Neonatal Acute Kidney Injury Association With Mortality—Culprit, Innocent Bystander, or Canary in the Coal Mine?

In their study on acute kidney injury (AKI) in extremely preterm infants, Aziz et al1 provide supportive information about the prevalence of AKI and its association with mortality in extremely low-birthweight (ELBW) neonates. Using a contemporary neonatal AKI definition, this retrospective, observational, single-center cohort study of 436 ELBW infants shows a prevalence of early AKI of 44%, and those with any AKI had a 2.77 (95% CI, 1.63-4.72) higher odds of death compared with those without AKI (odds ratio for severe AKI, 3.52; 95% CI, 2.15-5.76). Similar findings have been reported by other groups in retrospective and prospective multicenter neonatal studies,2,3 as well as large, prospective, multicenter epidemiology studies in pediatric4 and adult5 critical care patients. This study then addresses another critical question.1 Does AKI directly cause death or is it an innocent bystander (ie, not contributory)? Using the Shapley Additive Explanations (SHAP) analysis, a machine learning approach that shows the relative association of each variable being measured with a given outcome, they found that, after controlling for vasoactive inotrope score (VIS) and the neonatal Sequential Organ Failure Assessment (nSOFA) measure, AKI was not associated with mortality. Like the adult and pediatric SOFA scores, the nSOFA measure incorporates hematologic (platelet counts) respiratory, and cardiovascular scores. However, as opposed to the adult and pediatric SOFA scores, the nSOFA score does not include markers of liver, kidney, and central nervous system dysfunction. A few possible reasons could explain these results. First, it is possible that early AKI has nothing to do with the causative pathway between sickness and death. If true, this reason negates the work in the basic and translational science fields that suggest that AKI is not an innocent bystander in multiorgan disease failure but instead has a central role in the systemic inflammatory process, with direct effects on the heart, lungs, brain, gut, liver, and immune system. If indeed AKI is not contributory to clinical outcomes in ELBW infants, this population would be unique, given that the association been AKI and outcomes has been clearly shown in multiple pediatric4 and adult4 critically ill populations, even after adjustment for comorbidities and severity of ill scores (ie, SOFA). A second possible reason to explain these findings is that, although the investigators use the most contemporary definition of neonatal AKI, it is suboptimal. This empirical definition, which was borrowed from the adult literature, has empowered the community with a standard way to define AKI allowing comparison of studies; however, it has important limitations, especially in the first postnatal week. At birth, neonatal and maternal serum creatinine (sCr) levels are identical. Over the next 36 to 48 hours, the neonate attains a sCr steady state level that will be determined by nephron mass and gestational age. If the maternal sCr value is low (ie, 0.6 mg/dL [to convert to micromoles per liter, multiply by 88.4]) and the neonate is extremely premature, an expected increase in the SCr level in 48 hours (ie, 1.1 mg/dL) is expected. This change can be confused with worsening kidney function. For these reasons, several groups have eliminated the first 2 postnatal days from the calculation of the baseline values.3,6 In addition, an absolute sCr level increased threshold is superior to percent sCr increase in the first postnatal week, and incorporating percent sCr decreases the predictability of mortality.7 Finally, recent studies require a minimum sCr level of 0.4 mg/dL to eliminate a diagnosis of AKI based on small changes that could be due to variability in laboratory error (ie, sCr increase from 0.2 to 0.3 mg/dL is a 50% increase).3,6 The AKI definition used by Aziz et al1 comprised any prior sCr value (including day 0 and 1) to define the baseline, did not use minimum sCr values, and in most cases, met the sCr percent change criterion, resulting in very low peak sCr values + Related article