In recent years, there have been significant advancements in our understanding of acute kidney injury (AKI) and its impact on outcomes across medicine. Research based on single-center cohorts suggests that neonatal AKI is very common and associated with poor outcomes. In this state-of-the-art review on neonatal AKI, we highlight the unique aspects of neonatal renal physiology, definition, risk factors, epidemiology, outcomes, evaluation, and management of AKI in neonates. The changes in renal function with gestational and chronologic age are described. We put forth and describe the neonatal modified Kidney Diseases: Improving Global Outcomes AKI criteria and provide the rationale for its use as the standardized definition of neonatal AKI. We discuss risk factors for neonatal AKI and suggest which patient populations may warrant closer surveillance, including neonates <1500 g, infants who experience perinatal asphyxia, near term/ term infants with low Apgar scores, those treated with extracorporeal membrane oxygenation, and those requiring cardiac surgery. We provide recommendations for the evaluation and treatment of these patients, including medications and renal replacement therapies. We discuss the need for long-term follow-up of neonates with AKI to identify those children who will go on to develop chronic kidney disease. This review highlights the deficits in our understanding of neonatal AKI that require further investigation. In an effort to begin to address these needs, the Neonatal Kidney Collaborative was formed in 2014 with the goal of better understanding neonatal AKI, beginning to answer critical questions, and improving outcomes in these vulnerable populations.
- AKI —
- acute kidney injury
- CRRT —
- continuous renal replacement therapy
- CKD —
- chronic kidney disease
- ECMO —
- extracorporeal membrane oxygenation
- ELBW —
- extremely low birth weight
- GFR —
- glomerular filtration rate
- KDIGO —
- Kidney Diseases: Improving Global Outcomes
- NIDDK —
- National Institute of Diabetes and Digestive and Kidney Diseases
- PD —
- peritoneal dialysis
- SCr —
- serum creatinine
- VLBW —
- very low birth weight infants
Over the past 15 years, there have been significant advancements in the study of acute kidney injury (AKI) regarding the diagnosis, recognition, intervention, and impact of AKI on morbidity and mortality in critically ill children.1–4 It has become apparent that children who survive an episode of AKI are at increased risk for chronic kidney disease (CKD) and warrant long-term follow-up.5,6 Neonatal AKI studies have begun to show similar conclusions: AKI is common and is associated with poor outcomes.7–12 These studies remain limited to small single-center cohorts using varying definitions of AKI, making generalization difficult.
Although progress has been made in our understanding of neonatal AKI, a tremendous amount of work is needed to optimize our ability to detect and intervene in newborns with AKI. To advance the field, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) sponsored a workshop dedicated to neonatal AKI in April 2013. An important result of this meeting was the recognition that collaboration between neonatologists and nephrologists is imperative to advance the study of neonatal AKI and to improve outcomes in these vulnerable patients. In this state-of-the-art review, we examine aspects of neonatal AKI, including neonatal renal physiology, definitions, risk factors, epidemiology and outcomes, and evaluation and management of AKI.
Neonatal Renal Physiology
Although a detailed discussion of renal development is outside the scope of this review, there are a number of features of neonatal renal physiology that are pertinent to AKI in neonates, including the duration of nephrogenesis, renal blood flow, glomerular filtration rate (GFR), and tubular immaturity. Nephrogenesis begins at the fifth week of gestation and continues until 34 to 36 weeks,13 yielding the adult complement of 200 000 to 2.7 million nephrons.14,15 The impact of prematurity, intrauterine growth restriction, and AKI on nephrogenesis has not been fully delineated, but small studies suggest that the extrauterine environment and AKI are detrimental to optimal nephrogenesis.16–19
There are significant changes in neonatal renal blood flow after birth that are relevant to the study of AKI in neonates. In comparison with the 20% to 25% of cardiac output received by the adult kidney, at birth the kidneys receive 2.5% to 4.0% of the cardiac output. Over time, this increases to 6% at 24 hours of life, 10% at 1 week, and 15% to 18% at 6 weeks of age.20–23 The changes in renal blood flow after birth result from increased renal perfusion pressure, increased systemic arteriolar resistance, and decreased renal vascular resistance due to neurohumoral changes with angiotensin II and prostaglandins playing major roles.24
In the fetal and neonatal period, the renin-angiotensin system is critical to normal renal development and blood flow. Angiotensin II, the effector molecule of the renin-angiotensin system, causes vasoconstriction at the afferent and efferent arterioles with the greatest impact at the efferent arteriole.25,26 Prostaglandins represent the most important counter-regulatory molecules in the neonatal period and lead to afferent arteriole dilatation.27 The importance of each of these systems is seen in the exacerbated response that critically ill neonates have to inhibition of these systems by medications when oliguria and/or AKI develops after exposure.
GFR represents the most recognized measure of kidney function. In term infants, the GFR improves from 10 to 20 mL/min/1.73 m2 during the first days of life to 30 to 40 mL/min/1.73 m2 by 2 weeks of life. In premature infants, the GFR at birth is even lower and increases slower than in term infants. The GFR improves steadily over the first few months of life, reaching the adult GFR by 2 years of age.28–30 The dynamic nature of the neonatal GFR has implications for the care of neonates particularly with regard to drug exposures, dosing, and susceptibility to the development of AKI.
The term neonate has more mature renal tubular function, which can appropriately respond to homeostatic needs. The tubular function is immature in premature infants, with a decreased ability to reabsorb electrolytes and protein and to concentrate urine. This has important implications for the management and diagnosis of AKI in premature infants, who rely on the clinician to appropriately prescribe fluids and replace electrolyte losses. The immaturity of these mechanisms in the neonatal kidneys explains some of the subtleties of urinary findings (fractional excretion of sodium) in neonatal AKI that differ from that in older children.
Definition of Neonatal AKI
AKI is classically defined as a sudden decline in kidney function resulting in derangements in fluid balance, electrolytes, and waste products.31 Currently, the diagnosis of AKI is dependent on a rise in serum creatinine (SCr) or decrease in urine output. Unfortunately, SCr is a suboptimal biomarker as it is a marker of kidney function, not damage. As a result, there is a significant delay in the rise of SCr after an insult (48–72 hours) and a significant amount of function has to be lost before SCr will rise (>50% of the GFR). SCr also has unique challenges in the neonatal population, including the presence of maternal creatinine, varying degrees of creatinine reabsorption in the proximal tubules, overall lower GFRs, and maturational differences.32–35 As a result, there has been a significant amount of research to identify novel biomarkers of damage to allow for the earlier identification of neonates with AKI (up to 48 hours before SCr rise). These novel biomarkers include urine neutrophil gelatinase-associated lipocalin, cystatin-c, kidney injury molecule-1, and others.36–42 By detecting earlier stages of kidney injury, these biomarkers may allow for prevention of or early intervention in AKI in neonates. Although these biomarkers continue to show promise, currently SCr is the standard used for the diagnosis of AKI in all populations.
In 2005, an empirical definition for AKI was introduced into the adult and pediatric literature that recognized stages of severity based on a decrease in GFR and/or urine output. This definition was developed based on evidence that even small changes in SCr were associated with increased morbidity and mortality. Current definitions have demonstrated that even small degrees of AKI are associated with increased morbidity and mortality in children and adults.1,3,43 This empirical definition has evolved based on observational data from millions of patients and hundreds of studies into the Kidney Diseases: Improving Global Outcomes (KDIGO) AKI definition published in 2013, maintaining a 3-tiered categorical staging model depicting mild, moderate, and severe stages of AKI.44 The use of standardized definitions of AKI has allowed comparison between studies and was a fundamental first step that has been integral to the study of AKI in medicine.
Before 2008, most neonatal AKI studies used arbitrary definitions of AKI frequently defined by an absolute SCr ≥1.5 mg/dL. In response to the trends in the diagnosis of AKI, a number of neonatal studies were performed by using the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) and Acute Kidney Injury Network (AKIN) definitions of AKI.8,45 One such standardized definition of AKI described in detail by Jetton and Askenazi is based on a modification of the KDIGO definition termed the neonatal modified KDIGO criteria (Table 1). This definition stages AKI based on an absolute rise in SCr from a previous trough and should be used in children <120 days of age. In April 2013, neonatologists and pediatric nephrologists participating in the NIDDK workshop carefully scrutinized this definition. They concluded that, at this time, this definition offers a reasonable starting point and would allow for consistency throughout studies. As this definition is empirical, large multicenter studies are greatly needed to validate this definition and address all aspects of the definitions, including the degree of SCr rise, age of utilization, and how to deal with a rise in SCr from 0.2 to 0.3 mg/dL, which technically represents a 1.5-fold increase and would qualify as AKI. Some have suggested that the SCr should rise to an absolute value of >0.5 mg/dL and meet the previous criteria to qualify as AKI.1,12
Risk Factor for Neonatal AKI
The change in renal function that defines AKI should be thought of as the result of a combination of susceptibility factors and exposures.44 Although neonates are subject to the same risk factors present in critically ill children of all ages, special consideration must be made to risk factors inherent to neonatal renal development and physiology. Therefore, we will review perinatal and postnatal risk factors associated with AKI, including perinatal events/exposures, sepsis, and nephrotoxic medication exposure that may identify neonates who require enhanced vigilance (Table 2).
Perinatal Exposures and Events
As a result of the unique neonatal renal physiology, a number of maternal exposures and perinatal events can lead to neonatal AKI. For example, maternal exposure to nonsteroidal anti-inflammatory drugs predisposes neonates to oliguria and AKI.47 The multiple roles of the renin-angiotensin system in renal development prenatally, as well as the maintenance of renal blood flow postnatally, can lead to a broad range of outcomes in the newborns exposed to angiotensin-converting enzyme inhibitors ranging from renal agenesis to AKI, depending on the timing and duration of exposure. Perinatal risk factors associated with the development of AKI are outlined in Table 2 and include low Apgar scores, intubation, low cord pH, and asystole.8–10,12,45,47–50
Sepsis is a cause of significant morbidity and mortality in neonates. Sepsis has been consistently shown to be a risk factor for the development of AKI across neonatal populations, contributing to up to 78% of the cases of AKI.51–54 Mathur et al55 described 200 term neonates with sepsis of whom 52 developed AKI. Those who developed AKI had a lower birth weight and were more likely to have meningitis, disseminated intravascular coagulation, and septic shock. Neonates who develop sepsis are classically thought to be predisposed to AKI secondary to the hypotension associated with systemic inflammation, but there also appears to be a direct impact on the kidneys.56 Furthermore, AKI may develop despite the maintenance of systemic blood pressures and renal blood flow, suggesting that sepsis may directly damage the kidney by effects on microvasculature.56–59
Nephrotoxic medications are known to be a cause of AKI across the spectrum of critically ill and hospitalized children.60,61 Exposure to nephrotoxic medications is also associated with AKI in neonates and may represent a modifiable risk factor.47,48,62 Table 3 provides a description of common nephrotoxic medications used in the NICU. In 2013, Rhone et al62 evaluated the epidemiology and impact of nephrotoxic medication exposure in 107 very low birth weight (VLBW) infants. In this study, 87% of neonates were exposed to at least 1 nephrotoxic medication and on average these neonates were exposed to 14 days of nephrotoxic medications during their NICU stay. Although this study represents an important step, the epidemiology of exposure to nephrotoxic medications in general NICU populations remains unstudied.
Epidemiology and Outcomes of Neonatal AKI
There have been a number of single-center studies that have evaluated the impact of AKI in VLBW neonates, extremely low birth weight (ELBW) neonates, sick near-term/term neonates, neonates on extracorporeal membrane oxygenation (ECMO), and asphyxiated newborns showing that AKI is common and associated with poor outcomes (Table 4).8–12,45,62–64 Here we review AKI studies in some exemplar patient populations.
VLBW and ELBW Neonates
There have been 3 large single-center studies to date that have evaluated AKI in VLBW neonates (500–1500 g).10,65,66 In 2011, Koralkar et al10 reported on 229 VLBW infants followed prospectively from birth until 36 weeks postmenstrual age. The incidence of AKI, by using the neonatal modified KDIGO criteria, was 18%. The mortality in infants with AKI was significantly higher than those without AKI (42% vs 5%, P < .001). After adjusting for potential confounders, those with AKI had a significantly higher chance of death (hazard ratio 2.4, 95% confidence interval [CI] 0.95–6.0; P < .06). Viswanathan et al65 reported similar findings in a retrospective single-center study, where 12.5% (59/472) of all ELBW infants developed AKI and mortality among those with AKI was significantly higher than controls (70% vs 22%, respectively). In a large retrospective study of VLBW infants, Carmody et al66 examined 455 VLBW infants and found an AKI incidence of 39.8%. In this study, AKI was independently associated with increased mortality (odds ratio 4.0, 95% CI 1.4–11.5) and length of stay (11.7 hospital days, 95% CI 5.1–18.4).
Infants with perinatal asphyxia have been recognized as a group that is at high risk of AKI. Recently there have been 2 single-center studies that have looked at the incidence of AKI by using modern AKI definitions. Kaur et al9 reported an incidence of AKI of 41.7%. Selewski et al12 evaluated newborns undergoing therapeutic hypothermia for perinatal asphyxia and found that 36 (38%) of 96 had AKI. Even after controlling for important potential confounders, children with AKI on average were ventilated 4 days longer (P < .001) and hospitalized 3.4 days longer (P = .023). In addition, these investigators also showed that AKI during therapeutic hypothermia was associated with abnormal brain MRI findings at 7 to 10 days of life, implicating AKI as a potential marker for neurologic outcomes.11
Neonates supported with ECMO represent a unique patient population that is particularly prone to AKI based on the severity of their illness and the inflammatory response that accompanies exposure to the extracorporeal circuit.67,68 Zwiers et al69 evaluated AKI in 242 neonates on ECMO over a 14-year period showing an AKI incidence of 64% and a mortality of 65% when AKI progressed to the highest stage. These mirror the findings of Gadepalli et al8 in neonates with congenital diaphragmatic hernia on ECMO where AKI occurred in 71% of neonates, and those with the highest stage of AKI had a mortality of 73%.
Neonatal Cardiac Surgery
The association of AKI with cardiac surgery in older children has been well studied and the association of AKI with increased mortality is clear. Alabbas et al64 published a retrospective study of 122 neonates (<28 days) showing that AKI occurred in 62% of the neonates. The highest stage of AKI was associated with increased mortality and increased ICU length of stay. These findings are similar to the findings reported by Blinder et al7 in 430 infants (<90 days) undergoing cardiac surgery.
Evaluation and Management of Neonatal AKI
The evaluation of a neonate who develops AKI requires a systematic approach, which frequently involves evaluating prerenal, intrinsic, and postrenal causes. We highlight important aspects of the evaluation. A detailed clinical history should include assessment of gestational age, antenatal (ultrasounds), maternal (nephrotoxic medication), birth (fetal heart rate monitoring and resuscitation), and postnatal (nephrotoxic medications, hypotension) events. The physical examination should focus on volume status and vital signs. A thorough evaluation of volume status also requires assessment of serum electrolytes, fluid balance, and, importantly, body weight. Utilization of these 3 measurements can assist in determining both hypovolemia from insensible losses, as well as hypervolemia from fluid overload. Assessment of fractional excretion of sodium can help to differentiate the prerenal (hypovolemia) from intrinsic (acute tubular necrosis) causes of AKI, although in premature infants this metric may not be as helpful. Finally, to evaluate potential postrenal (obstruction) causes of AKI, an ultrasound should be obtained.
After the diagnosis of AKI, it becomes important to prevent the development of sequelae. Daily evaluation of medications and the participation of a pharmacist are paramount in the management of the critically ill neonate to monitor drug levels and avoid nephrotoxic exposures when clinically feasible. Strict documentation of all fluid input and output, serum electrolytes, and weight is essential to optimize fluid status. Tracking cumulative fluid overload provides a global assessment of fluid status. Hypervolemia may dictate intervention and nephrology consultation.
There are sparse data documenting interventions that can prevent AKI in at-risk patients or ameliorate AKI once it is established. In neonates with perinatal asphyxia, adenosine receptor antagonists (theophylline) may prevent AKI by inhibiting the adenosine-induced vasoconstriction. Several independent randomized studies in asphyxiated infants have shown that prophylactic theophylline, given early after birth, was associated with better kidney function.70–73 As a result, the KDIGO guidelines recommend a single dose of theophylline for asphyxiated infants at risk for AKI.44 Caution must be taken, as theophylline has some potentially harmful neurologic effects.74 Other drugs that have been studied to prevent the development of AKI and improve renal blood flow include dopaminergic agonists (dopamine and fenoldopam).75–77 Although each of these agents has shown promise in the prevention of AKI, the clinical studies have been mixed, and firm recommendations on their use cannot be made.
Diuretics are frequently used in patients with AKI in attempts to maintain urine output. Studies in critically ill patient populations have not demonstrated a beneficial effect of diuretics on outcomes and have occasionally demonstrated worse outcomes in patients with AKI treated with diuretics. For example, in a retrospective case-control study, bumetanide was shown to improve the urine output of ELBW infants with AKI at the expense of increasing their SCr.78 In another study, bumetanide was also shown to increase significantly the urine output, in premature infants with oliguric AKI, but at the expense of a transient increase in SCr.79 Despite the lack of evidence in neonates, a trial of diuretics in oliguric neonates with AKI is warranted given the complexity of renal replacement therapy. Large-scale multicenter trials of these medications in neonates are greatly needed.
Because of the lack of successful strategies to prevent or ameliorate AKI, the primary therapy for severe cases of AKI is renal replacement therapy. Indications for renal replacement therapy in neonates include refractory acidosis, uremia, electrolyte abnormalities, inability to provide adequate nutrition, and fluid overload. The association between fluid overload and mortality in critically ill patients is one of the hottest topics in acute care nephrology and warrants special mention. Pediatricians have been at the forefront of identifying fluid overload as a risk factor for mortality in critically ill patients.80 This is highlighted by the findings of the prospective pediatric continuous renal replacement therapy (CRRT) registry. Sutherland et al81 showed in a prospective registry of 227 children who were on CRRT that those with a percentage fluid overload <20% at initiation of renal replacement therapy had improved rates of survival compared with those with a cumulative fluid balance >20% (46% vs 68%, P < .01). These findings have since been verified in a number of different pediatric patient populations highlighting the importance of fluid overload and the timing of renal replacement therapy in critically ill children.82–85
Recent data extend these findings to critically ill children and adults independent of renal replacement therapy.86–88 The impact of fluid overload is highlighted in the practice guidelines proposed by the American College of Critical Care Medicine for pediatric and neonatal septic shock, which recommend that interventions to address fluid balance are warranted when critically ill children amass 10% volume overload.89 Limited data are available on fluid overload in neonates. Askenazi et al63 showed that sick late preterm neonates with AKI had a higher median fluid overload at day of life 3 than those without AKI (+8.2% vs –4%, P < .001). As fluid overload is a potentially modifiable risk factor for mortality, research into its impact on neonatal outcomes is critical to provide information to clinicians about fluid provision and the timing of renal replacement therapy.
Throughout adult and pediatric intensive care medicine, renal replacement therapy has transitioned from being a “last-ditch effort” to an early therapy directed at supporting the critically ill patient by maintaining electrolyte homeostasis, allowing for provision of adequate nutrition, and preventing/reducing hypervolemia. This mindset of early intervention has not fully reached the neonatal population, possibly because of the added risk of dialysis machines, ethical considerations, and a lack of studies that illustrate the role of fluid overload on poor outcomes in these patients. Renal replacement therapy poses particular challenges in the neonate, as most equipment was designed for older children. Currently, peritoneal dialysis (PD) is the modality of choice in infants. PD is technically easier, as there is no need for vascular access or an extracorporeal blood circuit.90 If peritoneal dialysis is felt to be a short-term requirement, a temporary catheter can be placed. Several studies describe successful peritoneal dialysis by several different techniques in critically ill neonates as small as 830 g.91–95
When PD is technically difficult because of abdominal wall defects, skin infections, communication to the pleural space, or high ultrafiltration needs, CRRT can be performed. CRRT is performed with a hemodialysis catheter placed in a central location and either regional or systemic anticoagulation. The volume of the extracorporeal circuit is particularly critical in the neonatal population and often these neonates will require that the CRRT machine be primed with blood if the circuit volume exceeds 10% to 15% of the total blood volume.96 In the United States, current CRRT machines are approved only for those weighing >20 kg, but these machines have been used off-label in children <5 kg.97 There are a number of considerations when evaluating CRRT in a neonate, including center expertise, prescription, and error rates of current machines, which has been recognized and led to the development of neonatal CRRT machines.98 CRRT systems, such as CARPEDIEM99 (Bellco, Mirandola, Italy) and Nidus,100 are being used in countries outside the United States in neonates. These machines show promise, as they have smaller extracorporeal volumes and are highly accurate. Despite these recent advances, the evidence on the practice of renal replacement therapy in neonates is limited to single-center case series with a complete lack of multicenter data.
Consequences and Follow-up of Neonatal AKI
Previously, it was assumed that those who survived an episode of AKI would recover kidney function without long-term effects. Recent data from animals,101 critically ill children,5,6 and adults102 with AKI suggest that survivors are at risk for the development of CKD. Mammen et al5 reported that 10% of children who developed AKI in the PICU had GFR <60 mL/min/1.73 m2, 1 to 3 years later. Perhaps even more alarming was the finding that nearly 50% of this cohort was found to be “at risk” for CKD.
The role that AKI plays in the development of CKD in the neonatal population is unknown. Several case reports document that CKD occurs in infants who had AKI; however, these studies are small, single-center retrospective reports. Recognizing the long-term implications of AKI, the most recent KDIGO practice guidelines recommend that all patients who experience AKI be evaluated after 3 months for new onset or worsening of CKD.44 They caution that even if CKD is not present at that time, those with AKI are considered to have increased risk for CKD long-term. Although these recommendations are likely pertinent to infants, currently there is not enough firm evidence to make formal follow-up recommendations after episodes of neonatal AKI. General pediatricians should consider neonates who have suffered AKI at increased risk and monitor blood pressure with consideration of further testing on a case-by-case basis. Large longitudinal multicenter studies designed to follow neonates after critical illness are greatly needed to define the most appropriate surveillance protocols, as well as identify those most at risk.
Neonatal AKI represents a rapidly evolving area in clinical research, but a significant amount of work remains to improve the outcomes in these patients. An important first step moving forward is the development of a standardized definition of AKI. Initially, the neonatal modified KDIGO AKI definition will be used as common nomenclature to unify and compare research in neonatal AKI. Although this definition represents the best available, it remains limited in that it has not been systematically studied in a multicenter manner evaluating the association of AKI with outcomes. Further work in neonatal AKI needs to focus on defining risk factors, the implications of fluid balance, renal replacement therapy, and the long-term outcomes, including the development of CKD in this susceptible population.
After the NIDDK-sponsored workshop on neonatal AKI, an international, multi-institutional, multidisciplinary group, the Neonatal Kidney Collaborative, was formed. This group aims to answer some of the questions surrounding neonatal AKI with the goal of improving outcome and optimizing care for these vulnerable patients.
- Accepted March 16, 2015.
- Address correspondence to Jennifer R. Charlton MD, MS, Department of Pediatrics, University of Virginia, Box 800386, Charlottesville, VA 22908. E-mail:
Dr Selewski conceptualized and designed the outline of the manuscript, and reviewed and revised the manuscript; Drs Charlton, Jetton, and Kent provided substantial acquisition and assimilation of the data, drafted sections of the manuscript, and critically revised the manuscript; Drs Guillet, Mhanna, and Askenazi critically revised the manuscript; and all authors approved the final manuscript as submitted.
FINANCIAL DISCLOSURE: Dr Askenazi is a speaker for the AKI Foundation; the other authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
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- Copyright © 2015 by the American Academy of Pediatrics