Drug-associated acute kidney injury in neonates

Introduction

Acute kidney injury (AKI) is defined as sudden impairment in kidney function that results in the inability to maintain adequate fluid, electrolyte, and waste product homeostasis. AKI occurs commonly in critically ill children, with varying degrees of severity, and it is associated with increased morbidity and mortality. AKI can have important short-term consequences (e.g., longer duration of mechanical ventilation or ICU hospitalization) and long-term consequences (e.g., chronic kidney disease, hypertension). Critically ill newborns represent a high-risk population for developing drug-associated renal injury because of incomplete maturation of the kidney; furthermore, they are often exposed to numerous nephrotoxic medications. Drug-associated AKI may compromise the formation and development of nephrons, particularly in preterm neonates, who have incomplete nephrogenesis. There is no treatment for established AKI in this vulnerable population. Because of this, the focus has shifted to identifying modifiable risk factors that could prevent or delay the progression of AKI. In particular, nephrotoxic medications are a prevalent and potentially preventable cause of AKI in newborns. The purpose of this chapter is to briefly summarize what is known about drug-associated nephrotoxicity in neonates, highlighting the potential long-term implications of neonatal AKI.

Background

The Assessment of Worldwide Acute Kidney injury Epidemiology in Neonates (AWAKEN) study reported that AKI occurred in 30% of critically ill neonates and was associated with increased length of stay, duration of mechanical ventilation, and mortality. The traditional approach to determine renal injury in neonates is based on two classical biochemical markers, serum creatinine (SCr) and blood urea nitrogen. Although these indices are valid indicators of renal function, their use in the neonatal period is associated with some limitations. Neonatal SCr initially reflects maternal values, and, rather than maintaining a steady state, these levels then decline at varying rates over days to weeks depending on gestational age, such that changes (or lack of change) in SCr may be difficult to interpret when evaluating for AKI. Rather than using arbitrary, binary AKI definitions (SCr >1.5 mg/dL, urine output <0.5 mL/kg/hr), several new neonatal studies have used modifications of the Acute Kidney Injury Network (AKIN) staging system or the risk, injury, failure, loss, and end-stage renal disease (RIFLE) classification. These standardized frameworks have allowed better comparisons across studies, have shown consistently that even mild degrees of AKI portend poor outcomes, and have demonstrated worse outcomes with progressive AKI severity. Alternatively, Jetton and Askenazi proposed a standardized neonatal AKI definition based on the Kidney Disease Improving Global Outcomes (KDIGO) definition adopted in 2012. In this modified KDIGO definition, the baseline SCr is assumed to be the lowest SCr level noted in each infant. Also, the SCr threshold for stage 3 AKI was reduced to 2.5 mg/dL rather than the usual KDIGO threshold of 4 mg/dL. The neonatal modified KDIGO definition and classification of AKI ( Table 17.1 ) have been adopted by many researchers.

AKI epidemiologic data in neonates are sparse and mostly from single-center studies. AKI has been reported in 18% of very-low-birth-weight (VLBW) infants, 30% to 50% of infants following congenital heart surgery, 71% of neonates with congenital diaphragmatic hernia receiving extracorporeal membrane oxygenation, and 38% of neonates with perinatal asphyxia. In addition to the unique nature of neonatal renal development and physiology, several perinatal and postnatal risk factors predispose critically ill neonates to AKI. Insults such as hypoperfusion and nephrotoxic medication exposure can be classified as pre-renal or intrinsic. Hypoperfusion is a result of cardiovascular decompensation and hypotension due to a variety of reasons, such as hypoxemia, blood loss, sepsis, or patent ductus arteriosus. In these settings, healthy regulation of blood flow via dilatation of the afferent arterioles by prostaglandins and vasoconstriction of both efferent and afferent arterioles by angiotensin is often impaired, resulting in oliguria. Nephrotoxic insults cause AKI by decreasing renal perfusion, causing direct tubular injury, triggering an episode of interstitial nephritis, or causing tubular obstruction. Although a few studies have evaluated drug-induced AKI epidemiology in older children, data on neonatal nephrotoxic medication–associated AKI are scarce. The most widely used nephrotoxic medications in the neonatal intensive care unit (NICU) are antibiotics, antifungals, non-steroidal anti-inflammatory drugs (NSAIDs), and diuretics. In a retrospective cohort study of 52,061 infants in 127 NICUs, the median antibiotic exposure was close to one-quarter of all patient days, with a range across units from 2.4% to 97%. At all levels of care, from intermediate to units that provide the highest level of critical care, antibiotic use was independent of proven infection, necrotizing enterocolitis, surgical volume, or mortality, with a 40-fold variation in NICU antibiotic use.

AKI was independently associated with increased mortality and length of hospitalization in VLBW infants. Early recognition and ongoing surveillance of modifiable risk factors that could prevent or delay progression of AKI in neonates is important. Because of the limitations of traditional definitions and biomarkers of AKI and because in most cases the etiology of AKI is multifactorial, drug-associated AKI represents the most common potentially avoidable type of AKI in neonates.

Nephrotoxin-induced AKI

Drug-associated AKI occurs through a variety of mechanisms. The underlying neonatal susceptibility to drug toxicity plays an important role in AKI development. Additionally, the inherent nephrotoxicity of drugs and the transport and metabolism of medications by the kidneys are important factors in the progression of AKI. In hospitalized children, predisposing factors such as age, pharmacogenetics, underlying disease, dosage of the nephrotoxin, and concomitant medication determine and influence the severity of nephrotoxic insult. Critically ill neonates are at higher risk for nephrotoxicity in the setting of hypotension, organ ischemia, multiple organ dysfunction, and concurrent nephrotoxic medication exposure. Renal blood flow is proportionally reduced in preterm infants compared with full-term infants, making the preterm kidney more vulnerable to hypoperfusion.

A meta-analysis of risk factors for AKI in critically ill adult patients showed 53% greater odds of developing AKI with each additional nephrotoxic drug received (odds ratio, 1.53; confidence interval [CI], 1.09–2.14). Moffett et al. found that both the number of nephrotoxic drugs and duration of exposure were positively correlated with development of AKI in hospitalized non-critically ill children. In this cohort, age was protective, so infants were at higher risk of developing AKI. The majority of nephrotoxic medications to which patients were exposed were antimicrobial agents (52%). A pharmacoepidemiologic study of exposure to nephrotoxic medications among critically ill children in a pediatric intensive care unit (PICU) showed that furosemide (administered to 67.8% of patients), vancomycin (28.7%), and gentamicin (21.4%) were the most frequently administered. Patients who developed AKI were more likely to be exposed to at least one nephrotoxic medication, and risk increased with an increasing number of nephrotoxic medications.

The potential for adverse drug events among neonates is likely greater than that among children. However, neonates remain an understudied population. In the U.S. Food and Drug Administration (FDA) database for pediatric studies submitted between 1997 and 2010 involving 406 pediatric labeling changes, only 6% of the studies included new neonatal information. A retrospective review of a national database collected prospectively showed that only 35% of the most commonly prescribed medications in NICUs are FDA approved for infants. In this large cohort, the 10 most commonly reported medication exposures were ampicillin, gentamicin, caffeine, vancomycin, beractant, furosemide, fentanyl, dopamine, midazolam, and calfactant. For extremely low-birth-weight (ELBW) infants, the 10 most commonly reported drug exposures were gentamicin, ampicillin, caffeine, vancomycin, furosemide, dopamine, beractant, indomethacin, fentanyl, and albuterol. A single-center study of nephrotoxic medication exposure in VLBW neonates showed that 86.9% were exposed to at least one nephrotoxic medication during their hospital stay, and the neonates with the greatest cumulative exposure were at the highest risk of acquiring AKI. This study showed that VLBW infants were exposed to approximately 2 weeks of nephrotoxic medications before discharge, or on 1 of every 6 days of hospitalization. The greatest exposures occurred among the smallest and most immature infants and in those who experienced AKI.

Although many medications are eliminated by the kidneys, data about renal processing of medications used in neonates are limited. Medication-induced AKI occurs through mechanisms that involve their inherent toxicity, as well as their transport and handling by the kidneys. Neonatal variability in developmental pharmacokinetics, pharmacodynamics, and pharmacogenetics, combined with heterogeneity in the underlying pathophysiology of nephrotoxicity, leads to uneven responses to medications. The two major pathways that mediate drug clearance are glomerular filtration and tubular secretion (sometimes in combination). Therefore, tubular cells and the surrounding interstitium are exposed to potentially nephrotoxic medications via apical contact and cellular uptake or by transport from the basolateral circulation through cells with subsequent apical efflux into the urine. Then, as drugs are concentrated as they move from the proximal tubules into the loop of Henle and distal tubules, there is increased potential for tubulointerstitial injury. Additionally, distal nephrons can be injured secondary to precipitation of drug crystals within tubule lumens with the formation of obstructive drug-containing casts. A panel of international pediatric and adult nephrologists and pharmacists developed a standardized description of the phenotype for drug-associated kidney disease in hospitalized patients. The four general categories include AKI, glomerular disorders, nephrolithiasis, and tubular dysfunction. Underlying mechanisms can be either dose dependent or dose independent (as in acute interstitial nephritis). Each phenotype is based on primary and secondary criteria, and at least one primary criterion must be met for all drugs suspected of causing drug-induced kidney disease. For each phenotype definition, the following critical elements from the Bradford–Hill causation criteria must be met:

• 1.

  The drug exposure must be at least 24 hours preceding the event.

• 2.

  There should be biological plausibility for the causal drug, based on known mechanisms of drug effect, metabolism, and immunogenicity.

• 3.

  Complete data surrounding the period of drug exposure (including but not limited to comorbidities, additional nephrotoxic exposures, exposure to contrast agents, surgical procedures, blood pressure, and urine output) are required to account for concomitant risks.

• 4.

  The strength of the relationship between the attributable drug and the phenotype should be based on drug exposure duration, extent of primary and secondary criteria met, and the time course of the injury.

Nephrotoxic medications