Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury.
Sensitive and specific biomarkers are needed to detect early kidney injury. The objective of the present work was to develop a sensitive quantitative urinary test to identify renal injury in the rodent to facilitate early assessment of pathophysiological influences and drug toxicity. Two mouse monoclonal antibodies were made against the purified ectodomain of kidney injury molecule-1 (Kim-1), and these were used to construct a sandwich Kim-1 ELISA. The assay range of this ELISA was 50 pg/ml to 5 ng/ml, with inter- and intra-assay variability of <10%. Urine samples were collected from rats treated with one of three doses of cisplatin (2.5, 5, or 7.5 mg/kg). At one day after each of the doses, there was an approximately three- to fivefold increase in the urine Kim-1 ectodomain, whereas other routinely used biomarkers measured in this study [plasma creatinine, blood urea nitrogen (BUN), urinary N-acetyl-beta-glucosaminidase (NAG), glycosuria, proteinuria] lacked the sensitivity to show any sign of renal damage at this time point. When rats were subjected to increasing periods (10, 20, 30, or 45 min) of bilateral ischemia, there was an increasing amount of urinary Kim-1 detected. After only 10 min of bilateral ischemia, Kim-1 levels on day 1 were 10-fold higher (5 ng/ml) than control levels, whereas plasma creatinine and BUN were not increased and there was no glycosuria, increased proteinuria, or increased urinary NAG levels. Thus urinary Kim-1 levels serve as a noninvasive, rapid, sensitive, reproducible, and potentially high-throughput method to detect early kidney injury in pathophysiological studies and in preclinical drug development studies for risk-benefit profiling of pharmaceutical agents.
Vaidya
Vishal S
VS
Renal Division, Brigham and Women's Hospital, Harvard Medical School, 4 Blackfan Circle, Harvard Institutes of Medicine, Rm. 550, Boston, MA 02115, USA.
Ramirez
Victoria
V
Ichimura
Takaharu
T
Bobadilla
Norma A
NA
Bonventre
Joseph V
JV
D000818:Animals; D000911:Antibodies, Monoclonal; D015415:Biomarkers / Q000652:urine*; D016466:CHO Cells; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000652:urine*; D002945:Cisplatin; D006224:Cricetinae; D003412:Cricetulus; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005069:Evaluation Studies as Topic; D066298:In Vitro Techniques; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007674:Kidney Diseases / Q000139:chemically induced / Q000175:diagnosis* / Q000652:urine; D007684:Kidney Tubules / Q000187:drug effects / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000276:immunology / Q000652:urine*; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology*; D012680:Sensitivity and Specificity; D014162:Transfection
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D015815:Cell Adhesion Molecules; D002945:Cisplatin; D008565:Membrane Proteins; C110936:Havcr1 protein, rat