Urinary 28-kD Calbindin-D as a New Marker for Damage to Distal Renal Tubules Caused by Cisplatin-Based Chemotherapy

Abstract

Calbindin-D, a vitamin D-dependent calcium-binding protein of 28 kD, is found predominantly in the distal tubules of the kidney and central nervous system tissues in humans. To evaluate damage to the renal tubules caused by cisplatin-based chemotherapy, levels of urinary and serum calbindin-D were determined in patients treated with cisplatin- or carboplain-based chemotherapies using a highly sensitive enzyme immunoassay system developed in our laboratory. Levels of urinary 28-kD calbindin-D were also determined in patients with benign and malignant urological diseases. The mean urinary calbindin-D level was 2.44 ± 0.31 (mean ± SE) ng/mg creatinine in 40 healthy subjects. Urinary calbindin-D levels were elevated ( > 10 ng/mg creatinine) in 2 of 33 patients (6%) with benign and 1 of 50 (2%) with malignant urological diseases. Urinary calbindin-D levels were significantly increased after cisplatin-based chemotherapy in 14 patients, with peaks (71.8 ± 13.5 ng/mg creatinine) being found 8 days after administration of cisplatin, and then a gradual return to the baseline. On the other hand, 7 patients receiving carboplatin-based chemotherapy demonstrated no significant elevation (highest level 7.7 ± 2.5 ng/mg creatinine). In 7 patients treated with cisplatin-based chemotherapy the serum calbindin-D level was also raised after treatment, with a good correlation to urinary values. These findings suggest that urinary and serum calbindin-D may be kidney-derived and that 28-kDa calbindin-D is a useful marker for damage to the distal renal tubules associated with cisplatin-based chemotherapy.

Characterization of renal biomarkers for use in clinical trials: biomarker evaluation in healthy volunteers

“…Therefore, a smaller difference between predose and postdose values of KIM-1 would be needed to classify a compound as nephrotoxic compared with calbindin. However, there was an approximately 30-fold difference in calbindin levels (normalized to creatinine) between healthy volunteers and subjects treated with cisplatin,34 that is well above the 60% intrasubject variability. Thus, none of the biomarkers should be excluded from progressing into the next steps of biomarker qualification based on intrasubject variability.…”

An Extensive Targeted Proteomic Analysis of Disease-Related Protein Biomarkers in Urine from Healthy Donors

“…HSA is the most abundant protein in blood plasma and it is estimated that approximately 0.06% of plasma albumin is transferred into urine through glomerular filtration [22]. Several other members of class 1 have been previously examined as biomarkers of renal and urological health including calbindin [23], clusterin [24]–[26], A1A [27]–[29], and MPO [30]. Urine levels of OPN, a multifunctional protein implicated in bone remodeling and inflammation, have been associated with rheumatoid arthritis and ovarian cancer [4], [31].…”

Meso Scale Discovery and Luminex Comparative Analysis of Calbindin D28K

“…Similar to the Luminex assay, this assay had a lld equivalent to 100 pg/mL. While the earlier-described immunoassay detected calbindin D28K in healthy individuals [5], urinary analysis of both normal rats and human indicated that the calbindin D28K level was below the detection limit in both the MSD and Luminex immunoassay (data not shown). Furthermore, it was not possible to accurately measure urinary spiked recombinant calbindin D28K, due to the recombinant protein instability in urine.…”

“…Previous studies have demonstrated the inhibitory effect of nephro-toxicants such as Cyclosporin A on the expression of calbindin D28K in distal tubules [4]. Furthermore, urinary analysis of patients treated with Cisplatin as well as patients treated by extracorporeal shock wave lithotripsy has indicated that the expression of calbindin D28K can be increased under pathological conditions [5, 6]. The specific localization of calbindin D28K in distal tubules along with its pathophysiological release in urine makes this protein a potential biomarker for distal tubule damage.…”