Pediatric Nephrology

, Volume 26, Issue 4, pp 509–522 | Cite as

Acute kidney injury in childhood: should we be worried about progression to CKD?

  • Stuart L. GoldsteinEmail author
  • Prasad Devarajan


While emerging evidence indicates that the incidence of both acute kidney injury (AKI) and chronic kidney disease (CKD) in children is rising and that the etiologies are dramatically changing, relatively little is currently known regarding the potential for transition from AKI to CKD. Major barriers to assessing for a potential AKI to CKD link have included lack of a standard pediatric AKI definition, narrow focus only on children with AKI who receive renal replacement therapy, and reliance on serum creatinine as the main biomarker to detect and diagnose AKI and CKD. Recent data have validated a multi-dimensional AKI classification system for children and have suggested chronic kidney sequelae in pediatric populations with AKI or at risk for AKI. In addition, a number of novel AKI biomarkers are being rigorously validated as early indicators of incipient CKD. Our goals for this article are to (1) review the recent changes in pediatric AKI and CKD epidemiology, (2) explore the evidence for a potential AKI to CKD link, and (3) propose new clinical and research paradigms to better elucidate the progression from AKI to CKD.


Acute kidney injury Chronic kidney disease Urinary biomarkers Progression 


  1. 1.
    McDonald SP, Craig JC (2004) Long-term survival of children with end-stage renal disease. N Engl J Med 350:2654–2662PubMedGoogle Scholar
  2. 2.
    Chavers BM, Li S, Collins AJ, Herzog CA (2002) Cardiovascular disease in pediatric chronic dialysis patients. Kidney Int 62:648–653PubMedGoogle Scholar
  3. 3.
    Symons JM, Chua AN, Somers MJ, Baum MA, Bunchman TE, Benfield MR, Brophy PD, Blowey D, Fortenberry JD, Chand D, Flores FX, Hackbarth R, Alexander SR, Mahan J, McBryde KD, Goldstein SL (2007) Demographic characteristics of pediatric continuous renal replacement therapy: a report of the prospective pediatric continuous renal replacement therapy registry. Clin J Am Soc Nephrol 2:732–738PubMedGoogle Scholar
  4. 4.
    Hui-Stickle S, Brewer ED, Goldstein SL (2005) Pediatric ARF Epidemiology at a Teritary Care Center from 1999 to 2001. Am J Kidney Dis 45:96–101PubMedGoogle Scholar
  5. 5.
    Collins AJ, Foley RN, Herzog C, Chavers B, Gilbertson D, Ishani A, Kasiske B, Liu J, Mau LW, McBean M, Murray A, St Peter W, Guo H, Li Q, Li S, Peng Y, Qiu Y, Roberts T, Skeans M, Snyder J, Solid C, Wang C, Weinhandl E, Zaun D, Arko C, Chen SC, Dalleska F, Daniels F, Dunning S, Ebben J, Frazier E, Hanzlik C, Johnson R, Sheets D, Wang X, Forrest B, Constantini E, Everson S, Eggers P, Agodoa L (2009) United States Renal Data System 2008 Annual Data Report. Am J Kidney Dis 53:S1–374Google Scholar
  6. 6.
    Warady BA, Bunchman T (2000) Dialysis therapy for children with acute renal failure: survey results. Pediatr Nephrol 15:11–13PubMedGoogle Scholar
  7. 7.
    Vachvanichsanong P, Dissaneewate P, Lim A, McNeil E (2006) Childhood acute renal failure: 22-year experience in a university hospital in southern Thailand. Pediatrics 118:e786–791PubMedGoogle Scholar
  8. 8.
    Andreoli SP (2002) Acute renal failure. Curr Opin Pediatr 14:183–188PubMedGoogle Scholar
  9. 9.
    Flynn JT (2002) Choice of dialysis modality for management of pediatric acute renal failure. Pediatr Nephrol 17:61–69PubMedGoogle Scholar
  10. 10.
    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
  11. 11.
    Bailey D, Phan V, Litalien C, Ducruet T, 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 8:29–35PubMedGoogle Scholar
  12. 12.
    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 365:1231–1238PubMedGoogle Scholar
  13. 13.
    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:R127PubMedGoogle Scholar
  14. 14.
    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 3:665–673PubMedGoogle Scholar
  15. 15.
    Kellum JA, Angus DC (2002) Patients are dying of acute renal failure. Crit Care Med 30:2156–2157PubMedGoogle Scholar
  16. 16.
    Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW (2005) Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 16:3365–3370PubMedGoogle Scholar
  17. 17.
    Price JF, Mott AR, Dickerson HA, Jefferies JL, Nelson DP, Chang AC, O'Brian Smith E, Towbin JA, Dreyer WJ, Denfield SW, Goldstein SL (2008) Worsening renal function in children hospitalized with decompensated heart failure: evidence for a pediatric cardiorenal syndrome? Pediatr Crit Care Med 9:279–284PubMedGoogle Scholar
  18. 18.
    Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P (2004) Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8:R204–212PubMedGoogle Scholar
  19. 19.
    Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL (2007) Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int 71:1028–1035PubMedGoogle Scholar
  20. 20.
    Hoste EA, Kellum JA (2006) RIFLE criteria provide robust assessment of kidney dysfunction and correlate with hospital mortality. Crit Care Med 34:2016–2017PubMedGoogle Scholar
  21. 21.
    Srisawat N, Hoste EE, Kellum JA (2010) Modern Classification of Acute Kidney Injury. Blood Purif 29:300–307PubMedGoogle Scholar
  22. 22.
    Plotz FB, Bouma AB, van Wijk JA, Kneyber MC, Bokenkamp A (2008) Pediatric acute kidney injury in the ICU: an independent evaluation of pRIFLE criteria. Intensive Care Med 34:1713–1717PubMedGoogle Scholar
  23. 23.
    Palmieri T, Lavrentieva A, Greenhalgh D (2009) An assessment of acute kidney injury with modified RIFLE criteria in pediatric patients with severe burns. Intensive Care Med 35:2125–2129PubMedGoogle Scholar
  24. 24.
    Zappitelli M, Parikh CR, Akcan-Arikan A, Washburn KK, Moffett BS, Goldstein SL (2008) Ascertainment and epidemiology of acute kidney injury varies with definition interpretation. Clin J Am Soc Nephrol 3:948–954PubMedGoogle Scholar
  25. 25.
    Schneider J, Khemani R, Grushkin C, Bart R (2010) Serum creatinine as stratified in the RIFLE score for acute kidney injury is associated with mortality and length of stay for children in the pediatric intensive care unit. Crit Care Med 38:933–939PubMedGoogle Scholar
  26. 26.
    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:R84PubMedGoogle Scholar
  27. 27.
    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 23:566–572PubMedGoogle Scholar
  28. 28.
    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:R31PubMedGoogle Scholar
  29. 29.
    Goldstein SL, Chawla LS (2010) Renal angina. Clin J Am Soc Nephrol 5:943–949PubMedGoogle Scholar
  30. 30.
    D'Amico G (1995) Comparability of the different registries on renal replacement therapy. Am J Kidney Dis 25:113–118PubMedGoogle Scholar
  31. 31.
    Neu AM, Ho PL, McDonald RA, Warady BA (2002) Chronic dialysis in children and adolescents. The 2001 NAPRTCS Annual Report. Pediatr Nephrol 17:656–663PubMedGoogle Scholar
  32. 32.
    Furth SL, Cole SR, Moxey-Mims M, Kaskel F, Mak RH, Schwartz G, Wong C, Munoz A, Warady BA (2006) Design and methods in the chronic kidney disease in children (CKiD) prospective cohort study. Clin J Am Soc Nephrol 1:1005–1015Google Scholar
  33. 33.
    Schwartz GJ, Brion LP, Spitzer A (1987) The use of plasma creatinine concentration for estimating glomerular filtration rate in infants, children, and adolescents. Pediatr Clin North Am 34:571–590PubMedGoogle Scholar
  34. 34.
    Schwartz GJ, Munoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, Furth SL (2009) New equations to estimate GFR in children with CKD. J Am Soc Nephrol 20:629–637PubMedGoogle Scholar
  35. 35.
    Zappitelli M, Joseph L, Gupta IR, Bell L, Paradis G (2007) Validation of child serum creatinine-based prediction equations for glomerular filtration rate. Pediatr Nephrol 22:272–281PubMedGoogle Scholar
  36. 36.
    Zappitelli M, Parvex P, Joseph L, Paradis G, Grey V, Lau S, Bell L (2006) Derivation and validation of cystatin C-based prediction equations for GFR in children. Am J Kidney Dis 48:221–230PubMedGoogle Scholar
  37. 37.
    Mitsnefes MM, Kathman TS, Mishra J, Kartal J, Khoury PR, Nickolas TL, Barasch J, Devarajan P (2007) Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in children with chronic kidney disease. Pediatr Nephrol 22:101–108PubMedGoogle Scholar
  38. 38.
    Nickolas TL, Barasch J, Devarajan P (2008) Biomarkers in acute and chronic kidney disease. Curr Opin Nephrol Hypertens 17:127–132PubMedGoogle Scholar
  39. 39.
    Venkatachalam MA, Griffin KA, Lan R, Geng H, Saikumar P, Bidani AK (2010) Acute kidney injury: a springboard for progression in chronic kidney disease. Am J Physiol Renal Physiol 298:F1078-F1094Google Scholar
  40. 40.
    Azuma H, Nadeau K, Takada M, Mackenzie HS, Tilney NL (1997) Cellular and molecular predictors of chronic renal dysfunction after initial ischemia/reperfusion injury of a single kidney. Transplantation 64:190–197PubMedGoogle Scholar
  41. 41.
    Basile DP (2007) The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function. Kidney Int 72:151–156PubMedGoogle Scholar
  42. 42.
    Kinsey GR, Li L, Okusa MD (2008) Inflammation in acute kidney injury. Nephron Exp Nephrol 109:e102–107PubMedGoogle Scholar
  43. 43.
    Askenazi DJ, Feig DI, Graham NM, Hui-Stickle S, Goldstein SL (2006) 3-5 year longitudinal follow-up of pediatric patients after acute renal failure. Kidney Int 69:184–189PubMedGoogle Scholar
  44. 44.
    Garg AX, Suri RS, Barrowman N, Rehman F, Matsell D, Rosas-Arellano MP, Salvadori M, Haynes RB, Clark WF (2003) Long-term renal prognosis of diarrhea-associated hemolytic uremic syndrome: a systematic review, meta-analysis, and meta-regression. JAMA 290:1360–1370PubMedGoogle Scholar
  45. 45.
    Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM (1981) Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol 241:F85–93PubMedGoogle Scholar
  46. 46.
    White SL, Perkovic V, Cass A, Chang CL, Poulter NR, Spector T, Haysom L, Craig JC, Salmi IA, Chadban SJ, Huxley RR (2009) Is low birth weight an antecedent of CKD in later life? A systematic review of observational studies. Am J Kidney Dis 54:248–261PubMedGoogle Scholar
  47. 47.
    Reulen RC, Winter DL, Frobisher C, Lancashire ER, Stiller CA, Jenney ME, Skinner R, Stevens MC, Hawkins MM (2010) Long-term cause-specific mortality among survivors of childhood cancer. JAMA 304:172–179PubMedGoogle Scholar
  48. 48.
    Michael M, Kuehnle I, Goldstein SL (2004) Fluid overload and acute renal failure in pediatric stem cell transplant patients. Pediatr Nephrol 19:91–95PubMedGoogle Scholar
  49. 49.
    Kist-van Holthe JE, Goedvolk CA, Brand R, van Weel MH, Bredius RG, van Oostayen JA, Vossen JM, van der Heijden BJ (2002) Prospective study of renal insufficiency after bone marrow transplantation. Pediatr Nephrol 17:1032–1037PubMedGoogle Scholar
  50. 50.
    Hingorani S, Guthrie KA, Schoch G, Weiss NS, McDonald GB (2007) Chronic kidney disease in long-term survivors of hematopoietic cell transplant. Bone Marrow Transplant 39:223–229PubMedGoogle Scholar
  51. 51.
    Van Why SK, Friedman AL, Wei LJ, Hong R (1991) Renal insufficiency after bone marrow transplantation in children. Bone Marrow Transplant 7:383–388PubMedGoogle Scholar
  52. 52.
    Gronroos MH, Bolme P, Winiarski J, Berg UB (2007) Long-term renal function following bone marrow transplantation. Bone Marrow Transplant 39:717–723PubMedGoogle Scholar
  53. 53.
    Frisk P, Bratteby LE, Carlson K, Lonnerholm G (2002) Renal function after autologous bone marrow transplantation in children: a long-term prospective study. Bone Marrow Transplant 29:129–136PubMedGoogle Scholar
  54. 54.
    Jones DP, Spunt SL, Green D, Springate JE (2008) Renal late effects in patients treated for cancer in childhood: a report from the Children's Oncology Group. Pediatr Blood Cancer 51:724–731PubMedGoogle Scholar
  55. 55.
    Arjmandi-Rafsanjani K, Hooman N, Vosoug P (2008) Renal function in late survivors of Iranian children with cancer: single centre experience. Indian J Cancer 45:154–157PubMedGoogle Scholar
  56. 56.
    Jetton JG, Ocku F, Dreyer ZE, Goldstein SL (2009) Pediatric Cancer Survivors Are at High Risk for CKD. J Am Soc Nephrol 20:748AGoogle Scholar
  57. 57.
    Parikh CR, Lu JC, Coca SG, Devarajan P (2010) Tubular proteinuria in acute kidney injury: a critical evaluation of current status and future promise. Ann Clin Biochem 47:301–312PubMedGoogle Scholar
  58. 58.
    Devarajan P (2007) Proteomics for biomarker discovery in acute kidney injury. Semin Nephrol 27:637–651PubMedGoogle Scholar
  59. 59.
    Dharnidharka VR, Kwon C, Stevens G (2002) Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 40:221–226PubMedGoogle Scholar
  60. 60.
    Roos JF, Doust J, Tett SE, Kirkpatrick CM (2007) Diagnostic accuracy of cystatin C compared to serum creatinine for the estimation of renal dysfunction in adults and children–a meta-analysis. Clin Biochem 40:383–391PubMedGoogle Scholar
  61. 61.
    Andersen TB, Eskild-Jensen A, Frokiaer J, Brochner-Mortensen J (2009) Measuring glomerular filtration rate in children; can cystatin C replace established methods? A review. Pediatr Nephrol 24:929–941PubMedGoogle Scholar
  62. 62.
    Schwartz GJ, Work DF (2009) Measurement and estimation of GFR in children and adolescents. Clin J Am Soc Nephrol 4:1832–1843PubMedGoogle Scholar
  63. 63.
    Stickle D, Cole B, Hock K, Hruska KA, Scott MG (1998) Correlation of plasma concentrations of cystatin C and creatinine to inulin clearance in a pediatric population. Clin Chem 44:1334–1338PubMedGoogle Scholar
  64. 64.
    Bouvet Y, Bouissou F, Coulais Y, Seronie-Vivien S, Tafani M, Decramer S, Chatelut E (2006) GFR is better estimated by considering both serum cystatin C and creatinine levels. Pediatr Nephrol 21:1299–1306PubMedGoogle Scholar
  65. 65.
    Krawczeski CD, Vandevoorde RG, Kathman T, Bennett MR, Woo JG, Wang Y, Griffiths RE, Devarajan P (2010) Serum Cystatin C Is an early predictive biomarker of acute kidney injury after pediatric cardiopulmonary bypass. Clin J Am Soc Nephrol. doi: 10.2215/CJN.02040310
  66. 66.
    Soto K, Coelho S, Rodrigues B, Martins H, Frade F, Lopes S, Cunha L, Papoila AL, Devarajan P (2010) Cystatin C as a marker of acute kidney injury in the emergency department. Clin J Am Soc Nephrol. doi: 10.2215/CJN.00690110
  67. 67.
    Nejat M, Pickering JW, Walker RJ, Endre ZH (2010) Rapid detection of acute kidney injury by plasma cystatin C in the intensive care unit. Nephrol Dial Transplant. doi: 10.1093/ndt/gfq176
  68. 68.
    Hemmelgarn BR, Manns BJ, Lloyd A, James MT, Klarenbach S, Quinn RR, Wiebe N, Tonelli M (2010) Relation between kidney function, proteinuria, and adverse outcomes. JAMA 303:423–429PubMedGoogle Scholar
  69. 69.
    Hallan SI, Ritz E, Lydersen S, Romundstad S, Kvenild K, Orth SR (2009) Combining GFR and albuminuria to classify CKD improves prediction of ESRD. J Am Soc Nephrol 20:1069–1077PubMedGoogle Scholar
  70. 70.
    Levey AS, Cattran D, Friedman A, Miller WG, Sedor J, Tuttle K, Kasiske B, Hostetter T (2009) Proteinuria as a surrogate outcome in CKD: report of a scientific workshop sponsored by the National Kidney Foundation and the US Food and Drug Administration. Am J Kidney Dis 54:205–226PubMedGoogle Scholar
  71. 71.
    Chaudhary K, Phadke G, Nistala R, Weidmeyer CE, McFarlane SI, Whaley-Connell A (2010) The emerging role of biomarkers in diabetic and hypertensive chronic kidney disease. Curr Diab Rep 10:37–42PubMedGoogle Scholar
  72. 72.
    Merchant ML, Perkins BA, Boratyn GM, Ficociello LH, Wilkey DW, Barati MT, Bertram CC, Page GP, Rovin BH, Warram JH, Krolewski AS, Klein JB (2009) Urinary peptidome may predict renal function decline in type 1 diabetes and microalbuminuria. J Am Soc Nephrol 20:2065–2074PubMedGoogle Scholar
  73. 73.
    Perkins BA, Ficociello LH, Ostrander BE, Silva KH, Weinberg J, Warram JH, Krolewski AS (2007) Microalbuminuria and the risk for early progressive renal function decline in type 1 diabetes. J Am Soc Nephrol 18:1353–1361PubMedGoogle Scholar
  74. 74.
    Perkins BA, Ficociello LH, Silva KH, Finkelstein DM, Warram JH, Krolewski AS (2003) Regression of microalbuminuria in type 1 diabetes. N Engl J Med 348:2285–2293PubMedGoogle Scholar
  75. 75.
    Devarajan P, Krawczeski CD, Nguyen MT, Kathman T, Wang Z, Parikh CR (2010) Proteomic Identification of Early Biomarkers of Acute Kidney Injury After Cardiac Surgery in Children. Am J Kidney Dis. doi: 10.1053/j.ajkd.2010.04.014 PubMedGoogle Scholar
  76. 76.
    Supavekin S, Zhang W, Kucherlapati R, Kaskel FJ, Moore LC, Devarajan P (2003) Differential gene expression following early renal ischemia/reperfusion. Kidney Int 63:1714–1724PubMedGoogle Scholar
  77. 77.
    Devarajan P (2006) Update on mechanisms of ischemic acute kidney injury. J Am Soc Nephrol 17:1503–1520PubMedGoogle Scholar
  78. 78.
    Nguyen MT, Devarajan P (2008) Biomarkers for the early detection of acute kidney injury. Pediatr Nephrol 23:2151–2157PubMedGoogle Scholar
  79. 79.
    Kronenberg F (2009) Emerging risk factors and markers of chronic kidney disease progression. Nat Rev Nephrol 5:677–689PubMedGoogle Scholar
  80. 80.
    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 80:365–376PubMedGoogle Scholar
  81. 81.
    Mishra J, Mori K, Ma Q, Kelly C, Barasch J, Devarajan P (2004) Neutrophil gelatinase-associated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity. Am J Nephrol 24:307–315PubMedGoogle Scholar
  82. 82.
    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 14:2534–2543PubMedGoogle Scholar
  83. 83.
    Mishra J, Mori K, Ma Q, Kelly C, Yang J, Mitsnefes M, Barasch J, Devarajan P (2004) Amelioration of ischemic acute renal injury by neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 15:3073–3082PubMedGoogle Scholar
  84. 84.
    Haase M, Bellomo R, Devarajan P, Schlattmann P, Haase-Fielitz A (2009) Accuracy of neutrophil gelatinase-associated lipocalin (NGAL) in diagnosis and prognosis in acute kidney injury: a systematic review and meta-analysis. Am J Kidney Dis 54:1012–1024PubMedGoogle Scholar
  85. 85.
    Hirsch R, Dent C, Pfriem H, Allen J, Beekman RH 3rd, Ma Q, Dastrala S, Bennett M, Mitsnefes M, Devarajan P (2007) NGAL is an early predictive biomarker of contrast-induced nephropathy in children. Pediatr Nephrol 22:2089–2095PubMedGoogle Scholar
  86. 86.
    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 21:856–863PubMedGoogle Scholar
  87. 87.
    Wheeler DS, Devarajan P, Ma Q, Harmon K, Monaco M, Cvijanovich N, Wong HR (2008) Serum neutrophil gelatinase-associated lipocalin (NGAL) as a marker of acute kidney injury in critically ill children with septic shock. Crit Care Med 36:1297–1303PubMedGoogle Scholar
  88. 88.
    Nickolas TL, O'Rourke MJ, Yang J, Sise ME, Canetta PA, Barasch N, Buchen C, Khan F, Mori K, Giglio J, Devarajan P, Barasch J (2008) Sensitivity and specificity of a single emergency department measurement of urinary neutrophil gelatinase-associated lipocalin for diagnosing acute kidney injury. Ann Intern Med 148:810–819PubMedGoogle Scholar
  89. 89.
    Devarajan P (2010) Neutrophil gelatinase-associated lipocalin: a promising biomarker for human acute kidney injury. Biomark Med 4:265–280PubMedGoogle Scholar
  90. 90.
    Schmidt-Ott KM, Mori K, Li JY, Kalandadze A, Cohen DJ, Devarajan P, Barasch J (2007) Dual action of neutrophil gelatinase-associated lipocalin. J Am Soc Nephrol 18:407–413PubMedGoogle Scholar
  91. 91.
    Yang J, Goetz D, Li JY, Wang W, Mori K, Setlik D, Du T, Erdjument-Bromage H, Tempst P, Strong R, Barasch J (2002) An iron delivery pathway mediated by a lipocalin. Mol Cell 10:1045–1056PubMedGoogle Scholar
  92. 92.
    Ko GJ, Grigoryev DN, Linfert D, Jang HR, Watkins T, Cheadle C, Racusen L, Rabb H (2010) Transcriptional analysis of kidneys during repair from AKI reveals possible roles for NGAL and KIM-1 as biomarkers of AKI-to-CKD transition. Am J Physiol Renal Physiol 298:F1472–1483PubMedGoogle Scholar
  93. 93.
    Mori K, Lee HT, Rapoport D, Drexler IR, Foster K, Yang J, Schmidt-Ott KM, Chen X, Li JY, Weiss S, Mishra J, Cheema FH, Markowitz G, Suganami T, Sawai K, Mukoyama M, Kunis C, D'Agati V, Devarajan P, Barasch J (2005) Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury. J Clin Invest 115:610–621PubMedGoogle Scholar
  94. 94.
    Ding H, He Y, Li K, Yang J, Li X, Lu R, Gao W (2007) Urinary neutrophil gelatinase-associated lipocalin (NGAL) is an early biomarker for renal tubulointerstitial injury in IgA nephropathy. Clin Immunol 123:227–234PubMedGoogle Scholar
  95. 95.
    Nishida M, Kawakatsu H, Okumura Y, Hamaoka K (2010) Serum and urinary NGAL levels in children with chronic renal diseases. Pediatr Int 52:563–568PubMedGoogle Scholar
  96. 96.
    Bolignano D, Coppolino G, Campo S, Aloisi C, Nicocia G, Frisina N, Buemi M (2007) Neutrophil gelatinase-associated lipocalin in patients with autosomal-dominant polycystic kidney disease. Am J Nephrol 27:373–378PubMedGoogle Scholar
  97. 97.
    Paragas N, Nickolas TL, Wyatt C, Forster CS, Sise M, Morgello S, Jagla B, Buchen C, Stella P, Sanna-Cherchi S, Carnevali ML, Mattei S, Bovino A, Argentiero L, Magnano A, Devarajan P, Schmidt-Ott KM, Allegri L, Klotman P, D'Agati V, Gharavi AG, Barasch J (2009) Urinary NGAL marks cystic disease in HIV-associated nephropathy. J Am Soc Nephrol 20:1687–1692PubMedGoogle Scholar
  98. 98.
    Bolignano D, Coppolino G, Campo S, Aloisi C, Nicocia G, Frisina N, Buemi M (2008) Urinary neutrophil gelatinase-associated lipocalin (NGAL) is associated with severity of renal disease in proteinuric patients. Nephrol Dial Transplant 23:414–416PubMedGoogle Scholar
  99. 99.
    Bolignano D, Lacquaniti A, Coppolino G, Campo S, Arena A, Buemi M (2008) Neutrophil gelatinase-associated lipocalin reflects the severity of renal impairment in subjects affected by chronic kidney disease. Kidney Blood Press Res 31:255–258PubMedGoogle Scholar
  100. 100.
    Bolignano D, Lacquaniti A, Coppolino G, Donato V, Fazio MR, Nicocia G, Buemi M (2009) Neutrophil gelatinase-associated lipocalin as an early biomarker of nephropathy in diabetic patients. Kidney Blood Press Res 32:91–98PubMedGoogle Scholar
  101. 101.
    Yang YH, He XJ, Chen SR, Wang L, Li EM, Xu LY (2009) Changes of serum and urine neutrophil gelatinase-associated lipocalin in type-2 diabetic patients with nephropathy: one year observational follow-up study. Endocrine 36:45–51PubMedGoogle Scholar
  102. 102.
    Malyszko J, Bachorzewska-Gajewska H, Sitniewska E, Malyszko JS, Poniatowski B, Dobrzycki S (2008) Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in non-diabetic patients with stage 2-4 chronic kidney disease. Ren Fail 30:625–628PubMedGoogle Scholar
  103. 103.
    Bolignano D, Lacquaniti A, Coppolino G, Donato V, Campo S, Fazio MR, Nicocia G, Buemi M (2009) Neutrophil gelatinase-associated lipocalin (NGAL) and progression of chronic kidney disease. Clin J Am Soc Nephrol 4:337–344PubMedGoogle Scholar
  104. 104.
    Bolignano D, Coppolino G, Lacquaniti A, Nicocia G, Buemi M (2008) Pathological and prognostic value of urinary neutrophil gelatinase-associated lipocalin in macroproteinuric patients with worsening renal function. Kidney Blood Press Res 31:274–279PubMedGoogle Scholar
  105. 105.
    Zachwieja J, Soltysiak J, Fichna P, Lipkowska K, Stankiewicz W, Skowronska B, Kroll P, Lewandowska-Stachowiak M (2010) Normal-range albuminuria does not exclude nephropathy in diabetic children. Pediatr Nephrol 25:1445–1451PubMedGoogle Scholar
  106. 106.
    Thrailkill KM, Moreau CS, Cockrell GE, Chan-Hee J, Bunn RC, Morales-Pozzo AE, Lumpkin CK, Fowlkes JL (2010) Disease and gender-specific dysregulation of NGAL and MMP-9 in type 1 diabetes mellitus. Endocrine 37:336–343PubMedGoogle Scholar
  107. 107.
    Wasilewska A, Zoch-Zwierz W, Taranta-Janusz K, Michaluk-Skutnik J (2010) Neutrophil gelatinase-associated lipocalin (NGAL): a new marker of cyclosporine nephrotoxicity? Pediatr Nephrol 25:889–897PubMedGoogle Scholar
  108. 108.
    Brunner HI, Mueller M, Rutherford C, Passo MH, Witte D, Grom A, Mishra J, Devarajan P (2006) Urinary neutrophil gelatinase-associated lipocalin as a biomarker of nephritis in childhood-onset systemic lupus erythematosus. Arthritis Rheum 54:2577–2584PubMedGoogle Scholar
  109. 109.
    Pitashny M, Schwartz N, Qing X, Hojaili B, Aranow C, Mackay M, Putterman C (2007) Urinary lipocalin-2 is associated with renal disease activity in human lupus nephritis. Arthritis Rheum 56:1894–1903PubMedGoogle Scholar
  110. 110.
    Suzuki M, Wiers KM, Klein-Gitelman MS, Haines KA, Olson J, Onel KB, O'Neil K, Passo MH, Singer NG, Tucker L, Ying J, Devarajan P, Brunner HI (2008) Neutrophil gelatinase-associated lipocalin as a biomarker of disease activity in pediatric lupus nephritis. Pediatr Nephrol 23:403–412PubMedGoogle Scholar
  111. 111.
    Rubinstein T, Pitashny M, Levine B, Schwartz N, Schwartzman J, Weinstein E, Pego-Reigosa JM, Lu TY, Isenberg D, Rahman A, Putterman C (2010) Urinary neutrophil gelatinase-associated lipocalin as a novel biomarker for disease activity in lupus nephritis. Rheumatology (Oxford) 49:960–971Google Scholar
  112. 112.
    Hinze CH, Suzuki M, Klein-Gitelman M, Passo MH, Olson J, Singer NG, Haines KA, Onel K, O'Neil K, Silverman ED, Tucker L, Ying J, Devarajan P, Brunner HI (2009) Neutrophil gelatinase-associated lipocalin is a predictor of the course of global and renal childhood-onset systemic lupus erythematosus disease activity. Arthritis Rheum 60:2772–2781PubMedGoogle Scholar
  113. 113.
    Kuwabara T, Mori K, Mukoyama M, Kasahara M, Yokoi H, Saito Y, Yoshioka T, Ogawa Y, Imamaki H, Kusakabe T, Ebihara K, Omata M, Satoh N, Sugawara A, Barasch J, Nakao K (2009) Urinary neutrophil gelatinase-associated lipocalin levels reflect damage to glomeruli, proximal tubules, and distal nephrons. Kidney Int 75:285–294PubMedGoogle Scholar
  114. 114.
    Bolignano D, Coppolino G, Aloisi C, Romeo A, Nicocia G, Buemi M (2008) Effect of a single intravenous immunoglobulin infusion on neutrophil gelatinase-associated lipocalin levels in proteinuric patients with normal renal function. J Investig Med 56:997–1003PubMedGoogle Scholar
  115. 115.
    Kasahara M, Mori K, Satoh N, Kuwabara T, Yokoi H, Shimatsu A, Sugawara A, Mukoyama M, Nakao K (2009) Reduction in urinary excretion of neutrophil gelatinase-associated lipocalin by angiotensin receptor blockers in hypertensive patients. Nephrol Dial Transplant 24:2608–2609, author reply 2609-2610PubMedGoogle Scholar
  116. 116.
    Malyszko J, Malyszko JS, Koc-Zorawska E, Kozminski P, Mysliwiec M (2009) Neutrophil gelatinase-associated lipocalin in dialyzed patients is related to residual renal function, type of renal replacement therapy and inflammation. Kidney Blood Press Res 32:464–469PubMedGoogle Scholar
  117. 117.
    Bolignano D, Coppolino G, Romeo A, Lacquaniti A, Buemi M (2010) Neutrophil gelatinase-associated lipocalin levels in chronic haemodialysis patients. Nephrology (Carlton) 15:23–26Google Scholar
  118. 118.
    Sise ME, Barasch J, Devarajan P, Nickolas TL (2009) Elevated urine neutrophil gelatinase-associated lipocalin can diagnose acute kidney injury in patients with chronic kidney diseases. Kidney Int 75:115–116, author reply 116PubMedGoogle Scholar
  119. 119.
    Devarajan P (2007) Neutrophil gelatinase-associated lipocalin: new paths for an old shuttle. Cancer Ther 5:463–470PubMedGoogle Scholar
  120. 120.
    Devarajan P (2010) The promise of biomarkers for personalized renal cancer care. Kidney Int 77:755–757PubMedGoogle Scholar
  121. 121.
    Malyszko J, Bachorzewska-Gajewska H, Malyszko JS, Pawlak K, Dobrzycki S (2008) Serum neutrophil gelatinase-associated lipocalin as a marker of renal function in hypertensive and normotensive patients with coronary artery disease. Nephrology (Carlton) 13:153–156Google Scholar
  122. 122.
    Hemdahl AL, Gabrielsen A, Zhu C, Eriksson P, Hedin U, Kastrup J, Thoren P, Hansson GK (2006) Expression of neutrophil gelatinase-associated lipocalin in atherosclerosis and myocardial infarction. Arterioscler Thromb Vasc Biol 26:136–142PubMedGoogle Scholar
  123. 123.
    Yilmaz A, Sevketoglu E, Gedikbasi A, Karyagar S, Kiyak A, Mulazimoglu M, Aydogan G, Ozpacaci T, Hatipoglu S (2009) Early prediction of urinary tract infection with urinary neutrophil gelatinase associated lipocalin. Pediatr Nephrol 24:2387–2392PubMedGoogle Scholar
  124. 124.
    Ichimura T, Bonventre JV, Bailly V, Wei H, Hession CA, Cate RL, Sanicola M (1998) Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury. J Biol Chem 273:4135–4142PubMedGoogle Scholar
  125. 125.
    Ichimura T, Asseldonk EJ, Humphreys BD, Gunaratnam L, Duffield JS, Bonventre JV (2008) Kidney injury molecule-1 is a phosphatidylserine receptor that confers a phagocytic phenotype on epithelial cells. J Clin Invest 118:1657–1668PubMedGoogle Scholar
  126. 126.
    Vaidya VS, Ramirez V, Ichimura T, Bobadilla NA, Bonventre JV (2006) Urinary kidney injury molecule-1: a sensitive quantitative biomarker for early detection of kidney tubular injury. Am J Physiol Renal Physiol 290:F517–529PubMedGoogle Scholar
  127. 127.
    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 18:904–912PubMedGoogle Scholar
  128. 128.
    Han WK, Waikar SS, Johnson A, Betensky RA, Dent CL, Devarajan P, Bonventre JV (2008) Urinary biomarkers in the early diagnosis of acute kidney injury. Kidney Int 73:863–869PubMedGoogle Scholar
  129. 129.
    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 14:423–431PubMedGoogle Scholar
  130. 130.
    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 76:108–114PubMedGoogle Scholar
  131. 131.
    van Timmeren MM, van den Heuvel MC, Bailly V, Bakker SJ, van Goor H, Stegeman CA (2007) Tubular kidney injury molecule-1 (KIM-1) in human renal disease. J Pathol 212:209–217PubMedGoogle Scholar
  132. 132.
    van Timmeren MM, Vaidya VS, van Ree RM, Oterdoom LH, de Vries AP, Gans RO, van Goor H, Stegeman CA, Bonventre JV, Bakker SJ (2007) High urinary excretion of kidney injury molecule-1 is an independent predictor of graft loss in renal transplant recipients. Transplantation 84:1625–1630PubMedGoogle Scholar
  133. 133.
    Waanders F, Vaidya VS, van Goor H, Leuvenink H, Damman K, Hamming I, Bonventre JV, Vogt L, Navis G (2009) Effect of renin-angiotensin-aldosterone system inhibition, dietary sodium restriction, and/or diuretics on urinary kidney injury molecule 1 excretion in nondiabetic proteinuric kidney disease: a post hoc analysis of a randomized controlled trial. Am J Kidney Dis 53:16–25PubMedGoogle Scholar
  134. 134.
    Vaidya VS, Ozer JS, Dieterle F, Collings FB, Ramirez V, Troth S, Muniappa N, Thudium D, Gerhold D, Holder DJ, Bobadilla NA, Marrer E, Perentes E, Cordier A, Vonderscher J, Maurer G, Goering PL, Sistare FD, Bonventre JV (2010) Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat Biotechnol 28:478–485PubMedGoogle Scholar
  135. 135.
    Portilla D, Dent C, Sugaya T, Nagothu KK, 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 73:465–472PubMedGoogle Scholar
  136. 136.
    Ferguson MA, Vaidya VS, Waikar SS, Collings FB, Sunderland KE, Gioules CJ, Bonventre JV (2010) Urinary liver-type fatty acid-binding protein predicts adverse outcomes in acute kidney injury. Kidney Int 77:708–714PubMedGoogle Scholar
  137. 137.
    Kamijo-Ikemori A, Sugaya T, Obama A, Hiroi J, Miura H, Watanabe M, Kumai T, Ohtani-Kaneko R, Hirata K, Kimura K (2006) Liver-type fatty acid-binding protein attenuates renal injury induced by unilateral ureteral obstruction. Am J Pathol 169:1107–1117PubMedGoogle Scholar
  138. 138.
    Kamijo A, Sugaya T, Hikawa A, Yamanouchi M, Hirata Y, Ishimitsu T, Numabe A, Takagi M, Hayakawa H, Tabei F, Sugimoto T, Mise N, Omata M, Kimura K (2006) Urinary liver-type fatty acid binding protein as a useful biomarker in chronic kidney disease. Mol Cell Biochem 284:175–182PubMedGoogle Scholar
  139. 139.
    Nakamura T, Sugaya T, Kawagoe Y, Ueda Y, Osada S, Koide H (2005) Effect of pitavastatin on urinary liver-type fatty acid-binding protein levels in patients with early diabetic nephropathy. Diab Care 28:2728–2732Google Scholar
  140. 140.
    Ishimitsu T, Ohta S, Saito M, Teranishi M, Inada H, Yoshii M, Minami J, Ono H, Hikawa A, Shibata N, Sugaya T, Kamijo A, Kimura K, Ohrui M, Matsuoka H (2005) Urinary excretion of liver fatty acid-binding protein in health-check participants. Clin Exp Nephrol 9:34–39PubMedGoogle Scholar

Copyright information

© IPNA 2010

Authors and Affiliations

  1. 1.Center for Acute Care Nephrology, Cincinnati Children’s Hospital Medical CenterUniversity of Cincinnati College of MedicineCincinnatiUSA
  2. 2.Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical CenterUniversity of Cincinnati College of MedicineCincinnatiUSA

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