lisinopril and Proteinuria

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

Lisinopril is an angiotensin-converting-enzyme inhibitor that is largely administered for off-label uses. This study aims to provide a comprehensive review of off-label uses of lisinopril to aid physicians to make evidence-based decisions.. The following bibliographic databases were searched from inception up to 30 March 2017: PubMed, EMBASE, the Cochrane Library, Cochrane Central Register of Controlled Trials, Scopus, Ovid and Proquest. This systematic review sought all randomized trials conducted on adult individuals comparing lisinopril on its off-label uses with alternative drugs or placebos and reported direct or alternative clinical outcomes. Risk of bias assessment by using the Cochrane Collaboration risk-of-bias tool and quality evaluation took place.. Included studies demonstrated significant positive effects of lisinopril on proteinuric kidney disease; however, lisinopril caused a slight reduction of glomerular filtration rate (GFR) especially for patients with GFR < 90 ml min. The identified studies showed that lisinopril was highly effective for proteinuric kidney disease with a minor but inconsiderable decrease in GFR. Positive effects of lisinopril were demonstrated in seven other off-label uses; however, lisinopril cannot be recommended as the first choice for these until further clinical trials confirm these positive effects.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Evidence-Based Medicine; Glomerular Filtration Rate; Humans; Kidney Diseases; Lisinopril; Off-Label Use; Proteinuria; Randomized Controlled Trials as Topic

Topics: Abdominal Pain; Angioedema; Angiotensin-Converting Enzyme Inhibitors; Ascites; Duodenal Diseases; Female; Humans; Intestinal Diseases; Jejunal Diseases; Lisinopril; Middle Aged; Proteinuria; Tomography, X-Ray Computed

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Enalapril; Heart Failure; Humans; Hypertension; Lisinopril; Proteinuria

Persistent proteinuria seems to be a risk factor for progression of renal disease. Its reduction by angiotensin-converting inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) is renoprotective. Our previous pilot study showed that 2-year lisinopril therapy is effective and safe for children with mild IgA nephropathy. When combined with ACEI and ARB, reported results are of greater decrease in proteinuria than monotherapy in chronic glomerulonephritis, including IgA nephropathy. To date, however, there have been no randomized controlled trials in children.. This is an open-label, multicenter, prospective, and randomized phase II controlled trial of 63 children with biopsy-proven proteinuric mild IgA nephropathy. We compared efficacy and safety between patients undergoing lisinopril monotherapy and patients undergoing combination therapy of lisinopril and losartan to determine better treatment for childhood proteinuric mild IgA nephropathy.. There was no difference in proteinuria disappearance rate (primary endpoint) between the two groups (cumulative disappearance rate of proteinuria at 24 months: 89.3% vs 89% [combination vs monotherapy]). Moreover, there were no significant differences in side effects between the two groups.. We propose lisinopril monotherapy as treatment for childhood proteinuric mild IgA nephropathy as there are no advantages of combination therapy.. Clinical trial registry, UMIN ID C000000006, https://www.umin.ac.jp .

Topics: Adolescent; Child; Child, Preschool; Drug Therapy, Combination; Female; Glomerulonephritis, IGA; Humans; Kidney Glomerulus; Lisinopril; Losartan; Male; Prospective Studies; Proteinuria; Severity of Illness Index; Treatment Outcome

Previous randomized controlled trials evaluating the efficacy of mycophenolate mofetil (MMF) in patients with immunoglobulin A nephropathy (IgAN) have produced varying results.. Double-blind placebo-controlled randomized controlled trial.. 52 children, adolescents, and adults with biopsy-proven IgAN in 30 centers in the United States and Canada. Entry criteria: age older than 7 to younger than 70 years; urine protein-creatinine ratio (UPCR), ≥0.6g/g (males) or ≥0.8g/g (females); and estimated glomerular filtration rate ≥ 50mL/min/1.73m(2) (≥40mL/min/1.73m(2) if receiving angiotensin-converting enzyme inhibitor). Mean age, 32±12 (SD) years; 62% men; and 73% white.. Lisinopril (or losartan) plus a highly purified omega-3 fatty acid (Omacor [Pronova Biocare]) was given to 94 patients for 3 months; 52 of the patients with persistent UPCR≥0.6g/g (males) and ≥0.8g/g (females) were randomly assigned to MMF or placebo (target dose, 25-36mg/kg/d) in addition to lisinopril/losartan plus Omacor.. Change in UPCR after 6 and 12 months treatment with MMF/placebo and 12 months after the end of treatment.. UPCR measured on 24-hour urine samples. Glomerular filtration rate estimated with the Schwartz (age < 18 years) or Cockcroft-Gault (age ≥ 18 years) formula.. 44 patients completed 6 months of treatment with MMF (n=22) or placebo (n=22). The trial was terminated early at the recommendation of the Data Monitoring Committee because of the lack of benefit. No patient achieved a complete remission (UPCR<0.2g/g). Mean UPCRs at randomization and after 6 months were 1.45 (95% CI, 1.16-1.75) and 1.40 (95% CI, 1.09-1.70) for MMF and 1.41 (95% CI, 1.17-1.65) and 1.58 (95% CI, 1.13-2.04) for placebo, respectively. The mean difference in UPCR change between these groups (MMF minus placebo) was -0.22 (95% CI, -0.75 to 0.31; P=0.4). Adverse events were rare apart from nausea (MMF, 8.7%; placebo, 3.7%); one of these MMF patients withdrew.. Low patient enrollment and short follow-up.. MMF did not reduce proteinuria significantly in patients with IgAN who had persistent proteinuria after lisinopril/losartan plus Omacor.

Topics: Adolescent; Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Child; Creatinine; Dietary Supplements; Docosahexaenoic Acids; Double-Blind Method; Drug Combinations; Drug Therapy, Combination; Eicosapentaenoic Acid; Female; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Lisinopril; Losartan; Male; Middle Aged; Mycophenolic Acid; Proteinuria; Remission Induction; Treatment Outcome; Young Adult

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

LDL-receptor deficiency may provide a mechanism which contributes to atherogenic lipoprotein abnormalities in experimental nephrosis and in humans with glomerular proteinuria. The proprotein convertase subtilisin-kexin type 9 (PCSK9) pathway plays a key role in lipoprotein metabolism by promoting LDL-receptor degradation. We tested whether plasma PCSK9 is elevated in proteinuric states, and determined relationships of PCSK9 with lipoprotein responses to proteinuria reduction.. Thirty-nine kidney patients (e-GFR 61 ± 29 mL/min/1.73 m(2), proteinuria 1.9 [0.9-3.3] g/day; 19 on statin treatment) were studied during 2 randomized double-blind 6-week periods on either lisinopril (40 mg/day) and a regular sodium diet (194 ± 49 mmol Na+/day; baseline treatment) or lisinopril plus valsartan (320 mg/day) and a low sodium diet (102 ± 52 mmol Na(+)/day; maximal treatment), and compared to age- and sex-matched controls. Maximal treatment decreased proteinuria to 0.5 [0.3-1.1] g/day (P < 0.001).. Plasma PCSK9 was increased at baseline in proteinuric subjects (213 [161-314] vs. 143 [113-190] ug/L in controls, P ≤ 0.001), irrespective of statin use, e-GFR and BMI. PCSK9 correlated with proteinuria at baseline (R = 0.399, P = 0.018) and at maximal antiproteinuric treatment (R = 0.525, P = 0.001), but did not decrease during proteinuria reduction (P = 0.84). Individual changes in total cholesterol (R = 0.365, P = 0.024), non-HDL cholesterol (R = 0.333, P = 0.041), and LDL cholesterol (R = 0.346, P = 0.033) were correlated positively with individual PCSK9 responses. PCSK9 at baseline independently predicted the total/HDL cholesterol ratio response to treatment (P = 0.04).. Plasma PCSK9 was elevated in proteinuria, predicted lipoprotein responses to proteinuria reduction but remained unchanged after proteinuria reduction. Inhibition of the PCSK9 pathway may provide a novel treatment strategy in proteinuric subjects.

Topics: Adult; Diet, Sodium-Restricted; Female; Humans; Lipoproteins; Lisinopril; Male; Middle Aged; Proprotein Convertase 9; Proprotein Convertases; Proteinuria; Serine Endopeptidases; Tetrazoles; Valine; Valsartan

The angiotensin converting enzyme inhibitors (ACEIs) are a group of pharmaceuticals that are used primarily in treatment of hypertension and congestive heart failure, in some cases as the drugs of first choice. The renin-angiotensin system is activated in response to hypotension, decreased sodium concentration in the distal tubule, decreased blood volume and in renal sympathetic nerve stimulation. This study examines the effects of angiotensin converting enzyme inhibitor (Lisinopril) on blood pressure (BP) 131 ± 2.4 and proteinuria 0.198 ± 0.005 in Kurd hypertensive patients, mean arterial blood pressure and proteinuria excretion were measured weekly along the period of 12 weeks. Lisinopril significantly reduced mean arterial blood pressure, and attenuated proteinuria level in patients subjected to this study in lisinopril 10mg dose dependent manner (p<0.05, n=24). In conclusion, lisinopril is of beneficial of renoprotection and in lowering BP.

Topics: Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Creatinine; Female; Humans; Hypertension; Iraq; Lisinopril; Male; Proteinuria; Urinalysis

To compare the effects on proteinuria and blood pressure of addition of dietary sodium restriction or angiotensin receptor blockade at maximum dose, or their combination, in patients with non-diabetic nephropathy receiving background treatment with angiotensin converting enzyme (ACE) inhibition at maximum dose.. Multicentre crossover randomised controlled trial.. Outpatient clinics in the Netherlands.. 52 patients with non-diabetic nephropathy.. All patients were treated during four 6 week periods, in random order, with angiotensin receptor blockade (valsartan 320 mg/day) or placebo, each combined with, consecutively, a low sodium diet (target 50 mmol Na(+)/day) and a regular sodium diet (target 200 mmol Na(+)/day), with a background of ACE inhibition (lisinopril 40 mg/day) during the entire study. The drug interventions were double blind; the dietary interventions were open label.. The primary outcome measure was proteinuria; the secondary outcome measure was blood pressure.. Mean urinary sodium excretion, a measure of dietary sodium intake, was 106 (SE 5) mmol Na(+)/day during a low sodium diet and 184 (6) mmol Na(+)/day during a regular sodium diet (P<0.001). Geometric mean residual proteinuria was 1.68 (95% confidence interval 1.31 to 2.14) g/day during ACE inhibition plus a regular sodium diet. Addition of angiotensin receptor blockade to ACE inhibition reduced proteinuria to 1.44 (1.07 to 1.93) g/day (P=0.003), addition of a low sodium diet reduced it to 0.85 (0.66 to 1.10) g/day (P<0.001), and addition of angiotensin receptor blockade plus a low sodium diet reduced it to 0.67 (0.50 to 0.91) g/day (P<0.001). The reduction of proteinuria by the addition of a low sodium diet to ACE inhibition (51%, 95% confidence interval 43% to 58%) was significantly larger (P<0.001) than the reduction of proteinuria by the addition of angiotensin receptor blockade to ACE inhibition (21%, (8% to 32%) and was comparable (P=0.009, not significant after Bonferroni correction) to the reduction of proteinuria by the addition of both angiotensin receptor blockade and a low sodium diet to ACE inhibition (62%, 53% to 70%). Mean systolic blood pressure was 134 (3) mm Hg during ACE inhibition plus a regular sodium diet. Mean systolic blood pressure was not significantly altered by the addition of angiotensin receptor blockade (131 (3) mm Hg; P=0.12) but was reduced by the addition of a low sodium diet (123 (2) mm Hg; P<0.001) and angiotensin receptor blockade plus a low sodium diet (121 (3) mm Hg; P<0.001) to ACE inhibition. The reduction of systolic blood pressure by the addition of a low sodium diet (7% (SE 1%)) was significantly larger (P=0.003) than the reduction of systolic blood pressure by the addition of angiotensin receptor blockade (2% (1)) and was similar (P=0.14) to the reduction of systolic blood pressure by the addition of both angiotensin receptor blockade and low sodium diet (9% (1)), to ACE inhibition.. Dietary sodium restriction to a level recommended in guidelines was more effective than dual blockade for reduction of proteinuria and blood pressure in non-diabetic nephropathy. The findings support the combined endeavours of patients and health professionals to reduce sodium intake. Trial registration Netherlands Trial Register NTR675.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Chronic Disease; Combined Modality Therapy; Cross-Over Studies; Diet, Sodium-Restricted; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypertension; Kidney Diseases; Lisinopril; Male; Middle Aged; Patient Compliance; Proteinuria; Sodium Chloride, Dietary; Tetrazoles; Treatment Outcome; Valine; Valsartan

Angiotensin-converting enzyme inhibitors in native nephropathies reduce proteinuria and delay progression to renal failure. Data in renal transplantation remain limited. A negative effect on glomerular filtration rate was concluded in a recent systematic review.. In this novel randomized controlled trial, 47 patients with chronic allograft nephropathy, severe renal impairment, and more than or equal to 1 g/24 hr proteinuria were randomized to lisinopril (group A) or other hypotensives (group B) for 1 year. Sodium bicarbonate was given to all patients to treat metabolic acidosis prophylactically (acidosis increases significantly with lisinopril). The annual rate of decline of graft function was measured isotopically (primary outcome) and 24 hr proteinuria, genotyping, radiolabeled polypeptide aprotinin proximal tubular catabolic studies (in group A only) as secondary outcome measurements were undertaken.. At baseline, groups were comparable except for greater proteinuria in group A. After 1 year, the rate of decline of graft function and graft survival were comparable in both groups. Proteinuria decreased significantly in group A patients only. Lisinopril also significantly reduced radiolabeled aprotinin uptake and metabolism, plasma aldosterone, and ammonia excretion. Plasma potassium, bicarbonate, and mean arterial pressures were comparable in both groups. Patients with more than or equal to 30% reduction in proteinuria had a significant association with rs699 polymorphism in the angiotensinogen gene.. The rate of decline of renal graft function in patients with chronic allograft nephropathy was not adversely affected by lisinopril therapy given for 1 year. Lisinopril significantly reduced proteinuria, renal proximal tubular polypeptide catabolism, plasma aldosterone, and ammonia excretion suggesting relative preservation of graft function. Treating metabolic acidosis allowed safe and prolonged use of angiotensinogen-converting enzyme inhibitors.

Topics: Ammonia; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Cadaver; Creatinine; Genotype; Glomerular Filtration Rate; Humans; Kidney Transplantation; Kidney Tubules; Lisinopril; Living Donors; Polymorphism, Single Nucleotide; Proteinuria; Survival Analysis; Survivors; Tissue Donors; Transplantation, Homologous

In this prospective study, the effects of an angiotensin-converting enzyme inhibitor [lisinopril (LIS)] and an angiotensin II receptor antagonist [losartan (LOS)] were compared in nephrotic patients with idiopathic membranous nephropathy.. Twenty-seven patients (13 males, mean age +/- SD 51.3 +/- 15.4 years) were treated with LIS (13 patients, six males, mean age 52.1 +/- 15.3 years) or LOS (14 patients, seven males, mean age 50.5 +/- 15.5 years) for 12 months. At baseline and after the treatment period, serum albumin, total cholesterol, estimated glomerular filtration rate (GFR), 24 h proteinuria and mean arterial pressure were determined.. Proteinuria (g/24 h) was significantly reduced in both groups (LIS from 4.82 +/- 1.26 to 1.75 +/- 0.64, p < 0.0001; LOS from 4.55 +/- 1.09 to 2.54 +/- 1.94, p = 0.002) (all results +/- SD). Serum albumin levels (g/dl) increased significantly in both groups (LIS 2.27 +/- 0.41 to 3.17 +/- 0.63, p < 0.0001; LOS 2.93 +/- 0.40 to 3.55 +/- 0.44, p < 0.0001). GFR (ml/min x 1.73 m(2)) did not change significantly in either group (LIS 55 +/- 17 to 56 +/- 17, p = 0.65; LOS 64 +/- 18 to 59 +/- 16, p = 0.13). Total cholesterol (mg/dl) was significantly reduced only in the lisinopril group (LIS 347 +/- 81 to 266 +/- 64, p < 0.0001; LOS 306 +/- 58 to 263 +/- 77, p = 0.138). Mean arterial pressure (mmHg) was reduced in both groups (LIS 107 +/- 12 to 95 +/- 6, p < 0.0001; LOS 104 +/- 10 to 96 +/- 5, p = 0.003). In the comparison between the two groups, serum albumin levels were higher in the losartan group at baseline (p < 0.0001) and after 12 months (p = 0.029). There were no significant differences between the baseline and end-of-study values for the rest of the studied parameters.. Treatment with lisinopril and losartan in nephrotic patients with idiopathic membranous nephropathy results in similar (and significant) effects on renal function, hypoalbuminaemia, proteinuria and blood pressure.

Topics: Adult; Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Female; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Humans; Hypercholesterolemia; Lisinopril; Losartan; Male; Middle Aged; Nephrotic Syndrome; Prevalence; Prospective Studies; Proteinuria

Even in children with mild immunoglobulin (Ig)A nephropathy (IgA-N) showing minimal/focal mesangial proliferation, persistent proteinuria seems to be a risk factor for progression of the disease, indicating the need for an effective and safe treatment even in such cases. Studies carried out to date have indicated that angiotensin-converting enzyme inhibitors (ACEIs) reduce urinary protein excretion and preserve renal function in adult IgA-N. However, no prospective study of ACEI only for childhood IgA-N has yet been carried out. In this prospective single-arm pilot trial, we administered lisinopril (0.4 mg/kg per day) as therapeutic treatment to 40 children with mild IgA-N with proteinuria [morning urinary protein/creatinine ratio (uP/Cr) >or= 0.2 g/g]. Thirty-three patients reached the primary endpoint (uP/Cr < 0.2) during the 2-year treatment period. The cumulative disappearance rate of proteinuria determined by the Kaplan-Meier method was 80.9%. Mean uP excretion was reduced from 0.40 to 0.18 g/m(2)/day (p < 0.0001). Of the 40 patients treated, five (12.5%) showed dizziness, and four of these five needed the lisinopril dose reduced. However, lisinopril therapy was continued in all patients during the 2-year treatment period. No other side effect, such as cough, was observed. We conclude that the efficacy and safety of lisinopril is seemingly acceptable for the treatment of children with mild IgA-N.

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Child; Child, Preschool; Dizziness; Female; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Lisinopril; Male; Pilot Projects; Prospective Studies; Proteinuria; Treatment Outcome

Renoprotection is predicted by the antiproteinuric efficacy of a pharmacological agent. Non-steroidal anti-inflammatory drugs (NSAIDs) interfering non-selectively in the prostaglandin system have strong antiproteinuric potency without reduction of systemic blood pressure. The effect of the selective COX-2 inhibitor rofecoxib in proteinuric patients is unknown, granted recently reported detrimental effects in non-renal patients. Short-term effects of rofecoxib on proteinuria and blood pressure as compared to NSAID and RAAS blockade were studied.. Sixteen stable patients [mean proteinuria 4.4 g/ day; MAP 103 mmHg)] were included after a wash-out period. Hydrochlorothiazide 12.5 mg QD was given throughout. Additional blood pressure control was ensured by non-RAAS blocking antihypertensive agents. Patients received rofecoxib 25 mg QD, 50 mg QD and indomethacin 75 mg BID in randomized order for 4 weeks. Thereafter, a subset of the included patients (n = 11) received lisinopril 40 mg QD for 6 weeks preceded by a wash-out period.. Rofecoxib exerted a dose-dependent antiproteinuric effect. As compared to rofecoxib 25 and 50 mg, indomethacin was more effective [-18, -28 versus -49% (n = 16; P < 0.05)]. As compared to rofecoxib 50 mg, lisinopril was more effective [-21 versus -51% (n = 11; P < 0.05)]. No significant blood pressure changes were observed after rofecoxib and indomethacin, whereas lisinopril had a significant antihypertensive effect.. Selective COX-2 inhibition reduces proteinuria without reduction of systemic blood pressure, pointing towards a specific renal effect, and may serve as a novel non-hypotensive adjunct antiproteinuric treatment.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Female; Humans; Indomethacin; Kidney; Kidney Diseases; Lactones; Lisinopril; Male; Middle Aged; Proteinuria; Sulfones

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

Obesity increases the risk of proteinuria and chronic renal insufficiency and hastens the progression of renal diseases. Increased activity of renin-angiotensin-aldosterone system and elevated levels of aldosterone are common in obese patients. No studies have compared the efficacy of the currently available antiproteinuric strategies (ACE inhibitors -ACEI-, angiotensin receptor blockers -ARB-, aldosterone antagonists) in obese patients with proteinuric renal diseases.. Single centre, prospective, randomized study. Twelve obese patients (body mass index > 30 Kg/m2) with proteinuria > 0.5 g/24 h were selected from our outpatient renal clinic. Patients were consecutively treated during 6 weeks with an ACEI (lisinopril 20 mg/day), combined therapy ACEI+ARB (lisinopril 10 mg/day + candesartan 16 mg/day) and eplerenone (25 mg/day) in random order. A drug washout period of 6 weeks was established between the different treatment periods. The primary outcome point was the change in 24-h proteinuria at the end of each treatment period and the number of patients showing a proteinuria reduction greater than 25% of baseline.. The reduction in proteinuria induced by lisinopril (11.3+/-34.8%) was not statistically significant with respect to baseline, whereas that of lisinopril plus candesartan (26.9+/-30.6%) and eplerenone (28.4+/-31.6%) showed a statistically significant difference both with respect to baseline values and to lisinopril group. The number of patients who showed a greater than 25% proteinuria reduction was significantly higher with eplerenone (67%) and lisinopril+candesartan (67%) than with lisinopril (25%).. Monotherapy with an aldosterone antagonist and combination therapy with ACEI+ARB were more effective than ACEI monotherapy to reduce proteinuria in obese patients with proteinuric renal diseases.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Eplerenone; Female; Humans; Lisinopril; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Obesity; Prospective Studies; Proteinuria; Spironolactone; Tetrazoles

Agents that interfere with the renin-angiotensin system (RAS) reduce proteinuria and afford renal protection. The combination of different measures that serve maximization of RAS blockade is thought to improve the antiproteinuric efficacy. The feasibility and the efficacy of such a combination strategy were studied in nondiabetic patients with residual proteinuria during previous RAS blockade by individual antiproteinuric titration. Previous medication was replaced by irbesartan 300 mg combined with a diuretic. Lisinopril was added in increasing doses until a maximal dose of 40 mg/d. Titration stopped when target proteinuria (< 1 g/d) was reached or further dose titration was not tolerated because of side effects. Residual proteinuria (median, 3.2 g/d; 95% confidence interval, 1.8 to 5.2 g/d) was significantly reduced with 55.6% (95% confidence interval, 16.0 to 73.2%; P < 0.02) on the maximal additional tolerated dose of lisinopril. The maximal dose of lisinopril was 10 mg in two of eight, 20 mg in two of eight, 30 mg in one of eight, and 40 mg in three of eight patients. At this dose, target proteinuria of < 1 g/d was reached in two of eight patients. The number of patients with adverse events during dose titration was five of eight patients: two had cough; two had hyperkalemia (> 5.5 mmol/L), one of whom had > 50% increase of serum creatinine; and one had dizziness. In conclusion, individual titration for maximal RAS blockade, entailing dose titration of angiotensin-converting enzyme inhibitors on top of high-dose angiotensin II antagonists with diuretic, induces further reduction of residual proteinuria. However, this occurs at the expense of adverse events. To further improve renoprotective treatment strategies, it is important to explore other modes of antiproteinuric intervention in patients with residual proteinuria during RAS blockade.

Topics: Adolescent; Adult; Aged; Biological Availability; Biphenyl Compounds; Confidence Intervals; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Irbesartan; Kidney Diseases; Kidney Function Tests; Lisinopril; Male; Maximum Tolerated Dose; Middle Aged; Patient Selection; Probability; Proteinuria; Renin-Angiotensin System; Risk Assessment; Severity of Illness Index; Tetrazoles; Treatment Outcome; Urinalysis

IgAN is the most common type of glomerulonephritis in the world. Between 15 and 40 percent of adults and children diagnosed with IgAN eventually progress to ESRD. Despite the need for effective treatment strategies, very few RCTs for IgAN have been performed. The most effective therapies for IgAN appear to be corticosteroids, ACEi, and FOS that contain a high concentration of omega 3 fatty acids. While ACEi and FOS are generally well tolerated with minimal side effects, the use of high dose steroids over a long course of therapy is often associated with significant morbidity.. The objective of the study is to test the hypothesis that treatment with the immunosuppressive agent, MMF, will lead to significant and sustained improvement in urinary protein excretion in patients with IgAN who have been pre-treated (and continue to be treated) with ACEi and FOS compared to a placebo control group of patients receiving comparable doses of ACEi and FOS without MMF.. After a three month treatment period with the ACEi, lisinopril and the FOS, Omacor, 100 (2 x 50) patients with IgAN and a urinary P/C ratio > or = 0.6 (males) and > or = 0.8 (females) and an estGFR > or = 40 ml/min/1.73 m2 will be randomized to treatment with either MMF or placebo for one year. All patients will be followed off study drug for a second year, but will continue treatment with lisinopril and Omacor for the two year duration of the study. The primary outcome measure of change in urine P/C ratio will be assessed at the end of years one and two.

Topics: Angiotensin-Converting Enzyme Inhibitors; Docosahexaenoic Acids; Drug Combinations; Drug Therapy, Combination; Eicosapentaenoic Acid; Female; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Lisinopril; Male; Mycophenolic Acid; Proteinuria; Research Design; Treatment Outcome

Dyslipidemia frequently complicates chronic nephropathies and increases the risk of renal and cardiovascular events. This might be ameliorated by drugs, such as angiotensin-converting enzyme inhibitors, which effectively reduce proteinuria.. In this longitudinal study, we evaluated the extent to which uptitration of the ACE inhibitor lisinopril to maximum tolerated doses (median [range]: 30 [10 to 40] mg/d) ameliorated proteinuria and dyslipidemia in 28 patients with nondiabetic chronic nephropathies. Maximum lisinopril doses significantly and safely reduced proteinuria, serum total, LDL cholesterol, and triglycerides without substantially affecting serum HDL and renal hemodynamics. Proteinuria already decreased at 10 mg/d. Serum lipids progressively and dose-dependently decreased during uptitration to maximum doses. Reduction in total and LDL cholesterol correlated with increases in serum albumin/total protein concentration and oncotic pressure, peaked at lisinopril maximum doses, and persisted after treatment withdrawal. Despite less proteinuria reduction, hypercholesterolemia decreased more (and reflected the increase in serum albumin) in hypoalbuminemic than in normoalbuminemic patients who, despite more proteinuria reduction, had less decrease in cholesterol and no changes in serum albumin. Changes in serum triglycerides were independent of changes in serum proteins, were strongly correlated with lisinopril doses (r=-0.89, P=0.003) and recovered promptly after treatment withdrawal. Lisinopril was well tolerated, did not affect renal hemodynamics, and caused symptomatic, reversible hypotension in only two patients.. In chronic nephropathies, angiotensin converting enzyme inhibitor uptitration to maximum tolerated doses safely ameliorated hypertriglyceridemia by a direct, dose-dependent effect, and hypercholesterolemia through amelioration of the nephrotic syndrome, particularly in patients with more severe hypoalbuminemia.

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Chronic Disease; Diuretics; Dose-Response Relationship, Drug; Female; Hemodynamics; Humans; Hypercholesterolemia; Hypoalbuminemia; Hypotension; Kidney Diseases; Kidney Function Tests; Lisinopril; Longitudinal Studies; Male; Maximum Tolerated Dose; Middle Aged; Proteinuria; Sodium, Dietary; Treatment Outcome; Triglycerides

Chemokines play an important role in the pathogenesis of diabetic nephropathy. Angiotensin II induces several fibrogenic chemokines, namely monocyte chemoattractant protein-1 (MCP-1) and transforming growth factor-beta. The progression of diabetic nephropathy can be retarded by ACE inhibitors (ACEIs) in patients with type 1 and type 2 diabetes. We examined if blockade of the renin-angiotensin system lowered urinary levels of the chemokine MCP-1 and correlated urinary MCP-1 (uMCP-1) with parameters of renal function and glucose and lipid metabolism before and after 1 year of treatment with an ACE inhibitor.. In 22 patients with type 2 diabetes and diabetic nephropathy in stages 3-5, treatment with the ACEI lisinopril was initiated. Before treatment and after 12 months of continuous therapy, proteinuria, creatinine clearance, uMCP-1 levels, BMI, HbA(1c), and serum cholesterol were assessed.. Lisinopril treatment improved renal function. Proteinuria decreased from 410 +/- 662 mg per 24 h to 270 +/- 389 mg per 24 h. Creatinine clearance rose from 61 +/- 26 to 77 +/- 41 ml/min. Urinary MCP-1 levels decreased from 0.456 +/- 0.22 ng/mg creatinine to 0.08 +/- 0.096 ng/mg creatinine. The change in uMCP-1 correlated significantly (r = 0.61, P < 0.001) with the change in proteinuria. No other parameter correlated with the improvement in renal function.. Blockade of the renin-angiotensin system in type 2 diabetic patients with diabetic nephropathy reduces uMCP-1 levels and improves renal function. Because MCP-1 induces monocyte immigration and differentiation to macrophages, which augment extracellular matrix production and tubulointerstitial fibrosis, pharmacological reduction of angiotensin II may also exert its beneficial effects in diabetic nephropathy by downregulation of renal MCP-1.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Chemokine CCL2; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Female; Humans; Hypertension, Renal; Kidney; Lisinopril; Male; Middle Aged; Proteinuria; Renin-Angiotensin System; Treatment Outcome

The antiproteinuric effect of combining the angiotensin-converting enzyme (ACE) inhibitor lisinopril and the angiotensin II (Ang II) antagonist losartan was compared to that of the optimal antiproteinuric doses of monotherapy.. To this purpose, lisinopril and losartan were studied in 9 nondiabetic renal patients with median proteinuria 4.5 g/day (95% CI, 3.5, 6.4), creatinine clearance of 80 mL/min (95% CI, 66, 96), and mean arterial pressure (MAP) of 102 mm Hg (95% CI, 93, 112). First, in two protocols with six-week treatment periods per dose, the optimal antiproteinuric dose of each drug was established in each patient. Losartan and lisinopril were used in randomized order, each preceded by a baseline period without medication. The doses of losartan (mg/day) were 50, 100, 150, and again 50. The lisinopril doses were 10, 20, 40, and again 10. After the second protocol, patients were treated with a combination, using the optimal antiproteinuric doses established for the individual drugs.. The antiproteinuric response by losartan was optimal at 100 mg (-46%; 95% CI, -60, -24%), being larger than at the 50 mg dose (-27%; 95% CI, -42, -4%, P < 0.05), but not different from the 150 mg dose (-46%; 95% CI, -58; -20%). Proteinuria decreased further at each up-titration step of lisinopril to -75% (95% CI, -85, -43%) at the 40 mg dose. Combination therapy reduced proteinuria more effectively (-85%; 95% CI, -96, -58) than monotherapy with losartan, and to a lesser extent than with lisinopril. Optimal blood pressure responses were obtained at similar doses.. Dose-titration with a renin-angiotensin system blocker, followed by add-on therapy is highly effective in order to reduce proteinuria. The safety of this regimen needs to be addressed in future studies.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Blood Pressure; Drug Therapy, Combination; Female; Humans; Lisinopril; Losartan; Male; Middle Aged; Proteinuria; Renin-Angiotensin System

Blockade of the renin-angiotensin system (RAS) with angiotensin converting enzyme (ACE) inhibitors or with angiotensin II type 1 (AT1) receptor blockers has been shown to reduce proteinuria and to slow down the progression of renal disease in diabetic and non-diabetic primary proteinuric nephropathies. Additionally, this beneficial effect is not dependent on blood pressure control.. To assess and compare the effects of lisinopril (up to 40 mg/day), candesartan (up to 32 mg/day) and combination therapy (lisinopril up to 20 mg/day plus candesartan up to 16 mg/day) on urinary protein excretion, 45 patients with primary proteinuric nephropathies (urinary protein/creatinine ratio 3.8+/-2.4 g/g) and normal or slightly reduced renal function (CCr 95+/-33 mL/min) were enrolled in a six month multicenter, prospective, open, randomized, active-controlled and parallel-group trial with 1:1:1 allocation. Blood pressure goal was set at or below 125/75 mm Hg for all patients, with additional antihypertensive medication prescribed if required.. Renal function, estimated by creatinine clearance, remained stable throughout the study. Hyperkalemia (K>5.5 mmol/L) was detected in 3.1% of all measurements in follow-up, and was more frequent in patients treated with lisinopril alone or lisinopril plus candesartan (P<0.001) than in those on candesartan alone. No other relevant adverse event was recorded. The blood pressure goal (<125/75 mm Hg) was achieved by week 4 in all treatment groups (P<0.005 when compared to baseline), and afterwards the mean systolic and diastolic blood pressure remained below these values until the end of the trial with no statistically significant differences between groups. Urinary protein/creatinine ratio (percentage reduction 95% confidence intervals CI) decreased in patients treated with lisinopril alone to -33% (CI -12-56) to -31% (CI 0-68) and to -50% (CI -9-90), in patients treated with candesartan to -28% (CI -12-45), to -41% (CI -30-52) and to -48% (CI -32-63), in patients treated with the combination of both to -60% (CI -44-77) to -54% (CI -38-69) and to -70% (CI -57-83) at two, three, and six months, respectively. All comparisons with baseline achieved statistical significance and treatment with combination therapy was statistically more effective in proteinuria reduction than treatment with candesartan alone at two and six months (P=0.004 and P=0.023, respectively) and than treatment with lisinopril only at two months (P=0.03).. Dual blockade of the renin-angiotensin system with ACE inhibitors and AT1 receptor blockers produces a beneficial antiproteinuric effect that could not be explained only by the systemic blood pressure reduction. All treatments were well tolerated.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Creatinine; Drug Therapy, Combination; Female; Humans; Kidney Diseases; Lisinopril; Male; Middle Aged; Prospective Studies; Proteinuria; Renin-Angiotensin System; Spain; Tetrazoles; Time Factors; Treatment Outcome

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

Administration of prednisolone causes an abrupt rise in proteinuria in patients with a nephrotic syndrome.. To clarify the mechanisms responsible for this increase in proteinuria we have performed a placebo controlled study in 26 patients with a nephrotic syndrome. Systemic and renal haemodynamics and urinary protein excretion were measured after prednisolone and after placebo.. After i.v. administration of 125-150 mg prednisolone total proteinuria increased from 6.66+/-4.42 to 9.37+/-6.07 mg/min (P<0.001). By analysing the excretion of proteins with different charge and weight (albumin, transferrin, IgG, IgG4 and beta2-microglobulin) it became apparent that the increase of proteinuria was the result of a change in size selectivity rather than a change in glomerular charge selectivity or tubular protein reabsorption. Glomerular filtration rate rose from 83+/-34 ml to 95+/-43 ml/min (P<0.001) after 5 h, whereas effective renal plasma flow and endogenous creatinine clearance remained unchanged. As a result filtration fraction was increased, compatible with an increased glomerular pressure, which probably contributes to the size selectivity changes. Since corticosteroids affect both the renin-angiotensin system and renal prostaglandins, we have evaluated the effects of prednisolone on proteinuria after pretreatment with 3 months of the angiotensin-converting enzyme inhibitor lisinopril or after 2 weeks of the prostaglandin synthesis inhibitor indomethacin. Neither drug had any effect on prednisolone-induced increases of proteinuria.. Prednisolone increases proteinuria by changing the size selective barrier of the glomerular capillary. Neither the renin-angiotensin axis nor prostaglandins seem to be involved in these effects of prednisolone on proteinuria.

Topics: Adolescent; Adult; Aged; Albuminuria; Angiotensin-Converting Enzyme Inhibitors; beta 2-Microglobulin; Blood Pressure; Cyclooxygenase Inhibitors; Female; Glomerular Filtration Rate; Heart Rate; Hemodynamics; Humans; Immunoglobulin G; Indomethacin; Injections, Intravenous; Lisinopril; Male; Middle Aged; Nephrotic Syndrome; Placebos; Prednisolone; Proteinuria; Renal Circulation; Transferrin

We evaluated blood concentrations of bcl-2, a proto-oncogene that can inhibit apoptotic phenomena, in a group of patients with immunoglobulin A (IgA) nephropathy. Concentrations of bcl-2 were higher in patients with proteinuria than in those without proteinuria. A 6-month course of 5 mg/day lisinopril given to subjects with proteinuria significantly reduced blood bcl-2 concentrations and caused a reduction in proteinuria. Therefore increased blood bcl-2 concentrations may be considered an index of risk in subjects with IgA nephropathy, and the positive effects of angiotensin-converting enzyme inhibitors on proteinuria in patients with IgA nephropathy may be attributed, at least in part, to their effect on the mechanisms that regulate apoptosis. This is of fundamental importance in resolving glomerular hypercellularity in the course of glomerulonephritis.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Apoptosis; Female; Genes, bcl-2; Glomerulonephritis, IGA; Humans; Lisinopril; Male; Middle Aged; Proteinuria; Proto-Oncogene Mas; Treatment Outcome

Double-blind, randomized controlled studies of longer than 1 week in duration comparing the antiproteinuric potential of long-acting dihydropyridine calcium channel blockers with that of angiotensin converting enzyme (ACE) inhibitors are lacking. Therefore, we performed such a study in patients with nondiabetic renal disease and proteinuria. After a 4-week wash-out period in which patients did not use any medication known to affect proteinuria, 21 patients were randomized in a double-blind fashion to receive either the calcium channel blocker amlodipine (Amlo, 5 to 10 mg) or the ACE-inhibitor lisinopril (Lis, 5 to 10 mg). Throughout the 16-week study period, blood pressure, creatinine clearances, and proteinuria were measured every 2 weeks. In addition, device-measured blood pressure and renal hemodynamic studies were performed at the start and end of the study. Systolic blood pressure fell in the Lis group from 163+/-7 (SEM) to 140+/-8 mm Hg (P < .01) and from 157+/-10 to 147+/-6 mm Hg in the Amlo group; diastolic blood pressure fell from 101+/-3 to 86+/-7 mm Hg in the Lis group and from 98+/-3 to 91+/-2 mm Hg in the Amlo group. Renal hemodynamics were not affected by amlodipine treatment, whereas a fall in glomerular filtration rate (GFR) was seen in lisinopril-treated patients (from 55+/-11 to 50+/-10 mL/min; P < .01). Amlodipine did not significantly affect proteinuria. Lisinopril induced a decline in the protein-creatinine ratio with a maximal effect reached after 12 to 16 weeks of therapy (from 0.39+/-0.17 to 0.26 +/-0.11 g/mmol; P < .009). In conclusion, we could not demonstrate an antiproteinuric effect of the long-acting dihydropyridine calcium channel blocker amlodipine, whereas therapy with the ACE-inhibitor lisinopril resulted in a decrease in proteinuria. Amlodipine did not affect renal hemodynamics, whereas lisinopril induced a fall in GFR.

Topics: Adolescent; Adult; Aged; Amlodipine; Angiotensin-Converting Enzyme Inhibitors; Calcium Channel Blockers; Double-Blind Method; Female; Humans; Lisinopril; Male; Middle Aged; Prospective Studies; Proteinuria; Renal Insufficiency

The antiproteinuric effect of angiotensin converting enzyme (ACE) inhibition in patients with renal disease is well known, but the results of clinical studies appear to vary considerably from a partial decrease to a fall of 100% in urinary protein excretion. This may have been due to the use of different doses of ACE inhibitor, different renal pathology and non-standardized sodium intake. In 16 proteinuric patients with biopsy-proven IgA nephropathy, with normal renal function and blood pressure, maintained at controlled sodium intake < or = 80 mEqII, the efficacy of increasing doses of the ACE inhibitor lisinopril was studied. The lisinopril doses were 5, 10, 15 and 20 mg, administered for 4 weeks. Between each dose increment a placebo period of 3 weeks was interposed. Proteinuria stepwise decreased from the control period by 39%, 44%, 61% and 67% with lisinopril at 5, 10, 15 and 20 mg, respectively. The blood pressure decreased by 22% with lisinopril 5 mg; a similar fall was observed with the dose increment. Although the glomerular filtration rate remained unchanged, the renal plasma flow increased by 21%, 26%, 24% and 28% and the filtration fraction increased by 28% mean. The ACE plasma levels decreased by 33%, 64%, 76% and 83%. A close correlation was found between an increase in lisinopril dosage and the fall in urinary protein excretion (r = 0.88, p < 0.001). The antiproteinuric effect of lisinopril is dose-related and may be attributable to some extent to the fall in systemic (and intraglomerular) blood pressure, but it is best attributed to the modification of glomerular sieving function.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Pressure; Dose-Response Relationship, Drug; Female; Glomerular Filtration Rate; Glomerulonephritis, IGA; Humans; Kidney; Lisinopril; Male; Middle Aged; Peptidyl-Dipeptidase A; Proteinuria

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 effect of two angiotensin-converting enzyme (ACE) inhibitors, lisinopril and captopril, on proteinuria and renal haemodynamics was investigated in 11 hypertensives (9 men, 2 women; mean age 46 +/- 16 years) with proteinuria (> 1.5 g/24 h) due to chronic glomerulonephritis and impaired renal function (glomerular filtration rate < 75 ml/min). In a randomized and double-blind cross-over trial the patients received, each time for six weeks, either lisinopril (5 mg/d, sometimes increased to 10 mg/d after 3 weeks) or captopril (twice daily 12.5 mg, sometimes increased to twice 25 mg after 3 weeks). Initially and between the individual treatment phases they were on a placebo phase for 4 weeks. The following were measured: protein excretion, including fractional clearance of albumin and IgG, plasma-renin activity and renal haemodynamics. Protein excretion was not significantly reduced by either drug (placebo: 7.1 +/- 4.0 g/d; lisinopril: 5.1 +/- 2.8 g/d; captopril: 5.4 +/- 3.0 g/d). Albumin excretion and fractional albumin clearance were significantly decreased only by lisinopril (P < 0.05), not by captopril. Plasma-renin activity was increased more by lisinopril than captopril (Placebo: 1.0 +/- 0.9 ng/ml.h; lisinopril: 5.2 +/- 2.8 ng/ml.h [P < 0.05]; captopril: 1.8 +/- 1.3 ng/ml.h [P < 0.05]). The renal haemodynamics was only slightly influenced by either drug, but captopril significantly decreased the filtration fraction in the presence of chronic glomerulonephritis and renal failure. - Resulting from their influence on the renin-angiotensin-aldosterone system, ACE inhibitors have, in addition to their known action on renal haemodynamics, an independent effect on the loading barrier of the basal membrane of the kidney.

Topics: Adult; Aged; Captopril; Chronic Disease; Double-Blind Method; Female; Glomerulonephritis; Humans; Lisinopril; Male; Middle Aged; Proteinuria

Renal transplantation is frequently accompanied by systemic hypertension. In the present study we evaluated the effect of 2.5 mg lisinopril in 12 hypertensive and proteinuric renal graft recipients with stable graft function over 3 months. Only patients with absence of renal artery stenosis, at least as judged by technetium-scan imaging, were included. Lisinopril was effective in lowering systemic blood pressure. Mean arterial pressure was unchanged despite reduction of concomitant antihypertensive medication. Mean serum creatinine was unchanged during the study (1.95 +/- 0.8 mg/dl in the pretreatment period vs. 1.77 +/- 0.76 mg/dl in the intervention period, n.s.). Glomerular filtration rate remained stable (62.75 +/- 21.96 vs. 60.17 +/- 18.27 ml/min/1.73 m2, n.s.) whereas renal plasma flow increased (224.75 +/- 91.66 vs. 244.92 +/- 94.13 ml/min/1.73m2, P < 0.01), leading to a drop in filtration fraction (31.4 +/- 12.4 vs. 26.8 +/- 8.6, n.s.). Renal vascular resistance was significantly reduced following angiotensin-converting enzyme (ACE) inhibitor therapy (26,447 +/- 14,574 vs. 23,425 +/- 12,430 dyne sec cm-5/1.73 m2, P < 0.01). Mean daily proteinuric decreased significantly (2.98 +/- 2.06 vs. 2.06 +/- 2.29 g, P < 0.01) whereas in a group of patients with comparable blood pressure but without ACE inhibitor therapy and similar degree of proteinuria, 24-hr proteinuria remained stable. No severe side effects were observed--in particular, mean serum potassium showed only a slight increase and no clinically significant hyperkalemic condition was observed. When lisinopril therapy was withdrawn after 3 months, blood pressure increased in all patients, requiring reinstitution of additional antihypertensive medication. Renal hemodynamic parameters and daily proteinuria returned to baseline values. We conclude that 2.5 mg lisinopril daily was safe and effective in this group of renal transplant recipients and showed a good antihypertensive as well as antiproteinuric effect.

Topics: Adult; Dipeptides; Female; Hemodynamics; Humans; Hypertension, Renal; Kidney; Kidney Function Tests; Kidney Transplantation; Lisinopril; Male; Middle Aged; Proteinuria

To study the effects of an angiotensin converting enzyme inhibitor, lisinopril, on renal function in incipient diabetic nephropathy, a prospective double-blind randomised placebo-controlled single centre study was set up at our outpatient diabetic-renal clinic. There were 27 patients with Type I and Type II diabetes with an albumin excretion rate of between 20 micrograms/min and 200 micrograms/min, respectively and no hypertension. Intervention treatment with placebo or low dose lisinopril was for 48 weeks. The main outcome changes were in urinary albumin excretion rate, urinary prostaglandin excretion, and glomerular filtration rate. Secondary outcome measures included changes in BP and heart rate. Of the 32 patients entered into the study, 27 completed 48 weeks treatment (12 lisinopril, 15 placebo). Mean (+/- SD) urinary albumin excretion rate fell from 57.6 (25.7) micrograms/min (n = 15) at visit 1 to 26.8 (26.7) micrograms/min (n = 12) at visit 7 after 48 weeks treatment in the lisinopril group but not in the placebo group: 119.2 (116.6) micrograms/min (n = 17) vs. 113.7 (77.0) micrograms/min (n = 15). There was a least squares mean treatment difference of -67.6 micrograms/min (95% confidence interval (CI), -115.0 to -20.2, P < 0.01) in favour of lisinopril compared with placebo. After 48 weeks treatment seven lisinopril treated patients were normoalbuminuric and five were microproteinuric; three placebo treated patients were normoalbuminuric, nine were microalbuminuric and three were macroproteinuric. Excretion of prostaglandin-F1 alpha (PGF1 alpha) and thromboxane-B2 (TXB2) fell in the lisinopril treated group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Blood Pressure; Diabetic Nephropathies; Double-Blind Method; Female; Heart Rate; Humans; Kidney; Lisinopril; Male; Middle Aged; Placebos; Prospective Studies; Prostaglandins; Proteinuria; Reference Values

The objective of this study was to compare the effects of an angiotensin converting enzyme inhibitor, lisinopril, with those of a calcium blocker, nifedipine, on BP control and renal function, in a prospective randomised double-blind, double-dummy trial lasting 19 weeks in patients with diabetic nephropathy. We enrolled 28 diabetic patients with hypertension and macroproteinuria from the out-patient diabetic-renal clinic. The antihypertensive treatment consisted of lisinopril or nifedipine, and their effect on arterial BP, urinary albumin excretion, glomerular filtration rate, and renal blood flow were measured. BPs at entry were 166/99 (SD 23/9) mmHg for the lisinopril group and 165/99(21/7) mmHg for the nifedipine group. BPs fell to 143/88 (17/13) mmHg for the lisinopril group and 148/85(25/10) mmHg for the nifedipine group at the end of the study. The albumin excretion rate fell in the lisinopril group from 738.7 (635.2) micrograms/min to 644.6 (965.2) micrograms/min and rose in the nifedipine group from 981.2 (1022.2) micrograms/min to 1072.5 (908.5) micrograms/min (P = NS). Glomerular filtration rates fell from 105.2 (57.5) ml/min per 1.73 m2 to 72.1 (39.4) ml/min per 1.73 m2 in the lisinopril group and from 109.9 (50.0) ml/min per 1.73 m2 to 82.9 (53.9) ml/min per 1.73 m2 in the nifedipine treated group. Renal blood flow fell from 446.8 (217.9) ml/min per 1.73 m2 to 435.1 (243.3) ml/min per 1.73 m2 for the lisinopril group and from 473.0 (216.4) ml/min per 1.73 m2 to 419.0 (278.6) ml/min per 1.73 m2 for the nifedipine group. Differences between the groups were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Calcium Channel Blockers; Diabetic Angiopathies; Diabetic Nephropathies; Double-Blind Method; Female; Humans; Hypertension; Kidney; Lisinopril; Male; Middle Aged; Nifedipine; Prospective Studies; Proteinuria

This study was undertaken to test the hypothesis that, given equal arterial pressure reductions, the combination of an angiotensin converting enzyme (ACE) inhibitor and calcium antagonist slows declines in renal function and yields greater reductions in albuminuria over either agent alone. This hypothesis was evaluated in four groups of hypertensive, non-insulin dependent, diabetic subjects with renal insufficiency (N = 30). Renal hemodynamics, albuminuria and metabolic parameters were evaluated for a period of one year. Subjects were all placed on a 90 mEq sodium, 0.8 g/kg protein, 1500 calorie American Diabetes Association diet for the entire length of the study. Subjects were followed for two weeks off antihypertensive medications and were subsequently randomized to either lisinopril, alone (group I), sustained release verapamil, alone (group II), reduced doses of both lisinopril and sustained release verapamil (group III), and hydrochlorothiazide with guanfacine (group IV). At the end of one year group III had the greatest reduction in albuminuria (78 +/- 7%, group III vs. 59% +/- 4, group I: P less than 0.05). In addition, the decline in glomerular filtration rate (GFR) was the lowest in this group (0.28 +/- 0.07, group III vs. 0.69 +/- 0.12, group I; P less than 0.05) although there was no significant difference between groups II and IV. The highest side effect profiles were noted in group IV, the least in group III. The greatest reductions in renal hemodynamics occurred in all groups within the first month; however, striking differences between groups were noted (7.4 +/- 2%, group I vs. 1.4 +/- 2%, group III; P less than 0.05). We conclude that the combination of reduced doses of an ACE inhibitor and calcium antagonist attenuate both albuminuria and the rate of decline in glomerular filtration rate. Furthermore, the combination of these classes of agents appear to yield the lowest side effect profile over either agent alone. Lastly, high doses of ACE inhibition alone may be detrimental to renal function in late stage diabetics with renal insufficiency.

Topics: Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Dipeptides; Drug Combinations; Female; Hemodynamics; Humans; Hydrochlorothiazide; Hypertension; Lisinopril; Male; Middle Aged; Proteinuria; Renal Circulation; Verapamil

1. Both the angiotensin-converting enzyme inhibitor, lisinopril, and the non-steroidal anti-inflammatory drug, indomethacin, lower urinary protein excretion in renal disease and improve the selectivity of the residual proteinuria. Despite the clearly different renal haemodynamic profiles of the two drugs, we hypothesize that the antiproteinuric effect has a final common pathway that is a reduction in glomerular filtration pressure. 2. We studied the effects of lisinopril and indomethacin, separately and in combination, on urinary protein excretion, selectivity of proteinuria and renal haemodynamics in nine non-diabetic patients with overt proteinuria. 3. Urinary protein excretion was 5.4 +/- 2.5 g/24 h in the control period. Lisinopril monotherapy lowered urinary protein excretion by 53 +/- 26%. During indomethacin treatment urinary protein excretion was reduced by 63 +/- 24%. After adding indomethacin to lisinopril, urinary protein excretion fell by a further 58 +/- 23%, resulting in a 79 +/- 17% decrease during combined therapy. 4. Although both lisinopril and indomethacin monotherapy appeared to result in an improvement in glomerular protein permeselectivity, no further improvement was seen during the combination therapy. 5. The change in proteinuria were associated with changes in glomerular filtration rate, which showed a pronounced fall with combination therapy. The renal haemodynamic profiles during the different therapies suggest a post-glomerular vasodilatation by lisinopril and a pre-glomerular vasoconstriction by indomethacin, and the combination of both during the combined treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Drug Therapy, Combination; Enalapril; Female; Glomerular Filtration Rate; Humans; Indomethacin; Lisinopril; Male; Middle Aged; Proteinuria

Angiotensin converting enzyme (ACE) inhibitors are known to lower urinary protein excretion in human renal disease. This proteinuria lowering effect of ACE inhibition has been hypothesized to be a result of renal hemodynamic changes due to the inhibition of angiotensin II (Ang II) production. To test this hypothesis we studied the short-term effects of different doses of exogenous Ang II (5%, 10% and 20% of the pressor dose) on renal hemodynamics and urinary protein excretion in comparison with placebo infusion in six non-diabetic normotensive proteinuric patients, both before and after three months treatment with the ACE inhibitor, lisinopril. Lisinopril lowered proteinuria from 7.5 +/- 1.9 to 2.7 +/- 0.6 g/24 hr and induced a fall in blood pressure, renal vascular resistance and filtration fraction, whereas plasma Ang II levels were similar to the pre-treatment values. Ang II infusion induced typical effects which appeared to be similar before and during lisinopril treatment: a dose-related fall in renal plasma flow and rise in systemic blood pressure, renal vascular resistance and filtration fraction, while the glomerular filtration rate remained relatively stable. However, neither before nor during lisinopril therapy did any changes in urinary protein loss occur during the infusions of Ang II, despite the fact that Ang II reversed the long-term systemic and renal hemodynamic changes induced by the ACE inhibitor. We conclude that the long-term antiproteinuric effect of the ACE inhibitor, lisinopril, is neither mediated through changes in circulatory Ang II levels nor influenced by acute changes in systemic and renal hemodynamics, suggesting a non-hemodynamic mechanism of action.

Topics: Adult; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalapril; Female; Humans; Lisinopril; Male; Middle Aged; Proteinuria; Renal Circulation

Topics: Angiotensin-Converting Enzyme Inhibitors; Clinical Trials as Topic; Diabetes Complications; Diltiazem; Enalapril; Female; Humans; Lisinopril; Male; Middle Aged; Prospective Studies; Proteinuria

We studied the efficacy of the ACE inhibitor lisinopril in treating overt proteinuria in comparison with the NSAID indomethacin, and evaluated some of the conditions that could influence this antiproteinuric effect. In 12 patients with a proteinuria varying from 3.2 to 10.5 g/24 hr, a diastolic BP ranging from 64 to 105 mm Hg, and a GFR varying from 34 to 127 ml/min, the effect of different lisinopril doses and of changing dietary sodium intake was evaluated. Proteinuria fell by 27 +/- 20% from 6.1 +/- 2.1 to 4.5 +/- 1.9 g/24 hr on a low dose (median 5 mg/day) lisinopril and by 50 +/- 17% to 3.1 +/- 1.4 g/24 hr on a higher dose (median 10 mg/day), irrespective of initial proteinuria, BP, or GFR. This antiproteinuric effect was abolished by increasing salt intake from 50 to 200 mmol/day, and was recovered again by re-instituting the sodium restricted diet. The antiproteinuric effect of 10 mg/day lisinopril was comparable to the reduction in proteinuria (by 57 +/- 21% to 2.8 +/- 2.0 g/24 hr) on 150 mg/day indomethacin, while adverse effects were less and renal hemodynamic effects were more favorable during lisinopril. In some patients it took several weeks before the effect of the ACE inhibitor on proteinuria was stabilized. Thus, the antiproteinuric effect of the ACE inhibitor lisinopril appears to be dose and time related, and is strongly dependent on dietary sodium restriction, whereas it does not depend on initial proteinuria, BP, or GFR. The effect is comparable to that of indomethacin, while adverse effects are less.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diet, Sodium-Restricted; Enalapril; Female; Glomerular Filtration Rate; Humans; Indomethacin; Kidney Diseases; Lisinopril; Male; Proteinuria; Renal Circulation; Sodium, Dietary; Vascular Resistance

The safety and tolerability of lisinopril were assessed in 1,476 patients [1,165 hypertensives and 311 patients with congestive heart failure (CHF)] and 211 normal volunteers. The duration of lisinopril therapy ranged from 1 day to 16 months, with a mean duration of 105 days. In the hypertensive population, the most frequent clinical adverse experiences on lisinopril alone were headache, dizziness, cough, and diarrhea. Not all of these adverse experiences were thought to be drug related. Five percent of patients were discontinued because of adverse clinical experiences; cough and dizziness were the most common reasons for discontinuation. Two of 1,165 (0.17%) hypertensive patients treated with lisinopril died, compared to 0.41% of hypertensive patients on other therapies. Neither case was considered to be drug related. In patients with CHF, the most frequent clinical adverse experiences were dizziness, diarrhea, hypotension, fatigue, headache, and rash. Not all of these adverse experiences were thought to be drug related. The percent of CHF patients discontinuing because of an adverse clinical experience was 7.4%; the most frequent causes for discontinuation were hypotension, dizziness, or renal impairment. Twelve deaths occurred in 311 CHF patients treated with lisinopril (3.9%) compared to 4/104 (3.8%) of CHF patients treated with placebo and 2/65 (3.1%) treated with captopril. Hypotension, orthostatic effects, or dizziness following the initial lisinopril dose occurred infrequently in patients treated with lisinopril. In hypertensive patients with normal renal function, including those treated previously or concomitantly with diuretic therapy, a first-dose hypotensive episode was reported in six of 955, or 0.6%. The incidence was higher (6.7%) in hypertensive patients with impaired renal function.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Angiotensin-Converting Enzyme Inhibitors; Blood Cell Count; Clinical Trials as Topic; Creatinine; Drug Tolerance; Enalapril; Female; Hemoglobins; Humans; Hypertension; Lisinopril; Male; Middle Aged; Potassium; Proteinuria

Diabetes, hypertension, and aging are major contributors to cardiovascular and chronic kidney disease (CKD). Sodium/glucose cotransporter 2 (SGLT2) inhibitors have become a preferred treatment for type II diabetic patients since they have cardiorenal protective effects. However, most elderly diabetic patients also have hypertension, and the effects of SGLT2 inhibitors have not been studied in hypertensive diabetic patients or animal models. The present study examined if controlling hyperglycemia with empagliflozin, or given in combination with lisinopril, slows the progression of renal injury in hypertensive diabetic rats. Studies were performed using hypertensive streptozotocin-induced type 1 diabetic Dahl salt-sensitive (STZ-SS) rats and in deoxycorticosterone-salt hypertensive type 2 diabetic nephropathy (T2DN) rats. Administration of empagliflozin alone or in combination with lisinopril reduced blood glucose, proteinuria, glomerular injury, and renal fibrosis in STZ-SS rats without altering renal blood flow (RBF) or glomerular filtration rate (GFR). Blood pressure and renal hypertrophy were also reduced in rats treated with empagliflozin and lisinopril. Administration of empagliflozin alone or in combination with lisinopril lowered blood glucose, glomerulosclerosis, and renal fibrosis but had no effect on blood pressure, kidney weight, or proteinuria in hypertensive T2DN rats. RBF was not altered in any of the treatment groups, and GFR was elevated in empagliflozin-treated hypertensive T2DN rats. These results indicate that empagliflozin is highly effective in controlling blood glucose levels and slows the progression of renal injury in both hypertensive type 1 and type 2 diabetic rats, especially when given in combination with lisinopril to lower blood pressure.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Fibrosis; Hypertension; Lisinopril; Proteinuria; Rats; Rats, Inbred Dahl

Topics: Child; Glomerulonephritis, IGA; Humans; Lisinopril; Losartan; Proteinuria

The Renin-Angiotensin System (RAS) possesses a counter-regulatory axis composed of angiotensin converting enzyme (ACE)2, angiotensin-(1-7) [Ang-(1-7)] and the Mas receptor, which opposes many AT1-receptor-mediated effects of ligand angiotensin II. Ang-(1-7), as a ligand of the Mas receptor, has inhibitory effects on renal inflammation and fibrosis in experimental diabetes. However, Ang-(1-7) has a short half-life in plasma, which may render it unsuitable for use in clinics. Here, we investigated the effects of the lanthionine-stabilized Ang-(1-7), cyclic (c)Ang-(1-7), a lanthipeptide that is more peptidase-resistant than the linear peptide, in BTBR ob/ob mice with type 2 diabetic nephropathy. BTBR ob/ob mice received vehicle, cAng-(1-7), or the ACE inhibitor lisinopril. The treatment started at ten weeks of age, when the animals had already developed albuminuria, and ended at 19-20 weeks of age. cAng-(1-7) limited albuminuria progression, and limited podocyte dysfunction similarly to lisinopril. cAng-(1-7), unlike lisinopril, reduced glomerular fibrosis and inflammation, and counteracted glomerular capillary rarefaction. Furthermore, when cAng-(1-7) was combined with lisinopril, a superior antiproteinuric effect than with lisinopril alone was found, in association with better preservation of podocyte proteins and amelioration of capillary density. Thus, adding cAng-(1-7) to ACE-inhibitor therapy could benefit those diabetic patients who do not respond completely to ACE-inhibitor therapy.

Topics: Alanine; Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Disease Models, Animal; Drug Therapy, Combination; Half-Life; Humans; Kidney Glomerulus; Lisinopril; Male; Mice; Mice, Transgenic; Microscopy, Electron, Transmission; Peptide Fragments; Peptides, Cyclic; Proteinuria; Sulfides

Renin-angiotensin-aldosterone system (RAAS) blockade provides renoprotective effects in chronic kidney disease (CKD); yet progressive renal function loss remains common. Dietary sodium restriction potentiates the renoprotective effects of RAAS blockade. Vitamin D receptor activator (VDRA) treatment reduces proteinuria, inflammation and fibrosis, but whether these effects depend on sodium intake has not been studied. We hypothesized that the renoprotective effects of VDRA treatment, with or without RAAS blockade, are modulated by sodium intake.. Six weeks after the induction of adriamycin nephrosis in Wistar rats, i.e. with established proteinuria, animals were treated with the VDRA paricalcitol, lisinopril, the combination, or vehicle; each treatment was given during either a high- (2% NaCl) or a low-sodium (0.05% NaCl) diet for 6 weeks. We assessed proteinuria, blood pressure, renal macrophage accumulation and renal expression of the pre-fibrotic marker alpha-smooth muscle actin (α-SMA) at the end of the treatment.. Both paricalcitol and lisinopril individually, as well as in combination, reduced proteinuria and glomerular and interstitial inflammation during a low-sodium diet, but not during a high-sodium diet. All interventions also reduced focal glomerulosclerosis and interstitial expression of α-SMA during the low-sodium diet, while similar trends were observed during the high-sodium diet. The renoprotective effects of paricalcitol were not accompanied by blood pressure reduction. As proteinuria was already abolished by lisinopril during the low-sodium diet, the addition of paricalcitol had no further effect on proteinuria or downstream inflammatory or pre-fibrotic changes.. The renoprotective effects of the VDRA paricalcitol are blood pressure independent but do depend on dietary sodium status. The combination of RAAS blockade, dietary sodium restriction and VDRA may be a promising intervention to further retard renal function loss in CKD.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Bone Density Conservation Agents; Diet, Sodium-Restricted; Ergocalciferols; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Kidney; Lisinopril; Male; Peptidyl-Dipeptidase A; Proteinuria; Rats; Rats, Wistar; Receptors, Calcitriol; Renin-Angiotensin System; Sodium Chloride, Dietary; Sodium, Dietary

In healthy rats, the physiological variation of baseline endothelial function of intrarenal arteries correlates with the severity of renal damage in response to a subsequent specific renal injury. However, whether such a variation in endothelial function may also condition or predict the variable response to angiotensin-converting enzyme-inhibiting treatment in these individuals has not been addressed before. To study this, 5/6 nephrectomy was performed to induce renal injury and chronic kidney disease in a group of healthy Wistar rats. At the time of nephrectomy, interlobar arteries were obtained from the extirpated right kidney and studied in vitro for endothelium-dependent relaxation to acetylcholine. Six weeks thereafter, treatment with lisinopril was started (n = 11) and continued for 9 wk. Proteinuria (metabolic cages) and systolic blood pressure (SBP; tail cuff) were evaluated weekly, and these were analyzed in relation to renal endothelial function at baseline. 5/6 Nephrectomy induced an increase in SBP and progressive proteinuria. Treatment with lisinopril reduced SBP and slowed proteinuria, albeit to a variable degree among individuals. The acetylcholine-induced renal artery dilation at baseline negatively correlated with lisinopril-induced reduction of proteinuria (r(2) = 0.648, P = 0.003) and with the decrease in SBP (r(2) = 0.592, P = 0.006). Our data suggest that angiotensin-converting enzyme-inhibitor attenuates the progression of renal damage the most in those individuals with decreased basal renal endothelial-mediated vasodilation.

Topics: Acetylcholine; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Endothelium, Vascular; In Vitro Techniques; Lisinopril; Nephrectomy; Proteinuria; Random Allocation; Rats, Wistar; Renal Artery; Renal Insufficiency, Chronic; Vasodilation

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Creatinine; Drug Therapy, Combination; Humans; Lisinopril; Losartan; Proteinuria

This study examined the effect of long-term control of hyperglycemia with a new sodium glucose cotransporter 2 inhibitor, luseogliflozin, given alone or in combination with lisinopril on the progression of renal injury in the T2DN rat model of type 2 diabetic nephropathy. Chronic treatment with luseogliflozin (10 mg/kg/day) produced a sustained increase in glucose excretion and normalized blood glucose and glycosylated hemoglobin levels to the same level as seen in the rats treated with insulin. It had no effect on blood pressure. In contrast, lisinopril (10 mg/kg/day) reduced mean blood pressure from 140 to 113 mmHg. Combination therapy significantly reduced blood pressure more than that seen in the rats treated with lisinopril. T2DN rats treated with vehicle exhibited progressive proteinuria, a decline in glomerular filtration rate (GFR), focal glomerulosclerosis, renal fibrosis, and tubular necrosis. Control of hyperglycemia with luseogliflozin prevented the fall in GFR and reduced the degree of glomerular injury, renal fibrosis, and tubular necrosis. In contrast, control of hyperglycemia with insulin had no effect on the progression of renal disease in T2DN rats. Reducing blood pressure with lisinopril prevented the fall in GFR and reduced proteinuria and the degree of glomerular injury and tubular necrosis. Combination therapy reduced the degree of glomerular injury, renal fibrosis, and tubular necrosis to a greater extent than administration of either drug alone. These results suggest that control of hyperglycemia with luseogliflozin slows the progression of diabetic nephropathy more than that seen with insulin, and combination therapy is more renoprotective than administration of either compound alone.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Blood Pressure; Body Weight; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Eating; Glomerular Filtration Rate; Hypoglycemic Agents; Insulin; Kidney; Lisinopril; Male; Proteinuria; Rats; Renal Circulation; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; Sorbitol

Transactivation of epidermal growth factor receptor (EGFR) signaling by G protein-coupled receptors has been implicated in several cardiovascular (CV) conditions, including hypertension, heart failure, and cardiac and vascular hypertrophy. However, the therapeutic potential of EGFR inhibition in these conditions is currently unknown. The main objective of the present study was to investigate cardiac, vascular, and renal effects of EGFR inhibition by 4-[4-[[(1R)-1-phenylethyl]amino]-7H-pyrrolo[2,3-d]pyrimidin-6-yl]phenol (PKI-166) in the hypertensive chronic kidney disease model. Rats underwent 5/6 nephrectomy (5/6Nx) and were treated with PKI-166, lisinopril or vehicle from week 6 after disease induction until week 12. Sham animals received either PKI-166 or vehicle. Treatment with PKI-166 did not affect the development of the characteristic renal features in 5/6Nx, including proteinuria, diminished creatinine clearance, and increased glomerulosclerosis, whereas these were attenuated by lisinopril. Despite absence of effects on progressive renal damage, PKI-166 attenuated the progression of hypertension and maintained cardiac function (left ventricle end-diastolic pressure) to a similar extent as lisinopril. Also, PKI-166 attenuated the increase in phosphorylated EGFR in the heart as induced by 5/6Nx. Moreover, PKI-166 and lisinopril restored the impaired contraction of isolated thoracic aortic rings to phenylephrine and angiotensin II and impaired myogenic constriction of small mesenteric arteries in 5/6Nx rats. Blockade of the EGFR displays a CV benefit independent of limiting the progression of renal injury. Our findings extend the evidence on EGFR signaling as a target in CV disorders.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Blood Pressure; Cardiotonic Agents; ErbB Receptors; Hypertension, Renal; Immunohistochemistry; Kidney; Lisinopril; Male; Mesenteric Arteries; Muscle Contraction; Muscle Tonus; Muscle, Smooth, Vascular; Nephrectomy; Proteinuria; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptors, Adrenergic, alpha-1

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

Proteinuria is an important cause of progressive tubulo-interstitial damage. Whether proteinuria could trigger a renal lymphangiogenic response has not been established. Moreover, the temporal relationship between development of fibrosis, inflammation and lymphangiogenesis in chronic progressive kidney disease is not clear yet. Therefore, we evaluated the time course of lymph vessel (LV) formation in relation to proteinuria and interstitial damage in a rat model of chronic unilateral adriamycin nephrosis. Proteinuria and kidneys were evaluated up to 30 weeks after induction of nephrosis. LVs were identified by podoplanin/VEGFR3 double staining. After 6 weeks proteinuria was well-established, without influx of interstitial macrophages and myofibroblasts, collagen deposition, osteopontin expression (tubular activation) or LV formation. At 12 weeks, a ∼3-fold increase in cortical LV density was found (p<0.001), gradually increasing over time. This corresponded with a significant increase in tubular osteopontin expression (p<0.01) and interstitial myofibroblast numbers (p<0.05), whereas collagen deposition and macrophage numbers were not yet increased. VEGF-C was mostly expressed by tubular cells rather than interstitial cells. Cultured tubular cells stimulated with FCS showed a dose-dependent increase in mRNA and protein expression of VEGF-C which was not observed by human albumin stimulation. We conclude that chronic proteinuria provoked lymphangiogenesis in temporal conjunction with tubular osteopontin expression and influx of myofibroblasts, that preceded interstitial fibrosis.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Line; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Humans; Kidney Diseases; Kidney Tubules; Lisinopril; Lymphangiogenesis; Lymphatic Vessels; Male; Proteinuria; Rats; Vascular Endothelial Growth Factor C

The study has been designed to investigate the effect of benfotiamine and fenofibrate in diabetes-induced experimental vascular endothelial dysfunction (VED) and nephropathy. The single administration of streptozotocin (STZ) (50 mg/kg, i.p.) produced diabetes, which was noted to develop VED and nephropathy in 8 weeks. The diabetes produced VED by attenuating acetylcholine-induced endothelium dependent relaxation, impairing the integrity of vascular endothelium, decreasing serum nitrite/nitrate concentration and increasing serum TBARS and aortic superoxide anion generation. Further, diabetes altered the lipid profile by increasing the serum cholesterol, triglycerides and decreasing the high density lipoprotein. The nephropathy was noted to be developed in the diabetic rat that was assessed in terms of increase in serum creatinine, blood urea, proteinuria, and glomerular damage. The benfotiamine (70 mg/kg, p.o.) and fenofibrate (32 mg/kg, p.o.) or lisinopril (1 mg/kg, p.o., a standard agent) treatments were started in diabetic rats after 1 week of STZ administration and continued for 7 weeks. The treatment with benfotiamine and fenofibrate either alone or in combination attenuated diabetes-induced VED and nephropathy. In addition, the combination of benfotiamine and fenofibrate was noted to be more effective in attenuating the diabetes-induced VED and nephropathy when compared to treatment with either drug alone or lisinopril. Treatment with fenofibrate normalizes the altered lipid profile in diabetic rats, whereas benfotiamine treatment has no effect on lipid alteration in diabetic rats. It may be concluded that diabetes-induced oxidative stress, lipids alteration, and consequent development of VED may be responsible for the induction of nephropathy in diabetic rats. Concurrent administration of benfotiamine and fenofibrate may provide synergistic benefits in preventing the development of diabetes-induced nephropathy by reducing the oxidative stress and lipid alteration, preventing the VED and subsequently improving the renal function.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Glucose; Chelating Agents; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Endothelium, Vascular; Fenofibrate; Humans; Hypolipidemic Agents; Lisinopril; Oxidative Stress; Proteinuria; Rats; Rats, Wistar; Superoxides; Thiamine; Thiobarbituric Acid Reactive Substances; Vascular Diseases; Vasodilation

Angiotensin-converting enzyme (ACE) inhibition induces glomerular repair in the Munich Wistar Frömter (MWF) rat, a model of spontaneous glomerular injury. In this study, we investigated whether this effect is related to changes in glomerular cell number, particularly of podocytes, which are progressively lost with age. MWF rats with advanced nephropathy were studied at both 40 weeks and after 20 weeks of observation either with or without treatment with the ACE inhibitor lisinopril. Forty-week-old Wistar rats were used as controls. In untreated MWF rats, proteinuria, hypertension, glomerulosclerosis, and renal function worsened, while lisinopril induced regression of both functional and structural changes. Despite glomerular hypercellularity in untreated MWF rats, the number of endothelial cells per glomerulus did not change, and podocyte number even decreased. ACE inhibition halted the progressive increase in glomerular cell number and enhanced endothelial cell volume density. Surprisingly, lisinopril not only halted age-related podocyte loss but also increased the number of glomerular podocytes above baseline, which was associated with an increased number of proliferating Wilms tumor 1-positive cells, loss of cyclin-dependent kinase inhibitor p27 expression, and increased number of parietal podocytes. These data indicate that ACE inhibition restructures glomerular capillary, primarily by restoring the podocyte population in this model of glomerular injury. Increased parietal podocyte number in lisinopril-treated MWF rats suggests that the remodeling of Bowman's capsule epithelial cells contributes to this effect.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cell Division; Glomerulosclerosis, Focal Segmental; Hypertension; Kidney Function Tests; Kidney Glomerulus; Lisinopril; Male; Podocytes; Proteinuria; Rats; Rats, Inbred WF; Rats, Wistar

Pharmacological inhibition of the renin-angiotensin-aldosteron system (RAAS) constitutes a cornerstone strategy in the management of patients with chronic nephropaties and proteinuria. Angiotensin converting enzyme inhibitors (ACEI) as well as angiotensin II subtype 1 receptor antagonists (ARA) have been shown to decrease proteinuria, reduce the local renal inflammatory processes and slow the progression of renal insufficiency. Despite recent progress, there is still no optimal therapy which inhibits progression of renal disease. It is possible that pentoxifilline (PTX) an old medication which is still used to treat peripheral vascular disease will be the new adjunct to RAAS blockade. In addition, PTX has been shown to decrease the production of pro inflammatory cytokines and reactive oxygen species. 61-Year-old man with nephrotic proteinuria, diabetes type 2, hypertension, chronic viral hepatitis type C and slightly impaired renal function was desribed. Proteinuria as daily urine protein excretion (DPE), serum creatinine and eGFR (MDRD mode) were measured. Proteinuria was diagnosed in 2003 (DPE 3.5 g), creatinine 1.3-1.5 mg/dl. The patient had been examined in Department of Nephrology but exact reason of nephrotic syndrome was not recognized because he refused kidney biopsy. Therapy was started with ACEI and temporary effect as decrease of DPE to 0.2 g, eGFR was about 60 ml/min. and serum creatinine in normal range. In 2004 DPE increased to 8.98-9.42 g, serum creatinine 1.1-1.3 mg/dl. The dose of ACEI was increased and after then ARA was added. After one month of combined therapy DPE fell to 7.7 g, next the doses of both drugs were increased to maximum (losartan 100 mg and lisinopril 40 mg) and DPE fell to 6.8 g, serum creatinine was 1.4 mg/dl and potassium 5.4 mmol/l. Next PTF 800 mg/day was added and DPE fell to 0.55 g after 2 months' therapy. Similar DPE was after 6 months (0.53 g) since we started with combination of IKA, ARA and PTF.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Hepatitis C; Humans; Hypertension; Kidney Diseases; Lisinopril; Losartan; Male; Middle Aged; Pentoxifylline; Proteinuria

Advanced glycation end products (AGEs) are involved in diabetic nephropathy. The AGE inhibitor pyridoxamine (PM) is renoprotective in experimental chronic allograft nephropathy supporting its potential in non-diabetic renal damage.. We studied the effects of PM in adriamycin nephropathy (AN; 1.5 mg/kg i.v.). Six weeks after disease induction, treatment started with vehicle (VEH), lisinopril (ACEi; 75 mg/l drinking water), PM (2 g/l) and PM + lisinopril (PM/ACEi) (n = 12 per group) for 18 weeks. Age-matched healthy rats (n = 6) served as controls (CON).. ACEi reduced proteinuria, blood pressure, and renal damage. PM gradually increased blood pressure and not affected proteinuria. In PM/ACEi the antiproteinuric and blood pressure-lowering effects of ACEi were abrogated during long-term treatment. Remarkably, creatinine, focal glomerulosclerosis and interstitial fibrosis were considerably increased under PM/ACEi. Pronounced hypercholesterolemia, which occurred in both PM-treated groups, was accompanied by marked glomerular lipid deposition.. PM was not renoprotective in AN. By contrast, renal damage was aggravated when PM was combined with ACEi. Despite the fact that there is no current evidence that these findings apply to the drug as used in human diabetic nephropathy, we emphasize the importance of close monitoring of blood pressure, lipids and possible direct toxic effects in future studies with PM in renal patients, especially when combining PM with ACEi.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Doxorubicin; Drug Interactions; Drug Therapy, Combination; Glycation End Products, Advanced; Kidney Diseases; Lipids; Lisinopril; Proteinuria; Pyridoxamine; Rats

To report the role of retinal hypoxia in development of diabetic macular edema and its management--a new concept.. A 24-year-old diabetic female was seen with bilateral visual blurring for 3 weeks, associated with marked diabetic macular edema, diabetic retinopathy, and non-arteritic anterior ischemic optic neuropathy (NA-AION) in both eyes. She was taking three blood pressure lowering drugs for diabetic neuropathy and nephropathy. Stopping two of those arterial hypotensive drugs, without any of the conventional treatments for diabetic macular edema, resulted in rapid improvement of visual acuity from counting fingers to 20/50 in the right eye, and from 20/80 to 20/25 in the left eye, and complete resolution of macular edema and improvement of retinopathy. Similarly, visual field defects in both eyes improved to almost normal.. The evidence from this diabetic patient suggests that hypoxia caused by fall in perfusion pressure in the retinal capillaries may be playing an important role in the development of diabetic macular edema in some, perhaps many, of these cases.

Topics: Adult; Blood Pressure; Diabetic Nephropathies; Diabetic Retinopathy; Female; Fluorescein Angiography; Follow-Up Studies; gamma-Aminobutyric Acid; Humans; Hypoxia; Insulin; Lisinopril; Macular Edema; Optic Neuropathy, Ischemic; Pregabalin; Proteinuria; Retinal Diseases; Tomography, Optical Coherence; Tramadol; Vision Disorders; Visual Acuity; Visual Field Tests; Visual Fields

Proteinuria plays a pathogenic role in the development of end stage renal disease. Angiotensin converting enzyme (ACE) inhibitors lower proteinuria and are renoprotective. However, large inter-individual variation in antiproteinuric response to ACE inhibitors exists. In this study, we explored the mechanism of therapeutic resistance to an ACE inhibitor in the rat 5/6 nephrectomy model. At week 6 after 5/6 nephrectomy, treatment with lisinopril was initiated for 6 weeks. Proteinuria and blood pressure were evaluated weekly. At the end of the experiment, rats were divided into tertiles according to their antiproteinuric response: (1) responders (n=9), (2) intermediate responders (n=8) and (3) non-responders to ACE inhibitor therapy (n=9). At the start of treatment, proteinuria had progressively increased to 154 (95% confidence interval [CI]: 123-185) mg/24 h in the entire cohort, with comparable proteinuria and blood pressure in all groups. Following treatment with ACE inhibitor, proteinuria was significantly lower in the responders (68, CI: 46-89 mg/24 h) compared to the non-responders (251, CI: 83-420) mg/24 h). Similarly, blood pressure was reduced in the responders, but unaffected in the non-responders. At autopsy, renal ACE activity and renal ACE expression were significantly lower in the responders compared to the non-responders. Although lisinopril intake was comparable in all animals, urinary drug excretion was increased in the non-responders, demonstrating increased drug clearance. Average urinary lisinopril excretion was correlated with antiproteinuric response (R(2)=0.32, P=0.003). In conclusion, both pharmacodynamic and -kinetic factors account for the non-response to lisinopril. Whether these can be overcome simply by increasing drug dosage in non-responders should be investigated.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Disease Models, Animal; Drug Resistance; Lisinopril; Male; Nephrectomy; Peptidyl-Dipeptidase A; Proteinuria; Rats; Rats, Wistar

The blockade of the renin-angiotensin-aldosterone system may limit the progression of graft dysfunction in patients receiving kidney transplantations. We retrospectively evaluated the safety and efficacy of angiotensin-converting enzyme inhibitors (ACEI) in renal allograft recipients. Fifty-seven cadaveric kidney recipients (58% of recipients), were prescribed an ACEI (lisinopril). The indications for ACEI were isolated proteinuria (1 patient), erythrocytosis (6 patients), and arterial hypertension (50 patients). The choice of an ACEI for blood pressure control was due to presence of left ventricular hypertrophy (2 patients), mild proteinuria (4 patients), and high hemoglobin (4 patients). There was a significant reduction in the mean arterial pressure after 1 month (P = .0004) and 1 year (P = .0002) of therapy. Overall, the estimated glomerular filtrate rate (eGFR), calculated using the Cockcroft-Gault equation, remained unchanged. Among patients who had serum creatinine values above 2.0 mg/dL at the beginning of ACEI therapy, there was a significant rise in eGFR from 39.3 +/- 13.2 to 44.1 +/- 16.8 mL/min after 6 months (P = .01), and 43.3 +/- 17.3 mL/min after 1 year (P = .04). In patients with erythrocytosis, the hemoglobin showed a significant and sustained reduction after 1 month (P = .004) and 1 year (P = .001). Six patients suspended ACEI owing to adverse events: cough (n = 4), worsening of graft function (n = 1), and hypotension (n = 1). Six patients required erythropoiesis-stimulating agents. No patient suspended treatment owing to hyperkalemia. In conclusion, ACEI were well tolerated, safe, and effective antihypertensive agents in kidney graft recipients. They seemed to have some beneficial effect in preserving GFR in patients with worse graft function.

Topics: Angiotensin-Converting Enzyme Inhibitors; Cadaver; Glomerular Filtration Rate; Humans; Hypertension; Kidney Transplantation; Lisinopril; Polycythemia; Postoperative Complications; Proteinuria; Renin-Angiotensin System; Retrospective Studies; Tissue Donors

Topics: Blood Pressure; Diabetic Retinopathy; Fluorescein Angiography; gamma-Aminobutyric Acid; Humans; Hypoxia; Insulin; Lisinopril; Macular Edema; Optic Neuropathy, Ischemic; Pregabalin; Proteinuria; Retinal Diseases; Retinal Vein Occlusion; Tomography, Optical Coherence; Tramadol; Vision Disorders; Visual Acuity; Visual Fields

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

Nephrin, podocin, CD2AP, and alpha-actinin-4 are important podocyte proteins that help maintain the integrity of the slit diaphragm and prevent proteinuria. Studies have shown that angiotensin-converting enzyme inhibitors, glucocorticoids, and all-trans retinoic acid (ATRA) have antiproteinuric effects. However, it is still unclear whether these drugs, with different pharmacological mechanisms, lead to a reduction in proteinuria by changing the expression and distribution of these important podocyte proteins. In this study, changes in the expression and distribution of nephrin, podocin, CD2AP, and alpha-actinin-4 were dynamically detected in Adriamycin-induced nephrotic (ADR) rats treated with three different drugs: lisinopril, prednisone, and ATRA. Nephropathy was induced by an intravenous injection of Adriamycin. After Adriamycin injection, rats received lisinopril, prednisone, and ATRA treatment, respectively. Renal tissues were collected at Days 3, 7, 14, and 28. The distribution and the expression of messenger RNA and protein of nephrin, podocin, CD2AP, and alpha-actinin-4 were detected by indirect immunofluorescence, real-time polymerase chain reaction, and Western blotting, respectively. With the intervention of lisinopril, prednisone, and ATRA, changes in the expression of nephrin, podocin, and CD2AP were diverse, which was different from that detected in ADR rats. After lisinopril and prednisone intervention, podocin exhibited prominent earlier changes compared with those of nephrin and CD2AP, whereas CD2AP showed more prominent changes after ATRA intervention. There was no change in the expression of alpha-actinin-4 molecule. In summary, we conclude that the antiproteinuric effects of lisinopril, prednisone, and ATRA were achieved by changes in the expression and distribution of the important podocyte molecules nephrin, podocin, CD2AP, and alpha-actinin-4. The pattern in the change of podocyte molecules after lisinopril and prednisone intervention was similar, but the pattern in the change of podocyte molecules after ATRA intervention was different from that of lisinopril or prednisone intervention.

Topics: Actinin; Adaptor Proteins, Vesicular Transport; Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Doxorubicin; Glucocorticoids; Intracellular Signaling Peptides and Proteins; Kidney Glomerulus; Lisinopril; Male; Membrane Proteins; Microfilament Proteins; Nephrosis; Podocytes; Prednisone; Proteinuria; Random Allocation; Rats; Rats, Sprague-Dawley; Tretinoin

Although recurrent diabetic nephropathy is common in patients with type I diabetes after kidney transplantation, the development of focal segmental glomerulosclerosis (FGS) is rare, and its development generally takes several years. We report here a case of type I diabetes mellitus with secondary FGS accompanied by proteinuria 10 months following kidney transplantation. Episode biopsy showed secondary FGS, evidenced by glomerular capillary collapse and large epithelial cells with ballooning degeneration. Exudative dense deposition of IgM in a diffuse global mesangial pattern and enlarged glomerular diameters were observed, suggestive of glomerular hyperfiltration which can lead to secondary FGS. An imbalance in body size between donor and recipient and/or uncontrolled diabetes are potential causes of glomerular hyperfiltration. We administered angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker to reduce hyperfiltration-induced renal damage; the combination therapy reduced proteinuria from 2346 to 258 mg/d. Secondary FGS should be a consideration after kidney transplantation in patients with type I diabetes mellitus.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzimidazoles; Biphenyl Compounds; Diabetes Mellitus, Type 1; Glomerulosclerosis, Focal Segmental; Humans; Kidney Transplantation; Lisinopril; Male; Proteinuria; Tetrazoles

The use of combined therapy with an angiotensin-converting enzyme (ACE) inhibitor and an angiotensin II receptor blocker (ARB) for treatment of proteinuria has been gaining support. Limited data are available regarding this treatment in the pediatric population. This report describes a case of acute compromise of renal function associated with hypotension in a 7-year-old boy treated with the ACE inhibitor lisinopril and the ARB losartan. It emphasizes the need for close surveillance of renal function and blood pressure during such therapy even in patients with relative preservation of renal function. Further investigation into the utility and safety of dual therapy with an ACE inhibitor plus an ARB in pediatric patients is warranted. Key Words: renal failure, proteinuria, angiotensin-converting enzyme inhibitor, ACEI, angiotensin II receptor blocker, ARB.

Topics: Acute Kidney Injury; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Child; Drug Therapy, Combination; Humans; Hypotension; Lisinopril; Losartan; Male; Proteinuria

Topics: Adolescent; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Autoantigens; Basement Membrane; Benzimidazoles; Biopsy; Biphenyl Compounds; Collagen Type IV; Diagnosis, Differential; Drug Therapy, Combination; Glomerulonephritis; Hearing Loss, Sensorineural; Hematuria; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Immunosuppressive Agents; Kidney Glomerulus; Lisinopril; Male; Microscopy, Fluorescence; Nephritis, Hereditary; Nephrotic Syndrome; Prednisone; Proteinuria; Tetrazoles

Advanced glycation end-products (AGEs) contribute to the pathogenesis of diabetic glomerulopathy. The role of AGEs in non-diabetic renal damage is not well characterized. First, we studied whether renal AGE accumulation occurs in non-diabetic proteinuria-induced renal damage and whether this is ameliorated by renoprotective treatment. Secondly, we investigated whether renal AGE accumulation was due to intrarenal effects of local protein trafficking.. Pentosidine was measured (by high-performance liquid chromatography) in rats with chronic bilateral adriamycin nephropathy (AN), untreated and treated with lisinopril. Age-matched healthy rats served as negative controls. Secondly, we compared renal pentosidine in mild proteinuric and non-proteinuric kidneys of unilateral AN and in age-matched controls at 12 and 30 weeks. Intrarenal localization of pentosidine was studied by immunohistochemistry.. Renal pentosidine was elevated in untreated AN (0.14+/-0.04 micromol/mol valine) vs healthy controls (0.04+/-0.01 micromol/mol valine, P<0.01). In lisinopril-treated AN, pentosidine was lower (0.09+/-0.02 micromol/mol valine) than in untreated AN (P<0.05). In unilateral proteinuria, pentosidine was similar in non-proteinuric and proteinuric kidneys. After 30 weeks of unilateral proteinuria, pentosidine was increased in both kidneys (0.26+/-0.10 micromol/mol valine) compared with controls (0.18+/-0.06 micromol/mol valine, P<0.05). Pentosidine (AN, week 30) was also increased compared with AN at week 12 (0.16+/-0.06 micromol/mol valine, P<0.01). In control and diseased kidneys, pentosidine was present in the collecting ducts. In proteinuric kidneys, in addition, pentosidine was present in the brush border and cytoplasm of dilated tubular structures, i.e. at sites of proteinuria-induced tubular damage.. Pentosidine accumulates in non-diabetic proteinuric kidneys in damaged tubules, and renoprotective treatment by angiotensin-converting enzyme (ACE) inhibitors inhibits AGE accumulation, supporting a relationship between abnormal renal protein trafficking, proteinuria-induced tubular damage and tubular pentosidine accumulation. Future studies, applying specific AGE inhibitors, should be conducted to provide insight into the pathophysiological significance of renal AGEs in non-diabetic renal disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Blood Pressure; Cholesterol; Creatinine; Doxorubicin; Glycation End Products, Advanced; Immunohistochemistry; Kidney; Lisinopril; Lysine; Male; Proteinuria; Rats; Rats, Wistar

Control of blood pressure (BP) and optimal reduction of proteinuria (Uprot) are necessary for long-term renoprotection. Unfortunately, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II (Ang II) antagonists are not effective during sodium repletion. Vasopeptidase inhibitors (VPI) cause dual inhibition of ACE and neutral endopeptidase, the latter resulting in decreased atrial natriuretic peptide (ANP) breakdown and thus enhanced natriuresis. Therefore, in contrast with ACEI, VPI may be effective during high sodium intake.. To test this hypothesis, the renoprotective actions of the new VPI gemopatrilat (GEM) were studied during low (0.05% NaCl) and high (3.0% NaCl) sodium diets in normotensive Wistar rats with established adriamycin nephrosis. The ACEI lisinopril (LIS) was used as control. Rats received either GEM (0.3 mg/g chow), an equihypotensive dose of LIS (75 mg/L drinking water), or vehicle (VEH) from week 6 (that is, established Uprot) until sacrifice. The effect of therapy was monitored by measuring systolic BP and Uprot (weekly) and structural renal damage at the end of study (week 16).. During low sodium, GEM effectively reduced Uprot (-48 +/- 4%), but LIS was more effective (-80 +/- 2%), while Uprot slightly increased in VEH (+23 +/- 2%). The focal glomerulosclerosis (FGS) score after GEM (38 +/- 14) was lower than in the VEH group (79 +/- 27), although this was not significant. LIS (18 +/- 6) reduced FGS significantly. Remarkably, on high sodium, GEM was completely ineffective in reducing BP, Uprot and structural renal injury, just like LIS.. The renoprotective actions of VPI depend on dietary sodium intake in normotensive nephrotic rats: therapeutic efficacy is fully blunted by a high sodium diet. During a low sodium diet, gemopatrilat was renoprotective, but less effective than lisinopril. Whether higher doses of the VPI could improve its renoprotective efficacy remains to be elucidated.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Azepines; Blood Pressure; Creatinine; Enzyme Inhibitors; Lisinopril; Male; Nephrosis; Neprilysin; Proteinuria; Rats; Rats, Wistar; Sodium, Dietary

Several factors such as proteinuria and renal fibrosis may be important in the progression of many forms of chronic renal diseases. The purposes of the current study were to investigate the progressive renal failure of the rats with surgical renal mass reduction (RMR) and the effect of the angiotensin-converting enzyme (ACE) inhibitor, lisinopril, and to document correlation of several factors associated with progressive renal failure. Rats were subtotal (5/6) nephrectomized by resection of the renal poles and sham-operated. The functional, histological and haematological changes of the rats were studied for up to 10 weeks. After 2 weeks of RMR, oral administration of lisinopril (10 mg kg(-1) per day) was performed for 8 weeks. RMR resulted in progressive renal failure with proteinuria, monocyte/macrophage (ED1+) infiltration, anaemia as assessed by haemoglobin and haematocrit (Htc), renal hypertrophy as assessed by left kidney to body weight ratio (BKW/BW), and renal fibrosis as assessed by glomerular lesions and tubulointerstitial changes. Lisinopril exhibited renoprotection with antiproteinuric effect and inhibition of monocyte/macrophage (ED1+) infiltration. However, beneficial effect of lisinopril on anaemia was not observed. At 10 weeks after surgery, severity of proteinuria positively correlated with plasma creatinine (Pcr), BKW/BW, histological damage, and systolic blood pressure, and negatively correlated with haemoglobin. Severity of tubulointerstitial changes positively correlated with Pcr and blood urea nitrogen, and negatively correlated with haemoglobin and Htc. Moreover, monocyte/macrophage (ED1+) infiltration positively correlated with severity of proteinuria and tubulointerstitial changes. These findings strongly support that proteinuria, monocyte/macrophage infiltration and renal fibrosis appear to play principal roles in the progressive renal failure with anaemia and renoprotection of ACE inhibition may be mediated by multiple actions of ACE inhibitor. The present study confirms that rats with RMR is useful to explore target molecules for renoprotective drugs and evaluate renoprotective effect of new molecular entities.

Topics: Analysis of Variance; Anemia; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Disease Models, Animal; Disease Progression; Kidney; Lisinopril; Male; Proteinuria; Rats; Rats, Wistar; Renal Insufficiency

A direct consequence of glomerular protein leakage is an increased exposure of proximal tubular cells to proteins. The aim of the present study was to examine whether chronic proteinuria affects the tubular handling of proteins and whether anti-proteinuric therapy by angiotensin-converting-enzyme (ACE) inhibition restores this tubular function. Renal uptake and catabolic rate of the low-molecular-weight protein (LMWP) myoglobin was determined in anaesthetized control and adriamycin-induced nephrotic rats by external counting after radiolabelling. Proteinuria correlated with the uptake as well as the catabolism of myoglobin. The higher the proteinuria, the lower was the renal uptake of myoglobin (r =0.72, P =0.002). Also, the catabolic rate of myoglobin (r =0.80, P =0.0002) was lower with increasing severity of proteinuria. During treatment with the ACE inhibitor lisinopril, proteinuria was lowered by 79+/-9% (mean+/-S.E.M.). Renal uptake and catabolic rate of the LMWP were not restored by ACE inhibition. The catabolic rate of myoglobin was even decreased further with 48+/-5% compared with pretreatment levels. In summary, adriamycin-induced proteinuria is associated with a lower uptake and a lower catabolic rate of LMWP in the proximal tubule. ACE inhibition lowers proteinuria, but does not restore the affected LMWP uptake and rate of catabolism. The rate of LMWP catabolism is even decreased further. In contrast, the urinary excretion of N -acetyl glucosaminidase, the tubular marker of toxicity, was effectively returned to normal levels during ACE inhibition. Taken together, the data suggest that proteinuria is toxic for the proximal tubular cells and that ACE inhibition protects the remaining functional tubular cells directly against destruction through decreasing hypercatabolism.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Doxorubicin; Iodine Radioisotopes; Kidney Tubules; Lisinopril; Male; Models, Animal; Myoglobin; Nephrosis; Proteinuria; Rats; Rats, Wistar

Topics: Adolescent; Angiotensin-Converting Enzyme Inhibitors; Child; Child, Preschool; Drug Resistance; Female; Humans; Lisinopril; Male; Nephrotic Syndrome; Nigeria; Proteinuria; Retrospective Studies; Steroids

Despite angiotensin-converting enzyme (ACE) inhibition is a very powerful therapy, it may not be uniformly renoprotective in patients with proteinuric nephropathies who might refer late in the course of the disease. In accelerated passive Heymann nephritis (PHN), a severe rat model of human membranous nephropathy, with proteinuria and increased urinary excretion of endothelin-1 (ET-1), early treatment with an ACE inhibition limited proteinuria as well as the exuberant formation of renal ET-1, while late treatment reduced urinary proteins not to a significant extent. Since biologic effects and production of ET-1 within the kidney are counteracted by nitric oxide, we studied the effect of combining lisinopril and l-arginine, the natural precursor of nitric oxide, starting late in the disease.. Uninephrectomized PHN rats were divided in four groups (N = 10) and daily given orally: vehicle; 1.25 g/L l-arginine; 40 mg/L lisinopril; and l-arginine + lisinopril. Treatments started at 2 months, when rats had massive proteinuria, until 9 months. Six normal rats served as control.. Increase in systolic blood pressure was significantly limited by l-arginine. Lisinopril alone and the combination were more effective. Renal function impairment was not affected by l-arginine, partially ameliorated by ACE inhibitor and normalized by the combined therapy. In rats given l-arginine, proteinuria levels were similar to vehicle. ACE inhibitor kept proteinuria at values comparable to pretreatment and numerically lower than vehicle. Addition of l-arginine to lisinopril was more effective, with values significantly lower than vehicle. Glomerular and tubular changes were limited by the ACE inhibitor and further ameliorated by the combined therapy. Exaggerated urinary ET-1 of PHN was reduced by 23% and 40% after l-arginine and lisinopril, respectively, and by 62% with the combination. Defective urinary excretion of cyclic guanosine monophosphate (cGMP) was partially restored by lisinopril, while normalized by the combined therapy.. Combining l-arginine with ACE inhibitors would represent a novel strategy for patients with severe nephropathy not completely responsive to ACE inhibition. Restoring the nitric oxide/ET-1 balance could be of benefit in halting renal disease progression.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arginine; Blood Pressure; Cyclic GMP; Disease Progression; Drug Combinations; Endothelin-1; Glomerulonephritis; Kidney; Lisinopril; Male; Proteinuria; Rats; Rats, Sprague-Dawley; Systole

Normalization of proteinuria and even regression of glomerulosclerosis seem to occur in progressive renal disease upon blockade of the renin-angiotensin system. Here we quantified the effect of a combination of an angiotensin converting enzyme (ACE) inhibitor and an angiotensin II (Ang II) receptor antagonist on renal function and structure in spontaneous overt nephropathy in male Munich Wistar Fromter (MWF) rats.. Three groups of MWF rats were used: group 1 was studied at 25 weeks to provide baseline renal function and structure; group 2 was followed until 40 weeks of age; group 3 was treated with lisinopril (40 mg/L) and valsartan (180 mg/L) in drinking water from 25 to 40 weeks. A group of untreated Wistar rats (group 4, 40 weeks) was used as the control. At the end of the study renal hemodynamics, kidney tissue morphology, accumulation of type III collagen and evaluation of interstitial inflammatory cells were performed.. MWF rats spontaneously developed hypertension, proteinuria, glomerulosclerosis, interstitial volume expansion and protein cast accumulation. Combined treatment completely reversed protein excretion and ameliorated renal plasma flow and the glomerular ultrafiltration coefficient. The combined therapy was effective in halting progressive glomerulosclerosis, particularly in glomeruli with mild sclerotic lesions, and reduced interstitial volume expansion. Type III collagen accumulation and protein cast also were reversed. Infiltrating cells were massively present in the interstitium already at 25 weeks, and augmented at 40 weeks in untreated rats. Combined treatment reduced infiltrating cells to values comparable to normal controls.. These data indicate that in animals with spontaneous overt nephropathy, Ang II antagonism normalized proteinuria, eliminated inflammatory cell infiltration, and ameliorated glomerular and tubular structural changes.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Body Weight; Collagen Type III; Disease Progression; Kidney Diseases; Kidney Glomerulus; Lisinopril; Macrophages; Male; Monocytes; Proteinuria; Rats; Rats, Wistar; Renal Circulation; Tetrazoles; Valine; Valsartan

Angiotensin-converting enzyme (ACE) inhibitors provide renoprotection, but there is considerable interindividual variability in therapeutic efficacy, with residual proteinuria and progressive renal function loss in many individuals. This requires additional strategies to optimize therapy response, particularly for individuals with a poor response to ACE inhibition. We studied whether co-treatment with an angiotensin II subtype 1 (AT1) receptor antagonist (AII-A) improves the individual antiproteinuric response of maximal ACE inhibition in established adriamycin nephrosis.. Rats were instituted on lisinopril (75 mg/L) six weeks after disease induction. After two weeks rats were re-stratified for residual proteinuria to continue this regimen, to a higher dose of lisinopril (150 mg/L) or to co-treatment with the AII-A L 158,809 for another four weeks. Groups on monotherapy AII-A and vehicle served as controls (all groups N=15).. Lisinopril lowered proteinuria by 63% from 741 to 246 g/day (range of percentage change -90 to +2%). Neither increasing the dose of the ACE inhibitor nor addition of AII-A to ACE inhibition improved the antiproteinuric efficacy on a group or individual level: non-responders remained non-responders. All drug categories reduced hard end-points of focal glomerulosclerosis to a similar degree.. ACE inhibition has variable renal protective efficacy in the adriamycin model. Neither increasing the dose of the ACE inhibitor beyond the optimal level nor co-treatment with AII-A overcome the individual therapy resistance. Thus, in established adriamycin nephrosis, blockade of the renin-angiotensin system at two different levels offers no additional benefit over ACE inhibition alone, either on the group or individual level.

Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Antineoplastic Agents; Blood Pressure; Body Weight; Disease Models, Animal; Doxorubicin; Drug Resistance; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Imidazoles; Lisinopril; Male; Nephrosis; Proteinuria; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Tetrazoles

Angiotensin-converting enzyme (ACE) inhibitor therapy given soon after disease induction uniformly prevents proteinuria in virtually all models of disease progression. This does not necessarily apply to patients with proteinuric nephropathies, who might be referred late in the course of their disease. Here we used a severe rat model of passive Heymann nephritis (PHN), which may mimic advanced phases of human membranous nephropathy, to study the response to ACE inhibitor alone or in combination with a HMG CoA reductase inhibitor (statin) that independently of the cholesterol-lowering effect influences pathways involved in inflammatory and fibrogenic processes. Therapies started when animals had massive proteinuria and renal lesions.. PHN was accelerated by uninephrectomy seven days after IV injection of rabbit anti-FX1A antibody. Four months later, when massive proteinuria and renal lesions were present, the rats were divided into five groups and daily given orally: vehicle; lisinopril 40 mg/L; lisinopril 400 mg/L; simvastatin 2 mg/kg b.i.d; or lisinopril 40 mg/L plus simvastatin. Six normal rats served as controls. Animals were sacrificed at 10 months.. By the end of the study three PHN rats died in the vehicle group, four in the group given lisinopril at 40 mg/L and two in the group at 400 mg/L, whereas all rats on simvastatin or combined therapy were alive. Blood pressure increased during time in PHN and was normalized by treatment with ACE inhibitor and combined therapy. Even at the high dose lisinopril failed to reduce proteinuria. Simvastatin only partially affected proteinuria. However, combining lisinopril with simvastatin had a remarkable antiproteinuric effect, such that at 10 months the urinary proteins were comparable to pre-treatment values and significantly lower than either the vehicle or lisinopril groups. Hypercholesterolemia of PHN rats was limited by combined therapy, and a positive correlation was found between serum cholesterol and proteinuria. Renal function was only partially ameliorated by simvastatin but significantly improved by combined therapy. Drug combination significantly limited glomerulosclerosis, tubular damage and interstitial inflammation, compared to vehicle or drugs alone. Up-regulation of monocyte chemoattractant protein-1 (MCP-1) mRNA in PHN kidneys was not affected by lisinopril, it was inhibited by 30% after simvastatin, and almost completely normalized by lisinopril plus simvastatin.. These data suggest that a combined ACE inhibitor and statin approach could represent a therapeutic option for patients with advanced renal disease in whom ACE inhibitors alone fail to lower proteinuria and injury to any substantial extent.

Topics: Alanine Transaminase; Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartate Aminotransferases; Blood Pressure; Body Weight; CD4-Positive T-Lymphocytes; Chemokine CCL2; Cholesterol; Disease Models, Animal; Drug Therapy, Combination; Eating; Glomerulonephritis; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney; Lisinopril; Male; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger; Simvastatin; Triglycerides

ACE inhibition exerts an antiproteinuric and renoprotective effect. However, residual proteinuria is often present. As residual proteinuria is associated with a poor renal outcome, identification of its determinants is important. We found previously that the systemic sequelae of proteinuria enhance renal damage in untreated nephrotic rats. The impact of systemic nephrosis on renal therapy response, however, is unclear. In the present study we therefore investigated whether the severity of systemic nephrosis, estimated from plasma cholesterol, predicts residual proteinuria during ACE inhibition.. Sixty male Wistar rats with established adriamycin nephrosis were studied. Six weeks after the induction of nephrosis, rats were stratified for proteinuria and treated for 2 weeks with lisinopril (75 mg/l) or vehicle.. At the start of treatment, median proteinuria was 744 mg/day (95% confidence interval (CI) 609-860) and plasma cholesterol was 10.4 mmol/l (95% CI 8.0-12.6), reflecting the state of systemic nephrosis. Lisinopril, but not vehicle, reduced blood pressure and proteinuria (-62%; range -70 to -48; P<0.001). Residual proteinuria was 275 mg/day, with a wide range (47-1119 mg/day). Pre-treatment proteinuria and pre-treatment cholesterol correlated positively with residual proteinuria. By multivariate analysis (r(2) of model =0.92), both pre-treatment cholesterol and pre-treatment proteinuria were independent predictors of residual proteinuria. The quantitative impact of this multivariate analysis is illustrated by the difference in residual proteinuria between rats with a cholesterol:proteinuria ratio less than, compared with greater than, the median (residual proteinuria 298 mg/day (CI 129-496) vs 439 mg/day (CI 158-670), respectively). Blood pressure response was not predicted by the tested predictor variables.. In this model of proteinuria-induced renal damage, not only proteinuria as such, but also the concomitant nephrotic alterations predict residual proteinuria. Further studies, applying specific interventions, are needed to determine which components of the systemic derangements could play a causal role in the modulation of therapy response.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cholesterol; Doxorubicin; Drug Administration Schedule; Lisinopril; Male; Nephrosis; Prognosis; Proteinuria; Rats; Rats, Wistar; Severity of Illness Index

In proteinuric nephropathies with increasingly severe defects of the glomerular filtering barrier, interstitial fibrogenesis is a major effector of scarring. An early event in this process is the peritubular accumulation of myofibroblasts that express alpha-smooth muscle actin (alpha-SMA) and contribute to abnormal matrix production. Common trigger factors are poorly understood. Enhanced protein trafficking may play a role by up-regulating inflammatory and fibrogenic genes in proximal tubular cells.. The remnant kidney model in rats was used to (1) analyze interactions between activated proximal tubular cells, peritubular cells expressing the myofibroblast marker, and inflammatory cells at time intervals (days 7, 14, and 30) after surgery, and (2) evaluate the effects of angiotensin-converting enzyme inhibitor (ACEi) on protein trafficking, fibrogenic signaling, and alpha-SMA expression.. Abnormal uptake of ultrafiltered proteins by proximal tubular cells (IgG staining) occurred at an early stage (day 7) and was subsequently associated with macrophage and alpha-SMA+ cell accumulation into the peritubular interstitium. alpha-SMA+ cells clustered with macrophages into the interstitium. These changes were associated with appearance of transforming growth factor-beta1 (TGF-beta1) mRNA in proximal tubular cells and in the infiltrating cells with time. At day 30, focal alpha-SMA staining also was found in the tubular cells and in peritubular endothelial cells on semithin ultracryosections. ACEi prevented both proteinuria and abnormal protein accumulation in tubular cells, as well as the inflammatory and fibrogenic reaction with peritubular alpha-SMA expression.. Profibrogenic signaling from both proximal tubular cells on challenge with filtered protein and inflammatory cells is implicated as a key candidate trigger of progressive tubulointerstitial injury.

Topics: Actins; Angiotensin-Converting Enzyme Inhibitors; Animals; Cell Division; Fibroblasts; Fibrosis; Immunoglobulin G; Kidney Tubules; Kidney Tubules, Proximal; Lisinopril; Macrophages; Male; Muscle, Smooth; Proteins; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger; Staining and Labeling; Tissue Distribution; Transforming Growth Factor beta; Transforming Growth Factor beta1

The gradual onset of the antiproteinuric effects of ACE inhibition suggests that structural effects on the glomerular basement membrane (GBM) may be involved in their renoprotective action. To test this hypothesis, we studied the effects of lisinopril (5 mg/kg/24 h) on proteinuria, focal glomerulosclerosis (FGS) and glomerular heparan sulfate (HS) proteoglycan (HSPG) GBM staining in rats with established Adriamycin nephrosis. Treatment was started 6 weeks after disease induction. As expected, lisinopril reduced blood pressure, proteinuria and the FGS score. In control rats, Adriamycin nephrosis was associated with significantly impaired GBM staining for both HSPG core protein (assessed from BL-31 staining) and HS staining (assessed from JM-403 staining) 12 weeks after disease induction. In rats treated with lisinopril (5 mg/kg/24 h) GBM staining was significantly better preserved for HS as well as for HSPG core protein. These data suggest that structural effects on the GBM, improving glomerular permselectivity, may be involved in the renoprotective effects of ACE inhibition in proteinuria-induced renal damage.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Basement Membrane; Doxorubicin; Glomerulosclerosis, Focal Segmental; Heparan Sulfate Proteoglycans; Kidney Glomerulus; Lisinopril; Male; Nephrosis; Proteinuria; Rats; Rats, Wistar

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

Long-term renin-angiotensin system blockade is beneficial in a variety of renal diseases. This study examines the long-term (34 weeks) effects of the angiotensin-converting enzyme inhibitor lisinopril and the angiotensin II receptor type I blocker L158,809 in the Fisher to Lewis rat model of chronic renal transplant failure. Treatment in allografted rats with lisinopril or L158,809 was initiated 10 days after transplantation, or at the time when proteinuria exceeded 50 mg/24 h. Untreated allografts and syngrafts served as controls. In contrast to syngrafts, untreated allografts developed proteinuria, hypercholesterolaemia, interstitial damage, and glomerulosclerosis. Lisinopril or L158,809 treatment in allografts starting at day 10 after transplantation completely prevented this, with the exception of interstitial damage, but this treatment also caused a reduction in blood pressure and renal function. Moreover, the intimal surface area of the renal arteries was dramatically increased in allografts treated with either lisinopril or L158,809 compared with untreated allografted rats. Treatment once proteinuria had developed was less effective in preventing glomerulosclerosis, but also caused less intimal expansion. Thus, chronic renin-angiotensin system blockade preserves glomerular morphology in the absence of proteinuria, but enhances intimal hyperplasia and reduces renal function in experimental transplantation. In view of these results, it should be questioned whether such treatment benefits renal transplant patients in the long term.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Glomerulonephritis; Hyperplasia; Kidney Transplantation; Lisinopril; Male; Oligopeptides; Postoperative Complications; Postoperative Period; Proteinuria; Rats; Rats, Inbred F344; Rats, Inbred Lew; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renal Artery; Renin-Angiotensin System; Tunica Intima

In proteinuric nephropathies tubular atrophy leads to glomerular-tubule disconnection through an unknown mechanism. Here we studied whether proteinuria promoted glomerular-tubule disconnection in individual nephrons and whether this phenomenon was prevented by an angiotensin-converting enzyme (ACE) inhibitor. Passive Heymann nephritis (PHN) and control rats were studied at 4 and 8 months. Two additional groups of PHN rats received lisinopril (40 mg/L) or a calcium channel blocker (lacidipine, 3 mg/kg) from day 7 after surgery to 8 months. At sacrifice, kidneys were serially sectioned to identify glomerular- tubule abnormalities in individual nephrons and changes in interstitial volume. In PHN rats, the time-dependent increase in proteinuria was paralleled by tubular atrophy leading to glomerular-tubule disconnection and interstitial volume enlargement. Marked apoptosis was invariably found in atrophic tubules in contrast to the absent or very mild terminal dUTP nick-end labeling staining in tubules normally connected to glomeruli in PHN animals. Treatment with an ACE inhibitor prevented hypertension, proteinuria, the formation of atrophic tubuli, glomerular-tubule disconnection and limited the fractional interstitial volume expansion. Although lacidipine limited hypertension, it did not reduce proteinuria or prevent tubular atrophy and disconnection. Multivariate analysis showed that the appearance of atubular glomeruli and the increase in interstitial volume were better predicted by proteinuria than blood pressure. This study suggests that ACE inhibitors effectively prevent glomerular-tubule disconnection possibly by their ability of reducing proteinuria, which in turn favors proximal tubular cell apoptosis. Agents that only reduced hypertension but not proteinuria do not affect tubular behavior.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Apoptosis; Atrophy; Calcium Channel Blockers; Dihydropyridines; Glomerulonephritis; Kidney; Kidney Glomerulus; Kidney Tubules; Lisinopril; Male; Proteinuria; Rats; Rats, Sprague-Dawley; Reference Values

This study compared the cardiovascular and renal effects of long-term telmisartan (3 and 10 mg/kg/day)and lisinopril (10 mg/kg/day) in an animal model combining hypertension and diabetes mellitus. It was a parallel-group study of diabetic, spontaneously hypertensive rats (SHR), treated with control or active treatment for eight months. A non-diabetic SHR control group was run in parallel. Diabetes was induced by streptozotocin (45 mg/kg i.v.) in SHRs aged 9-10 weeks. Animals were treated with telmisartan (3 or 10mg/kg/day), lisinopril (10 mg/kg/day) or vehicle. Plasma glucose levels, blood pressure (BP), and urinary protein and albumin excretion were measured monthly. Telmisartan treatment significantly reduced BP of diabetic SHRs in a dose-dependent manner (p<0.05, low-dose, n= 18; p<0.01, high-dose, n=15). The BP reduction in the lisinopril group was similar to that in the telmisartan 10 mg/kg/day group. Compared with non-diabetic SHRs, untreated diabetic SHRs developed severe proteinuria and albuminuria over the experimental period (p<0.01). In diabetic SHRs, proteinuria and albuminuria were dose-dependently and significantly attenuated by treatment with telmisartan (p<0.01 with the higher dose) and lisinopril (p<0.01). Compared with the untreated diabetic SHRs, cardiac hypertrophy was significantly reduced after treatment with both doses of telmisartan and with lisinopril. Telmisartan, 10 mg/kg/day, but not lisinopril, significantly attenuated the diabetes-induced increase in glomerular volume. In conclusion, telmisartan, 10 mg/kg/day, is at least as beneficial as lisinopril, 10 mg/kg/day, in lowering BP, reducing cardiac hypertrophy and attenuating renal excretion of protein and albumin in this model.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Benzoates; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Hyperglycemia; Hypertension; Kidney; Kidney Glomerulus; Lisinopril; Male; Organ Size; Proteinuria; Rats; Rats, Inbred SHR; Reference Values; Telmisartan

Angiotensin-converting enzyme (ACE) inhibition reduces proteinuria in established adriamycin nephrosis. To investigate whether the reduction in proteinuria is due to decreased generation of angiotensin II (AngII) or to decreased degradation of bradykinin, four series of experiments in established adriamycin nephrosis were performed. In the first series, 2 mg/kg lisinopril reduced BP from 117 +/- 4 to 67 +/- 2 mmHg and proteinuria from 335 +/- 66 to 57 +/- 10 mg/24 h after 2 wk of treatment. Subsequent continuous intraperitoneal infusion of AngII (250 ng/kg per min) for 2 wk partially restored proteinuria to 180 +/- 42 mg/24 h, whereas BP increased to 97 +/- 3 mmHg. Subsequent withdrawal of AngII restored the antiproteinuric effects of lisinopril, whereas subsequent withdrawal of lisinopril restored proteinuria to pretreatment values. In the second series, AT1 receptor blockade induced a fall in BP and proteinuria similar to that by lisinopril. In the third series, lisinopril reduced BP from 121 +/- 5 to 68 +/- 2 mmHg and proteinuria from 355 +/- 90 to 101 +/- 10 mg/24 h. Subsequent intraperitoneal infusion of bradykinin antagonist (HOE 140; 1 mg/kg per 24 h) for 2 wk did not affect BP (72 +/- 2 mmHg) or proteinuria (92 +/- 15 mg/24 h). In the fourth series, bradykinin (3 mg/kg per 24 h) was infused for 2 wk to mimic decreased bradykinin breakdown. This did not affect proteinuria, but induced a fall in BP from 114 +/- 3 to 93 +/- 4 mmHg. The BP-lowering effect of exogenous bradykinin was completely reversed by 1 wk infusion of HOE 140 (93 +/- 4 to 113 +/- 4 mmHg), while proteinuria remained unchanged. In conclusion, the antiproteinuric effect of ACE inhibition appears to be independent of bradykinin in this model, supporting a main role for reduction of AngII in the antiproteinuric action of ACE inhibition.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Bradykinin; Doxorubicin; Injections, Intraperitoneal; Lisinopril; Male; Nephrosis; Proteinuria; Rats; Rats, Wistar; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Time Factors

The mechanism(s) by which angiotensin-converting enzyme (ACE) inhibitors prevent glomerular membrane loss of permselective function is still not understood. In male MWF rats, which develop spontaneous proteinuria with age, ACE inhibitors prevent proteinuria and increase glomerular ultrafiltration coefficient. These renoprotective effects are not associated with ultrastructural changes of capillary wall components. This study was undertaken to investigate whether ACE inhibitors modulate functional properties of glomerular basement membrane (GBM) and/or of epithelial cells, both of which have been suggested to play a role in the maintenance of the glomerular filtration barrier. The hydraulic and macromolecular permeability of the GBM were determined, by an in vitro filtration system, in untreated or lisinopril-treated rats and in Wistar rats taken as controls. By indirect immunofluorescence and immunoelectron microscopy, glomerular distribution of the tight junction protein zonula occludens- (ZO-1), a component of the slit diaphragm, was also studied. Results document that spontaneous proteinuria in MWF rats develops without significant changes in the permeability of the GBM to water and albumin, or in the ultrastructure of the podocyte foot processes, but is associated with an important alteration in the distribution of ZO-1 at the glomerular level. Lisinopril, which prevented proteinuria, also prevented glomerular redistribution of the protein. Thus, renoprotective effects of ACE inhibitors are not associated with changes in intrinsic functional properties of GBM, or ultrastructural changes of the epithelial cells, but rather with preservation of glomerular ZO-1 distribution and slit diaphragm function, which are essential for maintaining the filtration barrier.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Basement Membrane; Fluorescent Antibody Technique, Indirect; In Vitro Techniques; Kidney Glomerulus; Lisinopril; Male; Membrane Proteins; Microscopy, Immunoelectron; Permeability; Phosphoproteins; Proteinuria; Rats; Rats, Mutant Strains; Tissue Distribution; Zonula Occludens-1 Protein

Reduction of proteinuria is a prerequisite for successful long-term renoprotection. To investigate whether individual patient factors are determinants of antiproteinuric efficacy, we analyzed individual responses to different modes of antiproteinuric intervention in nondiabetic and diabetic patients, obtained in prior studies comparing the efficacy of various pharmacological regimens. The individual antiproteinuric response to angiotensin-converting enzyme (ACE) inhibition positively correlated to the response to angiotensin type I (AT1) receptor blockade in diabetic (r = 0.67, P < 0.01, N = 16) as well as nondiabetic patients (r = 0.75, P < 0.01, N = 12). This corresponded to the correlations for antihypertensive efficacy between ACE inhibition and AT1 receptor blockade in diabetic (r = 0.73, P < 0.001) as well as nondiabetic patients (r = 0.55, P < 0.05). Remarkably, the antiproteinuric response to ACE inhibition also correlated positively to the antiproteinuric response to indomethacin (r = 0.63, P < 0.05, N = 9). Thus, patients responding favorably to one class of antiproteinuric drugs also respond favorably to other classes of available drugs, supporting a main role for individual patient factors in responsiveness or resistance to antiproteinuric intervention. In the search for strategies to improve response in these high risk patients, combination-treatment (combining different drugs, and combining drugs with dietary measures like sodium and protein restriction), and the use of higher doses may provide more fruitful strategies to optimize renoprotection than shifting to other classes of the available drugs.

Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Diabetic Nephropathies; Enalapril; Humans; Indomethacin; Kidney Diseases; Lisinopril; Losartan; Proteinuria

In proteinuric glomerulopathies, the excess traffic of proteins into the renal tubule is a candidate trigger of interstitial inflammatory and immune events leading to progressive injury, and a key target for the renoprotective action of antiproteinuric drugs. Among proteins trafficked to the proximal tubule, the third component of complement (C3) can be activated locally and contribute to inflammation at sites of protein reabsorption. Experiments were performed in rats with renal mass reduction (RMR, 5/6 nephrectomy) with the following aims: (1) to study Ig (IgG) and complement deposition in proximal tubules, and interstitial macrophage infiltration and MHC class II expression at intervals after surgery by double immunofluorescence analysis; (2) to assess whether lisinopril (angiotensin-converting enzyme inhibitor [ACEi], 25 mg/L in the drinking water, from either day 1 or day 7) limited IgG and C3 accumulation and interstitial inflammation at day 30. In 7-d remnant kidneys, intracellular staining for both IgG and C3 was detectable in proximal tubules in focal areas; C3 was restricted to IgG-positive tubular cells, and there were no interstitial ED-1 macrophage and MHC II-positive cellular infiltrates. In 14-d and 30-d remnant kidneys, proximal tubular IgG and C3 staining was associated with the appearance of interstitial infiltrates that preferentially localized to areas of tubules positive for both proteins. RMR rats given ACEi had no or limited increases in levels of urinary protein excretion, tubular IgG, and C3 reactivity, and interstitial cellular infiltrates in kidneys at 30 d, even when ACEi was started from day 7 after surgery. These findings document that (1) in RMR, IgG and C3 accumulation in proximal tubular cells is followed by leukocyte infiltration and MHC II overexpression in the adjacent interstitium; (2) ACEi while preventing proteinuria limits both tubular accumulation of IgG and C3 and interstitial inflammation. The data suggest that ACE inhibition can be renoprotective by limiting the early abnormal protein traffic in proximal tubule and consequent deleterious effects of excess protein reabsorption, including the accumulation and local activation of complement as well as the induction of chemokines and endothelin genes known to promote interstitial inflammation and fibrosis.

Topics: Analysis of Variance; Animals; Complement C3 Nephritic Factor; Culture Techniques; Disease Models, Animal; Genes, MHC Class II; Immunoglobulin G; Immunohistochemistry; Inflammation; Kidney Tubules, Proximal; Lisinopril; Macrophages; Male; Nephrectomy; Nephritis, Interstitial; Proteinuria; Rats; Rats, Sprague-Dawley; Reference Values

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

Proteinuria is associated with a progressive loss of renal function; we recently found that both intrarenal effects of proteinuria and the state of systemic nephrosis play an independent role in proteinuria-induced renal damage. Reduction of proteinuria is an important mechanism underlying the renoprotective effect of angiotensin-converting enzyme inhibition (ACEi). Both the reduction of proteinuria and the attenuation of the systemic state of nephrosis may be involved in the renoprotection by ACEi.. This article entails a post hoc analysis of a previous study on the renoprotective effect of ACEi lisinopril in adriamycin nephrosis. It was attempted to modify therapeutic efficacy of ACEi by increasing lisinopril dose and by dietary sodium restriction, respectively. In this analysis, we aimed to delineate the contribution of proteinuria reduction and the reduction of other intermediate parameters such as hyperlipidemia and blood pressure on the protection against focal glomerulosclerosis (FGS).. We found that in adriamycin nephrosis, ACEi significantly reduced proteinuria, lipids, and blood pressure and provided protection against FGS. Treatment modification by increasing the lisinopril dose resulted in a further reduction of FGS without significant effects on intermediate parameters (proteinuria, hyperlipidemia, and blood pressure), whereas surprisingly, treatment modification by sodium restriction resulted in a further attenuation of intermediate parameters, without additional protection against FGS.. The renoprotective benefit of an obtained attenuation of intermediate parameters is modified by other factors. Further optimization of renoprotective therapy requires identification of such factors and explicit consideration of therapeutic efficacy on intermediate parameters as well as hard end points.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cholesterol; Dose-Response Relationship, Drug; Doxorubicin; Glomerulosclerosis, Focal Segmental; Lisinopril; Male; Peptidyl-Dipeptidase A; Proteinuria; Rats; Rats, Wistar; Sodium, Dietary; Survival Analysis; Triglycerides

Experimental data consistently indicate that renal disease progression is fully prevented in proteinuric glomerulopathies by long-enough angiotensin-converting enzyme (ACE) inhibition therapy. Whether regression of established proteinuria to normal can be achieved is, however, ill defined. The current study was designed with the aim to clarify whether ACE inhibition may induce regression of established proteinuria and renal structural damage in MWF rats, a genetic model of progressive proteinuria and renal injury. Animals treated with the ACE inhibitor lisinopril from 20 weeks of age (time when proteinuria is already important) and age-matched untreated rats were followed for 10 weeks. ACE inhibition normalized systolic blood pressure and progressively reduced proteinuria (from 172 +/- 79 to 81 +/- 23 mg/24 hours). In these animals, a highly significant correlation was obtained between baseline proteinuria and antiproteinuric response. At variance in untreated rats, proteinuria showed a marked increase in the 10-week follow-up period (from 165 +/- 57 to 325 +/- 86 mg/24 hours). Lisinopril prevented the progression of renal damage, as documented by a significantly lower incidence of glomeruli affected by sclerotic lesions (P < 0.01) than in untreated animals after the 10-week study period. Kidney tissue damage was comparable in lisinopril-treated rats and in untreated animals at 20 weeks of age, indicating that structural changes were arrested by the treatment. Thus, in proteinuric MWF rats, late-onset ACE inhibition normalized blood pressure, effectively and progressively restored high protein excretion rate toward normal values, and arrested progression of tissue damage.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Gene Expression; Humans; Kidney Function Tests; Kidney Glomerulus; Lisinopril; Male; Models, Genetic; Nephritis, Hereditary; Proteinuria; Rats; Rats, Inbred Strains; Treatment Outcome

We evaluated the effect of blocking angiotensin II (AngII) on the development of proteinuria and glomerular injury in antithymocyte serum (ATS) glomerulonephritis. Disease was induced in Sprague-Dawley rats by a single intravenous injection of rabbit ATS. Three groups of rats were considered: group 1 (n = 13), ATS rats with no therapy; group 2 (n = 13), ATS rats treated with angiotensin-converting enzyme inhibitor (40 mg/L lisinopril in the drinking water); and group 3 (n = 13), ATS rats treated with AngII receptor antagonist (50 mg/L L-158,809 in the drinking water). Treatment started 3 hours after ATS injection and lasted 4 days. An additional group of control rats (group 4, n = 13) received preimmune serum. At day 4, ATS rats developed proteinuria (46+/-5 mg/d v control 12+/-1 mg/d; P < 0.01), which was prevented by both lisinopril and L-158,809 (14+/-0.2 mg/d and 15+/-1.6 mg/d, respectively, P < 0.01 v ATS). Systolic blood pressure was comparable in ATS rats and in controls (119+/-4 mm Hg v 120+/-2 mm Hg). Systolic blood pressure values were significantly decreased after either lisinopril or L-158,809 (104+/-3 mm Hg and 101+/-5 mm Hg, respectively; P < 0.01 v ATS). Serum creatinine levels were similar in all groups. Quantitation of proliferating cells and macrophages by analysis of proliferating cell nuclear antigen-positive and ED1-positive cells/glomerular cross-section showed a marked increase in proliferating cell nuclear antigen-positive cells in glomeruli of ATS rats over controls (12.6+/-0.5 cells/glomerular cross-section v 1.9+/-0.2 cells/glomerular cross-section; P < 0.01), which was significantly (P < 0.01) prevented by both treatments (lisinopril, 5.7+/-1.0 cells/glomerular cross-section; L-158,809, 4.8+/-1.5 cells/glomerular cross-section). The increase in ED1-positive cells (10+/-0.7 cells/glomerular cross-section v controls, 1.8+/-0.2 cells/glomerular cross-section; P < 0.01) was also significantly (P < 0.01) reduced by lisinopril and L-158,809 (4.1+/-0.7 cells/glomerular cross-sections and 2.6+/-0.6 cells/glomerular cross-section, respectively). Blocking of AngII activity prevented almost completely the formation of microaneurysms in ATS rats (percent of glomeruli with microaneurysms: ATS, 11.5%+/-3.5%; ATS + lisinopril, 0.4%+/-0.2%; ATS + L-158,809, 0.8%+/-0.8%; controls, 0%). Because AngII is a potent inducer of renal transforming growth factor-beta (TGF-beta), a cytokine involved in the regulation of cell proliferation, matrix deposi

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Antilymphocyte Serum; Blood Pressure; Cell Division; Creatinine; Glomerulonephritis, Membranoproliferative; Immunoglobulin G; Kidney; Kidney Glomerulus; Lisinopril; Macrophages; Male; Monocytes; Proteinuria; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta

Chronic nephropathies are associated with enhanced renal synthesis of endothelin (ET)-1. A recent study demonstrated that an ET(A) receptor antagonist given to diabetic rats at the moment of disease induction prevented the development of renal injury. Here we investigated whether an unselective ET(A)/ET(B) receptor antagonist, PD 142,893, was renoprotective when given to streptozotocin diabetic rats when animals were already proteinuric. The effect of PD 142,893 was compared with that of an ACE inhibitor, lisinopril, known to retard progressive renal disease in experimental and human diabetes. PD 142,893 normalized systemic blood pressure, reduced urinary protein and albumin excretion, and ameliorated renal blood flow in diabetic rats, but it did not affect such parameters in control rats. Lisinopril had a renoprotective effect comparable to PD 142,893, although lisinopril controlled systemic blood pressure better. Northern blot analysis of ET-1 mRNA revealed upregulation of ET-1 gene in the diabetic kidney. Similar results were obtained by in situ hybridization in glomeruli and tubuli of diabetic rats. Both treatments remarkably attenuated exaggerated renal ET-1 gene expression. These data suggest that ET-1 is a contributory mediator of kidney damage in diabetes and indicate that ET receptor antagonists may represent a new therapeutic mean for treatment of progressive diabetic nephropathy.

Topics: Albuminuria; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Cohort Studies; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Follow-Up Studies; In Situ Hybridization; Kidney; Lisinopril; Male; Oligopeptides; Pilot Projects; Proteinuria; Rats; Rats, Sprague-Dawley; RNA, Messenger; Time Factors

1. Progression to renal failure may be linked to the degree of proteinuria through tubulo-interstitial mechanisms. However, there are no data in man on the kinetics of proximal renal tubular protein catabolism or markers of tubular injury before and after lisinopril. We developed a method to allow such studies, and found increased tubular catabolism of 99mTc-labelled aprotinin (Trasylol) in patients with nephrotic range proteinuria which was associated with increased ammonia excretion. 2. In this study, 10 patients with mild renal impairment (51Cr-EDTA clearance 63.7 +/- 8.3 ml.min-1.1.73 m-2) and heavy proteinuria (8.2 +/- 2.3 g/ 24 h) were given lisinopril (10-20 mg) for 6 weeks. Renal tubular catabolism of intravenous aprotinin was measured before and after lisinopril by renal imaging and urinary excretion of the free radiolabel over 26 h. Fractional degradation was calculated from these data. Fresh timed urine collections were also analysed for ammonia excretion every fortnight from 6 weeks before treatment. Total urinary N-acetyl-beta-D-glucosaminidase and the more tubulo-specific N-acetyl-beta-D-glucosaminidase 'A2' isoenzyme were also measured. 3. After lisinopril proteinuria fell significantly as expected (from 9.5 +/- 1.6 to 4.5 +/- 1.0 g/24 h, P < 0.01). This was associated with a reduction in metabolism over 26 h (from 1.7 +/- 0.1 to 1.2 +/- 0.1% dose/h, P < 0.01) and in fractional degradation of aprotinin (from 0.08 +/- 0.02 to 0.04 +/- 0.007/h, P < 0.04). Ammonia excretion also fell significantly (from 1.2 +/- 0.1 to 0.6 +/- 0.1 mmol/h, P < 0.0001), as did both total urinary N-acetyl-beta-D-glucosaminidase (P < 0.0001) and the N-acetyl-beta-D-glucosaminidase 'A2' isoenzyme (P < 0.015). These observations after lisinopril treatment have not been described previously. There was no significant change in blood pressure nor in glomerular haemodynamics.

Topics: Acetylglucosaminidase; Adult; Ammonia; Angiotensin-Converting Enzyme Inhibitors; Aprotinin; Female; Humans; Isoenzymes; Kidney Tubules, Proximal; Lisinopril; Male; Middle Aged; Proteinuria; Serine Proteinase Inhibitors; Technetium

Dietary sodium restriction enhances the antiproteinuric and blood pressure lowering effect of ACE inhibition. In clinical practice, however, long-term compliance to a low-sodium diet may be difficult to obtain. We therefore investigated whether the blunting of the antiproteinuric and blood pressure lowering efficacy of ACE inhibition by high sodium intake can be restored by the addition of a diuretic.. Seven proteinuric patients with non-diabetic renal disease on chronic ACE inhibition were studied during three consecutive 4-week periods: low sodium (50 mmol/day), high sodium (200 mmol/day) and high sodium plus hydrochlorothiazide (50 mg o.i.d.).. During low sodium intake proteinuria was 3.1 (0.7-5.2) g/day, during high sodium intake proteinuria increased to 4.5 (1.6-9.2) g/day (P < 0.05). Interestingly, addition of hydrochlorothiazide again reduced proteinuria to 2.8 (0.6-5.8) g/day (P < 0.05). Mean arterial blood pressure was 89 (84-96), 98 (91-104) and 89 (83-94) mmHg (P < 0.05) during the three periods, respectively.. Addition of hydrochlorothiazide can overcome the blunting of the therapeutic efficacy of ACE inhibition on proteinuria and blood pressure by a high sodium intake.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Diet, Sodium-Restricted; Diuretics; Drug Therapy, Combination; Enalapril; Female; Humans; Hydrochlorothiazide; Hypertension; Lisinopril; Male; Middle Aged; Proteinuria; Sodium; Sodium Chloride Symporter Inhibitors; Sodium, Dietary

In several models of renal disease progression, angiotensin-converting enzyme (ACE) inhibitors reduced proteinuria and limited glomerulosclerosis, which suggested that reduction of renal angiotensin II (Ang II) activity is crucial for the preservation of glomerular structure and function. However, it cannot be ruled out that other hormonal systems, including inhibition of the bradykinin breakdown, also play a role. We compared the effects of chronic treatment with the ACE inhibitor lisinopril with those of a specific Ang II receptor antagonist, L-158,809, on proteinuria and renal injury in passive Heymann nephritis (PHN), a model of immune renal disease that closely resembles human membranous nephropathy, with long-lasting proteinuria followed by tubulointerstitial damage and glomerulosclerosis. Passive Heymann nephritis was induced with 0.5 mL/100 g of rabbit anti-Fx1A antibody in 24 male Sprague-Dawley rats. The animals were divided into three groups of eight rats each, and were given the following in the drinking water on a daily basis: lisinopril (40 mg/L), L-158,809 (50 mg/L), or no therapy. Treatment started at day 7 (proteinuria was already present) and lasted 12 months. Eight normal rats were used as controls. Untreated PHN rats developed hypertension, while rats with PHN given lisinopril or L-158,809 all had systolic blood pressure values even lower than those of normal rats. Urinary protein excretion progressively increased with time in untreated PHN rats, who developed tubulointerstitial damage and glomerulosclerosis. Both lisinopril and L-158,809 exhibited a potent antiproteinuric effect and preserved glomerular and tubular structural integrity at a similar extent. Renal gene expression of transforming growth factor-beta and extracellular matrix proteins was also effectively reduced by the two treatments. These results indicate that ACE inhibitors and Ang II receptor antagonists are equally effective in preventing renal injury in PHN and suggest that the renoprotective effects of ACE inhibitors in this model are solely due to inhibition of Ang II.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Chronic Disease; Extracellular Matrix Proteins; Glomerular Filtration Rate; Glomerulonephritis, Membranous; Imidazoles; Kidney; Lisinopril; Male; Proteinuria; Rats; Rats, Sprague-Dawley; Renal Plasma Flow; Tetrazoles; Transforming Growth Factor beta

The therapeutic effects of angiotensin converting enzyme inhibitor, lisinopril, on puromycin aminonucleoside (PAN)-induced nephrosis were investigated using unilaterally nephrectomized rats. Lisinopril showed potent dual effects on PAN nephrosis. Lisinopril treatment (50 mg/l in drinking water) from day 5 or day 9 reduced urinary protein excretion and suppressed the development of glomerular sclerosis at 8 weeks after PAN injection (150 mg/kg, i.p.), indicating a therapeutic effect on the nephrosis. Recovery of decreased anionic charge sites on the glomerular basement membrane was involved, at least in part, in the therapeutic action of lisinopril against proteinuria. On the other hand, oliguria and progressive azotemia derived from continuous deterioration of the renal function was induced if the treatment of lisinopril was started on the same day as PAN injection. The renal dysfunction induced by simultaneous administration of lisinopril with PAN could be abolished by combination dosing with sarcosine, an angiotensin II (AII)-receptor agonist. These results indicate that lisinopril treatment attenuates proteinuria by ameliorating the anionic charge barrier on the glomerular basement membrane and that it also protects against the development of chronic renal disease with segmental glomerular sclerosis, although AII depletion during the acute nephrotic stage exacerbates the renal damage in PAN nephrosis of unilaterally nephrectomized rats.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Anti-Bacterial Agents; Basement Membrane; Body Weight; Drug Interactions; Injections, Intraperitoneal; Kidney Glomerulus; Lisinopril; Male; Microscopy, Electron; Nephrectomy; Nephrosis; Oliguria; Proteinuria; Puromycin; Rats; Rats, Wistar; Receptors, Angiotensin; Sarcosine; Uremia

The renal response to ACE inhibition is known to vary between individuals. The ACE genotype is a determinant of the ACE concentrations in plasma and tissue, and therefore might affect the renal response to ACE inhibition in renal patients.. To test this hypothesis we studied the short-term response to ACE inhibition (enalapril or lisinopril 10/20 mg/d) in 61 stable proteinuric patients (> 1.0 g/day) in relation to the ACE genotype (DD N = 16, ID N = 32, II N = 13).. Baseline values were not significantly different for the three groups. ACE inhibition significantly reduced proteinuria, mean arterial pressure, GFR and FF in all genotype groups. The reduction in proteinuria, MAP, GFR and FF was not different between the genotype groups. ERPF increased significantly and to the same extent in all three groups.. We conclude that in proteinuric patients the short-term responses to ACE inhibition of proteinuria, blood pressure, and renal haemodynamics are not determined by ACE genotype. Thus, ACE gene polymorphism does not account for the known interindividual variation in the short-term renal response to ACE inhibition.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Enalapril; Female; Genotype; Glomerular Filtration Rate; Humans; Kidney; Kidney Diseases; Lisinopril; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Proteinuria; Time Factors

Two substrains of the fawn-hooded (FH) rat have been developed, one of which develops progressive hypertension and proteinuria, the FHH, and one which shows little increase in blood pressure and no renal damage, the FHL. Other hypertensive rodent models show primary metabolic disturbances before the development of renal damage, notably hypertriglyceridemia, which may also contribute to progression of renal disease. In this study we evaluated whether hyperlipidemia is a primary disturbance in FHH, or only occurs secondary to proteinuria. Lipid levels were determined before and after development of proteinuria, and compared to those found in age-matched FHL. We also determined whether reducing proteinuria with lisinopril would normalize lipid levels in aging FHH. At 4 weeks of age, proteinuria was very low (2-3 mg/day) in both FHH and FHL. While proteinuria increased steadily in aging FHH, reaching 350 +/- 62 mg/day at 40 weeks, much less increase was observed in FHL over the same period (32 +/- 5 mg/day at 40 weeks). Blood pressure was markedly higher in adult FHH than in FHL (158 +/- 2 vs. 129 +/- 2 mm Hg, p < 0.01). In 4-week-old FHL and FHH, plasma cholesterol levels were similar. Subsequently, cholesterol increased in FHH, reaching 3.4 +/- 0.9 mmol/l at 40 weeks, whereas cholesterol was barely affected by aging in FHL (2.1 +/- 0.2 mmol/l at 40 weeks). At 4 weeks, triglyceride levels were lowest in FHH. Subsequently, triglycerides increased in FHH, reaching 3.5 +/- 1.5 mmol/l at 40 weeks, as compared to 1.3 +/- 0.2 mmol/l in FHL. Besides a transient increase in triglyerides in lisinopril-treated FHH at 11 weeks, increments in blood pressure, proteinuria, cholesterol, triglycerides and apolipoproteins A-I, B and E aging FHH were effectively prevented by lisinopril. These data strongly suggest that there is no primary difference in lipid metabolism between FHH and FHL and that changes in plasma lipids in FHH as compared to FHL are all secondary to proteinuria.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Apolipoproteins; Blood Pressure; Body Weight; Cholesterol; Creatinine; Disease Models, Animal; Hyperlipidemias; Hypertension; Lisinopril; Male; Osmotic Pressure; Proteinuria; Rats; Rats, Inbred Strains; Statistics as Topic; Triglycerides

The hereditary nephritides are often progressive, resulting in kidney failure and the need for renal replacement therapy. There is no currently known beneficial treatment for these disorders. We observed three patients with hereditary glomerulonephritis with plasma creatinine concentrations ranging from 1.7 to 2.0 mg/dL who were treated with angiotensin-converting enzyme inhibitors (ACEIs) for 3.5 to 6 years. Angiotensin-converting enzyme inhibitor therapy was accompanied by a decrease in the mean arterial pressure (MAP) from 115 +/- 10 mm Hg to 93 +/- 2 mm Hg (+/- SD), a decrease in the mean urinary protein/creatinine ratio from 2,910 +/- 1,720 mg/g to 391 +/- 355 mg/g, and stabilization of the decline of creatinine clearance with time in two of the three patients. Based on this apparent benefit of ACEIs in hereditary nephritis, we suggest that a prospective controlled trial of ACEIs should be undertaken among a large group of such patients. Pending the results of such a study, ACEIs should be considered for the treatment of patients with proteinuric and progressive hereditary nephritis.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Disease Progression; Enalapril; Glomerulonephritis; Humans; Lisinopril; Male; Middle Aged; Pedigree; Proteinuria; Time Factors

1. The mechanism of renal protection by angiotensin-converting enzyme inhibition is still the subject of debate. Inhibition of proteinuria might play a role. If so, a good antiproteinuric response to angiotensin-converting enzyme inhibition should predict subsequent protection against renal structural damage. This hypothesis has not been tested in models where treatment is started after the renal disease is well established, i.e. models that mimic the clinical situation. 2. We therefore investigated this hypothesis in 96 male Wistar rats with established adriamycin nephrosis. Reduction of proteinuria was achieved by lisinopril (0, 2, 5 and 10 mg day-1 kg-1) on two different sodium diets (0.3% and 0.05% NaCl). Therapy started 6 weeks after adriamycin (at stable proteinuria) and was continued for 6 weeks. 3. Lisinopril reduced blood pressure by 32 +/- 4% and proteinuria by an average of 72 +/- 7%, with stabilization after 2 weeks. Considerable interindividual differences in antiproteinuric response was found. Glomerulosclerosis score was reduced by 15 +/- 5%. All the effects of angiotensin-converting enzyme inhibitors were enhanced by sodium depletion, but sodium depletion in itself did not affect blood pressure (124 +/- 4 mmHg), proteinuria (664 +/- 68 mg/day) or glomerulosclerosis score (30 +/- 5%). Interestingly, the more proteinuria was reduced initially in an individual rat, the less sclerosis was found in the long term in that rat. 4. In conclusion, angiotensin-converting enzyme inhibition lowers proteinuria and prevents glomerulosclerosis in established adriamycin nephrosis. These effects are enhanced by sodium depletion. The individual short-term antiproteinuric effect predicts the protection against ultimate glomerular damage. This is consistent with the hypothesis that reduction of proteinuria is a mechanism by which angiotensin-converting enzyme inhibitors exert renoprotection.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antibiotics, Antineoplastic; Blood Pressure; Doxorubicin; Glomerulosclerosis, Focal Segmental; Lisinopril; Male; Nephrosis; Proteinuria; Rats; Rats, Wistar; Sodium

Topics: Aged; Amlodipine; Anti-Infective Agents; Antihypertensive Agents; Clonidine; Creatinine; Diuretics; Female; Furosemide; Humans; Indomethacin; Isosorbide Dinitrate; Lisinopril; Nephrotic Syndrome; Norfloxacin; Proteinuria; Urinary Tract Infections

Topics: Angiotensin-Converting Enzyme Inhibitors; Anticholesteremic Agents; Cholesterol; Diet, Reducing; Female; Glomerulonephritis, IGA; Hematuria; Humans; Lisinopril; Lovastatin; Middle Aged; Obesity; Proteinuria; Weight Loss

This study was performed to evaluate the effect of angiotensin-converting enzyme inhibitor (ACEI) therapy and dietary protein restriction on nephropathy involving a remnant kidney.. Five patients with proteinuria > or = 5 years following partial removal of a solitary kidney were treated with a low-protein diet and an ACEI agent. Four patients had biopsy-proven focal segmental glomerulosclerosis. The daily urinary protein excretion ranged from 1240 to 10,032 mg. The serum creatinine levels ranged from 1.2 to 3.1 mg/dL.. The post-treatment follow-up interval ranged from 18 to 30 months. The treatment regimen was well tolerated in all patients. Four patients experienced a reduction in the urinary protein level while maintaining stable overall renal function. In 1 patient, the urinary protein level increased and renal function gradually deteriorated following ACEI therapy.. These preliminary data suggest that ACEI therapy and a low-protein diet may mitigate nephropathy associated with a remnant kidney.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Combined Modality Therapy; Diet, Protein-Restricted; Enalapril; Female; Follow-Up Studies; Glomerulosclerosis, Focal Segmental; Humans; Kidney Diseases; Lisinopril; Male; Middle Aged; Nephrectomy; Proteinuria

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

To clarify whether angiotensin converting enzyme (ACE) inhibitors prevent progressive renal injury directly by their antihypertensive effect we administered the ACE inhibitor lisinopril to male MWF/Ztm rats as a single daily dose that lowered blood pressure for only 9 of 24 h. We investigated the effects of this treatment in short- and long-term studies and compared them with another antihypertensive drug, the calcium channel blocker nitrendipine, given to partially control blood pressure as done with the ACE inhibitor. In untreated animals systemic hypertension, proteinuria, and glomerulosclerosis developed spontaneously with age, and lisinopril reduced systemic hypertension and prevented proteinuria and glomerular lesions. Nitrendipine, despite similar blood pressure control, was ineffective in preventing both proteinuria and glomerulosclerosis. After 2 mo of treatment glomerular capillary pressure was significantly reduced by lisinopril and slightly but significantly increased by nitrendipine, compared with untreated controls. The ultrafiltration coefficient was significantly higher in lisinopril than in controls and not significantly changed by nitrendipine. With both drugs, however, glomerular hemodynamic effects were observed only at a few hours after administration and were abolished before the next administration. No significant changes in glomerular tuft volume were observed in treated and untreated animals after 2 and 6 mo of observation. Thus ACE inhibitor, despite only partial control of systemic blood pressure, effectively prevented proteinuria and glomerular injury. Comparable blood pressure control obtained with a calcium channel blocker was not associated with renal protection. These results suggest that ACE inhibitors could protect glomerular microcirculation by a mechanism that is not directly related to their antihypertensive action.

Topics: Alpha-Globulins; Angiotensin-Converting Enzyme Inhibitors; Animals; Disease Models, Animal; Electrophoresis, Polyacrylamide Gel; Glomerulonephritis; Hemodynamics; Hypertension; Kidney; Kidney Diseases; Kinetics; Lisinopril; Male; Nitrendipine; 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 long-term effects of different antihypertensive regimens were studied in uninephrectomized beagles with alloxan-induced diabetes mellitus. Mean arterial pressure (MAP) was elevated (P < 0.05) in untreated diabetic dogs. Treatment of diabetic dogs with an angiotensin converting enzyme inhibitor (ACEI; lisinopril), a calcium antagonist (CA;TA-3090), or both lowered MAP. At one year, the RBF, GFR, and SNGFR were similarly elevated (P < 0.05) in all groups of diabetic dogs. The increase in SNGFR present in untreated diabetic dogs was primarily attributable to an increased (P < 0.05) glomerular capillary pressure (PGC). Treatment with lisinopril lowered the PGC to a mean value that was indistinguishable from that for nondiabetic dogs. In contrast, diabetic dogs treated with TA-3090 had an elevated PGC. While untreated diabetic dogs exhibited marked increases in glomerular volume (P < 0.05 vs. nondiabetic dogs), treatment with lisinopril and TA-3090, either alone or in combination, blunted the extent of glomerular hypertrophy observed in diabetic dogs (P < 0.05 vs. untreated diabetic dogs). Proteinuria was similarly reduced (P < 0.05 vs. untreated diabetic dogs) in dogs treated with lisinopril and TA-3090. Combination therapy of diabetic dogs produced a further significant (P < 0.05) decrement in proteinuria. We conclude that although treatment of diabetic dogs with either lisinopril or TA-3090 results in differential effects on PGC; each produces a similar decrement in proteinuria. Further, combination therapy has a greater effect on proteinuria than either agent alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Calcium Channel Blockers; Diabetes Mellitus, Experimental; Diltiazem; Dipeptides; Dogs; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Hemodynamics; Homeostasis; Kidney; Lisinopril; Male; Proteinuria; Renal Circulation

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Atrial Natriuretic Factor; Blood Pressure; Dipeptides; Drinking; Hypothalamus; Lisinopril; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; Sodium; Urine

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Enalapril; Female; Humans; Indomethacin; Lisinopril; Male; Metabolic Clearance Rate; Middle Aged; Molecular Weight; Proteinuria

We studied the effects of lisinopril on mean arterial blood pressure (MAP), plasma renin activity (PRA), and renal hemodynamics in nine patients with chronic renal disease and hypertension, before, and after three months of therapy. Lisinopril normalized blood pressure in five of nine patients (responders) and did not in the remaining four (nonresponders). PRA rose after lisinopril (4.8 +/- 2.6 ng/mL/h to 25 +/- 15 ng/mL/h, P less than 0.05) in responders, but not in nonresponders (2.0 +/- 1.4 ng/mL/h to 3.4 +/- 2.9 ng/mL/h). Glomerular filtration rate remained stable in both groups (responders: 43 +/- 11 mL/min to 43 +/- 22 mL/min; nonresponders: 39 +/- 25 mL/min to 32 +/- 21 mL/min). In the responders renal hemodynamics remained stable after lisinopril (renal plasma flow: 223 +/- 80 mL/min to 216 +/- 91 mL/min; filtration fraction: .20 +/- .04 to .20 +/- .05; renal vascular resistance: 386 +/- 179 to 326 +/- 209 units). In the nonresponders, renal plasma flow decreased (228 +/- 141 mL/min to 162 +/- 117 mL/min, P less than 0.005), filtration fraction increased (.19 +/- .08 to .24 +/- .12, P less than 0.05), and renal vascular resistance increased (695 +/- 747 to 1265 +/- 1574 units, P less than 0.05) after chronic lisinopril therapy. We conclude (1) there is a heterogeneous response to lisinopril in patients with chronic renal disease and hypertension, (2) lisinopril monotherapy may result in effective blood pressure control without renal hemodynamic compromise, and (3) an increase in PRA following converting enzyme inhibition may identify those in whom the circulating renin angiotensin system is participating in systemic hypertension and intrarenal hemodynamic changes.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Chronic Disease; Drug Evaluation; Enalapril; Glomerular Filtration Rate; Hemodynamics; Humans; Hypertension, Renal; Kidney; Kidney Diseases; Lisinopril; Middle Aged; Potassium; Proteinuria; Renin

Nineteen essential hypertensive patients were entered into a protocol to assess the BP, humoral and renal effects of the angiotensin converting enzyme inhibitor, lisinopril (MK 521, 20 to 80 mg once daily), administered for 52 weeks. Specifically monitored prior to, and following 12 and 52 weeks of lisinopril monotherapy were plasma renin activity and plasma aldosterone, the clearances of creatinine, inulin and para-aminohippurate, and the 24-hour urinary excretion of protein. BP was well controlled. Plasma renin activity was stimulated, and plasma aldosterone was suppressed throughout the entire protocol. In contrast to the reported short-term and long-term renal effects of enalapril, lisinopril (a lysine analog of enalapril) had no short-term effect on renal function: glomerular filtration rate, effective renal plasma flow, filtration fraction (FF), renal vascular resistance (RVR), and protein excretion were all unchanged. However, following long-term therapy, both FF and RVR were decreased. Lisinopril appears to convey no specific renal pharmacological benefit.

Topics: Aldosterone; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Electrolytes; Enalapril; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Lisinopril; Male; Proteinuria; Pulse; Renal Circulation; Renin; Vascular Resistance

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

The effects of the angiotensin converting enzyme (ACE) inhibitor lisinopril on blood pressure, proteinuria and renal hemodynamics were evaluated in 13 patients with renal disease of different origin. A comparison was made with the effects of conventional antihypertensive therapy. Both drug regimens significantly lowered blood pressure, while only after 12 weeks of treatment with lisinopril, blood pressure was significantly lower than during conventional therapy. Lisinopril reduced proteinuria (by 61 +/- 40%), whereas conventional therapy had no significant effect on protein excretion. During the first eight weeks of treatment with lisinopril, there was a comparable degree of blood pressure reduction with both treatment regimens, whereas urinary protein loss was significantly less during ACE inhibition. There was only a nearly-significant positive correlation between the fall in proteinuria during lisinopril and the concomitant decrease in mean arterial pressure. Glomerular filtration rate decreased from 26.3 +/- 11.6 to 20.6 +/- 9.4 ml/min during treatment with lisinopril. This decrease was not correlated with the fall in proteinuria. A significant positive correlation existed between the fall in urinary protein excretion and both the decrease in overall renal vascular resistance, and the fall in filtration fraction. Although blood pressure lowering by itself could contribute to the antiproteinuric effect of lisinopril, our results suggest that this effect of ACE inhibition is also due to efferent (postglomerular) vasodilation. We conclude that the ACE inhibitor lisinopril effectively reduces blood pressure and proteinuria in renal disease. The latter effect is not only the result of a lower blood pressure, but is probably also due to a fall in intraglomerular capillary pressure.

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Creatinine; Enalapril; Female; Glomerular Filtration Rate; Humans; Lisinopril; Male; Middle Aged; Proteinuria; Renal Circulation; Vascular Resistance