Skip to main content
SpringerLink
Log in

Hypercalciuria in patients with CLCN5 mutations

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Hypercalciuria is regarded as a characteristic symptom of Dent disease, an X-linked recessive tubulopathy characterized by low molecular weight (LMW) proteinuria, nephrocalcinosis/nephrolithiasis, and progressive renal failure due to mutations in the CLCN5 gene. As the presence of hypercalciuria may affect the decision to consider a CLCN5 mutation in the differential diagnosis, the phenotypic spectrum and the relative frequency of hypercalciuria in patients with CLCN5 mutations was determined. We assessed renal calcium excretion in 34 male patients with proven CLCN5 mutations, who had been referred because of LMW proteinuria and at least one additional symptom of Dent disease. Hypercalciuria was defined as renal calcium excretion exceeding 0.1 mmol/kg per day. Data obtained were compared with all series of CLCN5-positive patients identified by a systematic literature survey. In 7 of our 19 families, at least 1 affected male had normal calcium excretion. Hypercalciuria was observed in 22 of 31 patients tested (71%) compared to 85 of 90 (94.4%) in series from Europe and North America and 74.4% from Japan. LMW proteinuria was present in all CLCN5-positive patients; 25% of the patients in European and North American series, 45% of the Japanese, and 41% in the present series had only two of the four principal symptoms of Dent disease. Therefore, a CLCN5 mutation should be considered irrespective of the presence of hypercalciuria in a patient with LMW proteinuria and one additional symptom of Dent disease.

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

Similar content being viewed by others

References

  1. Dent CE, Friedman M (1964) Hypercalciuric rickets associated with renal tubular damage. Arch Dis Child 39:240–249

    Article  PubMed  CAS  Google Scholar 

  2. Wrong OM, Norden AGW, Feest TG (1994) Dent’s disease; a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure and a marked male predominance. QJM 87:473–493

    PubMed  CAS  Google Scholar 

  3. Fisher SE, Bakel IV, Lloyd SE, Pearce SH, Thakker RV, Craig IW (1995) Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis). Genomics 29:598–606

    Article  PubMed  CAS  Google Scholar 

  4. Scheel O, Zdebik AA, Lourdel S, Jentsch TJ (2005) Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins. Nature 436:424–427

    Article  PubMed  CAS  Google Scholar 

  5. Picollo A, Pusch M (2005) Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5. Nature 436:420–423

    Article  PubMed  CAS  Google Scholar 

  6. Thakker RV (2000) Pathogenesis of Dent’s disease and related syndromes of X-linked nephrolithiasis. Kidney Int 57:787–793

    Article  PubMed  CAS  Google Scholar 

  7. Bonnardeaux A, Bichet DG (2000) Inherited disorders of the renal tubule. In: Brenner BM (ed) The kidney, 6th edn. Saunders, Philadelphia, pp 1656–1659

    Google Scholar 

  8. Lloyd SE, Pearce SHS, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, Harding B, Bolino A, Devoto M, Goodyer P, Rigden SPA, Wrong O, Jentsch TJ, Craig IW, Thakker RV (1996) A common molecular basis for three inherited kidney stone diseases. Nature 379:445–449

    Article  PubMed  CAS  Google Scholar 

  9. Igarashi T, Hayakawa H, Shigara H, Kawato H, Yan K, Kawaguchi H, Yamanaka T, Tsuchida S, Akagi K (1995) Hypercalciuria and nephrocalcinosis in patients with idiopathic low-molecular-weight proteinuria in Japan: is the disease identical to Dent’s disease in the United Kingdom? Nephron 69:242–247

    Article  PubMed  CAS  Google Scholar 

  10. Igarashi T, Günther W, Sekine T, Inatomi J, Shiraga H, Takahashi S, Suzuki J, Tsuru N, Yanagihara T, Shimazu M, Jentsch TJ, Thakker RV (1998) Functional characterization of renal chloride channel, CLCN5, mutations associated with Dent’s Japan disease. Kidney Int 54:1850–1856

    Article  PubMed  CAS  Google Scholar 

  11. Nakazato H, Hattori S, Furuse A, Kawano T, Karashima S, Tsuruta M, Yoshimuta J, Endo F, Matsuda I (1997) Mutation in the CLCN5 gene in Japanese patients with familial idiopathic low molecular weight proteinuria. Kidney Int 52:895–900

    Article  PubMed  CAS  Google Scholar 

  12. Scheinman SJ (1998) X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int 53:3–17

    Article  PubMed  CAS  Google Scholar 

  13. Devuyst O, Christie PT, Courtoy PJ, Beauwens R, Thakker RV (1999) Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent’s disease. Hum Mol Genet 8:247–257

    Article  PubMed  CAS  Google Scholar 

  14. Günther W, Piwon N, Jentsch TJ (2003) The ClC-5 chloride channel knock-out mouse—an animal model for Dent’s disease. Pflugers Arch 445:456–462

    PubMed  Google Scholar 

  15. Piwon N, Günther W, Schwake M (2000) ClC-5 Cl-channel disruption impairs endocytosis in a mouse model for Dent’s disease. Nature 408:369–373

    Article  PubMed  CAS  Google Scholar 

  16. Ludwig M, Beck A, Wickert L, Bolkenius U, Tittel B, Hinkel K, Bidlingmaier F (1998) Female pseudohermaphroditism associated with a novel homozygous G-to-A (V370-to-M) substitution in the P-450 aromatase gene. J Pediatr Endocrinol Metab 11:657–664

    PubMed  CAS  Google Scholar 

  17. Ludwig M, Doroszewicz J, Seyberth HW, Bökenkamp A, Balluch B, Nuutinen M, Utsch B, Waldegger S (2005) Functional evaluation of Dent’s disease-causing mutations: implications for ClC-5 channel trafficking and internalization. Hum Genet 117:228–237

    Article  PubMed  Google Scholar 

  18. Ludwig M, Waldegger S, Nuutinen M, Bökenkamp A, Reissinger A, Steckelbroeck S, Utsch B (2003) Four additional CLCN5 exons encode a widely expressed novel long CLC-5 isoform but fail to explain Dent’s phenotype in patients without mutations in the short variant. Kidney Blood Press Res 26:176–184

    Article  PubMed  CAS  Google Scholar 

  19. Besbas N, Ozaltin F, Jeck N, Seyberth H, Ludwig M (2005) CLCN5 mutation (R347X) associated with hypokalaemic metabolic alkalosis in a Turkish child: an unusual presentation of Dent’s disease. Nephrol Dial Transplant 20:1476–1479

    Article  PubMed  CAS  Google Scholar 

  20. Hoopes RR Jr, Hueber PA, Reid RJ Jr, Braden GL, Goodyer PR, Melnyk AR, Midgley JP, Moel DI, Neu AM, VanWhy SK, Scheinman SJ (1998) CLCN5 chloride channel mutation in six new North American families with X-linked nephrolithiasis. Kidney Int 54:698–705

    Article  PubMed  CAS  Google Scholar 

  21. Hoopes RR Jr, Raja KM, Koich A, Hueber P, Reid R, Knohl SJ, Scheinman SJ (2004) Evidence for genetic heterogeneity in Dent’s disease. Kidney Int 65:1615–1620

    Article  PubMed  CAS  Google Scholar 

  22. Oudet C, Martin-Coignard D, Pannetier S, Praud E, Champion G, Hanauer A (1997) A second family with XLRH displays the mutation S244L in the CLCN5 gene. Hum Genet 99:781–784

    Article  PubMed  CAS  Google Scholar 

  23. Kelleher CL, Buckalew VM, Frederickson ED, Rhodes DJ, Conner DA, Seidman JG, Seidman CE (1998) CLCN5 mutation Ser244Leu is associated with X-linked renal failure without X-linked recessive hypophosphatemic rickets. Kidney Int 53:31–37

    Article  PubMed  CAS  Google Scholar 

  24. Friedrich T, Breiderhoff T, Jentsch TJ (1999) Mutational analysis demonstrates that ClC-4 and ClC-5 directly mediate plasma membrane currents. J Biol Chem 274:896–902

    Article  PubMed  CAS  Google Scholar 

  25. Akuta N, Lloyd SE, Igarashi T, Shiraga H, Matsuyama T, Yokoro S, Cox JPD, Thakker RV (1997) Mutations of CLCN5 in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and nephrocalcinosis. Kidney Int 52:911–916

    Article  PubMed  CAS  Google Scholar 

  26. Morimoto T, Uchida S, Sakamoto H, Kondo Y, Hanamizu H, Fukui M, Tomino Y, Nagano N, Sasaki S, Marumo F (1998) Mutations in CLCN5 chloride channel in Japanese patients with low molecular weight proteinuria. J Am Soc Nephrol 9:811–818

    PubMed  CAS  Google Scholar 

  27. Takemura T, Hino S, Ikeda M, Okada M, Igarashi T, Inatomi J, Yoshioka K (2001) Identification of two novel mutations in the CLCN5 gene in Japanese patients with familial idiopathic low molecular weight proteinuria (Japanese Dent’s disease). Am J Kidney Dis 37:138–143

    Article  PubMed  CAS  Google Scholar 

  28. Cheong HI, Lee JW, Zheng SH, Lee JH, Kang JH, Kang HG, Ha IS, Lee SJ, Choi Y (2005) Phenotype and genotype of Dent’s disease in three Korean boys. Pediatr Nephrol 20:455–459

    Article  PubMed  Google Scholar 

  29. National Kidney Foundation (2002) K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification and stratification. Am J Kidney Dis 39:S1–S266

    Google Scholar 

  30. Lloyd SE, Pearce SHS, Günther W, Kawaguchi H, Igarashi T, Jentsch TJ, Thakker RV (1997) Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5). J Clin Invest 99:967–974

    Article  PubMed  CAS  Google Scholar 

  31. Lloyd SE, Günther W, Pearce SHS, Thomson A, Bianchi ML, Bosio M, Craig IW, Fisher SE, Scheinman SJ, Wrong O, Jentsch TJ, Thakker RV (1997) Characterisation of renal chloride channel, CLCN5, mutations in hypercalciuric nephrolithiasis (kidney stones) disorders. Hum Mol Genet 6:1233–1239

    Article  PubMed  CAS  Google Scholar 

  32. Langlois V, Bernard C, Scheinman SJ, Thakker RV, Cox JPD, Goodyer PR (1998) Clinical features of X-linked nephrolithiasis in childhood. Pediatr Nephrol 12:625–629

    Article  PubMed  CAS  Google Scholar 

  33. Nakazato H, Yoshimuta J, Karashima S, Matsumoto S, Endo F, Matsuda I, Hattori S (1999) Chloride channel CLCN5 mutations in Japanese children with familial idiopathic low molecular weight proteinuria. Kidney Int 55:63–70

    Article  PubMed  CAS  Google Scholar 

  34. Bosio M, Bianchi ML, Lloyd SE, Thakker RV (1999) A familial syndrome due to Arg648Stop mutation in the X-linked renal chloride channel gene. Pediatr Nephrol 13:278–283

    Article  PubMed  CAS  Google Scholar 

  35. Cox JPD, Yamamoto K, Christie PT, Wooding C, Feest T, Flinter FA, Goodyer PR, Leumann E, Neuhaus T, Reid C, Williams PF, Wrong O, Thakker RV (1999) Renal chloride channel, CLCN5, mutation in Dent’s disease. J Bone Miner Res 14:1536–1542

    Article  PubMed  CAS  Google Scholar 

  36. Yamamoto K, Cox JPDT, Friedrich T, Christie PT, Bald M, Houtman PN, Lapsley MJ, Patzer L, Tsimaratos M, Van’t Hoff WG, Yamaoka K, Jentsch TJ, Thakker RV (2000) Characterization of renal chloride channel (CLCN5) mutations in Dent’s disease. J Am Soc Nephrol 11:1460–1468

    PubMed  CAS  Google Scholar 

  37. Igarashi T, Inatomi J, Ohara T, Kuwahara T, Shimadzu M, Thakker RV (2000) Clinical and genetic studies of CLCN5 mutations in Japanese families with Dent’s disease. Kidney Int 58:520–527

    Article  PubMed  CAS  Google Scholar 

  38. Carballo-Trujillo I, Garcia-Nieto V, Moya-Angeler FJ, Antón-Gamero M, Loris C, Méndez-Alvarez S, Claverie-Martin F (2003) Novel truncating mutations in the CLC-5 chloride channel gene in patients with Dent’s disease. Nephrol Dial Transplant 18:717–723

    Article  PubMed  CAS  Google Scholar 

  39. Claverie-Martin F, González-Acosta H, Flores C, Antón-Gamero M, García-Nieto V (2003) De novo insertion of an Alu sequence in the coding region of the CLCN5 gene results in Dent’s disease. Hum Genet 113:480–485

    Article  PubMed  CAS  Google Scholar 

  40. Matsuyama T, Awazu M, Oikawa T, Inatomi J, Sekine T, Igarashi T (2004) Molecular and clinical studies of Dent’s disease in Japan: biochemical examination and renal ultrasonography do not predict carrier state. Clin Nephrol 61:231–237

    PubMed  CAS  Google Scholar 

  41. Brakemeier S, Si H, Gollasch M, Höffler D, Buhl M, Köhler R, Hoyer J, Eichler I (2004) Dent’s disease: identification of a novel mutation in the renal chloride channel CLCN5. Clin Nephrol 62:387–390

    PubMed  CAS  Google Scholar 

  42. Yanagida H, Ikeoka M, Kuwajima H, Wada N, Tabata N, Sugimoto K, Okada M, Takemura T (2004) A boy with Japanese Dent’s disease exhibiting abnormal calcium metabolism and osseous disorder of the spine: defective megalin expression at the brushborder of renal proximal tubules. Clin Nephrol 62:306–312

    PubMed  CAS  Google Scholar 

  43. Luyckx VA, Leclercq B, Dowland LK, Yu ASL (1999) Diet-dependent hypercalciuria in transgenic mice with reduced CLC-5 chloride channel expression. Proc Natl Acad Sci USA 96:12174–12179

    Article  PubMed  CAS  Google Scholar 

  44. Wang SS, Devuyst O, Courtoy PJ, Wang XT, Wang H, Wang Y, Thakker RV, Guggino S, Guggino WB (2000) Mice lacking renal chloride channel, CLC-5, are a model for Dent’s disease, a nephrolithiasis disorder associated with defective receptor-mediated endocytosis. Hum Mol Genet 9:2937–2945

    Article  PubMed  CAS  Google Scholar 

  45. Silva IV, Cebotaru V, Wang H, Wang XT, Wang SS, Guo G, Devuyst O, Thakker RV, Guggino WB, Guggino SE (2003) The ClC-5 knockout mouse model of Dent’s disease has renal hypercalciuria and increased bone turnover. J Bone Miner Res 18:615–623

    Article  PubMed  CAS  Google Scholar 

  46. Reinhart SC, Norden AGW, Lapsley M, Thakker RV, Pang J, Moses AM, Frymoyer PA, Favus MJ, Hoepner JA, Scheinman SJ (1995) Characterization of carrier females and affected males with X-linked recessive nephrolithiasis. J Am Soc Nephrol 5:1451–1461

    PubMed  CAS  Google Scholar 

  47. Foreman JW (2004) Cystinosis and Fanconi syndrome. In: Avner ED, Harmon WE, Niaudet P (eds) Pediatric nephrology, 5th edn. Lippincott Williams & Wilkins, Philadelphia, pp 789–806

    Google Scholar 

  48. Yu ASL (2001) Role of ClC-5 in the pathogenesis of hypercalciuria: recent insights from transgenic mouse models. Curr Opin Nephrol Hypertens 10:415–420

    Article  PubMed  CAS  Google Scholar 

  49. Hoopes RR Jr, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, Simckes A, Tasic V, Toenshoff B, Suchy SF, Nussbaum RL, Scheinman SJ (2005) Dent disease with mutations in OCRL1. Am J Hum Genet 76:260–267

    Article  PubMed  CAS  Google Scholar 

  50. Barbano G, Ghiggeri GM, Fierro S, Tosetto E, Anglani F, Perfumo F (2005) Isolated low molecular weight proteinuria as presenting syndrome of Dent’s disease in children: relationship between calciuria, calcium (Ca) and phosphorus (P) intake, PTH and bone homeostasis (abstract). Pediatr Nephrol 20:C62

    Google Scholar 

  51. Raja KM, Schurman S, D’Mello RG, Blowey D, Goodyer P, Van Why S, Ploutz-Snyder RJ, Asplin J, Scheinman SJ (2002) Responsiveness of hypercalciuria to thiazide in Dent’s disease. J Am Soc Nephrol 13:2938–2944

    Article  PubMed  Google Scholar 

  52. Cebotaru V, Kaul S, Devuyst O, Cai H, Racusen L, Guggino WB, Guggino SE (2005) High citrate diet delays progression of renal insufficiency in the ClC-5 knockout mouse model of Dent’s disease. Kidney Int 68:642–652

    Article  PubMed  CAS  Google Scholar 

  53. Sayer JA, Simmons NL (2002) Urinary stone formation: Dent’s disease moves understanding forward. Exp Nephrol 10:176–181

    Article  PubMed  CAS  Google Scholar 

  54. Lieske JC, Norris R, Swift H, Toback FG (1997) Adhesion, internalization and metabolism of calcium oxalate monohydrate crystals by renal epithelial cells. Kidney Int 52:1291–1301

    Article  PubMed  CAS  Google Scholar 

  55. Sayer JA, Carr G, Pearce SH, Goodship TH, Simmons NL (2003) Disordered calcium crystal handling in antisense CLC-5-treated collecting duct cells. Biochem Biophys Res Commun 300:305–310

    Article  PubMed  CAS  Google Scholar 

  56. Sayer JA, Carr G, Simmons NL (2004) Calcium phosphate and calcium oxalate crystal handling is dependent upon CLC-5 expression in mouse collecting duct cells. Biochim Biophys Acta 1689:83–90

    PubMed  CAS  Google Scholar 

  57. Carr G, Simmons NL, Sayer JA (2006) Disruption of clc-5 leads to redistribution of annexin A2 and promotes calcium crystal agglomeration in collecting duct epithelial cells. Cell Mol Life Sci 63:367–377

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors express their sincere appreciation to the patients and their families for their participation in this study. Pia Uerdingen is acknowledged for excellent technical assistance and Sigrid Bruinsma for secretarial assistance with the preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Clinical Biochemistry, University of Bonn, Sigmund-Freud-Str. 25, 53105, Bonn, Germany

    Michael Ludwig

  2. Department of Pediatrics, University of Erlangen-Nuremberg, Erlangen, Germany

    Boris Utsch

  3. Gottfried von Preyer’sches Kinderhospital, Vienna, Austria

    Bernd Balluch

  4. Department of Pediatrics, University Children’s Hospital, Münster, Germany

    Stefan Fründ & Eberhard Kuwertz-Bröking

  5. Division of Pediatric Nephrology, Dept. of Pediatrics, Vrije Universiteit Medical Center, Amsterdam, The Netherlands

    Arend Bökenkamp

Authors
  1. Michael Ludwig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Boris Utsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bernd Balluch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stefan Fründ
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eberhard Kuwertz-Bröking
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Arend Bökenkamp
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Ludwig.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ludwig, M., Utsch, B., Balluch, B. et al. Hypercalciuria in patients with CLCN5 mutations. Pediatr Nephrol 21, 1241–1250 (2006). https://doi.org/10.1007/s00467-006-0172-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-006-0172-9

Keywords

Search

Navigation