Profiling of Kidney Injury Biomarkers in Patients Receiving Cisplatin: Time-dependent Changes in the Absence of Clinical Nephrotoxicity

Abstract

The success of cisplatin-containing regimens to treat solid tumors is limited, in part, by nephrotoxicity. In rodents, several urinary proteins have emerged that are sensitive indicators of cisplatin-induced kidney injury. We sought to characterize time-dependent changes in the urinary concentrations of 12 proteins, including kidney injury molecule-1 (KIM-1), calbindin, beta 2-microglobulin (β2M), and trefoil factor 3 (TFF3) after cisplatin therapy. Urine was collected at baseline, 3 days (range, 2-5 days), and 10 days (range, 9-11 days) from 57 patients with solid tumors receiving outpatient cisplatin therapy (≥25 mg/m² ). Serum creatinine was largely unchanged after cisplatin infusion. However, compared with baseline values, several novel biomarkers were significantly increased in the urine, including β2M, which was threefold higher by day 3 (P < 0.0001). Urinary KIM-1 and TFF3 were elevated twofold by day 10 (P = 0.002 and P = 0.002, respectively), whereas calbindin levels were increased eightfold (P < 0.0001). We report novel time-dependent changes in the urinary excretion of noninvasive markers of subclinical kidney injury after cisplatin treatment.

Figure 1. Time-Dependent Changes in Absolute Urinary Concentrations of Protein Biomarkers following Cisplatin Infusion

Urinary protein concentrations were measured using a Bio-Plex assay at baseline (n=57), 3 (range of 2-5, n=50) days and 10 (range of 9-11, n=47) days post cisplatin-infusion during the first or second cycle of chemotherapy. Concentrations were measured in urine supernatants and presented as ng/mL. Scatter plots show individual levels (n=57) and mean ± SD concentration at each time point. Solid lines represent statistically significant differences (p<0.05) compared to baseline protein levels.