Adverse effects of α-ketoglutarate/malate in a rat model of acute kidney injury.

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.