SpringerLink
Log in

Guaifenesin stone matrix proteomics: a protocol for identifying proteins critical to stone formation

  • Original Paper
  • Published:
Urolithiasis Aims and scope Submit manuscript

Abstract

Drug-related kidney stones are a diagnostic problem, since they contain a large matrix (protein) fraction and are frequently incorrectly identified as matrix stones. A urine proteomics study patient produced a guaifenesin stone during her participation, allowing us to both correctly diagnose her disease and identify proteins critical to this drug stone-forming process. The patient provided three random midday urine samples for proteomics studies; one of which contained stone-like sediment with two distinct fractions. These solids were characterized with optical microscopy and Fourier transform infrared spectroscopy. Immunoblotting and quantitative mass spectrometry were used to quantitatively identify the proteins in urine and stone matrix. Infrared spectroscopy showed that the sediment was 60 % protein and 40 % guaifenesin and its metabolite guaiacol. Of the 156 distinct proteins identified in the proteomic studies, 49 were identified in the two stone-components with approximately 50 % of those proteins also found in this patient’s urine. Many proteins observed in this drug-related stone have also been reported in proteomic matrix studies of uric acid and calcium containing stones. More importantly, nine proteins were highly enriched and highly abundant in the stone matrix and 8 were reciprocally depleted in urine, suggesting a critical role for these proteins in guaifenesin stone formation. Accurate stone analysis is critical to proper diagnosis and treatment of kidney stones. Many matrix proteins were common to all stone types, but likely not related to disease mechanism. This protocol defined a small set of proteins that were likely critical to guaifenesin stone formation based on their high enrichment and high abundance in stone matrix, and it should be applied to all stone types.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

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

Abbreviations

BMI:

Body mass index

FTIR:

Fourier transform infrared spectroscopy

GC:

Guaifenesin.guaiacol crystal mixture

GF:

Orange stone sediment containing guaifenesin and guaiacol crystals)

IRB:

Institutional Review Board

LC–MS:

Liquid chromatography coupled with mass spectrometry

MCW:

Medical College of WISCONSIN

MIS.MAC:

Mandel International Stone and Molecular Analysis Center

MS:

Mass spectrometry

MX:

Matrix strand stone sediment containing few drug crystals

P/C:

Protein/creatinine ratio in urine (mg/g)

SG:

Specific gravity

UA:

Uric acid stone matrix

UM:

Urine macromolecules

VA:

US Department of Veterans Affairs

% SC:

Percentage of total assigned scan counts attributable to an individual or group of proteins

All protein abbreviations are defined in Table 3

References

  1. Boyce Garvey FK (1956) The amount and nature of the organic matrix in urinary calculi: a review. J Urol 76:213–227

    CAS  PubMed  Google Scholar 

  2. Aggarwal KP, Narula S, Kakkar M, Tandon C (2013) Nephrolithiasis: molecular mechanism of renal stone formation and the critical role played by modulators. Biomed res int. doi:10.1155/2013/292953

    Google Scholar 

  3. Mandel NS, Mandel GS (1989) Urinary tract stone disease in the united states veteran population. I. Geographical frequency of occurrence. J Urol 142:1513–1515

    CAS  PubMed  Google Scholar 

  4. Krambeck AE, Lingeman JE, McAteer JA, Williams JC Jr (2010) Analysis of mixed stones is prone to error: a study with US laboratories using micro CT for verification of sample content. Urol Res 38:469–475. doi:10.1007/s00240-010-0317-y

    Article  PubMed  Google Scholar 

  5. Gage H, Beal HW (1908) V. fibrinous calculi in the kidney. Ann Surg 48:378–387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bani-Hani AH, Segura JW, Leroy AJ (2005) Urinary matrix calculi: our experience at a single institution. J Urol 173:120–123

    Article  PubMed  Google Scholar 

  7. Dussol B, Geider S, Lilova A, Leonetti F, Dupuy P, Daudon M, Berland Y, Dagorn JC, Verdier JM (1995) Analysis of the soluble organic matrix of five morphologically different kidney stones. evidence for a specific role of albumin in the constitution of the stone protein matrix. Urol Res 23:45–51

    Article  CAS  PubMed  Google Scholar 

  8. Khan SR, Atmani F, Glenton P, Hou Z, Talham DR, Khurshid M (1996) Lipids and membranes in the organic matrix of urinary calcific crystals and stones. Calcif Tissue Int 59:357–365

    Article  CAS  PubMed  Google Scholar 

  9. Canales BK, Anderson L, Higgins L, Ensrud-Bowlin K, Roberts KP, Wu B, Kim IW, Monga M (2010) Proteome of human calcium kidney stones. Urology 76:1017.e13–1017.e20. doi:10.1016/j.urology.2010.05.005

    Article  Google Scholar 

  10. Jou YC, Fang CY, Chen SY, Chen FH, Cheng MC, Shen CH, Liao LW, Tsai YS (2012) Proteomic study of renal uric acid stone. Urology 80:260–266. doi:10.1016/j.urology.2012.02.019

    Article  PubMed  Google Scholar 

  11. Kaneko K, Kobayashi R, Yasuda M, Izumi Y, Yamanobe T, Shimizu T (2012) Comparison of matrix proteins in different types of urinary stone by proteomic analysis using liquid chromatography-tandem mass spectrometry. Int J Urol 19:765–772. doi:10.1111/j.1442-2042.2012.03005.x

    Article  CAS  PubMed  Google Scholar 

  12. Assimos DG, Langenstroer P, Leinbach RF, Mandel NS, Stern JM, Holmes RP (1999) Guaifenesin and ephedrine induced stones. J Endourol 13:665–667

    Article  CAS  PubMed  Google Scholar 

  13. Bennett S, Hoffman N, Monga M (2004) Ephedrine- and guaifenesin-induced nephrolithiasis. J Altern Complement Med 10:967–969

    Article  PubMed  Google Scholar 

  14. Pickens CL, Milliron AR, Fussner AL, Dversdall BC, Langenstroer P, Ferguson S, Fu X, Schmitz FJ, Poole EC (1999) Abuse of guaifenesin-containing medications generates an excess of a carboxylate salt of beta-(2-methoxyphenoxy)-lactic acid, a guaifenesin metabolite, and results in urolithiasis. Urology 54:23–27

    Article  CAS  PubMed  Google Scholar 

  15. Kolbach AM, Afzal O, Halligan B, Sorokina E, Kleinman JG, Wesson JA (2012) Relative deficiency of acidic isoforms of osteopontin from stone former urine. Urol Res 40:447–454. doi:10.1007/s00240-012-0459-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mani N, Jun HW, Beach JW, Nerurkar J (2003) Solubility of guaifenesin in the presence of common pharmaceutical additives. Pharm Dev Technol 8:385–396

    Article  CAS  PubMed  Google Scholar 

  17. Mandel IC, Mandel NS (2007) Chapter 5. Structural and compositional analysis of kidney stones. In: Stoller ML, Meng MV (eds) Urinary stone disease: the practical guide to medical and surgical management. Humana Press, USA, pp 69–81

    Chapter  Google Scholar 

  18. Viswanathan P, Rimer JD, Kolbach AM, Ward MD, Kleinman JG, Wesson JA (2011) Calcium oxalate monohydrate aggregation induced by aggregation of desialylated tamm–horsfall protein. Urol Res 39:269–282. doi:10.1007/s00240-010-0353-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yu H, Wakim B, Li M, Halligan B, Tint GS, Patel SB (2007) Quantifying raft proteins in neonatal mouse brain by ‘tube-gel’ protein digestion label-free shotgun proteomics. Proteome Sci 5:17

    Article  PubMed  PubMed Central  Google Scholar 

  20. Lemann J Jr, Pleuss JA, Worcester EM, Hornick L, Schrab D, Hoffmann RG (1996) Urinary oxalate excretion increases with body size and decreases with increasing dietary calcium intake among healthy adults. Kidney Int 49:200–208

    Article  CAS  PubMed  Google Scholar 

  21. Li M, Gray W, Zhang H, Chung CH, Billheimer D, Yarbrough WG, Liebler DC, Shyr Y, Slebos RJ (2010) Comparative shotgun proteomics using spectral count data and quasi-likelihood modeling. J Proteome Res 9:4295–4305. doi:10.1021/pr100527g

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Canales BK, Anderson L, Higgins L, Frethem C, Ressler A, Kim IW, Monga M (2009) Proteomic analysis of a matrix stone: a case report. Urol Res 37:323–329. doi:10.1007/s00240-009-0213-5

    Article  PubMed  Google Scholar 

  23. Okumura N, Tsujihata M, Momhara C, Yoshioka I, Suto K, Nonomura N, Okuyama A, Toshifumi T (2013) Diversity in protein profiles of individual calcium oxalate kidney stones. PLoS One 8(7):e68624. doi:10.1371/journal.pone.0068624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Brahm NC, Yeager LL, Fox MD, Farmer KC, Palmer TA (2010) Commonly prescribed medications and potential false-positive urine drug screens. Am J Health Syst Pharm 67:1344–1350. doi:10.2146/ajhp090477

    Article  PubMed  Google Scholar 

  25. Ramsdell CM, Postlethwaite AE, Kelley WN (1974) Uricosuric effect of glyceryl guaiacolate. J Rheumatol 1:114–116

    CAS  PubMed  Google Scholar 

  26. Bellei E, Cuoghi A, Monari E, Bergamini S, Fantoni LI, Zappaterra M, Guerzoni S, Bazzocchi A, Tomasi A, Pini LA (2012) Proteomic analysis of urine in medication-overuse headache patients: possible relation with renal damages. J Headache Pain 13:45–52. doi:10.1007/s10194-011-0390-9

    Article  CAS  PubMed  Google Scholar 

  27. Riaz S, Alam SS, Srai SK, Skinner V, Riaz A, Akhtar MW (2010) Proteomic identification of human urinary biomarkers in diabetes mellitus type 2. Diabetes Technol Ther 12:979–988. doi:10.1089/dia.2010.0078

    Article  CAS  PubMed  Google Scholar 

  28. Merchant ML, Cummins TD, Wilkey DW, Salyer SA, Powell DW, Klein JB, Lederer ED (2008) Proteomic analysis of renal calculi indicates an important role for inflammatory processes in calcium stone formation. Am J Physiol Renal Physiol 295:F1254–F1258. doi:10.1152/ajprenal.00134.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Matlaga BR, Shah OD, Assimos DG (2003) Drug-induced urinary calculi. Rev urol 5:227–231

    PubMed  Google Scholar 

  30. Riese RJ, Kleinman JG, Wiessner JH, Mandel GS, Mandel NS (1990) Uric acid crystal binding to renal inner medullary collecting duct cells in primary culture. J Am Soc Nephrol 1:187–192

    CAS  PubMed  Google Scholar 

  31. Riese RJ, Mandel NS, Wiessner JH, Mandel GS, Becker CG, Kleinman JG (1992) Cell polarity and calcium oxalate crystal adherence to cultured collecting duct cells. Am J Physiol (Renal Fluid Electrolyte Physiol) 262(31):F117–F184

    Google Scholar 

  32. Cockerill PA, de Cogain MR, Krambeck AE (2013) Acute bilateral ureteral obstruction secondary to guaifenesin toxicity. Can J Urol 20:6971–6973

    PubMed  Google Scholar 

  33. Seagrave J, Albrecht H, Park YS, Rubin B, Solomon G, Kim KC (2011) Effect of guaifenesin on mucin production, rheology, and mucociliary transport in differentiated human airway epithelial cells. Exp Lung Res 37:606–614. doi:10.3109/01902148.2011.623116

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We gratefully acknowledge the primary financial support provided in part with resources and the use of facilities at the Clement J. Zablocki Department of Veterans Affairs Medical Center, Milwaukee, WI, and in part by the National Institutes of Health/National Institute for Diabetes, Digestive, and Kidney Diseases (DK 82550) (JAW). Additional financial support was provided by the Medical College of Wisconsin and in part by the National Institutes of Health/National Institute for Diabetes, Digestive, and Kidney Diseases (DK 74741) (JGK). We also gratefully acknowledge the technical support MIS.MAC (Mandel International Stone and Molecular Analysis Center), Milwaukee, WI, for stone analysis and the technical support of Brian Halligan, PhD, for proteomic analysis.

Author information

Authors and Affiliations

  1. Division of Nephrology, Department of Medicine, Zablocki VA Medical Center, 5000 W. National Avenue, Milwaukee, WI, 53295, USA

    N. S. Mandel & J. A. Wesson

  2. Medical College of Wisconsin, 9200 W Wisconsin Avenue, Milwaukee, WI, 53226, USA

    A. M. Kolbach-Mandel, N. S. Mandel, S. R. Cohen, J. G. Kleinman, F. Ahmed, I. C. Mandel & J. A. Wesson

Authors
  1. A. M. Kolbach-Mandel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. N. S. Mandel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S. R. Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. G. Kleinman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. I. C. Mandel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J. A. Wesson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. A. Wesson.

Ethics declarations

Funding

This study was primarily funded with resources and the use of facilities at the Clement J. Zablocki Department of Veterans Affairs Medical Center, Milwaukee, WI, and in part by a grant from the National Institutes of Health (NIDDK, DK 82550-JAW). Additional financial support was provided by the Medical College of Wisconsin and in part by the National Institutes of Health (NIDDK, DK 74741-JGK).

Conflict of interest

None of the authors has any conflicts of interest to report.

Human studies

The participating patient in this study was recruited with informed consent to an established study under VA IRB approval (VA-IRB protocol: 9305-01P). All procedures performed in these studies were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments.

Additional information

The contents do not represent the views of the US Department of Veterans Affairs or the United States Government.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 198 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kolbach-Mandel, A.M., Mandel, N.S., Cohen, S.R. et al. Guaifenesin stone matrix proteomics: a protocol for identifying proteins critical to stone formation. Urolithiasis 45, 139–149 (2017). https://doi.org/10.1007/s00240-016-0907-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00240-016-0907-4

Keywords

Search

Navigation