Figure 118

Syndromes of X-linked nephrolithiasis have been reported under various names, including Dent's disease in the United Kingdom, X-linked recessive hypophos-phatemic rickets in Italy and France, and a syndrome of low molecular weight (LMW) proteinuria with hyper-calciuria and nephrocalcinosis in Japanese schoolchildren. Mutations in a gene encoding a voltage-gated chloride channel (ClC-5) are present in all of these syndromes, establishing that they represent variants of one disease [10]. The disease occurs most often in boys, with microscopic hematuria, proteinuria, and hypercal-ciuria. Many but not all have recurrent nephrolithiasis from an early age. Affected males excrete extremely large quantities of LMW proteins, particularly P2-microglobulin and retinol-binding protein. Other defects of proximal tubular function, including hypophos-phatemia, aminoaciduria, glycosuria, or hypokalemia, occur variably and often intermittently. Many affected males have mild to moderate polyuria and nocturia, and they often exhibit this symptom on presentation. Urinary acidification is usually normal, and patients do not have acidosis in the absence of advanced renal insufficiency. Nephrocalcinosis is common by the teenage years, and often earlier. Renal failure is common and often progresses to end-stage renal disease by the fourth or fifth decade, although some patients escape it. Renal biopsy documents a nonspecific pattern of interstitial fibrosis and tubular atrophy, with glomerular sclerosis that is probably secondary [11].

Rickets occurs early in childhood in some patients but is absent in most patients with X-linked nephrolithiasis (Dent's disease). In a few families, all affected males have had rickets. In other families, rickets is present in only one of several males sharing the same mutation. At present, the variability of this feature and other features of the disease is unexplained and may reflect dietary or environmental factors or the participation of other genes in the expression of the phenotype.

Females who are carriers often have mild to moderate LMW proteinuria. This abnormality can be used clinically as a screening test, but LMW protein excretion will not be abnormal in all heterozygous females. Approximately half of women who are carriers have hypercalciuria, but other biochemical abnormalities are rare. Although symptomatic nephrolithiasis and even renal insufficiency have been reported in female carriers, they are very uncommon.

The gene for ClC-5 that is mutated in X-linked nephro-lithiasis (Dent's disease) is expressed in the endosomal vacuoles of the proximal tubule; it appears to be important in acidification of the endosome. Thus, defective endosomal function would explain the LMW proteinuria. The mechanism of hypercalcinuria remains unexplained at present. This gene belongs to the family of voltage-gated chloride channels that includes ClC-Kb, one of the gene mutations in some patients with Bartter syndrome. To date, 32 mutations have been reported in 40 families, and nearly all are unique [11].

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