OBJECTIVE To assess the nephrotoxicity of imipenem and to correlate the pathogenesis of lesions in the kidney with changes in urinary biomarkers of kidney toxicity.METHODS Study #1,11 monkeys(2-3 /sex /group) were given vehicle or imipenem(180 mg·kg-1,iv infusion once daily for 7 d) and urine was collected on days xxxxx for biomarker assessment.In Study #2,24 monkeys(3 /sex /group) were given of vehicle or imipenem(45,90 or 180 mg·kg-1,iv infusion once daily for 7 d).The following endpoints were assessed in both studies: clinical observations,body weight,food consumption,haematology,coagulation,blood chemistry,urine analysis,imipenem concentration /toxicokinetics (TK) and gross and microscopic pathology.RESULTS Study #1: Imipenem causes minor body weight loss,increased urea and creatinine,and decreased phosphate in plasma.Increased total protein and bilirubin were observed in the urine.These effects were progressive and most pronounced at days 7 and 8.Absolute and relative kidney weights were increased in both sexes.Correlating histopathological findings were present in kidneys of the dosed monkeys,consisting of minimal to moderate tubular necrosis /degeneration /regeneration.Five biomarkers(α-1 and β-2 microglobulin,clusterin,Tamm-Horsfall protein and vascular endothelial growth factor) increased progressively and significantly from day 2 onward and preceded notable changes in urinalysis or plasma chemistry on day 7 or 8,respectively.Study #2: There were similar findings to Study #1 in the 180 mg·kg-1 imipenem treatment group.Increased total bilirubin and decreased of phosphate in plasma and an increase of urinary urobilinogen /ketones were observed in a dose related manner.Exposure to imipenem 〔Cmax and AUC(0-3 h) 〕increased in proportion from 45-90 mg·kg-1 but more than in proportion from 90-180 mg·kg-1.CONCLUSION The no observed adverse effect level(NOAEL) for the imipenem induced kidney injury was identified as 90 mg·kg-1.Early increases of five urinary biomarkers of kidney toxicity preceded notable changes in conventional indices of kidney injury,suggesting their potential utility for early detection of renal injury. OBJECTIVE To assess the nephrotoxicity of imipenem and to correlate the pathogenesis of lesions in the kidney with changes in urinary biomarkers of kidney toxicity. METHODS Study # 1, 11 monkeys (2-3 / sex / group) were given vehicle or imipenem (180 mg · Kg-1, iv infusion once daily for 7 d) and urine was collected on days xxxxx for biomarker assessment. Study # 2,24 monkeys (3 / sex / group) were given of vehicle or imipenem (45, 90 or 180 The following endpoints were assessed in both studies: clinical observations, body weight, food consumption, haematology, coagulation, blood chemistry, urine analysis, imipenem concentration / toxicokinetics (TK) and gross and microscopic pathology. RESULTS Study # 1: Imipenem causes minor body weight loss, increased urea and creatinine, and decreased phosphate in plasma. Created total protein and bilirubin were observed in the urine. These effects were progressive and most pronounced at days 7 and 8. Absolute and relative kidney wei ghts were increased in both sexes. Correlating histopathological findings were present in kidneys of the dosed monkeys, consisting of minimal to moderate tubular necrosis / degeneration / regeneration. Live biomarkers (α-1 and β-2 microglobulin, clusterin, Tamm-Horsfall protein and vascular endothelial growth factor) increased progressively and significantly from day 2 onward and preceded notable changes in urinalysis or plasma chemistry on day 7 or 8, respectively. Study # 2: There were similar findings to Study # 1 in the 180 mg · kg -1 imipenem treatment group. Increased total bilirubin and decreased of phosphate in plasma and an increase of urinary urobilinogen / ketones were observed in a dose related manner. Posture to imipenem [Cmax and AUC (0-3 h)] increased in proportion from 45-90 mg · kg-1 but more than in proportion from 90-180 mg · kg -1 .CONCLUSION The no observed adverse effect level (NOAEL) for the imipenem induced kidney injury was identified as 90 mg · kg -1. Early increases of five uri nary biomarkers of kidney toxicity preceded notable changes in conventional indices of kidney injury, suggesting their potential utility for early detection of renal injury.