Dent's disease

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.

"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.^[1]

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History

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.^[2] 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.

Genetics

  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.

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.^[3] 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.^[4]

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.^[5]

Symptoms

Dent's disease often produces symptoms of:

• Extreme thirst combined with dehydration which leads to frequent urination
• Nephrolithiasis (kidney stones)
• Hypercalciuria (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:

• Aminoaciduria (amino acids in urine)
• Phosphaturia (phosphate in urine)
• Glycosuria (glucose in urine)
• Kaliuresis (potassium in urine)
• Uricosuria (excessive amounts of uric acid in the urine.)
• Impaired urinary acidification
• Rickets

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.^[6]

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:

• Thiazide diuretics (i.e. Hydrochlorothiazide) which have been used with success in reducing the calcium output in urine, but they are also known to cause hypokalemia.
  • 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.^[7]
• Amiloride 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)."^[8]
• For patients with osteomalacia, Vitamin D or derivatives have been employed, apparently with success.
• 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.^[9]

References