Pediatric Nephrology

, Volume 23, Issue 6, pp 977–984 | Cite as

Metabonomics of acute kidney injury in children after cardiac surgery

  • Richard D. Beger
  • Ricky D. Holland
  • Jinchun Sun
  • Laura K. Schnackenberg
  • Page C. Moore
  • Catherine L. Dent
  • Prasad Devarajan
  • Didier Portilla
Original Article


Acute kidney injury (AKI) is a major complication in children who undergo cardiopulmonary bypass surgery. We performed metabonomic analyses of urine samples obtained from 40 children that underwent cardiac surgery for correction of congenital cardiac defects. Serial urine samples were obtained from each patient prior to surgery and at 4 h and 12 h after surgery. AKI, defined as a 50% or greater rise in baseline level of serum creatinine, was noted in 21 children at 48–72 h after cardiac surgery. The principal component analysis of liquid chromatography/mass spectrometry (LC/MS) negative ionization data of the urine samples obtained 4 h and 12 h after surgery from patients who develop AKI clustered away from patients who did not develop AKI. The LC/MS peak with mass-to-charge ratio (m/z) 261.01 and retention time (tR) 4.92 min was further analyzed by tandem mass spectrometry (MS/MS) and identified as homovanillic acid sulfate (HVA-SO4), a dopamine metabolite. By MS single-reaction monitoring, the sensitivity was 0.90 and specificity was 0.95 for a cut-off value of 24 ng/μl for HVA-SO4 at 12 h after surgery. We concluded that urinary HVA-SO4 represents a novel, sensitive, and predictive early biomarker of AKI after pediatric cardiac surgery.


Metabonomics Acute renal failure Acute kidney injury Biomarkers Homovanillic acid sulfate 


  1. 1.
    Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A (2007) Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11:R31PubMedCrossRefGoogle Scholar
  2. 2.
    Morelli S, Ricci Z, Di Chiara L, Stazi GV, Polito A, Vitale V, Giorni C, Iacoella C, Picardo S (2007) Renal replacement therapy in neonates with congenital heart disease. In: Ronco C, Bellomo R, Kellum JA (eds) Contributions to nephrology, vol 156. Karger, Basel, pp 428–433Google Scholar
  3. 3.
    Skippen PW, Krahn GE (2005) Acute renal failure in children undergoing cardiopulmonary bypass. Crit Care Resusc 7:286–291PubMedGoogle Scholar
  4. 4.
    Bailey D, Phan V, Litalien C, Ducruet CT, Merouani A, Lacroix J, Gauvin F (2007) Risk factors of acute renal failure in critically ill children: a prospective descriptive epidemiological study. Pediatr Crit Care Med 8:29–35PubMedCrossRefGoogle Scholar
  5. 5.
    Williams DM, Sreedhar SS, Mickell JJ, Chan JC (2002) Acute kidney failure: a pediatric experience over 20 years. Arch Pediatr Adolesc Med 156:893–900PubMedGoogle Scholar
  6. 6.
    Moghal NE, Brocklebank JT, Meadow SR (1998) A review of acute renal failure in children: incidence, etiology and outcome. Clin Nephrol 49:91–95PubMedGoogle Scholar
  7. 7.
    Goldstein SL (2006) Pediatric acute kidney injury: it’s time for real progress. Pediatr Nephrol 21:891–895PubMedCrossRefGoogle Scholar
  8. 8.
    Nguyen MT, Devarajan P (2007) Biomarkers for the early detection of acute kidney injury. Pediatr Nephrol DOI 10.1007/s00467-007-0470-x
  9. 9.
    Portilla D, Dent C, Sugaya T, Nagothu K, Kundi I, Moore P, Noiri E, Devarajan P (2008) Liver fatty acid binding protein as a biomarker of acute kidney injury after cardiac surgery. Kidney Int 73:465–472Google Scholar
  10. 10.
    Fiehn O (2002) Metabolomics—the link between genotypes and phenotypes. Plant Mol Biol 48:155–171PubMedCrossRefGoogle Scholar
  11. 11.
    Nicholson JK, Lindon JC, Holmes E (1999) ‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 29:1181–1189PubMedCrossRefGoogle Scholar
  12. 12.
    Dunn WB, Ellis DI (2005) Metabolomics: current analytical platforms and methodologies. Trends Anal Chem 24:285–294CrossRefGoogle Scholar
  13. 13.
    Robertson DG (2005) Metabonomics in toxicology: a review. Toxicol Sci 85:809–822PubMedCrossRefGoogle Scholar
  14. 14.
    Lenz EM, Wilson ID (2007) Analytical strategies in metabonomics. J Proteome Res 6:443–458PubMedCrossRefGoogle Scholar
  15. 15.
    Lenz EM, Bright J, Knight R, Westwood FR, Davies D, Major H, Wilson ID (2005) Metabonomics with 1H-NMR spectroscopy and liquid chromatography-mass spectrometry applied to the investigation of metabolic changes caused by gentamicin-induced nephrotoxicity in the rat. Biomarkers 10:173–187PubMedCrossRefGoogle Scholar
  16. 16.
    Devarajan P, Mishra J, Supavekin S, Patterson LT, Steven Potter S (2003) Gene expression in early ischemic renal injury: clues towards pathogenesis, biomarker discovery, and novel therapeutics. Mol Genet Metab 80:365–376PubMedCrossRefGoogle Scholar
  17. 17.
    Mishra J, Ma Q, Prada A, Mitsnefes M, Zahedi K, Yang J, Barasch J, Devarajan P (2003) Identification of neutrophil gelatinase-associated lipocalin as a novel early urinary biomarker for ischemic renal injury. J Am Soc Nephrol 4:2534–2543CrossRefGoogle Scholar
  18. 18.
    Supavekin S, Zhang W, Kucherlapati R, Kaskel FJ, Moore LC, Devarajan P (2003) Differential gene expression following early renal ischemia/reperfusion. Kidney Int 63:1714–1724PubMedCrossRefGoogle Scholar
  19. 19.
    Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, Ruff SM, Zahedi K, Shao M, Bean J, Mori K, Barasch J, Devarajan P (2005) Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 365:1231–1238PubMedCrossRefGoogle Scholar
  20. 20.
    Parikh CR, Abraham E, Ancukiewicz M, Edelstein CL (2005) Urine IL-18 is an early diagnostic marker for acute kidney injury and predicts mortality in the intensive care unit. J Am Soc Nephrol 16:3046–3052PubMedCrossRefGoogle Scholar
  21. 21.
    Parikh CR, Mishra J, Thiessen-Philbrook H, Dursun B, Ma Q, Kelly C, Dent C, Devarajan P, Edelstein CL (2006) Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int 70:199–203PubMedCrossRefGoogle Scholar
  22. 22.
    Goldstein DS, Mezey E, Yamamoto T, Aneman A, Friberg P, Eisenhofer G (1995) Is there a third peripheral catecholaminergic system? Endogenous dopamine as an autocrine/paracrine substance derived from plasma DOPA and inactivated by conjugation. Hypertens Res 18:S93–S99PubMedCrossRefGoogle Scholar
  23. 23.
    Lee MR (1993) Dopamine and the kidney: ten years on. Clin Sci 84:357–375PubMedGoogle Scholar
  24. 24.
    Wolfovitz E, Grossman E, Folio CJ, Keiser HR, Kopin IJ, Goldstein DS (1993) Derivation of urinary dopamine from plasma dihydroxyphenylalanine in humans. Clin Sci 84:549–557PubMedGoogle Scholar
  25. 25.
    Anggard E, Lewander T, Sjoquist B (1974) Determination of homovanillic acid turnover in man. Life Sci 15:111–122PubMedCrossRefGoogle Scholar
  26. 26.
    Shimada M, Terazawa R, Kamiyama Y, Honma W, Nagata K, Yamazoe Y (2004) Unique properties of a renal sulfotransferase, St1d1, in dopamine metabolism. J Pharmacol Exp Ther 310:808–814PubMedCrossRefGoogle Scholar
  27. 27.
    Sampaio-Maia B, Moreira-Rodrigues M, Pestana M (2006) Role of chronic inhibition of dopamine-metabolizing enzymes in the regulation of renal sodium and phosphate excretion in the rat remnant kidney. Nephron Physiol 103:14–24CrossRefGoogle Scholar

Copyright information

© IPNA 2008

Authors and Affiliations

  • Richard D. Beger
    • 1
  • Ricky D. Holland
    • 1
  • Jinchun Sun
    • 1
  • Laura K. Schnackenberg
    • 1
  • Page C. Moore
    • 2
  • Catherine L. Dent
    • 3
  • Prasad Devarajan
    • 4
  • Didier Portilla
    • 5
  1. 1.Division of Systems ToxicologyUnited States Food and Drug Administration, National Center for Toxicological ResearchJeffersonUSA
  2. 2.Department of BiostatisticsUniversity of Arkansas for Medical SciencesLittle RockUSA
  3. 3.Cardiology, Cincinnati Children’s Hospital Medical CenterUniversity of Cincinnati School of MedicineCincinnatiUSA
  4. 4.Nephrology & Hypertension, Cincinnati Children’s Hospital Medical CenterUniversity of Cincinnati School of MedicineCincinnatiUSA
  5. 5.Division of Nephrology, Department of Internal MedicineUniversity of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare SystemLittle RockUSA

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