Abstract
Objective:
To evaluate the risk of nonsteroidal anti-inflammatory drug (NSAID) therapy-associated acute kidney injury (AKI) among neonates diagnosed with patent ductus arteriosus (PDA) who are treated with gentamicin.
Study Design:
Multicenter retrospective observational study of patients ⩽44 postmenstrual weeks of age diagnosed with PDA who received gentamicin during hospitalization between January 2006 and December 2014. Patients with and without NSAID exposure were matched on covariates associated with AKI and NSAID therapy. The primary end point, AKI, was defined according to Kidney Disease Improving Global Outcomes neonatal criteria.
Results:
The rate of AKI for the entire cohort (n=594) was 12% (n=71). Among neonates receiving NSAIDS, 14.8% (n=44) experienced an AKI as compared to 9.1% (n=27) for those who were not exposed (relative risk, 1.6; 95% confidence interval, 1.0 to 2.6). Therefore, the attributable risk of NSAID use was 5.7% (95% confidence interval, 0.5 to 11.0).
Conclusion:
Among neonates with PDA and receiving gentamicin, NSAID therapy increases the risk of AKI by about 6%.
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References
Benitz WE . Treatment of persistent patent ductus arteriosus in preterm infants: time to accept the null hypothesis? J Perinatol 2010; 30 (4): 241–252.
Slaughter JL, Reagan PB, Bapat RV, Newman TB, Klebanoff MA . Nonsteroidal anti-inflammatory administration and patent ductus arteriosus ligation, a survey of practice preferences at US children's hospitals. Eur J Pediatr 2016; 175 (6): 775–783.
Pacifici GM . Clinical pharmacology of ibuprofen and indomethacin in preterm infants with patent ductus arteriosus. Curr Pediatr Rev 2014; 10 (3): 216–237.
Weintraub AS, Connors J, Carey A, Blanco V, Green RS . The spectrum of onset of acute kidney injury in premature infants less than 30 weeks gestation. J Perinatol 2016; 36 (6): 474–480.
Koralkar R, Ambalavanan N, Levitan EB, McGwin G, Goldstein S, Askenazi D . Acute kidney injury reduces survival in very low birth weight infants. Pediatr Res 2011; 69 (4): 354–358.
Viaud M, Llanas B, Harambat J . Renal outcome in long-term survivors from severe acute kidney injury in childhood. Pediatr Nephrol 2012; 27 (1): 151–152.
Gubhaju L, Sutherland MR, Horne RS, Medhurst A, Kent AL, Ramsden A et al. Assessment of renal functional maturation and injury in preterm neonates during the first month of life. Am J Physiol Renal Physiol 2014; 307 (2): F149–F158.
Girardi A, Raschi E, Galletti S, Poluzzi E, Faldella G, Allegaert K et al. Drug-induced renal damage in preterm neonates: state of the art and methods for early detection. Drug Saf 2015; 38 (6): 535–551.
Sutherland MR, Gubhaju L, Moore L, Kent AL, Dahlstrom JE, Horne RS et al. Accelerated maturation and abnormal morphology in the preterm neonatalkidney. J Am Soc Nephrol 2011; 22 (7): 1365–1374.
Stojanovic V, Barisic N, Milanovic B, Doronjski A . Acute kidney injury in preterm infants admitted to a neonatal intensive care unit. Pediatr Nephrol 2014; 29 (11): 2213–2220.
Constance JE, Balch AH, Stockmann C, Linakis MW, Korgenski EK, Roberts JK et al. A propensity-matched cohort study of vancomycin-associated nephrotoxicity in neonates. Arch Dis Child Fetal Neonatal Ed 2016; 101 (3): F236–F243.
Ibrahim J, Maffei D, El-Chaar G, Islam S, Ponnaiya S, Nayak A et al. Should gentamicin trough levels be routinely obtained in term neonates? J Perinatol 2016; 36 (11): 962–965.
Valitalo PA, van den Anker JN, Allegaert K, de Cock RF, de Hoog M, Simons SH et al. Novel model-based dosing guidelines for gentamicin and tobramycin in preterm and term neonates. J Antimicrob Chemother 2015; 70 (7): 2074–2077.
Brash AR, Hickey DE, Graham TP, Stahlman MT, Oates JA, Cotton RB . Pharmacokinetics of indomethacin in the neonate. Relation of plasma indomethacin levels to response of the ductus arteriosus. N Engl J Med 1981; 305 (2): 67–72.
Selewski DT, Charlton JR, Jetton JG, Guillet R, Mhanna MJ, Askenazi DJ et al. Neonatal acute kidney injury. Pediatrics 2015; 136 (2): e463–e473.
Akima S, Kent A, Reynolds GJ, Gallagher M, Falk MC . Indomethacin and renal impairment in neonates. Pediatr Nephrol 2004; 19 (5): 490–493.
Zappitelli M, Selewski D, Askenazi D . Nephrotoxic medication exposure and acute kidney injury in neonates. Neoreviews 2012; 13 (7): e420–e427.
Allegaert K . The impact of ibuprofen or indomethacin on renal drug clearance in neonates. J Matern Fetal Neonatal Med 2009; 22 (Suppl 3): 88–91.
Moss AJ, Emmanouilides G, Duffie ER Jr . Closure of the ductus arteriosus in the newborn infant. Pediatrics 1963; 32: 25–30.
Irmesi R, Marcialis MA, Anker JV, Fanos V . Non-steroidal anti-inflammatory drugs (NSAIDs) in the management of patent ductus arteriosus (PDA) in preterm infants and variations in attitude in clinical practice: a flight around the world. Curr Med Chem 2014; 21 (27): 3132–3152.
Johnston PG, Gillam-Krakauer M, Fuller MP, Reese J . Evidence-based use of indomethacin and ibuprofen in the neonatal intensive care unit. Clin Perinatol 2012; 39 (1): 111–136.
Carmody JB, Swanson JR, Rhone ET, Charlton JR . Recognition and reporting of AKI in very low birth weight infants. Clin J Am Soc Nephrol 2014; 9 (12): 2036–2043.
Gubhaju L, Sutherland MR, Black MJ . Preterm birth and the kidney: implications for long-term renal health. Reprod Sci 2011; 18 (4): 322–333.
Goldstein SL, Devarajan P . Acute kidney injury in childhood: should we be worried about progression to CKD? Pediatr Nephrol 2011; 26 (4): 509–522.
Kidney disease: improving global outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury 2012.
Lozano G, Fuhrman B . Acute kidney injury in critically ill infants and children. Pediatr Crit Care Med 2016; 17 (5): 472–473.
Bertram JF, Goldstein SL, Pape L, Schaefer F, Shroff RC, Warady BA . Kidney disease in children: latest advances and remaining challenges. Nat Rev Nephrol 2016; 12 (3): 182–191.
ACOG committee opinion No 579: definition of term pregnancy. Obstet Gynecol 2013; 122 (5): 1139–1140.
Martin JA, Hamilton BE, Ventura SJ, Osterman MJ, Kirmeyer S, Mathews TJ et al. Births: final data for 2009. Natl Vital Stat Rep 2011; 60 (1): 1–70.
Askenazi DJ, Koralkar R, Hundley HE, Montesanti A, Patil N, Ambalavanan N . Fluid overload and mortality are associated with acute kidney injury in sick near-term/term neonate. Pediatr Nephrol 2013; 28 (4): 661–666.
Thayyil S, Sheik S, Kempley ST, Sinha A . A gestation- and postnatal age-based reference chart for assessing renal function in extremely premature infants. J Perinatol 2008; 28 (3): 226–229.
Miall LS, Henderson MJ, Turner AJ, Brownlee KG, Brocklebank JT, Newell SJ et al. Plasma creatinine rises dramatically in the first 48 hours of life in preterm infants. Pediatrics 1999; 104 (6): e76.
Bateman DA, Thomas W, Parravicini E, Polesana E, Locatelli C, Lorenz JM . Serum creatinine concentration in very-low-birth-weight infants from birth to 34-36 wk postmenstrual age. Pediatr Res 2015; 77 (5): 696–702.
Ho DIK, King G, Stuart E . Matching as nonparametric preprocessing for reducing model dependence in parametric causal inference. Polit Anal 2007; 15 (3): 199–236.
Austin PC . An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011; 46 (3): 399–424.
Luo Z, Gardiner JC, Bradley CJ . Applying propensity score methods in medical research: pitfalls and prospects. Med Care Res Rev 2010; 67 (5): 528–554.
Micallef L, Rodgers P . eulerAPE: drawing area-proportional 3-Venn diagrams using ellipses. PLoS ONE 2014; 9 (7): e101717.
Carmody JB, Harer MW, Denotti AR, Swanson JR, Charlton JR . Caffeine exposure and risk of acute kidney injury in a retrospective cohort of very low birth weight neonates. J Pediatr 2016; 172: 63–68.
Viswanathan S, Manyam B, Azhibekov T, Mhanna MJ . Risk factors associated with acute kidney injury in extremely low birth weight (ELBW) infants. Pediatr Nephrol 2012; 27 (2): 303–311.
Pacifici GM . Differential renal adverse effects of ibuprofen and indomethacin in preterm infants: a review. Clin Pharmacol 2014; 6: 111–116.
Walker MW, Clark RH, Spitzer AR . Elevation in plasma creatinine and renal failure in premature neonates without major anomalies: terminology, occurrence and factors associated with increased risk. J Perinatol 2011; 31 (3): 199–205.
Rhone ET, Carmody JB, Swanson JR, Charlton JR . Nephrotoxic medication exposure in very low birth weight infants. J Matern Fetal Neonatal Med 2014; 27 (14): 1485–1490.
Toth-Heyn P, Drukker A, Guignard JP . The stressed neonatal kidney: from pathophysiology to clinical management of neonatal vasomotor nephropathy. Pediatr Nephrol 2000; 14 (3): 227–239.
Basu RK, Zappitelli M, Brunner L, Wang Y, Wong HR, Chawla LS et al. Derivation and validation of the renal angina index to improve the prediction of acute kidney injury in critically ill children. Kidney Int 2014; 85 (3): 659–667.
Kellum JA, Bellomo R, Ronco C . Kidney attack. JAMA 2012; 307 (21): 2265–2266.
Sosenko IR, Fajardo MF, Claure N, Bancalari E . Timing of patent ductus arteriosus treatment and respiratory outcome in premature infants: a double-blind randomized controlled trial. J Pediatr 2012; 160 (6): 929–935 e921.
Hirt D, Van Overmeire B, Treluyer JM, Langhendries JP, Marguglio A, Eisinger MJ et al. An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamicstudy. Br J Clin Pharmacol 2008; 65 (5): 629–636.
Shaffer CL, Gal P, Ransom JL, Carlos RQ, Smith MS, Davey AM et al. Effect of age and birth weight on indomethacin pharmacodynamics in neonates treated for patent ductus arteriosus. Crit Care Med 2002; 30 (2): 343–348.
Joyce EL, Kane-Gill SL, Fuhrman DY, Kellum JA . Drug-associated acute kidney injury: who's at risk? Pediatr Nephrol 2016; 32: 59–69.
Aranda JV, Clyman R, Cox B, Van Overmeire B, Wozniak P, Sosenko I et al. A randomized, double-blind, placebo-controlled trial on intravenous ibuprofen L-lysine for the early closure of nonsymptomatic patent ductus arteriosus within 72 hours of birth in extremely low-birth-weight infants. Am J Perinatol 2009; 26 (3): 235–245.
Zwiers AJ, de Wildt SN, Hop WC, Dorresteijn EM, Gischler SJ, Tibboel D et al. Acute kidney injury is a frequent complication in critically ill neonates receiving extracorporeal membrane oxygenation: a 14-year cohort study. Crit Care 2013; 17 (4): R151.
Souter D, Harding J, McCowan L, O'Donnell C, McLeay E, Baxendale H . Antenatal indomethacin—adverse fetal effects confirmed. Aust N Z J Obstet Gynaecol 1998; 38 (1): 11–16.
Stoops C, Sims B, Griffin R, Askenazi DJ . Neonatal acute kidney injury and the risk of intraventricular hemorrhage in the very low birth weight infant. Neonatology 2016; 110 (4): 307–312.
Ment LR, Vohr B, Allan W, Westerveld M, Sparrow SS, Schneider KC et al. Outcome of children in the indomethacin intraventricular hemorrhage prevention trial. Pediatrics 2000; 105 (3 Pt 1): 485–491.
Fowlie PW, Davis PG, McGuire W . Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants. Cochrane Database Syst Rev 2010; (7): CD000174.
Gal P . Optimum use of therapeutic drug monitoring and pharmacokinetics-pharmacodynamics in the NICU. J Pediatr Pharmacol Ther 2009; 14 (2): 66–74.
Van Overmeire B, Smets K, Lecoutere D, Van de Broek H, Weyler J, Degroote K et al. A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus. N Engl J Med 2000; 343 (10): 674–681.
Schmidt B, Davis P, Moddemann D, Ohlsson A, Roberts RS, Saigal S et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med 2001; 344 (26): 1966–1972.
Reese J, Veldman A, Shah L, Vucovich M, Cotton RB . Inadvertent relaxation of the ductus arteriosus by pharmacologic agents that are commonly used in the neonatal period. Semin Perinatol 2010; 34 (3): 222–230.
Schreuder MF, Bueters RR, Huigen MC, Russel FG, Masereeuw R, van den Heuvel LP . Effect of drugs on renal development. Clin J Am Soc Nephrol 2011; 6 (1): 212–217.
Hanna MH, Askenazi DJ, Selewski DT . Drug-induced acute kidney injury in neonates. Curr Opin Pediatr 2016; 28 (2): 180–187.
Alexander F, Chiu L, Kroh M, Hammel J, Moore J . Analysis of outcome in 298 extremely low-birth-weight infants with patent ductus arteriosus. J Pediatr Surg 2009; 44 (1): 112–117.
Macedo E, Bouchard J, Soroko SH, Chertow GM, Himmelfarb J, Ikizler TA et al. Fluid accumulation, recognition and staging of acute kidney injury in critically-ill patients. Crit Care 2010; 14 (3): R82.
Goldstein SL . Renal recovery at different ages. Nephron Clin Pract 2014; 127 (1–4): 21–24.
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Constance, J., Reith, D., Ward, R. et al. Risk of nonsteroidal anti-inflammatory drug-associated renal dysfunction among neonates diagnosed with patent ductus arteriosus and treated with gentamicin. J Perinatol 37, 1093–1102 (2017). https://doi.org/10.1038/jp.2017.80
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DOI: https://doi.org/10.1038/jp.2017.80
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