Aminophylline for Acute Kidney Injury After Pediatric Cardiac Surgery

Since the publication of acute kidney injury (AKI) definitions, many studies have shown that AKI in critically ill children is a strong risk factor of hospital morbidity (longer ventilation and hospital stay) and mortality (1, 2). AKI may incur risk of chronic kidney disease (3). These studies have contributed to the paradigm shift in thinking that children do not only die with AKI but that AKI independently contributes to poor outcome. A large amount of research is devoted to validating new biomarkers of AKI for early diagnosis. The essential missing piece to the AKI puzzle has been identifying AKI treatments; despite several therapies proven in animals, almost no human studies have demonstrated benefit of pharmacologic therapies to treat AKI. There is, thus, international consensus that AKI treatments must be evaluated for their effect on AKI prevalence and improving outcomes, in order to move this field forward. Yet, almost no AKI clinical trials have been performed. It is no light endeavour to begin studying treatments in pediatric diseases, where almost no treatments have been tried before. In this issue of Pediatric Critical Care Medicine, Axelrod et al (4) have taken that big needed step. They report a single-center double-blinded randomized clinical trial of aminophylline versus placebo to treat AKI in 144 children undergoing cardiac surgery (CS) with cardiopulmonary bypass (CPB). The intervention was initiated about 4 hours after admission to postoperative ICU and then every 6 hours for 72 hours. Aminophylline did not reduce postoperative AKI (60% aminophylline vs 50% placebo). Their choice to investigate aminophylline was rational. Aminophylline is a renal vasodilator that competitively antagonizes adenosine-induced afferent vasoconstriction and attenuates efferent arteriolar dilatation (5). In fact, theophylline (closely related to aminophylline) is the only drug recommended for treating AKI in the Kidney Disease: Improving Global Outcomes guidelines (6), a recommendation limited to asphyxiated neonates, because of several clinical trials demonstrating benefits (7). Given the role of ischemia in CS-AKI pathophysiology, it makes sense to study aminophylline. Despite concerns about negative effects of aminophylline in young children, the authors confirmed that it was well tolerated. Another benefit of aminophylline is that serum levels may be measured. The choice of study population was ideal. CS-AKI prevalence is well described and repeatedly shown to be associated with outcome. Timing of CS-AKI occurrence is known (during surgery and CPB), facilitating intervention planning. The CS population is relatively homogeneous, reducing “noise” in interpreting results. The authors note that their decision to restrict the study to patients with a predicted ICU stay of at least 3 days may have impacted generalizability. However, this was the right thing to do as 1) this increased likelihood of completing the study procedures and 2) patients admitted to the ICU for less than 3 days are probably at lower AKI risk. If the drug was unhelpful in high-risk patients, it would unlikely be helpful in lower risk patients. The groups were balanced in characteristics, except for a higher intervention group proportion with prior CS. This may have been associated with higher AKI prevalence in the intervention group, but it unlikely explains the lack of aminophylline treatment effect. Given prior literature, it could be argued that aminophylline may have benefitted neonates only, but the study was not powered to examine subgroups. A main limitation to this study was the timing of aminophylline intervention that was only several hours postoperatively. AKI occurs early after CS, and AKI biomarkers rise within hours of CPB (1, 8). Given knowledge that early intervention is key to AKI prevention, their intervention may have simply been given too late; thus, this study did not address AKI “prevention” but AKI “treatment.” Clearly, one solution would have been to treat preoperatively or at the time of CPB. However, another potential solution for future studies might be to include patients who, at the time of intervention, do not yet have serum creatinine (SCr) rise or better yet, rise in AKI biomarkers. It is likely that many patients in this study had AKI at the time of intervention. The authors found no difference in plasma neutrophil gelatinase-associated lipocalin between intervention and control groups. However, in a large study of children undergoing CS, it was urine AKI biomarkers and not plasma markers, which were most strongly associated with AKI (8). Future studies should consider using urine biomarkers for intervention versus placebo group comparisons. The authors used SCr to define AKI. This is reasonable because current AKI definition is SCr based (6). They should not be faulted for ignoring urine criteria for AKI definition because these criteria have not been well studied or validated in children. However, there is an issue in that neonatal AKI definition differs from definition in older children (9). Using preoperative SCr for defining AKI may be inappropriate in neonates given that SCr decreases physiologically in early life. That said, the age distribution between intervention and placebo groups was similar; thus, this issue unlikely affected final study conclusions. Finally, given that SCr is not an accurate marker of renal function, it would be interesting in future studies to define AKI using serum cystatin C, which is less affected by nonrenal factors and is a more accurate marker of renal function (10, 11), and determine if this leads to differences in conclusions of intervention effects on AKI prevalence. AKI clinical trials are desperately needed. All published evidence to date shows that AKI impacts negatively on outcome. We need to know whether this is true, and if so, we need to do something about it. The study by Axelrod et al (4) was a brave step in the right direction, the direction that AKI research needs to go in. They showed that such studies are feasible. Although this was a negative study, the limitations above must be acknowledged (and were by the authors), and aminophylline cannot be discounted yet. Future studies should focus on finding the right dose, using the most accurate methods for evaluating renal injury (including biomarkers, age-specific AKI definitions), but most importantly, they should focus on AKI “prevention” and not treatment. This study by Axelrod et al (4) will likely be a springboard for many future child AKI intervention trials.

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