fumarates and Kidney-Tubular-Necrosis--Acute

Acute kidney injury (AKI) is a common and important medical problem, affecting 10% of hospitalized patients, and it is associated with significant morbidity and mortality. The most frequent cause of AKI is acute tubular necrosis (ATN). Current imaging techniques and biomarkers do not allow ATN to be reliably differentiated from important differential diagnoses, such as acute glomerulonephritis (GN). We investigated whether (13)C magnetic resonance spectroscopic imaging (MRSI) might allow the noninvasive diagnosis of ATN. (13)C MRSI of hyperpolarized [1,4-(13)C(2)]fumarate and pyruvate was used in murine models of ATN and acute GN (NZM2410 mice with lupus nephritis). A significant increase in [1,4-(13)C(2)]malate signal was identified in the kidneys of mice with ATN early in the disease course before the onset of severe histological changes. No such increase in renal [1,4-(13)C(2)]malate was observed in mice with acute GN. The kidney [1-(13)C]pyruvate/[1-(13)C]lactate ratio showed substantial variability and was not significantly decreased in animals with ATN or increased in animals with GN. In conclusion, MRSI of hyperpolarized [1,4-(13)C(2)]fumarate allows the detection of early tubular necrosis and its distinction from glomerular inflammation in murine models. This technique may have the potential to identify a window of therapeutic opportunity in which emerging therapies might be applied to patients with ATN, reducing the need for acute dialysis with its attendant morbidity and cost.

Topics: Animals; Carbon Isotopes; Early Diagnosis; Folic Acid; Fumarates; Humans; Kidney; Kidney Tubular Necrosis, Acute; Kinetics; Lupus Nephritis; Magnetic Resonance Imaging; Malates; Mice; Mice, Inbred C57BL; Pyruvic Acid

Reduction of naphthoquinones by DT-diaphorase is often described as a detoxification reaction. This is true for some naphthoquinone derivatives, such as alkyl and di-alkyl naphthoquinones, but the situation with other substances, such as 2-hydroxy-1,4-naphthoquinone, is more complex. In the present study, the effect of several substances that are known to increase tissue activities of DT-diaphorase on the toxicity of 2-amino-1,4-naphthoquinone has been investigated. Like 2-hydroxy-1,4-naphthoquinone, the 2-amino-derivative was found to cause both haemolytic anaemia and renal tubular necrosis in rats. Again like 2-hydroxy-1,4-naphthoquinone, the severity of the haemolysis induced by the 2-amino derivative was increased in animals pre-treated with inducers of DT-diaphorase, but the degree of nephrotoxicity was decreased. With these substances, therefore, DT-diaphorase both activates and detoxifies the quinone, depending on the target organ. It is not possible to generalize with regard to the effects of modulation of tissue levels of DT-diaphorase on naphthoquinone toxicity in vivo, since this may change not only the severity of the toxic effects, but also the target organ specificity. In evaluating the possible therapeutic applications of such compounds, the possibility of toxic effects upon the blood and kidney must be borne in mind. In man, renal damage by compounds such as 2-hydroxy- and 2-amino-1,4-naphthoquinone may be a particular problem, because of the low level of DT-diaphorase in human liver.

Topics: Anemia, Hemolytic; Animals; Biotransformation; Butylated Hydroxyanisole; Butylated Hydroxytoluene; Dimethyl Fumarate; Disulfiram; Enzyme Induction; Ethoxyquin; Female; Fumarates; Hemolysis; Inactivation, Metabolic; Kidney; Kidney Tubular Necrosis, Acute; NAD(P)H Dehydrogenase (Quinone); Naphthoquinones; Rats; Rats, Sprague-Dawley