In our study, the incidence of AKI among asphyxiated neonates receiving therapeutic hypothermia is 35%. Our study reveals that there were 13 (57%) patients whose diagnosis of AKI was made after 72-h of age. Although certain characteristics including a lower gestational age, lower hemoglobin level at birth, higher lactate before and after therapeutic hypothermia and higher troponin-I after therapeutic hypothermia appeared to be statistically significant on our initial univariate analysis, only a higher troponin-I level after therapeutic hypothermia stood out to be independently associated with AKI, especially at level > 0.3 ng/ml. This is the first study to associate a common biochemical marker, troponin-I, with the occurrence of AKI in asphyxiated neonates undergoing therapeutic hypothermia.
In the past, comparison of studies on neonatal AKI among asphyxiated neonates was difficult as different diagnostic criteria were used. Definitions frequently used included using an absolute SCr > 1.5 mg/dl, the pediatric Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (pRIFLE) and Acute Kidney Injury Network (AKIN)12,13,14,15. In 2013, the neonatal modified KDIGO criteria was proposed as a standardized definition to allow for consistency throughout studies7. A number of studies on AKI in very low birth weight infants (VLBW) have utilized this definition16,17 but only two studies on AKI in asphyxiated neonates have used the neonatal modified KDIGO definition. Both Selewski et al. and Sarkar et al. investigated the incidence of AKI in asphyxiated neonates who underwent therapeutic hypothermia and have reported an incidence of 38% and 39% respectively using this definition18,19. The findings of these studies are consistent with the results of our study, reporting an incidence of 35% AKI among neonates with perinatal asphyxia who undergo therapeutic hypothermia.
The various definitions used to define AKI in neonates, including the neonatal modified KDIGO criteria are based on serum creatinine or urine output. Most studies on neonatal AKI have used SCr and its changes as the sole criteria for AKI. However, using a creatinine-based definition has its limitations. SCr is a marker of kidney function and not damage. Thus, a delay of 48–72 h rise of SCr is observed after an insult and about 50% of glomerular filtration rate has to be lost before an increase in SCr is evident20,21. This has led to intensification of research on biomarkers that would allow for earlier identification of AKI. Novel biomarkers that have shown promising results includes the urine neutrophil gelatinase-associated lipocalin, cystatin-c, kidney injury molecule-1, and interleukin-1822. However, these biomarkers are not available in most settings. The results of our study show that the level of cardiac troponin-I after 72-h of therapeutic hypothermia can help clinicians identify those at risk of AKI with a delayed rise in SCr.
The cardiac troponin-I is a specific cellular marker released by cardiomyocytes during cardiac injury. In neonates with perinatal asphyxia, it is a well-established marker for detection of myocardial ischemic changes and its levels correlate with the severity of hypoxic ischemic insult23,24,25. A randomized controlled trial by Rakesh et al. found that the troponin-I level decreased significantly in asphyxiated neonates who underwent hypothermia when compared with the normothermia group26. Another study by Liu et al. also suggested that hypothermia was cardio-protective in neonates with perinatal asphyxia, observing a significant reduction of cardiac troponin-I release following the therapeutic hypothermia27. In our study, this cardio-protective effect was observed in the non-AKI group, with the median troponin-I decreasing to normal after 72-h of therapeutic hypothermia while that in the AKI group remained high at 0.47 ng/ml.
The relationship between troponin-I and acute kidney injury in asphyxiated neonates can be explained by two possible mechanisms. First the higher level of troponin-I in the AKI group before and after therapeutic hypothermia could be due to a more severe degree myocardial injury, leading to decreased perfusion of the kidneys. This is also reflected in the higher lactate levels both before and after therapeutic hypothermia in the AKI group. Secondly, the impaired renal function in the AKI group could affect the excretion of troponin-I, causing the levels to remain high despite receiving therapeutic hypothermia. In adults, a study by Song et al. found that cardiac troponins including troponin-I were found to be elevated in subjects with AKI. In this study, patients with conditions known to cause elevated troponins were excluded, suggesting that impaired renal function during AKI is sufficient to influence the clearance of plasma troponins28. To date, there has been no studies in neonates linking AKI with the level of cardiac troponin-I.
Our study showed that with a cut-off value of troponin-I at 0.3 ng/ml after therapeutic hypothermia, the ROC yielded an AUC of 0.858 indicating troponin-I as good predictive tool for AKI at this value. This finding is important as it could provide clinician with the first clue of AKI in more than 50% of the asphyxiated neonates undergoing therapeutic hypothermia. With earlier recognition of AKI, management strategies including judicious use of fluids and diuretics, correction of acid–base and electrolyte imbalance, avoidance of nephrotoxic drugs could prevent further injury to the poorly functioning kidney.
Despite the significant findings of our study, we acknowledge that there are important limitations. Due to its retrospective design, the SCr data used for diagnosis of AKI was based on our standardized protocol for asphyxiated neonates undergoing therapeutic hypothermia. According to our therapeutic hypothermia protocol, the troponin-I is measured only before and after therapeutic hypothermia. Thus, whether a 24-h or 48-h troponin-I would allow for earlier prediction of AKI is a question yet to be answered by future prospective studies. Although limited by our small sample size, we report an incidence of AKI in asphyxiated neonates undergoing therapeutic hypothermia which is similar to the only two other studies that have used the recommended neonatal modified KDIGO criteria. We also highlight the use troponin-I level following therapeutic hypothermia to predict AKI. In patients whose rise in SCr is delayed beyond 72-h, this can be helpful to clinicians in making clinical judgements and thereby improving the outcome of these patients.