some time has passed, for example, after a biopsy has been taken or a necropsy performed.

  • It should be translational; that is, it should bridge across species.

  • It should be associated with a known mechanism. Many current biomarkers are identified through statistical analysis of gene expression, as discussed in Chapter 4, but one should be able to understand the biomarker and what is really going on in a biomolecular sense when it appears.

  • A biomarker should be able to localize damage. For example, it should pinpoint the particular area of the kidney that has been damaged rather than just indicating kidney toxicity in general.

Given this extensive list of characteristics, a panel of biomarkers rather than any single ideal biomarker will likely be needed to characterize nephrotoxicity.

QUALIFICATION OF NEPHROTOXICITY BIOMARKERS

Before attempting to establish pathways for clinical qualification of biomarkers, Novartis qualified a set of nephrotoxicity biomarkers in animals. The qualification study was performed with 10 compounds: 8 nephrotoxicants plus 2 hepatotoxicants as negative controls. For each compound, the researchers used 96 rats: four dose levels, including the control, which was a zero dose; four termination time points; and six animals per group. The duration of each exposure was 2–3 weeks. In addition to the traditional toxicology analysis, the researchers performed gene expression analysis on kidney and liver tissue and also multiplex ELISA (enzyme-linked immunosorbent assay) on kidney, liver, urine, and plasma.

The nephrotoxicants were chosen to have a variety of modes of toxicity, including oxidative stress and damage to podocytes. The hepatotoxicants were known to cause cholangitis and liver cancer. The team chose 15 biomarkers, representing 85 percent of the markers being used by the Predictive Safety Testing Consortium (PSTC),2 from various sources and publications, including some early gene expression work and some known proteomics work. The researchers attempted not to be selective about the source of the markers and to cover most of those that were interesting. Before running the studies, they performed a series of prestudies on the nephrotoxicants, in which they determined the correct doses to create lesions between grades 1 and 3.

2

The PSTC public–private partnership, comprising members from industry, academia, and government, was established to identify and clinically qualify safety biomarkers. Novartis is a participant in the PSTC’s efforts to identify and qualify nephrotoxicity biomarkers.



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