title: Adverse effects of α-ketoglutarate/malate in a rat model of acute kidney injury.
abstract: Acute kidney injury (AKI) is the most common kidney disease in hospitalized patients with high mortality. Ischemia and reperfusion (I/R) is one of the major causes of AKI. The combination of α-ketoglutarate+malate (αKG/MAL) showed the ability to reduce hypoxia-induced damage to isolated proximal tubules. The present study utilizes a rat model of I/R-induced AKI accompanied by intensive biomonitoring to examine whether αKG/MAL provides protection in vivo. AKI was induced in male Sprague-Dawley rats by bilateral renal clamping (40 min) followed by reperfusion (240 min). αKG/MAL was infused continuously for 60 min before and 45 min after ischemia. Normoxic and I/R control groups received 0.9% NaCl solution. The effect of αKG/MAL was evaluated by biomonitoring, blood and plasma parameters, histopathology, and immunohistochemical staining for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), as well as by determination of tissue ATP and nonesterified fatty acid concentrations. Intravenous infusion of αKG/MAL at a cumulative dose of 1 mmol/kg each (146 mg/kg αKG and 134 mg/kg MAL) did not prevent I/R-induced increases in plasma creatinine, histopathological alterations, or cortical ATP depletion. On the contrary, the most notable adverse affect in animals receiving αKG/MAL was the decrease in mean arterial blood pressure, which was also accompanied by a reduction in heart rate. Supplementation with αKG/MAL, which is very protective against hypoxia-induced injury in isolated proximal tubules, does not protect against I/R-induced renal injury in vivo, possibly due to cardiovascular depressive effects.
authors.affiliation: Department of Nephrology, University Duisburg-Essen, Germany. anja.bienholz@uk-essen.de
authors.forename: Anja
authors.initials: A
authors.lastname: Bienholz
authors.forename: Frank
authors.initials: F
authors.lastname: Petrat
authors.forename: Patricia
authors.initials: P
authors.lastname: Wenzel
authors.forename: Philipp
authors.initials: P
authors.lastname: Ickerott
authors.forename: Joel M
authors.initials: JM
authors.lastname: Weinberg
authors.forename: Oliver
authors.initials: O
authors.lastname: Witzke
authors.forename: Andreas
authors.initials: A
authors.lastname: Kribben
authors.forename: Herbert
authors.initials: H
authors.lastname: de Groot
authors.forename: Thorsten
authors.initials: T
authors.lastname: Feldkamp
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects*; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D007656:Ketoglutaric Acids / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008293:Malates / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control
chemical_list: D015815:Cell Adhesion Molecules; D007656:Ketoglutaric Acids; D008293:Malates; C110936:Havcr1 protein, rat; C030298:malic acid