Skip to main content
Top
Published in: BMC Pediatrics 1/2018

Open Access 01-12-2018 | Research article

Serum and urine FGF23 and IGFBP-7 for the prediction of acute kidney injury in critically ill children

Authors: Zhenjiang Bai, Fang Fang, Zhong Xu, Chunjiu Lu, Xueqin Wang, Jiao Chen, Jian Pan, Jian Wang, Yanhong Li

Published in: BMC Pediatrics | Issue 1/2018

Login to get access

Abstract

Background

Fibroblast growth factor 23 (FGF23) and insulin-like growth factor binding protein 7 (IGFBP-7) are suggested to be biomarkers for predicting acute kidney injury (AKI). We compared them with proposed AKI biomarker of cystatin C (CysC), and aimed (1) to examine whether concentrations of these biomarkers vary with age, body weight, illness severity assessed by pediatric risk of mortality III score, and kidney function assessed by estimated glomerular filtration rate (eGFR), (2) to determine the association between these biomarkers and AKI, and (3) to evaluate whether these biomarkers could serve as early independent predictors of AKI in critically ill children.

Methods

This prospective single center study included 144 critically ill patients admitted to the pediatric intensive care unit (PICU) regardless of diagnosis. Serum and spot urine samples were collected during the first 24 h after PICU admission. AKI was diagnosed based on the AKI network (AKIN) criteria.

Results

Twenty-one patients developed AKI within 120 h of sample collection, including 11 with severe AKI defined as AKIN stages 2 and 3. Serum FGF23 levels were independently associated with eGFR after adjustment in a multivariate linear analysis (P < 0.001). Urinary IGFBP-7 (Adjusted OR = 2.94 per 1000 ng/mg increase, P = 0.035), serum CysC (Adjusted OR = 5.28, P = 0.005), and urinary CysC (Adjusted OR = 1.13 per 1000 ng/mg increase, P = 0.022) remained significantly associated with severe AKI after adjustment for body weight and illness severity, respectively. Urinary IGFBP-7 level was predictive of severe AKI and achieved the AUC of 0.79 (P = 0.001), but was not better than serum (AUC = 0.89, P < 0.001) and urinary (AUC = 0.88, P < 0.001) CysC in predicting severe AKI.

Conclusions

Serum FGF23 levels were inversely related to measures of eGFR. In contrast to serum and urinary FGF23 which are not associated with AKI in a general and heterogeneous PICU population, an increased urinary IGFBP-7 level was independently associated with the increased risk of severe AKI diagnosed within the next 5 days after sampling, but not superior to serum or urinary CysC in predicting severe AKI in critically ill children.
Literature
1.
go back to reference Singbartl K, Kellum JA. AKI in the ICU: definition, epidemiology, risk stratification, and outcomes. Kidney Int. 2012;81:819–25.CrossRefPubMed Singbartl K, Kellum JA. AKI in the ICU: definition, epidemiology, risk stratification, and outcomes. Kidney Int. 2012;81:819–25.CrossRefPubMed
2.
go back to reference Alkandari O, Eddington KA, Hyder A, Gauvin F, Ducruet T, Gottesman R, et al. Acute kidney injury is an independent risk factor for pediatric intensive care unit mortality, longer length of stay and prolonged mechanical ventilation in critically ill children: a two-center retrospective cohort study. Crit Care. 2011;15:R146.CrossRefPubMedPubMedCentral Alkandari O, Eddington KA, Hyder A, Gauvin F, Ducruet T, Gottesman R, et al. Acute kidney injury is an independent risk factor for pediatric intensive care unit mortality, longer length of stay and prolonged mechanical ventilation in critically ill children: a two-center retrospective cohort study. Crit Care. 2011;15:R146.CrossRefPubMedPubMedCentral
3.
go back to reference Sanchez-Pinto LN, Goldstein SL, Schneider JB, Khemani RG. Association between progression and improvement of acute kidney injury and mortality in critically ill children. Pediatr Crit Care Med. 2015;16:703–10.CrossRefPubMed Sanchez-Pinto LN, Goldstein SL, Schneider JB, Khemani RG. Association between progression and improvement of acute kidney injury and mortality in critically ill children. Pediatr Crit Care Med. 2015;16:703–10.CrossRefPubMed
4.
go back to reference Volpon LC, Sugo EK, Consulin JC, Tavares TL, Aragon DC, Carlotti AP. Epidemiology and outcome of acute kidney injury according to pediatric risk, injury, failure, loss, end-stage renal disease and kidney disease: Improving Global Outcomes Criteria in Critically Ill Children-A Prospective Study. Pediatr Crit Care Med. 2016;17:e229–38.CrossRefPubMed Volpon LC, Sugo EK, Consulin JC, Tavares TL, Aragon DC, Carlotti AP. Epidemiology and outcome of acute kidney injury according to pediatric risk, injury, failure, loss, end-stage renal disease and kidney disease: Improving Global Outcomes Criteria in Critically Ill Children-A Prospective Study. Pediatr Crit Care Med. 2016;17:e229–38.CrossRefPubMed
5.
go back to reference Coca SG, Yalavarthy R, Concato J, Parikh CR. Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int. 2008;73:1008–16.CrossRefPubMed Coca SG, Yalavarthy R, Concato J, Parikh CR. Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review. Kidney Int. 2008;73:1008–16.CrossRefPubMed
6.
go back to reference Li Y, Fu C, Zhou X, Xiao Z, Zhu X, Jin M, et al. Urine interleukin-18 and cystatin-C as biomarkers of acute kidney injury in critically ill neonates. Pediatr Nephrol. 2012;27:851–60.CrossRefPubMedPubMedCentral Li Y, Fu C, Zhou X, Xiao Z, Zhu X, Jin M, et al. Urine interleukin-18 and cystatin-C as biomarkers of acute kidney injury in critically ill neonates. Pediatr Nephrol. 2012;27:851–60.CrossRefPubMedPubMedCentral
7.
go back to reference Vanmassenhove J, Vanholder R, Nagler E, Van Biesen W. Urinary and serum biomarkers for the diagnosis of acute kidney injury: an in-depth review of the literature. Nephrol Dial Transplant. 2013;28:254–73.CrossRefPubMed Vanmassenhove J, Vanholder R, Nagler E, Van Biesen W. Urinary and serum biomarkers for the diagnosis of acute kidney injury: an in-depth review of the literature. Nephrol Dial Transplant. 2013;28:254–73.CrossRefPubMed
8.
go back to reference Ataei N, Bazargani B, Ameli S, Madani A, Javadilarijani F, Moghtaderi M, et al. Early detection of acute kidney injury by serum cystatin C in critically ill children. Pediatr Nephrol. 2014;29:133–8.CrossRefPubMed Ataei N, Bazargani B, Ameli S, Madani A, Javadilarijani F, Moghtaderi M, et al. Early detection of acute kidney injury by serum cystatin C in critically ill children. Pediatr Nephrol. 2014;29:133–8.CrossRefPubMed
9.
go back to reference Volpon LC, Sugo EK, Carlotti AP. Diagnostic and prognostic value of serum cystatin C in critically ill children with acute kidney injury. Pediatr Crit Care Med. 2015;16:e125–31.CrossRefPubMed Volpon LC, Sugo EK, Carlotti AP. Diagnostic and prognostic value of serum cystatin C in critically ill children with acute kidney injury. Pediatr Crit Care Med. 2015;16:e125–31.CrossRefPubMed
10.
go back to reference Sellmer A, Bech BH, Bjerre JV, Schmidt MR, Hjortdal VE, Esberg G, et al. Urinary neutrophil gelatinase-associated Lipocalin in the evaluation of patent ductus arteriosus and AKI in very preterm neonates: a cohort study. BMC Pediatr. 2017;17:7.CrossRefPubMedPubMedCentral Sellmer A, Bech BH, Bjerre JV, Schmidt MR, Hjortdal VE, Esberg G, et al. Urinary neutrophil gelatinase-associated Lipocalin in the evaluation of patent ductus arteriosus and AKI in very preterm neonates: a cohort study. BMC Pediatr. 2017;17:7.CrossRefPubMedPubMedCentral
12.
go back to reference Lameire NH, Vanholder RC, Van Biesen WA. How to use biomarkers efficiently in acute kidney injury. Kidney Int. 2011;79:1047–50.CrossRefPubMed Lameire NH, Vanholder RC, Van Biesen WA. How to use biomarkers efficiently in acute kidney injury. Kidney Int. 2011;79:1047–50.CrossRefPubMed
13.
go back to reference Kovesdy CP, Quarles LD. FGF23 from bench to bedside. Am J Physiol Renal Physiol. 2016;310:F1168–74.CrossRefPubMed Kovesdy CP, Quarles LD. FGF23 from bench to bedside. Am J Physiol Renal Physiol. 2016;310:F1168–74.CrossRefPubMed
14.
go back to reference Zhang M, Hsu R, Hsu CY, Kordesch K, Nicasio E, Cortez A, et al. FGF-23 and PTH levels in patients with acute kidney injury: a cross-sectional case series study. Ann Intensive Care. 2011;1:21.CrossRefPubMedPubMedCentral Zhang M, Hsu R, Hsu CY, Kordesch K, Nicasio E, Cortez A, et al. FGF-23 and PTH levels in patients with acute kidney injury: a cross-sectional case series study. Ann Intensive Care. 2011;1:21.CrossRefPubMedPubMedCentral
15.
go back to reference Leaf DE, Wolf M, Waikar SS, Chase H, Christov M, Cremers S, et al. FGF-23 levels in patients with AKI and risk of adverse outcomes. Clin J Am Soc Nephrol. 2012;7:1217–23.CrossRefPubMedPubMedCentral Leaf DE, Wolf M, Waikar SS, Chase H, Christov M, Cremers S, et al. FGF-23 levels in patients with AKI and risk of adverse outcomes. Clin J Am Soc Nephrol. 2012;7:1217–23.CrossRefPubMedPubMedCentral
16.
go back to reference Christov M, Waikar SS, Pereira RC, Havasi A, Leaf DE, Goltzman D, et al. Plasma FGF23 levels increase rapidly after acute kidney injury. Kidney Int. 2013;84:776–85.CrossRefPubMedPubMedCentral Christov M, Waikar SS, Pereira RC, Havasi A, Leaf DE, Goltzman D, et al. Plasma FGF23 levels increase rapidly after acute kidney injury. Kidney Int. 2013;84:776–85.CrossRefPubMedPubMedCentral
17.
go back to reference Neyra JA, Moe OW, Hu MC. Fibroblast growth factor 23 and acute kidney injury. Pediatr Nephrol. 2015;30:1909–18.CrossRefPubMed Neyra JA, Moe OW, Hu MC. Fibroblast growth factor 23 and acute kidney injury. Pediatr Nephrol. 2015;30:1909–18.CrossRefPubMed
18.
go back to reference Leaf DE, Christov M, Juppner H, Siew E, Ikizler TA, Bian A, et al. Fibroblast growth factor 23 levels are elevated and associated with severe acute kidney injury and death following cardiac surgery. Kidney Int. 2016;89:939–48.CrossRefPubMedPubMedCentral Leaf DE, Christov M, Juppner H, Siew E, Ikizler TA, Bian A, et al. Fibroblast growth factor 23 levels are elevated and associated with severe acute kidney injury and death following cardiac surgery. Kidney Int. 2016;89:939–48.CrossRefPubMedPubMedCentral
19.
go back to reference Ali FN, Hassinger A, Price H, Langman CB. Preoperative plasma FGF23 levels predict acute kidney injury in children: results of a pilot study. Pediatr Nephrol. 2013;28:959–62.CrossRefPubMed Ali FN, Hassinger A, Price H, Langman CB. Preoperative plasma FGF23 levels predict acute kidney injury in children: results of a pilot study. Pediatr Nephrol. 2013;28:959–62.CrossRefPubMed
20.
go back to reference Aregger F, Uehlinger DE, Witowski J, Brunisholz RA, Hunziker P, Frey FJ, et al. Identification of IGFBP-7 by urinary proteomics as a novel prognostic marker in early acute kidney injury. Kidney Int. 2014;85:909–19.CrossRefPubMed Aregger F, Uehlinger DE, Witowski J, Brunisholz RA, Hunziker P, Frey FJ, et al. Identification of IGFBP-7 by urinary proteomics as a novel prognostic marker in early acute kidney injury. Kidney Int. 2014;85:909–19.CrossRefPubMed
21.
go back to reference Konvalinka A. Urine proteomics for acute kidney injury prognosis: another player and the long road ahead. Kidney Int. 2014;85:735–8.CrossRefPubMed Konvalinka A. Urine proteomics for acute kidney injury prognosis: another player and the long road ahead. Kidney Int. 2014;85:735–8.CrossRefPubMed
22.
go back to reference Lameire N, Vanmassenhove J, Van Biesen W, Vanholder R. The cell cycle biomarkers: promising research, but do not oversell them. Clin Kidney J. 2016;9:353–8.CrossRefPubMedPubMedCentral Lameire N, Vanmassenhove J, Van Biesen W, Vanholder R. The cell cycle biomarkers: promising research, but do not oversell them. Clin Kidney J. 2016;9:353–8.CrossRefPubMedPubMedCentral
23.
go back to reference Wetz AJ, Richardt EM, Wand S, Kunze N, Schotola H, Quintel M, et al. Quantification of urinary TIMP-2 and IGFBP-7: an adequate diagnostic test to predict acute kidney injury after cardiac surgery? Crit Care. 2015;19:3.CrossRefPubMedPubMedCentral Wetz AJ, Richardt EM, Wand S, Kunze N, Schotola H, Quintel M, et al. Quantification of urinary TIMP-2 and IGFBP-7: an adequate diagnostic test to predict acute kidney injury after cardiac surgery? Crit Care. 2015;19:3.CrossRefPubMedPubMedCentral
24.
go back to reference Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013;17:R25.CrossRefPubMedPubMedCentral Kashani K, Al-Khafaji A, Ardiles T, Artigas A, Bagshaw SM, Bell M, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care. 2013;17:R25.CrossRefPubMedPubMedCentral
26.
go back to reference Liu Y, Wu M, Ling J, Cai L, Zhang D, Gu HF, et al. Serum IGFBP7 levels associate with insulin resistance and the risk of metabolic syndrome in a Chinese population. Sci Rep. 2015;5:10227.CrossRefPubMedPubMedCentral Liu Y, Wu M, Ling J, Cai L, Zhang D, Gu HF, et al. Serum IGFBP7 levels associate with insulin resistance and the risk of metabolic syndrome in a Chinese population. Sci Rep. 2015;5:10227.CrossRefPubMedPubMedCentral
27.
go back to reference Tucker BJ, Anderson CM, Thies RS, Collins RC, Blantz RC. Glomerular hemodynamic alterations during acute hyperinsulinemia in normal and diabetic rats. Kidney Int. 1992;42:1160–8.CrossRefPubMed Tucker BJ, Anderson CM, Thies RS, Collins RC, Blantz RC. Glomerular hemodynamic alterations during acute hyperinsulinemia in normal and diabetic rats. Kidney Int. 1992;42:1160–8.CrossRefPubMed
28.
go back to reference Guidelines for developing admission and discharge policies for the pediatric intensive care unit. American Academy of Pediatrics. Committee on hospital care and section of critical care. Society of Critical Care Medicine. Pediatric section admission criteria task force. Pediatrics. 1999;103:840–2.CrossRef Guidelines for developing admission and discharge policies for the pediatric intensive care unit. American Academy of Pediatrics. Committee on hospital care and section of critical care. Society of Critical Care Medicine. Pediatric section admission criteria task force. Pediatrics. 1999;103:840–2.CrossRef
29.
go back to reference Bai Z, Zhu X, Li M, Hua J, Li Y, Pan J, et al. Effectiveness of predicting in-hospital mortality in critically ill children by assessing blood lactate levels at admission. BMC Pediatr. 2014;14:83.CrossRefPubMedPubMedCentral Bai Z, Zhu X, Li M, Hua J, Li Y, Pan J, et al. Effectiveness of predicting in-hospital mortality in critically ill children by assessing blood lactate levels at admission. BMC Pediatr. 2014;14:83.CrossRefPubMedPubMedCentral
30.
go back to reference Pollack MM, Patel KM, Ruttimann UE. PRISM III: an updated pediatric risk of mortality score. Crit Care Med. 1996;24:743–52.CrossRefPubMed Pollack MM, Patel KM, Ruttimann UE. PRISM III: an updated pediatric risk of mortality score. Crit Care Med. 1996;24:743–52.CrossRefPubMed
31.
go back to reference Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11:R31.CrossRefPubMedPubMedCentral Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute kidney injury network: report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11:R31.CrossRefPubMedPubMedCentral
32.
go back to reference Pickering JW, Endre ZH. Back-calculating baseline creatinine with MDRD misclassifies acute kidney injury in the intensive care unit. Clin J Am Soc Nephrol. 2010;5:1165–73.CrossRefPubMedPubMedCentral Pickering JW, Endre ZH. Back-calculating baseline creatinine with MDRD misclassifies acute kidney injury in the intensive care unit. Clin J Am Soc Nephrol. 2010;5:1165–73.CrossRefPubMedPubMedCentral
33.
go back to reference Li Y, Wang J, Bai Z, Chen J, Wang X, Pan J, et al. Early fluid overload is associated with acute kidney injury and PICU mortality in critically ill children. Eur J Pediatr. 2016;175:39–48.CrossRefPubMed Li Y, Wang J, Bai Z, Chen J, Wang X, Pan J, et al. Early fluid overload is associated with acute kidney injury and PICU mortality in critically ill children. Eur J Pediatr. 2016;175:39–48.CrossRefPubMed
34.
go back to reference Bouvet Y, Bouissou F, Coulais Y, Seronie-Vivien S, Tafani M, Decramer S, et al. GFR is better estimated by considering both serum cystatin C and creatinine levels. Pediatr Nephrol. 2006;21:1299–306.CrossRefPubMed Bouvet Y, Bouissou F, Coulais Y, Seronie-Vivien S, Tafani M, Decramer S, et al. GFR is better estimated by considering both serum cystatin C and creatinine levels. Pediatr Nephrol. 2006;21:1299–306.CrossRefPubMed
35.
go back to reference Finney H, Newman DJ, Thakkar H, Fell JM, Price CP. Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates, and older children. Arch Dis Child. 2000;82:71–5.CrossRefPubMedPubMedCentral Finney H, Newman DJ, Thakkar H, Fell JM, Price CP. Reference ranges for plasma cystatin C and creatinine measurements in premature infants, neonates, and older children. Arch Dis Child. 2000;82:71–5.CrossRefPubMedPubMedCentral
36.
go back to reference Fatani T, Binjab A, Weiler H, Sharma A, Rodd C. Persistent elevation of fibroblast growth factor 23 concentrations in healthy appropriate-for-gestational-age preterm infants. J Pediatr Endocrinol Metab. 2015;28:825–32.CrossRefPubMed Fatani T, Binjab A, Weiler H, Sharma A, Rodd C. Persistent elevation of fibroblast growth factor 23 concentrations in healthy appropriate-for-gestational-age preterm infants. J Pediatr Endocrinol Metab. 2015;28:825–32.CrossRefPubMed
37.
go back to reference Lima F, El-Husseini A, Monier-Faugere MC, David V, Mawad H, Quarles D, et al. FGF-23 serum levels and bone histomorphometric results in adult patients with chronic kidney disease on dialysis. Clin Nephrol. 2014;82:287–95.CrossRefPubMedPubMedCentral Lima F, El-Husseini A, Monier-Faugere MC, David V, Mawad H, Quarles D, et al. FGF-23 serum levels and bone histomorphometric results in adult patients with chronic kidney disease on dialysis. Clin Nephrol. 2014;82:287–95.CrossRefPubMedPubMedCentral
38.
go back to reference Samadfam R, Richard C, Nguyen-Yamamoto L, Bolivar I, Goltzman D. Bone formation regulates circulating concentrations of fibroblast growth factor 23. Endocrinology. 2009;150:4835–45.CrossRefPubMed Samadfam R, Richard C, Nguyen-Yamamoto L, Bolivar I, Goltzman D. Bone formation regulates circulating concentrations of fibroblast growth factor 23. Endocrinology. 2009;150:4835–45.CrossRefPubMed
39.
go back to reference Deng F, Finer G, Haymond S, Brooks E, Langman CB. Applicability of estimating glomerular filtration rate equations in pediatric patients: comparison with a measured glomerular filtration rate by iohexol clearance. Transl Res. 2015;165:437–45.CrossRefPubMed Deng F, Finer G, Haymond S, Brooks E, Langman CB. Applicability of estimating glomerular filtration rate equations in pediatric patients: comparison with a measured glomerular filtration rate by iohexol clearance. Transl Res. 2015;165:437–45.CrossRefPubMed
40.
go back to reference Dhayat NA, Ackermann D, Pruijm M, Ponte B, Ehret G, Guessous I, et al. Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function. Kidney Int. 2016;90:648–57.CrossRefPubMed Dhayat NA, Ackermann D, Pruijm M, Ponte B, Ehret G, Guessous I, et al. Fibroblast growth factor 23 and markers of mineral metabolism in individuals with preserved renal function. Kidney Int. 2016;90:648–57.CrossRefPubMed
41.
go back to reference Scialla JJ, Wolf M. Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease. Nat Rev Nephrol. 2014;10:268–78.CrossRefPubMed Scialla JJ, Wolf M. Roles of phosphate and fibroblast growth factor 23 in cardiovascular disease. Nat Rev Nephrol. 2014;10:268–78.CrossRefPubMed
42.
go back to reference Prie D, Forand A, Francoz C, Elie C, Cohen I, Courbebaisse M, et al. Plasma fibroblast growth factor 23 concentration is increased and predicts mortality in patients on the liver-transplant waiting list. PLoS One. 2013;8:e66182.CrossRefPubMedPubMedCentral Prie D, Forand A, Francoz C, Elie C, Cohen I, Courbebaisse M, et al. Plasma fibroblast growth factor 23 concentration is increased and predicts mortality in patients on the liver-transplant waiting list. PLoS One. 2013;8:e66182.CrossRefPubMedPubMedCentral
Metadata
Title
Serum and urine FGF23 and IGFBP-7 for the prediction of acute kidney injury in critically ill children
Authors
Zhenjiang Bai
Fang Fang
Zhong Xu
Chunjiu Lu
Xueqin Wang
Jiao Chen
Jian Pan
Jian Wang
Yanhong Li
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Pediatrics / Issue 1/2018
Electronic ISSN: 1471-2431
DOI
https://doi.org/10.1186/s12887-018-1175-y

Other articles of this Issue 1/2018

BMC Pediatrics 1/2018 Go to the issue