Biochemical mechanisms of nephrotoxicity: application for metabolomics

Abstract

This review describes biochemical pathways of nephrotoxicity and the application of metabolic biomarkers as they relate to nephrotoxicity. Specific and sensitive biomarkers constitute the missing link in the continuum of exposure to toxins and susceptibility, disease development and possible therapeutic intervention. Important requirements for biomarker development are a detailed understanding of biochemical pathways involved in nephrotoxicity, minimal invasiveness and capacity to screen large at-risk populations. Lastly, possible biomarker candidates should be organ specific and equally applicable in preclinical drug testing as well as in clinical care of patients. This review discusses four major metabolic pathways associated with disturbed renal homeostasis: i) direct metabolic evidence of abnormal excretion of endogenous metabolites; ii) disturbances in kidney osmolarity and renal osmolyte homeostasis; iii) impaired energy state followed by dysregulation of glucose, fatty acid and ketone body metabolism; and iv) oxidative stress in renal tissues. Each of these pathways can be monitored by specific surrogate markers in urine and blood using modern metabolomics technologies.

Keywords::

• drug-induced nephrotoxicity
• immunosuppressants
• metabolic biomarkers
• metabolomics
• NMR
• renal biochemistry
• transplantation

Acknowledgements

The authors would like to thank J Klein for his help with graphical design and A Merz for her help in preparing the manuscript.

Disclosure

This review was in part supported by a grant from the Foundation of Anesthesia Research and Education (C.U.N.) and P30 CA046934 (UCHSC Cancer Center Core Grant, N.J.S.).

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