Preventing Acute Kidney Injury (AKI) in Neonates

  • STATUS
    Recruiting
  • End date
    Feb 1, 2022
  • participants needed
    120
  • sponsor
    Le Bonheur Children's Hospital
Updated on 23 January 2021

Summary

The purpose of the study is compare the effects of peri-operative administration of aminophylline (non-specific adenosine receptor antagonist) versus saline placebo in the preservation of renal function and the attenuation of renal injury in newborns, and young infants following cardiac palliative/correction surgery.

The study rationale is 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.

Description

Cardiac palliative/ correction surgeries in the newborns, infants, and children involve significant morbidity and mortality risks. Kidney function is frequently affected from cardiothoracic 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 complexity of the underlying heart disease and the surgical procedure, duration of cardiopulmonary by-pass, 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.

Newborns (term and preterm) and young infants are known to have physiological renal failure with their glomerular filtration rates (GFR) averaging 25-35 ml/min/1.73 m2. The newborn renal vasculature constriction response to intravascular depletion or poor renal perfusion is more vigorous than an older kidney's response. This adaptive response to preserve the intravascular volume and tonicity cannot be easily reversed even if the perfusion pressures are restored. Renal adenosine and Angiotensin II (AT-II) are important intra-renal vasoconstrictors resulting in worsening GFR and diuretic resistance. The young kidney is dependent on Angiotensin II-mediated efferent arteriole vasoconstriction to maintain GFR. Therefore, AT-II blockade in newborns and young infants results in oligo-anuric acute kidney injury and is not a safe option in this age group. However, blocking the actions of adenosine may restore the glomerular blood flow and recover GFR.

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 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.

Adenosine has documented effect through its other receptors that are also important in renal ischemia-reperfusion injury (IRI). A2a receptors (A2a R, glomerular epithelium and capillaries cortex, medulla, whole kidney) are an example of this action and they are also widely distributed both in the renal as well as non-renal tissues. Several functional studies have shown that activation of A2a R positively affects the glomerular filtration rate and can reverse the vasoconstriction of AT II on the descending vasa recta. Both the afferent and efferent vasodilatory responses of adenosine can be blocked by specific A2A R antagonists. The above information suggests that while adenosine can contribute negatively to IRI with vasoconstriction through A1 R, there might be some beneficial action through the activation of A2a R.

The impact of adenosine and its blockade goes actually beyond its effect on the afferent and efferent arterioles. It was shown that both infusions of adenosine and the selective A2a R agonists protected the kidney after IRI. Rat kidney studies showed that kidney damage was significantly reduced when an A2a R agonist (ATL146e) was infused prior to or at the same time of IRI. This positive effect had a dose-response curve and was independent of the vascular effects of adenosine. Similar protection for IRI was achieved with A2a R agonists when the target organ was the bowel, heart, lungs or the spinal cord, suggesting a common pathway for ischemia-reperfusion related tissue injury. The immune response has since been nominated for being the common mechanism. There is now evidence that bone marrow-derived cells are the primary target of A2a R agonists and the damage of IRI requires more than vasoactive responses including macrophages, neutrophils, T-lymphocytes and even platelets. All these cells harbor A2a R and specific activation of this receptor on the cluster of differentiation 4 (CD4) T-lymphocytes may be responsible for protection from IRI. The above information suggests that uniformly blocking all adenosine action during IRI may not be the best strategy and A1 R blockade along with A2a R stimulation may offer a better outcome.

Details
Condition Renal Failure, Acute renal failure, Kidney Failure (Pediatric), Kidney Failure, acute kidney injury, acute kidney injuries
Treatment placebos, Aminophylline
Clinical Study IdentifierNCT03897335
SponsorLe Bonheur Children's Hospital
Last Modified on23 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Cohort 1
All children undergoing open heart surgery for congenital heart defects with
or
without circulatory arrest
Neonates (<28 days old) and infants (<1 years of age)
Hypoplastic L heart syndrome or its variants
Coarctation with aortic arch hypoplasia
Interrupted aortic arch
TAPVR (Total anomalous pulmonary venous return)
Patients with complex congenital heart defects
Cohort 2
Orthotopic heart transplantation patients
Congenital heart defects
Cardiomyopathy (Dilated/ hypertrophic)

Exclusion Criteria

Children under the age of 12 months undergoing bypass for any condition that is not categorized as congenital heart defect
History of seizures
History of significant tachyarrhythmia
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