Dent Disease

Dent disease is a rare genetic disease that affects the kidneys of male patients. Typical clinical consequences include:

• high levels of calcium in the urine (hypercalciuria)
• low levels of phosphorous in the blood (hypophosphatemia)
• spillage of small proteins into the urine
• calcification of the kidneys (nephrocalcinosis)
• renal failure and weak bones (osteomalacia)

The clinical course varies greatly between affected persons. Individuals have recently been identified that have a mutation in the gene which causes Lowe Syndrome, but who resemble other Dent patients and lack certain key features of Lowe Syndrome such as dense cataracts and mild cognitive impairment. On the other hand many Lowe Syndrome patients do have kidney defects typical of Dent Disease such as hypercalciuria and proteinuria.

The most common symptoms that patients with Dents disease experience are related to the passage of kidney stones, such as pain or blood in the urine. Some patients develop renal failure, and if so can develop signs and symptoms related to loss of kidney function that include anemia, fatigue, loss of appetite and weight. If patients develop osteomalacia (weak bones) they might experience boney pain.

A physician may suspect Dent Disease by observing a number of clinical markers including but not limited to

• Protein in the urine
• Excessive urinary amino acid excretion
• Excessive urinary calcium excretion
• Reduced levels of parathyroid hormone
• Increased levels of vitamin D
• A presence of calcium oxalate/calcium phosphate kidney stones

A definitive diagnosis can be made by genetic testing of the patient. If the patient's genetic material includes Dent Disease-specific mutations, the diagnosis is confirmed. If you are concerned about Dent Disease, ask your doctor about testing by commercial laboratory or as part of an ongoing research study.

More detailed information regarding the specifics of diagnosis is available in the Disease Information for Physicians section.

Treatment efforts are targeted to reducing kidney scarring and preventing kidney failure associated with Dent Disease. Unfortunately, the mechanisms by which these outcomes occur are poorly understood, and no treatment trials are available to help physicians choose the best therapy. Available recommendations come from those doctors with the most experience caring for these patients. Since we assume that kidney calcification and kidney stones are caused by the high levels of calcium in the urine, treatment typically is targeted at reducing those levels. This is commonly achieved by administering a diuretic to increase renal calcium reabsorption and thereby reduce levels of calcium in the final urine. While these drugs have been shown to reduce levels of calcium in the urine of Dent disease patients, no information is available whether or not this can reduce the number of stones or protect kidney function.

Recently, studies in an animal model have suggested that a high citrate diet may delay the loss of kidney function. However there is no data on the use of citrate-containing medications in human patients with Dent disease.

For Dent disease patients with osteomalacia (weak bones) vitamin D and related compounds have been used, apparently improving bone strength. However, use of vitamin D may also increase levels of calcium in the urine, so its use must be carefully monitored.

Finally, patients that develop renal failure have been given kidney transplants with good success.

Significant advances have been made in the genetic study of Dent Disease. The gene responsible for type-1 Dent Disease (a collection of disease manifestations known as "Dent Disease 1") has been identified. Differences in disease expression between families and individuals within the same family remain poorly understood.

Recently, a second genetic cause for Dent Disease has been discovered. Patients who show no mutations in the CLCN5 gene may instead have mutations in a gene named OCRL1. The product of this gene is very different from the product of the CLCN5 gene, but the disease state caused by dysfunction of each are very similar. Therefore, disease caused by a mutation in the OCRL1 gene is named "Dent Disease 2".

In addition, much has been learned regarding the transporter product of the CLCN5 gene, named the ClC-5 channel, as well as the product of OCRL1 gene expression. However, the mechanism(s) whereby the defective ClC-5 channel activity or defective OCRL1 gene product cause disease is not completely understood, and is a topic of ongoing research. Small differences in the disease state between Dent Disease type 1 and type 2 patients may provide clues to better understanding the unique pathogenesis of each type.

More detailed information regarding Dent Disease research is available in the Disease Information for Physicians section.

Many aspects of Dent Disease are not yet well defined, and there has been little opportunity to critically evaluate treatment interventions. Due to its rarity, physicians will typically have only limited experience with Dent Disease patients over the course of a normal practice. In an effort to unify international research efforts and centralize information, a Dent Disease Registry has been established at the Mayo Clinic. Data collected in this registry will expand clinical and research-based understanding of the disease in a manner that no individual researcher at a single center could accomplish alone. The goal of the registry is to allow the development of consensus, evidence-based guidelines for the diagnosis and management of Dent Disease, and identify patient cohorts for clinical trials. By making this data available to the appropriate clinicians and biomedical researchers, new ideas can be tested and research progress can be made on an accelerated cooperative scale.

To learn more about the Dent Disease registry at the Mayo Clinic, please visit their website or contact study coordinator Julie Olson at (800) 270-4637 or send e-mail to hyperoxaluriacenter[at]mayo.edu.

Currently, no patient support organizations have been formed for Dent disease. However, a small subset of Lowe Syndrome patients have urinary findings similar to Dent Disease, and a Lowe Syndrome Association is quite active."

Lowe Syndrome Association

The Lowe Syndrome Association (LSA) is an international voluntary non-profit organization made up of parents, professionals and friends. The LSA is dedicated to helping children with Lowe syndrome and their families. The primary purposes of the LSA are to provide information, foster communication among families, and encourage and support medical research. Major activities include publishing a newsletter (On the Beam) and an informational booklet (Living with Lowe Syndrome: A guide for Families, Friends and Professionals), sponsoring conferences every two years, and awarding medical research grants. The LSA has a previous history of collaboration with the Primary Hyperoxaluria registry. In 2006 members of the association visited Mayo Clinic to learn first hand processes that were used to establish the Primary Hyperoxaluria Registry. Plans are to adapt these processes for a Lowe’s syndrome registry. Since a subset of patients with OCRL1 mutations have Lowe’s syndrome, while others have Dent disease, it seems likely that underlying pathophysiologic processes may be common for both. Therefore, the LSA enthusiastically supports our Registry. They will promote our Registry via their active web page, newsletter, and annual meetings. As the science evolves, it is possible our efforts may become even more closely aligned.