Preventing Acute Kidney Injury (AKI) in Pediatric Patients (AKI)

Description

Cardiac palliative/ correction surgeries in pediatric patients involve significant morbidity and mortality risks. Kidney function is frequently affected from cardiac surgery in these children. Studies identify the incidence of acute kidney injury (AKI) to be approximately 54% when defined by serum biomarkers (e.g. serum creatinine) and urine output criteria. The need for renal replacement therapy (RRT) for newborns and infants after cardiac surgery is reported as 2% to 17% in the literature. There are several reported risk factors for the development of AKI in this population. These are the complexities of the underlying heart disease and the surgical procedure, duration of cardiopulmonary bypass, functional single ventricle heart disease, circulatory arrest and low cardiac output syndrome in the post-operative period. AKI can cause worsening fluid overload compromising ventilation and lung function, predisposition to overwhelming infections and cytokine-mediated inflammatory state. The presence of AKI significantly increases the mortality that is associated with cardiac surgery in these very young patients, reported as high as 79% in the literature. There have been several reports suggesting that early intervention with AKI using renal replacement therapy (RRT) may improve patient mortality. Successful prevention strategies for AKI have not been reported for this high-risk population.

Adenosine has been demonstrated to regulate renal circulation and metabolism. It is a breakdown product of adenosine triphosphate/adenosine diphosphate (ATP/ADP) metabolism and accumulates in AKI. At baseline, the barely detectable renal parenchymal adenosine levels can increase to 10-100 times following an ischemic insult. These are typical seven trans-membrane spanning domains with a coupled G-protein at the intracellular end. Adenosine receptors are located ubiquitously in many tissues. Adenosine acts as a vasodilator in all other tissues but the renal parenchyma. The interaction of AT-II with adenosine converts adenosine to a vasoconstrictor in renal microvasculature. Adenosine acts on the A1 receptors (A1 R) in the afferent arterioles, causing reduced glomerular blood flow and glomerular filtration rate (GFR), as well as stimulating renin release from the kidney parenchyma. Adenosine plays an important role in generating the vasoconstrictive response in the renal vasculature to hypoxia and ischemia. Early interventions by blocking the actions of adenosine on A1 R may restore glomerular blood flow and recover GFR.

The study rationale is that Aminophylline and Theophylline are competitive non-selective inhibitors of adenosine. Therefore, even though aminophylline infusion (iv) has no effect on renal blood flow rate at baseline, it can ameliorate the decrease in renal blood flow rate following adenosine infusion. This property can improve renal function when the main mechanism of insult induces vasoconstriction. Both early and late administration of aminophylline protects renal function after ischemia-reperfusion injury in rats. Aminophylline has also been reported to successfully reverse newborn renal failure, prevent renal failure in perinatal asphyxia, and reverse acute kidney injury secondary to calcineurin induced nephropathy. Both theophylline and aminophylline have been used for prophylaxis of renal impairment during aorto-coronary bypass surgery in adults and the results have not been consistent for either a positive or negative effect. There have been no trials reported on the effect of aminophylline or theophylline to prevent or ameliorate acute kidney injury in children with congenital heart defects going through cardiac surgery.

Additionally, we are examining the components of serotonin biosynthesis to determine if these levels can act as markers of acute kidney injury in pediatric patients undergoing open heart surgery.

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