75.9% versus 66.3%; P=0.04), lower 30-day mortality (4.7% versus 15.0%; P<0.01), and lower hazard for development of the primary study end point (hazard ratio, 0.60; 95% confidence interval, 0.37 to 0.98).. Dual renin-angiotensin system blockade was associated with an increased risk of AKI compared with monotherapy, but AKI in the setting of monotherapy was associated with lower rates of recovery of kidney function, higher mortality, and higher risk of progression of kidney disease.

Topics: Acute Kidney Injury; Aged; Albuminuria; Blood Pressure; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Heart Failure; Humans; Incidence; Kidney Failure, Chronic; Lisinopril; Losartan; Male; Middle Aged; Recovery of Function; Renin-Angiotensin System; Risk Factors

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

Vitamin D deficiency is common in chronic kidney disease (CKD). Increased urinary loss of vitamin D binding protein (VDBP), the main transporter of 25-hydroxyvitamin D(3) in the circulation, has been postulated to contribute to vitamin D deficiency in proteinuria. To test this hypothesis we analyzed urinary and plasma levels of VDBP, 25-hydroxyvitamin D(3) and 1,25-dihydroxyvitamin D(3) from proteinuric patients, before and after antiproteinuric interventions. We performed a post-hoc analysis of a clinical trial in CKD patients (n=13, creatinine clearance median 60 (range 25-177) ml/min) subjected to the following study periods: washout (no antiproteinuric treatment, 4 weeks), lisinopril 40mg QD (ACEi, 6 weeks), or indomethacin 75mg BID (NSAID, 4 weeks) in randomized sequence. Healthy subjects screened for donation (n=10) served as controls. Plasma and urine VDBP levels were measured by ELISA, 25-hydroxyvitamin D(3) levels by LC-MS and 1,25-dihydroxyvitamin D(3) levels by radioimmunoassay. In CKD patients urinary VDBP excretion was strongly increased (median (range) 5413 (155-211,027) μg/24h) as compared to healthy controls (64 (23-111) μg/24h, p<0.001). Both NSAID and ACEi significantly decreased urinary VDBP excretion, in proportion to proteinuria reduction. Plasma VDBP, 25-hydroxyvitamin D(3) and 1,25-dihydroxyvitamin D(3) levels, however, were similar between patients and controls and not affected by antiproteinuric intervention. Urinary VDBP excretion is markedly increased in proteinuria and responds to antiproteinuric treatment. Urinary VDBP loss is not associated with plasma VDBP or vitamin D(3) levels, suggesting that urinary loss of VDBP does not affect vitamin D status.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Cyclooxygenase Inhibitors; Drug Therapy, Combination; Female; Humans; Hydroxycholecalciferols; Indomethacin; Kidney Failure, Chronic; Lactones; Lisinopril; Male; Middle Aged; Proteinuria; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Sulfones; Vitamin D Deficiency; Vitamin D-Binding Protein

There is ongoing controversy whether angiotensin-converting enzyme inhibitors (ACE-I) contribute to anaemia by causing hyporesponsiveness to erythropoiesis-stimulating agents (ESA). However, it is unknown whether or not plasma levels or area under the curve (AUC) of ACE-I are associated with responsiveness to ESA therapy.. We examined the association between lisinopril AUC, lisinopril plasma levels and ESA requirements that was assessed using an ESA index [(ESA IU/week/body weight kg)/(haemoglobin g/dL)]. After screening 184 haemodialysis patients, 14 fulfilled the inclusion criteria, mainly long-term use of oral lisinopril in the upper end of dosage range for this population with stable haemoglobin levels and intravenous ESA therapy. Lisinopril plasma levels were measured at eight different time points (predialysis, immediate post-dialysis and hourly for 6h thereafter; AUC1), and the seven post-dialysis lisinopril plasma levels were used for calculation of AUC2.. The mean ESA index of all patients was 27·90±25·84 (IU/week/kg)/(g/dL). Average lisinopril AUC1 was 1212·48±1209·75 [mg*h/L], whereas AUC2 averaged 947·67±977·07 [mg*h/L]. Two patients (14%) had no detectable lisinopril plasma levels, indicating their noncompliance. There was no association between ESA index and AUC or plasma levels of lisinopril at any time point for all 14 or for the 12 compliant patients.. Our study shows that long-term, high-dose lisinopril therapy has no effect on ESA responsiveness. Thus, avoidance or a dose reduction of ACE-I in dialysis patients will not necessarily lead to reduced ESA requirements and costs.

Topics: Anemia; Angiotensin-Converting Enzyme Inhibitors; Area Under Curve; Cross-Sectional Studies; Female; Hematinics; Humans; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Renal Dialysis

The aim of this study was to develop and characterize a rat glomerulonephritis model, which progresses to renal fibrosis and renal failure. A single immunization of female WKY rats with more than 10 microg of recombinant alpha3(IV)NC1 protein caused severe proteinuria followed by progressive increases in plasma creatinine and blood urea nitrogen (BUN) level within 42 days. Sequential histopathological evaluation revealed crescent formation in glomeruli followed by tubular dilation and interstitial fibrosis. Hydroxyproline content and expression of type I collagen and smooth muscle actin genes in the renal cortex increased as renal dysfunction progressed. Furthermore, the TGF-beta1 level in the renal cortex also increased. In the evaluation of antinephritic agents in this model, prednisolone and mycophenolate mofetil (MMF) treatment significantly decreased plasma creatinine and BUN, and suppressed renal fibrosis and histological changes involving crescent formation, compared with the vehicle-treated nephritic rats, whereas lisinopril treatment failed to improve renal function and histology. We demonstrated that immunization of female WKY rats with a sufficient dose of recombinant alpha3(IV)NC1 induces end-stage kidney disease accompanied by renal fibrosis. The relatively short period needed to induce the disease and the high incidence of functional and structural changes were considered a great advantage of this model for clarifying the mechanisms of progressive glomerulonephritis and for evaluating agents used to treat renal failure.

Topics: Actins; Animals; Autoantigens; Collagen Type I; Collagen Type IV; Creatinine; Disease Models, Animal; Female; Gene Expression; Glomerulonephritis; Hydroxyproline; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Lisinopril; Mycophenolic Acid; Prednisolone; Rats; Rats, Inbred WKY; Recombinant Proteins; Transforming Growth Factor beta1

A 67-year old patient underwent a kidney biopsy because of newly diagnosed hypertension, haemolytic anemia with fragmentocytes and acute kidney failure requiring dialysis therapy. The biopsy showed thrombotic microangiopathy. Since last winter Raynaud's phenomenon and changes of hands and lips were recognised.. Initial immunological tests revealed anti-nuclear antibodies (ANA) but neither anti-centromere nor anti-Scl70 antibodies. The positive analysis of anti-RNA polymerase III antibodies confirmed the clinical suspicion of scleroderma renal crisis in the setting of first diagnosis of systemic sclerosis.. After diagnosis therapy with lisinopril, candesartan and amlodipin was established. Four months after discharge dialysis dependency persisted.. Scleroderma renal crisis is an important differential diagnosis in the setting of acute kidney failure. Medical history, clinical examination and immunological test confirm the diagnosis. The mainstay of therapy is aggressive blood pressure control with ACE-inhibitors (or angiotensin receptor blocking agents).

Topics: Aged; Amlodipine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antibodies, Antinuclear; Benzimidazoles; Biopsy; Biphenyl Compounds; Combined Modality Therapy; Diagnosis, Differential; Humans; Kidney; Kidney Failure, Chronic; Kidney Glomerulus; Lisinopril; Male; Plasmapheresis; Renal Dialysis; RNA Polymerase II; Scleroderma, Systemic; Tetrazoles; Thrombotic Microangiopathies; Vasodilator Agents

Hyperkalemia is an electrolyte abnormality that can lead to severe consequences. Paralysis induced by hyperkalemia has been described in only a few reports. We describe a 60-year-old man who experienced paralysis presumably due to hyperkalemia. He presented to the emergency department with severe weakness in all extremities. The patient's serum potassium concentration was greater than 8 mEq/L and his serum creatinine concentration was 7 mg/dl. Findings on electrocardiography were abnormal. Of note, his drug therapy included lisinopril and naproxen. After treatment for hyperkalemia, the patient's symptoms resolved; however, he was admitted for further workup for renal failure. The patient was discharged after approximately 1 week with a diagnosis of end-stage renal disease. Use of the Naranjo adverse drug reaction probability scale indicated a probable relationship (score of 5) between the patient's paralysis and hyperkalemia. Although hyperkalemia as a cause of paralysis is extremely rare, clinicians should be aware of this potentially life-threatening, noncardiac toxicity.

Topics: Creatinine; Humans; Hyperkalemia; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Naproxen; Paralysis

The number of patients with chronic kidney disease (CKD) has continuously grown worldwide. Treatment with antihypertensive agents reduces the rate of progression of CKD, however, there is still a large unmet need to develop strategies for the treatment of CKD. Although we have previously reported that the antifibrotic agent, SMP-534 inhibits the progression of CKD, it is unknown whether combination therapy with SMP-534 and antihypertensive agent shows additive effects on CKD. In present study, we examined whether combination therapy with SMP-534 and the antihypertensive agent, lisinopril is more effective than single therapy with SMP-534 or lisinopril on five-sixths nephrectomized (5/6Nx) rat model. Combination therapy with SMP-534 (50 mg/kg) and lisinopril (5 mg/kg) significantly decreased urinary albumin excretion, blood urea nitrogen (BUN) and serum creatinine and increased creatinine clearance in 5/6Nx rats. On the other hands, single treatment with SMP-534 or lisinopril did not improve renal function at this dose. In addition, combination therapy with SMP-534 and lisinopril significantly decreased extracellular matrix (ECM) accumulation in renal glomeruli and tubulointerstitial injury. These data suggest that combination therapy with an antifibrotic agent and an antihypertensive agent may offer a new therapeutic option for suppressing the progression of CKD.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzamides; Blood Urea Nitrogen; Creatinine; Disease Models, Animal; Drug Therapy, Combination; Extracellular Matrix; Kidney; Kidney Failure, Chronic; Lisinopril; Male; Nephrectomy; Protective Agents; Rats; Rats, Sprague-Dawley

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Antimanic Agents; Bipolar Disorder; Diuretics; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hydrochlorothiazide; Hypertension, Renal; Kidney Failure, Chronic; Lisinopril; Lithium; Middle Aged; Renal Dialysis; Risk Factors

Zhao et al. demonstrated that chronic renal failure was associated with lipid redistribution in the kidney and other organs. We discuss three types of lipid redistribution in the context of inflammatory stress, which might help to explain many conflicting clinical observations in relation to lipid-mediated renal and vascular injury. An assessment of lipid redistribution may provide a new target for therapeutic intervention.

Topics: Adipocytes; Animals; Disease Models, Animal; Intra-Abdominal Fat; Kidney; Kidney Failure, Chronic; Lipid Metabolism; Lisinopril; Nephrectomy; Rats; Rats, Sprague-Dawley; Subcutaneous Fat; Time Factors

Lipid derangements are assumed to contribute to the elevated cardiovascular risk in proteinuric patients. The impact of proteinuria on reverse cholesterol transport (RCT) is unknown. The first step in RCT, cellular cholesterol efflux to plasma, may be altered in proteinuria, consequent to changes in pre-beta high-density lipoprotein (HDL) formation and plasma phospholipid transfer protein (PLTP) activity.. In six non-diabetic male patients with nephrotic-range proteinuria and 12 matched healthy men, plasma (apo)lipoproteins, pre-beta HDL formation, PLTP activity as well as the ability of plasma to promote cholesterol efflux out of cultured human skin fibroblasts were determined. These variables were also measured in response to antiproteinuric treatment, consisting of single and dual RAAS blockade by losartan and lisinopril.. Plasma total cholesterol (P<0.05), triglycerides (P<0.05), apolipoprotein (apo) A-I (P<0.001), apo B (P<0.001), PLTP activity (P<0.005) and pre-beta HDL formation (P<0.001) were higher in proteinuric patients. Cellular cholesterol efflux to plasma from proteinuric patients was 41% higher than to plasma from healthy subjects (P<0.001). Reduction of proteinuria from 5.0 to 1.4 g/day by dual RAAS blockade was associated with a 23% reduction in plasma apo B levels (P<0.05). Pre-beta HDL formation and plasma PLTP activity did not change significantly. Combined antiproteinuric treatment did not reduce the elevated cellular cholesterol efflux.. Cellular cholesterol efflux to plasma from patients with nephrotic-range proteinuria is enhanced, in conjunction with elevated pre-beta HDL formation and plasma PLTP activity. These changes may attenuate the cardiovascular risk associated with proteinuria-associated hyperlipidaemia. Antiproteinuric therapy lowers plasma apo B, but does not affect cell-derived cholesterol efflux, suggesting that this therapy beneficially affects cardiovascular risk in proteinuric patients.

Topics: Adult; Analysis of Variance; Apolipoproteins; Biological Transport; Case-Control Studies; Cholesterol, HDL; Humans; Hyperlipidemias; Kidney Failure, Chronic; Kidney Function Tests; Lisinopril; Losartan; Male; Middle Aged; Phospholipid Transfer Proteins; Probability; Prognosis; Proteinuria; Reference Values; Risk Factors; Sensitivity and Specificity; Severity of Illness Index

Topics: Aged; Amlodipine; Antihypertensive Agents; Cardiovascular Diseases; Chlorthalidone; Chronic Disease; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney Diseases; Kidney Failure, Chronic; Lisinopril; Male; Middle Aged; Risk Factors

Topics: Angiotensin-Converting Enzyme Inhibitors; Creatinine; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Lisinopril; Middle Aged; Practice Guidelines as Topic; Prospective Studies; Renal Dialysis; Renin-Angiotensin System; Time Factors

Chronic renal failure (CRF) is associated with altered systemic arterial tone and hypertension. Myogenic constriction and endothelium-derived hyperpolarizing factor (EDHF)-dependent relaxation represent major vasoregulatory mechanisms in small systemic arteries. Elevated myogenic response and impaired EDHF might participate in the development of essential hypertension; however, their role in CRF-related hypertension is unknown. We investigated whether myogenic response and EDHF are altered in subtotally nephrectomized (sNX) rats and whether these changes are modifiable by chronic treatment with angiotensin-converting enzyme (ACE) inhibitor.. In a pressure arteriograph, myogenic constriction and EDHF-mediated relaxation were evaluated in small mesenteric arteries isolated from male Wistar rats 15 weeks after either sham operation (n = 7) (SHAM), sNX (n = 12) or sNX followed by 9 weeks of treatment with lisinopril (sNX + LIS, 2.5 mg/kg, n = 13).. Surprisingly, myogenic response was reduced in hypertensive CRF rats (maximal myogenic tone: 37 +/- 2 and 18 +/- 4%, P < 0.01; peak myogenic index: -0.80 +/- 0.08 and -0.40 +/- 0.12%/mmHg, P < 0.05 in SHAM and sNX respectively). At the same time EDHF-mediated relaxation was also impaired (maximal response: 92 +/- 2 and 77 +/- 5%, P < 0.01; pD2: 6.5 +/- 0.1 and 5.9 +/- 0.1, P < 0.05). Both myogenic response and EDHF were inversely related to the severity of renal failure and restored by treatment with lisinopril to levels found in SHAM animals.. Major constrictive (myogenic) and dilatory (EDHF) mechanisms of small systemic arteries are impaired in hypertensive CRF rats. These alterations do not seem to participate in the development of hypertension, being rather directly related to the severity of renal impairment. Both systemic vascular changes might be restored by renoprotective treatment with ACE inhibitor.

Topics: Angiography; Angiotensin-Converting Enzyme Inhibitors; Animals; Biological Factors; Hypertension; Kidney Failure, Chronic; Lisinopril; Male; Mesenteric Arteries; Models, Animal; Muscle Contraction; Muscle, Smooth; Nephrectomy; Rats; Rats, Wistar; Vasoconstriction; Vasodilation

Topics: Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Drug Therapy, Combination; Humans; Kidney Failure, Chronic; Lisinopril; Losartan; Male; Polycythemia; Treatment Outcome

Impaired renal function occurs in about 50% of patients suffering from type 2 diabetes, and diabetic nephropathy has become the leading cause of endstage renal disease. Reduction of blood pressure to levels around 120/80 mmHg is one of the most effective way to slow progression of diabetic nephropathy. Recent meta-analyses, however, have emphasized on the fact that ACE inhibitors (ACEI) and non-dihydropyridine calcium channel blockers (NDHP-CCB) exert nephro-protective effects which go beyond the effect of blood pressure reduction. This has lately been confirmed by a prospective trial in comparison to the betablocker atenolol. Based on these data, demographics of the Swiss population, literature data on mortality rates of type 2 diabetics with impaired renal function and studies on true costs of antihypertensives, we calculated the costs of a longterm intervention (20 years) with antihypertensives in 3536 middle-aged Swiss patients with type 2 diabetes and macro-albuminuria whose antihypertensive regimen was based either on the ACEI lisinopril, or the ND-HP-CCB verapamil, or the betablocker atenolol. Under atenolol, acquisition costs were lowest, whereas faster loss of renal function over time increased mortality rate and thus reduced the number of patients to be treated. Nevertheless, due to the fact that patients reached uremia and had to be dialyzed, 20 years of atenolol-based regimen with costs of 316 millions of Swiss francs turned out to be much more expensive than the lisinopril- or the verapamil-based regimen with 121 and 38 millions of Swiss francs, respectively. Thus, low acquisition cost is not necessarily the only important determinant of overall costs of drug therapy.

Topics: Adult; Antihypertensive Agents; Atenolol; Cost Savings; Cost-Benefit Analysis; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Drug Costs; Female; Humans; Kidney Failure, Chronic; Kidney Function Tests; Lisinopril; Male; Middle Aged; Models, Economic; Switzerland; Verapamil

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: Aged; Angiotensin-Converting Enzyme Inhibitors; Beverages; Diabetes Mellitus, Type 1; Humans; Hyperkalemia; Kidney Failure, Chronic; Lisinopril; Male; Rosales

Chronic renal diseases progress to organ insufficiency, which may require replacement therapy within one to three decades even independently of the type of initial insults. In the majority of cases, the degrees of proteinuria and interstitial leukocyte infiltration and scarring are strictly correlated with the rate of disease progression. This study tests the hypothesis that excess intrarenal protein traffic may cause lymphocyte-dependent interstitial injury that, while not fully controlled by antiproteinuric therapy, can be further inhibited by concomitant immunosuppression. A primarily nonimmune model was used to reproduce progressive renal disease due to a critical loss of nephron mass. Angiotensin-converting enzyme (ACE) inhibitor limited proteinuria, interstitial inflammation, MHC class II antigen expression, and severe lesions. Combined treatment with ACE inhibitor and a specific antilymphocyte agent, mycophenolate mofetil, dramatically attenuated macrophage and T cell infiltration, MHC-class II overexpression, dendritic cells, and all manifestations of the disease. Evidence of lymphocyte-mediated renal injury in the setting of excess protein traffic provides the basis for combining ACE inhibition and immunosuppression to halt progression of proteinuric kidney disease and minimize the need for dialysis or transplantation.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Disease Models, Animal; Immunosuppressive Agents; Kidney; Kidney Failure, Chronic; Lisinopril; Lymphocytes; Male; Mycophenolic Acid; Proteinuria; Rats; Rats, Sprague-Dawley

Topics: Antihypertensive Agents; Dysgeusia; Female; Humans; Hypertension; Kidney Failure, Chronic; Lisinopril; Losartan; Middle Aged; Polycystic Kidney, Autosomal Dominant; Stomatitis, Aphthous

Many studies have consistently documented that angiotensin converting enzyme (ACE) inhibitors prevent proteinuria and glomerulosclerosis in progressive renal disease, but very few data are available on whether they also prevent renal failure and death. The mechanisms of the beneficial effect of ACE inhibition are only partially understood. Recent data suggest that angiotensin II modulates renal synthesis of endothelin-1, a vasoactive peptide implicated in the process of renal injury. Here we investigated in a long-term study whether ACE inhibition ameliorated renal function in uninephrectomized (UNx) male MWF/Ztm rats. Three groups of rats at nine weeks of age underwent UNx or sham-operation. Nephrectomized animals were left untreated or treated with the ACE inhibitor lisinopril in drinking water. In untreated UNx animals systolic blood pressure, serum creatinine, urinary protein and renal synthesis of endothelin-1, evaluated by its urinary excretion, were significantly increased, as compared with control animals with two kidneys. End-stage renal failure developed in all untreated UNx rats that died within 9 to 14 months from UNx. ACE inhibitor significantly reduced systolic blood pressure, completely prevented proteinuria and renal function deterioration, and reduced endothelin-1 excretion. All UNx rats treated with lisinopril were alive 14 months after UNx. These results show that ACE inhibition prevents end-stage renal failure induced by UNx in male MWF/Ztm, and that the beneficial effects of angiotensin II inhibition in this model are related to modulation of renal synthesis of endothelin-1.

Topics: Aging; Animals; Blood Pressure; Creatinine; Disease Models, Animal; Endothelins; Kidney Failure, Chronic; Lisinopril; Male; Nephrectomy; Proteinuria; Rats

We investigated the effects of lisinopril, verapamil, and amlodipine in 26 hypertensive patients with chronic renal disease of varying etiologies. Blood pressure, urine protein excretion, glomerular filtration rate (GFR), and renal blood flow (RBF) (inulin and para-aminohippurate clearance) were determined before and after 2 to 3 months of therapy. All three agents lowered blood pressure with minimal side effects in many, but not all, patients. Patients who had a significant lowering of blood pressure in response to lisinopril and verapamil had favorable renal hemodynamic responses as well--GFR remained stable, RBF was stable or increased, and filtration fraction, renal vascular resistance, and proteinuria tended to decrease. Patients whose blood pressure did not decrease had less favorable responses. In the small number of patients who received amlodipine, lowering of blood pressure was associated with a small decrease in GFR. Our results demonstrate a heterogeneity in response to antihypertensive agents in patients with renal disease. We therefore conclude that treatment of such patients should be individualized, and suggest that choice of therapy depend on adequate blood pressure response in conjunction with stabilization of renal function and urine protein excretion. Our data do not support the use of a drug in these circumstances if it does not lower systemic blood pressure.

Topics: Amlodipine; Antihypertensive Agents; Dipeptides; Hemodynamics; Humans; Kidney Failure, Chronic; Lisinopril; Middle Aged; Potassium; Proteinuria; Renal Circulation; Renin; Verapamil

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

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

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

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

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

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