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)

Experimental evidence suggests that lipid lowering therapy could slow the progression of renal disease in humans. We have conducted a double-blind, placebo controlled trial of the HMG CoA reductase inhibitor simvastatin in patients with the nephrotic syndrome or significant proteinuria (> 1 g/day) and hypercholesterolemia (> or = 6.5 mmol/liter). Patients were placed on a lipid lowering diet for at least 10 weeks before randomization. After a four-week placebo run-in, 30 adults were randomized to simvastatin or placebo therapy (10 mg/day, increasing to 20 to 40 mg/day as required) for 24 weeks. There were seven dropouts, none of whom were "definitely" related to drug therapy. Total and LDL cholesterol levels fell by a mean of 33 and 31%, respectively, in simvastatin treated patients, compared with only 5 and 1% in patients on placebo (P < 0.001, P = 0.002, respectively). Apolipoprotein B100 levels fell by a mean of 31% in the simvastatin group but rose 0.3% in the placebo group (P = 0.014). There were no significant changes in HDL levels. There were no significant differences between the groups in their urine protein levels, their rise in plasma creatinine, or decline in plasma inulin clearance. Simvastatin is a safe, effective therapy for hypercholesterolemia in proteinuric states. A much larger trial is needed to show if potent lipid-lowering therapy slows progression of hypercholesterolemic proteinuric diseases.
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PMID:Simvastatin therapy for hypercholesterolemic patients with nephrotic syndrome or significant proteinuria. 826 45

This study was undertaken to determine the role of angiotensin II (AII) in the development of glomerulosclerosis, using an AII receptor antagonist in an animal model of hyperlipidemia. Hyperlipidemic Imai rats were employed because they spontaneously develop glomerulosclerosis; this is especially true in males. Group 1 (n = 5) received no specific therapy. Group 2 (n = 5) was treated with enalapril at a dosage of 50 mg/l in drinking water starting at 6 weeks of age. Group 3 (n = 5) and group 4 (n = 6) were treated with the AII receptor antagonist DuP 753 at a respective dosage of 15 mg/l (low-dose DuP) and 150 mg/l (high-dose DuP) in drinking water. Body weight, blood pressure, urinary protein, serum albumin, cholesterol, BUN and serum creatinine were measured and compared among the groups from 12 to 24 weeks of age. Enalapril and high-dose DuP were almost equally effective in controlling systemic hypertension. Each treatment significantly reduced proteinuria (172 +/- 112 and 152 +/- 72 mg/kg/day at 24 weeks) as compared with that in the controls (421 +/- 147 mg/kg/day; p < 0.05 and p < 0.01, respectively). Hypercholesterolemia also decreased (82 +/- 4 and 89 +/- 6 mg/dl) as compared with that of the controls (141 +/- 48 mg/dl; both p < 0.05). Glomerulosclerosis index (SI) was significantly higher in the untreated control rats (55 +/- 26) than in the enalapril-treated rats (2 +/- 3; p < 0.005) and the high-dose-DuP-treated rats (6 +/- 6, p < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of an angiotensin II receptor antagonist on the progression of renal failure in hyperlipidemic Imai rats. 828 94

Oxidized low-density lipoproteins (Ox-LDL) have been shown to be involved in the pathogenesis of atherosclerosis. Because of the similarities between atherosclerosis and focal glomerulosclerosis, a study was performed to demonstrate whether Ox-LDL could be detected in the glomeruli in experimental FGS. FGS was induced in 12 rats on a 4% cholesterol-1% choline diet by seven injections of puromycin aminonucleoside over a 10 week period. Eight rats on a normal diet served as controls. Fourteen weeks after the start of the experiment all rats were sacrificed. The test animals showed marked hypercholesterolemia and proteinuria. About 20% of glomeruli in test animals showed FGS and variable amounts of glomerular lipid were demonstrated. Immunohistochemical staining using five specific monoclonal antibodies against various forms of Ox-LDL showed positive staining of a variable number of glomeruli in the test rats. The staining pattern appeared to be intracellular. Staining with ED1 showed significantly increased numbers of intraglomerular monocytes in the test rats (test vs. control 2.4 +/- 1.1 vs. 0.4 +/- 0.1 monocytes per glomerulus, P < 0.0001). Control animals showed no segmental sclerosis, no glomerular lipid, and no staining for Ox-LDL. Lipid analysis of isolated glomeruli showed increased cholesterol, increased arachidonic acid and decreased eicosapentaenoic acid in test animals compared to controls. The findings suggest a role for Ox-LDL in the pathogenesis of experimental FGS and support the hypothesis that FGS is analogous to atherosclerosis.
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PMID:Oxidized low-density lipoprotein in experimental focal glomerulosclerosis. 831 38

The appearance of nephrotic syndromes such as proteinuria, hypoalbuminemia, hypercholesterolemia and increase in blood nitrogen urea, induced in rats by injection of puromycin aminonucleoside was markedly inhibited by oral administration of Dup 753 (losartan), a novel angiotensin II receptor antagonist, at a dose of 1 or 2 mg/kg per day. The results suggest a possible involvement of the renin-angiotensin system in the development of puromycin aminonucleoside-induced nephrosis.
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PMID:Dup 753 prevents the development of puromycin aminonucleoside-induced nephrosis. 831 60

The scarce literature on dietary manipulation of dyslipidemia in patients with nephrotic syndrome and in patients with chronic renal insufficiency is reviewed. Our favorable personal experience in both clinical conditions is illustrated as well. A special low-protein soy diet given for 2 or 4 months partially corrected hypercholesterolemia in nephrotic patients, and a low-protein diet also low in cholesterol and rich in polyunsaturated fatty acids corrected hypertriglyceridemia and hypercholesterolemia in patients with progressive renal damage. The soy diet had an additional favorable effect on proteinuria of nephrotic patients that might have been a direct consequence of the partial correction of the hypercholesterolemia. The addition of 5 g/d of fish oil to the soy diet did not modify the effects of the soy diet on proteinuria nor was it able to correct the hypertriglyceridemia of nephrotic patients. Dietary intervention should be the first-line treatment for the dyslipidemia of these renal diseases, since it can be used for long periods of time and is devoid of side effects so long as good nutritional status is maintained.
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PMID:Influence of diet on lipid abnormalities in human renal disease. 832 78

In a prospective follow-up of 30 patients with type 1 diabetes and nephropathy, serum cholesterol, triglycerides, apolipoprotein Al and B, and lipoprotein(a) were determined to study their relationship to the rate of decline in glomerular filtration rate. The patients had proteinuria and advanced nephropathy with a mean +/- SD glomerular filtration rate of 39 mL/min/1.73 m2. The decline in glomerular filtration rate was determined during 2.5 +/- 0.5 years. High serum cholesterol, triglycerides, and apolipoprotein B were correlated to a more rapid deterioration in kidney function. The rate of decline in glomerular filtration rate was 1.0 +/- 2.5 mL/min/yr in the 10 patients with the lowest cholesterol level, compared with 4.5 +/- 3.2 mL/min/yr in the patients with the highest serum cholesterol (P = 0.015). The combined effect of the measured lipids, blood pressure, type of antihypertensive treatment, protein intake, proteinuria, and hemoglobin A1C on the rate of decline in glomerular filtration rate was assessed by multiple regression analysis. The measured factors together had a high explanatory power for the rate of decline in glomerular filtration rate. In this model, 73% of the variation in decline in glomerular filtration rate was explained by the measured variables (multiple r2 = 0.73). Low cholesterol and treatment with an angiotensin-converting enzyme inhibitor were the strongest predictors of a favorable renal prognosis. This suggests that hypercholesterolemia is an important risk factor for diabetic nephropathy.
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PMID:Cholesterol: a renal risk factor in diabetic nephropathy? 832 83

Hyperlipidemic Imai rats spontaneously develop hypercholesterolemia, proteinuria and glomerulosclerosis. The aim of the present study was to clarify whether two different antihypertensive regimens (enalapril and a combination of reserpine, hydralazine and hydrochlorothiazide) would offer similar degrees of protection against glomerular injury in male hyperlipidemic Imai rats. Group 1 (n = 4) received no specific therapy. Group 2 (n = 4) was treated with enalapril at a dose of 50 mg/l in drinking water starting at 6 weeks of age. Group 3 (n = 5) was treated with the triple drug regimen (reserpine 5 mg/l, hydralazine 80 mg/l and hydrochlorothiazide 25 mg/l in drinking water). Body weight, blood pressure, urinary protein, serum albumin, cholesterol, BUN and serum creatinine were checked and compared among groups. Although enalapril and triple drug therapy were almost equally effective in controlling systemic hypertension, there were striking differences between the two treated groups in proteinuria, hypercholesterolemia and glomerular injury. Enalapril treatment significantly reduced proteinuria (731 +/- 23 vs. 256 +/- 144 mg/kg/day at 36 week; p < 0.005) and hypercholesterolemia (264 +/- 17 vs. 104 +/- 17 mg/dl at 38 weeks; p < 0.001). Triple drug therapy failed to prevent the development of proteinuria (909 +/- 75 mg/kg/day at 38 weeks) and hypercholesterolemia (330 +/- 61 mg/dl at 38 weeks). The glomerulosclerosis index was significantly higher in untreated control rats (229 +/- 65) and in triple drug-treated rats (218 +/- 59) than in the enalapril-treated group (24 +/- 12; p < 0.05, and p < 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of antihypertensive drugs on the progress of renal failure in hyperlipidemic Imai rats. 844 71

The N-hydroxyurea derivatives 70C ((E)-N-[3-[3- (4-fluorophenoxy)phenyl[-1-(R,S)-methylprop-2-enyl]-N-hydroxyurea) and its (R) 225C and (S) 404C enantiomers, which were being developed as 5-lipoxygenase inhibitors for the treatment of certain allergic and inflammatory conditions, were found to cause severe glomerulonephropathy in the rat. The lesion appeared to be of greater severity in female rats compared with male rats. In addition, 70C and 225C treated animals appeared more severely affected than 404C treated animals. Detailed examination of the lesion in animals dosed with 225C showed that there was a clear relationship between the onset of the lesion and the dose given, i.e. the higher the dose the sooner the lesion developed. The earliest changes detected in the kidney by transmission electron microscopy were noted in the glomeruli, in which the visceral cells appeared enlarged and showed varying degrees of foot process loss. In the more advanced lesion, the degree of foot process loss became more obvious and changes in the kidney tubules were seen by light microscopy. The morphological changes were mirrored by a dose-related increase in water consumption, an increased kidney to body weight ratio and gastrointestinal oedema, suggesting impaired renal function. Shortly after the onset of foot process loss, decreases in the total plasma protein and albumin and increases in the plasma cholesterol, triglycerides, urea and creatinine were recorded. These changes, particularly the foot-process loss, together with increased proteinuria, hypoalbuminaemia, hypercholesterolaemia and lipaemia, are all characteristic of "minimal change nephrotic syndrome". Because of the serious nature of the kidney lesion caused by these N-hydroxyureas in the rat, it was considered that it precluded their development as therapeutic agents for use in man.
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PMID:Nephrotic syndrome associated with N-hydroxyureas, inhibitors of 5-lipoxygenase. 852 44

Fifty-four patients with noninsulin-dependent diabetes mellitus, who had established nephropathy, were examined to evaluate the risk factors for the progression of diabetic nephropathy. Time-averaged values of blood pressure, serum total cholesterol and fasting plasma glucose concentrations, and the degree of proteinuria during their follow-up period (4.2 +/- 0.5 years) were calculated. The correlation between these values and the slope of the regression line for the reciprocal of serum creatinine concentration over time, as an index of the speed of the progression of nephropathy, was examined. Age (61 +/- 1 years), mean arterial pressure (109 +/- 1 mm Hg), and the degree of the proteinureia (2.1 +/- 0.1 in dipstick test) were correlated with the slope. Effects of hypercholesterolemia and smoking on the slope were also examined. Mean arterial pressure was correlated with the slope significantly in patients without hypercholesterolemia (p < 0.05) and there was a tendency between these two in smokers (p < 0.06), while was no correlation found in patients with hypercholesterolemia or in nonsmokers. In addition, the relation between the slope and mean arterial pressure was relatively stronger in smokers without hypercholesterolemia than in nonsmokers with hypercholesterolemia. Our data suggest that blood pressure control as well as smoking avoidance may be important in preventing the progression of noninsulin-dependent diabetic nephropathy.
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PMID:Risk factors for progression of diabetic nephropathy. 854 70

Increased production and depressed catabolism of lipoproteins play major roles in the pathogenesis of hypercholesterolemia of nephrotic syndrome (NS). However, the effect, if any, of NS on cholesterol biosynthetic capacity is uncertain. We examined the gene expression of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR, the rate limiting step in cholesterol biosynthesis) during the induction and chronic phase of puromycin (PAN)-induced NS in rats. The rats were randomized to NS (given i.p. puromycin aminonucleoside 130 mg/kg on day 1 and 60 mg/kg on day 14) and placebo-treated control groups. Subgroups of animals were sacrificed at days 5, 10, 20 and 30. The liver was harvested between 7 and 9 p.m. for measurements of HMG-CoAR and actin mRNAs, HMG-CoAR enzymatic activity and microsomal cholesterol concentration. In separate experiments, subgroups of animals with chronic NS (day 30) were studied in fed and 20-hour fasting states. A marked but transient rise in hepatic HMG-CoAR mRNA and HMG-CoAR enzymatic activity was observed following the onset and exacerbation of proteinuria within a few days after each puromycin injection. On each occasion, HMG-CoAR fell to the baseline level despite persistent severe hypercholesterolemia. In an attempt to examine the possible acute effect of PAN per se, experiments were repeated before and at short intervals (8 and 24 hr) after puromycin injection when proteinuria was absent and the drug exposure prominent. The HMG-CoAR mRNA and activity were virtually unchanged during this period, suggesting the lack of an acute effect of puromycin. Twenty-hour fasting led to a marked rise in HMG-CoAR mRNA and activity in animals with chronic NS but not in the controls. Microsomal cholesterol remained unchanged and comparable in the two groups at all points. Thus, the marked but transient rise in hepatic HMG-CoAR gene expression observed during the induction phase and with fasting during the chronic phase of PAN-induced NS may contribute to the generation and maintenance of hypercholesterolemia in this animal model.
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PMID:Hepatic HMG-CoA reductase gene expression during the course of puromycin-induced nephrosis. 858 61


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