Novel urinary kidney safety biomarkers have been identified recently that may outperform or add value to the conventional renal function biomarkers, blood urea nitrogen (BUN) and serum creatinine (SCr). To assess the relative performance of the growing list of novel biomarkers, a comprehensive evaluation was conducted for 12 urinary biomarkers in 22 rat studies including 12 kidney toxicants and 10 compounds with toxicities observed in organs other than kidney. The kidney toxicity studies included kidney tubular toxicants and glomerular toxicants. The 12 urinary biomarkers evaluated included Kim-1, clusterin, osteopontin, osteoactivin, albumin, lipocalin-2, GST-α, β2-microglobulin, cystatin C, retinol binding protein 4, total protein, and N-acetyl-β-D-glucosaminidase. Receiver operator characteristic (ROC) curves were generated for each biomarker and for BUN and SCr to compare the relative performance of the 12 biomarkers in individual animals against the microscopic histomorphologic changes observed in the kidney. Among the kidney toxicity biomarkers analyzed, Kim-1, clusterin, and albumin showed the highest overall performance for detecting drug-induced renal tubular injury in the rat in a sensitive and specific manner, whereas albumin showed the highest performance in detecting drug-induced glomerular injury. Although most of the evaluated kidney biomarkers were more sensitive in detecting kidney toxicity compared with BUN and SCr, all biomarkers demonstrated some lack of specificity, most notably NGAL and osteopontin, illustrating the need for caution when interpreting urinary biomarker increases in rat samples when organ toxicity is unknown.
Traditional kidney biomarkers are insensitive indicators of acute kidney injury, with meaningful changes occurring late in the course of injury. The aim of this work was to demonstrate the diagnostic potential of urinary osteopontin (OPN) and neutrophil gelatinase-associated lipocalin (NGAL) for drug-induced kidney injury (DIKI) in rats using data from a recent regulatory qualification submission of translational DIKI biomarkers and to compare performance of NGAL and OPN to five previously qualified DIKI urinary biomarkers. Data were compiled from 15 studies of 11 different pharmaceuticals contributed by Critical Path Institute's Predictive Safety Testing Consortium (PSTC) Nephrotoxicity Working Group (NWG). Rats were given doses known to cause DIKI or other target organ toxicity, and urinary levels of the candidate biomarkers were assessed relative to kidney histopathology and serum creatinine (sCr) and blood urea nitrogen (BUN).OPN and NGAL outperformed sCr and BUN in identifying DIKI manifested as renal tubular epithelial degeneration or necrosis. In addition, urinary OPN and NGAL, when used with sCr and BUN, increased the ability to detect renal tubular epithelial degeneration or necrosis. NGAL and OPN had comparable or improved performance relative to Kim-1, clusterin, albumin, total protein, and beta-2 microglobulin. Given these data, both urinary OPN and NGAL are appropriate for use with current methods for assessing nephrotoxicity to identify and monitor DIKI in regulatory toxicology studies in rats. These data also support exploratory use of urinary OPN and NGAL in safety monitoring strategies of early clinical trials to aid in the assurance of patient safety.
Drug-associated vascular injury can be caused by phosphodiesterase (PDE) IV inhibitors and drugs from several other classes. The pathogenesis is poorly understood, but it appears to include vascular and innate immunological components. This research was undertaken to identify changes in peripheral blood associated with vascular injury caused by PDE IV inhibitors. We evaluated twelve proteins, serum nitrite, and leukocyte populations in peripheral blood of rats treated with experimental PDE IV inhibitors. We found that these compounds produced histological microvascular injury in a dose-and time-dependent manner. Measurement of these serum proteins showed changes in eight of the twelve examined. Changes were seen in the levels of: tissue inhibitor of metalloproteinase-1, α1-acid glycoprotein, GRO/CINC-1, vascular endothelial growth factor, C-reactive protein, haptoglobin, thrombomodulin, and interleukin-6. No changes were seen in levels of tumor necrosis factor-α, hepatocyte growth factor, nerve growth factor, and granulocyte-monocyte colony stimulating factor. Serum levels of nitrite were also increased. Circulating granulocyte numbers were increased, and lymphocyte numbers were decreased. The changes in these parameters showed both a dose-and timedependent association with histopathologic changes. These biomarkers could provide an additional tool for the nonclinical and clinical evaluation of investigational compounds.
Newer urinary protein kidney safety biomarkers can outperform the conventional kidney functional biomarkers blood urea nitrogen (BUN) and serum creatinine (SCr) in rats. However, there is far less experience with the relative performance of these biomarkers in dogs and nonhuman primates. Here, we report urine protein biomarker performance in tenofovir-treated cynomolgus monkeys and beagle dogs. Tenofovir intravenous daily dosing in monkeys for 2 or 4 weeks at 30 mg/kg/day resulted in minimal to moderate tubular degeneration and regeneration, and tenofovir disoproxil fumarate oral dosing in dogs for 10 days at 45 mg/kg/day resulted in mild to marked tubular degeneration, necrosis, and regeneration. Among biomarkers tested, kidney injury molecule 1 (Kim-1) and clusterin (CLU) clearly outperformed BUN and SCr and were the most reliable in detecting the onset and progression of tenofovir-induced tubular injury. Cystatin C, retinol binding protein 4, β2-microglobulin, neutrophil gelatinase-associated lipocalin, albumin, and total protein also performed better than BUN and SCr and added value when considered together with Kim-1 and CLU. These findings demonstrate the promising utility of these urinary safety biomarkers in monkeys and dogs and support their further evaluation in human to improve early detection of renal tubular injury.
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