Comparison of changes in urinary and blood levels of biomarkers associated with proximal tubular injury in rat models

To investigate useful biomarkers associated with proximal tubular injury, we assessedchanges in levels of a focused set of biomarkers in urine and blood. Male ratsadministered a single dose or four doses of gentamicin (GM, 240 mg/kg/day) or a singledose of cisplatin (CDDP, 5 mg/kg) were euthanized on days 2 (the day after initial dosing)5, or 12. At each time point, histopathological examination of the kidney andimmunohistochemistry for biomarkers, kidney injury molecule-1 (Kim-1), lipocalin (NGAL),clusterin (CLU), cystatin C (CysC) and β2-microglobulin (β2M) were performed. Biomarkerlevels were measured in urine and blood. In both treatment groups, degenerated/necroticproximal tubules and regenerated tubules were mainly observed on days 5 and 12,respectively. At the same time as these tubular injuries, urinary Kim-1, CysC and β2Mlevels were increased. Moreover, urinary levels of CysC and β2M in GM-treated animals andKim-1 in CDDP-treated animals increased (on day 2) prior to tubular injury on day 5. Thiswas considered to reflect the characteristics of drug toxicity. Although almost all of thebiomarkers in blood were not sufficiently sensitive to detect proximal tubular injury,urinary and plasma β2M levels simultaneously increased. Therefore, in addition to urinaryKim-1, CysC and β2M levels, plasma β2M levels were also considered useful for detectingproximal tubular injury.