Dent disease

The specific symptoms and severity of Dent disease can vary greatly, even among members of the same family.^[3] Signs of Dent disease usually appear in childhood and worsen over time. Common signs of Dent disease include:

• a large amount of protein in the urine (proteinuria)
• excess calcium in the urine (hypercalciuria)
• calcium deposits in the kidneys (nephrocalcinosis)
• kidney stones which may cause abdominal pain and blood in the urine (hematuria)

Less commonly, people with Dent disease develop rickets, a bone disorder due to low levels of vitamin D and certain minerals in the blood. Rickets can be associated with weakening of the bones, bone pain, bowed legs, and difficulty walking.^[1]

Most affected males experience progressive kidney problems that lead to end-stage renal disease (kidney failure) in early to mid-adulthood.

Some people with Dent disease have features that affect other organ systems, such as mild intellectual impairment, weak muscle tone (hypotonia) and cataracts. The occurrence of these features, when caused by a mutation in the OCRL gene, is referred to as Dent disease type 2.^[4]

Mutations in the CLCN5 gene cause Dent disease type 1 (60% of cases), and mutations in the OCRL gene cause Dent disease type 2 (15% of cases). In the remaining 25% of cases, the genetic cause is unknown.

The CLCN5 and OCRL genes give the body instructions to make proteins needed for normal kidney function - particularly the function of the proximal tubules. The proximal tubules help to reabsorb nutrients, water, and other substances that have been filtered from the bloodstream. Studies suggest that mutations in these genes impair the ability of the proximal tubules to reabsorb, leading to the kidney problems in people with Dent disease.^[1]

The inheritance of Dent disease is X-linked recessive.^[1] X-linked recessive conditions usually occur in males, who only have one X chromosome (and one Y chromosome). Females have two X chromosomes, so if they have a gene mutation on one of them, they still have a normal copy on their other X chromosome. For this reason, females are typically unaffected. A female with one mutated gene responsible for an X-linked recessive condition is referred to as a carrier. While females can have an X-linked recessive condition, it is very rare.

If a mother is a carrier of an X-linked recessive condition and the father is not, the risk to children depends on each child's sex.

• Each male child has a 50% chance to be unaffected, and a 50% chance to be affected
• Each daughter has a 50% chance to be unaffected, and a 50% chance to be an unaffected carrier

If a father has the condition and the mother is not a carrier, all sons will be unaffected, and all daughters will be carriers.

Due to random X-chromosome inactivation, some female carriers may have hypercalciuria (and rarely renal calculi and moderate LMW proteinuria). Females rarely, if ever, develop chronic kidney disease.^[2]

A diagnosis of Dent disease is suspected in people with the following 3 criteria, when there is no other known cause of proximal tubule dysfunction:

• Low molecular-weight (LMW) proteinuria at least five times above the upper limit of normal (the pathognomonic finding of Dent disease) - no known cases of Dent disease have been missed using this screening
• Hypercalciuria (excessive calcium in the urine)
• At least one of the following:
  • nephrocalcinosis
  • kidney stones
  • hematuria (blood in the urine)
  • hypophosphatemia (low phosphorus in the blood)
  • chronic kidney disease
  • family history consistent with X-linked inheritance

A possible diagnosis of Dent disease is considered if LMW proteinuria and at least one other finding are present.

In 75% of males with the above criteria, genetic testing confirms the diagnosis by finding a mutation in the CLCN5 (Dent disease 1) or OCRL (Dent disease 2) gene. About 25% of people with a clinical diagnosis of Dent disease do not have a mutation in either of these genes, suggesting that other, yet unidentified genes may also cause the condition.^[2]

No standard guidelines have been established for the treatment of Dent disease. The main goals of treatment are to decrease hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of chronic kidney disease (CKD).

Thiazide diuretics in doses greater than 0.4 mg/kg/day have decreased urinary calcium excretion by more than 40% in boys with Dent disease. However, frequent side effects included hypokalemia, volume depletion, and cramping. Careful dosing and close monitoring for these side effects are necessary.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been used in children with proteinuria to prevent or delay further loss of kidney function. However, their effectiveness has not been clear.

Although a high citrate diet has been used in the treatment of Dent disease (aiming to slow progression of CKD), no human trials have proven its effectiveness.

If males with Dent disease progress to end-stage renal disease (kidney failure), renal replacement therapy becomes necessary. Hemodialysis, peritoneal dialysis, and renal transplantation are appropriate options. Because Dent disease features are largely localized in the kidney, the disease will not recur.^[2]