Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To establish if the benefit of angiotensin converting enzyme inhibitor therapy in retarding progressive diabetic renal injury is due to a specific intrarenal effect of the systemic hypotensive effect, we studied the effect of long-term ramipril treatment on blood pressure, glomerular filtration rate, and urinary protein excretion in streptozotocin-diabetic spontaneously hypertensive rats. The hypotensive effect of ramipril was prevented by a high salt diet, which did not alter the degree of renal angiotensin converting enzyme inhibition. Three weeks after uninephrectomy and induction of diabetes, rats were allocated to three groups. Groups 1 and 2 were given 1% NaCl, whereas group 3 was given water as drinking solution. One week later, groups 2 and 3 received 0.4 mg/kg/day ramipril in their drinking solution, which was continued over a 2-month period. Ramipril produced a blood pressure fall only in water-drinking rats (group 3) despite a similar reduction in plasma and renal angiotensin converting enzyme activity in groups 2 and 3. Salt-loaded rats had a progressive increase in urinary protein excretion over the duration of study. Ramipril treatment prevented an increase in protein excretion only in animals given water and with a reduced systolic blood pressure. Glomerular filtration rate was similar in all three groups. Ramipril treatment improved animal survival independently of a reduction in blood pressure or an effect on proteinuria. Although it is possible that angiotensin converting enzyme inhibitors have specific intrarenal effects reducing progression of diabetic proteinuria, concomitant control of systemic blood pressure appears to be necessary to demonstrate a benefit.
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PMID:Salt blocks the renal benefits of ramipril in diabetic hypertensive rats. 182 92

The existence of tissue renin angiotensin system (RAS) has been widely suggested in the recent literature by 2 main approaches: first, a dissociation between antihypertensive effects of angiotensin converting enzyme (ACE) inhibitors and the levels of stimulation of the circulating RAS; secondly, by the demonstration of the presence of the 3 key-proteins of the system (angiotensinogen, creatinine, and converting enzyme) within the 3 main target-organs of hypertension (i.e. kidney, heart and vessels). Those organs are capable to synthetize locally angiotensin II. Ramipril, a new ACE inhibitor (Triatec), which possesses a high affinity for tissue CE of those organs, according to previous publications by Unger, has been used as a tool for the investigations of the inhibition of those systems in human hypertension: a decrease of micro proteinuria has been without antihypertensive effects. In binephrectomized patients, ramipril has been shown to possess an antihypertensive effect. Finally, an important improvement of myocardial hypertrophy has been shown in hypertensive patients. Furthermore, this effect has been observed in animals (rats with aortic stenosis) even with low doses without antihypertensive effects. Further studies with new methodological approaches are still necessary.
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PMID:[Tissue renin-angiotensin system. Physiology and physiopathological value of their inhibition by ramipril]. 214 94

Chronic renal disease evolves to end-stage renal failure through events, including enhanced intraglomerular pressure and plasma protein ultrafiltration, mediated at least in part by angiotensin II. Angiotensin-converting enzyme inhibitors reduce intracapillary pressure and ameliorate glomerular size-selective function, which may account for their antiproteinuric effect and renoprotective potential. Thus, the Ramipril Efficacy in Nephropathy study found a significant correlation between enhanced urinary protein excretion and faster disease progression in non-diabetic patients with proteinuric chronic renal disease. In proteinuric non-diabetic renal disease at comparable levels of blood pressure control, angiotensin-converting enzyme inhibitors reduce proteinuria and slow disease progression to end-stage renal failure safely and more effectively than non-angiotensin-converting enzyme therapy. On the contrary, most non-proteinuric chronic renal diseases progress slowly and do not benefit specifically from angiotensin-converting enzyme inhibition therapy.
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PMID:Angiotensin-converting enzyme inhibitor therapy for non-diabetic progressive renal disease. 932 10

The aim of the present study was to investigate the influence of age and an increased intake of dietary sodium on the cardiovascular and renal effects of the angiotensin converting enzyme inhibitor, ramipril. Male spontaneously hypertensive rats (SHR) aged 10 and 60 weeks received either control or a high level of sodium (0.3% vs. 2.6% Na) and ramipril (2 mg/kg/day) mixed in the chow for 6 weeks. Blood pressure was measured weekly by tail-cuff method. Arterial functions were determined by measuring vascular contractile and relaxation responses of mesenteric arterial rings in vitro at the end of the study. An age-related increase in systolic blood pressure, left ventricular (LVH) and renal hypertrophy (RH) as well as proteinuria were found in SHR. The vascular relaxation to nitroprusside was impaired in aged SHR. The high sodium intake accelerated the development of hypertension only in young SHR but increased LVH and RH in both age groups. Ramipril effectively lowered blood pressure in both age groups, but decreased the LVH significantly only in young rats. Ramipril markedly improved the vascular relaxation to acetylcholine and nitroprusside only in young rats. The vascular contractile responses to noradrenaline and potassium chloride were not affected by age, sodium intake or ramipril treatment. The high sodium intake markedly attenuated the cardiovascular effects of ramipril. The high-sodium diet enhanced the urinary excretion of cyclic GMP in both age groups, while it increased urinary excretion of protein in young SHR only. In conclusion, the cardiovascular effects of ramipril were impaired with advanced age even in the presence of a control intake of sodium. A high sodium intake attenuated or even abolished the cardiovascular effects of ramipril in both young and aged SHR.
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PMID:Influence of age and dietary sodium on the cardiovascular and renal effects of ramipril in spontaneously hypertensive rats. 937 79

We correlated baseline parameters with glomerular filtration rate (GFR) decline and kidney survival in 274 patients with proteinuric non-diabetic chronic nephropathies (creatinine clearance 20 to 70 ml/min/1.73 m2 and proteinuria > 1 g/24 hr over the last three months) enrolled in the Ramipril Efficacy In Nephropathy (REIN) trial. The GFR, evaluated at baseline, one, three and six months after randomization then every six months, declined linearly by 0.52 +/- 0.83 ml/min/1.73 m2/month (mean +/- SD) over a follow-up (median: range) of 21:3 to 52 months, and kidney survival was 64%. In multivariate analysis, higher baseline proteinuria (P = 0.006), and lower GFR (P = 0.0001) and creatinine clearance (P = 0.0001) correlated with a faster GFR decline. Higher proteinuria was the only baseline predictor of a shorter kidney survival (P = 0.0007) and its predictive value was independent of the underlying renal disease, treatment randomization, and blood pressure control during the followup. Patients in the lowest tertile of baseline proteinuria (< 2.5 g/24 hr) had the slowest rate of GFR decline (-0.25 +/- 0.72 ml/min/1.73 m2/month) and the highest kidney survival (94%), compared with patients in the middle tertile (proteinuria 2.5 to 4.3 g/24 hr; delta GFR, -0.59 +/- 0.82 ml/min/1.73 m2/month, P = 0.008; kidney survival 57%, P = 0.0011) and in the highest tertile (proteinuria > 4.3 g/24 hr; delta GFR, -0.79 +/- 0.87 ml/min/1.73 m2/month, P = 0.0001, kidney survival 44%, P = 0.0001). Kidney survival significantly differed even between the middle and highest tertiles (P < 0.05). Thus, in non-diabetic chronic nephropathies proteinuria is an independent and accurate predictor of disease progression and ESRF.
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PMID:Proteinuria predicts end-stage renal failure in non-diabetic chronic nephropathies. The "Gruppo Italiano di Studi Epidemiologici in Nefrologia" (GISEN). 940 22

To study the effectiveness of ACE-inhibitors in diabetic nephropathy (DN) 12 male and 16 female patients aged 13-21 years with DN having normal blood pressure (BP) were given ramipril (tritace) in a dose 2.5-5 mg/day in the course of 12-24 weeks. Efficacy and safety of the treatment were assessed by changes in albuminuria and proteinuria, BP. Reduction of albuminuria occurred in 19(79.1%) out of 24 patients with microalbuminuria, in 13(54.1%) of them urine excretion of albumin returned to normal levels. All the patients with proteinuria and macroalbuminuria benefited from ramipril therapy because their proteinuria diminished or even disappeared (2 cases). The persistence of the antiproteinuria effect on posttreatment week 12 was 66.6%. Ramipril effect on BP was minimal. It is inferred that ramipril is effective in the treatment of DN at the stage of microalbuminuria and proteinuria in patients with normal BP.
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PMID:[The effectiveness of ramipril in the treatment of diabetic nephropathy in normotensive children and adolescents]. 950 15

We investigated the predictors of the rate of glomerular filtration rate decline (delta GFR) and progression to end-stage renal failure (ESRF) in the 352 patients with proteinuric non-diabetic chronic nephropathies [urinary protein excretion rate (UProt) > or = 1 g/24 hr, creatinine clearance 20 to 70 ml/min/1.73 m2] enrolled in the Ramipril Efficacy In Nephropathy (REIN) study. Overall the GFR declined linearly by 0.46 +/- 0.05 ml/min/1.73 m2/month (mean rate +/- SEM) over a median follow-up of 23 months (range 3 to 64 months), and progression to ESRF was 17.3%. Using multivariate analysis, higher UProt and mean arterial pressure (MAP) independently correlated with a faster delta GFR (P = 0.0001 and P = 0.0002, respectively) and progression to ESRF (P = 0.0001 and P = 0.003, respectively). Mean UProt and systolic blood pressure during follow-up were the only time-dependent covariates that significantly correlated with delta GFR (P = 0.005 and P = 0.003, respectively) and ESRF (P = 0.006 and P = 0.0001, respectively). After stratification for baseline UProt, patients in the lowest tertile (UProt < 1.9 g/24 hr) had the slowest delta GFR (0.16 +/- 0.07 ml/min/1.73 m2/month) and progression to ESRF (4.3%) as compared with patients in the middle tertile (UProt 2.0 to 3.8 g/24hr; delta GFR, 0.55 +/- 0.09 ml/min/1.73 m2/month, P = 0.0002; ESRF, 15.3%, P = 0.0001) and in the highest tertile (UProt 3.9 to 18.8 g/24 hr; delta GFR, 0.70 +/- 0.11 ml/min/1.73 m2/month, P = 0.0001; ESRF, 32.5%, P = 0.0001). Both delta GFR (P = 0.01) and progression to ESRF (P = 0.01) significantly differed even between the middle and the highest tertiles. On the contrary, stratification in tertiles of baseline MAP failed to segregate subgroups of patients into different risk levels. Patients with the highest proteinuria and blood pressure were those with the fastest progression (delta GFR, 0.91 +/- 0.23; ESRF 34.7%). Of interest, at each level of baseline MAP, a higher proteinuria was associated with a faster delta GFR and progression to ESRF. On the other hand, at each level of proteinuria, a faster delta GFR was associated with MAP only in the highest tertile (> 112 mm Hg) and the risk of ESRF was independent of the MAP. Thus, in chronic nephropathies proteinuria is the best independent predictor of both disease progression and ESRF. Arterial hypertension may contribute to the acceleration of renal injury associated with enhanced traffic of plasma proteins. Antihypertensive drugs that most effectively limit protein traffic at comparable levels of blood pressure are those that most effectively slow disease progression and delay or prevent ESRF in proteinuric chronic nephropathies.
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PMID:Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. "Gruppo Italiano di Studi Epidemiologici in Nefrologia" (GISEN). 957 35

Dihydropyridine-type calcium channel blockers (dihydropyridine CCB) adversely affect renal function in diabetes. The effects of dihydropyridine CCB on 24-h urinary protein excretion rate and GFR decline (deltaGFR) were prospectively evaluated in 117 nondiabetic patients with chronic, proteinuric nephropathies enrolled in the Ramipril Efficacy in Nephropathy study and randomized to angiotensin-converting enzyme inhibition (ACEI) or placebo plus conventional antihypertensive therapy. Sixty-three percent of patients were treated with dihydropyridine CCB. During follow-up, CCB-treated compared with no CCB patients had higher proteinuria (mean+/-SEM: 4.8+/-0.2 g/24 h versus 4.2+/-0.2 g/24 h, respectively, P = 0.015) and mean arterial BP (MAP). The difference in proteinuria was significant in the placebo group (5.1+/-0.2 g/24 h versus 4.3+/-0.3 g/24 h, P = 0.02), but not in the ACEI group (4.4+/-0.2 g/24 h versus 4.1+/-0.2 g/24 h). Of note, CCB-treated patients had significantly less proteinuria (P = 0.028) in the ACEI group compared with placebo. CCB-treated versus no CCB patients had a faster deltaGFR in the overall study population and in the placebo group, but not in the Ramipril group. Proteinuria was comparable in CCBtreated and no CCB patients for MAP < or = 100 mmHg, but was higher in CCB-treated patients for MAP >100 mmHg. Similarly, proteinuria was comparable in the placebo and in the ACEI group for MAP < or = 100 mmHg, but was higher in the placebo group for MAP >100 mmHg. In CCB- and placebo-treated patients, a linear correlation (P = 0.006 for both groups) was found between proteinuria and MAP values. MAP, proteinuria, and deltaGFR in patients given nifedipine versus those given other dihydropyridine CCB were comparable. Thus, in nondiabetic proteinuric nephropathies, dihydropyridine CCB may have an adverse effect on renal protein handling that depends on the severity of hypertension and is minimized by ACEI therapy or tight BP control. ACE inhibitors may electively limit proteinuria in patients on dihydropyridine CCB treatment and/or with uncontrolled hypertension.
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PMID:Effects of dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibition, and blood pressure control on chronic, nondiabetic nephropathies. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). 980 96

The aim of this study was to investigate whether the renoprotective effect of angiotensin-converting enzyme inhibitors (ACEIs) following 5/6 renal mass reduction is due in part to the potentiation of kinins. Three groups of rats with 5/6 renal mass reduction were studied during the 14 weeks following surgery. One group received no therapy (control); the second group was treated from the beginning with the ACEI ramipril (1 mg/kg/day) added to the drinking water, and the last group received ramipril plus a beta2-bradykinin antagonist, HOE 140 (500 microg/kg/day) via osmotic minipumps. Plasma creatinine did not change in any group during the study. Urinary protein excretion rose in the controls from 9.18+/-1.6 to 45.0+/-5.6 mg/24 h at the end of the study. In ramipril group proteinuria was prevented (initial 7.5+/-1.0 and final 8.6+/-0.8 mg/24h). The effect of ramipril was abolished by HOE 140 (initial 11.6+/-2.0 and final 38.9+/-11 mg/ 24 h). The systolic blood pressure of the controls increased from 106+/-2 to 144+/-5 mm Hg at the 14th week. Ramipril abolished the increase in systolic blood pressure. The effect of ramipril was reverted by HOE 140 (initial 108+/-2 and final 140+/-9 mmHg). Control rats had more severe histopathologic changes. Those animals receiving ramipril + HOE 140 displayed less severe glomerular changes, while rats treated only with ramipril had mild alterations. Thus the glomerular injury score was 2.11+/-0.32 for controls, 1.53+/-0.52 for rats treated with ramipril + HOE 140, and 0.06+/-0.04 for rats treated only with ramipril. The glomerular area was 20,886+/-1,410, 19,693+/-2,200 and 14,352+/-3,200 microm2, respectively, for the 3 groups. These results suggest that the protective effect of ACEIs in the development of chronic renal failure is partially mediated by kinins.
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PMID:Role of kinins in the renoprotective effect of angiotensin-converting enzyme inhibitors in experimental chronic renal failure. 985 20

The Ramipril Efficacy in Nephropathy Core and Follow-Up Study found that > or =36 mo of continued ramipril therapy decreased substantially the risk of end-stage renal failure (ESRF) in patients with chronic nephropathies and a urinary protein excretion rate > or =3 g/24 h. This study investigates the time-dependent changes in GFR in these patients and in control subjects who were randomized to conventional therapy during the Core period and switched to ramipril during the Follow-Up study. Analyses included 150 patients (continued ramipril: n = 74; switched to ramipril: n = 76) who had at least three GFR measurements (including baseline) during the whole observation period and a subgroup of 43 patients (continued ramipril: n = 26; switched to ramipril: n = 17) who had at least six GFR measurements, including at least three on the Core and at least three on the Follow-Up study. Ramipril (1.25 to 5 mg/d) and conventional therapy were targeted at achieving a diastolic BP below 90 mm Hg. The main efficacy variables were GFR and ESRF (need for dialysis). Analysis was by intention to treat. Throughout the study, the mean +/- SEM rate of GFR decline (deltaGFR) was significantly lower in patients continued on ramipril compared to those switched to ramipril (0.51+/-0.09 versus 0.76+/-0.10 ml/min per 1.73 m2 per mo, P<0.03). In patients on continued ramipril who had at least six GFR measured--but not in control subjects--deltaGFR progressively improved with time and, in the cohort with the longest follow-up, decreased from (in ml/min per 1.73 m2 per mo): 0.16+/-0.12 (at 18 mo) to 0.10+/-0.05 (at 60 mo). This rate was about 10-fold slower compared to patients on conventional therapy during the REIN Core study. Analyses of the individual slopes found that at the end of the follow-up, 10 of 26 patients on continued ramipril therapy had a positive deltaGFR and another 10 patients had an improvement of deltaGFR while on ramipril therapy. DeltaGFR significantly improved in parallel with a significant reduction in proteinuria. Changes in deltaGFR (P = 0.0001) and proteinuria (P = 0.04) were significantly different in the two groups. Baseline characteristics and changes in systolic and diastolic BP and 24-h urine urea and sodium excretion were comparable. The present results offer evidence that in chronic nephropathies, the tendency of GFR to decline with time can be effectively halted, even in patients with remarkably severe disease.
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PMID:In chronic nephropathies prolonged ACE inhibition can induce remission: dynamics of time-dependent changes in GFR. Investigators of the GISEN Group. Gruppo Italiano Studi Epidemiologici in Nefrologia. 1023 85


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