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

Despite improvements in kidney transplantation, complications, including cardiovascular morbidity and graft loss, contribute to reduced graft and patient survival. The amino acid homoarginine exerts a variety of beneficial effects that may be relevant for cardiovascular and graft outcomes, which is investigated in the present study.. Homoarginine was measured in 829 renal transplant recipients participating in the placebo group of the Assessment of Lescol in Renal Transplantation study. Mean follow-up was 6.7 years. By Cox regression analyses, we determined hazard ratios (HRs) to reach prespecified, adjudicated endpoints according to baseline homoarginine levels: major adverse cardiovascular events (n = 103), cerebrovascular events (n = 53), graft failure or doubling of serum creatinine (n = 140), noncardiovascular mortality (n = 51), and all-cause mortality (n = 107).. Patients mean age was 50 ± 11 years, homoarginine concentration was 1.96 ± 0.76 μmol/L, and 65% were men. Patients in the lowest homoarginine quartile (<1.40 μmol/L) had an adjusted 2.6-fold higher risk of cerebrovascular events compared to those in the highest quartile (>2.34 μmol/L) (HR, 2.56; 95% confidence interval [95% CI], 1.13-5.82). Similarly, the renal endpoint occurred at a significantly increased rate in the lowest homoarginine quartile (HR, 2.34; 95% CI, 1.36-4.02). For noncardiovascular and all-cause mortality, there was also increased risk associated with the lowest levels of homoarginine, with HRs of 4.34 (95% CI, 1.63-10.69) and 2.50 (95% CI, 1.38-4.55), respectively.. Low homoarginine is strongly associated with cerebrovascular events, graft loss and progression of kidney failure and mortality in renal transplant recipients. Whether interventions with homoarginine supplementation improve clinical outcomes requires further evaluation.

Topics: Adult; Biomarkers; Cardiovascular Diseases; Chi-Square Distribution; Creatinine; Disease Progression; Europe; Fatty Acids, Monounsaturated; Female; Fluvastatin; Graft Rejection; Graft Survival; Homoarginine; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; North America; Proportional Hazards Models; Prospective Studies; Renal Insufficiency; Risk Factors; Time Factors; Treatment Outcome

Elevated symmetric dimethylarginine (SDMA) has been shown to predict cardiovascular events and all cause mortality in diverse populations. The potential role of SDMA as a risk marker in renal transplant recipients (RTR) has not been investigated.. We analyzed SDMA in the placebo arm of the Assessment of Lescol in Renal Transplantation study, a randomized controlled trial of fluvastatin in RTR. Mean follow-up was 5.1 years. Patients were grouped into quartiles based on SDMA levels at study inclusion. Relationships between SDMA and traditional risk factors for graft function and all-cause mortality were analyzed in 925 RTR using univariate and multivariate survival analyses.. In univariate analysis, SDMA was significantly associated with renal graft loss, all-cause death, and major cardiovascular events. After adjustment for established risk factors including estimated glomerular filtration rate, an elevated SDMA-level (4th quartile, >1.38 μmol/L) was associated with renal graft loss; hazard ratio (HR), 5.51; 95% confidence interval (CI), 1.95-15.57; P=0.001, compared to the 1st quartile. Similarly, SDMA in the 4th quartile was independently associated with all-cause mortality (HR, 4.56; 95% CI, 2.15-9.71; P<0.001), and there was a strong borderline significant trend for an association with cardiovascular mortality (HR, 2.86; 95% CI, 0.99-8.21; P=0.051).. In stable RTR, an elevated SDMA level is independently associated with increased risk of all-cause mortality and renal graft loss.

Topics: Adult; Aged; Arginine; Biomarkers; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Graft Rejection; Humans; Indoles; Kidney; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Renal Insufficiency; Risk Factors; Time Factors; Transplant Recipients; Treatment Outcome

Dysglycemia and dyslipidemia are important metabolic complications of organ transplantation. Statins are widely used to control dyslipidemia; however, long-term use of statins is related to diabetes mellitus (DM) and impaired fasting glucose (IFG). The aim of this study was to evaluate the influence of statins on the development of dysglycemia (IFG and/or DM) in renal allograft recipients.. A total of 394 patients without previously known DM or IFG who underwent kidney transplantation were enrolled. Patients were grouped into the two groups according to the use of statin (control, n=149; statin, n=245). The major statins used were fluvastatin (80 mg/d, n=134) and atorvastatin (20 mg/d, n=111). We compared the incidence of IFG or DM during the follow-up period.. The incidence of IFG was higher in the statin group than that in the control group (28.6% vs. 8.7%, P<0.001). The incidence of dysglycemia was significantly higher in the statin group (40.0% vs. 15.4%, P=0.001). Time to development of dysglycemia after transplantation was shorter in the statin group than in the control group (38.8±29.7 vs. 47.2±23.3 months, P=0.002). Statin use was associated with an increased risk for dysglycemia after adjustment for age, sex, body mass index, hypertension, cholesterol levels, hepatitis C infection, and type of immunosuppressant (hazard ratio=3.08, 95% confidence interval=1.91-4.98). The dysglycemic effect was more profound in the patients who used atorvastatin than in those who used fluvastatin (hazard ratio=2.21, 95% confidence interval=1.02-4.76).. Statin treatment is associated with an elevation in fasting plasma glucose and in the development of dysglycemia in renal allograft recipients.

Topics: Adult; Anticholesteremic Agents; Atorvastatin; Blood Glucose; Diabetes Complications; Diabetes Mellitus; Dyslipidemias; Fasting; Fatty Acids, Monounsaturated; Female; Fluvastatin; Follow-Up Studies; Glomerular Filtration Rate; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperglycemia; Immunosuppressive Agents; Incidence; Indoles; Kidney Transplantation; Male; Middle Aged; Pyrroles; Renal Insufficiency

The objective of this study was to investigate the effects of fluvastatin on atherosclerosis, systemic and regional hemodynamics, and vascular reactivity in apolipoprotein E-deficient (ApoE(-/-)) mice.. Hemodynamics (fluospheres) and vasomotor responses of thoracic aorta and carotid artery were evaluated in male wild-type (WT) and untreated (ApoE(-/-) Control) or fluvastatin-treated (50 mg/kg per day for 20 weeks) ApoE(-/-) mice, all fed a Western-type diet. Plasma cholesterol and aortic root atherosclerotic lesions (ALs) were greater in ApoE(-/-) Control mice (19+/-1 mmol/L and 63,0176+/-38,785 micro m(2), respectively) than in WT mice (2+/-1 mmol/L and 1+/-1 micro m(2), respectively, P<0.01). Fluvastatin significantly decreased plasma cholesterol (-53%) but failed to limit ALs. Renal blood flow was significantly reduced in ApoE(-/-) Control versus WT (-25%, P<0.05) mice. This reduction was prevented by fluvastatin. Aortic and carotid endothelium-dependent relaxations to acetylcholine were not altered in ApoE(-/-) Control versus WT mice. In carotid arteries from WT mice, these responses were abolished after nitro-L-arginine (L-NA), whereas those from ApoE(-/-) Control were only partially inhibited after L-NA but fully abolished after L-NA+diclofenac. Thus, in carotid arteries from ApoE(-/-) mice, vasodilating prostanoids compensate the deficit in NO availability. Fluvastatin prevented this carotid NO deficit.. In ApoE(-/-) mice, chronic fluvastatin treatment preserved renal perfusion and vascular NO availability independently from atherosclerotic lesion prevention.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Apolipoproteins E; Arteriosclerosis; Carotid Arteries; Fatty Acids, Monounsaturated; Fluvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors; In Vitro Techniques; Indoles; Kidney; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Nitric Oxide; Nitroprusside; Perfusion; Renal Insufficiency; Vascular Resistance; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

To demonstrate a case of rhabdomyolysis with acute renal failure in a patient receiving fluvastatin and to present evidence that this was an adverse drug reaction to fluvastatin.. A 51-year-old white man with a past medical history significant for hyperlipidemia treated with fluvastatin presented with malaise, myalgias, nausea, and lumbar back pain. The patient had azotemia with elevated creatine kinase (CK), lactate dehydrogenase, and transaminases. He developed hematuria and proteinuria. Laboratory results demonstrated a normal antinuclear antibody, rheumatoid factor, angiotensin-converting enzyme, antineutrophil cytoplasmic antibody, and thyroid-stimulating hormone. Cytomegalovirus and Epstein-Barr virus titers were negative for recent infection. There were no signs of systemic infection; the white blood cell count was normal and blood and urine cultures were negative. Renal ultrasound showed hyperechoic renal cortices with no obstruction. The discontinuation of fluvastatin and hemodialysis led to a rapid decrease in CK and improvement in symptoms.. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have the potential to cause rhabdomyolysis. However, fluvastatin is rarely associated with rhabdomyolysis when compared to other statins. Differences in biochemical and pharmacokinetic properties between fluvastatin and other HMG-CoA reductase inhibitors may be important in the development of rhabdomyolysis.. Fluvastatin was the precipitating factor causing rhabdomyolysis in this case report. This patient had no other findings to suggest infection or other disorder inducing rhabdomyolysis. An objective causality assessment revealed that the adverse drug reaction was probable as determined by the Naranjo probability scale. Fluvastatin has the potential to cause serious adverse effects. Therefore, a heightened awareness by the patient and physician for potential signs of myopathy is recommended.

Topics: Anticholesteremic Agents; Bumetanide; Chlorothiazide; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Indoles; Male; Mannitol; Middle Aged; Renal Dialysis; Renal Insufficiency; Rhabdomyolysis

The pharmacokinetics (PK) and safety of fluvastatin, a hydroxymethylglutaryl-coenzyme A reductase inhibitor, were assessed in subjects with renal impairment and nephrotic syndrome. In a single-center, open-label, parallel-group study, a single dose of fluvastatin 40 mg was administered to subjects (8 per group, n = 48) with nephrotic syndrome (group II), healthy subjects (group I), and subjects with various degrees of renal impairment (groups III to VI). Subjects undergoing hemodialysis received two doses, one 2 days before and one just prior to hemodialysis. Blood samples to determine the PK parameters of fluvastatin were collected from 0 to 12 hours after drug intake. Noncompartmental PK evaluation and statistical analysis (descriptive and ANOVA) were performed. Safety was evaluated and vital signs were monitored. There was no difference in the PK parameters AUC0-infinity and Cmax of fluvastatin between healthy subjects and subjects with renal impairment. Fluvastatin was not removed from plasma by hemodialysis. In patients with nephrotic syndrome, the values for AUC0-infinity and Cmax were less than half of those obtained in the other groups; terminal half-life values, however, were comparable. Fluvastatin was well tolerated in all study participants. Only few adverse events of mild to moderate intensity were reported. There were no clinically relevant changes in laboratory parameters in the subjects with renal impairment. Renal impairment did not affect the PK of fluvastatin after a single oral dose. Exposure to fluvastatin was lower in subjects with nephrotic syndrome. Fluvastatin also was well tolerated in subjects with nephrotic syndrome.

Topics: Adult; Analysis of Variance; Area Under Curve; Fatty Acids, Monounsaturated; Fluvastatin; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Indoles; Middle Aged; Nephrotic Syndrome; Renal Dialysis; Renal Insufficiency