Abstract
Acute kidney injury (AKI) is common in premature infants and is associated with poor outcomes. Novel biomarkers can detect AKI promptly. Because premature infants are born with underdeveloped kidneys, baseline biomarker values may differ. We describe baseline values of urinary neutrophil gelatinase-associated lipocalin (NGAL), IL-18, kidney injury molecule-1 (KIM-1), osteopontin (OPN), beta-2 microglobulin (B2mG), and Cystatin-C (Cys-C). Next, we test the hypothesis that these biomarkers are inversely related to GA. Candidate markers were compared according to GA categories in 123 infants. Mixed linear regression models were performed to determine the independent association between demographics/interventions and baseline biomarker values. We found that urine NGAL, KIM-1, Cys-C, and B2mG decreased with increasing GA. With correction for urine creatinine (cr), these markers and OPN/cr decreased with increasing GA. IL-18 (with or without correction for urine creatinine) did not differ across GA categories. Controlling for other potential clinical and demographic confounders with regression analysis shows that NGAL/cr, OPN/cr, and B2mG/cr are independently associated with GA. We conclude that urine values of candidate AKI biomarkers are higher in the most premature infants. These findings should be considered when designing and analyzing biomarker studies in newborn with AKI.
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Abbreviations
- AKI:
-
acute kidney injury
- AKIN:
-
Acute Kidney Injury Network
- B2mG:
-
beta-2 microglobulin
- cr:
-
creatinine
- Cys-C:
-
Cystatin-C
- 2-plex:
-
Duplex
- 4-plex:
-
four value multiplex
- KIM-1:
-
kidney injury molecule-1
- NGAL:
-
neutrophil gelatinase-associated lipocalin
- MSD:
-
Meso Scale Discovery
- OPN:
-
osteopontin
- SCr:
-
serum creatinine
- TPA:
-
tripropylamine
- VLBW:
-
very VLBW
References
Eichenwald EC, Stark AR 2008 Management and outcomes of very low birth weight. N Engl J Med 358: 1700–1711
Askenazi DJ, Griffin R, McGwin G, Carlo W, Ambalavanan N 2009 Acute kidney injury is independently associated with mortality in very low birthweight infants: a matched case-control analysis. Pediatr Nephrol 24: 991–997
Askenazi DJ, Ambalavanan N, Goldstein SL 2009 Acute kidney injury in critically ill newborns: what do we know? What do we need to learn?. Pediatr Nephrol 24: 265–274
Koralkar R, Ambalavanan N, Levitan EB, McGwin G, Goldstein S, Askenazi D 2011 Acute kidney injury reduces survival in very low birth weight infant. Pediatr Res 69: 354–358
Bennett M, Dent CL, Ma Q, Dastrala S, Grenier F, Workman R, Syed H, Ali S, Barasch J, Devarajan P 2008 Urine NGAL predicts severity of acute kidney injury after cardiac surgery: a prospective study. Clin J Am Soc Nephrol 3: 665–673
Coca SG, Yalavarthy R, Concato J, Parikh CR 2008 Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int 73: 1008–1016
Dent CL, Ma Q, Dastrala S, Bennett M, Mitsnefes MM, Barasch J, Devarajan P 2007 Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study. Crit Care 11: R127
Diamanti-Kandarakis E, Livadas S, Kandarakis SA, Margeli A, Papassotiriou I 2008 Serum concentrations of atherogenic proteins neutrophil gelatinase-associated lipocalin and its complex with matrix metalloproteinase-9 are significantly lower in women with polycystic ovary syndrome: hint of a protective mechanism?. Eur J Endocrinol 158: 525–531
Herrero-MorÃn JD, Málaga S, Fernández N, Rey C, Diéguez MA, SolÃs G, Concha Medina A, 2007 A Cystatin C and beta2-microglobulin: markers of glomerular filtration in critically ill children. Crit Care 11: R59
Liangos O, Tighiouart H, Perianayagam MC, Kolyada A, Han WK, Wald R, Bonventre JV, Jaber BL 2009 Comparative analysis of urinary biomarkers for early detection of acute kidney injury following cardiopulmonary bypass. Biomarkers 14: 423–431
Ling W, Zhaohui N, Ben H, Leyi G, Jianping L, Huili D, Jiaqi Q 2008 Urinary IL-18 and NGAL as early predictive biomarkers in contrast-induced nephropathy after coronary angiography. Nephron Clin Pract 108: c176–c181
Mishra J, Ma Q, Kelly C, Mitsnefes M, Mori K, Barasch J, Devarajan P 2006 Kidney NGAL is a novel early marker of acute injury following transplantation. Pediatr Nephrol 21: 856–863
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: 3046–3052
Zappitelli M, Washburn KK, Arikan AA, Loftis L, Ma Q, Devarajan P, Parikh CR, Goldstein SL 2007 Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study. Crit Care 11: R84
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: 1231–1238
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: 199–203
Goldstein SL 2007 Kidney function assessment in the critically ill child: is it time to leave creatinine behind?. Crit Care 11: 141
Parikh CR, Devarajan P 2008 New biomarkers of acute kidney injury. Crit Care Med 36: S159–S165
Devarajan P 2008 Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of kidney disease. Scand J Clin Lab Invest Suppl 241: 89–94
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 14: 2534–2543
Han WK, Bailly V, Abichandani R, Thadhani R, Bonventre JV 2002 Kidney Injury Molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney Int 62: 237–244
Liangos O, Perianayagam MC, Vaidya VS, Han WK, Wald R, Tighiouart H, MacKinnon RW, Li L, Balakrishnan VS, Pereira BJ, Bonventre JV, Jaber BL 2007 Urinary N-acetyl-beta-(d)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure. J Am Soc Nephrol 18: 904–912
Trof RJ, Di Maggio F, Leemreis J, Groeneveld AB 2006 Biomarkers of acute renal injury and renal failure. Shock 26: 245–253
Devarajan P 2007 Emerging biomarkers of acute kidney injury. Contrib Nephrol 156: 203–212
Parikh CR, Edelstein CL, Devarajan P, Cantley L 2007 Biomarkers of acute kidney injury: early diagnosis, pathogenesis, and recovery. J Investig Med 55: 333–340
Vaidya VS, Ford GM, Waikar SS, Wang Y, Clement MB, Ramirez V, Glaab WE, Troth SP, Sistare FD, Prozialeck WC, Edwards JR, Bobadilla NA, Mefferd SC, Bonventre JV 2009 A rapid urine test for early detection of kidney injury. Kidney Int 76: 108–114
Lavery AP, Meinzen-Derr JK, Anderson E, Ma Q, Bennett MR, Devarajan P, Schibler KR 2008 Urinary NGAL in premature infants. Pediatr Res 64: 423–428
Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, Levin A, Acute Kidney Injury Network 2007 Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 11: R31
Huynh TK, Bateman DA, Parravicini E, Lorenz JM, Nemerofsky SL, Sise ME, Bowman TM, Polesana E, Barasch JM 2009 Reference values of urinary neutrophil gelatinase-associated lipocalin in very low birth weight infants. Pediatr Res 66: 528–532
Washburn KK, Zappitelli M, Arikan AA, Loftis L, Yalavarthy R, Parikh CR, Edelstein CL, Goldstein SL 2008 Urinary interleukin-18 is an acute kidney injury biomarker in critically ill children. Nephrol Dial Transplant 23: 566–572
Du Y, Zappitelli M, Mian A, Bennett M, Ma Q, Devarajan P, Mehta R, Goldstein SL 2011 Urinary biomarkers to detect acute kidney injury in the pediatric emergency center. Pediatr Nephrol 26: 267–274
Acknowledgements
We thank Amy Logue, RN, BSN, Faisal Schwab, Shamima Akhter, Amandi Liwo, and Sonja Jordan for their assistance in data collection and management of the study. We thank all of the nurses in the NICU for their diligence in collecting samples.
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Supported by a pilot and feasibility grant from the NIH O'Brien Center for Acute Kidney Injury, the National Kidney Foundation Young Investigator's Award, and the Kaul Pediatric Research Institute grant.
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Askenazi, D., Koralkar, R., Levitan, E. et al. Baseline Values of Candidate Urine Acute Kidney Injury Biomarkers Vary by Gestational Age in Premature Infants. Pediatr Res 70, 302–306 (2011). https://doi.org/10.1203/PDR.0b013e3182275164
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DOI: https://doi.org/10.1203/PDR.0b013e3182275164
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