An Overview Of Dent's Disease

Dent's disease is a condition that most commonly affects the kidneys. It is typically characterized by hypercalciuria, proteinuria, and hematuria. 

Dent's disease is hereditary, meaning it is passed down from your parents; however, the responsible gene or mutation has yet to be elucidated in about 25% of those with Dent's disease.¹

Further signs and symptoms of Dent's disease are rickets/osteomalacia, kidney stones, kidney damage, or Fanconi syndrome. However, hemizygous females usually only have proteinuria and mild hypercalciuria.

What is Dent's disease?

This rare genetic kidney disease causes protein spillage in urine, kidney calcification, recurrent kidney stones, and chronic kidney failure. It affects almost exclusively males as it is X-linked recessive.

The disorder may sometimes progress into chronic kidney disease long after symptoms first appear during childhood. Affected individuals may also suffer from mild or moderate disease into old age. A person with kidney disease can eventually lose the function of their kidneys, which may occur by late childhood.

Subdivisions of Dent's disease

Dent’s disease is classified into two different types — type 1 and type 2. 

Dent’s disease type 1 results from mutations to the CLCN5 gene. OCRL1 gene causes type 2 of this condition. 

Conditions like rickets (softening and weakening of bones in children) and less-than-normal height can also be associated with Dent's disease. However, it is important to note that most people with Dent's disease do not have bone disease and have achieved a normal height.

Other names for Dent's disease

Dent's disease was first mentioned in 1964 by Dr. Charles Dent and Dr. M. Friedman, who reported kidney complications seen in two unrelated British boys. A full description of the disease wasn't created until the 1994 publication by Oliver Wrong et al., naming it Dent's disease. 

Dent's disease has been referred to by other names. These include:

• Dent syndrome

• Dent disease

• Low-molecular-weight proteinuria with hypercalciuria and nephrocalcinosis

• Renal Fanconi syndrome with nephrocalcinosis and renal stones

• X-linked recessive hypercalciuric hypophosphatemic rickets

• X-linked recessive nephrolithiasis

Signs and symptoms

The most frequent sign of Dent's disease is the presence of an abnormally large amount of proteins in the urine (tubular proteinuria). 

Other common signs of the disorder include:

• excess calcium in the urine (hypercalciuria)

• calcium deposits in the kidneys (nephrocalcinosis)

• kidney stones (nephrolithiasis)

In most affected males, progressive kidney problems lead to end-stage renal disease (ESRD) in early to mid-adulthood.

Rarely do people with Dent's disease develop rickets, a bone disorder caused by low vitamin D and certain minerals in the blood. 

Dent's disease can be passed on by female carriers of the altered gene. Typically, female carriers don't show any signs or symptoms of the disorder. However, some female carriers may exhibit mild symptoms of Dent's disease, like proteinuria and hypercalciuria. Severe kidney problems, including ESRD, are rare in female carriers of Dent's disease.

Diagnosis

Dent's disease is often underdiagnosed due to its rarity, its similarity to other kidney diseases, and the fact that mild symptoms may be difficult to identify. 

Dent's disease can be diagnosed through genetic testing, which looks for mutations in the CLCN5 or OCRL gene.

Mutations in the CLCN5 gene are responsible for Dent's disease type 1, which accounts for 60% of all cases. Mutations in the OCRL gene are responsible for Dent's disease type 2, which accounts for 15% of all cases. The genetic cause of Dent's disease is unknown in the remaining 25% of cases.²

It's essential to distinguish Dent's disease from other conditions that affect the proximal tubule (a part of the kidney), such as renal Fanconi syndrome and glomerular disease. Donnai-Barrow syndrome is a similar but different disease that also causes distinctive facial features.

Renal replacement therapy may be necessary if males with Dent's disease progress to ESRD. 

Treatment

Finding ways to manage Dent's disease can be challenging, but some interventions can help reduce its symptoms. The primary treatment goals for Dent's disease are to decrease proteinuria and hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of chronic kidney disease (CKD). 

Interventions to decrease hypercalciuria and prevent kidney stones and nephrocalcinosis have not been tested in randomized controlled trials. 

Thiazide diuretics can decrease urinary calcium excretion in boys with Dent's disease, but side effects limit their use. The effectiveness of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in preventing or delaying further loss of kidney function in children with proteinuria are unclear. 

Renal replacement therapy is necessary for those with end-stage renal disease. 

There are no guidelines established for the treatment of Dent's disease. Ultimately, treatment is tailored to an individual’s needs and may involve medications, dietary changes, or renal replacement therapy. The ultimate treatment would be a renal transplant; owing to the disease's genetic nature, this would be considered curative.

Cause

Dent's disease is inherited in an X-linked manner, meaning that the pathogenic variant responsible for the disease is located on the X chromosome.

The father of an affected male cannot be a carrier but can either be sick or healthy. However, this would bear no effect on the male offspring. 

If a mother has the problem gene, there is a 50% chance that she will pass it on to each of her children, regardless of their sex. Males who inherit the gene will have Dent's disease, while females who inherit it will usually just be carriers and not have symptoms.

Males with Dent's disease will pass the gene on to all of their daughters, who will also be carriers, but they will not pass it on to their sons. If someone in a family has Dent's disease, testing other family members to see if they are at risk of passing it on to their children is possible.

Investigational therapies

Dent's disease is an X-linked renal tubular disorder characterized by low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure. 

Studies have shown that a high-citrate diet may be effective in delaying the progression of the disease. The mice model of Dent's disease demonstrated that mice on a high citrate diet had normal renal function compared to those on a zero citrate diet. The latter mice had significantly increased tubular atrophy, interstitial fibrosis, cystic changes, and nephrocalcinosis compared to those on a high citrate diet. ³

High-citrate diet preserved renal function and delayed the progression of renal disease in ClC-5 knockout mice, even in the apparent absence of stone formation. Removing citrate from the diet has been found to accelerate renal insufficiency in ClC-5 knockout mice. Thus, a high citrate diet may be beneficial for preserving renal function and delaying the progression of Dent's disease, although there are no concordant human studies currently.

Pathophysiology

"Pathophysiology" means how a disease changes the body's physical and physiological functions. Dent's disease type 2 is caused by a mutation of the gene called OCRL1, which is supposed to help move proteins in cells. When the gene doesn't work right, it can cause problems like having too much calcium and protein in the urine and forming kidney stones.

Studies have found that Dent's disease is almost exclusively seen in males and has been observed to affect 250 families reported worldwide.⁴

It is clear that it is caused by a mutation in the OCRL1 gene, which decreases the activity of its associated protein and leads to electrolyte imbalances.

Affected populations — prevalence

Males may have manifestations of Dent’s disease from early childhood. LMW proteinuria is found in approximately 99% of affected males and may cause episodic night blindness in extremely rare cases.

Hypercalciuria and nephrocalcinosis are prevalent in 95% and 75% of affected males, respectively. Nephrolithiasis occurs in approximately 50% of affected males and can lead to end-stage renal failure between the 3rd and 5th decades of life in 30–80% of males. 

Females may have milder features of LMW proteinuria and hypercalciuria. Rare nephrolithiasis and end-stage renal failure cases have also been reported. Proteinuria and biopsy-proven focal glomerulosclerosis may occur in rare cases, referred to as Dent's disease.

Genetics

Understanding the genetics behind the condition is essential to developing a personalized treatment plan for those affected by Dent's disease. 

Research into the genetic basis of Dent's disease is ongoing, and recent advances have led to an improved understanding of its causes and potential treatments.

Genetic counseling is often recommended for families with a known or suspected history of Dent's disease. This type of counseling helps individuals understand the genetic implications of their diagnosis and offers insight into potential risks for future generations. Through genetic counseling, individuals can become more informed about their risk for developing Dent's disease and take proactive steps to reduce this risk. 

Management

When it comes to managing Dent's disease, there is, unfortunately, no cure so far. Treatment plans are based on managing the symptoms and preventing any long-term damage to the kidneys. This may include restricting dietary sodium and protein intake, regularly monitoring electrolyte and acid-base levels, and medication to control water and sodium retention. 

Dialysis may be necessary for some individuals in cases of severe renal impairment. Investigational therapies such as high citrate diets may also be used to reduce kidney stone formation. Additionally, people with Dent’s disease should also follow an exercise program and keep up with regular medical appointments to monitor their condition.

The lowdown

Dent's disease is a rare genetic disorder that affects the kidneys and liver. Symptoms include high levels of protein in your urine, low calcium levels in the blood, rickets, failure to thrive, and kidney stones. 

Diagnosis is made through urine and blood tests and imaging scans such as CT or MRI scans. Treatment includes managing symptoms and underlying conditions, medications, and dietary modifications. High citrate intake is also being studied as an investigational therapy. 

Dent's disease affects both adults and children but is more commonly seen in males. The genetics are complex and involve mutations in the CLCN5 gene. Management of this condition consists of regularly monitoring kidney function and treating any other medical conditions present.

Frequently asked questions

How rare is Dent's disease?

Dent's disease is a rare disorder that has been reported to affect about 250 families.⁵

Why does hypercalciuria cause Dent’s disease?

Hypercalciuria is an abnormally high calcium level in the urine associated with Dent's disease. This can occur due to an impaired ability of the kidneys to reabsorb calcium and increased intestinal absorption of calcium.

Is nephrocalcinosis common?

Nephrocalcinosis is a condition where there is an abnormal accumulation of calcium salts in the kidney, and it is usually found in people with Dent's disease. It is not very common, but it is more likely to be seen in those who are severely affected by Dent's disease.