(3S-5S-6E)-7-[3-(4-fluorophenyl)-1-(propan-2-yl)-1H-indol-2-yl]-3-5-dihydroxyhept-6-enoic-acid and Proteinuria

Previous studies showed that statins reduce the progression of kidney function decline and proteinuria, but whether specific types of statins are more beneficial than others remains unclear. We performed a network meta-analysis of randomized controlled trials (RCT) to investigate which statin most effectively reduces kidney function decline and proteinuria. We searched MEDLINE, Embase, Web of Science, and the Cochrane database until July 13, 2018, and included 43 RCTs (>110,000 patients). We performed a pairwise random-effects meta-analysis and a network meta-analysis according to a frequentist approach. We assessed network inconsistency, publication bias, and estimated for each statin the probability of being the best treatment. Considerable heterogeneity was present among the included studies. In pairwise meta-analyses, 1-year use of statins versus control reduced kidney function decline by 0.61 (95%-CI: 0.27; 0.95) mL/min/1.73 m

Topics: Atorvastatin; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Kidney; Kidney Diseases; Lovastatin; Network Meta-Analysis; Pravastatin; Proteinuria; Rosuvastatin Calcium; Simvastatin; Treatment Outcome

Chronic kidney disease (CKD) is extremely common in adults, although often undiagnosed and thus untreated. Cardiovascular disease is the leading cause of death among patients with CKD and reducing its risk in this population is an important priority. Dyslipidemia is almost always present when proteinuria is above 3 gr/24 hours. Roughly two thirds of all patients with end-stage renal failure and kidney transplants suffer from dyslipidemia and should receive lipid-lowering therapy, as suggested by recent Afssaps (French drug agency) and NKF-K/DOQI (National Kidney Foundation-Kidney Disease Outcomes Quality Initiative) guidelines. We reviewed recent studies on efficacy, tolerability and prescription recommendations of statins in CKD and renal transplant patients.. We searched Medline, the international medical database, to conduct a systematic review of the literature on the efficacy and tolerability of statins in CKD and renal transplant patients and on specific recommendations for dosage adjustments in this population.. The efficacy of statins in decreasing total cholesterol and LDL-cholesterol levels in dialysis and renal transplant patients is similar to that in the general population. On the other hand, large-scale randomized clinical trials among CKD (4D) and renal transplant (ALERT) patients do not demonstrate that statins significantly decrease rates of cardiovascular disease. They have a beneficial effect on proteinuria and lower the rate of kidney function deterioration in patients with dyslipidemia. Early introduction of a statin in transplant patients did not lead to improved kidney function or prevent loss of the graft. Although most statins are not excreted by the kidneys, the dosage of some must be adapted in CKD patients because of pharmacokinetic modifications induced by renal impairment.. Statins at appropriately adapted doses have the same efficacy in CKD patients as in subjects with normal kidney function, and tolerance is not a problem. Their effectiveness in cardiovascular prevention in this population has not been demonstrated to date. Results about statin-induced kidney protection are encouraging but further and more specific studies are needed.

Topics: Adult; Aged; Anticholesteremic Agents; Atorvastatin; Cardiovascular Diseases; Cholesterol; Cholesterol, LDL; Dyslipidemias; Fatty Acids, Monounsaturated; Fluorobenzenes; Fluvastatin; Graft Rejection; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Indoles; Kidney Failure, Chronic; Liver Transplantation; Middle Aged; Pravastatin; Primary Prevention; Prospective Studies; Proteinuria; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Renal Dialysis; Risk Factors; Rosuvastatin Calcium; Simvastatin; Sulfonamides; Time Factors

This open, prospective, randomized trial aimed to assess the effects of statins in chronic kidney disease patients on optimized antiproteinuric treatment with combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade.. After 1-month benazepril therapy followed by 1-month benazepril-valsartan combined therapy (run-in), 186 consenting patients with residual proteinuria >0.5 g/24 h were randomized to 6-month benazepril-valsartan therapy alone or combined with fluvastatin. Between-groups changes in proteinuria (primary outcome), serum lipids, and GFR were compared by ANCOVA. Analyses were blinded and by intention to treat.. During the run-in, proteinuria decreased more on benazepril-valsartan than on benazepril alone. Proteinuria reduction correlated with concomitant reduction in total, LDL, and HDL cholesterol, and apolipoprotein B and apolipoprotein A levels. After randomization, median proteinuria similarly decreased from 1.2 (0.6 to 2.2) to 1.1 (0.5 to 1.7) g/24 h on fluvastatin and from 1.5 (0.8 to 2.7) to 1.0 (0.5 to 2.4) g/24 h on benazapril-valsartan therapy alone. Fluvastatin further reduced total and LDL cholesterol and apolipoprotein B versus benazepril-valsartan alone, but did not affect serum triglycerides and GFR. Treatment was well tolerated.. In chronic kidney disease patients with residual proteinuria despite combined angiotensin-converting enzyme inhibitor and angiotensin receptor blockade therapy, add-on fluvastatin does not affect urinary proteins, but further reduces serum lipids and is safe. Whether combined angiotensin-converting enzyme inhibitor, angiotensin receptor blockade, and statin therapy may improve cardiovascular outcomes in this high-risk population is worth investigating.

Topics: Adult; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Blood Pressure; Chi-Square Distribution; Chronic Disease; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fluvastatin; Glomerular Filtration Rate; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Italy; Kidney Diseases; Lipids; Male; Middle Aged; Prospective Studies; Proteinuria; Renin-Angiotensin System; Tetrazoles; Time Factors; Treatment Outcome; Valine; Valsartan

In recent reports, some kinds of HMG-CoA reductase inhibitors were able to decrease proteinuria and to improve renal function. Here we aimed to clarify the effect of fluvastatin (an HMG-CoA reductase inhibitor) on proteinuria and renal function in children with mild IgA nephropathy.. We conducted a prospective controlled study of 30 children who had been recently diagnosed with normocholesterolemic IgA nephropathy following the detection of a minor lesion or of focal mesangial proliferation and moderate proteinuria. The 30 patients were randomly assigned to receive both of 20 mg of fluvastatin and 5 mg/kg of dipyridamole (group 1), or 5 mg/kg of dipyridamole only (group 2) for 1 year.. By the end of the trial, urinary protein, hematuria, BUN and serum creatinine levels had significantly decreased in the patients of group 1 as compared to baseline. Serum total cholesterol, triglyceride and LDL cholesterol levels had significantly decreased, while serum total protein and albumin, and creatinine clearance had significantly increased in group 1 as compared to baseline and group 2. The urinary protein level had significantly decreased in the group 2 patients as compared to baseline, but only slightly.. The results of this study suggest that fluvastatin and dipyridamole treatment yields an antiproteinuric effect and leads to the amelioration of renal function in moderately proteinuric patients with mild histological IgA nephropathy.

Topics: Adolescent; Child; Dipyridamole; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fluvastatin; Glomerulonephritis, IGA; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Kidney; Male; Prospective Studies; Proteinuria; Vasodilator Agents

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are established drugs for the treatment of hypercholesterolemia, but several studies have shown that benefits obtained with these drugs are not causally related only to regression of cholesterol lowering. Moreover, in experimental models of progressive renal disease, statins have reduced the extent of glomerulosclerosis. This study evaluated the antiproteinuric effect of a daily dose of 40 mg fluvastatin for 6 months in moderately proteinuric patients with immunoglobulin A nephropathy, stable renal function, and no indicators of poor long-term prognosis. The effects of therapy were evaluated on the basis of 24-hour proteinuria (total proteinuria and albuminuria), albuminemia, creatinine clearance, cholesterol, and triglyceride values. Renal function remained stable in all patients. A significant decrease in proteinuria was observed after 6 months of therapy and persisted for all the observations. An increase in serum albumin was observed after 6 months of therapy. This study suggests that there is an antiproteinuric effect of HMG-CoA reductase inhibitors in moderately proteinuric patients with immunoglobulin A nephropathy.

Topics: Adult; Blood Pressure; Cholesterol; Creatinine; Fatty Acids, Monounsaturated; Female; Fluvastatin; Glomerulonephritis, IGA; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Linear Models; Male; Middle Aged; Proteinuria

Combined ACE inhibitor, angiotensin-receptor-blocker, non-dihydropyridine calcium-channel-blocker, and statin therapy (Remission Clinic) reduced proteinuria and halted progression in non-diabetic nephropathies, but their efficacy in Alport syndrome (AS) nephropathy is unknown.. From February 2004 to September 2007, we included nine albuminuric AS adults with creatinine clearance >20 ml/min/1.73 m(2) in a single-center, open-label, prospective, off-on-off academic study. After the 1-month wash-out from RAS inhibition (Run-in), patients entered the 4-month, add-on, treatment period with benazepril (10-20 mg/day), valsartan (80-160 mg/day), diltiazem (60-120 mg/day), and fluvastatin (40-80 mg/day) followed by the 1-month wash-out (Recovery). The primary outcome was albuminuria at month 4. After recovery, patients were kept on the Remission Clinic protocol and followed until July 2014 (Extension).. The median (IQR) albuminuria progressively declined from 657.7 (292.7-1,089.6) μg/min at baseline to 71.4 (21.7-504.9) μg/min at treatment end (p = 0.009) and raised to 404.3 (167.9-446.8) μg/min after recovery. Albumin and IgG fractional clearances significantly (p ≤ 0.005) decreased from 66.9 (53.6-80.8) to 9.4 (4.6-26.0) and from 5.1 (3.0-8.4) to 1.1 (0.6-3.2), and then recovered toward baseline. Blood pressure and lipids significantly decreased on treatment, without changes in inulin-measured GFR or para-aminohippuric-measured RPF. After recovery, one patient refused to enter the extension, one with severe renal insufficiency at baseline reached ESRD, and seven retained normal serum creatinine until the end of the study. At the final visit, three were microalbuminuric and one was normoalbuminuric. Treatment was well tolerated.. The Remission Clinic approach safely ameliorated albuminuria, blood pressure, lipids, and glomerular selectivity in AS patients and halted long-term progression in those without renal insufficiency to start with.

Topics: Adult; Aged; Albuminuria; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Calcium Channel Blockers; Cohort Studies; Diltiazem; Drug Therapy, Combination; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Kidney Function Tests; Male; Middle Aged; Nephritis, Hereditary; Prospective Studies; Proteinuria; Valsartan

Recent studies have reported that statins have renoprotective effects, independent from lowering plasma cholesterol. In this study, we examined whether statins were beneficial in a murine model of HIV-associated nephropathy (HIVAN).. We used conditional transgenic mice that express one of the HIV-1 accessory genes, vpr, selectively in podocytes using podocin promoter and the Tet-on system. These mice develop aggressive collapsing focal segmental glomerular sclerosis with massive proteinuria and deterioration of renal function within 4 weeks following heminephrectomy and doxycycline administration. Fluvastatin was administrated simultaneously with doxycycline, and the effect was compared with untreated controls after 4 weeks.. Fluvastatin at 10 mg/kg/day significantly decreased urinary albumin excretion (87 versus 11 mg/day, P < 0.01) and glomerular sclerosis (2.4 versus 1.0, P < 0.01, assessed by semi-quantitative scoring: 0-4). Fluvastatin also decreased serum creatinine and total cholesterol, but these differences were not statistically significant (0.36 versus 0.32 mg/dl, P = 0.35; 492 versus 378 mg/dl, P = 0.11, respectively). Phenotypic changes in podocytes, as indicated by the downregulation of nephrin, Wilms' tumour 1 and synaptopodin, along with upregulation of proliferating cell nuclear antigen, were attenuated by fluvastatin, suggesting its protective effects against podocyte injuries. In cultured podocytes, angiotensin II treatment decreased nephrin expression to 13% of basal levels, which was reversed to 58% by adding fluvastatin.. In conclusion, fluvastatin was effective in treating experimental HIVAN. The beneficial effect of this drug might be caused, in part, by preserving nephrin expression in podocytes against angiotensin II-mediated injury.

Topics: AIDS-Associated Nephropathy; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Blotting, Western; Cells, Cultured; Disease Models, Animal; Fatty Acids, Monounsaturated; Fluorescent Antibody Technique; Fluvastatin; Genes, Wilms Tumor; Glomerulosclerosis, Focal Segmental; Immunoenzyme Techniques; Indoles; Kidney; Male; Membrane Proteins; Mice; Mice, Transgenic; Microfilament Proteins; Nephrectomy; Phenotype; Podocytes; Proteinuria

Statins have been reported to confer renoprotection in several experimental models of renal disease through pleiotropic actions. The roles of statins in glomerular podocytes have not been explored. The objective of this study was to evaluate the effects of fluvastatin on podocyte and tubulointerstitial injury in puromycin aminonucleoside (PAN)-induced nephrosis. PAN induced massive proteinuria and serum creatinine elevation on day 7, which were significantly suppressed by fluvastatin. Immunofluorescence studies of podocyte-associated proteins nephrin and podocin revealed diminished and discontinuous staining patterns in rats with PAN nephrosis, indicating severe podocyte injury. Fluvastatin treatment dramatically mitigated the abnormal staining profiles. Reduction of nephrin expression by PAN and its reversal by fluvastatin were confirmed by quantitative analyses. By electron microscopy, effacement of foot processes was ameliorated in fluvastatin-treated rats. Fluvastatin also mitigated tubulointerstitial damage in PAN nephrosis, with the repression of PAN-induced NF-kappaB and activator protein-1 activation in the kidneys. In addition, expression of activated membrane-bound small GTPase RhoA was markedly increased in the glomeruli of PAN nephrosis, which was inhibited by fluvastatin treatment. In cultured podocytes, fluvastatin suppressed PAN-evoked activation of RhoA and actin cytoskeletal reorganization. Furthermore, fasudil, a specific Rho-kinase inhibitor, successfully ameliorated PAN-induced podocyte damage and proteinuria. In summary, fluvastatin alleviated podocyte and tubulointerstitial injury in PAN nephrosis. The beneficial effects of fluvastatin on podocytes can be attributable to direct modulation of excessive RhoA activity. Our data suggest a therapeutic role for statins in clinical conditions that are relevant to podocyte injury.

Topics: Acute-Phase Proteins; Analysis of Variance; Animals; Blotting, Western; Disease Models, Animal; Fatty Acids, Monounsaturated; Fluvastatin; Immunohistochemistry; Indoles; Male; Podocytes; Probability; Proteinuria; Puromycin Aminonucleoside; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Sensitivity and Specificity; Signal Transduction

Diabetic nephropathy is related to glomerular extracellular matrix (ECM) accumulation that leads to glomerulosclerosis. Fluvastatin as a lipid-lowering medicine significantly prevents diabetic nephropathy, probably not only through its lipid-lowering action, but also mainly through its direct suppression of glomerular ECM accumulation. To test this hypothesis, in the present study, a five-sixths nephrectomized (5/6Nx) rat model to induce a renal ECM accumulation without coexistence of hyperlipidemia was used to investigate the effect of fluvastatin on renal function, glomerular ECM accumulation and expression of connective tissue growth factor (CTGF). 5/6Nx induced a significant nephropathy in rats at 13 weeks, indicated by renal dysfunction including increases in blood urine nitrogen, creatinine and urinary protein excretion, and renal histopathological changes. Administration of fluvastatin significantly prevented the renal dysfunction and histological abnormalities in the 5/6Nx rats. Furthermore, both significant suppression of matrix metalloproteinases (MMPs) activity such as MMP-2 and significant activation of tissue inhibitors of MMP (TIMPs) such as TIMP-2 observed in the 5/6Nx rats were almost completely prevented by fluvastatin, resulting in a significant prevention of glomerular ECM accumulation. For upstream mediator of ECM accumulation, 5/6Nx significantly up-regulated CTGF mRNA expression, but fluvastatin treatment prevented CTGF up-regulation. These results suggest that fluvastatin, as one of well-known lipid-lowering agents, plays an important role in the prevention of nephropathy, likely through suppression of CTGF-mediated ECM accumulation. Therefore, fluvastatin may be a potential candidate for developing a pharmaceutical approach to the prevention of diabetic nephropathy due to its both lipid-lowering and direct anti-renal ECM accumulation actions.

Topics: Animals; Anticholesteremic Agents; Blood Urea Nitrogen; Connective Tissue Growth Factor; Creatinine; Disease Models, Animal; Extracellular Matrix; Fatty Acids, Monounsaturated; Fluvastatin; Immediate-Early Proteins; Indoles; Intercellular Signaling Peptides and Proteins; Kidney Failure, Chronic; Kidney Glomerulus; Male; Matrix Metalloproteinase Inhibitors; Nephrectomy; Proteinuria; Rats; Rats, Wistar; RNA, Messenger; Tissue Inhibitor of Metalloproteinase-2; Up-Regulation

To investigate the connective tissue growth factor (CTGF) mRNA expression in the renal cortex of 5/6 nephrectomized rats and its modulation by fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.. Twenty-four rats underwent operation 2 times: during the first operation 2/3 of the left kidney was resected, and the right kidney was resected completely one week after. The 24 5/6 nephrectomized rats were randomly divided into 2 groups: untreated 5/6 nephrectomized group (model group, n=12) and fluvastatin-treated 5/6 nephrectomized group (treatment group, fluvastatin was orally administered 7 mg.kg(-1).d(-1) for 13 weeks, n=12), and 6 sham-operated rats served as control (sham operation group). In the weeks 2, 4, 8, and 13 after the second operation metabolic cage was used to collect the 24-hour urine 2 times. Urine protein was examined by biuret reaction so as to calculate urinary protein excretion. By the end of experiment blood was collected to examine the serum cholesterol, triglyceride, urea nitrogen, and creatinine contents. The rats were killed and their kidneys taken out. The CTGF mRNA expression in the renal cortex was detected by RT-PCR. Immunohistochemistry was used to examine the expression of transforming growth factor-beta1 (TGF-beta1), type IV collagen and fibronectin in the glomeruli. Renal pathological changes and glomerular sclerosis index (GSI) were evaluated as well.. At the end of the experiment, the mean urinary protein excretion in the model group was 305.4 mg/24 h, significantly higher than that in the treatment group (230.9 mg/24 h, P<0.01) and the sham operation group (5.6 mg/24 h, P<0.01) The serum urea nitrogen of the model group was (24.5 +/- 4.9) mmol/L, significantly higher than that of the treatment group [(15.8 +/- 3.9) mmol/L, P<0.05] and that of the sham-operated group (7.4 +/- 0.3 mmol/L, P<0.01). The serum creatinine (P<0.05) of the model group was 88 micromol/L +/- 14 micromol/L, significantly higher than that of the treatment group [(58 +/- 5) micromol/L, P<0.05)] and that of the sham-operated group [(54 +/- 5) micromol/L, P<0.05]. The creatinine clearance rate of the model group was (1.7 +/- 0.7) ml.min(-1).kg(-1), significantly lower than that of the treated group [(3.2 +/- 1.1) ml.min(-1).kg(-1), P<0.05] and that of the sham-operated group [(3.9 +/- 1.5) ml.min(-1).kg(-1), P<0.05]. The glomerular sclerosis index (GSI) in the model group was 41.8 +/- 11.5, significantly higher than that in the sham operation group (2.2 +/- 1.3, P<0.01) and the treatment group (23.4 +/- 6.1, P<0.05). The mean optical density of CTGF mRNA expression in the renal cortex of the model group was a 3 times that of the sham operation group, and the mean optical density of CTGF mRNA expression in the renal cortex of the treatment group was lower by 55.4% compared with that of the model group (P<0.01). The glomerular expressions of TGF-beta1, type IV collagen and fibronectin were significantly up-regulated in the model group in comparison with those in the sham operation group (all P<0.01). The glomerular protein expressions of TGF-beta1, type IV collagen and fibronectin were significantly weaker in the fluvastatin treatment group as compared with the model group (all P<0.01).. CTGF mRNA expression is markedly upregulated in the renal cortex of 5/6 nephrectomized rats. Fluvastatin suppresses the increased CTGF mRNA expression in renal cortex and ameliorates the glomerular extracellular matrix accumulation.

Topics: Animals; Blood Urea Nitrogen; Connective Tissue Growth Factor; Fatty Acids, Monounsaturated; Fluvastatin; Immediate-Early Proteins; Indoles; Intercellular Signaling Peptides and Proteins; Kidney; Kidney Cortex; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar; RNA, Messenger

Topics: Animals; Anticholesteremic Agents; Disease Models, Animal; Fatty Acids, Monounsaturated; Fluvastatin; Glomerulosclerosis, Focal Segmental; Indoles; Kidney; Male; Nephrectomy; Proteinuria; Rats; Rats, Wistar

Topics: Adult; Alanine Transaminase; Anticholesteremic Agents; Aspartate Aminotransferases; Cholesterol; Cholesterol, Dietary; Cholesterol, HDL; Cholesterol, LDL; Cholesterol, VLDL; Creatine Kinase; Creatinine; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hypercholesterolemia; Indoles; Kidney Transplantation; Middle Aged; Proteinuria; Triglycerides