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Dent disease (X-linked recessive nephrolithiasis)

Steven J Scheinman, MD
John C Lieske, MD
Section Editor
Stanley Goldfarb, MD
Deputy Editor
Albert Q Lam, MD


Dent disease is an X-linked recessive disorder of the proximal tubules that is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, kidney stones, renal failure, and rickets [1,2]. In most cases, it is due to mutations that inactivate a voltage-gated chloride transporter named CLC-5. In others, it is associated with mutations in the OCRL1 gene, which is also mutated in the oculocerebrorenal syndrome of Lowe. Further genetic heterogeneity is assumed to exist since there are patients with the distinctive phenotype of Dent disease without mutations in either of these genes [3]. (See 'Molecular genetics' below.)

The following topic review will present the genetics, clinical manifestations, and treatment of Dent disease.


Although different features of Dent disease predominated among early reports [4-7], an accurate description of the phenotype was offered in the report entitled, "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" [8].

"Dent disease" is accepted as the encompassing name of this disease, based upon this limited renal phenotype that includes a partial Fanconi syndrome. The disease is distinguished clinically from the Lowe syndrome by the absence of cataracts, mental developmental delay, and renal tubular acidosis [3].


In 60 percent of cases, Dent disease is due to mutations that inactivate a voltage-gated chloride transporter, CLC-5, which is expressed in the kidney and is encoded by a gene at Xp11.22 [9]. In another 15 percent of cases, it is associated with mutations in the OCRL1 gene, which is also mutated in the oculocerebrorenal syndrome of Lowe. Further genetic heterogeneity is assumed to exist since there are patients with the distinctive phenotype of Dent disease who do not have mutations in either of these genes [3].

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Literature review current through: Nov 2017. | This topic last updated: Oct 25, 2016.
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  1. Scheinman SJ. X-linked hypercalciuric nephrolithiasis: clinical syndromes and chloride channel mutations. Kidney Int 1998; 53:3.
  2. Devonald MA, Karet FE. Renal epithelial traffic jams and one-way streets. J Am Soc Nephrol 2004; 15:1370.
  3. Hoopes RR Jr, Shrimpton AE, Knohl SJ, et al. Dent Disease with mutations in OCRL1. Am J Hum Genet 2005; 76:260.
  4. Frymoyer PA, Scheinman SJ, Dunham PB, et al. X-linked recessive nephrolithiasis with renal failure. N Engl J Med 1991; 325:681.
  5. Igarashi T, Hayakawa H, Shiraga H, et al. Hypercalciuria and nephrocalcinosis in patients with idiopathic low-molecular-weight proteinuria in Japan: is the disease identical to Dent's disease in United Kingdom? Nephron 1995; 69:242.
  6. Bolino A, Devoto M, Enia G, et al. Genetic mapping in the Xp11.2 region of a new form of X-linked hypophosphatemic rickets. Eur J Hum Genet 1993; 1:269.
  7. Oudet C, Martin-Coignard D, Pannetier S, et al. A second family with XLRH displays the mutation S244L in the CLCN5 gene. Hum Genet 1997; 99:781.
  8. Wrong OM, Norden AG, Feest TG. 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 1994; 87:473.
  9. Lloyd SE, Pearce SH, Fisher SE, et al. A common molecular basis for three inherited kidney stone diseases. Nature 1996; 379:445.
  10. Scheinman SJ, Pook MA, Wooding C, et al. Mapping the gene causing X-linked recessive nephrolithiasis to Xp11.22 by linkage studies. J Clin Invest 1993; 91:2351.
  11. Pook MA, Wrong O, Wooding C, et al. Dent's disease, a renal Fanconi syndrome with nephrocalcinosis and kidney stones, is associated with a microdeletion involving DXS255 and maps to Xp11.22. Hum Mol Genet 1993; 2:2129.
  12. Fisher SE, van Bakel I, Lloyd SE, et al. Cloning and characterization of CLCN5, the human kidney chloride channel gene implicated in Dent disease (an X-linked hereditary nephrolithiasis). Genomics 1995; 29:598.
  13. Tosetto E, Casarin A, Salviati L, et al. Complexity of the 5'UTR region of the CLCN5 gene: eleven 5'UTR ends are differentially expressed in the human kidney. BMC Med Genomics 2014; 7:41.
  14. Devuyst O, Christie PT, Courtoy PJ, et al. Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent's disease. Hum Mol Genet 1999; 8:247.
  15. Hoopes RR Jr, Hueber PA, Reid RJ Jr, et al. CLCN5 chloride-channel mutations in six new North American families with X-linked nephrolithiasis. Kidney Int 1998; 54:698.
  16. Kelleher CL, Buckalew VM, Frederickson ED, et al. CLCN5 mutation Ser244Leu is associated with X-linked renal failure without X-linked recessive hypophosphatemic rickets. Kidney Int 1998; 53:31.
  17. Lloyd SE, Pearce SH, Günther W, et al. 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 1997; 99:967.
  18. Lloyd SE, Gunther W, Pearce SH, et al. Characterisation of renal chloride channel, CLCN5, mutations in hypercalciuric nephrolithiasis (kidney stones) disorders. Hum Mol Genet 1997; 6:1233.
  19. Igarashi T, Inatomi J, Ohara T, et al. Clinical and genetic studies of CLCN5 mutations in Japanese families with Dent's disease. Kidney Int 2000; 58:520.
  20. Cox JP, Yamamoto K, Christie PT, et al. Renal chloride channel, CLCN5, mutations in Dent's disease. J Bone Miner Res 1999; 14:1536.
  21. Yamamoto K, Cox JP, Friedrich T, et al. Characterization of renal chloride channel (CLCN5) mutations in Dent's disease. J Am Soc Nephrol 2000; 11:1460.
  22. Matsuyama T, Awazu M, Oikawa T, et al. Molecular and clinical studies of Dent's disease in Japan: biochemical examination and renal ultrasonography do not predict carrier state. Clin Nephrol 2004; 61:231.
  23. Tosetto E, Ghiggeri GM, Emma F, et al. Phenotypic and genetic heterogeneity in Dent's disease--the results of an Italian collaborative study. Nephrol Dial Transplant 2006; 21:2452.
  24. Hichri H, Rendu J, Monnier N, et al. From Lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes. Hum Mutat 2011; 32:379.
  25. Tosetto E, Ceol M, Mezzabotta F, et al. Novel mutations of the CLCN5 gene including a complex allele and A 5' UTR mutation in Dent disease 1. Clin Genet 2009; 76:413.
  26. Dinour D, Davidovitz M, Levin-Iaina N, et al. Truncating mutations in the chloride/proton ClC-5 antiporter gene in Seven Jewish Israeli families with Dent's 1 disease. Nephron Clin Pract 2009; 112:c262.
  27. Grand T, Mordasini D, L'Hoste S, et al. Novel CLCN5 mutations in patients with Dent's disease result in altered ion currents or impaired exchanger processing. Kidney Int 2009; 76:999.
  28. Wu F, Roche P, Christie PT, et al. Modeling study of human renal chloride channel (hCLC-5) mutations suggests a structural-functional relationship. Kidney Int 2003; 63:1426.
  29. Smith AJ, Reed AA, Loh NY, et al. Characterization of Dent's disease mutations of CLC-5 reveals a correlation between functional and cell biological consequences and protein structure. Am J Physiol Renal Physiol 2009; 296:F390.
  30. Mansour-Hendili L, Blanchard A, Le Pottier N, et al. Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1. Hum Mutat 2015; 36:743.
  31. Devuyst O, Thakker RV. Dent's disease. Orphanet J Rare Dis 2010; 5:28.
  32. Utsch B, Bökenkamp A, Benz MR, et al. Novel OCRL1 mutations in patients with the phenotype of Dent disease. Am J Kidney Dis 2006; 48:942.e1.
  33. Bökenkamp A, Böckenhauer D, Cheong HI, et al. Dent-2 disease: a mild variant of Lowe syndrome. J Pediatr 2009; 155:94.
  34. Zaniew M, Bökenkamp A, Kołbuc M, et al. Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort. Nephrol Dial Transplant 2016.
  35. Shrimpton AE, Hoopes RR Jr, Knohl SJ, et al. OCRL1 mutations in Dent 2 patients suggest a mechanism for phenotypic variability. Nephron Physiol 2009; 112:p27.
  36. Günther W, Lüchow A, Cluzeaud F, et al. ClC-5, the chloride channel mutated in Dent's disease, colocalizes with the proton pump in endocytotically active kidney cells. Proc Natl Acad Sci U S A 1998; 95:8075.
  37. Picollo A, Pusch M. Chloride/proton antiporter activity of mammalian CLC proteins ClC-4 and ClC-5. Nature 2005; 436:420.
  38. Piwon N, Günther W, Schwake M, et al. ClC-5 Cl- -channel disruption impairs endocytosis in a mouse model for Dent's disease. Nature 2000; 408:369.
  39. Wang SS, Devuyst O, Courtoy PJ, et al. 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 2000; 9:2937.
  40. Devuyst O, Guggino WB. Chloride channels in the kidney: lessons learned from knockout animals. Am J Physiol Renal Physiol 2002; 283:F1176.
  41. Hryciw DH, Wang Y, Devuyst O, et al. Cofilin interacts with ClC-5 and regulates albumin uptake in proximal tubule cell lines. J Biol Chem 2003; 278:40169.
  42. Reed AA, Loh NY, Terryn S, et al. CLC-5 and KIF3B interact to facilitate CLC-5 plasma membrane expression, endocytosis, and microtubular transport: relevance to pathophysiology of Dent's disease. Am J Physiol Renal Physiol 2010; 298:F365.
  43. Norden AG, Lapsley M, Igarashi T, et al. Urinary megalin deficiency implicates abnormal tubular endocytic function in Fanconi syndrome. J Am Soc Nephrol 2002; 13:125.
  44. Dressman MA, Olivos-Glander IM, Nussbaum RL, Suchy SF. Ocrl1, a PtdIns(4,5)P(2) 5-phosphatase, is localized to the trans-Golgi network of fibroblasts and epithelial cells. J Histochem Cytochem 2000; 48:179.
  45. Apodaca G. Endocytic traffic in polarized epithelial cells: role of the actin and microtubule cytoskeleton. Traffic 2001; 2:149.
  46. Luyckx VA, Leclercq B, Dowland LK, Yu AS. Diet-dependent hypercalciuria in transgenic mice with reduced CLC5 chloride channel expression. Proc Natl Acad Sci U S A 1999; 96:12174.
  47. Reinhart SC, Norden AG, Lapsley M, et al. Characterization of carrier females and affected males with X-linked recessive nephrolithiasis. J Am Soc Nephrol 1995; 5:1451.
  48. Silva IV, Cebotaru V, Wang H, et al. The ClC-5 knockout mouse model of Dent's disease has renal hypercalciuria and increased bone turnover. J Bone Miner Res 2003; 18:615.
  49. Norden AG, Lapsley M, Thakker RV. The tubular proteinuria of Dent's disease (CLCN5 mutation) comprises proteins in the mass range from insulin to intact immunoglobulin G and provides a new approach to estimation of in vivo glomerular sieving coefficients (abstract). J Am Soc Nephrol 2000; 11:93A.
  50. Claverie-Martín F, Ramos-Trujillo E, García-Nieto V. Dent's disease: clinical features and molecular basis. Pediatr Nephrol 2011; 26:693.
  51. Sekine T, Komoda F, Miura K, et al. Japanese Dent disease has a wider clinical spectrum than Dent disease in Europe/USA: genetic and clinical studies of 86 unrelated patients with low-molecular-weight proteinuria. Nephrol Dial Transplant 2014; 29:376.
  52. Blanchard A, Curis E, Guyon-Roger T, et al. Observations of a large Dent disease cohort. Kidney Int 2016; 90:430.
  53. Scheinman SJ. Nephrolithiasis. Semin Nephrol 1999; 19:381.
  54. Langlois V, Bernard C, Scheinman SJ, et al. Clinical features of X-linked nephrolithiasis in childhood. Pediatr Nephrol 1998; 12:625.
  55. Bosio M, Bianchi ML, Lloyd SE, Thakker RV. A familial syndrome due to Arg648Stop mutation in the X-linked renal chloride channel gene. Pediatr Nephrol 1999; 13:278.
  56. Copelovitch L, Nash MA, Kaplan BS. Hypothesis: Dent disease is an underrecognized cause of focal glomerulosclerosis. Clin J Am Soc Nephrol 2007; 2:914.
  57. Wang X, Anglani F, Beara-Lasic L, et al. Glomerular Pathology in Dent Disease and Its Association with Kidney Function. Clin J Am Soc Nephrol 2016; 11:2168.
  58. Frishberg Y, Dinour D, Belostotsky R, et al. Dent's disease manifesting as focal glomerulosclerosis: Is it the tip of the iceberg? Pediatr Nephrol 2009; 24:2369.
  59. Yanagida H, Ikeoka M, Kuwajima H, et al. 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 2004; 62:306.
  60. Fervenza FC. A patient with nephrotic-range proteinuria and focal global glomerulosclerosis. Clin J Am Soc Nephrol 2013; 8:1979.
  61. Ceol M, Tiralongo E, Baelde HJ, et al. Involvement of the tubular ClC-type exchanger ClC-5 in glomeruli of human proteinuric nephropathies. PLoS One 2012; 7:e45605.
  62. Besbas N, Ozaltin F, Jeck N, et al. CLCN5 mutation (R347X) associated with hypokalaemic metabolic alkalosis in a Turkish child: an unusual presentation of Dent's disease. Nephrol Dial Transplant 2005; 20:1476.
  63. Bockenhauer D, Bokenkamp A, van't Hoff W, et al. Renal phenotype in Lowe Syndrome: a selective proximal tubular dysfunction. Clin J Am Soc Nephrol 2008; 3:1430.
  64. Scheinman SJ, Cox JP, Lloyd SE, et al. Isolated hypercalciuria with mutation in CLCN5: relevance to idiopathic hypercalciuria. Kidney Int 2000; 57:232.
  65. Raja KA, Schurman S, D'mello RG, et al. Responsiveness of hypercalciuria to thiazide in Dent's disease. J Am Soc Nephrol 2002; 13:2938.
  66. Blanchard A, Vargas-Poussou R, Peyrard S, et al. Effect of hydrochlorothiazide on urinary calcium excretion in dent disease: an uncontrolled trial. Am J Kidney Dis 2008; 52:1084.
  67. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. N Engl J Med 1993; 328:833.
  68. Cebotaru V, Kaul S, Devuyst O, et al. High citrate diet delays progression of renal insufficiency in the ClC-5 knockout mouse model of Dent's disease. Kidney Int 2005; 68:642.