Dent’s Disease

Dent’s disease is a rare genetic kidney disorder that primarily affects males, causing proteins and calcium to leak into the urine, leading to kidney stones and, in many cases, progressive kidney damage that can result in kidney failure in adulthood.

Table of contents

• What is Dent’s disease?
• Who is affected by Dent’s disease?
• Types of Dent’s disease
• What causes Dent’s disease?
• Signs and symptoms
• How is Dent’s disease diagnosed?
• Treatment and management
• What to expect

What is Dent’s disease?

Dent’s disease is a rare genetic kidney disorder that leads to the development of kidney stones and often results in kidney failure^[1]. The condition occurs almost exclusively in males because of how it is inherited. Symptoms usually appear in childhood, though they can sometimes go unnoticed until adulthood^[3].

The main feature of the disease is the presence of small protein molecules in the urine, combined with increased excretion of calcium. This happens because of damage to structures in the kidneys called proximal tubules, which are tiny tubes that help the kidneys reabsorb important substances the body needs^[1]. When these tubules don’t work properly, valuable materials leak out into the urine instead of being returned to the bloodstream.

Each kidney contains about one million tiny filtering units called nephrons. Each nephron consists of a filter (called a glomerulus) and a tube (called a tubulus). The glomerulus filters blood to create primary urine, while the tubules recycle substances that are valuable to the body, such as water, minerals like calcium and phosphate, and proteins^[3].

The disease is likely underdiagnosed because it may not be identified in people with mild signs and symptoms, and because its features overlap with those of other kidney disorders^[1]. About 250 affected families have been reported worldwide^[1].

Who is affected by Dent’s disease?

Dent’s disease is inherited in an X-linked recessive pattern, which means the genes responsible for the condition are located on the X chromosome, one of the two sex chromosomes^[1]. This inheritance pattern explains why the disease primarily affects males.

Males have only one X chromosome. If that chromosome carries a mutation in one of the genes that causes Dent’s disease, they will develop the condition. In contrast, females have two X chromosomes. Because it is unlikely that both of their X chromosomes would carry the mutation, females are rarely affected by the full disease^[1].

In most cases, male children inherit the disorder from a carrier mother who has extremely mild symptoms of the disease, if any at all^[7]. When a mother is a known carrier of the CLCN5 or OCRL1 mutation, there is a 50 percent chance of passing that mutation on to her children of either gender. Males who inherit the mutation will have the disorder and will pass it to their daughters, but not their sons. Females who inherit the mutation will be carriers and could pass it on to either their sons or daughters^[7].

Due to random X-chromosome inactivation, some female carriers may show symptoms such as increased calcium in the urine and, rarely, kidney stones and moderate amounts of protein in the urine. However, females rarely develop chronic kidney disease^[2].

Types of Dent’s disease

Researchers have identified two main forms of Dent’s disease, which are distinguished by their genetic cause and pattern of signs and symptoms^[1].

Dent disease type 1 is caused by mutations in the CLCN5 gene and accounts for about 60 percent of all cases of Dent’s disease^[1]. This form is more common than Dent disease type 2.

Dent disease type 2 is caused by mutations in the OCRL gene (also called OCRL1) and accounts for about 15 percent of all cases^[1]. In addition to kidney problems, individuals with Dent disease type 2 may have additional symptoms, including mild intellectual disability, eye involvement such as clouding of the lens (cataracts), or diminished muscle tone (hypotonia)^[7]. The cataracts are often described as subclinical because they do not impair vision^[1]. Some researchers consider Dent disease type 2 to be a mild variant of a similar disorder called Lowe syndrome^[1].

In the remaining 25 percent of cases, the genetic cause of the disorder is unknown, suggesting that additional subtypes of Dent’s disease may exist^[7].

What causes Dent’s disease?

Dent’s disease is a genetic disorder caused by mutations in either the CLCN5 gene or the OCRL gene^[1]. Both genes are located on the X chromosome.

The CLCN5 gene encodes a protein called ClC-5, which belongs to a family of chloride channels and transporters. This protein acts as an electrogenic chloride/proton exchanger and plays a critical role in normal kidney function, particularly in the proximal tubules^[5]. These structures help reabsorb nutrients, water, and other materials that have been filtered from the bloodstream.

The OCRL gene encodes a specific enzyme called a phosphatidylinositol bisphosphate 5-phosphatase. This enzyme is also necessary for the proper reabsorption of low-molecular proteins and minerals such as potassium, phosphate, calcium, and bicarbonate in the proximal tubules^[3].

Studies suggest that mutations in either the CLCN5 or OCRL gene disrupt the reabsorption function of the proximal tubules, which leads to the progressive kidney problems found in people with Dent’s disease^[1]. When these genes don’t work properly, important substances leak out into the urine instead of being returned to the body.

Because the OCRL gene is active throughout the body, it is unclear why Dent disease 2 primarily affects the kidneys and, to a lesser extent, the brain, eyes, and other tissues^[1].

Signs and symptoms

The disease generally occurs only in males, and symptoms often develop gradually in childhood or early adulthood^[6]. Some patients are only mildly affected, while others experience more severe complications. The disease is very variable, even within the same family^[2].

Early signs

The most frequent sign of Dent’s disease is the presence of an abnormally large amount of proteins in the urine, specifically low-molecular-weight proteinuria^[1]. This is the characteristic finding in 100 percent of all patients with Dent’s disease and is not always detected in routine medical testing^[7]. Males younger than age ten years may show only this protein leakage and increased calcium in the urine, which are usually asymptomatic^[2].

Other common early signs include excess calcium in the urine (hypercalciuria), which is present in more than 95 percent of cases^[5]. In some patients, the condition is discovered accidentally when a routine test unexpectedly finds protein in the urine, or when an ultrasound scan happens to find calcium deposits in the kidneys^[6].

Kidney stones and calcium deposits

Many individuals develop kidney stones (nephrolithiasis) or calcium deposits in the kidneys (nephrocalcinosis)^[1]. Kidney stones occur in 20 to 30 percent of patients, while nephrocalcinosis occurs in 10 to 20 percent^[5]. Even if a patient doesn’t develop kidney stones, there is always an excess of calcium in the urine, and calcium gets deposited in the kidney^[6].

Kidney stones can cause abdominal pain if they cause a blockage to the flow of urine in the urinary system. This type of pain, known as renal colic, is felt in the back and sides and can move down into the groin. Typically the pain comes in waves, building up over several minutes and then settling down in a repeating cycle^[6]. Kidney stones can also cause blood in the urine (hematuria)^[1].

Patients with excess calcium in the urine may also have increased urine volume and extreme thirst combined with dehydration, which leads to frequent urination^[6].

Bone problems

Some people with Dent’s disease develop rickets, a bone disorder that results when the levels of vitamin D and certain minerals (including calcium) in the blood become too low^[1]. Rickets can be associated with weakening and softening of the bones, bone pain, bowed legs, and difficulty walking.

In some young boys, rickets can be severe, and the bones can become painful. If so, walking may be delayed. A small child may stop using a limb, appear to have muscle weakness, or cry on being picked up^[6]. Sometimes rickets is mild and only discovered on X-rays^[6].

Kidney failure

In most affected males, progressive kidney problems lead to end-stage renal disease (ESRD) in early to mid-adulthood^[1]. ESRD is a life-threatening failure of kidney function that occurs when the kidneys are no longer able to filter fluids and waste products from the body effectively. Thirty to 80 percent of affected males develop ESRD between ages 30 and 50 years, though in some instances ESRD does not develop until the sixth decade of life or later^[2].

Some patients maintain normal kidney function throughout life. However, severely affected patients may have deteriorating kidney function, which is made worse if they get stones that cause blockages to the urinary system^[6].

Additional symptoms in Dent disease type 2

Males with Dent disease type 2 may also have mild intellectual disability, cataracts, and elevated muscle enzymes^[2]. Nearly all patients have creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) levels above the normal range^[13]. Some individuals with Dent disease type 2 may also have hypotonia (decreased muscle tone)^[7].

How is Dent’s disease diagnosed?

A diagnosis may be suspected in individuals who present with three of the following: high levels of low-molecular-weight proteins in the urine, excess levels of calcium in the urine, and one of the following: kidney calcifications, kidney stones, blood in the urine, low phosphates, chronic kidney disease, or evidence of X-linked recessive inheritance^[7].

The diagnosis is based on the presence of all three of the following criteria: low-molecular-weight proteinuria, hypercalciuria, and at least one of the following: nephrocalcinosis, kidney stones, hematuria, hypophosphatemia, or renal insufficiency^[5].

Not only is there too much calcium in the urine, but there is an excess of certain proteins as well. This pattern of proteins can be identified by a laboratory test of a urine sample^[6]. Low molecular-weight proteinuria at least five times above the upper limit of normal is found in 100 percent of cases. No known cases of Dent’s disease have been missed using this screening^[7].

Clinical tests that can be done while awaiting genetic testing include elevated urinary excretion of beta-2 microglobulin or retinol binding protein, and urinalysis assessing for protein and blood^[7].

Molecular genetic testing is generally recommended to confirm the diagnosis, since it is becoming increasingly recognized that other genetic causes of nephrocalcinosis and chronic kidney disease share clinical features with Dent’s disease^[7]. The diagnosis is established in a male with typical clinical findings and a family history consistent with X-linked inheritance who has a pathogenic variant in either CLCN5 (known as Dent disease 1) or in OCRL (known as Dent disease 2)^[2].

Elevated CPK and LDH levels help distinguish Dent disease type 1 from type 2. When present, lens abnormalities and intellectual impairment also favor the diagnosis of Dent disease type 2^[13].

Treatment and management

There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of this disease, no treatment trials have been tested on a large group of patients^[7]. While there is no treatment that corrects the underlying disease process, treatment reduces the symptoms of Dent’s disease and improves quality of life^[6].

Primary treatment goals

The primary goals of treatment are to decrease hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of chronic kidney disease^[2]. Treatment is directed toward the specific symptoms that are apparent in each individual.

Lifestyle changes

In order to preserve kidney function, lifestyle changes can and should include: a low-salt diet, maintaining hydration, taking prescribed medication to help prevent kidney stones, and avoiding medications that can harm the kidneys, such as nonsteroidal anti-inflammatory drugs (NSAIDs) like Advil, Aleve, ibuprofen, or naproxen, and certain antibiotics^[7].

Patients should be cautious of contrast dyes in diagnostic tests such as CT scans, MRIs, and angiograms. It is important to let doctors know about the Dent’s disease diagnosis so they can be sure that the medication or test being prescribed does not have an associated toxic effect on the kidneys^[7].

Medications

Thiazide diuretics (water pills) have been used with success in reducing the calcium output in urine, though side effects limit their use^[2]. A diuretic called thiazide may be prescribed to help reduce the loss of calcium in the urine^[6].

The effectiveness of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in preventing or delaying further loss of kidney function in children with proteinuria is unclear^[2].

Treatment of bone disease

Rickets needs to be prevented or actively treated with dietary supplements such as vitamin D^[6]. Bone disease, when present, responds to vitamin D supplementation and phosphorus repletion^[2]. Substances lost in the urine, such as phosphate, bicarbonate, or citrate, may need to be supplemented^[6].

Growth problems

Growth failure may be treated with human growth hormone without adversely affecting kidney function^[2].

Kidney stones

Kidney stones may need surgical removal. If so, patients are best served by a multidisciplinary team involving expertise in radiology, urology, and nephrology^[6].

End-stage kidney disease

Renal replacement therapy is necessary in those with end-stage renal disease^[2]. In some cases, dialysis or a transplant may be needed^[7].

What to expect

The vital prognosis is good in the majority of patients. However, progression to end-stage renal failure occurs between the third and fifth decades of life in 30 to 80 percent of affected males^[5]. A few patients will require renal replacement therapy in the form of dialysis or a kidney transplant, though it is very rare for this to happen in childhood^[6].

The disease is very variable. Some patients are only mildly affected and may maintain normal kidney function throughout life^[6]. Disease severity can vary within the same family^[2]. Renal failure usually does not occur until 30 to 50 years of age and may not occur at all in some individuals^[7].

Patients need to be monitored at least annually for urinary calcium excretion, proteinuria, renal ultrasound examinations, and measurement of blood pressure and kidney function^[2].

• Kidneys
• Proximal tubules