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Urinary clusterin, cystatin C, β2-microglobulin and total protein as markers to detect drug-induced kidney injury


Earlier and more reliable detection of drug-induced kidney injury would improve clinical care and help to streamline drug-development. As the current standards to monitor renal function, such as blood urea nitrogen (BUN) or serum creatinine (SCr), are late indicators of kidney injury, we conducted ten nonclinical studies to rigorously assess the potential of four previously described nephrotoxicity markers to detect drug-induced kidney and liver injury. Whereas urinary clusterin outperformed BUN and SCr for detecting proximal tubular injury, urinary total protein, cystatin C and β2-microglobulin showed a better diagnostic performance than BUN and SCr for detecting glomerular injury. Gene and protein expression analysis, in-situ hybridization and immunohistochemistry provide mechanistic evidence to support the use of these four markers for detecting kidney injury to guide regulatory decision making in drug development. The recognition of the qualification of these biomarkers by the EMEA and FDA will significantly enhance renal safety monitoring.

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Figure 1: Receiver operator characteristic (ROC) analyses for animals from all ten rat studies demonstrating sensitivity and specificity of BUN, SCr and urinary clusterin with respect to a composite histopathology score for tubular injury.
Figure 2: Marker levels for proximal tubular injury.
Figure 3: ROC exclusion analysis for animals from all ten studies demonstrating sensitivity and specificity of BUN, SCr, urinary cystatin C, urinary β2-microglobulin and urinary total protein with respect to a composite histopathology score for glomerular alterations and/or damage.
Figure 4: Marker levels for glomerular injury.
Figure 5: Marker levels for glomerular injury.
Figure 6: Localization of clusterin, β2-microglobulin and cystatin C in kidneys.

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S. Leuillet and B. Palate from CIT are acknowledged for performing the in-life studies and the histopathology assessment. J. Mapes and D. Eisinger from Rules-Based Medicine are acknowledged for the development of the luminex assays. We thank the D. Moor and P. Brodmann from Biolytix for the validation and measurements of the RT-PCR assays.

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Authors and Affiliations



F.D. supervised the project, performed the data analysis and prepared the manuscript, E.P. designed the studies, supervised the histopathology and edited the manuscript, A.C. designed the studies and edited the manuscript, D.R.R. designed the studies, supervised the histopathology and edited the manuscript, P.V. performed the data analyses and edited the manuscript, O.G. performed the genomic analyses, S.P. performed the in situ hybridization and immunohistochemistry analyses and edited the manuscript, P.M. performed the in situ hybridization and immunohistochemistry and edited the manuscript, D.W. designed the database, A.M. designed the studies and edited the manuscript, P.E. performed the protein extraction and edited the manuscript, F.S. designed the studies and edited the manuscript, F.L. supervised the protein analyses, K.C. performed the regulatory submission and edited the manuscript, D.L. performed the regulatory submission and edited the manuscript, S.-D.C. supervised the project, J.V. supervised the project and G.M. supervised the project, designed the studies and edited the manuscript.

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Correspondence to Frank Dieterle.

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Competing interests

All authors are employees of Novartis.

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Data (XLS 441 kb)

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Dieterle, F., Perentes, E., Cordier, A. et al. Urinary clusterin, cystatin C, β2-microglobulin and total protein as markers to detect drug-induced kidney injury. Nat Biotechnol 28, 463–469 (2010).

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