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New biomarker-based strategies for a preventive and personalized diagnosis of acute kidney injury

Author:

Francisco J. López-Hernández

IBSAL-IECSCYL, University of Salamanca
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Abstract

Acute kidney injury (AKI) is a very relevant and increasing health and socioeconomic problem worldwide. In critically ill patients, mortality to AKI may reach up to 50-80% of the cases. Even mild, spontaneously reversible episodes of AKI have a significant impact on medium and long term morbidity and mortality. Drug nephrotoxicity is among the most important causes of AKI, with 25% of the 100 most used drugs in intensive care units being nephrotoxic. AKI has been traditionally diagnosed when extensive renal damage gave way to signs derived from renal dysfunction, such as the elevation of plasma creatinine concentration, according to well established methods of stratification, including the AKIN and RIFLE criteria. In the last decade, further advance was provided by the identification of earlier markers of kidney injury, including KIM-1 and NGAL. Yet, more sensitive and specific markers, or combinations of markers, are needed to improve AKI diagnosis. However, new facets of AKI diagnosis emerge for a more personalized and preventive handling of this disease. In the last years, our group has been working on two new diagnostic concepts, namely: i) pre-emptive detection of drug-induced predisposition to AKI, as differentiated from early diagnosis; and ii) aetiological (drug-specific) diagnosis of AKI, potentially applicable to polymedicated patients.

Drug-induced predisposition to acute renal failure (ARF) is a facet of nephrotoxicity hitherto mostly uncharacterized, quite underestimated, and impossible to diagnose, which potentially has a high human and socioeconomic impact. Our study has identified urinary GM2AP as the first of a new class of biomarkers of the enhanced risk of suffering an acute renal failure after a subnephrotoxic treatment with gentamicin. Gentamicin-predisposed animals with no sign of renal injury develop ARF when exposed to a second potentially nephrotoxic drug, also given at subnephrotoxic doses that are harmless to non-predisposed individuals. Subnephrotoxic gentamicin did not alter renal GM2AP gene expression or protein levels, determined by RT-PCR and Western blot and immunostaining, respectively, nor was its serum level modified. Further experiments indicate that, likely, the origin of the increased level of GM2AP in the urine might be a defective tubular handling of this protein as a consequence of gentamicin action. Markers of risk may revolutionize the prevention of ARF by enhancing our monitoring capacity of acquired predisposition to ARF, in a pre-emptive manner. With regard to the aetiological diagnosis of drug nephrotoxicity, we have identified regenerating isletderived protein III beta (reg IIIb) and gelsolin as potentially differential urinary markers of gentamicin’s nephrotoxicity. Indeed, both reg IIIb and gelsolin urinary levels differentiate the nephrotoxicity caused by gentamicin from that caused by cisplatin. Reg IIIb is over-expressed in the kidneys of gentamicin-treated rats and poured into the urine, whereas gelsolin proceeds from the glomerular ultrafiltrate. Our results pose a proof-of-concept for the aetiological diagnosis of AKI through the biochemical analysis of the urine, with potential application for an enhanced drug theranostic and a more personalized medicine of polimedicated and critically ill patients at multifactorial risk of AKI. Furthermore, our studies have identified new urinary markers that differentiate ischemic from toxic acute kidney injury.

How to Cite: López-Hernández, F.J., (2015). New biomarker-based strategies for a preventive and personalized diagnosis of acute kidney injury. New Horizons in Translational Medicine. 2(2), p.56. DOI: http://doi.org/10.1016/j.nhtm.2014.11.005
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Published on 07 Feb 2015.
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