cerivastatin and Acute-Kidney-Injury

Rosuvastatin is the first statin approved by the regulatory authorities since the withdrawal of cerivastatin. Although highly efficacious, this new statin has generated considerable controversy regarding its safety. Rosuvastatin was approved for clinical use based on the largest pre-approval database for all statins prior to commercial use. In this database, rosuvastatin had a similar safety profile to other approved statins up to the highest approval dose of 40 mg. As with all statins, there is a marked increase in adverse effects when the dose is titrated from 40 to 80 mg, and rosuvastatin demonstrates a similar dose/toxicity relationship. In the pre-approval data trials on 80 mg, there was a 1.0% (n = 16) incidence of myopathy and 7 patients developed rhabdomyolysis. However the

Topics: Acute Kidney Injury; Adverse Drug Reaction Reporting Systems; Biomarkers; Cholesterol, LDL; Creatine Kinase; Creatine Kinase, MM Form; Drug Approval; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperlipidemias; Incidence; Isoenzymes; Kidney Tubules; Muscular Diseases; Product Surveillance, Postmarketing; Proteinuria; Pyridines; Pyrimidines; Rhabdomyolysis; Rosuvastatin Calcium; Sulfonamides

Topics: Acute Kidney Injury; Aged; Drug Therapy, Combination; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Male; Pyridines; Rhabdomyolysis

Postischemic acute renal failure (ARF) is common and often fatal. Cellular mechanisms include cell adhesion, cell infiltration and generation of oxygen free radicals, and inflammatory cytokine production. Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") directly influence inflammatory mechanisms. The hypothesis that ischemia-induced ARF could be ameliorated with statin treatment was investigated and possible molecular mechanisms were analyzed in a uninephrectomized rat model. Male Sprague-Dawley rats were pretreated with cerivastatin (0.5 mg/kg) or vehicle for 3 d. Ischemic ARF was induced by left renal artery clipping for 45 min, while the right kidney was being removed. After 24 h of ARF, serum creatinine levels were increased 7.5-fold in vehicle-treated control animals with ARF, compared with sham-operated animals (P < 0.005). Statin treatment reduced the creatinine level elevation by 40% (P < 0.005). Simultaneously, ischemia-induced severe decreases in GFR were significantly ameliorated by statin treatment (sham operation, 0.95 +/- 0.09 ml/min, n = 13; ischemia without treatment, 0.06 +/- 0.02 ml/min, n = 9; ischemia with statin pretreatment, 0.21 +/- 0.03 ml/min, n = 11; P < 0.001). Furthermore, statin pretreatment prevented the occurrence of tubular necrosis, with marked loss of the brush border, tubular epithelial cell detachment, and tubular obstruction in the S3 segment of the outer medullary stripe. In addition, monocyte and macrophage infiltration was almost completely prevented, intercellular adhesion molecule-1 upregulation was greatly decreased, and inducible nitric oxide synthase expression was reduced. Fibronectin and collagen IV expression was reduced, approaching levels observed in sham-operated animals. In vehicle-treated rats with ARF, mitogen-activated protein kinase extracellular activated kinase-1/2 activity was increased and the transcription factors nuclear factor-kappaB and activator protein-1 were activated. Statin treatment reduced this activation toward levels observed in sham-operated rats. The data suggest that hydroxy-3-methylglutaryl coenzyme A reductase inhibition protects renal tissue from the effects of ischemia-reperfusion injury and thus reduces the severity of ARF. The chain of events may involve anti-inflammatory effects, with inhibition of mitogen-activated protein kinase activation and the redox-sensitive transcription factors nuclear factor-kappaB and activator protein-1.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Fibronectins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Intercellular Adhesion Molecule-1; Ischemia; Kidney Glomerulus; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; NF-kappa B; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Pyridines; Rats; Rats, Sprague-Dawley

Topics: Acute Kidney Injury; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Pyridines; Rhabdomyolysis

Rhabdomyolysis is an uncommon complication associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. We observed six cases of cerivastatin-associated rhabdomyolysis: two patients developed acute renal failure requiring hemodialysis, and one patient died. Four of the patients had impaired renal function, and five were prescribed drugs with the potential to interact with cerivastatin. Also, five of the six patients presented with symptoms of rhabdomyolysis 3-4 weeks after starting cerivastatin therapy.

Topics: Acute Kidney Injury; Aged; Creatine Kinase; Drug Interactions; Fatal Outcome; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Middle Aged; Pyridines; Renal Dialysis; Renal Insufficiency; Rhabdomyolysis

Topics: Acute Kidney Injury; Drug Therapy, Combination; Gemfibrozil; HIV Infections; HIV Protease Inhibitors; Humans; Hyperlipidemias; Hypolipidemic Agents; Male; Middle Aged; Pyridines; Rhabdomyolysis

Topics: Acute Kidney Injury; Aged; Drug Interactions; Gemfibrozil; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Male; Pyridines; Rhabdomyolysis

Topics: Acute Kidney Injury; Aged; Bezafibrate; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypolipidemic Agents; Influenza Vaccines; Male; Pyridines; Rhabdomyolysis