In this state-of-the-art review, we highlight the major advances over the last 5 years in neonatal acute kidney injury (AKI). Large multicenter studies reveal that neonatal AKI is common and independently associated with increased morbidity and mortality. The natural course of neonatal AKI, along with the risk factors, mitigation strategies, and the role of AKI on short- and long-term outcomes, is becoming clearer. Specific progress has been made in identifying potential preventive strategies for AKI, such as the use of caffeine in premature neonates, theophylline in neonates with hypoxic-ischemic encephalopathy, and nephrotoxic medication monitoring programs. New evidence highlights the importance of the kidney in “crosstalk” between other organs and how AKI likely plays a critical role in other organ development and injury, such as intraventricular hemorrhage and lung disease. New technology has resulted in advancement in prevention and improvements in the current management in neonates with severe AKI. With specific continuous renal replacement therapy machines designed for neonates, this therapy is now available and is being used with increasing frequency in NICUs. Moving forward, biomarkers, such as urinary neutrophil gelatinase–associated lipocalin, and other new technologies, such as monitoring of renal tissue oxygenation and nephron counting, will likely play an increased role in identification of AKI and those most vulnerable for chronic kidney disease. Future research needs to be focused on determining the optimal follow-up strategy for neonates with a history of AKI to detect chronic kidney disease.

Since the publication of the “Neonatal Acute Kidney Injury” review in 2015, our understanding of the epidemiology and impact of neonatal acute kidney injury (AKI) has exponentially increased.1  Single-center and multicenter work has clearly revealed that AKI occurs commonly in critically ill neonates and adversely impacts outcomes.24  In parallel to these advancements, our ability to identify AKI early, mitigate AKI, and provide renal replacement therapy (RRT) with devices designed for neonates has improved.5,6  In this state-of-the-art review, we will review neonatal kidney physiology, provide an update of neonatal AKI knowledge (definitions, prevalence, outcomes, and complications), discuss the current state of research, and appraise cutting edge data on therapeutics and devices that will improve care in the coming decade.

A basic understanding of kidney structure and function during development is essential to understand neonatal AKI and its consequences.1  Nephrogenesis begins at 5 weeks’ gestation and continues until 34 to 36 weeks’ gestation.7  The nephron number is highly variable at birth, ranging from 200 000 to 2.7 million, and is impacted by a multitude of factors, including prematurity.8,9 

There are several core principles of neonatal physiology that uniquely impact the diagnosis and management of neonatal AKI. First, both renal blood flow and perfusion pressure increase over the first weeks of life in neonates. The proportion of cardiac output delivered to the kidneys increases from 5% during fetal life to 20% by 2 years.10  Much of this increased blood flow occurs after birth, with renal blood flow doubling in the first 2 postnatal weeks. After birth, the distribution of blood flow transitions from deeper, more mature glomeruli to superficial, cortical glomeruli.11  This change in blood flow can be altered by medications (such as indomethacin), perinatal asphyxia, and maternal hemorrhage, which all predispose neonates to AKI. Second, congruent with the increased blood flow, the glomerular filtration rate (GFR) increases dramatically after birth and reaches adult levels by 2 years of age.12  The GFR is low in infants, both in absolute value and when corrected for body surface area (milliliters per minute per 1.73 meters2). For example, premature infants born at 26 weeks have a GFR as low as 0.7 mL/minute per kg on day 1 of age, which improves only slightly during the first several weeks of life.12  In neonates with a physiologically low GFR, additional stressors, such as sepsis, hypoxia, hypotension, or other clinical conditions common in prematurity, may increase the risk AKI. Third, urinary concentrating ability is low at birth and reaches adult levels by 1 year of age.13  Poor urinary concentrating ability, particularly in neonates with high insensible losses or critical illness, predisposes neonates to volume depletion and subsequent prerenal azotemia. Finally, neonatal kidneys appear to be particularly susceptible to ischemic injury to the renal tubules, even after a mild and short-term insult. This is further complicated when nephrotoxic medications, such as gentamicin and other aminoglycosides, are commonly prescribed to critically ill neonates and result in tubular injury.

The neonatal modified Kidney Disease: Improving Global Outcomes (KDIGO) definition is the most commonly used definition used in clinical practice and most epidemiological studies (Table 1). This empirical definition stages AKI severity on the basis of a rise in serum creatinine (SCr) levels from a previous trough and/or a decrease in urine output (UOP).14,15  The National Institutes of Health–sponsored Neonatal AKI Workshop in 2013 recommended that researchers and clinicians use the neonatal modified KDIGO definition to define AKI but emphasized that this definition should be a starting point for an iterative process, which is based on clinically meaningful and long-term outcomes.16 

TABLE 1

Neonatal AKI KDIGO Classification

StageSCrUOP
No change in SCr level or rise <0.3 mg/dL ≥0.5 mL/kg per h 
Increase in SCr level of ≥0.3 mg/dL within 48 h or rise in SCr level ≥1.5–1.9 times the reference SCr levela within 7 d <0.5 mL/kg per h for 6–12 h 
Rise in SCr level ≥2–2.9 times the reference SCr levela within 7 d <0.5 mL/kg per h for ≥12 h 
SCr level ≥3 times the reference SCr levela or SCr level >2.5 mg/dLb or receipt of RRT <0.3 mL/kg per h for ≥24 h or anuria for ≥12 h 
StageSCrUOP
No change in SCr level or rise <0.3 mg/dL ≥0.5 mL/kg per h 
Increase in SCr level of ≥0.3 mg/dL within 48 h or rise in SCr level ≥1.5–1.9 times the reference SCr levela within 7 d <0.5 mL/kg per h for 6–12 h 
Rise in SCr level ≥2–2.9 times the reference SCr levela within 7 d <0.5 mL/kg per h for ≥12 h 
SCr level ≥3 times the reference SCr levela or SCr level >2.5 mg/dLb or receipt of RRT <0.3 mL/kg per h for ≥24 h or anuria for ≥12 h 
a

Differences between the neonatal AKI definition and KDIGO definition: reference SCr level defined as the lowest previous SCr value.

b

Differences between the neonatal AKI definition and KDIGO definition: SCr value of 2.5 mg/dL represents <10 mL/min per 1.73m2.

Since the publication of this definition, there have been several observational studies highlighting potential areas for future refinement to account for chronological and gestational age (GA). For example, whereas some researchers advocate for excluding the SCr level from the first postnatal 48 hours when calculating the baseline SCr level, others believe that this value is a surrogate of the nephron number and is clinically meaningful.2,3,1719  Researchers have also pointed out that deviations in the GA-appropriate SCr trajectory (which steadily drops from birth in healthy term neonates) could signify AKI, but this is not captured in the current KDIGO definition.20 

The current neonatal modified KDIGO AKI definition incorporates UOP. Despite studies in older populations revealing that UOP is critically important to properly identify AKI, few studies in neonatal AKI have included UOP. One study using diaper weights every 3 hours found that UOP <1.5 mL/kg per hour was associated with increased mortality.21  Furthermore, they found that lower thresholds of UOP (<1 mL/kg per hour) were associated with an even higher mortality rate.21  Few studies, including the Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) study, included UOP measurement in the assessment of AKI, thus limiting the available data on which to base thresholds for diagnosis and determination of severity of AKI. In future studies, researchers should carefully measure UOP to determine the impact of UOP on AKI diagnosis in neonates.

Given the interest and focus on AKI diagnostic thresholds, it is likely that a refined definition of neonatal AKI will emerge. Two recent publications, including an analysis of the AWAKEN study, suggest an alternative definition for neonatal AKI.22,23  In this study, the authors proposed different cutoffs for the first postnatal week by GA, compared with the subsequent weeks, and provided cutoffs by GA group.23  For example, in infants ≤29 weeks’ GA, a rise in the SCr level of 0.6 mg/dL confers the highest prediction of mortality, whereas in infants >29 weeks’ GA, a rise of 0.3 mg/dL is of highest mortality prediction.23  Furthermore, we anticipate that novel approaches of using urine biomarkers, SCr thresholds, UOP thresholds, and fluid balance metrics will be used to enhance the current neonatal KDIGO definition. In the interim, we recommend that the neonatal modified KDIGO definition be used as the standard until newer definitions are widely validated in large multisite trials and correlated with long-term outcomes.

AKI is common in critically ill neonates. We present a summary of the risk factors associated with neonatal AKI (Table 2) and the most notable studies evaluating the epidemiology and impact of neonatal AKI in the last 5 years (Table 3). Much of this increased knowledge stems from the AWAKEN study, which enrolled neonates at risk for AKI (determined by >48 hours of intravenous fluids). In this cohort, the risk of AKI occurred in a bimodal pattern, with extremely low gestational age neonates (ELGANs) (<28 weeks) and term infants at the greatest risk.4  The AWAKEN study identified a clear variation in SCr monitoring practices across centers, with less than half of centers checking ≥5 SCr levels during hospital admission. Not surprisingly, the rates of AKI by center were directly correlated with the average number of SCr samples ascertained per subject.4  This practice variation is particularly notable in the context of the recent Baby Nephrotoxic Injury Negated by Just-in-Time Action (NINJA) publication, which revealed that by monitoring SCr more frequently in neonates with high nephrotoxic medication exposure, there was an increased awareness of the risk for AKI that, in turn, resulted in a lower rate and duration of AKI.17  These data suggest that critically ill neonates may benefit from protocolized SCr monitoring during high-risk events.

TABLE 2

Epidemiology, Risk Factors and Associated Findings with Neonatal AKI

PrenatalPerinatalPostnatal
Factors that increase risk of a preterm or LBW neonate, placental insufficiency Exposure to nephrotoxic medications (ACE inhibitors, NSAIDs), delivery complications resulting in hypoxia and/or asphyxia, HIE Prematurity, LBW, CHD, inborn errors of metabolism, sepsis, nephrotoxin exposure, PDA, extracorporeal therapies 
PrenatalPerinatalPostnatal
Factors that increase risk of a preterm or LBW neonate, placental insufficiency Exposure to nephrotoxic medications (ACE inhibitors, NSAIDs), delivery complications resulting in hypoxia and/or asphyxia, HIE Prematurity, LBW, CHD, inborn errors of metabolism, sepsis, nephrotoxin exposure, PDA, extracorporeal therapies 

ACE, angiotensin-converting enzyme; LBW, low birth weight.

TABLE 3

Summary of Neonatal AKI Studies Published Between 2015 and 2020

Author (Year), NStudy Design and Population DetailsMain Findings
Jetton et al4  (2017), N = 2162 Neonates requiring >48 h of intravenous fluids in the NICU AKI occurred in 45% of the infants at ≤28 wk GA and in 14% of infants at 29–36 wk GA. 
Charlton et al25,28  (2019), N = 2162 Secondary analysis of infants from the AWAKEN study Antimicrobial agents, methylxanthines, diuretics, NSAIDs, hypertensive disorders of pregnancy, and hypoglycemia were associated with lower odds of early AKI. In infants at 29–25 wk GA, outborn status, saline bolus during resuscitation, and more frequent SCr monitoring were associated with higher odds of early AKI. 
Askenazi et al2  (2000), N = 923 Prospective study of ELGANs in the PENUT trial Thirty-eight percent had at least 1 episode of stage 1 or higher AKI, and 18.2% had 1 episode of stage 2 or higher AKI. 
Selewski et al51  (2019), N = 645 Retrospective analysis of infants at ≥36 wk GA from the AWAKEN study Median peak fluid balance was 1.0% (IQR: −0.5 to 4.6) over the first postnatal week and occurred on postnatal d 3 (IQR: 1 to 5). Mechanical ventilation on postnatal d 7 was associated independently with the following measures of fluid balance over the first postnatal week: peak fluid balance (aOR: 1.12; 95% CI: 1.08 to 1.17), lowest fluid balance in first postnatal week (aOR: 1.14; 95% CI: 1.07 to 1.22), fluid balance on postnatal d 7 (aOR: 1.12; 95% CI: 1.07 to 1.17), and negative fluid balance at postnatal d 7 (aOR: 0.3; 95% CI: 0.16 to 0.67). 
Selewski et al53  (2020), N = 1007 Retrospective analysis of infants at <36 wk GA from the AWAKEN study Median peak fluid balance was 0% (IQR: −2.9 to 2) and occurred on postnatal d 2 (IQR: 1 to 5). Mechanical ventilation on postnatal d 7 was associated independently with the following measures of fluid balance over the first postnatal week: peak fluid balance (aOR: 1.14; 95% CI: 1.10 to 1.19), lowest fluid balance (aOR: 1.12; 95% CI: 1.07 to 1.16), fluid balance on postnatal d 7 (aOR: 1.10; 95% CI: 1.06 to 1.13), and negative fluid balance at postnatal d 7 protected against the need for mechanical ventilation at postnatal d 7 (aOR: 0.21; 95% CI: 0.12 to 0.35). 
Nour et al120  (2020), N = 30 Retrospective analysis in neonates with HIE who underwent cooling via selective head cooling No difference in AKI between the those receiving selective head cooling and those not. SCr levels and UOP were significantly improved on d 4 and d 10 samples compared with baseline samples in both groups regardless of cooling. There was a difference in NGAL levels, but not CysC levels, on d 4 and 10. 
Bellos et al90  (2019), N = 458 Meta-analysis of effectiveness of theophylline administration in neonates with perinatal asphyxia Incidence of AKI significantly lower in neonates receiving theophylline (OR: 0.24; 95% CI: 0.16 to 0.36), whereas mortality rates were similar between the 2 groups (OR: 0.86; 95% CI: 0.46 to 1.62). Theophylline administration was associated with significantly decreased SCr levels (MD: −0.57 mg/dL; 95% CI: −0.68 to −0.46) in the third day of life. 
Harer et al89  (2018), N = 675 Retrospective analysis of premature infants at <33 wk GA from the AWAKEN study AKI occurred less frequently in neonates who received caffeine in the first week of life than in those who were not treated with caffeine (11.2% vs 31.6%; P < .01). Neonates who received caffeine had more AKI risk factors, including lower average GA, lower birth wt, and high severity of illness scores, and were still less likely to develop stage 2 or 3 AKI. The No. needed to treat with caffeine to prevent 1 episode of AKI was 4.3. 
Stoops et al17  (2019) Prospective quality improvement effort to reduce nephrotoxic medication–associated AKI in the NICU Reduced high nephrotoxic medication exposures from 16.4 to 9.6 per 1000 patient-days (P = .03), reduced nephrotoxic medication–associated AKI from 30.9% to 11.0% (P < .001), and reduced AKI severity from 9.1 to 2.9 per 100 susceptible patient-days (P < .001) prevented 100 AKI episodes during the 18-mo sustainability era. 
Starr et al103  (2019), N = 546 Retrospective analysis of premature infants at <32 wk GA from the AWAKEN study Infants born between 29 and 32 wk GA with AKI had fourfold higher odds of moderate or severe BPD or death after controlling for multiple factors (aOR: 4.21; 95% CI: 2.07 to 8.61). 
Author (Year), NStudy Design and Population DetailsMain Findings
Jetton et al4  (2017), N = 2162 Neonates requiring >48 h of intravenous fluids in the NICU AKI occurred in 45% of the infants at ≤28 wk GA and in 14% of infants at 29–36 wk GA. 
Charlton et al25,28  (2019), N = 2162 Secondary analysis of infants from the AWAKEN study Antimicrobial agents, methylxanthines, diuretics, NSAIDs, hypertensive disorders of pregnancy, and hypoglycemia were associated with lower odds of early AKI. In infants at 29–25 wk GA, outborn status, saline bolus during resuscitation, and more frequent SCr monitoring were associated with higher odds of early AKI. 
Askenazi et al2  (2000), N = 923 Prospective study of ELGANs in the PENUT trial Thirty-eight percent had at least 1 episode of stage 1 or higher AKI, and 18.2% had 1 episode of stage 2 or higher AKI. 
Selewski et al51  (2019), N = 645 Retrospective analysis of infants at ≥36 wk GA from the AWAKEN study Median peak fluid balance was 1.0% (IQR: −0.5 to 4.6) over the first postnatal week and occurred on postnatal d 3 (IQR: 1 to 5). Mechanical ventilation on postnatal d 7 was associated independently with the following measures of fluid balance over the first postnatal week: peak fluid balance (aOR: 1.12; 95% CI: 1.08 to 1.17), lowest fluid balance in first postnatal week (aOR: 1.14; 95% CI: 1.07 to 1.22), fluid balance on postnatal d 7 (aOR: 1.12; 95% CI: 1.07 to 1.17), and negative fluid balance at postnatal d 7 (aOR: 0.3; 95% CI: 0.16 to 0.67). 
Selewski et al53  (2020), N = 1007 Retrospective analysis of infants at <36 wk GA from the AWAKEN study Median peak fluid balance was 0% (IQR: −2.9 to 2) and occurred on postnatal d 2 (IQR: 1 to 5). Mechanical ventilation on postnatal d 7 was associated independently with the following measures of fluid balance over the first postnatal week: peak fluid balance (aOR: 1.14; 95% CI: 1.10 to 1.19), lowest fluid balance (aOR: 1.12; 95% CI: 1.07 to 1.16), fluid balance on postnatal d 7 (aOR: 1.10; 95% CI: 1.06 to 1.13), and negative fluid balance at postnatal d 7 protected against the need for mechanical ventilation at postnatal d 7 (aOR: 0.21; 95% CI: 0.12 to 0.35). 
Nour et al120  (2020), N = 30 Retrospective analysis in neonates with HIE who underwent cooling via selective head cooling No difference in AKI between the those receiving selective head cooling and those not. SCr levels and UOP were significantly improved on d 4 and d 10 samples compared with baseline samples in both groups regardless of cooling. There was a difference in NGAL levels, but not CysC levels, on d 4 and 10. 
Bellos et al90  (2019), N = 458 Meta-analysis of effectiveness of theophylline administration in neonates with perinatal asphyxia Incidence of AKI significantly lower in neonates receiving theophylline (OR: 0.24; 95% CI: 0.16 to 0.36), whereas mortality rates were similar between the 2 groups (OR: 0.86; 95% CI: 0.46 to 1.62). Theophylline administration was associated with significantly decreased SCr levels (MD: −0.57 mg/dL; 95% CI: −0.68 to −0.46) in the third day of life. 
Harer et al89  (2018), N = 675 Retrospective analysis of premature infants at <33 wk GA from the AWAKEN study AKI occurred less frequently in neonates who received caffeine in the first week of life than in those who were not treated with caffeine (11.2% vs 31.6%; P < .01). Neonates who received caffeine had more AKI risk factors, including lower average GA, lower birth wt, and high severity of illness scores, and were still less likely to develop stage 2 or 3 AKI. The No. needed to treat with caffeine to prevent 1 episode of AKI was 4.3. 
Stoops et al17  (2019) Prospective quality improvement effort to reduce nephrotoxic medication–associated AKI in the NICU Reduced high nephrotoxic medication exposures from 16.4 to 9.6 per 1000 patient-days (P = .03), reduced nephrotoxic medication–associated AKI from 30.9% to 11.0% (P < .001), and reduced AKI severity from 9.1 to 2.9 per 100 susceptible patient-days (P < .001) prevented 100 AKI episodes during the 18-mo sustainability era. 
Starr et al103  (2019), N = 546 Retrospective analysis of premature infants at <32 wk GA from the AWAKEN study Infants born between 29 and 32 wk GA with AKI had fourfold higher odds of moderate or severe BPD or death after controlling for multiple factors (aOR: 4.21; 95% CI: 2.07 to 8.61). 

aOR, adjusted odds ratio; BPD, bronchopulmonary dysplasia; IQR, interquartile range; MD, mean difference; PENUT, Preterm Erythropoietin Neuroprotection Trial.

The risk of AKI increases markedly with decreasing GA.2,3  In cohorts of very low birth weight (VLBW) neonates, the incidence of AKI is reported between 18% and 40%.3,24  In ELGANs enrolled in the Preterm Erythropoietin Neuroprotection Trial, 38% had at least 1 episode of AKI.2  In the AWAKEN study, AKI occurred in 45% of neonates <29 weeks’ GA and in 14% of neonates 29 to 36 weeks’ GA. In the AWAKEN study, the potentially modifiable risk factors for early AKI in ELGANs were mainly medication exposures.25  Given immature tubular function and resulting poor urinary concentration ability, along with the increased insensible losses common in preterm neonates, volume depletion leading to prerenal azotemia is a common factor predisposing this population to AKI.

Patent ductus arteriosus (PDA) is an important clinical issue for preterm infants and is associated with a higher risk of AKI.26,27  PDA represents a clinical challenge because AKI may result if it is left untreated; however, classic PDA therapies may also be associated with AKI. Although nonsteroidal antiinflammatory drug (NSAID) treatment of PDA added an additional risk for mild AKI, severe AKI was less likely when NSAID treatment was effective.26 

In the AWAKEN study, the incidence of AKI in neonates born at ≥36 weeks and admitted to a NICU was 37%.4  The etiology of AKI in term neonates is often multifactorial and includes risk factors related to their illness and management (Table 2).25,28  Multiorgan dysfunction is common and occurs in up to 70% of neonates with AKI.2931  Some of the major risk factors for AKI include hypoxic-ischemic encephalopathy (HIE), cardiac disease, surgery, and nephrotoxic medications.

HIE

There is a general agreement that the presence of AKI in the setting of HIE is associated with poor outcomes (increased mortality, poor neurodevelopmental outcomes, longer hospital stay, and longer duration of mechanical ventilation).30,32,33  In addition, there is a correlation between severity of HIE and AKI, with 70% of those with stage III HIE having AKI, compared with 7.4% of those with stage II HIE.32 

Cardiac Disease and Extracorporeal Membrane Oxygenation

Infants who require cardiac surgery and those who need extracorporeal membrane oxygenation (ECMO) are at high risk for AKI. AKI occurs in 30% to 50% of patients undergoing surgery for congenital heart disease (CHD).3436  One single-center retrospective study of neonates with single ventricle physiology undergoing stage 1 Norwood palliation found that 21% developed AKI.36  A large Danish registry study revealed that 33% of neonates had AKI within 5 days of surgery.35  In a multicenter retrospective cohort study of 832 pediatric patients on ECMO, 74% had AKI.34  AKI was present at initiation of ECMO in the majority of cases and was associated with a longer ECMO duration and increased mortality.34  The risk of AKI in those on ECMO varies by underlying diagnosis; those with congenital diaphragmatic hernia were more likely to require RRT.37 

Surgery

The incidence of AKI is high in noncardiac surgery; 34% of neonates undergoing abdominal and thoracic surgery have an episode of AKI.38  Infants with AKI after surgery were more likely to have VLBW. They were also more likely to have sepsis, a longer duration of mechanical ventilation, an operative time >120 minutes, necrotizing enterocolitis (NEC), and a higher risk of mortality.38  Among infants with surgically managed NEC, almost 60% had severe AKI (stage 2 or 3).39 

Nephrotoxic Medications

Many neonates are exposed to nephrotoxic medications in the NICU, which can contribute to AKI. Although there are many nephrotoxic medications, these primarily include antimicrobial agents (eg, acyclovir, amphotericin B, aminoglycosides, vancomycin).25,28  It was recently reported in Baby NINJA, a single-center quality improvement program focused on reducing nephrotoxic medication–associated AKI, that attention to high-risk neonates, including daily SCr monitoring, reduces nephrotoxic medication exposures (P = .03), nephrotoxic medication–associated AKI (P < .001), and AKI duration (P < .001).17  This suggests that identification and monitoring of high-risk neonates, with a thoughtful consideration of nephrotoxic medications, may minimize AKI and its consequences in critically ill neonates.

The development of fluid overload is an independent predictor of adverse outcomes across pediatric critical care populations.4049  The development of fluid overload is often multifactorial, resulting from AKI, iatrogenic fluid administration, capillary leak from systemic inflammation, and aberrant homeostatic mechanisms.41  Additionally, fluid overload can make the diagnosis of AKI more challenging because SCr is diluted in the setting of a positive fluid balance, resulting in a potential underdiagnosis of AKI.41  Precise definitions are essential to understanding the epidemiology and impact of excessive fluid accumulation on outcomes in neonates (Table 4).50  The 2 most common methods used to calculate fluid balance are the cumulative fluid balance and weight-based methods. The weight-based method to describe fluid balance is used to calculate the degree of fluid overload on the basis of a change in weight from a baseline weight (birth weight or determined dry weight)51 : daily fluid balance = change in daily weight day to day; cumulative fluid balance = daily weight − baseline weight; percentage fluid overload44  = ([daily weight − baseline weight]/baseline weight) × 100.

TABLE 4

Definitions of Excessive Fluid Accumulation in Neonates

TermDefinition
Daily fluid balance Daily difference between input and output or change in wt over a 24-h period 
Cumulative fluid balance Change in fluid balance over a given duration 
Fluid overload Cumulative fluid balance expressed as a percentage of body wt; used to refer to the pathologic state of excessive fluid accumulation associated with the development of sequelae attributable to fluid accumulation and adverse outcomes 
TermDefinition
Daily fluid balance Daily difference between input and output or change in wt over a 24-h period 
Cumulative fluid balance Change in fluid balance over a given duration 
Fluid overload Cumulative fluid balance expressed as a percentage of body wt; used to refer to the pathologic state of excessive fluid accumulation associated with the development of sequelae attributable to fluid accumulation and adverse outcomes 

Although each method has been used in older children, the weight-based methods represent the standard in neonates because fluid balances have been shown to be inaccurate.5153  It is critical to use standardized weight measurement protocols to properly perform the weight-based technique.52,54 

Fluid balance in the early postnatal period can be challenging to interpret in the setting of normal postnatal diuresis and expected negative fluid balance. Although an average weight loss of 7% from birth weight is described in term neonates, the normal fluid balance for neonates of other GAs is less clearly defined, particularly in extremely preterm neonates with excessive skin permeability.55  Early positive postnatal fluid balance is associated with adverse short- (death, mechanical ventilation on day 7) and long-term outcomes (bronchopulmonary dysplasia) in neonates.51,53,5659  There remains a paucity of data defining the pathologic state of fluid overload in critically ill neonates, which in older children, is commonly defined as a cumulative positive fluid balance of ≥10% to 20%.48,60  Multiple critical gaps exist in our understanding of the causes and impact of abnormal fluid balance in neonates. These gaps include interpreting fluid balance in neonates, especially those who have spent a considerable time in the NICU. Research is greatly needed to understand the optimal threshold to define appropriate fluid balance and to understand the detrimental effects of neonatal fluid overload on extrarenal organ systems (eg, oxygenation index and cardiac dysfunction due to excessive fluid and reduced contractility). Understanding the role of fluid balance in various neonatal populations (premature versus term neonates) at critical time points (perinatal versus postnatal versus postsurgical) in the context of underlying disease process (NEC, lung disease, and sepsis) is a critical knowledge gap. Answers to these questions will drive therapeutic interventions designed to prevent and mitigate harm from fluids.

Proteins and metabolites are 2 examples of biomarkers that can be measured consistently and correlate with the disease occurrence or progression.61  Given the diversity of GA and etiologies of AKI in neonates, 1 biomarker does not appear to reliably predict AKI. However, more reference ranges are becoming available for novel urinary biomarkers by GA and postnatal age.62  SCr represents the current standard for diagnosing neonatal AKI. However, it is critical to understand the shortcomings of SCr and develop novel biomarkers that fill these gaps. A rise in the SCr level indicates a loss of kidney function, reflecting injury that occurred up to 48 to 72 hours before.63  As a result, biomarker studies, such as the ones below, have been focused on identifying injury and functional changes before permanent damage (Table 5).

TABLE 5

Biomarkers in Use or Under Study to Assist With AKI Prediction and Diagnosis

BiomarkerLocation of InjuryNotes
SCr Reflects kidney function, not injury; metabolic product of skeletal muscle creatine Delayed marker (48–72 h) of kidney function 
CysC Reflects kidney function, not injury (serum); proximal tubule injury (urine) Increase in the serum CysC level is thought to reflect a change in GFR or kidney function, whereas an elevated urinary CysC level is considered reflective of tubular injury 
NGAL Distal tubule and collecting duct Highly sensitive for ischemia and nephrotoxins 
Kidney injury molecule 1 Proximal tubule injury Regulates apoptosis, promotes epithelial regeneration 
TIMP-2 and IGFBP-7 Tubule cells Limits proliferation of damaged tubule cells; marker of early AKI 
BiomarkerLocation of InjuryNotes
SCr Reflects kidney function, not injury; metabolic product of skeletal muscle creatine Delayed marker (48–72 h) of kidney function 
CysC Reflects kidney function, not injury (serum); proximal tubule injury (urine) Increase in the serum CysC level is thought to reflect a change in GFR or kidney function, whereas an elevated urinary CysC level is considered reflective of tubular injury 
NGAL Distal tubule and collecting duct Highly sensitive for ischemia and nephrotoxins 
Kidney injury molecule 1 Proximal tubule injury Regulates apoptosis, promotes epithelial regeneration 
TIMP-2 and IGFBP-7 Tubule cells Limits proliferation of damaged tubule cells; marker of early AKI 

Cystatin C (CysC) is a cysteine protease inhibitor that is freely filtered by glomeruli and reabsorbed in the proximal tubule. Although both serum and urinary CysC have been assessed as early markers of AKI, a rise in the serum CysC level reflects a change in kidney function, whereas an elevated urinary CysC level is considered reflective of tubular injury.12,6468  A recent systematic review of neonates across all GA groups suggested that serum CysC may be superior to SCr for assessing the GFR.65  Furthermore, an elevated urinary CysC level has been shown to have an area under the curve of 0.85 (95% confidence interval [CI]: 0.81 to 0.88) in predicting a rise in the SCr level 24 to 96 hours later in neonates post surgery or after perinatal asphyxia.67 

There are several other biomarkers that may help identify injury and functional changes before permanent damage in neonates with AKI. Neutrophil gelatinase–associated lipocalin (NGAL) is a protein bound to neutrophil granules, filtered by the glomerulus, and reabsorbed by the proximal tubules.69  NGAL is highly sensitive (87%–93%) and specific (87%–93%) for AKI in neonates with perinatal asphyxia.70  The combination of G1 cell cycle arrest biomarkers urinary tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulinlike growth factor binding protein 7 (IGFBP-7) is promising for detecting early AKI. It has been shown to have a sensitivity of 89% and a specificity of 51% for predicting AKI in critically ill neonates.71  This combination has been evaluated in pediatric and adult populations and has been shown to perform well in predicting subsequent severe AKI.63  Both NGAL and TIMP-2 and IGFBP-7 are currently used off label in multiple pediatric and adult ICUs to evaluate for AKI, and there are several ongoing studies assessing their utility in pediatric AKI.72  Kidney injury molecule 1 is a transmembrane protein that is upregulated in kidney injury, and elevated levels have been shown to predict AKI.73  By using SCr as the gold standard, the areas under the curve of several of these biomarkers (in particular, NGAL and TIMP-2 and IGFBP-7) are highly predictive for AKI.73  It is imperative that we begin to incorporate novel biomarkers into future definitions of neonatal AKI and into clinical care.

In humans, there is wide variability in the nephron number present, even in the neonatal period because the completion of nephrogenesis occurs at 26 to 34 weeks.8,9,74  The mechanisms (in utero and ex utero) that influence nephrogenesis, and ultimately nephron endowment, and the processes regulating nephron loss are poorly understood.7  Preclinical advancements have been made in measuring the whole-kidney functional nephron number in vivo with a novel contrast agent. Cationic ferritin-enhanced MRI has been used to measure the glomerular number and size in health and disease.75,76  The radial glomerular count, a surrogate marker of glomerulogenesis, suggests that the nephron number is decreased in both premature neonates and in those with AKI.77  Further work is necessary to translate this technique to humans, including neonates, to further understand those at risk for future chronic kidney disease (CKD).78 

Noninvasive continuous monitoring of renal oxygen saturation with near-infrared spectroscopy (NIRS) is a new diagnostic tool that may lead to earlier diagnosis of AKI.79  Renal tissue oxygenation (RrSO2) monitoring is a surrogate for local tissue oxygen use. In neonates with CHD, NIRS monitoring of the kidney postoperatively can predict AKI.80  In premature neonates, those who subsequently develop AKI have lower RrSO2 in the first postnatal day or week.81,82  In postoperative cardiac patients, NIRS detected a decline in RrSO2 before AKI was defined by SCr or UOP.83  In those undergoing therapeutic hypothermia for HIE, neonates with AKI had higher RrSO2 values, likely pointing to a different cause or type of injury, than preterm infants or infants with CHD.84  Further work is needed to establish normative RrSO2 values in neonatal populations and treatment guidelines incorporating RrSO2 values.

Evaluating a neonate who develops AKI requires a systematic approach, which includes consideration of common factors contributing to AKI. A detailed history should be obtained to assess for risk factors for AKI, including birth weight and GA, antenatal events (including prenatal ultrasounds), pregnancy complications, birth history (interventions required at delivery), nephrotoxic medications exposure, and postnatal events. Physical examination should include an assessment of volume status, which should also include weight, daily fluid balance, and cumulative fluid balance. Fluid balance assessment is essential because volume depletion is a common cause of AKI and volume overload is a common complication of AKI. Positive fluid balance still may mean poor renal perfusion if neonates have ongoing third spacing due to capillary leak. Maintaining euvolemia is a challenging but essential management strategy in infants both to prevent AKI and to mitigate severe volume overload and complications. Focused laboratory evaluation should be performed, including measurement of serum electrolytes and serum urea nitrogen, as well as of SCr and/or CysC for GFR assessment.65  At this time, there is not a definitive role for urine biomarker assessment in all neonates, but growing data suggest that it may be useful in certain clinical settings to predict AKI.71  Fractional excretion of sodium may be helpful in some infants in differentiating volume depletion from intrinsic causes of AKI but can be challenging to interpret in premature infants because of tubular immaturity.12  We recommend that an ultrasound be obtained to evaluate for evidence of obstruction as well as congenital abnormalities of the kidney. An ultrasound can also determine kidney size. However, more studies are needed to know if kidney size is helpful in understanding clinically kidney-related meaningful outcomes.85 

Although the search for treatments or interventions for established neonatal AKI has remained elusive, medications have been evaluated in high-risk neonatal cohorts to prevent AKI. There have been multiple therapeutics evaluated for AKI prevention in neonates (without positive results), including erythropoietin, therapeutic hypothermia, remote ischemic preconditioning, and corticosteroids.8688  Methylxanthines have been evaluated in multiple neonatal populations and have had promise as a preventive treatment of AKI in high-risk populations.89,90 

After diagnosis of AKI, careful management of fluid balance and medications is essential to preventing the development of complications. Strict documentation of all fluid input and output, along with daily weights, is essential to optimizing fluid balance. Nephrotoxic medications should be assessed daily and reduced or eliminated whenever possible.17  Cumulative fluid balance should be carefully monitored to assess overall volume status. Infants with volume depletion may require additional fluid in the form of either enteral feeding, intravenous boluses, or drips. In infants with volume overload, diuretics can be trialed to maintain UOP.91  Response to furosemide (furosemide stress test) has been used as a functional biomarker for predicting severe AKI.92  Although furosemide has not been evaluated in all neonatal populations, term infants with CHD with a lower response to furosemide (median UOP at 2 hours after furosemide treatment 1.2 vs 3.4 mL/kg per hour; P = .01) have an increased risk for persistent AKI. Although furosemide responsiveness is a potential functional marker of kidney status, more studies in neonates are needed to standardize the dose and definitions used.

Theophylline and its related salt, aminophylline, have had success in increasing UOP and may prevent AKI in infants with HIE. Theophylline is an adenosine receptor antagonist that prevents AKI by inhibiting adenosine-induced renal vasoconstriction. A recent meta-analysis of 7 randomized controlled trials (458 neonates with asphyxia not receiving therapeutic hypothermia) found that theophylline administration was associated with a significantly lower incidence of AKI (odds ratio [OR]: 0.24; 95% CI: 0.16 to 0.36).90  On the basis of this evidence, a single dose of theophylline within the first 6 postnatal hours in newborns with HIE is endorsed in the 2012 KDIGO guidelines to prevent AKI.15  Aminophylline has also had promise as a rescue therapy in neonates with AKI treated with therapeutic hypothermia.93 

Caffeine is also an adenosine receptor antagonist that has been evaluated for renoprotective effects in preterm cohorts. Two studies revealed that AKI occurred less frequently in VLBW infants and preterm infants <33 weeks’ GA who received caffeine within the first postnatal week. In a retrospective study of 140 VLBW neonates,94  AKI occurred less frequently in those who received caffeine (17.8% vs 43.6%; P = .002). In a secondary analysis of the AWAKEN study, AKI occurred less frequently in neonates <33 weeks GA who received caffeine in the first postnatal week (11.2% vs 31.6%, P < .01).89  On the basis of these data, the number that needed to be exposed to caffeine to prevent 1 episode of AKI was 4.3.89 

RRT remains the primary therapy for the complications of severe AKI. The indications for RRT in neonates include acidosis, fluid overload, electrolyte abnormalities, and uremia refractory to medical management. The 2 most common modalities for RRT in neonates are peritoneal dialysis (PD) and continuous renal replacement therapy (CRRT). CRRT can be added to the extracorporeal circuit in infants receiving ECMO therapy. Between PD and CRRT, the choice often depends on the available resources, center experience, and patient characteristics.95  These therapies are complementary in that some neonates or situations will have a higher chance of success with PD, whereas others will benefit from CRRT. PD remains a common first choice for RRT in most institutions because it does not require vascular access, is more available, and is often technically easier in the smallest patients.95  PD can be performed by using a temporary catheter if the RRT requirement is thought to be short-term. Depending on the catheter used, PD can be successful in neonates as small as 830 g.96 

CRRT may be preferred in hemodynamically unstable infants, those with a history of abdominal surgery or NEC (which makes PD technically challenging), or those in whom tight control of volume status is necessary. In the past, the sole availability of CRRT equipment designed for adults and larger children presented a challenge to perform CRRT in neonates. This necessitated the use for larger catheters, tubing, and filters, resulting in high extracorporeal volumes and greater hemodynamic instability, often requiring either blood transfusions or blood priming with each circuit change. Recent advances have made CRRT increasingly accessible and successful for neonates. Introduction of smaller filters, such as the HF-20 (total extracorporeal vol of 60 mL), which was recently approved by the US Food and Drug Administration for use in the United States, has improved both the availability and acceptance of therapies by decreasing the extracorporeal volume and improving fluid removal precision.97 

In recent years, industry has made significant innovations in neonatal RRT by developing neonatal-specific CRRT machines and repurposing machines for neonatal use.98  The Cardio-Renal Pediatric Dialysis Emergency Machine (Medtronic, Minneapolis, MN) was approved for use in children between 2.5 and 8 kg the United States in 2020 and has been used in multiple countries outside the United States. This machine was developed specifically for neonates and small children.5  In contrast, Aquadex (Aquadex FlexFlow; CHF Solutions, Eden Prairie, MN) is an ultrafiltration device designed for adults but with an extracorporeal vol of 33 mL, making it ideal to adapt to safely provide CRRT to infants.5  Successful CRRT using Aquadex has been reported in infants as small as 1.4 kg.5  These machines and others, such as the Newcastle Infant Dialysis and Ultrafiltration System (Newcastle National Health Service Foundation Trust, Newcastle, United Kingdom), have begun to revolutionize the field of CRRT for neonates by lowering the associated risks and will change the conversation about when and in whom to initiate CRRT.6,99 

AKI has been shown to adversely impact other organs.100  Initially thought to be only an association, studies suggest a causal relationship in which AKI appears to drive other organ dysfunction and vice-versa, referred to as “crosstalk.”101  Experimental models describe a lung-focused inflammatory process, driven in part by cytokines such as interleukins after AKI, which are deleterious to the lungs.102  Both preterm and term infants with AKI have worse lung outcomes than their peers without AKI, including longer durations of mechanical ventilation and higher rates of bronchopulmonary dysplasia.103,104  Neonatal AKI has been shown to be an independent risk factor for neurologic complications, such as intraventricular hemorrhage, poor long-term neurocognitive outcomes, and cardiovascular disease (hypertension).105,106 

The risk of developing CKD or end-stage kidney disease after AKI is well detailed in adults.107  The evidence of progression from AKI to CKD is less established in children with AKI. In a systematic review of 346 children (mean follow-up 6.5 years), the incidence of an abnormal GFR <90 mL/minute per 1.73 m2 was 6.3% (95% CI: 5.1 to 7.5).108  The mechanisms for progression to CKD are incompletely understood but likely are secondary to maladaptive repair, ongoing inflammation, and disordered regeneration.109,110  Histologic findings of preterm neonates reveal abnormal glomeruli likely to develop sclerosis later, which could be the explanation for later CKD in those with AKI.111  These changes may be superimposed on a decreased nephron number and reduction in future development of nephrons due to prematurity.74 

The evidence for progression from AKI to CKD in neonates is less clear. Several studies have identified evidence of kidney abnormalities in preterm infants with a history of AKI.112,113  In contrast, other studies have failed to identify differences in CKD or GFR in follow-up of preterm infants who had AKI as neonates.86,114,115  The lack of appropriately powered studies, consensus definitions for AKI and CKD, and a consistent follow-up period are barriers to clearly defining the relationship between neonatal AKI and subsequent CKD. Although the Chronic Kidney Disease in Children study manages children with CKD and includes information on birth weight, it does not include detailed data on neonatal course and AKI. Large multicenter long-term follow-up studies of neonates after AKI are needed to completely understand the future risk of CKD.

Dramatic advances in the diagnosis and epidemiology of neonatal AKI and our ability to care for neonates with kidney disease have occurred in the last decade.116  New technologies and therapies designed to prevent and treat neonatal AKI augment these findings. Future work, including interventional trials of therapeutics to treat AKI (methylxanthines, RRT with novel devices), prospective long-term follow-up studies to understand risk factors for CKD development, and improved definitions of fluid overload, is needed. Additionally, continued integration of biomarkers into routine clinical use, more widespread availability and use of neonatal-specific extracorporeal devices for kidney support therapy, and standardization of monitoring and follow-up of neonates with AKI will continue to advance the field of neonatal AKI.117,118  Ongoing collaboration between neonatologists, pediatricians, and nephrologists (including the Neonatal Kidney Collaborative; www.babykidney.org) will help drive these research initiatives, mentor young faculty, educate clinicians, inform families, and advocate for neonates at risk for short- and long-term kidney-related disease.98,119 

Drs Starr and Harer conceptualized and designed this review, drafted the initial manuscript, and reviewed and revised the manuscript; Drs Charlton and Selewski conceptualized and designed this review, coordinated and provided oversight, and reviewed and revised the manuscript; Drs Guillet, Reidy, Tipple, Jetton, Kent, Abitbol, Ambalavanan, Mhanna, and Askenazi provided substantial acquisition and assimilation of the data, drafted sections of the manuscript, and critically revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

FUNDING: No external funding.

AKI

acute kidney injury

AWAKEN

Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates

CHD

congenital heart disease

CI

confidence interval

CKD

chronic kidney disease

CRRT

continuous renal replacement therapy

CysC

cystatin C

ECMO

extracorporeal membrane oxygenation

ELGAN

extremely low gestational age neonate

GA

gestational age

GFR

glomerular filtration rate

HIE

hypoxic-ischemic encephalopathy

IGFBP-7

insulinlike growth factor binding protein 7

KDIGO

Kidney Disease Improving Global Outcomes

NEC

necrotizing enterocolitis

NGAL

neutrophil gelatinase–associated lipocalin

NINJA

Nephrotoxic Injury Negated by Just-in-Time Action

NIRS

near-infrared spectroscopy

NSAID

nonsteroidal antiinflammatory drug

OR

odds ratio

PD

peritoneal dialysis

PDA

patent ductus arteriosus

RrSO2

Renal tissue oxygenation

RRT

renal replacement therapy

SCr

serum creatinine

TIMP-2

tissue inhibitor of metalloproteinase 2

UOP

urine output

VLBW

very low birth weight

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Competing Interests

POTENTIAL CONFLICT OF INTEREST: For full disclosure, we provide here an additional list of other authors’ commitments and funding sources that are not directly related to this study: Dr Askenazi is a consultant for Baxter, Nuwellis, Medtronic Bioporto, the Acute Kidney Injury Foundation, and Seastar; he receives grant funding for studies not related to this project from Baxter, Nuwellis, Medtronic, and the National Institutes of Health; the other authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.