Jennifer R. Charlton

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.

BACKGROUND AND OBJECTIVES: AKI is associated with both increased short-term morbidity and mortality and greater long-term risk for CKD. This study determined the prevalence of AKI among very low birth weight infants using a modern study definition, evaluated the frequency of AKI diagnosis reporting in the discharge summary, and determined whether infants were referred to a pediatric nephrologist for AKI follow-up. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Records of very low birth weight infants admitted to a level IV neonatal intensive care unit from 2008 to 2011 were reviewed. AKI was classified using the Kidney Disease: Improving Global Outcomes definition modified to include only serum creatinine. RESULTS: AKI occurred in 39.8% of 455 infants; 75 (16.5%) infants experienced multiple episodes of AKI, and 8 (2%) infants were discharged with an abnormal last creatinine. Updated clinical risk index for babies score >10 (odds ratio, 12.9; 95% confidence interval, 7.8 to 21.4) and gestational age <28 weeks (odds ratio, 10.6; 95% confidence interval, 6.8 to 16.7) were strongly associated with AKI in univariate analyses. AKI was associated with increased mortality (odds ratio, 4.0; 95% confidence interval, 1.4 to 11.5) and length of stay (11.7 hospital days; 95% confidence interval, 5.1 to 18.4), even after accounting for gestational age, birth weight, and updated clinical risk index for babies score. AKI was recorded in the discharge summary for only 13.5% of AKI survivors. No infants were referred to a nephrologist for AKI follow-up. CONCLUSIONS: AKI occurred in 40% of very low birth weight infants and was concentrated in the most premature and severely ill infants. One in six infants experienced multiple episodes of AKI, and a small number of infants was discharged with an elevated serum creatinine. Reporting a history of AKI in the discharge summary occurred infrequently, and referral to a nephrologist for AKI follow-up did not occur, highlighting areas for quality improvement.

OBJECTIVE: To quantify exposure to potentially nephrotoxic medications among very low birth weight (VLBW) infants and determine the relationship of nephrotoxic medication exposure to acute kidney injury (AKI) in this vulnerable population. METHODS: We reviewed 107 VLBW infants who survived to discharge from April 2011 to March 2012 and measured exposure to the following nephrotoxic medications: acyclovir, amikacin, amphotericin B, gentamicin, ibuprofen, indomethacin, iohexol, tobramycin and vancomycin. Acute kidney injury was determined by the KDIGO guidelines. RESULTS: Exposure to ≥ 1 nephrotoxic medication occurred in 87% of infants. The most common exposures were gentamicin (86%), indomethacin (43%) and vancomycin (25%). There was an inverse linear relationship between birth weight and nephrotoxic medications received per day (R(2) = 0.169, p < 0.001). Infants with AKI received more nephrotoxic medications per day than those who did not (0.24 versus 0.15; p = 0.003). CONCLUSIONS: VLBW infants are frequently exposed to nephrotoxic medications, receiving approximately two weeks of nephrotoxic medications before discharge or 1 for every 6 d of hospitalization. The greatest exposure occurred among the smallest, most immature infants and those who experienced AKI.

INTRODUCTION: Acute kidney injury (AKI) affects ~30% of hospitalized neonates. Critical to advancing our understanding of neonatal AKI is collaborative research among neonatologists and nephrologists. The Neonatal Kidney Collaborative (NKC) is an international, multidisciplinary group dedicated to investigating neonatal AKI. The AWAKEN study (Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates) was designed to describe the epidemiology of neonatal AKI, validate the definition of neonatal AKI, identify primary risk factors for neonatal AKI, and investigate the contribution of fluid management to AKI events and short-term outcomes. METHODS AND ANALYSIS: The NKC was established with at least one pediatric nephrologist and neonatologist from 24 institutions in 4 countries (USA, Canada, Australia, and India). A Steering Committee and four subcommittees were created. The database subcommittee oversaw the development of the web-based database (MediData Rave™) that captured all NICU admissions from 1/1/14 to 3/31/14. Inclusion and exclusion criteria were applied to eliminate neonates with a low likelihood of AKI. Data collection included: (1) baseline demographic information; (2) daily physiologic parameters and care received during the first week of life; (3) weekly "snapshots"; (4) discharge information including growth parameters, final diagnoses, discharge medications, and need for renal replacement therapy; and (5) all serum creatinine values. ETHICS AND DISSEMINATION: AWAKEN was proposed as human subjects research. The study design allowed for a waiver of informed consent/parental permission. NKC investigators will disseminate data through peer-reviewed publications and educational conferences. DISCUSSION: The purpose of this publication is to describe the formation of the NKC, the establishment of the AWAKEN cohort and database, future directions, and a few "lessons learned." The AWAKEN database includes ~325 unique variables and >4 million discrete data points. AWAKEN will be the largest, most inclusive neonatal AKI study to date. In addition to validating the neonatal AKI definition and identifying risk factors for AKI, this study will uncover variations in practice patterns related to fluid provision, renal function monitoring, and involvement of pediatric nephrologists during hospitalization. The AWAKEN study will position the NKC to achieve the long-term goal of improving the lives, health, and well-being of newborns at risk for kidney disease.