Pediatric Nephrology

, Volume 30, Issue 4, pp 665–676 | Cite as

Cystatin C in acute kidney injury diagnosis: early biomarker or alternative to serum creatinine?

  • Paola Lagos-Arevalo
  • Ana Palijan
  • Laura Vertullo
  • Prasad Devarajan
  • Michael R. Bennett
  • Venkata Sabbisetti
  • Joseph V. Bonventre
  • Qing Ma
  • Ronald D. Gottesman
  • Michael ZappitelliEmail author
Original Article



Early acute kidney injury (AKI) diagnosis is needed to pursue treatment trials. We evaluated cystatin C (CysC) as an early biomarker of serum creatinine (SCr)-AKI and an alternative to define AKI.


We studied 160 non-cardiac children in the intensive care unit (ICU). We measured daily CysC and SCr. AKI was staged by KDIGO (Kidney Disease: Improving Global Outcomes) guidelines using SCr and CysC (CysC-AKI). We calculated area under the curve (AUC) for (1) neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1) and urine CysC to diagnose SCr- and CysC-AKI; and (2) for CysC to diagnose SCr-AKI. We evaluated AKI associations with length of stay and ventilation duration.


We found that 44 % of patients developed SCr-AKI; 32 % developed CysC-AKI. Early ICU NGAL was most diagnostic of CysC-AKI (AUC 0.69, 95% CI 0.54–0.84); IL-18 was most diagnostic for SCr-AKI (AUC 0.69 95% CI 0.55–0.82). Combining SCr and CysC-AKI definition led to higher biomarker diagnostic AUC’s. CysC-AKI was not more strongly associated with clinical outcomes. Early ICU CysC predicted SCr-AKI development (AUC 0.70, 95 % CI 0.53–0.89).


Our findings do not support replacing SCr by CysC to define AKI. Early ICU CysC predicts SCr-AKI development and combined SCr-CysC-AKI definition leads to stronger AKI biomarker associations.


Diagnostic testing Urine biomarkers Acute renal failure Pediatric intensive care unit 



Dr. Zappitelli received institutional funding from the McGill University Health Centre Research Institute, the Kidney Research Scientist Core Education and National Training Program and the Fonds de Recherches en Santé du Quebec to support this work.


PD is a co-inventor on patents submitted for the use of NGAL as a biomarker of kidney injury.

JB is a co-inventor on patents involving KIM-1.


  1. 1.
    American Society of Nephrology (2005) American Society of Nephrology renal research report. J Am Soc Nephrol 16:1886–1903CrossRefGoogle Scholar
  2. 2.
    Al-Ismaili Z, Palijan A, Zappitelli M (2011) Biomarkers of acute kidney injury in children: discovery, evaluation, and clinical application. Pediatr Nephrol 26:29–40CrossRefPubMedGoogle Scholar
  3. 3.
    Devarajan P (2005) Cellular and molecular derangements in acute tubular necrosis. Curr Opin Pediatr 17:193–199CrossRefPubMedGoogle Scholar
  4. 4.
    Devarajan P (2010) Neutrophil gelatinase-associated lipocalin: a promising biomarker for human acute kidney injury. Biomark Med 4:265–280CrossRefPubMedCentralPubMedGoogle Scholar
  5. 5.
    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 77:708–714CrossRefPubMedCentralPubMedGoogle Scholar
  6. 6.
    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 73:863–869CrossRefPubMedCentralPubMedGoogle Scholar
  7. 7.
    Parikh CR, Devarajan P, Zappitelli M, Sint K, Thiessen-Philbrook H, Li S, Kim RW, Koyner JL, Coca SG, Edelstein CL, Shlipak MG, Garg AX, Krawczeski CD, TRIBE-AKI Consortium (2011) Postoperative biomarkers predict acute kidney injury and poor outcomes after pediatric cardiac surgery. J Am Soc Nephrol 22:1737–1747CrossRefPubMedCentralPubMedGoogle Scholar
  8. 8.
    Aydoğdu M, Gürsel G, Sancak B, Yeni S, Sarı G, Taşyürek S, Türk M, Yüksel S, Senez M, Ozis TN (2013) The use of plasma and urine neutrophil gelatinase associated lipocalin (NGAL) and cystatin-C in early diagnosis of septic acute kidney injury in critically ill patients. Dis Markers 4:237–246CrossRefGoogle Scholar
  9. 9.
    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 26:267–274CrossRefPubMedGoogle Scholar
  10. 10.
    Haase M, Devarajan P, Haase-Fielitz A, Bellomo R, Cruz DN, Wagener G, Krawczeski CD, Koyner JL, Murray P, Zappitelli M, Goldstein SL, Makris K, Ronco C, Martensson J, Martling CR, Venge P, Siew E, Ware LB, Ikizler TA, Mertens PR (2011) The outcome of neutrophil gelatinase-associated lipocalin-positive subclinical acute kidney injury: a multicenter pooled analysis of prospective studies. J Am Coll Cardiol 57:1752–1761CrossRefPubMedGoogle Scholar
  11. 11.
    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:R84CrossRefPubMedCentralPubMedGoogle Scholar
  12. 12.
    Bellomo R (2005) Defining, quantifying, and classifying acute renal failure. Crit Care Clin 21:223–237CrossRefPubMedGoogle Scholar
  13. 13.
    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:R31CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Kellum JA, Lameire N, KDIGO AKI Guideline Work Group (2013) Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care 17:204CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Atiyeh BA, Dabbagh SS, Gruskin AB (1996) Evaluation of renal function during childhood. Pediatr Rev 17:175–180CrossRefPubMedGoogle Scholar
  16. 16.
    Laterza OF, Price CP, Scott MG (2002) Cystatin C: an improved estimator of glomerular filtration rate? Clin Chem 48:699–707PubMedGoogle Scholar
  17. 17.
    Filler G, Lepage N (2003) Should the Schwartz formula for estimation of GFR be replaced by cystatin C formula? Pediatr Nephrol 18:981–985CrossRefPubMedGoogle Scholar
  18. 18.
    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 48:221–230CrossRefPubMedGoogle Scholar
  19. 19.
    Herget-Rosenthal S, Marggraf G, Hüsing J, Göring F, Pietruck F, Janssen O, Philipp T, Kribben A (2004) Early detection of acute renal failure by serum cystatin C. Kidney Int 66:1115–1122CrossRefPubMedGoogle Scholar
  20. 20.
    Fricker M, Wiesli P, Brändle M, Schwegler B, Schmid C (2003) Impact of thyroid dysfunction on serum cystatin C. Kidney Int 63:1944–1947CrossRefPubMedGoogle Scholar
  21. 21.
    Kos J, Stabuc B, Cimerman N, Brünner N (1998) Serum cystatin C, a new marker of glomerular filtration rate, is increased during malignant progression. Clin Chem 44:2556–2557PubMedGoogle Scholar
  22. 22.
    Manetti L, Genovesi M, Pardini E, Grasso L, Lupi I, Linda Morselli L, Pellegrini G, Martino E (2005) Early effects of methylprednisolone infusion on serum cystatin C in patients with severe Graves’ ophthalmopathy. Clin Chim Acta 356:227–228CrossRefPubMedGoogle Scholar
  23. 23.
    Manetti L, Pardini E, Genovesi M, Campomori A, Grasso L, Morselli LL, Lupi I, Pellegrini G, Bartalena L, Bogazzi F, Martino E (2005) Thyroid function differently affects serum cystatin C and creatinine concentrations. J Endocrinol Invest 28:346–349CrossRefPubMedGoogle Scholar
  24. 24.
    Pollack MM, Ruttimann UE, Getson PR (1988) Pediatric risk of mortality (PRISM) score. Crit Care Med 16:1110–1116CrossRefPubMedGoogle Scholar
  25. 25.
    Leteurtre S, Martinot A, Duhamel A, Proulx F, Grandbastien B, Cotting J, Gottesman R, Joffe A, Pfenninger J, Hubert P, Lacroix J, Leclerc F (2003) Validation of the paediatric logistic organ dysfunction (PELOD) score: prospective, observational, multicentre study. Lancet 362:192–197CrossRefPubMedGoogle Scholar
  26. 26.
    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 20:629–637CrossRefPubMedCentralPubMedGoogle Scholar
  27. 27.
    Fadrowski JJ, Neu AM, Schwartz GJ, Furth SL (2011) Pediatric GFR estimating equations applied to adolescents in the general population. Clin J Am Soc Nephrol 6:1427–1435CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Krawczeski CD, Woo JG, Wang Y, Bennett MR, Ma Q, Devarajan P (2011) Neutrophil gelatinase-associated lipocalin concentrations predict development of acute kidney injury in neonates and children after cardiopulmonary bypass. J Pediatr 158:1009–1015, e1CrossRefPubMedGoogle Scholar
  29. 29.
    Vaidya VS, Waikar SS, Ferguson MA, Collings FB, Sunderland K, Gioules C, Bradwin G, Matsouaka R, Betensky RA, Curhan GC, Bonventre JV (2008) Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans. Clin Transl Sci 1:200–208CrossRefPubMedCentralPubMedGoogle Scholar
  30. 30.
    Pencina MJ, D’Agostino RB Sr, D’Agostino RB Jr, Vasan RS (2008) Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 27:157–172, discussion 207-112CrossRefPubMedGoogle Scholar
  31. 31.
    Pencina MJ, D’Agostino RB Sr, Steyerberg EW (2011) Extensions of net reclassification improvement calculations to measure usefulness of new biomarkers. Stat Med 30:11–21CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Grubb A, Nyman U, Bjork J, Lindstrom V, Rippe B, Sterner G, Christensson A (2005) Simple cystatin C-based prediction equations for glomerular filtration rate compared with the modification of diet in renal disease prediction equation for adults and the Schwartz and the Counahan-Barratt prediction equations for children. Clin Chem 51:1420–1431CrossRefPubMedGoogle Scholar
  33. 33.
    Kwon SH, Hyun J, Jeon JS, Noh H, Han DC (2011) Subtle change of cystatin C, with or without acute kidney injury, associated with increased mortality in the intensive care unit. J Crit Care 26:566–571CrossRefPubMedGoogle Scholar
  34. 34.
    Lassus JP, Nieminen MS, Peuhkurinen K, Pulkki K, Siirilä-Waris K, Sund R, Harjola VP, FINN-AKVA study group (2010) Markers of renal function and acute kidney injury in acute heart failure: definitions and impact on outcomes of the cardiorenal syndrome. Eur Heart J 31:2791–2798CrossRefPubMedGoogle Scholar
  35. 35.
    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 25:3283–3289CrossRefPubMedGoogle Scholar
  36. 36.
    Zappitelli M, Krawczeski CD, Devarajan P, Wang Z, Sint K, Thiessen-Philbrook H, Li S, Bennett MR, Ma Q, Shlipak MG, Garg AX, Parikh CR, TRIBE-AKI consortium (2011) Early postoperative serum cystatin C predicts severe acute kidney injury following pediatric cardiac surgery. Kidney Int 80:655–662CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Briguori C, Visconti G, Rivera NV, Focaccio A, Golia B, Giannone R, Castaldo D, De Micco F, Ricciardelli B, Colombo A (2010) Cystatin C and contrast-induced acute kidney injury. Circulation 121:2117–2122CrossRefPubMedGoogle Scholar
  38. 38.
    Choi YS, Shim JK, Kim JC, Kang KS, Seo YH, Ahn KR, Kwak YL (2011) Effect of remote ischemic preconditioning on renal dysfunction after complex valvular heart surgery: a randomized controlled trial. J Thorac Cardiovasc Surg 142:148–154CrossRefPubMedGoogle Scholar
  39. 39.
    Cortjens B, Royakkers AA, Determann RM, van Suijlen JD, Kamphuis SS, Foppen J, de Boer A, Wieland CW, Spronk PE, Schultz MJ, Bouman CS (2012) Lung-protective mechanical ventilation does not protect against acute kidney injury in patients without lung injury at onset of mechanical ventilation. J Crit Care 27:261–267CrossRefPubMedGoogle Scholar
  40. 40.
    Haase M, Bellomo R, Devarajan P, Ma Q, Bennett MR, Möckel M, Matalanis G, Dragun D, Haase-Fielitz A (2009) Novel biomarkers early predict the severity of acute kidney injury after cardiac surgery in adults. Ann Thorac Surg 88:124–130CrossRefPubMedGoogle Scholar
  41. 41.
    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 5:1745–1754CrossRefPubMedCentralPubMedGoogle Scholar
  42. 42.
    Wald R, Liangos O, Perianayagam MC, Kolyada A, Herget-Rosenthal S, Mazer CD, Jaber BL (2010) Plasma cystatin C and acute kidney injury after cardiopulmonary bypass. Clin J Am Soc Nephrol 5:1373–1379CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Zhang Z, Lu B, Sheng X, Jin N (2011) Cystatin C in prediction of acute kidney injury: a systemic review and meta-analysis. Am J Kidney Dis 58:356–365CrossRefPubMedGoogle Scholar
  44. 44.
    Ataei N, Bazargani B, Ameli S, Madani A, Javadilarijani F, Moghtaderi M, Abbasi A, Shams S, Ataei F (2014) Early detection of acute kidney injury by serum cystatin C in critically ill children. Pediatr Nephrol 29:133–138CrossRefPubMedGoogle Scholar
  45. 45.
    Pickering JW, Endre ZH (2013) Linking injury to outcome in acute kidney injury: a matter of sensitivity. PLoS ONE 8:e62691CrossRefPubMedCentralPubMedGoogle Scholar

Copyright information

© IPNA 2014

Authors and Affiliations

  • Paola Lagos-Arevalo
    • 1
  • Ana Palijan
    • 1
  • Laura Vertullo
    • 1
  • Prasad Devarajan
    • 2
  • Michael R. Bennett
    • 2
  • Venkata Sabbisetti
    • 3
  • Joseph V. Bonventre
    • 3
  • Qing Ma
    • 2
  • Ronald D. Gottesman
    • 1
  • Michael Zappitelli
    • 1
    • 4
    Email author
  1. 1.Department of PediatricsMcGill University Health CentreMontrealCanada
  2. 2.Nephrology & HypertensionCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  3. 3.Renal Division, Brigham’s and Women’s HospitalHarvard Medical SchoolBostonUSA
  4. 4.Montreal Children’s HospitalMontrealCanada

Personalised recommendations