Dent’s disease is a rare inherited kidney disorder affecting the kidney’s ability to reabsorb substances back into the bloodstream. It is a tubulopathy, involving a defect in the proximal kidney tubules responsible for reabsorbing filtered substances. This condition can lead to kidney problems, potentially progressing to severe kidney dysfunction.
Genetic Basis
Dent’s disease is caused by mutations in specific genes, primarily CLCN5 (Dent disease 1) and OCRL1 (Dent disease 2). These genes are located on the X chromosome, leading to an X-linked inheritance pattern. Males are primarily affected and often experience more severe symptoms due to having only one X chromosome. Females, with two X chromosomes, are often carriers and may show milder symptoms or remain asymptomatic due to X-chromosome inactivation. The CLCN5 gene encodes the chloride/proton antiporter ClC-5, a protein involved in reabsorbing low-molecular-weight proteins in the kidney’s proximal tubules. Mutations in this gene impair endosomal acidification, disrupting tubule function. The OCRL1 gene encodes a phosphatidylinositol bisphosphate 5-phosphatase, a protein also involved in intracellular transport within proximal tubule cells.
Recognizing the Signs
The clinical manifestations of Dent’s disease stem from impaired proximal kidney tubule function. A consistent finding in affected males is low-molecular-weight (LMW) proteinuria, where small proteins appear in the urine. This can occur in infancy. Many individuals also experience hypercalciuria (excessive calcium in the urine), which can lead to kidney stones (nephrolithiasis) and calcium deposits within kidney tissue (nephrocalcinosis).
Other kidney issues may include hematuria (blood in the urine) and hypophosphatemia (low phosphorus in the blood). Progressive kidney problems can lead to chronic kidney disease (CKD) over time. In Dent disease 2, individuals may also present with mild intellectual disability, eye involvement like cataracts, or diminished muscle tone (hypotonia). Bone deformities such as rickets or osteomalacia can also occur due to calcium-phosphate imbalances.
Diagnostic Methods
Diagnosing Dent’s disease involves tests to assess kidney function and identify the genetic cause. Urine tests detect low-molecular-weight proteinuria and measure hypercalciuria. Specific protein measurements, like alpha 1 microglobulin and beta 2-microglobulin, are used. Blood tests evaluate kidney function and check for electrolyte imbalances, such as low phosphate levels.
Imaging studies, such as kidney ultrasounds, detect kidney stones or nephrocalcinosis. Definitive diagnosis often relies on molecular genetic testing for CLCN5 or OCRL1 gene mutations. However, 25% to 35% of patients with clinical signs may not have identified mutations in these two genes, suggesting other genetic variants. A diagnosis is clinically suspected with low-molecular-weight proteinuria, hypercalciuria, and at least one of these additional findings: hematuria, kidney stones, nephrocalcinosis, hypophosphatemia, or chronic kidney disease.
Managing the Condition
Currently, there is no cure for Dent’s disease, so management focuses on slowing its progression and alleviating symptoms. Maintaining adequate hydration is recommended to help prevent kidney stone formation. Medications, such as thiazide diuretics, are commonly used to reduce hypercalciuria by promoting calcium reabsorption in the distal kidney tubules.
Other treatments may include phosphate binders to manage phosphorus levels, especially if hypophosphatemia is present. Vitamin D supplements might also be prescribed to address deficiencies and support bone health, with careful monitoring to avoid exacerbating hypercalciuria. For kidney stones, interventions range from increased fluid intake to medical procedures if issues arise. Regular monitoring of kidney function through blood and urine tests is a standard part of ongoing care to track disease progression.
Outlook and Long-Term Care
The long-term prognosis for individuals with Dent’s disease varies, but it often involves a risk of progressive kidney dysfunction. While some experience mild to moderate disease into adulthood, others may develop chronic kidney disease (CKD). A significant percentage of affected males, ranging from 30% to 80%, may progress to end-stage renal disease (ESRD) between 30 and 50 years of age.
In cases of ESRD, dialysis or kidney transplantation becomes necessary. Kidney transplantation appears to be an effective treatment option, with no documented recurrences of Dent’s disease in transplanted kidneys. Lifelong follow-up with a nephrologist is important for monitoring kidney function, managing symptoms, and adjusting treatments. A multidisciplinary care team can provide comprehensive support, addressing kidney health and any associated symptoms or complications.