Jul 7, 2012 - Distinguish between drugs that cause direct renal injury versus those that predispose the kidney to more pronounced drug toxicity. 4. Develop ...
Article
renal disorders
Nephrotoxic Medication Exposure and Acute Kidney Injury in Neonates Michael Zappitelli, MD, MSc,* David T. Selewski, MD,† David J. Askenazi, MD, MSPH
‡
Author Disclosure Dr Zappitelli disclosed that he received salary support from the Fondation de Recherche en Sante´ du Que´bec; Dr Selewski disclosed that he was supported by
Abstract Nephrotoxic medication use is common in neonates. In older children, the use of nephrotoxic medication is known to be one of the most common causes of acute kidney injury (AKI) and to be associated with increased morbidity. In critically ill neonates, AKI significantly complicates fluid and electrolyte management and may be an important risk factor for mortality. Better understanding of methods to avoid and detect the presence of nephrotoxicity may lead to more intelligent use of these medications, which could ultimately reduce the incidence of AKI and improve outcomes. In this work, we summarize why neonates are predisposed to drug nephrotoxicity, review the mechanisms and clinical picture of the most common nephrotoxic medications used in neonates (aminoglycosides, vancomycin, amphotericin B, acyclovir, nonsteroidal antiinflammatory drugs, and radiocontrast agents), and discuss the roles of angiotensinconverting enzyme inhibitors and diuretics in nephrotoxicity. We also suggest ways to avoid and reduce the incidence and complications of neonatal nephrotoxicity.
a Research Training in Pediatric Nephrology grant (T-32 F023015); and Dr Askenazi disclosed that he is on the speakers bureau and serves as consultant for Gambro Renal Products. This commentary does contain a discussion of an unapproved/
Learning Objectives
After completing this article, readers should be able to:
1. Understand why the neonatal kidney is predisposed to acute kidney injury (AKI) and nephrotoxicity. 2. Understand the mechanisms by which most commonly used nephrotoxic drugs cause AKI in neonates. 3. Distinguish between drugs that cause direct renal injury versus those that predispose the kidney to more pronounced drug toxicity. 4. Develop an approach to minimizing and preventing nephrotoxic AKI in neonates.
Neonatal Acute Kidney Injury and Nephrotoxicity
Acute kidney injury (AKI) refers to abrupt renal dysfunction with a wide spectrum of severity, ranging from small rises in serum creatinine (SCr) with minor electrolyte abnormala commercial product/ ities to severe fluid overload, toxin accumulation, and dialysis requirement. An acute 50% device. rise in SCr is independently associated with increased risk of morbidity and mortality in critically ill children. (1) AKI epidemiologic data in neonates are sparse and mostly from single-center studies demonstrating that AKI occurs in 18% of very low birthweight infants, (2) 30% to 50% of infants following congenital heart surgery, (3) 71% of neonates with congenital diaphragmatic hernia receiving extracorporeal membrane oxygenation, (4) and Abbreviations w50% of neonates with perinatal depression. (5) These studies also suggest that neonates with AKI have higher risk for ACE: angiotensin-converting enzyme death, increased length of hospitalization, and prolonged meAKI: acute kidney injury chanical ventilation. The definitions of AKI vary, ranging ATN: acute tubular necrosis from a ‡50% SCr rise to the need for renal replacement GFR: glomerular filtration rate therapy. To standardize the definition of AKI in neonates, NSAIDs: nonsteroidal anti-inflammatory drugs Askenazi et al (6) proposed a modification for neonates of SCr: serum creatinine the internationally recognized Acute Kidney Injury Network investigative use of
*Division of Pediatrics, Montreal Children’s Hospital, McGill University Health Centre, Montreal, Canada. † Department of Pediatric Nephrology, University of Michigan, Ann Arbor, MI. ‡ Department of Pediatric Nephrology, University of Alabama at Birmingham, Birmingham, AL.
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staging (Table 1), based on rise in SCr from a previous trough level. This definition deals with the challenge unique to neonates of maternal creatinine concentrations and the physiologic SCr decrease in the first weeks after birth. The definition does not include evaluation of urine output because it is still unclear how to incorporate urine output criteria for AKI definition in children and neonates. Nephrotoxic medications constitute one of the most common causes of AKI in older children (7) and are commonly used in neonates. (2) The neonatal kidney has developmental characteristics that may increase the likelihood of nephrotoxicity: kidney development continues until 34 to 36 weeks’ gestational age, and there is a physiologically low glomerular filtration rate (GFR) in early life. (8) Interestingly, the unique neonatal renal physiology may theoretically protect the kidney from some nephrotoxicity. For example, certain drugs requiring renal tubular transport as an initial toxic pathway may not achieve their “full” toxic potential as in an older child, due to immature transport function (examples: aminoglycosides, vancomycin). (9) Critically ill neonates are “primed” for nephrotoxicity in the setting of hypotension, organ ischemia, multiple organ failure, and concurrent nephrotoxin exposure. (10) However, nephrotoxicity represents the most potentially avoidable cause of AKI in neonates. In this review, we will summarize briefly what is known about the more commonly used nephrotoxins in neonates, highlighting where future research is needed.
Proposed AKI Definition in Neonates*
Table 1.
Stage of Severity No AKI Stage 1
Stage 2 Stage 3
Criteria No SCr change or rise by 4 mEq/kg per day) may reduce the risk of nephrotoxicity via unclear mechanisms. (28) The use
of amphotericin B should be accompanied by careful assessment of hydration status, fluid and sodium intake, concomitant nephrotoxic medication use, close monitoring of electrolytes and renal function during treatment, and electrolyte supplementation. ANTIVIRAL AGENTS. Acyclovir is utilized in neonates for serious herpes simplex viral infections. Acyclovir is eliminated by the kidneys through filtration and secretion and is relatively insoluble in urine. Nephrotoxicity can be seen in up to 17% of patients and warrants diligent monitoring throughout treatment. (29) Acyclovir nephrotoxicity is classically attributed to tubular obstruction secondary to drug crystallization, though there may be evidence of direct tubular toxicity from acyclovir metabolites. (30) Nephrotoxicity is increased in patients who have impaired GFR or are receiving other nephrotoxic medications. (31) Proposed measures to decrease AKI incidence include aggressive hydration, administration over 1 to 2 hours, and dose adjustment for renal function. If continued therapy with acyclovir is mandatory and AKI develops, decreasing the dose is appropriate.
Nonantibiotics NONSTEROIDAL ANTI-INFLAMMATORY DRUGS. Neonates have high levels of circulating prostaglandins, which play an integral role in renal water clearance and afferent arteriolar vasodilatation. The neonatal kidney relies on prostaglandins to offset the highly vasoconstrictive milieu after birth. Inhibiting prostaglandin synthesis can profoundly decrease neonatal renal blood flow and GFR. (32) NSAIDs are mainly used in the NICU to decrease circulating prostaglandin for prevention of intraventricular hemorrhage or the treatment of patent ductus arteriosus. NSAID-induced renal insufficiency and oliguria are typically transient but can complicate fluid overload, electrolyte management, and medication dosing. The two most studied NSAIDs are indomethacin and ibuprofen. The nephrotoxic adverse effects of indomethacin with increased SCr and decreased urine output have long been known. Ibuprofen has been investigated extensively as a potential alternative to indomethacin for closure of the ductus arteriosus. Magnitude of SCr rise and extent of oliguria is less with ibuprofen; however, AKI still occurs. (33)(34)(35) Maintaining intravascular volume status is key to reducing the risk of AKI with NSAID treatment because hypovolemia will further exaggerate GFR reduction. When prescribing NSAIDs, one should also consider using the lowest effective dose and avoiding other nephrotoxins during treatment. The use of diuretics or dopamine to mitigate the effects of NSAIDs on NeoReviews Vol.13 No.7 July 2012 e423
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renal hemodynamics has not been useful. Finally, because of the direct effect of NSAIDs on GFR reduction, it is important to know if other administered medications are eliminated by the kidney, because they may require dose adjustment. ACE INHIBITORS. The potentially devastating effects of prenatal exposure to ACE inhibitors on fetal nephrogenesis have been well described, with consequences ranging from oliguria to oligohydramnios and Potter’s sequence. It may therefore be appropriate to avoid the use of ACE inhibitors in neonates
