The Role of Novel Biomarkers in Early Diagnosis and Prognosis of Acute Kidney Injury in Newborns

Abstract

Acute kidney injury (AKI) refers to the rapid loss of renal function. In clinical practice, AKI is common among hospitalized patients of all age groups including neonates and remains an important cause of morbidity and mortality due to its late diagnosis and therefore delayed therapeutic intervention. Although the precise incidence of AKI in newborn is unknown, several studies have reported that 8 to 24% of all critically ill newborns in neonatal intensive care units may develop the condition. We aim at reviewing the existing literature on novel serum and urinary biomarkers and discuss their role in the early diagnosis and prognosis of AKI in newborns. Specifically, this review will focus on cystatin C (CysC), neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) in serum and on CysC, NGAL, kidney injury molecule-1, and IL-18 in urine.

Keywords

acute kidney injury - newborns - biomarkers - creatinine

• References

• 1 Liangos O, Wald R, O'Bell JW, Price L, Pereira BJ, Jaber BL. Epidemiology and outcomes of acute renal failure in hospitalized patients: a national survey. Clin J Am Soc Nephrol 2006; 1: 43-51
• 2 Andreoli SP. Acute renal failure in the newborn. Semin Perinatol 2004; 28: 112-123
• 3 Durkan AM, Alexander RT. Acute kidney injury post neonatal asphyxia. J Pediatr 2011; 158 (2 Suppl) e29-e33
• 4 Askenazi DJ, Griffin R, McGwin G, Carlo W, Ambalavanan N. Acute kidney injury is independently associated with mortality in very low birthweight infants: a matched case-control analysis. Pediatr Nephrol 2009; 24: 991-997
• 5 Agras PI, Tarcan A, Baskin E, Cengiz N, Gürakan B, Saatci U. Acute renal failure in the neonatal period. Ren Fail 2004; 26: 305-309
• 6 Abitbol CL, Bauer CR, Montané B, Chandar J, Duara S, Zilleruelo G. Long-term follow-up of extremely low birth weight infants with neonatal renal failure. Pediatr Nephrol 2003; 18: 887-893
• 7 Askenazi DJ, Ambalavanan N, Goldstein SL. Acute kidney injury in critically ill newborns: what do we know? What do we need to learn?. Pediatr Nephrol 2009; 24: 265-274
• 8 Murray PT, Le Gall JR, Dos Reis Miranda D, Pinsky MR, Tetta C. Physiologic endpoints (efficacy) for acute renal failure studies. Curr Opin Crit Care 2002; 8: 519-525
• 9 Bariciak E, Yasin A, Harrold J, Walker M, Lepage N, Filler G. Preliminary reference intervals for cystatin C and beta-trace protein in preterm and term neonates. Clin Biochem 2011; 44: 1156-1159
• 10 Drukker A, Guignard JP. Renal aspects of the term and preterm infant: a selective update. Curr Opin Pediatr 2002; 14: 175-182
• 11 Stevens LA, Coresh J, Greene T, Levey AS. Assessing kidney function—measured and estimated glomerular filtration rate. N Engl J Med 2006; 354: 2473-2483
• 12 Parikh CR, Devarajan P. New biomarkers of acute kidney injury. Crit Care Med 2008; 36 (4 Suppl) S159-S165
• 13 Stevens LA, Coresh J, Schmid CH , et al. Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD. Am J Kidney Dis 2008; 51: 395-406
• 14 Dent CL, Ma Q, Dastrala S , et al. Plasma neutrophil gelatinase-associated lipocalin predicts acute kidney injury, morbidity and mortality after pediatric cardiac surgery: a prospective uncontrolled cohort study. Crit Care 2007; 11: R127
• 15 Kingsmore SF, Kennedy N, Halliday HL , et al. Identification of diagnostic biomarkers for infection in premature neonates. Mol Cell Proteomics 2008; 7: 1863-1875
• 16 Li Y, Fu C, Zhou X , et al. Urine interleukin-18 and cystatin-C as biomarkers of acute kidney injury in critically ill neonates. Pediatr Nephrol 2012; 27: 851-860
• 17 Du Y, Zappitelli M, Mian A , et al. Urinary biomarkers to detect acute kidney injury in the pediatric emergency center. Pediatr Nephrol 2011; 26: 267-274
• 18 Westhuyzen J. Cystatin C: a promising marker and predictor of impaired renal function. Ann Clin Lab Sci 2006; 36: 387-394
• 19 Plebani M, Mussap M, Bertelli L , et al. [Determination of blood cystatin C in pregnant women during labor and in their newborns]. Pediatr Med Chir 1997; 19: 325-329
• 20 Cataldi L, Mussap M, Bertelli L, Ruzzante N, Fanos V, Plebani M. Cystatin C in healthy women at term pregnancy and in their infant newborns: relationship between maternal and neonatal serum levels and reference values. Am J Perinatol 1999; 16: 287-295
• 21 Novo AC, Sadeck LdosS, Okay TS, Leone CR. Longitudinal study of Cystatin C in healthy term newborns. Clinics (Sao Paulo) 2011; 66: 217-220
• 22 Gokmen T, Erdeve O, Altug N, Oguz SS, Uras N, Dilmen U. Efficacy and safety of oral versus intravenous ibuprofen in very low birth weight preterm infants with patent ductus arteriosus. J Pediatr 2011; 158: 549-554 , e1
• 23 Lee BS, Byun SY, Chung ML , et al. Effect of furosemide on ductal closure and renal function in indomethacin-treated preterm infants during the early neonatal period. Neonatology 2010; 98: 191-199
• 24 Askenazi DJ, Koralkar R, Hundley HE , et al. Urine biomarkers predict acute kidney injury in newborns. J Pediatr 2012; 161 (2) 270-275 .e1. Epub 2012 Mar 16
• 25 Maruniak-Chudek I, Owsianka-Podleśny T, Wróblewska J, Jadamus-Niebrój D. Is serum cystatin C a better marker of kidney function than serum creatinine in septic newborns?. Postepy Hig Med Dosw (Online) 2012; 66: 175-180
• 26 Treiber M, Pecovnik-Balon B, Gorenjak M. Cystatin C versus creatinine as a marker of glomerular filtration rate in the newborn. Wien Klin Wochenschr 2006; 118 (Suppl. 02) 66-70
• 27 Armangil D, Yurdakök M, Canpolat FE, Korkmaz A, Yiğit S, Tekinalp G. Determination of reference values for plasma cystatin C and comparison with creatinine in premature infants. Pediatr Nephrol 2008; 23: 2081-2083
• 28 Nielsen EI, Sandström M, Honoré PH, Ewald U, Friberg LE. Developmental pharmacokinetics of gentamicin in preterm and term neonates: population modelling of a prospective study. Clin Pharmacokinet 2009; 48: 253-263
• 29 Parvex P, Combescure C, Rodriguez M, Girardin E. Is Cystatin C a promising marker of renal function, at birth, in neonates prenatally diagnosed with congenital kidney abnormalities?. Nephrol Dial Transplant 2012; 27 (9) 3477-3482
• 30 Bolignano D, Donato V, Coppolino G , et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. Am J Kidney Dis 2008; 52: 595-605
• 31 Mishra J, Ma Q, Prada A , et al. Identification of NGAL as a novel urine biomarker for ischemic injury. J Am Soc Nephrol 2003; 14: 2534-2543
• 32 Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P. Neutrophil gelatinase-associated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity. Am J Nephrol 2004; 24: 307-315
• 33 Mishra J, Ma Q, Kelly C , et al. Kidney NGAL is a novel early marker of acute injury following transplantation. Pediatr Nephrol 2006; 21: 856-863
• 34 Wasilewska A, Zoch-Zwierz W, Taranta-Janusz K, Michaluk-Skutnik J. Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of cyclosporine nephrotoxicity?. Pediatr Nephrol 2010; 25: 889-897
• 35 Lavery AP, Meinzen-Derr JK, Anderson E , et al. Urinary NGAL in premature infants. Pediatr Res 2008; 64: 423-428
• 36 Krawczeski CD, Woo JG, Wang Y, Bennett MR, Ma Q, Devarajan P. Neutrophil gelatinase-associated lipocalin concentrations predict development of acute kidney injury in neonates and children after cardiopulmonary bypass. J Pediatr 2011; 158: 1009-1015 , e1
• 37 Koch AM, Dittrich S, Cesnjevar R, Rüffer A, Breuer C, Glöckler M. Plasma neutrophil gelatinase-associated lipocalin measured in consecutive patients after congenital heart surgery using point-of-care technology. Interact Cardiovasc Thorac Surg 2011; 13: 133-136
• 38 Sarafidis K, Tsepkentzi E, Agakidou E , et al. Serum and urine acute kidney injury biomarkers in asphyxiated neonates. Pediatr Nephrol 2012; 27 (9) 1575-1582
• 39 Tadesse S, Luo G, Park JS , et al. Intra-amniotic infection upregulates neutrophil gelatinase-associated lipocalin (NGAL) expression at the maternal-fetal interface at term: implications for infection-related preterm birth. Reprod Sci 2011; 18: 713-722
• 40 Parravicini E, Nemerofsky SL, Michelson KA , et al. Urinary neutrophil gelatinase-associated lipocalin is a promising biomarker for late onset culture-positive sepsis in very low birth weight infants. Pediatr Res 2010; 67: 636-640
• 41 La Manna G, Galletti S, Capelli I , et al. Urinary neutrophil gelatinase-associated lipocalin at birth predicts early renal function in very low birth weight infants. Pediatr Res 2011; 70: 379-383
• 42 Bonventre JV. Kidney injury molecule-1 (KIM-1): a urinary biomarker and much more. Nephrol Dial Transplant 2009; 24: 3265-3268
• 43 Vaidya VS, Ramirez V, Ichimura T, Bobadilla NA, Bonventre JV. Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am J Physiol Renal Physiol 2006; 290: F517-F529
• 44 Zhou Y, Vaidya VS, Brown RP , et al. Comparison of kidney injury molecule-1 and other nephrotoxicity biomarkers in urine and kidney following acute exposure to gentamicin, mercury, and chromium. Toxicol Sci 2008; 101: 159-170
• 45 Ichimura T, Hung CC, Yang SA, Stevens JL, Bonventre JV. Kidney injury molecule-1: a tissue and urinary biomarker for nephrotoxicant-induced renal injury. Am J Physiol Renal Physiol 2004; 286: F552-F563
• 46 Askenazi DJ, Montesanti A, Hunley H , et al. Urine biomarkers predict acute kidney injury and mortality in very low birth weight infants. J Pediatr 2011; 159: 907-912 , e1
• 47 McWilliam SJ, Antoine DJ, Turner M , et al. Urinary KIM-1 as a biomarker of aminoglycoside-induced nephrotoxicity in premature neonates. Pediatr Res 2011; 70: 107
• 48 Dinarello CA, Novick D, Puren AJ , et al. Overview of interleukin-18: more than an interferon-γ inducing factor. J Leukoc Biol 1998; 63: 658-664
• 49 Melnikov VY, Ecder T, Fantuzzi G , et al. Impaired IL-18 processing protects caspase-1-deficient mice from ischemic acute renal failure. J Clin Invest 2001; 107: 1145-1152
• 50 Cusumano V, Midiri A, Cusumano VV , et al. Interleukin-18 is an essential element in host resistance to experimental group B streptococcal disease in neonates. Infect Immun 2004; 72: 295-300
• 51 Bender L, Thaarup J, Varming K, Krarup H, Ellermann-Eriksen S, Ebbesen F. Early and late markers for the detection of early-onset neonatal sepsis. Dan Med Bull 2008; 55: 219-223
• 52 Devarajan P. Proteomics for biomarker discovery in acute kidney injury. Semin Nephrol 2007; 27: 637-651
• 53 Bellomo R, Kellum JA, Ronco C. Defining and classifying acute renal failure: from advocacy to consensus and validation of the RIFLE criteria. Intensive Care Med 2007; 33: 409-413
• 54 Bagshaw SM, George C, Bellomo R. ANZICS Database Management Committee. A comparison of the RIFLE and AKIN criteria for acute kidney injury in critically ill patients. Nephrol Dial Transplant 2008; 23: 1569-1574
• 55 Mussap M, Degrandi R, Fravega M, Fanos V. Acute kidney injury in critically ill infants: the role of urine Neutrophil Gelatinase-Associated Lipocalin (NGAL). J Matern Fetal Neonatal Med 2010; 23 (Suppl. 03) 70-72
• 56 Krawczeski CD, Vandevoorde RG, Kathman T , et al. Serum cystatin C is an early predictive biomarker of acute kidney injury after pediatric cardiopulmonary bypass. Clin J Am Soc Nephrol 2010; 5: 1552-1557
• 57 Han WK, Waikar SS, Johnson A , et al. Urinary biomarkers in the early diagnosis of acute kidney injury. Kidney Int 2008; 73: 863-869
• 58 Parikh CR, Mishra J, Thiessen-Philbrook H , et al. Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int 2006; 70: 199-203
• 59 Harmoinen A, Ylinen E, Ala-Houhala M, Janas M, Kaila M, Kouri T. Reference intervals for cystatin C in pre- and full-term infants and children. Pediatr Nephrol 2000; 15: 105-108
• 60 Askenazi DJ, Koralkar R, Levitan EB , et al. Baseline values of candidate urine acute kidney injury biomarkers vary by gestational age in premature infants. Pediatr Res 2011; 70: 302-306
• 61 Parravicini E, Lorenz JM, Nemerofsky SL, O'Rourke M, Barasch J, Bateman D. Reference range of urinary neutrophil gelatinase-associated lipocalin in very low-birth-weight infants: preliminary data. Am J Perinatol 2009; 26: 437-440
• 62 Huynh TK, Bateman DA, Parravicini E , et al. Reference values of urinary neutrophil gelatinase-associated lipocalin in very low birth weight infants. Pediatr Res 2009; 66: 528-532
• 63 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: 354-358
• 64 Lindon JC, Holmes E, Bollard ME, Stanley EG, Nicholson JK. Metabonomics technologies and their applications in physiological monitoring, drug safety assessment and disease diagnosis. Biomarkers 2004; 9: 1-31
• 65 Pan Z, Raftery D. Comparing and combining NMR spectroscopy and mass spectrometry in metabolomics. Anal Bioanal Chem 2007; 387: 525-527
• 66 Weiss RH, Kim K. Metabolomics in the study of kidney diseases. Nat Rev Nephrol 2012; 8: 22-33
• 67 Atzori L, Xanthos T, Barberini L , et al. A metabolomic approach in an experimental model of hypoxia-reoxygenation in newborn piglets: urine predicts outcome. J Matern Fetal Neonatal Med 2010; 23 (Suppl. 03) 134-137
• 68 Beger RD, Holland RD, Sun J , et al. Metabonomics of acute kidney injury in children after cardiac surgery. Pediatr Nephrol 2008; 23: 977-984
• 69 Atzori L, Mussap M, Noto A , et al. Clinical metabolomics and urinary NGAL for the early prediction of chronic kidney disease in healthy adults born ELBW. J Matern Fetal Neonatal Med 2011; 24 (Suppl. 02) 40-43