Dent's disease
Encyclopedia
Dent's disease is a rare X-linked recessive
inherited condition that affects the proximal renal tubules of the kidney
. It is one cause of Fanconi syndrome
, and is characterized by tubular proteinuria
, hypercalciuria
, calcium nephrolithiasis, nephrocalcinosis
and chronic renal failure
.
"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.
associated with renal tubular damage characterized by hypercalciuria
, hyperphosphaturia, proteinuria
, and aminoaciduria
. This is a genetic disorder caused by the genetic mutations in the renal chloride channel
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.
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, 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.
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.
Dent's disease may also be associated with:
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.
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 expressed in males and in females who are homozygous for the gene mutation X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on...
inherited condition that affects the proximal renal tubules of the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
. It is one cause of Fanconi syndrome
Fanconi syndrome
Falconi syndrome is a disease of the proximal renal tubules of the kidney in which glucose, amino acids, uric acid, phosphate and bicarbonate are passed into the urine, instead of being reabsorbed. Fanconi syndrome affects the proximal tubule, which is the first part of the tubule to process fluid...
, and is characterized by tubular proteinuria
Tubular proteinuria
Low molecular weight proteins are normally filtered at the glomerulus and are normally reabsorbed by tubular cells, so that less than 150 mg per day should appear in the urine. Low molecular weight proteins appearing in larger quantities than this is tubular proteinurea and this points to...
, hypercalciuria
Hypercalciuria
Hypercalciuria or hypercalcinuria is the condition of elevated calcium in the urine. Chronic hypercalcinuria may lead to impairment of renal function, nephrocalcinosis, and renal insufficiency....
, calcium nephrolithiasis, nephrocalcinosis
Nephrocalcinosis
Nephrocalcinosis, once known as Albright's calcinosis after Fuller Albright, is a term originally used to describe deposition of calcium salts in the renal parenchyma due to hyperparathyroidism. It is now more commonly used to describe diffuse, fine, renal parenchymal calcification on radiology...
and chronic renal failure
Chronic renal failure
Chronic kidney disease , also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite...
.
"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.
History
Dent's disease was first described by Dent, C. E. and Friedman, M in 1964 when they reported 2 unrelated British boys with ricketsRickets
Rickets is a softening of bones in children due to deficiency or impaired metabolism of vitamin D, magnesium , phosphorus or calcium, potentially leading to fractures and deformity. Rickets is among the most frequent childhood diseases in many developing countries...
associated with renal tubular damage characterized by hypercalciuria
Hypercalciuria
Hypercalciuria or hypercalcinuria is the condition of elevated calcium in the urine. Chronic hypercalcinuria may lead to impairment of renal function, nephrocalcinosis, and renal insufficiency....
, hyperphosphaturia, proteinuria
Proteinuria
Proteinuria means the presence of anexcess of serum proteins in the urine. The protein in the urine often causes the urine to become foamy, although foamy urine may also be caused by bilirubin in the urine , retrograde ejaculation, pneumaturia due to a fistula, or drugs such as pyridium.- Causes...
, and aminoaciduria
Aminoaciduria
Aminoaciduria is the presence of amino acids in the urine. Small amounts of amino acids are also present in normal urine. Increased total urine amino acids may result from metabolic disorders, chronic liver disease or renal disorders. Aminoacidurias can be divided into primary and secondary...
. This is a genetic disorder caused by the genetic mutations in the renal chloride channel
Chloride channel
Chloride channels are a superfamily of poorly understood ion channels consisting of approximately 13 members.Chloride channels display a variety of important physiological and cellular roles that include regulation of pH, volume homeostasis, organic solute transport, cell migration, cell...
CLCN5
CLCN5
H/Cl exchange transporter 5 is a protein that in humans is encoded by the CLCN5 gene.- External links :...
which encodes a kidney-specific voltage gated chloride channel
Chloride channel
Chloride channels are a superfamily of poorly understood ion channels consisting of approximately 13 members.Chloride channels display a variety of important physiological and cellular roles that include regulation of pH, volume homeostasis, organic solute transport, cell migration, cell...
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
Idiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...
hypercalciuria
Hypercalciuria
Hypercalciuria or hypercalcinuria is the condition of elevated calcium in the urine. Chronic hypercalcinuria may lead to impairment of renal function, nephrocalcinosis, and renal insufficiency....
(IH), i.e. excess calcium in urine with undetermined causes.
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 renal failure in more severe cases.In humans, gene CLCN5
CLCN5
H/Cl exchange transporter 5 is a protein that in humans is encoded by the CLCN5 gene.- External links :...
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, 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.
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.
Symptoms
Dent's disease often produces symptoms of:- Extreme thirst combined with dehydrationDehydrationIn physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...
which leads to frequent urination - Nephrolithiasis (kidney stones)
- HypercalciuriaHypercalciuriaHypercalciuria or hypercalcinuria is the condition of elevated calcium in the urine. Chronic hypercalcinuria may lead to impairment of renal function, nephrocalcinosis, and renal insufficiency....
(high urine calcium - >300 mg/d or >4 mg/kg per d) with normal levels blood/serum calcium)
Dent's disease may also be associated with:
- AminoaciduriaAminoaciduriaAminoaciduria is the presence of amino acids in the urine. Small amounts of amino acids are also present in normal urine. Increased total urine amino acids may result from metabolic disorders, chronic liver disease or renal disorders. Aminoacidurias can be divided into primary and secondary...
(amino acids in urine) - Phosphaturia (phosphate in urine)
- GlycosuriaGlycosuriaGlycosuria or glucosuria is the excretion of glucose into the urine. Ordinarily, urine contains no glucose because the kidneys are able to reclaim all of the filtered glucose back into the bloodstream. Glycosuria is nearly always caused by elevated blood glucose levels, most commonly due to...
(glucose in urine) - KaliuresisKaliuresisKaliuresis is the process of excreting potassium in the urine.Thiazide diuretics are used to treat patients with heart failure. Their goal is to decrease the amount of salt in the body by decreasing the amount that the kidney reabsorbs...
(potassium in urine) - HyperuricosuriaHyperuricosuriaHyperuricosuria is a medical term referring to the presence of excessive amounts of uric acid in the urine. Notable direct causes of hyperuricosuria are dissolution of uric acid crystals in the kidneys or urinary bladder, and hyperuricemia...
(excessive amounts of uric acid in the urine.) - Impaired urinary acidification
- RicketsRicketsRickets is a softening of bones in children due to deficiency or impaired metabolism of vitamin D, magnesium , phosphorus or calcium, potentially leading to fractures and deformity. Rickets is among the most frequent childhood diseases in many developing countries...
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.
Treatment
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:- ThiazideThiazideThiazide is a term used to describe a type of molecule and a class of diuretics often used to treat hypertension and edema ....
diuretics (i.e. HydrochlorothiazideHydrochlorothiazideHydrochlorothiazide, abbreviated HCTZ, HCT, or HZT, is a first-line diuretic drug of the thiazide class that acts by inhibiting the kidneys' ability to retain water. This reduces the volume of the blood, decreasing blood return to the heart and thus cardiac output and, by other mechanisms, is...
) which have been used with success in reducing the calcium output in urine, but they are also known to cause hypokalemiaHypokalemiaHypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...
.- In rats with diabetes insipidusDiabetes insipidusDiabetes insipidus is a condition characterized by excessive thirst and excretion of large amounts of severely diluted urine, with reduction of fluid intake having no effect on the concentration of the urine. There are several different types of DI, each with a different cause...
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. The impairment of Na transport in the distal convoluted tubule, induces natriuresisNatriuresisNatriuresis is the process of excretion of sodium in the urine via action of the kidneys. Natriuresis is promoted by Brain and Atrial natriuretic peptides, and it is inhibited by chemicals such as aldosterone...
and water loss while increasing the reabsorption of calcium in this segment in a manner unrelated to sodium transport.
- In rats with diabetes insipidus
- AmilorideAmilorideAmiloride is a potassium-sparing diuretic, first approved for use in 1967 , used in the management of hypertension and congestive heart failure. Amiloride was also tested as treatment of cystic fibrosis, but it was revealed inefficient in vivo due to it's short time of action, therefore...
which 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, 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)."
- For patients with osteomalaciaOsteomalaciaOsteomalacia is the softening of the bones caused by defective bone mineralization secondary to inadequate amounts of available phosphorus and calcium, or because of overactive resorption of calcium from the bone as a result of hyperparathyroidism...
, Vitamin DVitamin DVitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....
or derivatives have been employed, apparently with success. - Some lab tests on mice with CLC-5 related tubular damage showed that a high citrateCitrateA citrate can refer either to the conjugate base of citric acid, , or to the esters of citric acid. An example of the former, a salt is trisodium citrate; an ester is triethyl citrate.-Other citric acid ions:...
diet preserved renal function and delayed progress of renal disease.