Urine or You’re Out?

Perspective of a Neonatologist

The goal of every neonatologist is to send home as many healthy babies as possible. Therefore, attention should be directed to any diagnosis that is independently associated with mortality. De Mul et al. (1) have found such an association with neonatal AKI, validating previous findings from studies like the Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates (AWAKEN) trial, which found 3.9 higher odds of mortality in preterm neonates with AKI (2). Further, the authors show that if you increase the threshold of urine output to 1.5 or 2 ml/kg per hour for classifying AKI, you observe a five-fold higher association with mortality compared with four-fold with the original 1 ml/kg per hour urine output definition. How closely should we monitor urine output, and could we clinically detect the difference between 1 or 2 ml/kg per hour?

Obtaining urine to measure urine output in the neonatal intensive care unit (NICU) is challenging. Although catheters are used to collect urine from many pediatric and adult patients hospitalized in intensive care units, neonates are prone to infection, and size of both the patients and the catheters limit the use of an indwelling catheter. For these reasons, diaper weights are the most common way to estimate urine output. However, this is prone to imprecise measurements from output mixed with stool, often overestimating urine volume. A limitation of the publication of De Mul et al. (1) is the lack of information on how “mixed” diapers were measured or how unmeasured voids were recorded. These are important details that could significantly shift the prevalence of AKI in these very preterm neonates and are important to know for future studies that attempt to replicate their findings.

There are multiple reasons why previous NICU AKI studies use a change in serum creatinine alone for diagnosing AKI. The first is the challenge with retrospectively collecting imprecise urine output data. The second is urine output criteria have been adapted from adult and pediatric definitions, but urine output in neonates during the first 10 days is particularly unique. Just after birth, most neonates enter a period of diuresis, producing 4–6 ml/kg per hour of urine output for 3–5 days. Therefore, testing more liberal thresholds of urine output has a physiologic basis. In a 2013 study of over 300 neonates, a range of urine output thresholds was evaluated for their ability to predict mortality (3). Like the study of De Mul et al. (1), they found that a urine output threshold of 1.5 ml/kg per hour also had the strongest adjusted association with mortality compared with lower thresholds. One caveat is that these studies have been done in a retrospective manner. Although these findings should prompt the reconsideration of the current urine output thresholds in the neonatal Kidney Disease Improving Global Outcomes definition, it would be premature to make these changes without prospective validation and correlation to long-term outcomes.

Beyond defining neonatal AKI for research purposes, we need to consider how these urine output thresholds might alter clinical practice in the NICU. Given the association of urine output changes with mortality, it is vital that we improve our monitoring of urine output in the NICU. This ultimately means that urine output should continue to be measured until babies are through the highest-risk phases of AKI. Stopping weighed diapers when babies reach full feeds is probably premature as neonates are at risk for AKI during late-onset sepsis and necrotizing enterocolitis, conditions that occur 2–6 weeks after birth. To successfully monitor urine output, we need urine collection devices made specifically for the smallest, most premature neonates, where an indwelling catheter is not feasible. Ideally, a device should be designed that allows for the continuous measurement of the urine output in an accurate and safe way, avoiding skin breakdown and infection in this vulnerable population.

Perspective of a Pediatric Nephrologist

There is no doubt that the definition of neonatal AKI should be anchored to important outcomes, such as mortality. However, pediatric nephrologists must also focus on the long game. A central responsibility of a pediatric nephrologist is to assess the risk for CKD in each patient and make every effort to reduce that individual’s risk for CKD progression. Nephrologists care for many preterm neonates until early adulthood and must convey their risk for CKD as they transition to adult providers. There is clear evidence that AKI is a risk factor for the development of CKD in adult and pediatric populations (4,5). The relationship between AKI and CKD is less obvious in neonates. Is this because AKI can occur in preterm neonates during the window of nephrogenesis and these neonates have the potential to form new nephrons following AKI? Or does the definition of neonatal AKI fail to capture the risk of CKD? An ideal definition of neonatal AKI would correlate with both the risk for mortality and the future risk for CKD. Does the change in urine output criteria for AKI proposed by De Mul et al. (1) have an effect on the long-term risk for CKD? This question remains unanswered.

The question of more liberal thresholds for the urine output criteria in neonatal AKI raised by De Mul et al. (1) highlights the complex nature of AKI, particularly in the developmentally immature preterm neonate. On one hand, a lower urine output in the setting of reduced circulating volume has been thought by some as acute kidney “success,” whereby the kidney can reduce further volume losses. If temporary, this may not result in kidney damage, despite meeting the current definitions of neonatal AKI. When does a low urine output represent irreversible damage? This may be an opportunity to evaluate urinary biomarkers of damage to provide further information beyond what is gained from the absolute urine output. In addition, urine output should be viewed as a single variable in the patient’s overall fluid balance equation. A “relatively” low urine output in the setting of increasing input is a recipe for positive fluid balance. Over the last decade, more attention has been focused on the state of fluid overload in mainly adult and pediatric populations. However, the concept of fluid balance in particular fluid overload may play a larger role in the overall health of the developing neonate and influence the development and function of other organs, particularly relevant for the lung. The concepts of organ crosstalk and fluid balance are particularly germane to the discussion of minimal urine output criteria in the AKI definition. Investigations of fluid balance have begun to emerge in the neonatal literature, including reports from the AWAKEN study (6). In a subgroup analysis of preterm neonates, multivariable models showed that a higher peak fluid balance in the first postnatal week was independently associated with mechanical ventilation at postnatal day 7. Therefore, fluid balance may be a better and more precise way of capturing the direct effect of a decreased urine output for a particular neonate. Furthermore, a weight-based determination of fluid balance has been shown to be practical and effective in several pediatric studies. However, neonatal AKI definitions that contain weights changes have not been directly compared with urine output cutoffs.

Within the NICU, there is a perception that pediatric nephrology consults for AKI may be increasing, but in published studies, the prevalence is still rare (7,8). In pediatric AKI studies, nephrology consults for AKI improve the rates of follow-up (9). Several institutions have begun to request pediatric nephrology follow-up for neonates with AKI, yet evidence-based guidelines still do not exist. Should decreased urine output prompt a pediatric nephrology consult? This will likely depend on whether higher urine output cutoffs are associated with CKD.

It is imperative to get the neonatal AKI definition “right.” A consistent and meaningful definition of AKI that incorporates the unique developmental aspects of the neonate is needed to be able to compare studies, risk stratify patients, and direct future therapeutic interventions. AKI is a complex syndrome with many etiologies and limited therapies. More work needs to be done to ensure that the components of the neonatal AKI definition are sensitive and specific in order to develop strategies to improve the health of newborns with or at risk for kidney disease.

Disclosures

J.R. Charlton reports consultancy agreements with Medtronics and XN Technologies, LLC and ownership interest in Sindri Technologies, LLC. The remaining author has nothing to disclose.

Funding

None.

Author Contributions

J.R. Charlton and M.W. Harer conceptualized the study, wrote the original draft, and reviewed and edited the manuscript.