Skip to main content

Advertisement

SpringerLink
Log in

Interfering parameters in the determination of urinary globotriaosylceramide (Gb3) in patients with chronic kidney disease

  • Original Article
  • Published:
Journal of Nephrology Aims and scope Submit manuscript

Abstract

Introduction

Globotriaosylceramide (Gb3, CD77) represents a pivotal part of the cell membrane. Measuring the urinary Gb3 content can be used to screen patients with chronic kidney disease (CKD) for Fabry disease, a disorder caused by hampered Gb3 degradation. However, little is known about factors influencing urinary Gb3 excretion other than Fabry disease. The aim of the present study was to identify routine diagnostic parameters as predictors of urinary Gb3 excretion in patients with CKD.

Methods

Our study included 609 subjects with CKD stage I–V. We analyzed the influence of age, gender, renal function, urinary cell content and chemical characteristics on urinary Gb3 concentrations (total Gb3, Gb3-24 isoform, and Gb3-24:18 isoform ratio), determined by direct electrospray ionization mass spectrometry.

Results

In 609 subjects the median total urinary Gb3 was 233 ng/mg and the Gb3-24:18 isoform ratio was 1.2. Twenty-one patients, none of whom had Fabry disease, had a Gb3-24:18 isoform ratio ≥2.3. Females excreted a higher total amount of Gb3, but the Gb3-24:18 isoform ratio was comparable to males. Renal function and age had no influence on total Gb3, Gb3 isoforms or the ratio. Only a distinct load of bacteria and leukocytes was associated with an increased Gb3 excretion. Urinary leukocytes, erythrocytes, bacteria, or protein content did not affect the Gb3-24:18 isoform ratio.

Conclusion

The Gb3-24:18 isoform ratio is unaffected by several potential influencing variables and may thus be applied for screening for Fabry disease in unselected cohorts of patients presenting with CKD.

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

Similar content being viewed by others

References

  1. Nudelman E, Kannagi R, Hakomori S, Parsons M, Lipinski M, Wiels J, Fellous M, Tursz T (1983) A glycolipid antigen associated with Burkitt lymphoma defined by a monoclonal antibody. Science 220:509–511

    Article  CAS  PubMed  Google Scholar 

  2. Fletcher KS, Bremer EG, Schwarting GA (1979) P blood group regulation of glycosphingolipid levels in human erythrocytes. J Biol Chem 254:11196–11198

    CAS  PubMed  Google Scholar 

  3. Waddell T, Head S, Petric M, Cohen A, Lingwood C (1988) Globotriosyl ceramide is specifically recognized by the Escherichia coli verocytotoxin 2. Biochem Biophys Res Commun 152:674–679 (pii: S0006-291X(88)80091-3)

    Article  CAS  PubMed  Google Scholar 

  4. Lingwood CA, Branch DR (2011) The role of glycosphingolipids in HIV/AIDS. Discov Med 11:303–313

    PubMed  Google Scholar 

  5. Fuller M, Sharp PC, Rozaklis T, Whitfield PD, Blacklock D, Hopwood JJ, Meikle PJ (2005) Urinary lipid profiling for the identification of fabry hemizygotes and heterozygotes. Clin Chem 51:688–694. doi:10.1373/clinchem.2004.041418

    Article  CAS  PubMed  Google Scholar 

  6. Mills K, Morris P, Lee P, Vellodi A, Waldek S, Young E, Winchester B (2005) Measurement of urinary CDH and CTH by tandem mass spectrometry in patients hemizygous and heterozygous for Fabry disease. J Inherit Metab Dis 28:35–48. doi:10.1007/s10545-005-5263-4

    Article  CAS  PubMed  Google Scholar 

  7. Paschke E, Fauler G, Winkler H, Schlagenhauf A, Plecko B, Erwa W, Breunig F, Urban W, Vujkovac B, Sunder-Plassmann G, Kotanko P (2011) Urinary total globotriaosylceramide and isoforms to identify women with Fabry disease: a diagnostic test study. Am J Kidney Dis 57:673–681. doi:10.1053/j.ajkd.2010.10.046

    Article  CAS  PubMed  Google Scholar 

  8. Fauler G, Rechberger GN, Devrnja D, Erwa W, Plecko B, Kotanko P, Breunig F, Paschke E (2005) Rapid determination of urinary globotriaosylceramide isoform profiles by electrospray ionization mass spectrometry using stearoyl-d35-globotriaosylceramide as internal standard. Rapid Commun Mass Spectrom 19:1499–1506. doi:10.1002/rcm.1948

    Article  CAS  PubMed  Google Scholar 

  9. An D, Na C, Bielawski J, Hannun YA, Kasper DL (2011) Membrane sphingolipids as essential molecular signals for Bacteroides survival in the intestine. Proc Natl Acad Sci USA 108(Suppl 1):4666–4671. doi:10.1073/pnas.1001501107

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Kotanko P, Kramar R, Devrnja D, Paschke E, Voigtländer T, Auinger M, Pagliardini S, Spada M, Demmelbauer K, Lorenz M, Hauser AC, Kofler HJ, Lhotta K, Neyer U, Pronai W, Wallner M, Wieser C, Wiesholzer M, Zodl H, Födinger M, Sunder-Plassmann G (2004) Results of a nationwide screening for Anderson-Fabry disease among dialysis patients. J Am Soc Nephrol 15:1323–1329. doi:10.1097/01.ASN.0000124671.61963.1E

    Article  CAS  PubMed  Google Scholar 

  11. Aerts JM, Groener JE, Kuiper S, Donker-Koopman WE, Strijland A, Ottenhoff R, van Roomen C, Mirzaian M, Wijburg FA, Linthorst GE, Vedder AC, Rombach SM, Cox-Brinkman J, Somerharju P, Boot RG, Hollak CE, Brady RO, Poorthuis BJ (2008) Elevated globotriaosylsphingosine is a hallmark of Fabry disease. Proc Natl Acad Sci USA 105:2812–2817. doi:10.1073/pnas.0712309105

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Auray-Blais C, Ntwari A, Clarke JT, Warnock DG, Oliveira JP, Young SP, Millington DS, Bichet DG, Sirrs S, West ML, Casey R, Hwu WL, Keutzer JM, Zhang XK, Gagnon R (2012) How well does urinary lyso-Gb3 function as a biomarker in Fabry disease? Clin Chim Acta 411:1906–1914. doi:10.1016/j.cca.2010.07.038

    Article  Google Scholar 

  13. Rombach SM, Dekker N, Bouwman MG, Linthorst GE, Zwinderman AH, Wijburg FA, Kuiper S, Vd Bergh Weerman MA, Groener JE, Poorthuis BJ, Hollak CE, Aerts JM (2010) Plasma globotriaosylsphingosine: diagnostic value and relation to clinical manifestations of Fabry disease. Biochim Biophys Acta 1802:741–748. doi:10.1016/j.bbadis.2010.05.003

    Article  CAS  PubMed  Google Scholar 

  14. Auray-Blais C, Boutin M, Gagnon R, Dupont FO, Lavoie P, Clarke JT (2012) Urinary globotriaosylsphingosine-related biomarkers for Fabry disease targeted by metabolomics. Anal Chem 84:2745–2753. doi:10.1021/ac203433e

    Article  CAS  PubMed  Google Scholar 

  15. Hozumi I, Nishizawa M, Ariga T, Miyatake T (1990) Biochemical and clinical analysis of accumulated glycolipids in symptomatic heterozygotes of angiokeratoma corporis diffusum (Fabry’s disease) in comparison with hemizygotes. J Lipid Res 31:335–340

    CAS  PubMed  Google Scholar 

  16. Schiffmann R, Waldek S, Benigni A, Auray-Blais C (2010) Biomarkers of Fabry disease nephropathy. Clin J Am Soc Nephrol 5:360–364. doi:10.2215/CJN.06090809

    Article  CAS  PubMed  Google Scholar 

  17. Vance DE, Sweeley CC (1967) Quantitative determination of the neutral glycosyl ceramides in human blood. J Lipid Res 8:621–630

    CAS  PubMed  Google Scholar 

  18. Young E, Mills K, Morris P, Vellodi A, Lee P, Waldek S, Winchester B (2005) Is globotriaosylceramide a useful biomarker in Fabry disease? Acta Paediatr Suppl 94:51–54 (discussion 37–58)

    Article  CAS  PubMed  Google Scholar 

  19. Mills K, Johnson A, Winchester B (2002) Synthesis of novel internal standards for the quantitative determination of plasma ceramide trihexoside in Fabry disease by tandem mass spectrometry. FEBS Lett 515:171–176 (pii: S0014579302024912)

    Article  CAS  PubMed  Google Scholar 

  20. Dawson G, Kruski AW, Scanu AM (1976) Distribution of glycosphingolipids in the serum lipoproteins of normal human subjects and patients with hypo- and hyperlipidemias. J Lipid Res 17:125–131

    CAS  PubMed  Google Scholar 

  21. Vedder AC, Linthorst GE, van Breemen MJ, Groener JE, Bemelman FJ, Strijland A, Mannens MM, Aerts JM, Hollak CE (2007) The Dutch Fabry cohort: diversity of clinical manifestations and Gb3 levels. J Inherit Metab Dis 30:68–78. doi:10.1007/s10545-006-0484-8

    Article  CAS  PubMed  Google Scholar 

  22. Durant B, Forni S, Sweetman L, Brignol N, Meng XL, Benjamin ER, Schiffmann R, Shen JS (2011) Sex differences of urinary and kidney globotriaosylceramide and lyso-globotriaosylceramide in Fabry mice. J Lipid Res 52:1742–1746. doi:10.1194/jlr.M017178

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. McCluer RH, Williams MA, Gross SK, Meisler MH (1981) Testosterone effects on the induction and urinary excretion of mouse kidney glycosphingolipids associated with lysosomes. J Biol Chem 256:13112–13120

    CAS  PubMed  Google Scholar 

  24. Koshida H, Takeda R, Miyamori I (1998) Lisinopril decreases plasma free testosterone in male hypertensive patients and increases sex hormone binding globulin in female hypertensive patients. Hypertens Res 21:279–282

    Article  CAS  PubMed  Google Scholar 

  25. Schiffmann R, Forni S, Swift C, Brignol N, Wu X, Lockhart DJ, Blankenship D, Wang X, Grayburn PA, Taylor MR, Lowes BD, Fuller M, Benjamin ER, Sweetman L (2014) Risk of death in heart disease is associated with elevated urinary globotriaosylceramide. J Am Heart Assoc 3:e000394. doi:10.1161/JAHA.113.000394

    Article  PubMed Central  PubMed  Google Scholar 

  26. Kuchar L, Asfaw B, Poupetova H, Honzikova J, Turecek F, Ledvinova J (2013) Direct tandem mass spectrometric profiling of sulfatides in dry urinary samples for screening of metachromatic leukodystrophy. Clin Chim Acta 425:153–159. doi:10.1016/j.cca.2013.06.027

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Forni S, Fu X, Schiffmann R, Sweetman L (2009) Falsely elevated urinary Gb3 (globotriaosylceramide, CTH, GL3). Mol Genet Metab 97:91. doi:10.1016/j.ymgme.2009.01.011

    Article  CAS  PubMed  Google Scholar 

  28. Auray-Blais C, Millington DS, Barr C, Young SP, Mills K, Clarke JT (2009) Gb(3)/creatinine biomarkers for Fabry disease: issues to consider. Mol Genet Metab 97:237. doi:10.1016/j.ymgme.2009.04.006

    Article  CAS  PubMed  Google Scholar 

  29. Cable WJ, McCluer RH, Kolodny EH, Ullman MD (1982) Fabry disease: detection of heterozygotes by examination of glycolipids in urinary sediment. Neurology 32:1139–1145

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge the help of Miriam Kunst, Ingrid Jachimow, Sylvia Taxer, Karin Voith, Danica Doric, Maria Villaluz, Gabi Rath, Violeta Tanacovic in conducting the study. Laboratory analyses were supported by an unrestricted grant from Sanofi-Genzyme (Sanofi-Genzyme Austria G.m.b.H., Vienna, Austria).

Conflict of interest

On behalf of all authors, the corresponding author states that there is no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The ethics committee of the Medical University of Vienna approved the study.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Author information

Authors and Affiliations

  1. Department of Medicine III, Division of Nephrology and Dialysis, Medical University Vienna, Vienna, Austria

    Martina Gaggl, Marlene Hofer, Stefanie Weidner, Julia Kleinert & Gere Sunder-Plassmann

  2. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Graz, Austria

    Günter Fauler

  3. Department of Internal Medicine IV, Section of Nephrology, Klinikum Wels-Grieskirchen, Wels, Austria

    Manfred Wallner

  4. Renal Research Institute, New York, NY, USA

    Peter Kotanko

  5. Department of Pediatrics, Medical University Graz, Graz, Austria

    Eduard Paschke

Authors
  1. Martina Gaggl
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marlene Hofer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefanie Weidner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Julia Kleinert
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Günter Fauler
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Manfred Wallner
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Peter Kotanko
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Eduard Paschke
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Gere Sunder-Plassmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Martina Gaggl.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (TIFF 4156 kb)

Supplementary material 2 (TIFF 18648 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gaggl, M., Hofer, M., Weidner, S. et al. Interfering parameters in the determination of urinary globotriaosylceramide (Gb3) in patients with chronic kidney disease. J Nephrol 28, 679–689 (2015). https://doi.org/10.1007/s40620-015-0193-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40620-015-0193-1

Keywords

Search

Navigation