Top

Published in:

Open Access 01-12-2019 | Acute Kidney Injury | Research

Fibroblast growth factor 23, endothelium biomarkers and acute kidney injury in critically-ill patients

Authors: Fernanda Macedo de Oliveira Neves, Camila Barbosa Araújo, Daniele Ferreira de Freitas, Bianca Fernandes Távora Arruda, Leonardo José Monteiro de Macêdo Filho, Vivian Brito Salles, Gdayllon Cavalcante Meneses, Alice Maria Costa Martins, Alexandre Braga Libório

Published in: Journal of Translational Medicine | Issue 1/2019

Abstract

Background

Fibroblast growth factor 23 (FGF23) and endothelium-related biomarkers have been related to AKI in critically-ill patients. Also, FGF23 is associated with endothelial dysfunction. In this study, we investigated if elevated FGF23 association with severe AKI is mediated by several endothelial/glycocalyx-related biomarkers.

Methods

Prospective cohort study with critically-ill patients. Blood samples were collected within the first 24 h after ICU admission. Severe AKI (defined according to KDIGO stage 2/3) was the analyzed outcome.

Results

265 patients were enrolled and 82 (30.9%) developed severe AKI—defined according to KDIGO stage 2/3. Blood samples to biomarkers measurement were collected within the first 24 h after ICU admission. After adjustment for several variables, FGF23, vascular cell adhesion protein 1 (VCAM-1), angiopoietin 2 (AGPT2), syndecan-1 and intercellular adhesion molecule-1 (ICAM-1) were associated with severe AKI. The individual indirect effects of VCAM-1, AGPT2 and syndecan-1 explained 23%, 31%, and 32% of the total observed effect of FGF23 on severe AKI, respectively. ICAM-1 showed no statistically significant mediation. When all three endothelium-related biomarkers were included in a directed acyclic graph (DAG), the Bayesian network learning suggested the following causal association pathway FGF-23 → syndecan-1 → VCAM-1 → AGPT2 → severe AKI.

Conclusions

The association between FGF23 and AKI are mediated by endothelium-related biomarkers, mainly VCAM-1, AGPT2 and syndecan-1. Moreover, the statistical models show that syndecan-1, a biomarker of endothelial glycocalyx dysfunction, seems to be the initial mediator between FGF23 and severe AKI.

Available only for authorised users

Singbartl K, Kellum JA. AKI in the ICU: definition, epidemiology, risk stratification, and outcomes. Kidney Int. 2012;81(9):819–25. https://doi.org/10.1038/ki.2011.339.CrossRefPubMed

Libório AB, Leite TT, De Oliveira Neves FM, Teles F, De Melo Bezerra CT. AKI complications in critically ill patients: association with mortality rates and RRT. Clin J Am Soc Nephrol. 2015. https://doi.org/10.2215/cjn.04750514.CrossRefPubMedPubMedCentral

Lafrance J-P, Miller DR. Acute kidney injury associates with increased long-term mortality. J Am Soc Nephrol. 2010;21(2):345–52. https://doi.org/10.1681/ASN.2009060636.CrossRefPubMedPubMedCentral

Martin KJ, González E. Metabolic bone disease in chronic kidney disease. J Am Soc Nephrol. 2007;18(3):875–85. https://doi.org/10.1681/asn.2006070771.CrossRefPubMed

Christov M, Waikar SS, Pereira RC, et al. Plasma FGF23 levels increase rapidly after acute kidney injury. Kidney Int. 2013;84(4):776–85. https://doi.org/10.1038/ki.2013.150.CrossRefPubMedPubMedCentral

Leaf DE, Wolf M, Waikar SS, et al. FGF-23 levels in patients with AKI and risk of adverse outcomes. Clin J Am Soc Nephrol. 2012;7(8):1217–23. https://doi.org/10.2215/CJN.00550112.CrossRefPubMedPubMedCentral

Leaf DE, Jacob KA, Srivastava A, et al. Fibroblast growth factor 23 levels associate with AKI and death in critical illness. J Am Soc Nephrol. 2017;28(6):1877–85. https://doi.org/10.1681/ASN.2016080836.CrossRefPubMed

Leaf DE, Christov M, Jüppner H, 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(4):939–48. https://doi.org/10.1016/j.kint.2015.12.035.CrossRefPubMedPubMedCentral

Leaf DE, Siew ED, Eisenga MF, et al. Fibroblast growth factor 23 associates with death in critically ill patients. Clin J Am Soc Nephrol. 2018. https://doi.org/10.2215/cjn.10810917.CrossRefPubMedPubMedCentral

10.

Zivin JR, Gooley T, Zager RA, Ryan MJ. Hypocalcemia: a pervasive metabolic abnormality in the critically ill. Am J Kidney Dis. 2001;37(4):689–98. https://doi.org/10.1016/S0272-6386(01)80116-5.CrossRefPubMed

11.

Lee P, Eisman JA, Center JR. Vitamin D deficiency in critically ill patients. N Engl J Med. 2009;360(18):1912–4. https://doi.org/10.1056/NEJMc0809996.CrossRefPubMed

12.

Leaf DE, Waikar SS, Wolf M, Cremers S, Bhan I, Stern L. Dysregulated mineral metabolism in patients with acute kidney injury and risk of adverse outcomes. Clin Endocrinol (Oxf). 2013;79(4):491–8. https://doi.org/10.1111/cen.12172.CrossRef

13.

Scialla JJ, Xie H, Rahman M, et al. Fibroblast growth factor-23 and cardiovascular events in CKD. J Am Soc Nephrol. 2014;25(2):349–60. https://doi.org/10.1681/ASN.2013050465.CrossRefPubMed

14.

Verma SK, Molitoris BA. Renal endothelial injury and microvascular dysfunction in acute kidney injury. Semin Nephrol. 2015;35(1):96–107. https://doi.org/10.1016/j.semnephrol.2015.01.010.CrossRefPubMed

15.

Zafrani L, Ince C. Microcirculation in acute and chronic kidney diseases. Am J Kidney Dis. 2015;66(6):1083–94. https://doi.org/10.1053/j.ajkd.2015.06.019.CrossRefPubMed

16.

Bhatraju PK, Robinson-Cohen C, Mikacenic C, et al. Circulating levels of soluble Fas (sCD95) are associated with risk for development of a nonresolving acute kidney injury subphenotype. Crit Care. 2017;21:1. https://doi.org/10.1186/s13054-017-1807-x.CrossRef

17.

Melo Bezerra Cavalcante CT, Castelo Branco KM, Pinto Júnior VC, et al. Syndecan-1 improves severe acute kidney injury prediction after pediatric cardiac surgery. J Thorac Cardiovasc Surg. 2016;152(1):178–86. https://doi.org/10.1016/j.jtcvs.2016.03.079.CrossRefPubMed

18.

de Oliveira Neves FM, Meneses GC, Sousa NEA, et al. Syndecan-1 in acute decompensated heart failure—association with renal function and mortality. Circ J. 2015. https://doi.org/10.1253/circj.cj-14-1195.CrossRef

19.

Jongman RM, Van Klarenbosch J, Molema G, et al. Angiopoietin/Tie2 dysbalance is associated with acute kidney injury after cardiac surgery assisted by cardiopulmonary bypass. PLoS ONE. 2015. https://doi.org/10.1371/journal.pone.0136205.CrossRefPubMedPubMedCentral

20.

Sporek M, Dumnicka P, Gala-Bladzinska A, et al. Angiopoietin-2 is an early indicator of acute pancreatic-renal syndrome in patients with acute pancreatitis. Mediators Inflamm. 2016. https://doi.org/10.1155/2016/5780903.CrossRefPubMedPubMedCentral

21.

Hepokoski M, Englert JA, Baron RM, et al. Ventilator-induced lung injury increases expression of endothelial inflammatory mediators in the kidney. Am j Physiol Ren Physiol. 2017. https://doi.org/10.1152/ajprenal.00523.2016.CrossRef

22.

Silswal N, Touchberry CD, Daniel DR, et al. FGF23 directly impairs endothelium-dependent vasorelaxation by increasing superoxide levels and reducing nitric oxide bioavailability. AJP Endocrinol Metab. 2014;307(5):E426–36. https://doi.org/10.1152/ajpendo.00264.2014.CrossRef

23.

Richter B, Haller J, Haffner D, Leifheit-Nestler M. Klotho modulates FGF23-mediated NO synthesis and oxidative stress in human coronary artery endothelial cells. Pflugers Arch Eur J Physiol. 2016;468(9):1621–35. https://doi.org/10.1007/s00424-016-1858-x.CrossRef

24.

Stevens KK, Denby L, Patel RK, et al. Deleterious effects of phosphate on vascular and endothelial function via disruption to the nitric oxide pathway. Nephrol Dial Transplant. 2016. https://doi.org/10.1093/ndt/gfw252.CrossRefPubMedCentral

25.

Rossaint J, Oehmichen J, Van Aken H, et al. FGF23 signaling impairs neutrophil recruitment and host defense during CKD. J Clin Invest. 2016;126(3):962–74. https://doi.org/10.1172/JCI83470.CrossRefPubMedPubMedCentral

26.

Singh S, Grabner A, Yanucil C, et al. Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int. 2016;90(5):985–96. https://doi.org/10.1016/j.kint.2016.05.019.CrossRefPubMedPubMedCentral

27.

Nagarajan R, Scutari M, Lèbre S. Bayesian networks in R: with applications in systems biology. Berlin: Springer; 2013. https://doi.org/10.1007/978-1-4614-6446-4.CrossRef

28.

Araújo CB, OliveiraNeves FM, Freitas DF, et al. Angiopoietin-2 as a predictor of acute kidney injury in critically ill patients and association with ARDS. Respirology. 2019. https://doi.org/10.1111/resp.13464.CrossRefPubMed

29.

Hayes A. Introduction to mediation, moderation, and conditional process analysis. New York NY Guilford. 2013;1:1.

30.

Scutari M. Learning Bayesian Networks with the bnlearn R Package | Scutari | Journal of Statistical Software. J Stat Softw. 2010;35(3):1–22. https://doi.org/10.18637/jss.v035.i03.CrossRef

31.

Wolf M. Update on fibroblast growth factor 23 in chronic kidney disease. Kidney Int. 2012;82(7):737–47. https://doi.org/10.1038/ki.2012.176.CrossRefPubMedPubMedCentral

32.

Bai X, Miao D, Xiao S, et al. CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders. J Clin Invest. 2016;126(2):667–80. https://doi.org/10.1172/JCI81928.CrossRefPubMedPubMedCentral

33.

Zhang X, Sun D, Song JW, et al. Endothelial cell dysfunction and glycocalyx—a vicious circle. Matrix Biol. 2018;72:421–31.CrossRef

34.

Wei S, Gonzalez Rodriguez E, Chang R, et al. Elevated Syndecan-1 after Trauma and Risk of Sepsis: a Secondary Analysis of Patients from the Pragmatic, Randomized Optimal Platelet and Plasma Ratios (PROPPR) Trial. J Am Coll Surg. 2018;227(6):587–95. https://doi.org/10.1016/j.jamcollsurg.2018.09.003.CrossRefPubMed

35.

Holzmann MS, Winkler MS, Strunden MS, Izbicki JR, Schoen G, Greiwe G, Pinnschmidt HO, Poppe A, Saugel B, Daum G, Goetz AE. Syndecan-1 as a biomarker for sepsis survival after major abdominal surgery. Biomark Med. 2018;12(2):119–27. https://doi.org/10.2217/bmm-2017-0231.CrossRefPubMed

36.

Reilly JP, Wang F, Jones TK, et al. Plasma angiopoietin-2 as a potential causal marker in sepsis-associated ARDS development: evidence from Mendelian randomization and mediation analysis. Intensive Care Med. 2018;44(11):1849–58. https://doi.org/10.1007/s00134-018-5328-0.CrossRefPubMed

Title: Fibroblast growth factor 23, endothelium biomarkers and acute kidney injury in critically-ill patients
Authors: Fernanda Macedo de Oliveira Neves
Camila Barbosa Araújo
Daniele Ferreira de Freitas
Bianca Fernandes Távora Arruda
Leonardo José Monteiro de Macêdo Filho
Vivian Brito Salles
Gdayllon Cavalcante Meneses
Alice Maria Costa Martins
Alexandre Braga Libório
Publication date: 01-12-2019
Publisher: BioMed Central
Keywords: Acute Kidney Injury
Acute Kidney Injury
Biomarkers
Published in: Journal of Translational Medicine / Issue 1/2019
Electronic ISSN: 1479-5876
DOI: https://doi.org/10.1186/s12967-019-1875-6

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Fibroblast growth factor 23, endothelium biomarkers and acute kidney injury in critically-ill patients

Abstract

Background

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2019

Influence of androgenic blockade with flutamide on pain behaviour and expression of the genes that encode the NaV1.7 and NaV1.8 voltage-dependent sodium channels in a rat model of postoperative pain

Single cell sequencing reveals gene expression signatures associated with bone marrow stromal cell subpopulations and time in culture

MLMDA: a machine learning approach to predict and validate MicroRNA–disease associations by integrating of heterogenous information sources

Orthostatic intolerance in chronic fatigue syndrome

Timing gone awry: distinct tumour suppressive and oncogenic roles of the circadian clock and crosstalk with hypoxia signalling in diverse malignancies

Tissue diagnosis during colorectal cancer surgery using optical sensing: an in vivo study

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page