Neonatal Acute Kidney Injury

Introduction

During the past decade, there have been extraordinary advances in our understanding of neonatal acute kidney injury (AKI). During this time, it has become clear that AKI occurs commonly in critically ill neonates and is associated with adverse outcomes irrespective of the specific neonatal population studied. AKI is no longer considered a symptom of illness severity but instead an independent risk factor for adverse outcomes, impacting short-term outcomes (length of mechanical ventilation, length of stay, and mortality) as well as long-term kidney health (subsequent chronic kidney disease [CKD] and hypertension).

Neonates with AKI represent some of the most challenging patients encountered in the intensive care unit. A firm understanding of AKI risk factors and pathophysiology is necessary for neonatal providers as well as an appreciation of the unique characteristics of neonatal AKI. This chapter provides a comprehensive overview of neonatal AKI including developmental considerations, definitions, epidemiology and risk factors, evaluation, novel approaches, management, and long-term outcomes.

Developmental Considerations

In order to appreciate the intricacies of neonatal AKI, an understanding of nephrogenesis and the dynamic kidney function changes that occur after birth is critical. A detailed understanding of these processes is outside the scope of this chapter, but this section will serve as a primer to better understand the pathophysiology and potential impact of neonatal AKI on outcomes.

Definitions of Neonatal AKI

AKI, previously referred to as “acute renal failure,” is defined by an abrupt change in GFR ( Fig. 58.1 ) identified by a rise in serum creatinine (SCr) or decrease in urine output. SCr is known to be an imperfect clinical biomarker for AKI but remains the gold standard for diagnosis at this time. In general, SCr is a delayed marker of AKI (elevated 48–72 hours after insult) and reflects changes in function rather than ongoing tubular damage. Defining AKI in neonates is further complicated by dynamic changes in renal physiology after birth, as noted above, and the presence of maternal SCr. With the increase in GFR that occurs in the first weeks of life, SCr slowly decreases. However, the trajectory of declining SCr is also highly dependent on gestational age (GA) with a slower decline seen in lower GA infants. ^,

During the past two decades there has been a transition from threshold-based definitions of AKI to staged definitions that represent the entire spectrum of injury that typifies AKI. These definitions include the Risk, Injury, Failure, Loss, and End stage renal disease (RIFLE), the Acute Kidney Injury Network classification (AKIN), and most recently, the Kidney Disease: Improving Global Outcomes (KDIGO) definition. A multitude of studies have been performed using these staged definitions of AKI in a variety of neonatal populations. This important work led to the development of a consensus neonatal definition of AKI.

In 2013, an expert working group consisting of neonatologists and nephrologists at a National Institutes of Health–sponsored neonatal AKI workshop agreed that the neonatal modified KDIGO definition should be used as a consensus definition for neonatal AKI ( Table 58.1 ). The modifications of the neonatal KDIGO definition include a reference SCr value, defined as the lowest previous SCr value and an absolute SCr cutoff of ≥2.5 mg/dL (221 μmol/L) to define severe AKI (stage 3). Using this definition, single-center studies and the multicenter AWAKEN (Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates) study have clearly shown AKI occurs commonly in the neonatal intensive care unit (NICU) and is associated with adverse outcomes.

In discussions about AKI definitions, it is critical to consider urine output. Although urine output criteria have been included in every AKI staging iteration, they have rarely been systematically studied. This largely stems from the challenges of quantifying urine output and retrieving this data from medical records. As a result, the contribution of urine output to AKI has largely been ignored in the AKI literature until recently. Recent multicenter work in critically ill children and neonates has clearly shown that AKI as defined by urine output identifies distinct episodes of AKI associated with adverse outcomes that would have been missed by SCr-based criteria alone. ^, Although there remain important questions about the optimal threshold and duration of oliguria, it is clear that urine output is a critical component to the definition of neonatal AKI.

It is important to appreciate that the authors of the consensus statement acknowledge the fact that the neonatal modified KDIGO definition represents a starting point for an iterative process in defining neonatal AKI. In an effort to begin to interrogate the current definition of neonatal AKI, a secondary analysis of the AWAKEN study data was undertaken to evaluate optimal definitions based on GA. The study identified a number of opportunities for optimization of the neonatal AKI definition, including unique SCr rise cutoffs for different GAs. The optimal absolute SCr rise thresholds to predict mortality were ≥0.3 mg/dL (≥26.5 μmol/L) for <29 weeks’ GA and ≥0.1 mg/dL (≥8.85 μmol/L) for ≥29 weeks GA. Further prospective studies are needed to determine the optimal SCr-based neonatal AKI definition for both clinicians and researchers. Until further work is done and subsequent consensus modifications of the neonatal AKI definition are published, it is recommended that clinicians and researchers use the neonatal modified KIDGO criteria to define neonatal AKI.

Epidemiology and Risk Factors for Neonatal AKI

Despite the many recent advances in our understanding of neonatal AKI, there are no evidence-based treatments for AKI. As a result, it is critical to understand which neonatal populations are at highest risk to develop AKI. Single-center work has clearly shown that there are identifiable patient factors and disease characteristics that predispose neonates to AKI. The AWAKEN study has provided a large, multicenter, retrospective review of risk factors for AKI in both the early (first 7 days) and later neonatal period. ^,

Several specific populations of neonates are known to be at high risk for AKI, including premature neonates (particularly very low birth weight [VLBW, i.e., birth weight <1,500 g] and extremely low birth weight [ELBW, i.e., birth weight <1,000 g] infants) and infants with specific diseases processes including sepsis, necrotizing enterocolitis (NEC), and hypoxic-ischemic encephalopathy (HIE), as well as those infants who reuire extracorporeal membrane oxygenation, and those with congenital heart disease requiring cardiac surgery. Preterm infants, especially VLBW and ELBW infants, are known to be at particularly high risk for AKI given the dynamic changes in renal blood flow and physiology after birth compounded by lower nephron endowment as described above. These vulnerable patients are also known to have prolonged hospitalizations with potential for multiple episodes of AKI and are particularly sensitive to other perinatal factors and nephrotoxins. Table 58.2 includes epidemiologic study findings for premature, VLBW, and ELBW infants, specifically. The epidemiology, as well as the pathophysiology believed to be underlying the increased risk for AKI in each of these conditions, is shown in Table 58.3 .