Dent Disease

Clinical characteristics: Dent disease, an X-linked disorder of proximal renal tubular dysfunction, is characterized by low molecular weight (LMW) proteinuria, hypercalciuria, and at least one additional finding including nephrocalcinosis, nephrolithiasis, hematuria, hypophosphatemia, chronic kidney disease (CKD), and evidence of X-linked inheritance. Males younger than age ten years may manifest only LMW proteinuria and/or hypercalciuria, which are usually asymptomatic. Thirty to 80% of affected males develop end-stage renal disease (ESRD) between ages 30 and 50 years; in some instances ESRD does not develop until the sixth decade of life or later. The disease may also be accompanied by rickets or osteomalacia, growth restriction, and short stature. Disease severity can vary within the same family. Males with Dent disease 2 (caused by pathogenic variants in OCRL) may also have mild intellectual disability, cataracts, and/or elevated muscle enzymes. Due to random X-chromosome inactivation, some female carriers may manifest hypercalciuria and, rarely, renal calculi and moderate LMW proteinuria. Females rarely develop CKD.

Diagnosis/testing: The diagnosis is established in a male proband with the 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). Heterozygous females are usually asymptomatic, but some exhibit LMW proteinuria and hypercalciuria, and others with kidney stones have also been described. Heterozygous females are most likely to be identified by familial molecular genetic testing related to a male proband.

Management: Treatment of manifestations: The primary goals of treatment are to decrease hypercalciuria, prevent kidney stones and nephrocalcinosis, and delay the progression of CKD. Interventions aimed at decreasing hypercalciuria and preventing kidney stones and nephrocalcinosis have not been tested in randomized controlled trials. Although thiazide diuretics can decrease urinary calcium excretion in boys with Dent disease, 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 is unclear. Renal replacement therapy is necessary in those with ESRD.

Prevention of secondary complications: Bone disease, when present, responds to vitamin D supplementation and phosphorus repletion. Growth failure may be treated with human growth hormone without adversely affecting kidney function.

Surveillance: Monitor at least annually urinary calcium excretion, renal function (glomerular filtration rate), and the parameters used to stage CKD (i.e., blood pressure, hematocrit/hemoglobin, and serum calcium and phosphorous concentrations). Monitor more frequently when CKD is evident.

Agents/circumstances to avoid: Exposure to potential renal toxins (nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, and intravenous contrast agents).

Evaluation of relatives at risk: Clarify the genetic status of at-risk male relatives either by molecular genetic testing (if the pathogenic variant in the family is known) or by measurement of urinary excretion of low molecular weight proteins (LMWPs).

Genetic counseling: Dent disease is inherited in an X-linked manner. The father of an affected male will not have the disease nor will he be hemizygous for the pathogenic variant. If the mother of the proband has a pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be significantly affected. Affected males pass the pathogenic variant to all of their daughters (who become carriers) and none of their sons. Carrier testing for at-risk female relatives and prenatal and preimplantation genetic testing are possible if the pathogenic variant in the family has been identified.