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)

The efficacy and safety of hydroxymethylglutaric coenzyme A reductase inhibitor (statins) in the treatment of hyperlipidemia were evaluated in 12 infants and children with steroid-resistant nephrotic syndrome followed prospectively for 1 to 5 years. All patients experienced a hypolipidemic response with a marked reduction in their total cholesterol (40%), low-density lipoprotein cholesterol (44%), and triglyceride levels (33%), but no appreciable change in high-density lipoprotein cholesterol. Statin therapy was well tolerated without clinical or laboratory adverse effects. In spite of a significant hypolipidemic response to statin therapy there were no changes observed in the degree of proteinuria, hypoalbuminemia, or in the rate of progression to chronic renal failure. Long-term controlled studies with statin therapy are needed to further document or negate their renoprotective role in refractory nephrotic syndrome.
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PMID:Management of hyperlipidemia in children with refractory nephrotic syndrome: the effect of statin therapy. 906 27

Nephrotic syndrome (N-S) is associated with elevated plasma concentration and impaired clearance of VLDL, chylomicrons (CM), and their atherogenic remnants. These abnormalities are largely due to lipoprotein lipase, hepatic triglyceride lipase, and VLDL receptor deficiencies and impaired HDL-mediated shuttling of apoE and apoC between the nascent and remnant VLDL and CM. LRP is a multifaceted endocytic receptor that is heavily expressed in the liver. LRP recognizes at least 30 different ligands including VLDL and CM remnants. These observations prompted the present study to discern the effect of N-S on hepatic LRP gene and protein expressions. The study further sought to explore the effect of lipid-lowering therapy on LRP expression in N-S. Sprague-Dawley rats were randomized to the N-S (given ip injections of puromycin aminonucleoside; 130 mg/kg on day 1, 60 mg/kg on day 14) and placebo-injected control groups. On day 14, animals were subdivided into statin-treated (rosuvastatin; 20 mg x kg(-1) x day(-1) mixed with powdered chow) and untreated groups and studied on day 28. The untreated N-S group exhibited severe proteinuria, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, and marked elevation of hepatic tissue LRP mRNA and protein abundance. Statin administration for 2 wk resulted in significant improvements of plasma lipid profile, proteinuria, and hypoalbuminemia as well as hepatic LRP mRNA and protein abundance. In contrast, statin administration had no significant effect on either plasma lipids or hepatic LRP levels in the normal control rats. In conclusion, N-S results in marked upregulation of hepatic LRP expression that is partly reversed with statin administration. These findings exclude depressed hepatic LRP expression as the primary cause of elevated plasma lipoprotein remnants in N-S.
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PMID:Upregulation of hepatic LDL receptor-related protein in nephrotic syndrome: response to statin therapy. 1558 92

Safety has become a central issue in the management of dyslipidemia with statins. A review of New Drug Applications (NDAs) and the US Food and Drug Administration (FDA) Web site was conducted for all 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or statins, with a major focus on cerivastatin and rosuvastatin. The findings provide insight into the incidence of adverse events for this class of drugs and support the significant benefits of statins relative to associated risks. These data delineate the nature of statin associated liver, muscle, and renal adverse events. Although transaminase levels increase in a dose-related fashion with statins, a definitive correlation between statin therapy and hepatotoxicity is not supported by statin NDA data. Statin-induced myopathy is a relatively rare event (1 in 1,000) and rhabdomyolysis is even rarer (1 in 10,000). The cerivastatin NDA, along with its supplementary NDA, was the first to demonstrate a clear statin dose-response relation with myopathy and a threshold effect above which myotoxicity increases significantly. Proteinuria was identified as a consequence of statin therapy with data from the rosuvastatin NDA, and subsequent analysis suggests a class effect that is dose related but transient. Studies in cell culture suggest the mechanism is a pharmacologic effect on the proximal renal tubule. The available evidence suggests no clear renal toxicity with currently approved statins, because no declines in renal function or glomerular filtration rate have been documented over time. Overall, currently marketed statins have a very favorable benefit-to-risk relation with respect to liver, muscle, and renal issues.
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PMID:Statin safety: lessons from new drug applications for marketed statins. 1658 28

Statins frequently are used to prevent cardiovascular events. Several recent studies suggest that statins also may have renal benefits, although this is controversial. This systematic review and meta-analysis were performed to assess the effect of statins on change in kidney function and urinary protein excretion. Medline, EMBASE, the Cochrane Central Register of Controlled Trials, conference proceedings, and the authors' personal files were searched. Published or unpublished randomized, controlled trials or crossover trials of statins that reported assessment of kidney function or proteinuria were included, and studies of individuals with ESRD were excluded. Data were extracted for study design, subject characteristics, type of statin and dose, baseline/change in cholesterol levels, and outcomes (change in measured or estimated GFR [eGFR] and/or urinary protein excretion). Weighted mean differences were calculated for the change in GFR between statin and control groups using a random-effects model. A random-effects model also was used to calculate the standardized mean difference for the change in urinary protein excretion between groups. Twenty-seven eligible studies with 39,704 participants (21 with data for eGFR and 20 for proteinuria or albuminuria) were identified. Overall, the change in the weighted mean differences for eGFR was statistically significant (1.22 ml/min per yr slower in statin recipients; 95% confidence interval [CI] 0.44 to 2.00). In subgroup analysis, the benefit of statin therapy was statistically significant in studies of participants with cardiovascular disease (0.93 ml/min per yr slower than control subjects; 95% CI 0.10 to 1.76) but was NS for studies of participants with diabetic or hypertensive kidney disease or glomerulonephritis. The standardized mean difference for the reduction in albuminuria or proteinuria as a result of statin therapy was statistically significant (0.58 units of SD greater in statin recipients; 95% CI 0.17 to 0.98). Statin therapy seems to reduce proteinuria modestly and results in a small reduction in the rate of kidney function loss, especially in populations with cardiovascular disease.
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PMID:Statins for improving renal outcomes: a meta-analysis. 1712 19

The renoprotective effect of statins has been recently disputed because of observations of proteinuria associated with rosuvastatin treatment, the newest drug of the class. Statin-induced proteinuria findings were mainly based on crudely quantitative dipstick assays. The authors quantitatively evaluated the effect of rosuvastatin at the recommended starting dose of 10 mg/d, on urine protein excretion in patients with primary dyslipidemia. Serum lipid and nonlipid parameters as well as urinary electrolyte, creatinine, and protein (total, albumin, immunoglobulin G, and alpha-1 microglobulin) levels were measured in 40 patients treated with rosuvastatin and 30 controls at baseline and after 12 weeks. The protein-to-creatinine ratios were used to assess urinary protein excretion. Rosuvastatin improved the lipid profile, produced no deterioration of kidney function, but induced a small but significant increase in the excretion of alpha-1 microglobulin (by 16%, P < .05) indicating that statin-related proteinuria involves low-molecular-weight proteins and is of proximal tubular origin.
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PMID:Rosuvastatin increases alpha-1 microglobulin urinary excretion in patients with primary dyslipidemia. 1705 Jul 99

Dyslipidemia is an important complication affecting kidney transplant recipients. Statins, the first-line therapy, are often insufficient. Ezetimibe may be effective in combination with statin therapy. We performed a retrospective study to determine the safety and efficacy of ezetimibe treatment in addition to statin therapy among 27 stable renal transplant patients with uncontrolled hypercholesterolemia. We obtained fasting lipid profiles at 3 and 6 months before ezetimibe therapy, while the patients were receiving statins at maximum tolerated doses. Statin doses were stable during the study. All patients received ezetimibe (10 mg) once daily. Fasting lipid profile, kidney function, liver enzymes, creatine kinase, and immunosuppressive drug levels were obtained at baseline as well as at 3 and 6 months post-ezetimibe initiation. Combination therapy resulted in median reductions in total cholesterol of 29% (interquartile range [IQR] 12-39; P = .0001) and 28% (IQR 9-38; P = .0001); in low-density lipoprotein cholesterol of 34% (IQR 16-61; P = .0001) and 44% (IQR 24-56; P = .0001); and in triglycerides of 14% (IQR 4-31; P = .01) and 19% (IQR 1-37; P = .006) at 3 and 6 months post-ezetimibe therapy, respectively. There were no significant differences in high-density lipoprotein cholesterol, renal function, proteinuria, creatine kinase, amylase, liver function, body mass index, or drug levels. There were no adverse drug reactions that mandated treatment withdrawal. When combined with statin therapy ezetimibe seemed to be a safe and effective treatment for uncontrolled dyslipidemia among renal transplant patients.
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PMID:Ezetimibe in the treatment of uncontrolled hyperlipidemia in kidney transplant patients. 1910 Apr 21

Macrophages are heterogeneous and include classically activated M1 and alternatively activated M2 macrophages, characterized by pro- and anti-inflammatory functions, respectively. Macrophages that express heme oxygenase-1 also exhibit anti-inflammatory effects. We assessed the anti-inflammatory effects of statin in experimental anti-glomerular basement membrane glomerulonephritis and in vitro, focusing on the macrophage heterogeneity. Rats were induced anti-glomerular basement membrane glomerulonephritis and treated with atorvastatin (20 mg/kg/day) or vehicle (control). Control rats showed infiltration of macrophages in the glomeruli at day 3 and developed crescentic glomerulonephritis by day 7, together with increased mRNA levels of the M1 macrophage-associated cytokines, interferon-gamma, tumor necrosis factor-alpha, and interleukin-12. In contrast, statin reduced the level of proteinuria, reduced infiltration of macrophages in glomeruli with suppression of monocyte chemotactic protein-1 expression, and inhibited the formation of necrotizing and crescentic lesions. The number of glomerular ED3-positive macrophages decreased with down-regulation of M1 macrophage-associated cytokines. Furthermore, statin augmented ED2-positive M2 macrophages with up-regulation of the M2 macrophage-associated chemokines and cytokines, chemokine (C-C motif) Iigand-17 and interleukin-10. Statin also increased the glomerular interleukin-10-expressing heme oxygenase-1-positive macrophages. Statin inhibited macrophage development, and suppressed ED3-positive macrophages, but augmented ED2-positive macrophages in M2-associated cytokine environment in vitro. We conclude that the anti-inflammatory effects of statin in glomerulonephritis are mediated through inhibition of macrophage infiltration as well as augmentation of anti-inflammatory macrophages.
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PMID:Statin attenuates experimental anti-glomerular basement membrane glomerulonephritis together with the augmentation of alternatively activated macrophages. 2151 53

Several cardiovascular (CV) risk factors may explain the high rate of CV death among patients with chronic kidney disease (CKD). Among them both traditional and uremia-related risk factors are implicated and, moreover, the presence of kidney disease represents "per se" a multiplier of CV risk. Plasma lipid and lipoprotein profiles are changed in quantitative, but above all in qualitative, structural, and functional ways, and lipoprotein metabolism is influenced by the progressive loss of renal function. Statin therapy significantly reduces cholesterol synthesis and both CV morbidity and mortality either directly, by reducing the lipid profile, or via pleiotropic effects; it is supposed to be able to reduce both the progression of CKD and also proteinuria. These observations derive from a post-hoc analysis of large trials conducted in the general population, but not in CKD patients. However, the recently published SHARP trial, including over 9200 patients, either on dialysis or pre-dialysis, showed that simvastatin plus ezetimibe, compared with placebo, was associated with a significant low-density lipoprotein cholesterol reduction and a 17% reduction in major atherosclerotic events. However, no benefit was observed in overall survival nor in preserving renal function in patients treated. These recent data reinforce the conviction among nephrologists to consider their patients at high CV risk and that lipid lowering drugs such as statins may represent an important tool in reducing atheromatous coronary disease which, however, represents only a third of CV deaths in patients with CKD. Therefore, statins have no protective effect among the remaining two-thirds of patients who suffer from sudden cardiac death due to arrhythmia or heart failure, prevalent among CKD patients. The safety of statins is demonstrated in CKD by several trials and recently confirmed by the largest SHARP trial, in terms of no increase in cancer incidence, muscle pain, creatine kinase levels, severe rhabdomyolysis, hepatitis, gallstones and pancreatitis; thus confirming the handiness of statins in CKD patients. Here we will review the latest data available concerning the effectiveness and safety of statin therapy in CKD patients.
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PMID:Treatment of dyslipidemia in chronic kidney disease: Effectiveness and safety of statins. 2417 58