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Idiopathic Hypercalciuria - A Major Metabolic Risk for Calcium Kidney Stone Disease
Abstract
Idiopathic hypercalciuria is defined as excessive urine calcium excretion in the absence of an identifiable cause. It has been strongly associated with the risk of calcium kidney stone formation. Animal and human studies have suggested excessive bone mineral loss or increased gastrointestinal calcium absorption with abnormal renal calcium excretion may contribute to this process. In this article we will review the complex pathophysiology of idiopathic hypercalciuria and discuss clinical management and challenges.
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Objectives:
The urinary excretion of organic and inorganic substances and their concentrations have attracted extensive attention for their role in the pathogenesis of urinary stone disease. The urinary excretion of specific factors associates with sex and age and seems to have a hereditary component, but the precise genomic determinants remain ill-defined.
Methods:
Genome-wide association studies previously conducted in 3 cohorts (Genetic Epidemiology Network of Arteriopathy study, January 1, 2006, through December 31, 2012; the combined Nurses' Health Study (NHS), NHS II, and Health Professionals Follow-up Study, January 1, 1994, through December 31, 2003; and the Prevention of Renal and Vascular End-stage Disease study, January 1, 1997, through December 31, 1998) were combined into meta-analyses to evaluate genetic associations with available urinary phenotypes relevant to stone pathogenesis (calcium, magnesium, and uric acid excretion; total urine volume).
Results:
One region on chromosome 9q21.13 showed strong evidence of an association with urinary magnesium excretion. The strongest signal in this region was near TRPM6, whose protein product mediates magnesium transport in the colon and kidney, and C9orf40, C9orf41, NMRK1, and OSTF1 (rs1176815; P=1.70×10-14, with each copy of the A allele corresponding to a daily 5.29-mg decrease in magnesium excretion). The single nucleotide polymorphism (SNP) that achieved genome-wide significance for calcium excretion (rs17216707 on chromosome 20; P=1.12×10-8) was previously associated with fibroblast growth factor 23 levels, which regulate phosphorus and vitamin D metabolism. Urine volume and uric acid excretion did not have any genome-wide significant SNPs.
Conclusion:
Common variants near genes important for magnesium metabolism and bone health associate with urinary magnesium and calcium excretion.
Calcium-sensing receptor (CaSR) is a plasma-membrane G protein-coupled receptor activated by extracellular calcium and expressed in kidney tubular cells. It inhibits calcium reabsorption in the ascending limb and distal convoluted tubule when stimulated by the increase of serum calcium levels; therefore, these tubular segments are enabled by CaSR to play a substantial role in the regulation of serum calcium levels. In addition, CaSR increases water and proton excretion in the collecting duct and promotes phosphate reabsorption and citrate excretion in the proximal tubule. These CaSR activities form a network in which they are integrated to protect the kidney against the negative effects of high calcium concentrations and calcium precipitates in urine. Therefore, the CaSR gene has been considered as a candidate to explain calcium nephrolithiasis. Epidemiological studies observed that calcium nephrolithiasis was associated with polymorphisms of the CaSR gene regulatory region, rs6776158, located within the promoter-1, rs1501899 located in the intron 1, and rs7652589 in the 5′-untranslated region. These polymorphisms were found to reduce the transcriptional activity of promoter-1. Activating rs1042636 polymorphism located in exon 7 was associated with calcium nephrolithiasis and hypercalciuria. Genetic polymorphisms decreasing CaSR expression could predispose individuals to stones because they may impair CaSR protective effects against precipitation of calcium phosphate and oxalate. Activating polymorphisms rs1042636 could predispose to calcium stones by increasing calcium excretion. These findings suggest that CaSR may play a complex role in lithogenesis through different pathways having different relevance under different clinical conditions.
Idiopathic hypercalciuria (IH) is a heterogeneous disorder frequently observed in patients with nephrolithiasis. At one extreme of its clinical spectrum is fasting hypercalciuria (FH), a condition characterized by increased bone resorption and turnover.
In previous studies we have shown that monocytes from patients with high turnover osteoporosis and from women in early postmenopause elaborate increased amounts of interleukin-1 (IL-1), a cytokine that stimulates bone resorption in vitro and in vivo. Since IL-1 could also mediate the resorptive mechanism of FH and cause a clinically significant bone loss, we have studied the relationship of IH, vertebral mineral density, bone turnover, and monocyte IL-1 activity in 47 patients with absorptive hypercalciuria (AH), 23 with FH, and 38 nonhypercalciuric subjects with recurrent nephrolithiasis (controls).
Vertebral mineral density, as measured by quantitative computer tomography, was decreased in each of the three patient groups, but was significantly lower in FH patients than in AH patients or control subjects. Twenty-four-hour total urinary hydroxyproline excretion was increased in FH patients compared to that in AH patients or controls, but blood levels of osteocalcin were not. Monocytes from FH subjects yielded significantly more IL-1 (α + β) activity than those from AH patients or controls; levels of IL-1 activity in monocytes of AH and control patients were similar. In IH subjects, significant correlations were found between IL-1 and hydroxyproline (r = 0.70; P < 0.0001), IL-1 and quantitative computer tomography values (r = −0.49; P < 0.005), and IL-1 and urinary calcium (r = −0.36; P < 0.05). Serum PTH levels were within normal limits in all subjects and were similar in the three study groups. 1,25-Dihydroxyvitamin D3 levels, although higher in IH patients than in controls, were not significantly different in FH and AH subjects.
Increased IL-1 activity and decreased vertebral mineral density are features of a subset of patients with IH. Although a cause-effect relationship remains to be established, increased monocytic IL-1 activity, rather than elevated PTH or 1,25-dihydroxyvitamin D3 levels, could underlie the resorptive component of FH.
In previous studies we have shown that monocytes from patients with high turnover osteoporosis and from women in early postmenopause elaborate increased amounts of interleukin-1 (IL-1), a cytokine that stimulates bone resorption in vitro and in vivo. Since IL-1 could also mediate the resorptive mechanism of FH and cause a clinically significant bone loss, we have studied the relationship of IH, vertebral mineral density, bone turnover, and monocyte IL-1 activity in 47 patients with absorptive hypercalciuria (AH), 23 with FH, and 38 nonhypercalciuric subjects with recurrent nephrolithiasis (controls).
Despite the important role of vitamin D in maintaining bone health, many clinicians are reluctant to treat vitamin D deficiency in kidney stone formers because of the theoretical risk of increasing urinary calcium excretion. This study examined the effect of vitamin D repletion on urinary calcium excretion among stone formers.
Participants (n=29) were recruited from urology clinics affiliated with New York Presbyterian Hospital. Enrollment criteria included a history of nephrolithiasis, urinary calcium excretion between 150 and 400 mg/d, and a serum 25-hydroxyvitamin D level <30 ng/ml. Participants were given oral ergocalciferol (50,000 IU/wk) for 8 weeks. Serum and 24-hour urine tests were repeated after 8 weeks.
Levels of 25-hydroxyvitamin D increased significantly after vitamin D repletion (17±6 and 35±10 ng/ml, P<0.001), but mean 24-hour urinary calcium excretion did not change (257±54 and 255±88 mg/d at baseline and follow-up, respectively, P=0.91). However, 11 participants had an increase in urinary calcium excretion ≥20 mg/d; these participants also had an increase in urine sodium excretion, likely reflecting dietary variability. No participant experienced adverse effects from vitamin D, including hypercalcemia.
Among stone formers with vitamin D deficiency, a limited course of vitamin D repletion does not seem to increase mean urinary calcium excretion, although a subset of individuals may have an increase. These data suggest that vitamin D therapy, if indicated, should not be withheld solely on the basis of stone disease, but 24-hour urinary calcium excretion should be monitored after repletion.
The classic definition of hypercalciuria, an upper normal limit of 200 mg/day, is based on a constant diet restricted in calcium, sodium, and animal protein; however, random diet data challenge this. Here our retrospective study determined the validity of the classic definition of hypercalciuria by comparing data from 39 publications analyzing urinary calcium excretion on a constant restricted diet and testing whether hypercalciuria could be defined when extraneous dietary influences were controlled. These papers encompassed 300 non-stone-forming patients, 208 patients with absorptive hypercalciuria type I (presumed due to high intestinal calcium absorption), and 234 stone formers without absorptive hypercalciuria; all evaluated on a constant restricted diet. In non-stone formers, the mean urinary calcium was well below 200 mg/day, and the mean for all patients was 127±46 mg/day with an upper limit of 219 mg/day. In absorptive hypercalciuria type I, the mean urinary calcium significantly exceeded 200 mg/day in all studies with a combined mean of 259±55 mg/day. Receiver operating characteristic curve analysis showed the optimal cutoff point for urinary calcium excretion was 172 mg/day on a restricted diet, a value that approximates the traditional limit of 200 mg/day. Thus, on a restricted diet, a clear demarcation was seen between urinary calcium excretion of kidney stone formers with absorptive hypercalciuria type I and normal individuals. When dietary variables are controlled, the classic definition of hypercalciuria of nephrolithiasis appears valid.
Nephrolithiasis remains a formidable health problem in the United States and worldwide. A very important but underaddressed area in nephrolithiasis is the accompanying bone disease. Epidemiologic studies have shown that osteoporotic fractures occur more frequently in patients with nephrolithiasis than in the general population. Decreased bone mineral density and defects in bone remodeling are commonly encountered in patients with calcium nephrolithiasis. The pathophysiologic connection of bone defects to kidney stones is unknown. Hypercalciuria and hypocitraturia are two important risk factors for stone disease, and treatments with thiazide diuretics and alkali, respectively, have been shown to be useful in preventing stone recurrence in small prospective trials. However, no studies have examined the efficacy of these agents or other therapies in preventing continued bone loss in calcium stone formers. This manuscript reviews the epidemiology, pathophysiology, and potential treatments of bone disease in patients with nephrolithiasis.
The cuase for the intestinal hyperabsorptionof calcium (Ca) in various forms of hypercalciurias was explored by a careful measurement of plasma 1 alpha, 25-dihydroxycholecalciferol [1 alpha, 25-(OH)I D] and by an assessment of intestinal Ca absorption and of parathyroid function. In 18 cases of primary hyperparathyroidism (PHPT), the mean plasma concentration of 1 alpha, 25-(OH)2D was significantly increased (4.9 +/- 2.2 SD ng/dl vs. 3.4 +/- 0.9 ng/dl for the control group), and was significantly correlated with fractional Ca absorption (alpha) (r = 0.80, P less than 0.001). Plasma 1 alpha, 25-(OH)2D was also correlated with urinary Ca (P less than 0.05), but not with serum Ca or phosphorus (P), P clearance, urinary cyclic AMP, or serum immunoreactive parathyroid hormone. In 21 cases of absorptive hypercalciuria (AH), plasma 1 alpha, 25-(OH)2D was elevated in one-third of cases, and the mean value of 4.5 +/- 1.1 ng/dl was significantly higher than that of the control group (P less than 0.01). Since relative hypoparathyroidism may be present, the normal absolute value of plasma 1 alpha, 25-(OH)2D, found in two-thirds of cases of AH, may be considered to be inappropriately high. Moreover, in the majority of cases of AH, the data points relating plasma 1 alpha, 25-(OH)2D and alpha fell within 95% confidence limits of values found in non-AH groups (including PHPT). The results suggest that the intestinal hyperabsorption of Ca in PHPT aw AH may be vitamin D dependent. However, the disturbance in vitamin D metabolism may not be the sole cause for the high Ca absorption in AH, since in some patients with AH, the intestinal Ca absorption appears to be inapp
The causes for the hypercalciuria and diagnostic criteria for the various forms of hypercalciuria were sought in 56 patients with hypercalcemia or nephrolithiasis (Ca stones), by a careful assessment of parathyroid function and calcium metabolism. A study protocol for the evaluation of hypercalciuria, based on a constant liquid synthetic diet, was developed. In 26 cases of primary hyperparathyroidism, characteristic features were: hypercalcemia, high urinary cyclic AMP (cAMP, 8.58+/-3.63 SD mumol/g creatinine; normal, 4.02+/-0.70 mumol/g creatinine), high immunoreactive serum parathyroid hormone (PTH), hypercalciuria, the urinary Ca exceeding absorbed Ca from intestinal tract (Ca(A)), high fasting urinary Ca (0.2 mg/mg creatinine or greater), and low bone density by (125)I photon absorption. The results suggest that hypercalciuria is partly secondary to an excessive skeletal resorption (resorptive hypercalciuria). The 22 cases with renal stones had normocalcemia, hypercalciuria, intestinal hyperabsorption of calcium, normal or low serum PTH and urinary cAMP, normal fasting urinary Ca, and normal bone density. Since their Ca(A) exceeded urinary Ca, the hypercalciuria probably resulted from an intestinal hyperabsorption of Ca (absorptive hypercalciuria). The primacy of intestinal Ca hyperabsorption was confirmed by responses to Ca load and deprivation under a metabolic dietary regimen. During a Ca load of 1,700 mg/day, there was an exaggerated increase in the renal excretion of Ca and a suppression of cAMP excretion. The urinary Ca of 453+/-154 SD mg/day was significantly higher than the control group's 211+/-42 mg/day. The urinary cAMP of 2.26+/-0.56 mumol/g creatinine was significantly lower than in the control group. In contrast, when the intestinal absorption of calcium was limited by cellulose phosphate, the hypercalciuria was corrected and the suppressed renal excretion of cAMP returned towards normal. Two cases with renal stones had normocalcemia, hypercalciuria, and high urinary cAMP or serum PTH. Since Ca(A) was less than urinary Ca, the hypercalciuria may have been secondary to an impaired renal tubular reabsorption of Ca (renal hypercalciuria). Six cases with renal stones had normal values of serum Ca, urinary Ca, urinary cAMP, and serum PTH (normocalciuric nephrolithiasis). Their Ca(A) exceeded urinary Ca, and fasting urinary Ca and bone density were normal. The results support the proposed mechanisms for the hypercalciuria and provide reliable diagnostic criteria for the various forms of hypercalciuria.
Tubular reabsorption and excretion of calcium were studied at different levels of filtered calcium by means of calcium infusion in normal and hypercalciuric subjects and in patients with idiopathic nephrolithiasis.
Calcium reabsorption and excretion rose linearly with filtered load and in no case was a maximum tubular reabsorptive capacity for calcium reached.
No decrease in tubular reabsorption of calcium was found in hypercalciuric as compared with normocalciuric subjects, and no difference in tubular reabsorption was found between patients with idiopathic nephrolithiasis and normal subjects.
Calcium excretion and reabsorption calculated from the endogenous creatinine clearance during calcium infusion were virtually identical with the corresponding values calculated from the inulin clearance.
As a model of human hypercalciuria, we have selectively inbred genetic hypercalciuric stone-forming (GHS) Sprague-Dawley rats whose mean urine calcium excretion is eight to nine times greater than that of controls. A large component of this excess urine calcium excretion is secondary to increased intestinal calcium absorption, which is not due to an elevation in serum 1,25(OH)2D3, but appears to result from an increased number of intestinal 1,25(OH)2D3 receptors (VDR). When GHS rats are fed a low-calcium diet, the hypercalciuria is only partially decreased and urine calcium excretion exceeds intake, suggesting that an additional mechanism contributing to the hypercalciuria is enhanced bone demineralization. To determine if GHS rat bones are more sensitive to exogenous 1,25(OH)2D3, we cultured calvariae from neonatal (2- to 3-day-old) GHS and control rats with or without 1,25(OH)2D3 or parathyroid hormone (PTH) for 48 h at 37 degrees C. There was significant stimulation of calcium efflux from GHS calvariae at 1 and 10 nM 1,25(OH)2D3, whereas control calvariae showed no significant response to 1,25(OH)2D3 at any concentration tested. In contrast, PTH induced similar bone resorption in control and GHS calvariae. Immunoblot analysis demonstrated a fourfold increase in the level of VDR in GHS calvariae compared with control calvariae, similar to the increased intestinal receptors described previously. There was no comparable change in VDR RNA levels as measured by slot blot analysis, suggesting the altered regulation of the VDR occurs posttranscriptionally. That both bone and intestine display an increased amount of VDR suggests that this may be a systemic disorder in the GHS rat and that enhanced bone resorption may be responsible, in part, for the hypercalciuria in the GHS rat.
The calcium-sensing receptor (CASR), expressed in parathyroid chief cells, thyroid C-cells, and cells of the kidney tubule, is essential for maintenance of calcium homeostasis. Here we show parathyroid, thyroid, and kidney CASR mRNA levels increased 2-fold at 15 h after intraperitoneal injection of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in rats. Human thyroid C-cell (TT) and kidney proximal tubule cell (HKC) CASR gene transcription increased approximately 2-fold at 8 and 12 h after 1,25(OH)2D3 treatment. The human CASR gene has two promoters yielding alternative transcripts containing either exon 1A or exon 1B 5'-untranslated region sequences that splice to exon 2 some 242 bp before the ATG translation start site. Transcriptional start sites were identified in parathyroid gland and TT cells; that for promoter P1 lies 27 bp downstream of a TATA box, whereas that for promoter P2, which lacks a TATA box, lies in a GC-rich region. In HKC cells, transcriptional activity of a P1 reporter gene construct was 11-fold and of P2 was 33-fold above basal levels. 10(-8) m 1,25(OH)2D3 stimulated P1 activity 2-fold and P2 activity 2.5-fold. Vitamin D response elements (VDREs), in which half-sites (6 bp) are separated by three nucleotides, were identified in both promoters and shown to confer 1,25(OH)2D3 responsiveness to a heterologous promoter. This responsiveness was lost when the VDREs were mutated. In electrophoretic mobility shift assays with either in vitro transcribed/translated vitamin D receptor and retinoid X receptor-alpha, or HKC nuclear extract, specific protein-DNA complexes were formed in the presence of 1,25(OH)2D3 on oligonucleotides representing the P1 and P2 VDREs. In summary, functional VDREs have been identified in the CASR gene and provide the mechanism whereby 1,25(OH)2D up-regulates parathyroid, thyroid C-cell, and kidney CASR expression.
Idiopathic hypercalciuria (IH) is the most common cause of calcium oxalate nephrolithiasis. Increased intestinal calcium absorption and bone resorption and decreased tubule calcium reabsorption may be caused by elevated serum 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] in some patients but not in those with normal serum 1,25(OH)(2)D(3) levels. Because 1,25(OH)(2)D(3) exerts its biological actions through binding to the cellular vitamin D receptor (VDR), the present study was undertaken to test the hypothesis that VDR levels are elevated in IH patients. Ten male IH calcium oxalate stone-formers were paired with controls matched in age within 5 yr and lacking a history of stones or family history of stones. Blood was obtained for serum, peripheral blood monocytes (PBMs) were separated from lymphocytes and other mononuclear cells, and PBM VDR content was measured by Western blotting. The PBM VDR level was 2-fold greater in IH men at 49 +/- 21 vs. 20 +/- 15 fmol/mg protein, mean +/- sd; P < 0.008. Serum 1,25(OH)(2)D(3) levels were not higher than controls (48 +/- 14 vs. 39 +/- 11 pg/ml; P < 0.068). In conclusion, PBM VDR levels are elevated in IH calcium oxalate stone-formers. The elevation could not be ascribed to increased serum 1,25(OH)(2)D(3) levels. These results suggest that the molecular basis for IH involves a pathological elevation of tissue VDR level, which may elevate intestinal calcium absorption and bone resorption and decrease renal tubule calcium reabsorption. The mechanism for increased VDR in IH patients with normal serum 1,25(OH)(2)D(3) levels is unknown.
Calcium balances and calcium kinetic studies using (47)Ca were performed in nine male patients with idiopathic hypercalciuria and in three normal male subjects. A sharp reduction in calcium intake in eight patients with idiopathic hypercalciuria caused a decrease in urinary calcium excretion, the latter remaining elevated above that reported for normal subjects on a low calcium diet. The hypercalciuric patients had an enlarged miscible calcium pool size, an increased calcium turnover rate, increased bone formation and bone resorption rates, and an elevated true intestinal calcium absorption rate, the increase of the latter three parameters being proportional to the increase of the turnover rate. The fraction of the calcium turnover rate excreted in the urine was elevated whereas that constituted by the endogenous fecal calcium excretion was decreased. Arguments are presented for the concept that the primary abnormality in idiopathic hypercalciuria is neither renal calcium hyperexcretion nor intestinal calcium hyperreabsorption, but a more fundamental disturbance in calcium metabolism of as yet unknown cause, leading to a high calcium turnover.
Absorptive hypercalciuria (AH), a common stone-forming condition characterized biochemically by intestinal hyperabsorption of calcium and hypercalciuria may be associated with bone loss. In AH type I (AH-1), hypercalciuria persists despite restriction in dietary calcium intake. We therefore hypothesized that the skeleton may contribute to the hypercalciuria in this subgroup of patients. Histomorphometric analysis of iliac crest biopsies were performed on nine stone-formers with AH-1 and on nine matched normal subjects. After stabilization on a stone-prevention diet, calcium homeostasis in the stone formers was then evaluated on inpatient constant metabolic diet before and after short-term blockade of bone resorption by alendronate (10 mg daily, 17 days total). Compared with controls, the stone-formers had lower indices of bone formation (osteoblast surface/bone surface 1.8+/-2.1 vs 3.0+/-1.5%, P=0.04; wall thickness 35.8+/-6.9 vs 47.2+/-7.6%, P=0.001) and relatively higher bone resorption (osteoclast surface/bone surface 0.4+/-0.2 vs 0.2+/-0.2%, P=0.05). In the stone-formers, a short-term course of alendronate treatment corrected fasting urinary calcium (0.14+/-0.06 to 0.06+/-0.04 mg Ca/mg Cr, P=0.001) and marginally reduced 24-h urinary calcium by 48 mg/day (P=0.06). Increased intestinal calcium absorption and hypercalciuria persisted, but estimated calcium balance improved (P=0.007). Our results suggest that the hypercalciuria of AH-1 originates primarily from intestinal hyperabsorption of calcium, but bone resorption in excess of bone formation may contribute.
An association between the R990G polymorphism of the CaSR gene, coding for calcium-sensing receptor, and primary hypercalciuria was found in kidney stone formers. To confirm this relationship, we investigated hypercalciuric women without stones and studied the effect of CaSR gene in human embryonic kidney cells (HEK-293). We genotyped for CaSR A986S, R990G, and Q1011E polymorphisms, 119 normocalciuric and 124 hypercalciuric women with negative history of kidney stones. Homozygous (n=2) or heterozygous (n=21) women for the 990G allele considered as one group had an increased risk to be hypercalciuric (odds ratio=5.2; P=0.001) and higher calcium excretion (P=0.005) in comparison with homozygous women for the 990R allele (n=220). HEK-293 cells were transfected with the variant allele at the three CaSR gene polymorphisms and with the most common allele with no variants. The transient increment of intracellular calcium caused by the stepwise increase of extracellular calcium was evaluated in stable transfected cells loaded with fura-2 AM. The extracellular calcium concentration producing the half-maximal intracellular calcium response was lower in HEK-293 cells transfected with the 990G allele than in those transfected with the wild-type allele (P=0.0001). Our findings indicate that R990G polymorphism results in a gain-of-function of the calcium-sensing receptor and increased susceptibility to primary hypercalciuria.
Objectives:
Biallelic pathogenic variants in CYPA24A1 and SLC34A1 are causes of idiopathic infantile hypercalcemia. Pathogenic variants in both may also give rise to hypercalciuria with nephrocalcinosis or nephrolithiasis without previous hypercalcemia (renal group). Our objective was to examine the frequency of CYP24A1 or SLC34A1 variants in children with early hypercalcemia or late-onset hypercalciuria.
Method:
Forty-one children from 7 centers across Canada were recruited. Local investigations were undertaken. The serum was evaluated by liquid chromatography tandem-mass spectrometry for the ratio of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3, (25-OH-D3:24,25-(OH)2D3), an elevation pathognomonic for the loss of function of the CYP24A1 enzyme. Mutational analyses were undertaken. Family cascade screening was performed if pathogenic variants were detected in probands.
Results:
Twenty-nine children had early-onset hypercalcemia; none had elevated 25-OH-D3:24,25-(OH)2D3 or variants. Interestingly, 2 of 12 in the renal group had elevated 25-OH-D3:24,25-(OH)2D3 and presented as preadolescents. In case 1, cascade testing revealed a sibling and parent with asymptomatic pathogenic variants in CYP24A1. Four CYP24A1 pathogenic variants were identified in these 2 probands: 3 have been described in European populations, and 1 is a rare variant in exon 7 (c931delC) that is likely pathogenic. No SLC34A1 pathogenic variants were detected.
Conclusion:
In Canada, pathogenic variants in CYP24A1 appear to manifest with late-onset hypercalciuria and its sequelae. The 25-OH-D3:24,25-(OH)2D3 ratio is an excellent tool for screening for biallelic pathogenic variants in CYP24A1. We confirm that cascade testing is important for these variants.
Idiopathic hypercalciuria increases the risk of urinary stones and osteoporosis. The aim of this review is to delineate our current understanding of idiopathic hypercalciuria in the context of bone health, specifi cally its defi nition, causes, epidemiology, laboratory evaluation, and potential treatments. KEY POINTS Idiopathic hypercalciuria is common in patients with kidney stones and is also present in up to 20% of postmenopausal women with osteoporosis but no history of kidney stones. Idiopathic hypercalciuria has been directly implicated as a cause of loss of trabecular bone, especially in men. But reversing the hypercalciuria in this condition has not been defi nitively shown to diminish fracture incidence. Patients with kidney stones who have low bone mass and idiopathic hypercalciuria should increase their daily fluid intake, follow a diet low in salt and animal protein, and take thiazide diuretics to reduce the risk of further calcium stone formation. Whether this approach also improves bone mass and strength and reduces fracture risk in this patient group requires further study.
Vitamin D is important in maintaining calcium homeostasis, but its role in kidney stone disease and its effect on stone formation are still not clear.
Kidney stone formers tend to experience enhanced intestinal calcium absorption, increased urinary calcium excretion, and excessive bone mineral loss. Although direct actions of active vitamin D have been implicated in all these processes, the effect of nutritional vitamin D (vitamin D2 or vitamin D3) use on calcium balance among stone formers is still not clear. In addition, the safety of nutritional vitamin D use in the stone forming population is also not established, considering the potential effect of its use on raising urinary calcium. However, most of the observational studies do not support a significant association between higher nutritional vitamin D store and increased risk of stone formation. Short-term nutritional vitamin D repletion in stone formers with vitamin D deficiency also does not appear to increase urinary calcium excretion.
The effect of nutritional vitamin D use in stone formers is still not clear. As vitamin D deficiency is highly prevalent among stone formers, future prospective studies are needed to establish the biological effect, as well as the safety and efficacy of nutritional vitamin D therapy in this unique patient population.
The frequency of hypercalciuria was determined in the families of nine hypercalciuric patients with idiopathic hypercaliuria who formed recurrent calcium oxalate renal stones. Idiopathic hypercalciuria occurred in 26 of 73 relatives, in three consecutive generations of two families and in two successive generations of four other families. Multiple siblings or children of the probands were affected in three families. Nineteen of 44 first-degree relatives (43 per cent) had idiopathic hypercalciuria, as compared to seven of 29 (29 per cent) other relatives; there was no relation to age or sex. Renal stones were formed by 19 of the 44 first-degree relatives but by none of the others; nine of the 19 were women. We conclude that there is a familial form of hypercalciuria, which appears to be transmitted as an autosomal dominant trait. Stone disease is frequent in first-degree relatives, and affects both sexes equally.
Forty-seven patients were identified as having persistent hypercalciuria during a period of low calcium intake (< 400 mg/24 hours). They were divided into two types on the basis of their serum immunoreactive parathyroid hormone (PTH) values: type 2 patients had increased, and type 3 patients had normal or low values. It was concluded that in type 3 patients hypercalciuria developed as a result of a primary renal phosphate leak.Type 2 patients were divided into two subtypes on the basis of their response to the administration of methylchlorothiazide and 25-hydroxyvitamin D3 (25(OH)D3). Type 2a patients responded to either treatment with little change in serum calcium, an increase in serum phosphate and a decrease in serum immunoreactive PTH concentration. They were classified as having suppressible hyperparathyroidism secondary to a primary renal calcium leak. Type 2b patients responded to both thiazide and 25(OH)D3 therapy with an increase in serum calcium concentration and no decrease in immunoreactive PTH. They were classified as having nonsuppressible normocalcemic hyperparathyroidism and underwent successful parathyroid surgery. However, they had persistent postoperative hypercalciuria, and several had suppressible hyperparathyroidism several years after their successful parathyroid surgery. On the basis of these facts, type 2b patients were also considered to have a long-standing primary renal calcium leak that led initially to secondary hyperparathyroidism but eventually to tertiary or nonsuppressible hyperparathyroidism.
Compared with age-matched control subjects, 15 patients with IH did not differ in serum Ca; had significantly lower serum iPTH, serum phosphorus, TmP/GFR; and significantly higher urine calcium, fractional enteral calcium absorption and serum 1,25-diOHD. Because serum iPTH was not higher than in controls, these patients were considered to have absorptive rather than renal hypercalciuria. In phosphorus-depleted animals, the low serum phosphorus or some closely associated factor is thought to be responsible for the high serum 1,25-diOHD, and this could apply to IH patients as well. In the IH group, the low TmP/GFR was directly related to and probably contributed to the low serum phosphorus. In pooled data (IH and control), there was a negative correlation between serum iPTH and log serum 1,25-diOHD which was still present when the effect of serum calcium was removed, consistent with the concept that 1,25-diOHD inhibits PTH secretion. In IH patients there was a negative correlation between serum phosphorus and urine Ca, perhaps reflecting the combined effects of a high serum 1,25-diOHD and a low serum iPTH to raise urine Ca. The high serum 1,25-diOHD and low serum iPTH both function to raise serum phosphorus and therefore cannot account for the low serum phosphorus and TmP/GFR in IH. Together, these findings are consistent with the concept that the primary defect in IH is impaired TRP, that the hormonal changes represent an attempt to correct the low serum phosphorus, and that the hypercalciuria is a consequence of this control mechanism.
Dual-energy x-ray absorptiometry and single-photon absorptiometry were used to determine bone density at the lumbar spine and radial shaft in 62 patients with absorptive hypercalciuria, 27 patients with fasting hypercalciuria, and 31 nonhypercalciuric stone formers. Lumbar bone density was significantly lower in patients with absorptive (-10%) as well as in those with fasting hypercalciuria (-12%), with 74 and 92% of patients displaying values below the normal mean, whereas only 48% of the nonhypercalciuric stone formers had bone density values below the normal mean. In contrast, radial bone density was similar in all three groups of renal stone formers investigated. The comparison of urinary chemistry in patients with absorptive hypercalciuria and low normal bone density compared to those with high normal bone density showed a significantly increased 24 h urinary calcium excretion on random diet and a trend toward a higher 24 h urinary uric acid excretion and a higher body mass index in patients with low normal bone density. Moreover, among the patients with absorptive hypercalciuria we found a statistically significant correlation between the spinal bone density and the 24 h sodium and sulfate excretion and the urinary pH. These results gave evidence for an additional role of environmental factors (sodium and animal proteins) in the pathogenesis of bone loss in absorptive hypercalciuria. In conclusion, our data suggest an osteopenia of trabecular-rich bone tissues in patients with fasting and absorptive hypercalciurias.
Using an in vitro method, the uptake of radio-labelled Ca2+ by jejunal biopsy specimens from control subjects, patients with idiopathic hypercalciuria and patients with renal stones without hypercalciuria, were compared. Radio-labelled Ca2+ uptake was investigated over the concentration range 0.1-5.0 mmol/l. For all subjects there was a linear relationship between Ca2+ uptake and medium concentration suggesting that Ca2+ uptake was a passive process. There was no significant difference in Ca2+ uptake between control subjects and patients with renal stones without hypercalciuria. Patients with idiopathic hypercalciuria, both absorptive and renal subtypes, showed increased Ca2+ uptake at all incubation medium concentrations. Assays of various biochemical parameters including alkaline phosphatase, Ca2+-activated ATPase, cyclic AMP and Ca2+-binding protein, in jejunal biopsy specimens showed no significant differences between control subjects and patients with idiopathic hypercalciuria. The results suggest that the intestinal abnormality in idiopathic hypercalciuria is due to enhanced permeability of the brush border membrane to Ca2+, possibly mediated by alterations in membrane lipids.
We compared the effects of four vitamin D metabolites, 1 alpha,25 dihydroxy vitamin D3 (1 alpha,25(OH)2D3), 1 alpha hydroxy vitamin D3 (1 alpha OH D3), 25 hydroxy vitamin D3 (25 OH D3), and 24R,25 dihydroxy vitamin D (24R,25(OH)sD3) on resorption and collagen synthesis in fetal rat bone maintained in organ culture. Resorption was quantitated by measuring the release of previously incorporated 45Ca from long bone shafts of 19-day fetal rats, and collagen synthesis was assessed by measuring the incorporation of 3H-proline into collagenase digestible protein (CDP) in calvaria from 21-day fetal rats. All four compounds stimulated bone resorption and inhibited collagen synthesis, but 1 alpha,25(OH)2D3 was approximately 1000 times more potent in both organ culture systems. Although the differences were small among the other three compounds, the order of potency was 1 alpha OH d3 > 25 OH D3 greater than or equal to 24R,25(OH)2D3. These results suggest that the receptor for 1 alpha 25(OH)2D3 in both bone resorbing and bone forming cells has similar affinities for several vitamin D metabolites.
Absorptive hypercalciuria (a stone-forming condition) is characterized by gut hyperabsorption of calcium, hypercalciuria, and reduced bone density. Inasmuch as these features implicate enhanced calcitriol action in gut and bone, we analyzed the vitamin D receptor (VDR) gene to ascertain whether an abnormality of this gene marks patients with intestinal hyperabsorption of calcium. We have compared the frequency of a restriction fragment length polymorphism (Bsm I) associated with different alleles of the VDR gene in a group of 33 well characterized absorptive hypercalciuric patients and a group of 36 normal race- and age-matched control subjects. There was no difference between the distribution of the VDR alleles in the patient population when compared with the normal population. The coding region of VDR messenger RNA was also normal, as determined by both DNA sequence analysis and chemical mismatch cleavage analysis of copy DNA from 11 index absorptive hypercalciuric patients. On the basis of these results, we propose that the enhanced intestinal calcium absorption invariably seen in absorptive hypercalciuria and attendant symptoms of this disorder are not attributable to mutations of the VDR and are not linked to a common VDR genotype.
To assess bone mineral density (BMD) in idiopathic calcium nephrolithiasis, dual-energy x-ray absorptiometry was performed at lumbar spine, upper femur (femoral neck, Ward's triangle, and total area), distal tibial diaphysis, and distal tibial epiphysis in 110 male idiopathic calcium stone formers (ICSF); 49 with and 61 without hypercalciuria on free-choice diet). Results were compared with those obtained in 234 healthy male controls, using (1) noncorrected BMD, (2) BMD corrected for age, height, and BMI, and (3) a skeletal score based on a tercile distribution of BMD values at following four sites: lumbar spine, Ward's triangle, tibial diaphysis, and tibial epiphysis. After correction, BMD--and therefore also skeletal score--tended to be lower in the stone formers than in controls at five of the six measurement sites, that is, lumbar spine, upper femur, Ward's triangle, tibial diaphysis, and tibial epiphysis, limit of significance being reached for the last two sites without difference between hypercalciuric (HCSF) and normocalciuric stone formers (NCSF). Estimated current daily calcium intake was significantly lower in patients (616 +/- 499 mg/24 h, mean +/- SEM) than in controls (773 +/- 532, p = 0.02). Of 17 patients who in the past had received a low-calcium diet for at least 1 year, 10 had a low skeletal score (4-6) whereas only 1 had a high score (10-12; p = 0.037). Of the 12 stone formers in the study with skeletal score 4 (i.e., the lowest), 8 had experienced in the past one or more fractures of any kind versus only 19 of the remaining 77 patients with skeletal score 5-12 (p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Evaluations of 1,270 patients with recurrent nephrolithiasis in an outpatient setting were analyzed for the purpose of updating the classification of nephrolithiasis. All but 4% had abnormal urinary biochemistry that placed them into one or more of 20 etiologic categories. A single diagnosis was documented in 41.3% of patients. The remaining 58.7% had more than one diagnosis. Hypercalciuric calcium (Ca) nephrolithiasis, encountered in 60.9% of patients, comprised six variants--absorptive hypercalciuria Type I and II, renal hypercalciuria, primary hyperparathyroidism, and unclassified hypercalciuria (renal phosphate leak and fasting hypercalciuria). Hyperuricosuria Ca nephrolithiasis (HUCN) and gouty diathesis (GD) accounted for 35.8% and 10.0% of patients, respectively. Distinguishing features were hyperuricosuria and normal urinary pH in HUCN, and normal urinary uric acid and low urinary pH (< 5.5) in GD. Hyperoxaluric Ca nephrolithiasis, occurring in 8.1% of patients, was subdivided into enteric, primary, and dietary variants. Hypocitraturic Ca nephrolithiasis affected 28% of patients in its idiopathic variant. Many of these patients' problems were probably dietary in origin, while some could have had incomplete renal tubular acidosis. Hypocitraturia due to renal tubular acidosis or chronic diarrheal syndrome affected only 3.3% of patients. Hypomagnesiuric Ca nephrolithiasis, infection stones, and cystinuria were uncommon, accounting for 6.8%, 5.9%, and 0.9% of patients, respectively. The acquired problem of low urine volume (< 1 L/d) was found in 15.3% of patients. The remaining 3.5% of patients were difficult to classify despite the presence of abnormal urinary biochemistry.
In humans, familial or idiopathic hypercalciuria (IH) is a common cause of hypercalciuria and predisposes to calcium oxalate nephrolithiasis. Intestinal calcium hyperabsorption is a constant feature of IH and may be due to either a vitamin D-independent process in the intestine, a primary overproduction of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], or a defect in renal tubular calcium reabsorption. Selective breeding of spontaneously hypercalciuric male and female Sprague-Dawley rats resulted in offspring with hypercalciuria, increased intestinal calcium absorption, and normal serum 1,25(OH)2D3 levels. The role of the vitamin D receptor (VDR) in the regulation of intestinal calcium absorption was explored in 10th generation male genetic IH rats and normocalciuric controls. Urine calcium excretion was greater in IH rats than controls (2.9 +/- 0.3 vs. 0.7 +/- 0.2 mg/24 h, P < 0.001). IH rat intestine contained twice the abundance of VDR compared with normocalciuric controls (536 +/- 73 vs. 243 +/- 42 nmol/mg protein, P < 0.001), with no difference in the affinity of the receptor for its ligand. Comparable migration of IH and normal intestinal VDR on Western blots and of intestinal VDR mRNA by Northern analysis suggests that the VDR in IH rat intestine is not due to large deletion or addition mutations of the wild-type VDR. IH rat intestine contained greater concentrations of vitamin D-dependent calbindin 9-kD protein. The present studies strongly suggest that increased intestinal VDR number and normal levels of circulating 1,25(OH)2D3 result in increased functional VDR-1,25(OH)2D3 complexes, which exert biological actions in enterocytes to increase intestinal calcium transport. Intestinal calcium hyperabsorption in the IH rat may be the first example of a genetic disorder resulting from a pathologic increase in VDR.
To study the effect of vitamin D on calcium (Ca2+) reabsorption by the kidney, we measured Ca2+ uptake by the basolateral and luminal membranes of proximal and distal tubules obtained from rabbits fed a vitamin D-deficient diet for 3 weeks. Results were compared to those obtained with a group of control animals fed a normal diet. Serum Ca2+ concentrations were comparable in both groups. In the control group, serum PTH, 25-hydroxyvitamin D3, and 1,25-dihydroxyvitamin D3 remained relatively stable. In the vitamin D-deficient animals, serum PTH levels slightly, but not significantly, increased, and the levels of vitamin D metabolites abruptly fell. Vitamin D depletion produced a 40% decrease in ATP-dependent Ca2+ uptake by the basolateral membrane of the distal tubule. There was no change in the activity of the Na+/Ca2+ exchanger. A very significant effect was also observed in the luminal membrane of the distal tubule, where a 50% decrease in Ca2+ uptake was observed after the third week of vitamin depletion. Administration of 0.1 microgram 1,25-dihydroxyvitamin D3 16 and 2 h before death partially reestablished normal uptake. In contrast, no change in Ca2+ uptake could be detected in the basolateral or luminal membranes of the proximal tubule. These observations provide the first evidence of an effect of vitamin D on Ca2+ transport at both the basolateral and luminal membranes of the distal segment of the nephron.
We determined the mode of inheritance of idiopathic hypercalciuria and its subtypes.
We evaluated 40 children with symptomatic idiopathic hypercalciuria and 129 of their first-degree relatives (80 parents and 49 siblings). In hypercalciuric individuals in families with at least 2 affected members the type of idiopathic hypercalciuria was determined by the calcium loading test.
Of the 40 affected children 19 (47.5%) had 1 or more affected first-degree relatives (23 of 80 parents and 2 of 49 siblings). In all 44 affected members of the 19 hypercalciuric families (19 index cases, 23 parents and 2 siblings) the type of idiopathic hypercalciuria was determined (absorptive in 38 and renal in 6). Study of the pedigree of the 19 families showed that idiopathic hypercalciuria appears to be transmitted as an autosomal dominant trait. With only 1 exception the subtype of disease was specific for members of the same family.
Idiopathic hypercalciuria has a familial or sporadic pattern. In the familial pattern an autosomal dominant inheritance is present. The type of the disease is identical in affected members of the same family. The absorptive subtype is more frequent.
Calcium is the principal crystalline constituent in up to 80% of kidney stones. Epidemiologic studies have suggested that genetic predisposition plays a major role in the etiology of this condition. This study evaluates by a candidate-gene approach whether the vitamin D receptor (VDR) locus on chromosome 12q12-14 is implicated in idiopathic hypercalciuria and calcium nephrolithiasis in a cohort of 47 French Canadian pedigrees. These comprised 54 sibships with a total of 303 pairs of siblings concordant for > or =1 stone episode. Evidence is provided for linkage to nephrolithiasis with microsatellite marker D12S339 (near the VDR locus, P = 0.01), as well as with flanking markers (D12S1663: P = 0.03 and D12S368: P = 0.01). Inclusion of unaffected sibs in the analyses also supported evidence for linkage. Quantitative trait linkage analysis of urinary calcium excretion yielded linkage to some, but not all, markers. This appears to be the first study to suggest linkage for idiopathic calcium stone formation.
Results of a 24-hour urine collection are integral to the selection of the most appropriate intervention to prevent kidney stone recurrence. However, the currently accepted definitions of normal urine values are not firmly supported by the literature. In addition, little information is available about the relationship between risk of stone formation and the levels of urinary factors. Unfortunately, the majority of previous studies of 24-hour urine chemistries were limited by the inclusion of recurrent stone formers and poorly defined controls.
We obtained 24-hour urine collections from 807 men and women with a history of kidney stone disease and 239 without a history who were participants in three large ongoing cohort studies: the Nurses' Health Study I (NHS I; mean age of 61 years), the Nurses' Health Study II (NHS II; mean age of 42 years), and the Health Professionals Follow-up Study (HPFS; mean age of 59 years).
Mean 24-hour urine calcium excretion was higher and urine volume was lower in cases than controls in NHS I (P < or = 0.01), NHS II (P < or = 0.13) and HPFS (P < or = 0.01), but urine oxalate and citrate did not differ. Among women, urine uric acid was similar in cases and controls but was lower in cases in men (P = 0.06). The frequency of hypercalciuria was higher among the cases in NHS I (P = 0.26), NHS II (P = 0.03), and HPFS (P = 0.02), but 27, 17, and 14% of the controls, respectively, also met the definition of hypercalciuria. The frequency of hyperoxaluria did not differ between cases and controls, but was three times more common among men compared with women. After adjusting for the other urinary factors, the relative risk of stone formation increased with increasing urine calcium levels and concentration in all three cohorts but not in a linear fashion. Compared with individuals with a urine calcium concentration of <75 mg/L, the relative risk of stone formation among those with a urine calcium concentration of > or =200 mg/L for NHS I was 4.34 (95% CI, 1.59 to 11.88), for NHS II was 51.09 (4.27 to 611.1), and for HPFS was 4.30 (1.71 to 10.84). There was substantial variation in the relative risks for stone formation for the concentration of other urine factors within the different cohorts.
The traditional definitions of normal 24-hour urine values need to be reassessed, as a substantial proportion of controls would be defined as abnormal, and the association with risk of stone formation may be continuous rather than dichotomous. The 24-hour urine chemistries are important for predicting risk of stone formation, but the significance and the magnitudes of the associations appear to differ by age and gender.
The epithelial Ca(2+) channel (ECaC) exhibits the defining properties for being the gatekeeper in 1,25-dihydroxyvitamin D(3)-regulated Ca(2+) (re)absorption. Its recently cloned human orthologue (ECaC1) could, therefore, represent a crucial molecule in human disorders related to Ca(2+)-wasting such as idiopathic hypercalciuria (IH).
Fifty-seven members of nine families with IH were investigated. Phenotyping was performed by measurements of urinary Ca(2+) excretion, while other underlying disorders were appropriately excluded. Initially, the recently suggested locus for kidney stone-associated hypercalciuria on chromosome 1q23.3-q24 was investigated. Next, direct mutation analysis of all 15 exons of the ECAC1 gene and 2.9 kb upstream from the start codon was performed. hECaC1, heterologously expressed in human embryonic kidney 293 cells, was characterized by patch-clamp analysis.
The mode of inheritance in the studied pedigrees is consistent with an autosomal dominant trait. Haplotype analysis did not implicate a role of the locus on chromosome 1. The coding sequence of the ECAC1 gene was not different between the affected and the non-affected family members. In the 5'-flanking region, three single nucleotide polymorphisms were encountered, but these polymorphisms were observed regardless of the affection status of the screened family members. Patch-clamp analysis of hECaC1 was performed as the putative pore region contains four non-conserved amino acid substitutions compared with the other species. This analysis revealed the distinctive properties of ECaC, including a high Ca(2+) selectivity, inward rectification, and Ca(2+)-dependent inactivation.
These results do not support a primary role for hECaC1 in IH in nine affected families. Because of the heterogeneity of the disease, however, the involvement of ECaC1 in other subtypes of IH cannot be excluded and needs further investigation. The electrophysiological properties of hECaC1 further substantiate its prime role in Ca(2+) (re)absorption.
To investigate the association between fasting idiopathic hypercalciuria (IHc), defined as IHc in the fasting state associated with normal parathyroid function, and ApaI, BsmI, and FokI polymorphisms of the vitamin D receptor (VDR) gene in 159 hypercalciuric recurrent stone formers. IHc contributes to the formation of calcium kidney stones in more than one half of reported cases.
We examined 62 patients with fasting IHc (24 women, mean age 42.8 +/- 11.1 years, body mass index 25.7 +/- 4.8 kg/m2), 97 patients with absorptive IHc (41 women, mean age 43.5 +/- 10.8 years, body mass index 26.1 +/- 4.4 kg/m2), and 124 healthy control subjects (52 women, mean age 41.9 +/- 10.4 years, body mass index 25.4 +/- 5.1 kg/m2) without a history of nephrolithiasis and without IHc. The bone mass density and VDR genotype and haplotype frequencies were determined in the studied populations.
A reduced bone mass density was observed in fasting IHc patients compared with absorptive IHc patients (P = 0.009) and control subjects (P = 0.006). The prevalence of ApaI and BsmI VDR genotypes and alleles in patients with fasting IHc was significantly different statistically (P <0.05) from that observed in patients with absorptive IHc and control subjects, and the ba haplotype was overrepresented in these patients. No statistically significant difference in the distribution of FokI VDR genotypes and alleles was found between the studied groups.
Our results suggest a genetic association between 3' VDR alleles, fasting IHc, and reduced bone mass density in patients with recurrent stone formation.
Ca(2+) is an essential ion in all organisms, where it plays a crucial role in processes ranging from the formation and maintenance of the skeleton to the temporal and spatial regulation of neuronal function. The Ca(2+) balance is maintained by the concerted action of three organ systems, including the gastrointestinal tract, bone, and kidney. An adult ingests on average 1 g Ca(2+) daily from which 0.35 g is absorbed in the small intestine by a mechanism that is controlled primarily by the calciotropic hormones. To maintain the Ca(2+) balance, the kidney must excrete the same amount of Ca(2+) that the small intestine absorbs. This is accomplished by a combination of filtration of Ca(2+) across the glomeruli and subsequent reabsorption of the filtered Ca(2+) along the renal tubules. Bone turnover is a continuous process involving both resorption of existing bone and deposition of new bone. The above-mentioned Ca(2+) fluxes are stimulated by the synergistic actions of active vitamin D (1,25-dihydroxyvitamin D(3)) and parathyroid hormone. Until recently, the mechanism by which Ca(2+) enter the absorptive epithelia was unknown. A major breakthrough in completing the molecular details of these pathways was the identification of the epithelial Ca(2+) channel family consisting of two members: TRPV5 and TRPV6. Functional analysis indicated that these Ca(2+) channels constitute the rate-limiting step in Ca(2+)-transporting epithelia. They form the prime target for hormonal control of the active Ca(2+) flux from the intestinal lumen or urine space to the blood compartment. This review describes the characteristics of epithelial Ca(2+) transport in general and highlights in particular the distinctive features and the physiological relevance of the new epithelial Ca(2+) channels accumulating in a comprehensive model for epithelial Ca(2+) absorption.
A body of evidence establishes that the occurrence of kidney stone disease has increased in some communities of industrialized countries. Information on recent temporal trends in the United States is lacking and population-based data on epidemiologic patterns are limited. Study objective was to determine whether kidney stone disease prevalence increased in the United States over a 20-year period and the influence of region, race/ethnicity, and gender on stone disease risk.
We measured the prevalence of kidney stone disease history from the United States National Health and Nutrition Examination Survey (II and III), population-based, cross-sectional studies, involving 15,364 adult United States residents in 1976 to 1980 and 16,115 adult United States residents in 1988 to 1994.
Disease prevalence among 20- to 74-year-old United States residents was greater in 1988 to 1994 than in 1976 to 1980 (5.2% vs. 3.8%, P < 0.05), greater in males than females, and increased with age in each time period. Among 1988 to 1994 adults, non-Hispanic African Americans had reduced risk of disease compared to non-Hispanic Caucasians (1.7% vs. 5.9%, P < 0.05), and Mexican Americans (1.7% vs. 2.6%, P < 0.05). Also, age-adjusted prevalence was highest in the South (6.6%) and lowest in the West (3.3%). Findings were consistent across gender and multivariate adjusted odds ratios for stone disease history, including all demographic variables, as well as diuretic use, tea or coffee consumption, and dietary intake of calcium, protein, and fat did not materially change the results.
Prevalence of kidney stone disease history in the United States population increased between 1980 and 1994. A history of stone disease was strongly associated with race/ethnicity and region of residence.
A decrease in renal phosphate reabsorption with mild hypophosphatemia (phosphate leak) is found in some hypercalciuric stone-formers. The NPT2a gene encodes a sodium-phosphate cotransporter, located in the proximal tubule, responsible for reclaiming most of the filtered phosphate load in a rate-limiting manner. To determine whether genetic variation of the NPT2a gene is associated with phosphate leak and hypercalciuria in a cohort of 98 pedigrees with multiple hypercalciuric stone-formers, we sequenced the entire cDNA coding region of 28 probands, whose tubular reabsorption of phosphate normalized for the glomerular filtration rate (TmP/GFR) was 0.7 mmol/l or lower. We performed genotype/phenotype correlations for each genetic variant in the entire cohort and expressed NPT2a variant RNAs in Xenopus laevis oocytes to test for cotransporter functionality. We identified several variants in the coding region including an in-frame 21 bp deletion truncating the N-terminal cytoplasmic tail of the protein (91del7), as well as other single-nucleotide polymorphisms that were non-synonymous (A133V and H568Y) or synonymous. Levels of TmP/GFR and urine calcium excretion were similar in heterozygote carriers of NPT2a variants compared to the wild-type (wt) homozygotes. The transport activity of the H568Y mutants was identical to the wt, whereas the N-terminal-truncated version and the 91del7 and A133V mutants presented minor kinetic changes and a reduction in the expression level. Although genetic variants of NPT2a are not rare, they do not seem to be associated with clinically significant renal phosphate or calcium handling anomalies in a large cohort of hypercalciuric stone-forming pedigrees.
We will describe the pathophysiology of hypercalciuria and the mechanism of the resultant stone formation in a rat model and draw parallels to human hypercalciuria and stone formation.
Through inbreeding we have established a strain of rats that excrete 8-10 times more urinary calcium than control rats. These genetic hypercalciuric rats absorb more dietary calcium at lower 1,25-dihydroxyvitamin D3 levels. Elevated urinary calcium excretion on a low-calcium diet indicated a defect in renal calcium reabsorption and/or an increase in bone resorption. Bone from hypercalciuric rats released more calcium when exposed to 1,25-dihydroxyvitamin D3. Bisphosphonate significantly reduced urinary calcium excretion in rats fed a low-calcium diet. Clearance studies showed a primary defect in renal calcium reabsorption. The intestine, bone and kidneys of the hypercalciuric rats had increased numbers of vitamin D receptors. When hydroxyproline is added to their diet they form calcium oxalate stones, the most common stone type in humans. Increased numbers of vitamin D receptors may cause hypercalciuria in these rats and humans.
Understanding the mechanism of hypercalciuria and stone formation in this animal model will help clinicians devise effective treatment strategies for preventing recurrent stone formation in humans.
In renal proximal tubules, VDR is transiently decreased by parathyroid hormone (PTH) during times of hypocalcemia and returns to normal levels with the rise in serum calcium (Ca). In this study we tested the hypothesis that elevated extracellular Ca induces VDR in a human renal proximal cell line (HK-2G) stably expressing PTH receptor type I. Exposure of HK-2G cells to increasing Ca concentration, up to 3mM, induced the expression of VDR. The increase in VDR occurred within 1h and was sustained over 24h. The increase in VDR was also dose-dependently increased using 20-100 nM gadolinium, suggesting the induction of VDR is regulated via the extracellular Ca sensing receptor (CaSR) with is naturally expressed in HK-2G cells. In conclusion, an extracellular Ca concentration in the physiological range is capable of direct increase of renal proximal VDR expression, and the induction mechanism represents a strategy the body may use to counterbalance effects of PTH on renal Vitamin D metabolism.
Idiopathic hypercalciuria (IH) is common among calcium stone formers (IHSF). The increased urinary calcium arises from increased intestinal absorption of calcium, but it is unclear whether increased filtered load or decreased renal tubular reabsorption of calcium is the main mechanism for the increased renal excretion. To explore this question, 10 IHSF and 7 normal subjects (N) were studied for 1 day. Urine and blood samples were collected at 30- to 60-min intervals while subjects were fasting and after they ate three meals providing known amounts of calcium, phosphorus, sodium, protein, and calories. Fasting and fed, ultrafiltrable calcium levels, and filtered load of calcium did not differ between N and IHSF. Urine calcium rose with meals, and fractional reabsorption fell in all subjects, but the change was significantly higher in IHSF. The changes in calcium excretion were independent of sodium excretion. Serum parathyroid hormone levels did not differ between N and IHSF, and they could not account for the greater fall in calcium reabsorption in IHSF. Serum magnesium and phosphorus levels in IHSF were below N throughout the day, and tubule phosphate reabsorption was lower in IHSF than N after meals. The primary mechanism by which kidneys ferry absorbed calcium into the urine after meals is via reduced tubule calcium reabsorption, and IHSF differ from N in the magnitude of the response. Parathyroid hormone is not likely to be a sufficient explanation for this difference.
Observational and epidemiologic studies alike have shown that idiopathic hypercalciuric (IH) stone-forming patients typically show bone mineral density scores that are significantly lower than those observed for age- and sex-matched normal subjects or those for nonhypercalciuric stone-forming patients. Most of these studies have relied on changes in bone mineral density and have not explored the mechanism(s) involved. There have been a small number of studies that have relied on dynamic bone histomorphometry to ascertain the nature of the bone defect in IH patients. When performed, these studies clearly have shown increased bone resorption and high bone turnover in patients with fasting hypercalciuria whereas suppressed bone formation indices are the most consistent finding in patients with the absorptive variant of IH. The causes of this apparent difference in bone remodeling between the 2 variants of IH still is uncertain. Available evidence suggests that potential mechanisms may be dependent in large part to genetic, metabolic, and nutritional causes of hypercalciuria and bone loss in patients with IH.
Idiopathic hypercalciuria (IH) is the most common metabolic abnormality in patients with calcium kidney stones. It is characterized by normocalcemia, absence of diseases that cause increased urine calcium, and calcium excretion that is greater than 250 mg/d in women and 300 mg/d in men. Subjects with IH have a generalized increase in calcium turnover, which includes increased gut calcium absorption, decreased renal calcium reabsorption, and a tendency to lose calcium from bone. Despite the increase in intestinal calcium absorption, a negative calcium balance is seen commonly in balance studies, especially on a low-calcium diet. The mediator of decreased renal calcium reabsorption is not clear; it is not associated with either an increase in filtered load of calcium or altered parathyroid hormone levels. There is an increased incidence of hypercalciuria in first-degree relatives of those with IH, but IH appears to be a complex polygenic trait with a large contribution from diet to expression of increased calcium excretion. Increased tissue vitamin D response may be responsible for the manifestations of IH in at least some patients.
Cytochrome P-450 metabolites mediate extracellular Ca(2+)-induced inhibition of apical K+ channels in the TAL
- W H Wang
- M Lu
- S C Hebert
Wang WH, Lu M, Hebert SC. Cytochrome P-450 metabolites mediate extracellular Ca(2+)-induced inhibition of apical K+ channels in the TAL. Am J Physiol 1996;271:C103-11.PMID:8760035