pitavastatin and Proteinuria

Since co-administration of ezetimibe, a specific inhibitor of cholesterol absorption into the intestine, has been shown to augment lipid-lowering effects of statins, ezetimibe plus statins is a novel therapeutic strategy for the treatment of dyslipidemia in high-risk patients. Statins have been shown to ameliorate renal function and reduce proteinuria in patients with chronic kidney disease (CKD). However, effects of co-administration of ezetimibe with statins on renal damage and dysfunction in CKD patients remain unknown. In this study, we examined whether co-administration of ezetimibe with pitavastatin could augment renoprotective properties of pitavastatin in non-diabetic CKD patients with dyslipidemia. Total cholesterol, LDL-cholesterol and triglycerides levels were reduced more by co-administration of ezetimibe (10mg/day) with pitavastatin (2mg/day) (n=10) than by pitavastatin alone (n=10). In addition, ezetimibe plus pitavastatin treatment produced significant incremental reduction in proteinuria related to pitavastatin therapy alone. In univariate analyses, proteinuria was correlated with plasma levels of total cholesterol, LDL-cholesterol, triglycerides, HDL-cholesterol (inversely), asymmetric dimethylarginine, an endogenous nitric oxide synthase inhibitor, and urinary excretion levels of L-fatty acid binding protein (L-FABP), a marker of tubular injury and 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker. Multiple stepwise regression analysis revealed that LDL-cholesterol (p<0.001) and urinary excretion levels of L-FABP (p=0.001) and 8-OHdG (p<0.001) were independently related to proteinuria (R(2)=0.969). Our present study demonstrated for the first time that co-administration of ezetimibe enhanced proteinuria-lowering effects of pitavastatin in non-diabetic CKD patients partly via a cholesterol-independent manner. Ezetimibe may have pleiotropic actions that could contribute to renoprotective properties of this lipid-lowering agent.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Adult; Anticholesteremic Agents; Arginine; Azetidines; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Deoxyguanosine; Drug Therapy, Combination; Dyslipidemias; Ezetimibe; Fatty Acid-Binding Proteins; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Diseases; Male; Middle Aged; Proteinuria; Quinolines; Severity of Illness Index; Treatment Outcome; Triglycerides

Urinary liver-type fatty-acid-binding protein (L-FABP) is a useful clinical marker in the monitoring of chronic kidney disease (CKD) associated with tubulointerstitial damage. Statins have been shown to be effective in the treatment of renal disease. The aim of the present study was to determine whether pitavastatin, a newly developed statin, modulates the urinary L-FABP levels in normolipidemic patients with CKD.. Thirty normolipidemic mild CKD patients (18 males and 12 females, mean age 40 years, mean serum creatinine level 1.0 mg/dl) were randomly assigned to two groups: (1) pitavastatin (1 mg/day, n = 15) and (2) placebo (n = 15). Urinary protein and urinary L-FABP levels were measured before the initiation of treatment and 3 and 6 months thereafter. Twenty age-matched healthy subjects were also studied as controls.. Before treatment, the urinary L-FABP levels in 30 CKD patients (84.0 +/- 68.5 microg/g creatinine) were significantly higher than those of healthy subjects (6.4 +/- 4.2 mug/g creatinine; p < 0.001). Pitavastatin slightly reduced serum total cholesterol and triglyceride levels, but this was not statistically significant. However, pitavastatin reduced the urinary protein excretion from 1.8 to 1.0 g/day (p < 0.01), while the urinary L-FABP levels fell from 88.5 +/- 70.5 to 28.0 +/- 16.5 mug/g creatinine (p < 0.01).. The present data suggest that pitavastatin ameliorates tubulointerstitial damage in CKD patients independent of the lipid-lowering effect.

Topics: Adult; Biomarkers; Cholesterol; Chronic Disease; Fatty Acid-Binding Proteins; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney Diseases; Male; Proteinuria; Quinolines; Triglycerides

Podocytes injury is involved in the development of diabetic nephropathy. This study was designed to confirm the reno- and podocyte-protective effects of pitavastatin in diabetic rats and clarify its mechanisms.. Wistar rats were divided into 4 treatment groups: control, streptozotocin (STZ; 55 mg/kg)-induced diabetes, STZ with pitavastatin (10 mg/kg/day), and STZ with tempol (1 mmol/l).. STZ-induced diabetic rats exhibited increases in urinary protein excretion and plasma creatinine, and a decrease in creatinine clearance. Pitavastatin significantly improved these parameters without reducing cholesterol levels, whereas tempol did not. The treatment with STZ-enhanced renal fibrosis, mesangial proliferation, transforming growth factor (TGF)-β, MCP-1 and suppressed Rho in association with decrement of bone morphogenetic protein (BMP)-7 expression in renal cortex. Moreover, STZ decreased podocyte related factors, podocin and nephrin, and BMP-7 in podocytes. Pitavastatin significantly ameliorated all these indices. On the other hand, improvement by tempol was found only in TGF-β, MCP-1 and histological changes.. Pitavastatin exhibited reno- and podocyte-protective effects accompanied by BMP-7 preservation and Rho suppression.

Topics: Animals; Bone Morphogenetic Protein 7; Chemokine CCL2; Creatinine; Diabetes Mellitus, Experimental; Gene Expression; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intracellular Signaling Peptides and Proteins; Kidney; Male; Malondialdehyde; Membrane Proteins; Nitrates; Nitrites; Protective Agents; Proteinuria; Quinolines; Rats, Wistar; rho-Associated Kinases; Transforming Growth Factor beta; Up-Regulation

We attempted to elucidate the relationship between cholesterol absorption and kidney damage by investigating the renoprotective effect of ezetimibe, a cholesterol absorption inhibitor, in 5/6 nephrectomized rats (Nx). The Nx or sham-operated rats (Sham) were fed 1% high-cholesterol diet (HC) containing ezetimibe (10 mg/[kg d]), pitavastatin (3 mg/[kg d]), or both for 8 weeks. Pathological changes, endothelial nitric oxide synthase (eNOS) messenger RNA (mRNA), and oxidative stress were assessed in the kidney. The Sham fed HC exhibited hypercholesterolemia and glomerulosclerosis with macrophage infiltration in the kidney, and ezetimibe attenuated these changes. The Nx exhibited hypercholesterolemia, increased urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), glomerulosclerosis with macrophage infiltration and interstitial fibrosis, and downregulation of eNOS mRNA. The HC increased cholesterol further and worsened the kidney damage with increased 8-OHdG. Ezetimibe attenuated the hypercholesterolemia, kidney dysfunction, and pathological changes. The beneficial effects of ezetimibe were significantly associated with reduced 8-OHdG (P < .01). Pitavastatin did not reduce cholesterol or 8-OHdG, but it did significantly suppress the kidney damage with upregulated eNOS mRNA by 2.5-fold (P < .02). The combination of ezetimibe and pitavastatin synergistically ameliorated the kidney damage. The kidney dysfunction and pathological changes were significantly associated with cholesterol, markers of cholesterol absorption (campesterol and cholestanol), and 8-OHdG (P < .001-.05). Multiple regression analysis revealed that the markers of cholesterol absorption were independently associated with the kidney damage. Ezetimibe confers renoprotective effects by inhibiting cholesterol absorption, which in turn reduces oxidative stress; and pitavastatin additively ameliorates kidney damage by increasing NO production via mechanisms independent of cholesterol reduction.

Topics: Animals; Anticholesteremic Agents; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Azetidines; Cholesterol; Cholesterol, Dietary; Cholesterol, HDL; Creatinine; Deoxyguanosine; Ezetimibe; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunohistochemistry; Kidney; Kidney Diseases; Kidney Function Tests; Male; Nephrectomy; Proteinuria; Quinolines; Rats; Rats, Wistar; Real-Time Polymerase Chain Reaction; RNA; Triglycerides

In addition to the risk of progression to end-stage renal disease (ESRD), chronic kidney disease (CKD) is also known to be associated with an elevated risk of cardiovascular disease (CVD). Statins may improve renal function in CKD patients.. The database of the LIVALO Effectiveness and Safety (LIVES) Study, a large-scale (n=20,279), long-term (104 weeks), prospective post-marketing surveillance study of hypercholesterolemic patients treated with pitavastatin, was used to evaluate the effects of pitavastatin on the estimated glomerular filtration rate (eGFR).. Of the 19,925 patients enrolled in the aforementioned study, data from 3,119 patients were analyzed to evaluate the effects of pitavastatin treatment for 104 weeks on the eGFR. In this subanalysis, 958 patients with a baseline eGFR of less than 60 mL/min/1.73 m(2) (30.7%) were analyzed. A significant increase of the eGFR (+5.4 mL/min/1.73 m(2)) was observed after 104 weeks of pitavastain treatment (p < 0.001; one-sample t-test). In the analysis of the time-course of changes in the eGFR in response to pitavastatin treatment, the eGFR was elevated by 2.4 mL/min/1.73 m(2) after 12 weeks' treatment, and by 5.6 mL/min/1.73 m(2) after 104 weeks' treatment (p < 0.001; repeated measures ANOVA). The results of multivariate analysis identified the presence/absence of proteinuria and the amount change of HDL-C as clinical factors associated with increased eGFR during pitavastatin treatment.. Increased eGFR was noted after 104 weeks of treatment with pitavastatin, which suggests a possible effect of the statin on CKD.

Topics: Aged; Cholesterol, HDL; Data Collection; Female; Glomerular Filtration Rate; Humans; Hypercholesterolemia; Male; Middle Aged; Multivariate Analysis; Proteinuria; Quinolines; Renal Insufficiency, Chronic