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| ==Overview== | | ==[[Dent's disease overview|Overview]]== |
| | ==[[Dent's disease historical perspective|Historical Perspective]]== |
| | ==[[Dent's disease pathophysiology |Pathophysiology]]== |
| | ==[[Dent's disease differential diagnosis|Differentiating Dent's disease from other Diseases]]== |
| | ==[[Dent's disease epidemiology and demographics|Epidemiology and Demographics]]== |
| | ==[[Dent's disease natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| | ==Diagnosis== |
| | [[Dent's disease history and symptoms|History and Symptoms]] | [[Dent's disease physical examination|Physical Examination]] | [[Dent's disease laboratory findings|Laboratory Findings]] | [[Dent's disease other diagnostic studies|Other Diagnostic Studies]] |
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| '''Dent's disease''' (or '''Dent disease''') is a rare [[X-linked recessive]] inherited condition that affects the [[kidney]]. It is one cause of [[Fanconi syndrome]], and is characterized by tubular proteinuria, [[hypercalciuria]], [[calcium nephrolithiasis]], [[nephrocalcinosis]] and [[chronic renal failure]].
| | ==Treatment== |
| | | [[Dent's disease medical therapy|Medical Therapy]] | [[Dent's disease future or investigational therapies|Future or Investigational Therapies]] |
| "Dent's disease" is often used to describe an entire group of familial disorders, including X-linked recessive [[nephrolithiasis]] with renal failure, X-linked recessive hypophosphataemic rickets, and both Japanese and idiopathic low molecular weight proteinuria.<ref>Mayo Clinic, Division of Nephrology and Hypertension, [http://mayoresearch.mayo.edu/mayo/research/nephrology/renal_stone_disease.cfm Mineral Metabolism and Stone Disease]</ref>
| | ==Case Studies== |
| | | :[[Dent's disease case study one|Case #1]] |
| == History == | |
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| Dent's disease was first described by Dent, C. E. and Friedman, M in 1964 when they reported 2 unrelated British boys with [[rickets]] associated with renal tubular damage characterized by [[hypercalciuria]], [[hyperphosphaturia]], [[proteinuria]], and [[aminoaciduria]].<ref>Dent CE, Friedman M. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=retrieve&db=pubmed&list_uids=14169453&dopt=Abstract Hypercalciuric rickets associated with renal tubular damage]</ref> This is a genetic disorder caused by the [[genetic mutations]] in the renal [[chloride channel]] [http://www.gene.ucl.ac.uk/nomenclature/data/get_data.php?gd_app_sym=CLCN5 ClCN5] which encodes a kidney-specific voltage gated [[chloride channel]] and a 746 amino acid protein (CLC-5), with 12 to 13 transmembrane domains; it manifests itself through low molecular weight proteinuria, hypercalciuria, aminoaciduria and hypophosphataemia. Because of its rather rare occurrence, Dent's disease is often diagnosed as [[idiopathic]] [[hypercalciuria]] (IH), i.e. excess calcium in urine with undetermined causes.
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| == Symptoms ==
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| Dent's disease often produces symptoms of: | |
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| * Extreme thirst combined with [[dehydration]] which leads to frequent urination
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| * [[Nephrolithiasis]] (kidney stones)
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| * [[Hypercalciuria]] (high urine calcium - ''>300 mg/d or >4 mg/kg per d'') with normal levels blood/serum calcium)
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| Dent's disease ''may'' also be associated with:
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| * [[Aminoaciduria]] ([[amino acids]] in urine)
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| * [[Phosphaturia]] (phosphate in urine)
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| * [[Glycosuria]] (glucose in urine)
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| * [[Kaliuresis]] (potassium in urine)
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| * [[Uricosuria]] (excessive amounts of uric acid in the urine.)
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| * Impaired urinary acidification
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| * [[Rickets]]
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| In a very large study of patients with Dent's disease, 9 out of 15 men, and 1 out of 10 women suffered [[end-stage renal failure]] by the age of 47.<ref>Helen K Burgess, Satishkumar A Jayawardene and Nestor Velasco [http://ndt.oxfordjournals.org/cgi/content/full/16/7/1512 Dent's disease: can we slow its progression?]</ref>
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| == Genetics ==
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| [[Image:XlinkRecessive.jpg|thumb|left|100px|X-linked recessive inheritance.]]
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| Because it is an X-linked recessive disorder, only males are affected with the disease, whereas females are asymptomatic carriers. The males are prone to manifesting symptoms in early adulthood with symptoms of calculi, rickets or even with renal failure in more severe cases.
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| In humans, gene CLCN5 is located on chromosome Xp11.22 and has a 2238-bp coding sequence that consists of 11 exons that span 25 to 30 kb of genomic DNA and encode a 746 amino acid protein.<ref>Fisher SE, Black GC, Lloyd SE, Hatchwell E, Wrong O, Thakker RV, Craig IW: [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=8575751&dopt=AbstractPlus Isolation and partial characterization of a chloride channel gene which is expressed in kidney and is a candidate for Dent's disease (an X-linked hereditary nephrolithiasis). Hum Mol Genet3 : 2053-2059,1994]</ref>
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| CLCN5 belongs to the family of voltage-gated chloride channel genes (CLCN1-CLCN7, and CLCKa and CLCKb) that have approximately 12 transmembrane domains. These chloride channels have an important role in the control of membrane excitability, transepithelial transport, and possibly cell volume.<ref>Jentsch TJ, Friedrich T, Schriever A, Yamada H: [http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=retrieve&db=pubmed&list_uids=10370055&dopt=AbstractPlus The CLC chloride channel family. Pflügers Arch 437:783 -795, 1999]</ref>
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| The mechanisms by which CLC-5 dysfunction results in hypercalciuria and the other features of Dent's disease remain to be elucidated. The identification of additional CLCN5 mutations may help in these studies, and we have pursued such studies in patients with Dent's disease.<ref>Katsusuke Yamamoto, [http://jasn.asnjournals.org/cgi/content/full/11/8/1460 Characterization of Renal Chloride Channel (CLCN5) Mutations in Dent's Disease, J Am Soc Nephrol 11:1460-1468, 2000]</ref>
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| == Treatment == | |
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| As of today, there is no agreed-upon treatment of Dent's disease and no therapy has been formally accepted. Most treatment measures are mostly supportive in nature and they include:
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| * [[Thiazide]] [[diuretics]] which have been used with success in reducing the calcium output in urine, but they are also known to cause [[hypokalemia]].
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| ** In rats with [[diabetes insipidus]] thiazide diuretics inhibit the NaCl co-transporter in the renal distal convoluted tubule leading indirectly to less water and solutes being delivered to the distal tubule.<ref>Johannes Loffing, JASN, [http://jasn.asnjournals.org/cgi/content/full/15/11/2948 Paradoxical Antidiuretic Effect of Thiazides in Diabetes Insipidus: Another Piece in the Puzzle]</ref>
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| * [[Amiloride]] which also increases distal tubular calcium reabsorption and has been used as a therapy for idiopathic hypercalciuria.
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| ** A combination of 25 mg of chlorthalidone plus 5 mg of amiloride daily led to a substantial reduction in urine calcium in Dent's patients, however urine pH was "significantly higher in patients with Dent’s disease than in those with idiopathic hypercalciuria (P < 0.03), and supersaturation for uric acid was consequently lower (P < 0.03)."<ref>JASN, [http://jasn.asnjournals.org/cgi/content/full/13/12/2938 Responsiveness of Hypercalciuria to Thiazide in Dent’s Disease]</ref>
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| * For patients with [[osteomalacia]], [[Vitamin D]] or derivatives have been employed, apparently with success.
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| * Some lab tests on mice with CLC-5 related tubular damage showed that a high [[citrate]] diet preserved renal function and delayed progress of renal disease.<ref>Johns Hopkins University School of Medicine, [http://cat.inist.fr/?aModele=afficheN&cpsidt=17008604 High citrate diet delays progression of renal insufficiency in the ClC-5 knockout mouse model of Dent's disease]</ref>
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| ==Resources== | | ==Resources== |
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| * [http://jasn.asnjournals.org/cgi/content/full/16/3/729#R5 Genetic Hypercalciuria] | | * [http://jasn.asnjournals.org/cgi/content/full/16/3/729#R5 Genetic Hypercalciuria] |
| * [http://jasn.asnjournals.org/cgi/content/full/13/12/2938 Responsiveness of Hypercalciuria to Thiazide in Dent’s Disease] | | * [http://jasn.asnjournals.org/cgi/content/full/13/12/2938 Responsiveness of Hypercalciuria to Thiazide in Dent’s Disease] |
| * [http://cat.inist.fr/?aModele=afficheN&cpsidt=17008604 High citrate diet delays progression of renal insufficiency in the ClC-5 knockout mouse model of Dent's disease]
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| * [http://www.orpha.net/static/GB/dent_disease.html Dent disease on Orphanet]
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| == References ==
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| {{reflist|2}}
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| {{WH}} | | {{WH}} |