Dent's disease (or Dent disease) is a rare

X-linked recessive X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...

inherited condition that affects the proximal renal tubules of the

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...

. It is one cause of

Fanconi syndrome Fanconi syndrome or Fanconi's syndrome (, ) is a syndrome of inadequate reabsorption in the proximal renal tubules of the kidney. The syndrome can be caused by various underlying congenital or acquired diseases, by toxicity (for example, from tox ...

, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium

kidney stones Kidney stone disease, also known as nephrolithiasis or urolithiasis, is a crystallopathy where a calculus (medicine), solid piece of material (kidney stone) develops in the urinary tract. Kidney stones typically form in the kidney and leave the ...

, nephrocalcinosis, and

chronic kidney failure Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, v ...

. "Dent's disease" is often used to describe an entire group of familial disorders, including X-linked recessive nephrolithiasis with kidney failure, X-linked recessive hypophosphatemic

rickets Rickets is a condition that results in weak or soft bones in children, and is caused by either dietary deficiency or genetic causes. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications ma ...

, and both Japanese and idiopathic low-molecular-weight proteinuria. About 60% of patients have mutations in the '' CLCN5'' gene (Dent 1), which encodes a kidney-specific chloride/proton antiporter, and 15% of patients have mutations in the '' OCRL1'' gene (Dent 2).

Signs and symptoms

Dent's disease often produces the following signs and symptoms: * Extreme thirst combined with

dehydration In physiology, dehydration is a lack of total body water, with an accompanying disruption of metabolic processes. It occurs when free water loss exceeds free water intake, usually due to exercise, disease, or high environmental temperature. Mil ...

, which leads to frequent urination * Nephrolithiasis (kidney stones) *

Hypercalciuria Hypercalciuria is the condition of elevated calcium in the urine. Chronic hypercalciuria may lead to impairment of renal function, nephrocalcinosis, and chronic kidney disease. Patients with hypercalciuria have kidneys that put out higher levels o ...

(high urine calcium - >300 mg/d or >4 mg/kg per d with normal levels blood/serum calcium) *

Aminoaciduria Aminoaciduria occurs when the urine contains abnormally high amounts of amino acids. In the healthy kidney, the glomeruli filter all amino acids out of the blood, and the renal tubules then reabsorb over 95% of the filtered amino acids back into ...

(

amino acids Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...

in urine) * Phosphaturia (phosphate in urine) *

Glycosuria Glycosuria is the excretion of glucose into the urine. Ordinarily, urine contains no glucose because the kidneys are able to reabsorb all of the filtered glucose from the tubular fluid back into the bloodstream. Glycosuria is nearly always caused ...

(glucose in urine) * Kaliuresis (potassium in urine) *

Hyperuricosuria Hyperuricosuria is a medical term referring to the presence of excessive amounts of uric acid in the urine. For men this is at a rate greater than 800 mg/day, and for women, 750 mg/day. Notable direct causes of hyperuricosuria are dissol ...

(excessive amounts of uric acid in the urine) * Impaired urinary acidification * Rickets In a study of 25 patients with Dent's disease, 9 of 15 men, and one of 10 women had

end-stage kidney disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...

by the age of 47.

Genetics

Dent disease 1

Dent's disease is a X-linked recessive disorder. The males are prone to manifesting symptoms in early adulthood with symptoms of calculi, rickets or even with kidney failure in more severe cases. 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. ''CLCN5'' belongs to the family of voltage-gated chloride channel genes (''CLCN1-CLCN7'', ''CLCKa'' and ''CLCKb'') that have about 12 transmembrane domains. These chloride channels have an important role in the control of membrane excitability, transepithelial transport, and possibly cell volume. 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.

Dent disease 2

Dent disease 2 (nephrolithiasis type 2) is associated with the '' OCRL'' gene. Both Lowe syndrome ( oculocerebrorenal syndrome) and Dent disease can be caused by truncating or missense mutations in ''OCRL''.

Diagnosis

Diagnosis is based on genetic study of CNCL5 gene.

Treatment

As of today, no agreed-upon treatment of Dent's disease is known and no therapy has been formally accepted. Most treatment measures are supportive in nature: *

Thiazide Thiazide () refers to both a class of sulfur-containing organic molecules and a class of diuretics based on the chemical structure of benzothiadiazine. The thiazide drug class was discovered and developed at Merck and Co. in the 1950s. The firs ...

diuretics A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics i ...

(i.e.

hydrochlorothiazide Hydrochlorothiazide is a diuretic medication often used to treat high blood pressure and swelling due to fluid build-up. Other uses include treating diabetes insipidus and renal tubular acidosis and to decrease the risk of kidney stones in ...

) have been used with success in reducing the calcium output in urine, but they are also known to cause

hypokalemia Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an abno ...

. ** In rats with

diabetes insipidus Diabetes insipidus (DI), recently renamed to Arginine Vasopressin Deficiency (AVP-D) and Arginine Vasopressin Resistance (AVP-R), is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced ...

, thiazide diuretics inhibit the NaCl cotransporter in the renal distal convoluted tubule, leading indirectly to less water and solutes being delivered to the distal tubule. The impairment of Na transport in the distal convoluted tubule induces natriuresis and water loss, while increasing the reabsorption of calcium in this segment in a manner unrelated to sodium transport. *

Amiloride Amiloride, sold under the trade name Midamor among others, is a medication typically used with other medications to treat high blood pressure or swelling due to heart failure or cirrhosis of the liver. Amiloride is classified as a potassium-spa ...

also increases distal tubular calcium reabsorption and has been used as a therapy for idiopathic hypercalciuria. ** 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, but 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)." * For patients with

osteomalacia Osteomalacia is a disease characterized by the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of bon ...

vitamin D Vitamin D is a group of Lipophilicity, fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group ar ...

or derivatives have been employed, apparently with success. * Some lab tests on mice with CLC-5-related tubular damage showed a high-

citrate Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in the ...

diet preserved kidney function and delayed progress of kidney disease.

History

Dent's disease was first described by

Charles Enrique Dent Charles Enrique Dent, (25 August 1911 – 19 September 1976) was a British professor of human metabolism at University College, London. After studying chemistry at Imperial College London, he gained a PhD for his work on copper phthalocyanin, th ...

and M. Friedman in 1964, when they reported two unrelated British boys with

associated with renal tubular damage characterized by

hypercalciuria Hypercalciuria is the condition of elevated calcium in the urine. Chronic hypercalciuria may lead to impairment of renal function, nephrocalcinosis, and chronic kidney disease. Patients with hypercalciuria have kidneys that put out higher levels o ...

, hyperphosphaturia,

proteinuria Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become foamy (although this symptom ma ...

, and

aminoaciduria Aminoaciduria occurs when the urine contains abnormally high amounts of amino acids. In the healthy kidney, the glomeruli filter all amino acids out of the blood, and the renal tubules then reabsorb over 95% of the filtered amino acids back into ...

. This set of symptoms was not given a name until 30 years later, when the nephrologist

Oliver Wrong Professor Oliver Murray Wrong (7 February 1925 – 24 February 2012) was an eminent academic nephrologist ( kidney specialist) and one of the founders of the speciality in the United Kingdom. From a background as a "salt and water" physician, he ...

more fully described the disease. Wrong had studied with Dent and chose to name the disease after his mentor. Dent's disease is a genetic disorder caused by

mutations In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...

in the gene ''CLCN5'', which encodes a kidney-specific voltage-gated

chloride channel Chloride channels are a superfamily of poorly understood ion channels specific for chloride. These channels may conduct many different ions, but are named for chloride because its concentration ''in vivo'' is much higher than other anions. Several ...

, 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 An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. From Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approximately "a disease of its own kin ...

, i.e., excess calcium in urine with undetermined causes.

References

External links

Genetic Hypercalciuria

{{Channelopathy Channelopathies Kidney diseases Congenital disorders of urinary system Rare diseases