Dent's disease (or Dent disease) is a rare
X-linked recessive ''Main Article'': Sex linkage
X-linked recessive inheritance is a mode of Mendelian inheritance, inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily hemizygous for ...
inherited condition that affects the
proximal renal tubule
The proximal tubule is the segment of the nephron in kidneys which begins from the renal (tubular) pole of the Bowman's capsule to the beginning of loop of Henle. At this location, the glomerular parietal epithelial cells (PECs) lining bowman’s ...
s of the
kidney
In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
. 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 t ...
, and is characterized by
tubular proteinuria,
excess calcium in the urine, formation of calcium
kidney stones
Kidney stone disease (known as nephrolithiasis, renal calculus disease, or urolithiasis) is a crystallopathy and occurs when there are too many minerals in the urine and not enough liquid or hydration. This imbalance causes tiny pieces of cr ...
,
nephrocalcinosis
Nephrocalcinosis, once known as Albright's calcinosis after Fuller Albright, is a term originally used to describe the deposition of poorly soluble calcium salts in the renal parenchyma due to hyperparathyroidism. The term nephrocalcinosis is u ...
, and
chronic kidney failure
Chronic kidney disease (CKD) is a type of long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three mo ...
.
"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, scientific nomenclature: rachitis (from Greek , meaning 'in or of the spine'), is a condition that results in weak or soft bones in children and may have either dietary deficiency or genetic causes. Symptoms include bowed legs, stun ...
, and both Japanese and idiopathic low-molecular-weight proteinuria. About 60% of patients have mutations in the ''
CLCN5
The H+/Cl- exchange transporter 5 is a protein that in humans is encoded by the ''CLCN5'' gene.
The chloride channel Cl-/H+ exchanger is mainly expressed in the kidney, in particular in proximal tubules where it participates to the uptake of alb ...
'' 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 that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...
, which leads to
frequent urination
Frequent urination, or urinary frequency (sometimes called pollakiuria), is the need to urinate more often than usual. Diuretics are medications that increase urinary frequency. Nocturia is the need of frequent urination at night. The most common ...
*
Nephrolithiasis
Kidney stone disease (known as nephrolithiasis, renal calculus disease, or urolithiasis) is a crystallopathy and occurs when there are too many minerals in the urine and not enough liquid or hydration. This imbalance causes tiny pieces of cr ...
(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 excrete higher levels ...
(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 over 500 amino acids exist in nature, by far the most important are the Proteinogenic amino acid, 22 α-amino acids incorporated into p ...
in urine)
*
Phosphaturia
Urine electrolyte levels can be measured in a medical laboratory for diagnostic purposes. The urine concentrations of sodium, chlorine and potassium may be used to investigate conditions such as abnormal blood electrolyte levels, acute kidney inj ...
(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 cause ...
(glucose in urine)
*
Kaliuresis
Kaliuresis () or kaluresis () is the condition 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 (sodium chloride) in the body by decreasing the amou ...
(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 disso ...
(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 long-term kidney disease, defined by the sustained presence of abnormal kidney function and/or abnormal kidney structure. To meet criteria for CKD, the abnormalities must be present for at least three m ...
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
The H+/Cl- exchange transporter 5 is a protein that in humans is encoded by the ''CLCN5'' gene.
The chloride channel Cl-/H+ exchanger is mainly expressed in the kidney, in particular in proximal tubules where it participates to the uptake of alb ...
'' 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
Oculocerebrorenal syndrome (also called Lowe syndrome) is a rare X-linked recessive disorder characterized by congenital cataracts, hypotonia, intellectual disability, proximal tubular acidosis, aminoaciduria and low-molecular-weight proteinuria. ...
) and Dent disease can be caused by truncating or missense mutations in ''OCRL''.
Diagnosis
Diagnosis is based on genetic study of ''CLCN5'' 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 in ...
(i.e.
hydrochlorothiazide
Hydrochlorothiazide, sold under the brand name Hydrodiuril among others, is a diuretic medication used to treat hypertension and swelling due to fluid build-up. Other uses include treating diabetes insipidus and renal tubular acidosis and t ...
) 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 a ...
.
** In rats with
diabetes insipidus
Diabetes insipidus (DI) is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced can be nearly 20 liters per day. Reduction of fluid has little effect on the concentration of the urine. ...
, 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
Natriuresis is the process of sodium excretion in the urine through the action of the kidneys. It is promoted by Brain natriuretic peptide, ventricular and atrial natriuretic peptides as well as calcitonin, and inhibited by chemicals such as aldost ...
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-spar ...
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 b ...
,
vitamin D
Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, along with numerous other biological functions. In humans, the most important compo ...
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 formula . It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry
Biochemistry, or biological chemistry, is the study of chemical processes within and relati ...
diet preserved kidney function and delayed progress of kidney disease.
History
Dent's disease was first described by
Charles Enrique Dent and M. Friedman in 1964, when they reported two unrelated British boys with
rickets
Rickets, scientific nomenclature: rachitis (from Greek , meaning 'in or of the spine'), is a condition that results in weak or soft bones in children and may have either dietary deficiency or genetic causes. Symptoms include bowed legs, stun ...
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 excrete higher levels ...
,
hyperphosphaturia
Hypophosphatemia is an electrolyte disorder in which there is a low level of phosphate in the blood. Symptoms may include weakness, trouble breathing, and loss of appetite. Complications may include seizures, coma, rhabdomyolysis, or softeni ...
,
proteinuria
Proteinuria is the presence of excess proteins in the urine. In healthy persons, urine contains very little protein, less than 150 mg/day; an excess is suggestive of illness. Excess protein in the urine often causes the urine to become fo ...
, 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 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, mitosi ...
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.
For some medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause ...
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 excrete higher levels ...
, 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
Diseases named after discoverers