Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury

Abstract

Vaidya, Vishal S., Victoria Ramirez, Takaharu Ichimura, Norma A. Bobadilla, and Joseph V. Bonventre. Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. sitive 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 Ͻ10%. 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-␤-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.

Comparison of Kidney Injury Molecule-1 and Other Nephrotoxicity Biomarkers in Urine and Kidney Following Acute Exposure to Gentamicin, Mercury, and Chromium

“…The upregulation of Kim-1/Havcr1 gene expression and the presence of the Kim-1 ectodomain in the urine has been reported in postischemic rat kidney; in a nontoxic model of acute massive proteinuria, protein-overload nephropathy; in humans with ischemic acute tubular necrosis and renal cell carcinoma; and after exposure to nephrotoxicants with different mechanisms of action: S-(1,1,2,2-tetrafluoroethyl)-L-cysteine, folic acid, and cisplatin (Han et al, 2002(Han et al, , 2005Ichimura et al, 2004;Kuehn et al 2002;Vaidya et al, 2006;van Timmeren et al, 2006). Therefore, Kim-1 has been suggested to serve as a useful general biomarker for renal proximal tubule injury in preclinical and clinical studies of drug safety evaluation, chemicalrelated renal injury, and the monitoring of renal disease states.…”

Urinary Expression of Novel Tissue Markers of Kidney Injury After Ureteroscopy, Shockwave Lithotripsy, and in Normal Healthy Controls

“…For example, hepatic parenchymal injury increases LDH levels, 19 GST needs a specific preservative added to the urine, GGT in urine is unstable after 4 hours and can be altered by the presence of different other urinary components, 20 IL-18 is nonspecific and can be elevated in various conditions including sepsis. 18 Overall, the investigative role of urinary biomarkers seems to be superior when the etiology and timing of renal injury is known, 21 rendering them a potential useful tool in assessing acute kidney injury after SWL.…”

“…Results, however, have been inconsistent, with NAG levels found to be altered by endogenous urea, nephrotoxic agents, impaired glucose tolerance, rheumatoid arthritis, hyperthyroidism, and after exercise, undermining its role as a biomarker. 20 KIM-1 is a type I transmembrane protein that appears to play an important role in the clearance of apoptotic debris from the tubular lumen. Despite the fact that KIM-1 outperformed all other tested kidney injury biomarkers, 5 …”

Focal Adhesion Kinase Signaling Mediates Acute Renal Injury Induced by Ischemia/Reperfusion

“…Expression of KIM-1 is absent in healthy kidney tissue but is strongly up-regulated at the brush border of proximal tubules after an ischemic insult. 19,21 KIM-1 was expressed in tubules of the OSOM and cortex of FAK loxP/loxP kidneys after ischemia, whereas in the FAK ⌬loxP/⌬loxP kidneys KIM-1 was predominantly found in the proximal tubules of the OSOM only, indicating attenuated renal injury in FAK ⌬loxP/⌬loxP animals ( Figure 3A). With the use of a semiquantitative scoring system for KIM-1 staining ( Figure 3B), we found that FAK ⌬loxP/⌬loxP kidneys had significantly less KIM-1 staining during I/R injury than FAK loxP/loxP kidneys ( Figure 3C).…”