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

Abstract

To investigate useful biomarkers associated with proximal tubular injury, we assessed changes in levels of a focused set of biomarkers in urine and blood. Male rats administered a single dose or four doses of gentamicin (GM, 240 mg/kg/day) or a single dose 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 and immunohistochemistry for biomarkers, kidney injury molecule-1 (Kim-1), lipocalin (NGAL), clusterin (CLU), cystatin C (CysC) and β2-microglobulin (β2M) were performed. Biomarker levels were measured in urine and blood. In both treatment groups, degenerated/necrotic proximal 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 β2M levels were increased. Moreover, urinary levels of CysC and β2M in GM-treated animals and Kim-1 in CDDP-treated animals increased (on day 2) prior to tubular injury on day 5. This was considered to reflect the characteristics of drug toxicity. Although almost all of the biomarkers in blood were not sufficiently sensitive to detect proximal tubular injury, urinary and plasma β2M levels simultaneously increased. Therefore, in addition to urinary Kim-1, CysC and β2M levels, plasma β2M levels were also considered useful for detecting proximal tubular injury.

Dietary Cadmium Intake and Its Effects on Kidneys

“…By virtue of its small mass (MW ~12 kDa), β2-MG is filtered completely, as internalized by the proximal convoluted tubule through megalin-mediated endocytosis, and degraded [ 112 , 113 , 114 ]. Approximately 0.3% of filtered β2-MG is excreted in urine.…”

Ectopic Adipose Tissue Storage in the Left and the Right Renal Sinus is Asymmetric and Associated With Serum Kidney Injury Molecule-1 and Fibroblast Growth Factor-21 Levels Increase

“…Chronic KIM-1 expression can promote further tubulointestinal inflammation and hypoxia, further inducing KIM-1 expression that culminate in chronic kidney disease (Humphreys et al, 2013). The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury (Bonventre, 2009, Kuwata et al, 2015, Jin et al, 2013). Recent study showed that KIM-1 may be released into the circulation and identified KIM-1 as a blood biomarker that specifically reflects injury to the proximal tubule of the kidney, the primary site of injury for ischemia and most nephrotoxicants (Sabbisetti et al, 2014, Bonventre et al, 2010).…”

Prognostic value of serum and urine kidney injury molecule-1 in infants with urinary tract infection

“…Blood elevation of KIM-1 is associated with lost polarity of tubule epithelial cells and increased trans-epithelial and microvascular permeability [26]. Experimental studies found significantly higher plasma KIM-1 (pKIM-1) levels in acute and chronic kidney injury [26,27]. In humans, the usefulness of blood (serum/plasma) KIM-1 was documented in AKI and CKD [21,26,28].…”