Skip to main content

Advertisement

SpringerLink
Log in

Identification of Biomarkers of Sepsis-Associated Acute Kidney Injury in Pediatric Patients Based on UPLC-QTOF/MS

  • Original Article
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Sepsis or septic shock is often accompanied by organ dysfunction, among which acute kidney injury (AKI) is the most frequent event that appears early during sepsis. To harness urinary metabolic profiling to discover potential biomarkers of septic acute kidney injury in pediatric patients at intensive care units, we collected urine samples from 27 septic children with AKI and 30 septic children without AKI. We used ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) for profiling and multiple regression analysis to explore the potential biomarkers of sepsis with AKI. We identified a clear distinction in the UPLC-QTOF/MS results for septic children with and without AKI after the development of sepsis, specifically 18 and 17 metabolites with different levels at 12 and 24 h, respectively. Metabolic pathways associated with septic AKI included lipid metabolism, particularly processes involving glycerophospholipid metabolism. L-Histidine, DL-indole-3-lactic acid, trimethylamine N-oxide, and caprylic acid were uncovered as potential biomarkers of septic AKI at 12 h, while gentisaldehyde, 3-ureidopropionate, N4-acetylcytidine, and 3-methoxy-4-hydroxyphenylglycol sulfate were identified as potential candidates at 24 h. We further found that combinations of metabolites were more effective diagnostic marker compared with individual metabolites, with an area under the receiver operating characteristics curve of 0.905 and 0.97 at 12 and 24 h, respectively. Our results indicated that metabolomic analysis could be a promising approach for identifying diagnostic biomarkers of pediatric septic AKI and helped elucidate the pathological mechanisms involved.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Singer, M., C.S. Deutschman, C.W. Seymour, M. Shankar-Hari, D. Annane, M. Bauer, R. Bellomo, G.R. Bernard, J.D. Chiche, C.M. Coopersmith, et al. 2016. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315: 801–810.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Bagshaw, S.M., C. George, and R. Bellomo. 2008. Early acute kidney injury and sepsis: a multicentre evaluation. Critical Care 12: R47.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Vincent, J.L., Y. Sakr, C.L. Sprung, V.M. Ranieri, K. Reinhart, H. Gerlach, R. Moreno, J. Carlet, J.R. Le Gall, and D. Payen. 2006. Sepsis in European intensive care units: results of the SOAP study. Critical Care Medicine 34: 344–353.

    Article  PubMed  Google Scholar 

  4. Fitzgerald, J.C., R.K. Basu, A. Akcan-Arikan, L.M. Izquierdo, B.E. Piñeres Olave, A.B. Hassinger, M. Szczepanska, A. Deep, D. Williams, A. Sapru, J.A. Roy, V.M. Nadkarni, N.J. Thomas, S.L. Weiss, S. Furth, and Sepsis PRevalence, OUtcomes, and Therapies Study Investigators and Pediatric Acute Lung Injury and Sepsis Investigators Network. 2016. Acute kidney injury in pediatric severe Sepsis: an independent risk factor for death and new disability. Critical Care Medicine 44: 2241–2250.

    Article  PubMed  Google Scholar 

  5. Kellum, J.A., and N. Lameire. 2013. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (part 1). Critical Care 17: 204.

    Article  PubMed Central  PubMed  Google Scholar 

  6. Umbro, I., G. Gentile, F. Tinti, P. Muiesan, and A.P. Mitterhofer. 2016. Recent advances in pathophysiology and biomarkers of sepsis-induced acute kidney injury. The Journal of Infection 72: 131–142.

    Article  PubMed  Google Scholar 

  7. Kalim, S., and E.P. Rhee. 2017. An overview of renal metabolomics. Kidney International 91: 61–69.

    Article  CAS  PubMed  Google Scholar 

  8. Liu, X., and J.W. Locasale. 2017. Metabolomics: a primer. Trends in Biochemical Sciences 42: 274–284.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Goldstein, B., B. Giroir, and A. Randolph. 2005. International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatric Critical Care Medicine 6: 2–8.

    Article  PubMed  Google Scholar 

  10. Corda, D., M.G. Mosca, N. Ohshima, L. Grauso, N. Yanaka, and S. Mariggiò. 2014. The emerging physiological roles of the glycerophosphodiesterase family. The FEBS Journal 281: 998–1016.

    Article  CAS  PubMed  Google Scholar 

  11. Tan, T.L., N.S. Ahmad, D.N. Nasuruddin, A. Ithnin, A.K. Tajul, I.Z. Zaini, and WZ. Wan Ngah. 2016. CD64 and group II secretory phospholipase A2 (sPLA2-IIA) as biomarkers for distinguishing adult sepsis and bacterial infections in the emergency department. PLoS One 11: e0152065.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Van Wyngene, L., J. Vandewalle, and C. Libert. 2018. Reprogramming of basic metabolic pathways in microbial sepsis: therapeutic targets at last. EMBO Molecular Medicine 08: 10(8).

    Google Scholar 

  13. Wischmeyer, P.E. 2007. Glutamine: mode of action in critical illness. Critical Care Medicine 35: S541–S544.

    Article  CAS  PubMed  Google Scholar 

  14. Cruzat, V., M. Macedo Rogero, K. Noel Keane, R. Curi, and P. Newsholme. 2018. Glutamine: metabolism and immune function, supplementation and clinical translation. Nutrients 10 (11).

  15. Wilmore, D.W. 2001. The effect of glutamine supplementation in patients following elective surgery and accidental injury. Journal of Nutrition 131: 2543S–2549S discussion 2550S-1S.

    Article  CAS  Google Scholar 

  16. Hu, Y.M., Y.C. Hsiung, M.H. Pai, and S.L. Yeh. 2018. Glutamine administration in early or late septic phase downregulates lymphocyte PD-1/PD-L1 expression and the inflammatory response in mice with polymicrobial sepsis. Journal of Parenteral and Enteral Nutrition 42 (3): 538–549.

    CAS  PubMed  Google Scholar 

  17. Wu, G. 2009. Amino acids: metabolism, functions, and nutrition. Amino Acids 37 (1): 1–17.

    Article  PubMed  Google Scholar 

  18. Poon, I.K., K.K. Patel, D.S. Davis, C.R. Parish, and M.D. Hulett. 2011. Histidine-rich glycoprotein: the Swiss Army knife of mammalian plasma. Blood 117 (7).

  19. Blank, M., and Y. Shoenfeld. 2008. Histidine-rich glycoprotein modulation of immune/autoimmune, vascular, and coagulation systems. Clinical Reviews in Allergy and Immunology 34: 307–312.

    Article  CAS  PubMed  Google Scholar 

  20. Kuroda, K., H. Wake, S. Mori, S. Hinotsu, M. Nishibori, and H. Morimatsu. 2018. Decrease in histidine-rich glycoprotein as a novel biomarker to predict sepsis among systemic inflammatory response syndrome. Critical Care Medicine 46: 570–576.

    Article  CAS  PubMed  Google Scholar 

  21. Subramaniam, S., and C. Fletcher. 2018. Trimethylamine N-oxide (TMAO): breathe new life. British Journal of Pharmacology 04: 175(8).

    Google Scholar 

  22. Tomlinson, James A.P., and David C. Wheeler. 2017. The role of trimethylamine N-oxide as a mediator of cardiovascular complications in chronic kidney disease. Kidney International 92: 809–815.

    Article  CAS  PubMed  Google Scholar 

  23. Manna, S.K., A.D. Patterson, Q. Yang, K.W. Krausz, J.R. Idle, A.J. Fornace, and F.J. Gonzalez. 2011. UPLC-MS-based urine metabolomics reveals indole-3-lactic acid and phenyllactic acid as conserved biomarkers for alcohol-induced liver disease in the Ppara-null mouse model. Journal of Proteome Research 10: 4120–4133.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Lemarie, F., E. Beauchamp, G. Drouin, P. Legrand, and V. Rioux. 2018. Dietary caprylic acid and ghrelin O-acyltransferase activity to modulate octanoylated ghrelin functions: what is new in this nutritional field? Prostaglandins, Leukotrienes, and Essential Fatty Acids 135: 121–127.

    Article  CAS  PubMed  Google Scholar 

  25. Hecker, M., N. Sommer, H. Voigtmann, O. Pak, A. Mohr, M. Wolf, I. Vadász, S. Herold, N. Weissmann, R.E. Morty, et al. 2014. Impact of short- and medium-chain fatty acids on mitochondrial function in severe inflammation. JPEN Journal of Parenteral and Enteral Nutrition 38: 587–594.

    Article  PubMed  Google Scholar 

  26. Janowitz, T., I. Ajonina, M. Perbandt, C. Woltersdorf, P. Hertel, E. Liebau, and U. Gigengack. 2010. The 3-ureidopropionase of Caenorhabditis elegans, an enzyme involved in pyrimidine degradation. The FEBS Journal 277: 4100–4109.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatric Intensive Care Unit, Children’s Hospital of Chongqing Medical University, 136 Second Zhongshan Road, Yuzhong district, Chongqing, 400014, China

    Sa Wang, Changxue Xiao, Chengjun Liu, Jing Li, Fang Fang, Xue Lu, Chao Zhang & Feng Xu

  2. Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), 136 Second Zhongshan Road, Yuzhong district, Chongqing, 400014, China

    Sa Wang, Changxue Xiao, Chengjun Liu, Jing Li, Fang Fang, Xue Lu, Chao Zhang & Feng Xu

  3. China International Science and Technology Cooperation base of Child Development and Critical Disorders, Chongqing Key Laboratory of Pediatrics, Chongqing, 400014, China

    Sa Wang, Changxue Xiao, Chengjun Liu, Jing Li, Fang Fang, Xue Lu, Chao Zhang & Feng Xu

Authors
  1. Sa Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Changxue Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chengjun Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fang Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xue Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Feng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Sa Wang is the principal author and takes responsibility for the integrity of the data and the accuracy of the data analysis. Sa Wang and Feng Xu contributed to the study conception and design; Changxue Xiao, Chengjun Liu, Jing Li, Fang Fang, Xue Lu, and Chao Zhang contributed to data collection and analysis. The first draft of the manuscript was written by Sa Wang, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Feng Xu.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, S., Xiao, C., Liu, C. et al. Identification of Biomarkers of Sepsis-Associated Acute Kidney Injury in Pediatric Patients Based on UPLC-QTOF/MS. Inflammation 43, 629–640 (2020). https://doi.org/10.1007/s10753-019-01144-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-019-01144-5

KEY WORDS

Search

Navigation