Bienholz Anja, Reis Jonas, Sanli Pinar, de Groot Herbert, Petrat Frank, Guberina Hana, Wilde Benjamin, Witzke Oliver, Saner Fuat H, Kribben Andreas, Weinberg Joel M, Feldkamp Thorsten
Department of Nephrology, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.
Institute of Physiological Chemistry, University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.
BMC Nephrol. 2017 Apr 10;18(1):130. doi: 10.1186/s12882-017-0546-1.
Ischemia and reperfusion (I/R) is one of the major causes of acute kidney injury (AKI). Citrate reduces hypoxia-induced mitochondrial energetic deficits in isolated proximal tubules. Moreover, citrate anticoagulation is now frequently used in renal replacement therapy. In the present study a rat model of I/R-induced AKI was utilized to examine renal protection by citrate in vivo.
AKI was induced by bilateral renal clamping (40 min) followed by reperfusion (3 h). Citrate was infused at three different concentrations (0.3 mmol/kg/h; 0.6 mmol/kg/h and 1.0 mmol/kg/h) continuously for 60 min before and 45 min after ischemia. Plasma calcium concentrations were kept stable by infusion of calcium gluconate. The effect of citrate was evaluated by biomonitoring, blood and plasma parameters, histopathology and tissue ATP content.
In comparison to the normoxic control group bilateral renal ischemia led to an increase of creatinine and lactate dehydrogenase activity and a decrease in tissue ATP content and was accompanied by a drop in mean arterial blood pressure. Infusion of 1.0 mmol/kg/h citrate led to lower creatinine and reduced LDH activity compared to the I/R control group and a tendency for higher tissue ATP content. Pre-ischemic infusion of 1.0 mmol/kg/h citrate stabilized blood pressure during ischemia.
Citrate has a protective effect during I/R-induced AKI, possibly by limiting the mitochondrial deficit as well as by beneficial cardiovascular effects. This strengthens the rationale of using citrate in continuous renal replacement therapy and encourages consideration of citrate infusion as a therapeutic treatment for AKI in humans.
缺血再灌注（I/R）是急性肾损伤（AKI）的主要原因之一。柠檬酸盐可减少离体近端小管中缺氧诱导的线粒体能量缺陷。此外，柠檬酸盐抗凝目前常用于肾脏替代治疗。在本研究中，使用I/R诱导的AKI大鼠模型来检测柠檬酸盐在体内的肾脏保护作用。
通过双侧肾夹闭（40分钟），然后再灌注（3小时）诱导AKI。在缺血前60分钟和缺血后45分钟连续输注三种不同浓度（0.3 mmol/kg/h；0.6 mmol/kg/h和1.0 mmol/kg/h）的柠檬酸盐，持续60分钟。通过输注葡萄糖酸钙使血浆钙浓度保持稳定。通过生物监测、血液和血浆参数、组织病理学和组织ATP含量评估柠檬酸盐的作用。
与常氧对照组相比，双侧肾缺血导致肌酐和乳酸脱氢酶活性增加，组织ATP含量降低，并伴有平均动脉血压下降。与I/R对照组相比，输注1.0 mmol/kg/h柠檬酸盐导致肌酐降低，LDH活性降低，并且组织ATP含量有升高趋势。缺血前输注1.0 mmol/kg/h柠檬酸盐可使缺血期间血压稳定。
柠檬酸盐在I/R诱导的AKI期间具有保护作用，可能是通过限制线粒体缺陷以及通过有益的心血管作用。这加强了在连续性肾脏替代治疗中使用柠檬酸盐的理论依据，并鼓励考虑将柠檬酸盐输注作为人类AKI的一种治疗方法。
