Skip to main content

Tamm-Horsfall protein in recurrent calcium kidney stone formers with positive family history: abnormalities in urinary excretion, molecular structure and function

Urological Research volume 35, pages 55–62 (2007)Cite this article

Abstract

Tamm-Horsfall protein (THP) powerfully inhibits calcium oxalate crystal aggregation, but structurally abnormal THPs from recurrent calcium stone formers may promote crystal aggregation. Therefore, increased urinary excretion of abnormal THP might be of relevance in nephrolithiasis. We studied 44 recurrent idiopathic calcium stone formers with a positive family history of stone disease (RCSFfam) and 34 age- and sex-matched healthy controls (C). Twenty-four-hour urinary THP excretion was measured by enzyme linked immunosorbent assay. Structural properties of individually purified THPs were obtained from analysis of elution patterns from a Sepharose 4B column. Sialic acid (SA) contents of native whole 24-h urines, crude salt precipitates of native urines and individually purified THPs were measured. THP function was studied by measuring inhibition of CaOx crystal aggregation in vitro (pH 5.7, 200 mM sodium chloride). Twenty-four-hour urine excretion of THP was higher in RCSFfam (44.0 ± 4.0 mg/day) than in C (30.9 ± 2.2 mg/day, P = 0.015). Upon salt precipitation and lyophilization, elution from a Sepharose 4B column revealed one major peak (peak A, cross-reacting with polyclonal anti-THP antibody) and a second minor peak (peak B, not cross-reacting). THPs from RCSFfam eluted later than those from C (P = 0.021), and maximum width of THP peaks was higher in RCSFfam than in C (P = 0.024). SA content was higher in specimens from RCSFfam than from C, in native 24-h urines (207.5 ± 20.4 mg vs. 135.2 ± 16.1 mg, P = 0.013) as well as in crude salt precipitates of 24-h urines (10.4 ± 0.5 mg vs. 7.4 ± 0.9 mg, P = 0.002) and in purified THPs (75.3 ± 9.3 μg/mg vs. 48.8 ± 9.8 μg/mg THP, P = 0.043). Finally, inhibition of calcium oxalate monohydrate crystal aggregation by 40 mg/L of THP was lower in RCSFfam (6.1 ± 5.5%, range −62.0 to +84.2%) than in C (24.9 ± 6.0%, range −39.8 to +82.7%), P = 0.022, and only 25 out of 44 (57%) THPs from RCSFfam were inhibitory (positive inhibition value) vs. 25 out of 34 (74%) THPs from C, P < 0.05. In conclusion, severely recurrent calcium stone formers with a positive family history excrete more THP than healthy controls, and their THP molecules elute later from an analytical column and contain more SA. Such increasingly aggregated THP molecules predispose to exaggerated calcium oxalate crystal aggregation, an important prerequisite for urinary stone formation.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

43,34 €

Price includes VAT (Finland)
Tax calculation will be finalised during checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Kumar S, Muchmore A (1990) Tamm-Horsfall protein—Uromodulin (1950–1990). Kidney Int 37:1395–1401

    PubMed  CAS  Google Scholar 

  2. Serrafini-Cessi F, Malagolini N, Cavallone D (2003) Tamm-Horsfall glycoprotein: biology and clinical relevance. Am J Kidney Dis 42:658–676

    Article  Google Scholar 

  3. Pak J, Pu Y, Zjang Z-T, Hasty DL, Wu X-R (2001) Tamm-Horsfall protein binds to type 1 fimbriated Escherichia coli and prevents E. coli from binding to uroplakin Ia and Ib receptors. J Biol Chem 276:9924–9930

    PubMed  Article  CAS  Google Scholar 

  4. Bates JM, Raffi HM, Prasadan K, Mascarenhas R, Laszik Z, Maeda N, Hultgren SJ, Kumar S (2004) Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication. Kidney Int 65:791–797

    PubMed  Article  CAS  Google Scholar 

  5. Wimmer T, Cohen G, Saemann MD, Hörl WH (2004) Effects of Tamm-Horsfall protein on polymorphonuclear leukocyte function. Nephrol Dial Transplant 19:2192–2197

    PubMed  Article  Google Scholar 

  6. Mo L, Huang H-Y, Zhu X-H, Shapiro E, Hasty DL, Wu X-R (2004) Tamm-Horsfall protein is a critical renal defense factor protecting against calcium oxalate crystal formation. Kidney Int 66:1159–1166

    PubMed  Article  CAS  Google Scholar 

  7. Hess B, Kok DJ (1996) Nucleation, growth and aggregation of stone-forming crystals. In: Coe FL, Favus MJ, Pak CYC, Parks JH, Preminger GM (eds) Kidney stones: medical and surgical management, Chap. 1. Lippincott-Raven Publishers, Philadelphia

    Google Scholar 

  8. Fleisch H (1987) Inhibitors and promoters of stone formation. Kidney Int 13:361–371

    Google Scholar 

  9. Kok DJ, Khan SR (1994) Calcium oxalate nephrolithiasis, a free or fixed particle disease. Kidney Int 46:847–854

    PubMed  CAS  Google Scholar 

  10. Khan SR (1997) Tubular surface events during nephrolithiasis. Curr Opin Urol 7:240–247

    Article  Google Scholar 

  11. Scurr DS, Robertson WG (1986) Modifiers of calcium oxalate crystallization found in urine. II. Studies on their mode of action in an artificial urine. J Urol 136:128–131

    PubMed  CAS  Google Scholar 

  12. Hess B (1994) Tamm-Horsfall glycoprotein and calcium nephrolithiasis. Miner Electrolyte Metab 20:393–398

    PubMed  CAS  Google Scholar 

  13. Hess B, Nakagawa Y, Coe FL (1989) Inhibition of calcium oxalate monohydrate crystal aggregation by urine proteins. Am J Physiol 257:F99–F106

    PubMed  CAS  Google Scholar 

  14. Hess B, Zipperle L, Jaeger Ph (1993) Citrate and calcium effects on Tamm-Horsfall glycoprotein as a modifier of calcium oxalate crystal aggregation. Am J Physiol 265:F784–F791

    PubMed  CAS  Google Scholar 

  15. Hess B, Nakagawa Y, Parks JH, Coe FL (1991) Molecular abnormality of Tamm-Horsfall glycoprotein in calcium oxalate nephrolithiasis. Am J Physiol 260:F569–F578

    PubMed  CAS  Google Scholar 

  16. Knörle R, Schnierle P, Koch A, Buchholz N-P, Hering F, Seiler H, Ackermann T, Rutishauser G (1994) Tamm-Horsfall glycoprotein: role in inhibition and promotion of renal calcium oxalate stone formation studied with Fourier-transform infrared spectrometry. Clin Chem 40:1739–1743

    PubMed  Google Scholar 

  17. Glauser A, Hochreiter W, Jaeger Ph, Hess B (2000) Determinants of urinary excretion of Tamm-Horsfall protein in non-selected kidney stone formers and healthy subjects. Nephrol Dial Transplant 14:1580–1587

    Article  Google Scholar 

  18. Reinhart HH, Obedeanu N, Walz D, Sobel JD (1989). A new ELISA method for the rapid quantification of Tamm-Horsfall protein in urine. Am J Pathol 92:199–205

    CAS  Google Scholar 

  19. Fletcher AP, Neuberger A, Ratcliffe WA (1970) Tamm-Horsfall urinary glycoprotein: the chemical composition. Biochem J 120:417–424

    PubMed  CAS  Google Scholar 

  20. Aminoff D (1961) Method for the quantitative estimation of N-acetylneuraminic acid and their application to hydrolysates of sialomucoids. Biochem J 81:384–392

    PubMed  CAS  Google Scholar 

  21. Bichler KH, Kirchner Ch, Ideler V (1976) Uromucoid excretion in normal individuals and stone formers. Br J Urol 47:733–738

    Article  Google Scholar 

  22. Samuell CT (1979) Uromucoid excretion in normal subjects, calcium stone formers and in patients with chronic renal failure. Urol Res 7:5–12

    PubMed  Article  CAS  Google Scholar 

  23. Thornley C, Dawnay A, Cattell WR (1985) Human Tamm-Horsfall glycoprotein: urinary and plasma levels in normal subjects and patients with renal disease determined by a fully validated radioimmunoassay. Clin Sci 68:529–535

    PubMed  CAS  Google Scholar 

  24. Erwin DT, Kok DJ, Alam J, et al (1994) Calcium oxalate stone agglomeration reflects stone forming activity: citrate inhibition depends on macromolecules larger than 30 kilodaltons. Am J Kidney Dis 24:893–900

    PubMed  CAS  Google Scholar 

  25. Romero MC, Nocera S, Nesse AB (1997) Decreased Tamm-Horsfall protein in lithiasic patients. Clin Biochem 30:63–67

    PubMed  Article  CAS  Google Scholar 

  26. Ganter K, Bongartz D, Hesse A (1999) Tamm-Horsfall protein excretion and its relation to citrate in urine of stone-forming patients. Urology 53:492–495

    PubMed  Article  CAS  Google Scholar 

  27. Bichler KH, Mittermüller B, Strohmaier WL, Feil G, Eipper E (1999) Excretion of Tamm-Horsfall protein in patients with uric acid stones. Urol Int 62:87–92

    PubMed  Article  CAS  Google Scholar 

  28. Sumitra K, Pragasam V, Sakthivel R, Kalaiselvi P, Varalakshmi P (2005) Beneficial effects of vitamin E supplementation on the biochemical and kinetic properties of Tamm-Horsfall glycoprotein in hypertensive and hyperoxaluric subjects. Nephrol Dial Transplant 20:1407–1415

    PubMed  Article  CAS  Google Scholar 

  29. Khan SR (2004) Role of renal epithelial cells in the initiation of calcium oxalate stones. Nephron Exp Nephrol 98:e55–e60

    PubMed  Article  CAS  Google Scholar 

  30. Coe FL, Evan A, Worcester E (2005) Kidney stone disease. J Clin Invest 115:2598–2608

    PubMed  Article  CAS  Google Scholar 

Download references

Acknowledgments

The study was partly supported by the Swiss National Science Foundation (Grant 32-43448.95) and by PHSN/NIDDK (grant DK 56788-06).

Author information

Affiliations

  1. Renal Stone Clinic and Stone Research Laboratory, Policlinic of Internal Medicine, University Hospital, Berne, Switzerland

    Markus Jaggi, Ljerka Zipperle & Bernhard Hess

  2. Kidney Stone Laboratory, University of Chicago, Chicago, IL, USA

    Yasushi Nakagawa

  3. Department of Anesthesiology, Kantonsspital, 6000, Lucerne, Switzerland

    Markus Jaggi

  4. Internal Medicine and Nephrology, Klinik Im Park, Bellariastrasse 38, 8038, Zurich, Switzerland

    Bernhard Hess

Authors
  1. Markus Jaggi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yasushi Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ljerka Zipperle
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bernhard Hess
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernhard Hess.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jaggi, M., Nakagawa, Y., Zipperle, L. et al. Tamm-Horsfall protein in recurrent calcium kidney stone formers with positive family history: abnormalities in urinary excretion, molecular structure and function. Urol Res 35, 55–62 (2007). https://doi.org/10.1007/s00240-007-0083-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00240-007-0083-7

Keywords

  • Nephrolithiasis
  • Positive family history
  • Calcium oxalate
  • Tamm-Horsfall protein
  • Sialic acid
  • Crystal aggregation inhibition