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Metabolic Disorders and Molecular Background of Urolithiasis in Childhood B

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Metabolic Disorders and Molecular Background of Urolithiasis in Childhood B Scanning Microscopy Vol. 13, No. 2-3, 1999 (Pages 267-280) 0891-7035/99$5.00+.25 Scanning Microscopy International, ChicagoMolecular (AMF mechanisms O’Hare), IL of60666 childhood USA urolithiasis METABOLIC DISORDERS AND MOLECULAR BACKGROUND OF UROLITHIASIS IN CHILDHOOD B. Hoppe1,* and A. Hesse2 1Northwestern University, Children’s Memorial Hospital, Chicago, IL 60614 2Division of Experimental Urology, Department of Urology, University of Bonn, Germany (Received for publication March 29, 1997 and in revised form August 15, 1997) Abstract Introduction Urolithiasis in childhood is less frequently observed than Interesting advances in the understanding of the in adults, but it still has a considerable morbidity. In contrast pathophysiology and the molecular mechanisms of uro- to the situation in adults, an infectious or metabolic cause lithiasis have been made during the last few years. Al- for stone formation is detected in the majority of pediatric though some of the molecular mechanisms found, have come patients. The underlying molecular mechanism of from studies in pediatric patients, they turn out to be urolithiasis has been shown in a number of conditions, and important for all groups of patients. Due to our better some of them have been discovered in pediatric patients. knowledge of both the metabolic basis and the molecular Mutations of the AGXT-gene (2q37.3) have been found to mechanism of stone disease, the management and treatment be responsible for the enzyme defect in primary has been greatly improved. hyperoxaluria type I, and two of the genes provoking Urolithiasis in children is far less common than in cystinuria have been identified (type I: 2p21, type III: adults, but still has a considerable morbidity [13]. The 19q13.1). In both xanthinuria and 2,8 dihydroxyadeninuria incidence of urolithiasis in adults increases with age af- mutations of the responsible gene have been discovered. fecting up to 12% of men and 5% of women by the age of 70 It is very likely that a molecular basis for the different types years. In contrast, the incidence is considerably lower in of hypercalciuria will also be found, like in X-linked hyper- children but differs between countries [7, 13, 81]. Within calciuric nephropathy with tubular proteinuria (Dent’s dis- the United States, urolithiasis is more common in the ease), or in X-linked recessive nephrolithiasis (Xp11.22). southeastern regions, where it may account for 1 in 1,000 to However, the molecular defect does not necessarily predict 1 in 7,600 hospital discharges [115]. the clinical course, even in monogenic diseases. Yet in In the majority of pediatric patients with urolithiasis, patients with the same disease genotype extreme differences a metabolic cause for stone formation can be identified and in the disease phenotype have been observed. This review several metabolic disorders are well-defined (e.g., cystinuria provides current understanding of the metabolic disorders or primary hyperoxaluria type 1). However, there is a large and molecular mechanisms of urolithiasis in childhood. subgroup of patients showing a subtle increase of urinary lithogenic factors (calcium, oxalate), or a reduction of stone- Key Words: Urinary calculi, urinary metabolism, genes, inhibitory substances, like urinary citrate [82]. If these latter molecular defect, calcium, oxalate, purine, cystine. abnormalities are also classified as metabolic disorders, as it is often done [86, 101, 143], then urolithiasis of metabolic origin constitutes the largest etiologic group. Accordingly, less than one third of all patients will have idiopathic urolithiasis. It is therefore, essential to perform metabolic examinations in all patients and to screen all family members if a metabolic disorder has been diagnosed. *Address for correspondence: Unlike the situation in adults, a metabolic cause for Bernd Hoppe stone formation is found in the majority of pediatric pa- Northwestern University tients. All children with urolithiasis should, therefore, Children’s Memorial Hospital undergo thorough investigation. The underlying molecu- 2300 Children’s Plaza # 37 lar mechanism has been determined in a number of diseases Chicago, IL 60614, USA and it is very likely that more common conditions, such as Telephone number: (773) 880 4326 certain forms of hypercalciuria, will also be shown to have a FAX number: (773) 880 6776 molecular basis. E-mail: [email protected] 267 B. Hoppe and A. Hesse Calcium Stones Table 1. Renal stone analysis in infants and children obtained with infrared-spectroscopy [13] Hypercalciuria Stones Girls Boys Hypercalciuria and stones composed of calcium-oxa- n = 350 n = 500 late are the most frequent conditions in both adult and pediatric patients with urolithiasis (Table 1, [13]). There is Calcium-oxalate no sharp differentiation between normal (up to 0.1 mmol (4 Weddellite (CaOx-dihydrate) 35.7% 29.0% mg)/kg per day [36, 45]) or abnormal levels of urinary calcium Whewellite (CaOx-monohydrate) 27.7% 29.2% excretion, so diagnosis of hypercalciuria is sometimes vague except for very high excretions (> 0.2 mmol/kg per day). 63.4% 58.2% Whether such children will form stones or develop nephrocalcinosis also depends on additional factors (urine Infectious volume, pH) and the concentration of other urinary Struvite 12.9% 15.0% lithogenic and stone-inhibitory substances, primarily of Carbonate-apatite 9.7% 12.8% oxalate and citrate [56, 69, 82]. Ammoniumhydrogen-urate 2.0% 1.2% Primary (idiopathic) hypercalciuria, which is sup- posed to have an autosomal-dominant inheritance, is the 24.6% 29.0% most common cause of calcium-containing stones [23]. Idiopathic hypercalciuria was primarily found to consist of Other Phosphate stones both intestinal hyperabsorption and urinary hyperexcretion Brushite 1.7% 3.2% of calcium [91]. It has traditionally been divided into a renal and an absorptive subtype, when urinary calcium excretion Uric acid 1.4% 2.2% in the fasting state is elevated in the renal but normal in the Uric acid dihydrate 0.3% 0.6% absorptive type [72, 143]. To differentiate both forms the Cystine 0.3% 1.2% oral calcium loading (1000 mg) test was introduced [54, 111, Protein 1.4% 1.6% 142], but is not always accepted and may be misleading Artefacts 6.9% 4.0% [54]. It was demonstrated, that the subtypes are not distinct entities, but rather two extremes [22], and many pediatric patients cannot easily be classified. chromosome 3q13.3-21 (Table 2, [75]). The CASR gene can The renal form is supposed to result from reduced either activate, as it does in this form of hypoparathyroidism, tubular calcium reabsorption. Hypocalcemia stimulates PTH or inactivate the calcium sensing receptor [1, 38]. secretion, which leads to an increase in bone resorption Hypocalcemia is associated with hypercalciuria and and intestinal calcium absorption and hence to higher treatment with vitamin D results in an increase of urinary vitamin D synthesis and hypercalciuria [84, 86]. The calcium excretion, nephrocalcinosis and later, possibly, in concept of absorptive hypercalciuria is based on an renal impairment [113]. increased intestinal absorption of calcium leading to ele- A molecular basis was also found in a rare but ex- vated serum calcium and hence to a suppression of the tremely severe form of idiopathic hypercalciuria with PTH secretion [12, 50]. As a result, the tubular reabsorption X-linked recessive nephrolithiasis (XRN) and renal im- of calcium is decreased, which leads to hypercalciuria [84]. pairment [42]. The primary defect of this renal tubular An increased affinity to vitamin D3, or an increased disorder is unknown, therefore, the mapping of the mutant production of 1.25(OH)2D3 might explain this condition, as gene to chromosome Xp11.22 was important to better define high plasma 1.25(OH)2D3 values have been found in patients this disease [135]. The mutant gene is close to several eye with hypercalciuria [84, 103, 120]. Relative disease genes, so patients have to be carefully screened hypoparathyroidism due to excess calcitriol production has opthalmologically [126]. Carrier females were said to be been demonstrated at least in adult stone formers with asymptomatic, however, a recent study showed, that they idiopathic hypercalciuria [51]. could also have (slight) hypercalciuria, and most of them A familial syndrome of hypocalcemia with hyper- showed low molecular weight proteinuria [126]. calciuria due to mutations in the calcium-sensing receptor X-linked hypercalciuric nephropathy, also called was recently observed. Autosomal dominant hypopara- Dent’s disease, is a form of Fanconi syndrome with tubular thyroidism with hypocalcemia is suspected to be due to a proteinuria, hypercalciuria, rickets, nephrocalcinosis, loss of calcium sensing receptor regulation. Five heter- urolithiasis and eventual renal failure (Table 2, [93]). A ogeneous missense mutations have been found on the cal- microdeletion of chromosome Xp11.22 was found to be cium sensing receptor gene (CASR), which is located on 268 Molecular mechanisms of childhood urolithiasis Table 2. Genetic defects in urolithiasis. Increased Disease Defect Gene Inheritance* excretion Calcium Familial idiopathic AD hypercalciuria Familial hypocalcemia Calcium-sensing receptor 3q13.3-21 AD with hypercalciuria (CASR) X-linked hypercalciuric Mutation of CLCN5-gene Xp 11.22 XL nephropathy with tubular (renal chloride channel gene) proteinuria (Dent’s disease) X-linked recessive Mutation of CLCN5-gene Xp 11.22 XL nephrolithiasis type I (XRN) X-linked-recessive hypophos-
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