Version May 2024
INTRODUCTION — Dent disease is an X-linked recessive disorder of the proximal tubules that is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, kidney stones, kidney failure, and rickets [1,2]. (See 'Molecular genetics' below.)
The following topic review will present the genetics, clinical manifestations, and treatment of Dent disease.
NOMENCLATURE — Although different features of Dent disease predominated early reports [3-6], an accurate description of the phenotype was offered in the report entitled, "Dent's disease: a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive kidney failure, and a marked male predominance" [7].
"Dent disease" is accepted as the encompassing name of this disease, based upon this limited kidney phenotype that includes a partial Fanconi syndrome. The disease is distinguished clinically from the Lowe (also known as oculocerebrorenal) syndrome by the absence of cataracts, mental developmental delay, and renal tubular acidosis [8].
MOLECULAR GENETICS — In 60 percent of cases, Dent disease is due to mutations in the CLCN5 gene that inactivate a voltage-gated chloride transporter, CLC-5, which is expressed in the kidney and is encoded by a gene at Xp11.22 [9]. In another 15 percent of cases, it is associated with mutations in the OCRL1 gene, which is also mutated in the Lowe (oculocerebrorenal) syndrome. Further genetic heterogeneity is assumed to exist since there are patients with the distinctive phenotype of Dent disease who do not have mutations in either of these genes [8].
CLCN5 gene (Dent disease 1) — The defective gene identified in the majority of patients with Dent disease, CLCN5, which encodes the CLC-5 protein, is located on the X chromosome and is a member of the CLC family of chloride transporters [10-12]. Unlike some members of the CLC family that act as chloride channels, CLC-5 functions as a chloride-proton antiporter. CLC-5 is found primarily in the kidneys. Although expression of CLCN5 has been detected in other tissues [13], there are no known extrarenal manifestations. In the kidney, CLC-5 is expressed in subapical endosomes in the proximal tubule, medullary thick ascending limb, and type A intercalated cells of the collecting duct [14]. CLC-5 expression has also been localized to podocytes, where abnormal CLC-5 function might play a role in the development of focal global sclerosis [15,16].
CLCN5 mutations have been reported in over 250 affected families with Dent disease 1 (Dent-1) [17]. From these kindreds [1,18-29], a large number of different mutations in this channel have been identified including nonsense, missense, donor splice, and other mutations that inactivate function of the protein in various ways [9,20,21,24,30]. However, there is no correlation between the nature of the mutation and the presence of particular clinical features or the overall severity of the disease [1].
OCRL1 gene (Dent disease 2) — Although most patients with Dent disease have a mutation in the CLCN5 gene, mutations in the OCRL1 gene occur in another 15 percent of affected patients [8,31]. This gene is also located on the X chromosome and encodes a phosphatidylinositol 4,5-bisphosphate 5-phosphatase. Patients with Dent disease who have mutations in the OCRL1 gene have been designated as having Dent disease 2 (Dent-2) [32]. As in Dent-1 disease, deterioration of kidney function does not correlate with the presence of nephrocalcinosis.
The kidney manifestations of Dent-1 and Dent-2 disease are essentially the same although an extensive review of published reports revealed small but statistically significant differences in the prevalence of glycosuria, hypophosphatemia, hypokalemia, nephrocalcinosis, and nephrolithiasis, which are in varying degrees less common in Dent-2, while kidney failure is reportedly more common in Dent-2 than in Dent-1 [33].
Dent disease 2 versus Lowe syndrome — Mutations in OCRL1 present as two different phenotypes: Dent-2 disease and Lowe syndrome. Chronic kidney disease (CKD) is a feature of both, but progression of CKD is faster in Lowe syndrome than in Dent-2 disease. The full Lowe syndrome features a range of mental developmental disorders and ophthalmologic findings, particularly cataracts, as well as renal tubular acidosis. These are generally absent in Dent-2 disease, although individuals with these features in a much milder form than in Lowe syndrome have been reported [27,34].
Phenotypic differences between patients with Lowe syndrome and those with Dent-2 disease may be explained by the nature of the mutations in each. Missense mutations in the phosphatase domain of the OCRL1 sequence occur in both disorders, but there is a distinct demarcation between the two conditions regarding termination (nonsense and frameshift) mutations. In the Lowe syndrome, these occur only in exons 8 through 23, while in Dent-2 disease termination mutations occur in the first seven exons (33,74) [34,35]. There are transcription initiation codons in exon 8, which would allow for transcripts that would still encode the phosphatase domain [34]. Such transcripts have been confirmed to be expressed in tissues of patients with Dent-2 [27,36]. Thus, early termination mutations would still allow expression of these shorter transcripts with phosphatase activity, which could explain the preservation of function in the brain and eye [27,34,36].
Alternatively, it has been speculated that variability of symptom severity or organ involvement could reflect variations in the expression of modifying phosphatase genes [34]. Cultured fibroblasts from patients with Dent-2 disease exhibit defects in actin fiber function that are intermediate between that in fibroblasts from patients with Lowe syndrome and those from normal controls, consistent with the view of Dent-2 disease as a milder phenotype of the Lowe syndrome [37].
No detectable mutation — Approximately 25 percent of patients who meet strict clinical criteria for Dent disease do not have mutations in the coding regions of either CLCN5 or OCRL1. No single gene has been identified to explain this group of patients [33]. A number of candidate genes have been sequenced in such patients, such as the genes encoding the endocytosis facilitator cofilin, the sodium/hydrogen exchanger NHE6, the amino acid transporter collectrin, or the chloride transporter CLC4; however, no mutations in these genes have been found to date. Isolated individuals with a Dent disease phenotype have been reported to have mutations in genes encoding a subunit of the epithelium sodium channel and megalin [33].
PATHOPHYSIOLOGY
Normal physiology — The chloride-proton exchanger CLC-5 is present in the membrane of subapical endosomes in the proximal tubule. Along with a proton-ATPase that is also present in the membrane, CLC-5 facilitates acidification of these endosomes and is functionally coupled to H-ATPase-mediated endosomal acidification, crucial for CLC-5 activation by depolarizing endosomes [38]. An on-and-off "burst" of CLC-5 activity appears critical for preventing chloride exit from endosomes and maintaining electrochemical gradients across the endosomal membrane. As illustrated in the figure, high endosomal chloride concentrations in the nascent endosome drive proton entry and acidification. In the mature endosome expressing the proton-ATPase, CLC-5 provides a route for proton exit from the endosome, thereby dissipating the positive charge generated by the proton pump (figure 1) [39,40]. Specific CLCN5 mutations can alter the effective coupling ratio, cause mistargeting of an otherwise functional protein, or result in a truncated protein that never exits the endoplasmic reticulum [38].
Mechanisms of proteinuria — All disease-causing mutations result in abnormal or absent CLC-5 function in endosomes and appear to explain the low-molecular-weight proteinuria in patients with Dent disease. Low-molecular-weight proteins are filtered freely at the glomerulus, adsorbed to receptors (including megalin) on the apical surface of the proximal tubular cells, and then endocytosed. Impaired endosomal acidification results in a failure to process adsorbed proteins (figure 1). This may also lead to decreased recycling of the endosomal membrane back to the apical surface. Studies in knockout mice have confirmed the importance of CLC-5 in receptor-mediated endocytosis [41-43].
The CLC-5 protein also interacts directly with components of the actin pathway [44] and with kinesin family member 3B (KIF3B), a protein involved in the translocation of intracellular organelles [45]. Thus, CLC-5 can substantially affect membrane trafficking in the proximal tubule. This is consistent with the observations that urinary megalin is reduced in patients with Dent disease [46] and in CLCN5-knockout mice [41]. Studies confirm apical CLC-5 expression in the proximal tubule of control individuals that is absent in patients with Dent-1 disease [47].
The discovery that mutations in OCRL1 can cause the Dent disease phenotype points to overlap in the physiological functions of the OCRL phosphatase and the CLC-5 protein. The OCRL phosphatase affects endosomal trafficking both through altered cellular levels of PIP2 [48] and through a direct interaction with clathrin, a protein involved in endosomal assembly [49]. One study in OCRL-deficient cultured human kidney cells demonstrated that inhibitors of PI3-kinase rescue the endocytic defect and correct the aberrant actin polymerization [50]. In Ocrl-deficient mice, PI3-kinase inhibitors improved proteinuria and restored cellular levels of megalin [50]. Beyond adding to our understanding regarding the mechanism by which OCRL deficiency leads to proximal tubular dysfunction, these findings raise the exciting possibility of a novel therapy since the PI3K inhibitor alpelisib is already US Food and Drug Administration (FDA) approved as a cancer therapeutic [50].
Mechanisms of hypercalciuria and hyperphosphaturia — Hypercalciuria in patients with Dent disease appears to be caused by hyperabsorption of calcium from the gastrointestinal tract instead of a calcium leak in the kidney. This is supported by the observation that CLCN5 knockout mice develop hypercalciuria that can be eliminated with a low-calcium diet [51,52]. Furthermore, affected patients and mice with partial inhibition of CLC-5 both have an exaggerated calciuretic response to oral calcium loading. Conversely, the hypercalciuria often corrects with dietary calcium restriction (which, however, is not recommended as therapy; see below). This pattern is consistent with a role for calcitriol (1,25-dihydroxyvitamin D) excess in the hypercalciuria. (See 'Treatment' below.)
A small degree of hypercalciuria persists when dietary calcium is severely restricted in CLCN5-knockout mice that also have biochemical evidence of increased bone turnover [53]. In this respect, these growing mice resemble children with Dent disease who have a component of fasting hypercalciuria [52]. However, in children and adults with Dent disease [52], as in the knockout mice [53], the largest component of hypercalciuria is diet dependent.
Studies of knockout mice demonstrate that recycling of phosphate transporters in the proximal tubule, although slowed, is intact. Thus, the hyperphosphaturia and increased 1 alpha-hydroxylation of 25-hydroxyvitamin D in knockout mice and patients with Dent disease cannot be explained by impaired trafficking of phosphate transporters [41].
Instead, hyperphosphaturia and increased 1 alpha-hydroxylation may be due to increased activation of parathyroid hormone (PTH) receptors on the apical membrane of the late proximal tubule by PTH. PTH is a low-molecular-weight protein that is filtered at the glomerulus, and, therefore, diminished low-molecular-weight protein reabsorption due to nonfunctional CLC-5 may lead to high levels of the hormone in the late proximal tubule, promoting receptor activation [2]. Urinary PTH excretion is high in both knockout mice [41] and humans with Dent disease [54]. Phosphaturia and increased activation of vitamin D may combine to promote the disorder in calcium and phosphate metabolism seen in Dent disease.
Activity of the intestinal calcium channel TRPV6 is suppressed by OCRL, and disease-associated mutations in OCRL alleviate this suppression [55]. Thus, intestinal calcium absorption may also be enhanced through mechanisms intrinsic to the gut, at least in Dent disease 2 (Dent-2).
CLINICAL MANIFESTATIONS
Common clinical presentation — Affected patients usually present in childhood with polyuria, microscopic hematuria, asymptomatic proteinuria, or kidney stones. The prevalence of these clinical features among affected males with documented mutations are summarized in the table (table 1). Symptomatic disease is almost exclusively confined to males, with inheritance being X-linked recessive [3]. Dent disease has been reported in multiple ethnic groups and geographic regions including Europe, North America, and Asia [1,56-58]. There are no known high-risk populations.
Proximal tubular reabsorptive failure and proteinuria — Significant low-molecular-weight proteinuria is present in affected males and, to a lesser degree, in many carrier females. Protein excretion of 1 to 2 g/day, approximately one-quarter of which consists of albumin, is present from early childhood and increases with age [1,58]. One-half of patients, whether Dent disease 1 (Dent-1) or Dent disease 2 (Dent-2), have proteinuria in the nephrotic range, but serum albumin levels are normal, and these patients typically do not develop nephrotic syndrome [59].
Other signs of proximal tubular dysfunction, such as glucosuria, aminoaciduria, and phosphaturia, are also common in affected males [58]. However, these findings vary among patients and can occur intermittently in a given patient. As an example, hypophosphatemia occurs in approximately one-third of patients and is usually mild. However, renal tubular acidosis is not typically seen in Dent disease, although it does occur in Lowe (oculocerebrorenal) syndrome. (See 'Lowe syndrome' below.)
Hypercalciuria, nephrocalcinosis, and kidney stones — Most affected males are hypercalciuric until kidney function starts to decline. The degree of hypercalciuria can be impressive in young children, who may excrete 8 to 10 mg per kg of body weight (normal is <4.0 mg/kg). However, in teenagers and adults, the hypercalciuria is usually moderate, comparable to that in patients with idiopathic hypercalciuria.
Nephrocalcinosis occurs in up to 75 percent of patients and is often evident in childhood [58,60]. Kidney stones occur in fewer than one-half of patients. These stones consist of calcium oxalate, calcium phosphate, or both. The main risk factor for stones is hypercalciuria; urinary excretion of oxalate and citrate is normal [1]. (See "Kidney stones in adults: Epidemiology and risk factors" and "Nephrocalcinosis" and "Kidney stones in children: Epidemiology and risk factors", section on 'Hypercalciuria'.)
Serum calcitriol tends to be normal or slightly elevated, serum calcium tends to be normal, and serum parathyroid hormone (PTH) tends to be normal or low [1,58,61]. In one study, elevated levels of calcitriol fell to normal when patients were given oral phosphate replacement [62]. However, it is unclear whether hypophosphatemia is the cause of high serum calcitriol concentrations.
Chronic kidney disease — Approximately two-thirds of affected males develop some degree of chronic kidney disease, with decreased creatinine clearance becoming evident in some patients by late childhood. A similar fraction of patients with CLCN5 mutations progress to end-stage kidney disease (ESKD), usually between the ages of 30 and 40 years [7,60]. Although most such patients have nephrocalcinosis, the development or progression of kidney failure does not consistently correlate with the presence or severity of nephrocalcinosis [1,58].
The cause of kidney failure is not known. It may be related to the development of glomerular sclerosis (see 'Kidney pathology' below); to the presence of bioactive low-molecular-weight hormones, growth factors, and cytokines in the tubule [54]; to the consequences of lysosomal protein overload; or to abnormal renal handling of proteins that may inhibit calcification, such as osteopontin. (See "Focal segmental glomerulosclerosis: Clinical features and diagnosis".)
Kidney pathology — Kidney biopsy findings are nonspecific. Focal global glomerulosclerosis is commonly seen without any basement membrane abnormalities, regardless of the degree of proteinuria; however, focal segmental sclerosis is rare [58,63-65]. The percentage of globally sclerotic glomeruli increases with age and is several-fold higher than that expected at any given age [64]. Tubular atrophy, varying degrees of interstitial inflammation, and interstitial fibrosis are also observed [58,66]. Thus, Dent disease needs to be considered in patients with focal global glomerulosclerosis or asymptomatic proteinuria since immunosuppressive therapies would not be effective and are potentially harmful [67].
Studies have detected the CLC-5 protein in the glomeruli of normal individuals and in those with proteinuric kidney diseases, but not in patients with Dent-1 disease [15], and podocyte CLC-5 expression may be upregulated in response to proteinuric kidney disease [16]. However, it is unclear whether abnormal CLC-5 protein function plays a role in the development of global glomerulosclerosis in Dent disease.
Hypokalemia — Hypokalemia occurs commonly among patients with Dent disease. In one study, plasma potassium concentrations decreased with age, and approximately one-half of patients over the age of 18 years were hypokalemic in spite of having impaired kidney function [58]. An analysis of six of these patients demonstrated inappropriate renal potassium losses. In one case report, a boy presented with prominent hypokalemia and metabolic alkalosis, features suggestive of Bartter syndrome [68]. The patient, however, also had hypophosphatemia, proteinuria, and nephrocalcinosis, as well as a verified defect in CLCN5. Dent disease patients also appear to be especially sensitive to the effects of thiazide diuretics (such as volume depletion and hypokalemia) [58].
Rickets or osteomalacia — Approximately 25 percent of affected males with Dent disease have rickets or osteomalacia, which can present in infancy with severe deforming bone disease. However, most patients paradoxically have no signs of bone disease, have normal bone mineral density, and achieve a normal height [52]. Most reports of rickets have been from Europe [5-7], although it has also occurred in North America [18,61]. (See "Epidemiology and etiology of osteomalacia".)
The presence of rickets does not correlate with particular mutations, as illustrated by the following observations:
●Rickets can occur in a single affected male within a family in which other affected males who share the same mutation are free of bone disease [7,9].
●The most common CLCN5 mutation involves a substitution of leucine for serine at codon 244 (S244L), which has been reported in seven unrelated families. In two European families with this mutation, all nine affected males had rickets [5,6]; however, in a large pedigree from the southern United States who shared the same mutation, none of the affected males had any evidence of rickets [19].
It is unknown whether the occurrence of rickets represents the effects of modifying genes, the severity of hypophosphatemia, diet, or other factors.
Other abnormalities — Patients with Dent disease often have nocturia and polyuria from early childhood, with relative resistance to antidiuretic hormone [7,52,62]. In adults, impaired concentrating ability correlates with the degree of kidney function impairment or nephrocalcinosis [7,52].
Urinary acidification is usually normal, and impaired acidification does not appear to be an intrinsic feature of the disease. Impaired acidification can occur in the settings of nephrocalcinosis or kidney function impairment, which are themselves sufficient explanations for the defect.
Lowe syndrome — The phenotype of the Lowe syndrome overlaps with that of Dent disease in that low-molecular-weight proteinuria and hypercalciuria are present in both disorders. However, patients with Lowe syndrome also have renal tubular acidosis, congenital cataracts, and intellectual disability, findings which are absent in Dent disease [8,31,32,69]. In addition, patients with the Lowe syndrome commonly have growth failure that corrects with alkali therapy and progressive kidney function impairment that is typically more aggressive and that occurs at an earlier age than the kidney function impairment in Dent disease.
DIAGNOSIS
When to suspect the diagnosis — The diagnosis of Dent disease can be suspected in individuals with the following three characteristics [17]:
●Low-molecular-weight proteinuria – Excessive urinary excretion of low-molecular-weight proteins is a hallmark of the disease and is typically 5- to 10-fold greater than the upper limit of the reference range. Low-molecular-weight proteins that can be measured in the clinical setting include retinol-binding protein, alpha-1-microglobulin, and beta-2-microglobulin [52]. Since beta-2-microglobulin can be degraded in an acidic urine, retinol-binding protein or alpha-1-microglobulin are preferred, when available. The elevation in low-molecular-weight proteinuria is usually marked (10-fold the reference range or greater) [70]. Thus, a random urine value indexed to creatinine is sufficient for the diagnosis. A random urinary protein-to-creatinine ratio >600 mg/g and albumin-to-total protein ratio <0.3 can also be used to screen for Dent disease [71].
●Hypercalciuria – Affected patients usually have more than 4 mg/kg of body weight in a 24-hour urine collection. This may be absent in patients whose kidney function has begun to decline.
●At least one of the following:
•Nephrocalcinosis
•Nephrolithiasis
•Hematuria
•Hypophosphatemia
•Chronic kidney disease
Confirming the diagnosis — A family history indicating an X-linked inheritance of one or more of the clinical characteristics discussed above supports the diagnosis, and identification of a mutation in either CLCN5 or OCRL1 confirms the diagnosis. Genetic testing for CLCN5 and OCRL1 is available through various commercial laboratories.
However, as noted above, not all affected patients have a mutation in one of these two genes. In addition, some patients with confirmed mutations in CLCN5 or OCRL1 will not fulfill all three clinical criteria. Thus, while the identification of a mutation in one of these two genes confirms the diagnosis in someone with suggestive clinical manifestations, a negative genetic test does not rule out the diagnosis of Dent disease. (See 'Molecular genetics' above.)
Family members of affected individuals may be at risk of having affected progeny, particularly females who are potentially heterozygous for the patient's mutation. Thus, asymptomatic family members should be offered genetic counseling when they reach adulthood [56].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of Dent disease includes other entities that can cause generalized proximal tubule dysfunction (Fanconi syndrome), such as cystinosis, galactosemia, multiple myeloma, ifosfamide, and Chinese herbs. Other monogenic causes of nephrocalcinosis and chronic kidney disease (eg, SLC34A1, SLC34A3, CLDN16 mutations) can also mimic certain features of Dent disease but typically lack markedly increased low-molecular-weight proteinuria. The absence of renal tubular acidosis would favor Dent disease over other diagnoses. Some individuals with Dent disease have presented with chronic kidney disease with proteinuria but without other typical features of Dent disease such as kidney stones, nephrocalcinosis, or bone disease [63,65]. In these cases, kidney biopsy revealed focal global glomerulosclerosis. These individuals illustrate that the spectrum of Dent disease includes persons with proteinuria and a biopsy consistent with focal glomerulosclerosis, and that the diagnosis must be considered in some individuals with this presentation (eg, younger males), prompting a screen for low-molecular-weight proteinuria.
●(See "Cystinosis".)
●(See "Galactosemia: Clinical features and diagnosis".)
●(See "Ifosfamide nephrotoxicity", section on 'Clinical manifestations'.)
TREATMENT — Although it is unknown to what extent hypercalciuria is responsible for the kidney failure in Dent disease, it is the major factor responsible for nephrolithiasis. Thus, an attempt to reduce calcium excretion is reasonable.
Reduction in calcium excretion — A reduction in calcium excretion should be approached by restricting dietary sodium intake (since sodium excretion promotes calcium excretion) and administering a thiazide diuretic, which stimulates the reabsorption of calcium. Anecdotal reports and the results of one trial indicate that thiazides can at least partially correct the hypercalciuria in patients with Dent disease when used in doses similar to those effective for idiopathic hypercalciuria (eg, in adults, chlorthalidone at 25 mg/day; and in children 0.3 mg/kg per day [maximum dose 25 mg]) [1,72]. (See "Kidney stones in adults: Prevention of recurrent kidney stones" and "Kidney stones in children: Prevention of recurrent stones", section on 'Hypercalciuria'.)
However, patients with Dent disease may develop symptomatic hypotension with these doses of thiazide diuretics, and blood pressure must therefore be monitored closely when such medications are initiated [73].
Restriction of dietary calcium intake is not recommended, because it may exacerbate the risk of bone disease. In addition, lower calcium intakes are associated with an increased annual incidence of kidney stones in the general population [74].
Other potential therapies
●Dietary citrate – In experimental models of Dent disease, a diet that is high in citrate has been effective in retarding the progression of the kidney disease, perhaps through the beneficial effect of enhancing urinary calcium solubility [75]. This has not been studied in humans. (See "Kidney stones in adults: Prevention of recurrent kidney stones".)
●Oral phosphate therapy and vitamin D supplementation – Improvement in bone disease has been reported with oral phosphate therapy [62] and supplementation with vitamin D [7]. Oral neutral phosphorus therapy may also reduce circulating 1,25 vitamin D and hypercalciuria but has not been extensively studied [62]. When using vitamin D, it is important to titrate the dose carefully, following both serum levels of alkaline phosphatase and urinary calcium excretion, to avoid exacerbating the hypercalciuria via increased intestinal calcium absorption.
●Angiotensin-converting enzyme (ACE) inhibitors – Data are scant on the value of ACE inhibitors in Dent disease. The pathology of the proteinuria is primarily tubulointerstitial, and therefore, it is not clear that ACE inhibitors would be expected to be of benefit. In addition, in patients treated with thiazides to reduce calcium excretion, ACE inhibitors might produce hypotension. In one retrospective study, the use of ACE inhibitors and/or angiotensin receptor blockers reduced proteinuria in approximately one-half of patients with Dent disease [76].
End-stage kidney disease — Patients with end-stage kidney disease (ESKD) do well on dialysis and are often excellent candidates for transplantation; the disease has not been reported to recur after transplantation [1]. Patients without preexisting rickets are not predisposed to renal osteodystrophy if they are compliant with conventional therapy.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney stones".)
SUMMARY AND RECOMMENDATIONS
●Overview – Dent disease is an X-linked recessive disorder of the proximal tubules that is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, kidney stones, kidney failure, and rickets. The disease is distinguished clinically from the Lowe (oculocerebrorenal) syndrome by the absence of cataracts, mental developmental delay, and renal tubular acidosis. (See 'Nomenclature' above.)
●Genetics – In 60 percent of cases, Dent disease is due to mutations in the CLCN5 gene that inactivate a voltage-gated chloride transporter, CLC-5, which is expressed in the kidney and is encoded by a gene at Xp11.22. In another 15 percent of cases, it is associated with mutations in the OCRL1 gene, which is also mutated in the Lowe syndrome. Further genetic heterogeneity is assumed to exist since there are patients with the distinctive phenotype of Dent disease who do not have mutations in either of these genes. (See 'Molecular genetics' above.)
●Pathophysiology – CLC-5 is present in the membrane of subapical endosomes in the proximal tubule. Inactivation of CLC-5 and the consequent endosomal dysfunction explain the low-molecular-weight proteinuria in patients with Dent disease (figure 1). The discovery that mutations in OCRL1 can cause the Dent disease phenotype points to overlap in the physiological functions of the OCRL phosphatase and the CLC-5 protein. The OCRL phosphatase also affects endosomal trafficking. Hypercalciuria reflects, at least in part, excessive intestinal calcium absorption and dysregulation of vitamin D metabolism. (See 'Pathophysiology' above.)
●Clinical manifestations – Clinical manifestations, which are usually present in childhood, include polyuria, microscopic hematuria, asymptomatic proteinuria, and kidney stones (associated with hypercalciuria and nephrocalcinosis). In addition, patients may have glucosuria, aminoaciduria, hyperphosphaturia, chronic kidney disease, hypokalemia, and rickets or osteomalacia. (See 'Clinical manifestations' above.)
Kidney manifestations of the Lowe syndrome include those of Dent disease. However, patients with Lowe syndrome also have renal tubular acidosis, congenital cataracts, and intellectual disability, findings which are typically absent in Dent disease. (See 'Lowe syndrome' above.)
●Diagnosis – The diagnosis of Dent disease can be suspected in individuals with the following three characteristics (see 'Diagnosis' above):
•Low-molecular-weight proteinuria
•Hypercalciuria
•At least one of the following – Nephrocalcinosis, nephrolithiasis, hematuria, hypophosphatemia, or chronic kidney disease.
Identification of a mutation in either CLCN5 or OCRL1 confirms the diagnosis. However, not all affected patients have a mutation in one of these two genes, and some patients with confirmed mutations in CLCN5 or OCRL1 will not fulfill all three clinical criteria. (See 'Confirming the diagnosis' above.)
●Treatment
•Reduction in calcium excretion – Hypercalciuria is the major factor responsible for nephrolithiasis in Dent disease. Thus, an attempt to reduce calcium excretion is reasonable. The principal approach to reducing calcium excretion should be to restrict dietary sodium intake. Administration of a thiazide diuretic, which stimulates the reabsorption of calcium, augments the benefit of sodium restriction. Dietary calcium intake should not be restricted, because it may exacerbate the risk of bone disease. (See 'Treatment' above.)
•Other potential therapies – Therapy with citrate, phosphate, and vitamin D may be helpful for other manifestations; vitamin D is important in managing those patients with bone disease, but it needs to be monitored carefully. Patients with end-stage kidney disease (ESKD) do well on dialysis and are often excellent candidates for transplantation; the disease has not been reported to recur after transplantation. (See 'Other potential therapies' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
