A functional allelic variant of the FGF23 gene is associated with renal phosphate leak in calcium nephrolithiasis.

BACKGROUND: A significant percentage of patients with calcium nephrolithiasis and normal parathyroid function have renal phosphate leak. This disorder is characterized by idiopathic hypophosphatemia and reduced renal phosphate threshold normalized for the glomerular filtration rate (TmPi/GFR). The majority of these patients harbor high or inappropriately normal circulating levels of fibroblast growth factor 23 (FGF23), a hormone regulating phosphate homeostasis. AIM: The aim of this study was to define the role of FGF23 allelic variants in the pathogenesis of hypophosphatemic nephrolithiasis. SUBJECTS AND METHODS: We sequenced the regulative and coding regions of the FGF23 gene in 106 stone formers, 17 of which had renal phosphate leak, and in 87 healthy controls. We subsequently performed in vitro studies. RESULTS: A C716T nonsynonymous change (T239M, rs7955866) in the FGF23 gene was detected in seven of the 17 stone formers with renal phosphate leak. The prevalence of the T allele and of the CT genotype in stone formers with renal phosphate leak was significantly higher compared to that observed in stone formers without renal phosphate leak and in controls (P < 0.03 in all cases). In the whole study population, FGF23(716T) subjects showed levels of serum phosphate and TmPi/GFR significantly lower compared to FGF23(716C) subjects. In vitro studies showed that the T239M change increases FGF23 secretion and that the FGF23(239M) variant induces a higher activation of the FGF receptor/ERK pathway compared to FGF23(239T). CONCLUSION: Our results highlight a novel significant association between the C716T missense variation in the FGF23 gene and calcium nephrolithiasis with renal phosphate leak.

A nonsynonymous TNFRSF11A variation increases NFκB activity and the severity of Paget's disease.

Mutations in the SQSTM1 gene were identified as a common cause of Paget's disease of bone (PDB) but experimental evidence demonstrated that SQSTM1 mutation is not sufficient to induce PDB in vivo. Here, we identified two nonsynonymous single nucleotide polymorphisms (SNPs) (C421T, H141Y and T575C, V192A) in the TNFRSF11A gene, associated with PDB and with the severity of phenotype in a large population of 654 unrelated patients that were previously screened for SQSTM1 gene mutations. The largest effect was found for the T575C variant, yielding an odds ratio of 1.29 (p = 0.003), with the C allele as the risk allele. Moreover, an even more significant p-value (p = 0.0002) was observed in the subgroup of patients with SQSTM1 mutation, with an odds ratio of 1.71. Interestingly, patients with the C allele also showed an increased prevalence of polyostotic disease (68%, 53%, and 51% in patients with CC, CT, and TT genotypes, respectively; p = 0.01), as well as an increased number of affected skeletal sites (2.9, 2.5, and 2.0 in patients with CC, CT, and TT genotypes, respectively, p = 0.008). These differences increased when analyses were restricted to cases with SQSTM1 mutation. In human cell lines, cotrasfection with mutated SQSTM1 and TNFRSF11A(A192) produced a level of activation of NFκB signaling greater than cotrasfection with wild-type SQSTM1 and TNFRSF11A(V192), confirming genetics and clinical evidences. These results provide the first evidence that genetic variation within the OPG/RANK/RANKL system influences the severity of PBD in synergistic action with SQSTM1 gene mutations.

The melatonin receptor 1A (MTNR1A) gene is associated with recurrent and idiopathic calcium nephrolithiasis.

BACKGROUND: Experimental evidence indicate that melatonin regulates some renal tubular functions via specific melatonin receptors (MTNRs) located in the kidney of several avian and mammalian species, including humans. We hypothesized that single nucleotide polymorphisms (SNPs) in the melatonin receptor 1A gene (MTNR1A) might influence the risk of calcium nephrolithiasis. METHODS: We performed a systematic analysis of the MTNR1A gene in 246 recurrent calcium stone formers (136 men, 110 women; mean age 40.2 ± 12.0 years; body mass index 25.8 ± 4.5 kg/m2) and 269 healthy controls comparable for age and gender without a history of nephrolithiasis. RESULTS: Two SNPs in Intron 1 of MTNR1A were significantly associated with calcium nephrolithiasis: rs13140012 (P = 0.0004) and rs6553010 (P = 0.009). The haplotypes resulting from the two SNPs were also differently distributed between stone formers and controls, the haplotype A-T being more represented among stone formers (P = 0.00001) and the haplotype T-C being more common in healthy controls (P = 0.00001). Preliminary functional studies showed that the SNP rs13140012 could modify the binding sites for transcription factors. CONCLUSION: The results of this case-control study indicate a strong association between allelic variants of MTNR1A and recurrent calcium nephrolithiasis.

Comparison of intravenous and intramuscular neridronate regimens for the treatment of Paget disease of bone.

Aminobisphosphonates actually represent the most common treatment for Paget disease of bone (PDB). In a previous study we demonstrated that either zoledronic acid (4 mg) or neridronate (200 mg) given as a single intravenous infusion showed a similar short-term efficacy in achieving biochemical remission in up to 90% of patient nonresponders to pamidronate. In this study we compared the long-term (36 months) effects of a same neridronate dose (200 mg) given as an intravenous (100-mg infusion for 2 consecutive days) or intramuscular (25-mg injection weekly for 2 months) regimen in 56 patients with active PDB. All patients were advised to receive calcium plus vitamin D supplementation throughout the study period. At 6 months, 92.6% and 96.5% of patients receiving intravenous and intramuscular neridronate, respectively, achieved a therapeutic response [defined as normalization of alkaline phosphatase (ALP) levels or a reduction of at least 75% in total ALP excess]. The response to treatment was significantly correlated with baseline ALP and 25-hydroxyvitamin D [25(OH)D] levels at 6 months. The decrease in ALP levels was highest in patients with higher baseline total or bone-specific ALP levels and with higher 25(OH)D levels at 6 months. Response rates were maintained at 12 months but decreased progressively at 24 and 36 months without significant differences between the two neridronate regimens. Both regimens were well tolerated. The only relevant side effect was an acute-phase response occurring in 14% of the patients. In conclusion, these results indicate that a 200-mg intramuscular neridronate course has a similar efficacy as an intravenous infusion of the same dose for the treatment of PDB and might be of particular value for patients intolerant to oral bisphosphonates and unwilling or unable to undergo intravenous infusions.

Characteristic clinical and biochemical profile of recurrent calcium-oxalate nephrolithiasis in patients with metabolic syndrome.

BACKGROUND: Metabolic syndrome is a risk factor for nephrolithiasis. This study was performed to evaluate the clinical and biochemical profile of calcium-oxalate nephrolithiasis in stone formers with metabolic syndrome. METHODS: A total of 526 recurrent stone formers, 184 of them with metabolic syndrome, and 214 controls were examined on a free diet and after a sodium-restricted diet (sodium intake < 100 mmol/24 h). RESULTS: On free diet, stone formers with metabolic syndrome showed higher sodium excretion [mean (95% confidence interval), 196 (176-218) vs 160 (150-168) mmol/24 h; P < 0.01] and lower citrate excretion [2.23 (1.99-2.58) vs 2.84 (2.51-3.17) mmol/24 h; P < 0.01] compared to controls, whereas stone formers without metabolic syndrome showed higher calcium and oxalate excretion [5.43 (5.01-5.82) vs 3.58 (2.84-4.19) and 0.34 (0.32-0.36) vs 0.26 (0.20-0.31)m mmol/24 h for calcium and oxalate, respectively; P < 0.01] and lower citrate excretion [2.18 (1.98-2.38) vs 2.84 (2.51-3.17) mmol/24 h; P < 0.01] compared to controls. The ion activity product of urinary calcium-oxalate salts was similar between stone formers with and without metabolic syndrome [1.41 (1.31-1.59) vs 1.40 (1.35-1.45); P > 0.05]. After the test diet, this index was lower in diet-compliant stone formers with metabolic syndrome compared to diet-compliant stone formers without metabolic syndrome [1.15 (1.10-1.21) vs 1.39 (1.31-1.45); P < 0.01]. CONCLUSIONS: The biochemical profiles and responses to the sodium-restricted diet were significantly different between stone formers with metabolic syndrome and those without. Dietary habits play a central role in the pathogenesis of nephrolithiasis in stone formers with metabolic syndrome.

[Diagnostic and therapeutic approach in patients with urinary calculi]. / Percorso diagnostico-terapeutico per il paziente con calcolosi urinaria.

The natural history of urolithiasis includes the risk of recurrence and of the development of chronic kidney and/or bone disease, which is why a thorough clinical and metabolic evaluation of these patients is of the utmost importance at disease onset. This paper is aimed at identifying the type of urolithiasis, the related risk factors, and the corresponding treatment options. The diagnostic and therapeutic approach described here includes 1) accurate history taking to detect secondary nephrolithiasis and screen for the main risk factors for kidney and bone disease; 2) metabolic evaluation graded according to different complexity levels based on the severity of the disease and the presence of risk factors; 3) carrying out appropriate imaging procedures. The resulting information allows to plan treatment based either on general rules of lifestyle and diet, or on selected medical intervention, if necessary. This report, which is based on current guidelines, was produced by the Gruppo Italiano di Studio Multidisciplinare per la Calcolosi Renale. It is addressed to all professionals involved in the management of patients suffering from nephrolithiasis, first of all general practitioners, who often become involved immediately at the onset of the disease.

FSHR gene polymorphisms influence bone mineral density and bone turnover in postmenopausal women.

OBJECTIVE: FSH, via its receptor (FSHR), influences bone remodeling and osteoclast proliferation and activity. The aim of this study was to evaluate the influence of two single nucleotide polymorphisms (SNPs) of the FSHR gene on bone mineral density (BMD) and bone turnover markers (bone alkaline phosphatase and type I collagen C-telopeptides) in postmenopausal women. METHODS: Two hundred and eighty-nine unrelated postmenopausal women were genotyped for the SNPs rs1394205 and rs6166. BMD was estimated using dual-energy X-ray absorptiometry and quantitative ultrasound (QUS) methodologies. RESULTS: AA rs6166 women showed a lower BMD (femoral neck and total body), lower stiffness index (calcaneal QUS), and higher serum levels of bone turnover markers compared to GG rs6166 women. The prevalence of osteoporosis was significantly higher in AA rs6166 women compared with GG rs6166 women. These results were not influenced by circulating levels of FSH and estrogens. CONCLUSION: The SNP rs6166 of the FSHR gene significantly influences BMD in postmenopausal women. In particular, AA rs6166 women are at increased risk of postmenopausal osteoporosis compared with GG rs6166 women, independently of circulating levels of FSH and estrogens. Previous studies have demonstrated that this SNP influences cell and tissue response to hyperstimulation of FSHR in vivo and in vitro. Our study results appear in agreement with these experimental data and with known biological actions of FSH/FSHR system in bone homeostasis.

SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone.

Even though SQSTM1 gene mutations have been identified in a consistent number of patients, the etiology of Paget's disease of bone (PDB) remains in part unknown. In this study we analyzed SQSTM1 mutations in 533 of 608 consecutive PDB patients from several regions, including the high-prevalence area of Campania (also characterized by increased severity of PDB, higher number of familial cases, and peculiar phenotypic characteristics as giant cell tumor). Eleven different mutations (Y383X, P387L, P392L, E396X, M401V, M404V, G411S, D423X, G425E, G425R, and A427D) were observed in 34 of 92 (37%) and 43 of 441 (10%) of familial and sporadic PDB patients, respectively. All five patients with giant cell tumor complicating familial PDB were negative for SQSTM1 mutations. An increased heterogeneity and a different distribution of mutations were observed in southern Italy (showing 9 of the 11 mutations) than in central and northern Italy. Genotype-phenotype analysis showed only a modest reduction in age at diagnosis in patients with truncating versus missense mutations, whereas the number of affected skeletal sites did not differ significantly. Patients from Campania had the highest prevalence of animal contacts (i.e., working or living on a farm or pet ownership) without any difference between patients with or without mutation. However, when familial cases from Campania were considered, animal contacts were observed in 90% of families without mutations. Interestingly, a progressive age-related decrease in the prevalence of animal contacts, as well as a parallel increase in the prevalence of SQSTM1 mutations, was observed in most regions except in the subgroup of patients from Campania. Moreover, patients reporting animal contacts showed an increased number of affected sites (2.54 +/- 2.0 versus 2.19 +/- 1.9, p < .05) over patients without animal contacts. This difference also was evidenced in the subgroup of patients with SQSTM1 mutations (3.84 +/- 2.5 versus 2.76 +/- 2.2, p < .05). Overall, these data suggest that animal-related factors may be important in the etiology of PDB and may interact with SQSTM1 mutations in influencing disease severity.

Clinical, historical and diagnostic findings associated with right ventricular dysfunction in patients with central and non-massive pulmonary embolism.

Right ventricular dysfunction during acute pulmonary embolism (PE) predisposes to hemodynamic instability and cardiogenic shock. Aim of this case-control study was to determine the clinical, historical and diagnostic findings associated with right ventricular dysfunction in patients with acute PE involving the main or segmental pulmonary arteries (central PE) and without hemodynamic instability on admission to the Emergency Department (ED) (non-massive PE). From January 1, 2002 to December 31, 2005, 211 patients with central PE were admitted to the Department of Emergency Medicine of the "Antonio Cardarelli" Hospital (Naples, Italy). One hundred eighteen of them had echocardiographic evidence of right ventricular dysfunction on admission to the ED. A history of type 2 diabetes mellitus and chronic obstructive pulmonary disease were significantly associated with an increased risk of this PE-related complication. Compared to patients without right ventricular dysfunction, those with right ventricular dysfunction showed higher levels of markers of cardiac damage, and a significant impairment of respiratory function. Echocardiographic evidence of right ventricular dysfunction on admission to the ED was significantly associated with the occurrence of hemodynamic instability and cardiogenic shock during the PE clinical course. The study results indicate that a history of type 2 diabetes mellitus and chronic obstructive pulmonary disease are significantly associated with the occurrence of right ventricular dysfunction in patients with non-massive and central PE independent of age, gender and other historical and clinical variables detectable on admission to the ED.

Bone turnover and the osteoprotegerin-RANKL pathway in tumor-induced osteomalacia: a longitudinal study of five cases.

To evaluate serum levels of osteoprotegerin (OPG), soluble receptor activator of the nuclear factor-kappaB (RANKL), and their relationship with FGF-23, lumbar bone mineral density (BMD), and bone turnover markers, five patients with tumor-induced osteomalacia (TIO) and 40 healthy controls were studied. TIO patients were followed for 360 days after surgical removal of underlying tumor (n = 2) or beginning of therapy with phosphate and calcitriol when surgical treatment was impossible (n = 3). At diagnosis, TIO patients had higher levels of FGF-23 and bone-specific alkaline phosphatase (bALP) and lower levels of cathepsin K (CathK), RANKL, and RANKL/OPG ratio compared to controls. During the follow-up, FGF-23 decreased significantly only in patients who underwent a surgical excision, while phosphate and BMD increased in all patients. The increases in BMD, phosphate, and renal phosphate reabsorption rate were directly related. In the first 60 days of follow-up, we observed a prolonged inhibition of RANKL, CathK, and bone resorption markers associated with a persistence of TIO symptoms and an increase in bALP. From day 60, levels of bone turnover markers returned progressively within the normal range and a clinical remission was observed. The inhibition of the RANKL/OPG pathway and the uncoupling of bone formation and resorption observed in patients with active TIO may be a compensatory mechanism, attempting to reduce worsening of osteomalacia. The BMD increase during TIO treatment is related to the improvement of phosphate rather than FGF-23 levels. A "hungry bone"-like syndrome was observed after surgical or pharmacological treatment.

The use of intravenous aminobisphosphonates for the treatment of Paget's disease of bone.

Paget's disease of bone is a focal skeletal disorder characterized by the formation of structurally abnormal bone, deformity and other complications leading to significant disability and bone pain. Recently, the availability of newer, more potent nitrogen-containing bisphosphonates has improved treatment outcomes, allowing a more effective and convenient management of this disorder.

Association between metabolic syndrome and nephrolithiasis in an inpatient population in southern Italy: role of gender, hypertension and abdominal obesity.

BACKGROUND: Metabolic syndrome (MetS) and nephrolithiasis (NL) are quite common disorders. While some of the components of MetS have been proposed as precursors of NL in population studies, no data are available about the possible association between NL and MetS as such. The primary objective of the study was to evaluate the relationship between MetS and NL. The secondary outcome was to examine the relationship between MetS single constitutive elements and NL considering the strict correlation occurring among these factors. METHODS: We studied 2132 Caucasian inpatients of the 'Spinelli' Hospital in southern Italy (males/females = 0.95; mean age 63.8 +/- 15.8 years; body mass index 26.1 +/- 3.9 kg/m(2)). The MetS diagnosis was performed according to the Heart Association/National Heart, Lung, and Blood Institute criteria. The presence of NL was assessed by ultrasound examination of the kidneys and upper urinary tract. RESULTS: Seven hundred twenty-five subjects (34.0%) had a positive diagnosis of MetS. Two hundred twenty subjects (10.3%) had echographic evidence of NL, while 199 subjects reported a past history of NL (9.3%). The presence of MetS, as well as the male sex, and the occurrence of a previous episode of NL (in male subjects only) were each independently related to echographic evidence of NL. Among the individual components of MetS, high blood pressure and abdominal obesity (in female individuals only) were also independently related to echographic evidence of NL. CONCLUSIONS: MetS is significantly associated with echographic evidence of NL. A gender-related difference in the clinical expression of NL was also observed.

Vitamin D receptor gene polymorphisms predict acquired resistance to clodronate treatment in patients with Paget's disease of bone.

Bisphosphonates are first-choice drugs for treatment of Paget's disease of bone (PDB); nevertheless, acquired resistance to bisphosphonate therapy has been described in PDB patients. The 1,25(OH)(2)D(3)/vitamin D receptor (VDR) system influences the effectiveness of antiresorptive treatments in metabolic bone disorders. This study evaluated the relationship between acquired resistance to clodronate treatment and BsmI, TaqI, and FokI VDR polymorphisms in Caucasian patients with polyostotic PDB (n = 84). We also evaluated the influence of mutations in exons 7 and 8 of the sequestosome 1 (SQSTM1) gene on the occurrence of this phenomenon. All patients were treated from diagnosis for several cycles with intravenous clodronate infusion (1500 mg/cycle). Acquired resistance to clodronate treatment was defined as the failure of total alkaline phosphatase serum levels to be suppressed to at least 50% of the patient's previous highest levels during a subsequent treatment course with the same compound, which produced a >50% response after the first exposure. During an observation period of 10.6 +/- 2.7 years, 31 PDB patients (36.9%) showed acquired resistance to clodronate. It was observed that the bb and TT VDR genotypes as well as a lower persistence of the biochemical response to the first treatment course were significantly and independently associated with the risk of developing resistance to clodronate treatment. SQSTM1 gene mutations, considered altogether, did not influence the occurrence of this phenomenon. Our results indicate that 3'VDR allelic variants and duration of biochemical response to the first treatment course are independent predictors of acquired resistance to clodronate treatment in patients with polyostotic PDB.

Metabolic syndrome and nephrolithiasis: can we hypotize a common background?

Metabolic syndrome and nephrolithiasis are quite common disorders presenting similar epidemiological characteristics. Belonging to genetic, environmental and hormonal interaction, they have high incidence and prevalence in the adult population of industrialised countries and are characterised by a high level of morbidity and mortality if not adequately identified and treated. Despite metabolic syndrome is considered a fundamental risk factor for chronic kidney diseases, is not actually known whether it is associated with nephrolithiasis beyond the effect of its individual components, in particular obesity, glucose intolerance, and hypertension. In this paper, the possible pathogenetic links between metabolic syndrome and nephrolithiasis will be presented and discussed.

Evidence for increased clinical severity of familial and sporadic Paget's disease of bone in Campania, southern Italy.

UNLABELLED: The analysis of 236 Italian patients with Paget's bone disease showed higher clinical severity and greater frequency of neoplastic degeneration among patients who live or descend from individuals living in the Campania region (southern Italy). A prevalent involvement of the spine and the skull, the sites preferentially involved in giant cell tumors complicating Paget's disease, was also shown in familial cases from this geographical region. INTRODUCTION: The Campania region in southern Italy has been recently indicated as a high prevalence area for Paget's disease of bone (PDB), and most pagetic families with multiple occurrence of neoplasms in affected members were from this geographical region. MATERIALS AND METHODS: We evaluated the PDB epidemiological characteristics in 125 patients from Campania in comparison with 111 patients from other Italian regions. Twenty-three patients from Campania and 26 patients from other Italian areas had at least one first-degree relative affected by PDB (familial cases). The remaining patients made up the sporadic cases. RESULTS: Among subjects from Campania, the patients in the familial group tended to come from larger families and showed at diagnosis higher serum total alkaline phosphatase, larger extension of disease, and earlier mean age with respect to patients with PDB of the sporadic group. The skull, spine, and humerus were the sites preferentially involved in the familial cases. In contrast, no such differences were observed between familial and sporadic PDB cases among patients from the other geographical areas, except for a lower age at diagnosis. An increased PDB clinical severity was finally observed in the PDB cohort from Campania in comparison with patients from other Italian regions. Neoplastic degeneration of pagetic bones (osteosarcoma and giant cell tumor) was exclusively observed in patients with polyostotic PDB from Campania. CONCLUSIONS: We showed a higher clinical severity of PDB with occurrence of neoplastic degeneration in the high prevalence area of Campania, with its maximum expression in cases with familial disease. This peculiar pattern might be traced to genetic predisposition and/or to the abnormal impact of a still undefined environmental trigger.

Fibroblast growth factor 23 is increased in calcium nephrolithiasis with hypophosphatemia and renal phosphate leak.

CONTEXT: Nephrolithiasis affects about 10% of the population in industrialized countries, with calcium salts composing more than 80% of renal stones. A significant percentage of patients with calcium nephrolithiasis and normal parathyroid function show hypophosphatemia and reduced renal phosphate reabsorption (i.e. a renal phosphate leak). OBJECTIVES: The objective of the study was to compare serum levels of fibroblast growth factor 23 (FGF23), a regulator of phosphate homeostasis, in 110 recurrent stone formers with or without renal phosphate leak, six patients affected by X-linked hypophosphatemic rickets, five patients affected by oncogenic osteomalacia, and 60 unrelated healthy controls. DESIGN: This was a prospective interventional study. METHODS: Renal phosphate leak was identified based on the occurrence of idiopathic hypophosphatemia [serum phosphate concentration < 2.50 mg/dl (<0.80 mmol/liter)] and reduced renal threshold phosphate concentration [<2.2 mg/liter (<0.70 mmol/liter)]. RESULTS: In 22 stone formers with renal phosphate leak, serum FGF23 concentration was significantly higher as compared with 88 stone formers without renal phosphate leak and with controls [83.3 (65.6-101.1) vs. 32.1 (26.8-37.4) and 24.5 (19.8-29.1) reference units (RU)/ml, respectively]. Stone formers with renal phosphate leak showed lower FGF23, compared with patients with oncogenic osteomalacia and X-linked hypophosphatemic rickets [572.3 (235.9-908.7) RU/ml]. Among stone formers and controls, serum FGF23 concentration displayed a strong inverse association with serum phosphate (r = -0.784, P = 0.009) and the rate of tubular phosphate reabsorption (r = -0.791, P = 0.008). CONCLUSIONS: In our study population, renal phosphate leak affected 20% of stone formers and was strongly associated with increased serum FGF23 concentration.

Interleukin-6 and osteoprotegerin systems in Paget's disease of bone: relationship to risedronate treatment.

Serum concentrations of interleukin-6 (IL-6), IL-6-soluble receptor (sIL-6R), IL-6 gp130-soluble receptor (sgp130), ligand of receptor activator of nuclear factor (NF)-kappaB (RANKL), and osteoprotegerin (OPG) were determined in 42 patients with polyostotic Paget's disease of bone (PDB) and acquired resistance to clodronate (M/F ratio 23:19; mean age 58.5 +/- 9.4 years) in acute phase of disease and after oral risedronate treatment (30 mg/day for 8 weeks). At baseline, pagetic patients showed higher levels of OPG, sIL-6R, and IL-6 with lower levels of sgp130 compared to 24 age- and sex-matched controls (respectively, 4.69 +/- 1.27 vs. 2.87 +/- 0.54 pmol/L; 40.89 +/- 8.61 vs. 30.98 +/- 4.24 ng/ml; 3.59 +/- 0.97 vs. 1.8 +/- 0.9 pg/ml; 327.34 +/- 43.41 vs. 411.7 +/- 79.5 ng/ml). Response to treatment is related to a significant increase of OPG levels in all patients (from 4.69 +/- 1.27 to 5.48 +/- 1.31 pmol/L). The disease remission, that is, total alkaline phosphatase (tALP) levels within the normal range after therapy, was associated with a simultaneous increase in OPG and sgp130 levels. In patients with tALP higher than the normal range after therapy, the OPG increase was associated with a parallel increase in RANKL levels. Our data suggest that serum levels of components of RANKL/OPG and IL-6 systems, before and after treatment, may be used to better define a therapeutical strategy in pagetic patients.

Association between vitamin D receptor gene polymorphisms and fasting idiopathic hypercalciuria in recurrent stone-forming patients.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Our results suggest a genetic association between 3' VDR alleles, fasting IHc, and reduced bone mass density in patients with recurrent stone formation.

The relationship of 3' vitamin D receptor haplotypes to urinary supersaturation of calcium oxalate salts and to age at onset and familial prevalence of nephrolithiasis.

BACKGROUND: Idiopathic hypercalciuria (IHc) and idiopathic hypocitraturia are frequently associated with calcium nephrolithiasis. We investigated the relationship of vitamin D receptor (VDR) polymorphisms (BsmI, TaqI and FokI) to urinary supersaturation of calcium oxalate salts in recurrent calcium oxalate stone formers with IHc and the clinical relevance of this relationship. METHODS: The study included 110 Caucasian stone formers with IHc and 127 unrelated healthy controls without history of nephrolithiasis. Age at onset of nephrolithiasis, familial history score (FHS) and the ion activity product of calcium oxalate salts in urine (AP(CaOx)) were tabulated. BsmI, TaqI and FokI VDR polymorphisms were evaluated in all participants. RESULTS: Patients and controls were classified as homozygous (bbTT and BBtt) or heterozygous in relation to BsmI and TaqI polymorphisms. Compared with BBtt patients, bbTT homozygous stone formers showed lower citrate excretion (1.91+/-0.89 vs 3.46+/-1.39 mmol/24 h, P = 0.004) and higher AP(CaOx) (2.02+/-0.51 vs 1.53+/-0.53, P = 0.006). Among controls, there were similar differences in citrate excretion and AP(CaOx) between the two groups, but they were not statistically significant. Compared with BBtt, bbTT patients showed lower mean age at onset of nephrolithiasis (29.7+/-12.1 vs 38.1+/-12.7 years, P = 0.008) and higher values of FHS (2.45+/-1.9 vs 0.83+/-0.7, P = 0.006). Similar results were obtained for individual BsmI and TaqI alleles. The analysis of FokI alleles was not informative. CONCLUSIONS: Recurrent calcium oxalate stone formers with IHc and the bT VDR haplotype have more aggressive kidney stone diseases as indicated by a higher familial incidence and lower mean age at onset. This clinical severity is associated with the higher urinary supersaturation of calcium oxalate salts and abnormalities of renal citrate handling.