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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.

Journal for ImmunoTherapy of Cancer, 3 (S1), ISSN:2051-1426

● Background: Patients with idiopathic hypercalciuria are predisposed to osteoporosis despite their high enteral calcium absorption. Conversely, low calcium absorption has been reported in patients with osteoporosis. Because bone loss occurs earlier in women, this work explores the relationship between bone mineral density (BMD) and calcium absorption in premenopausal and postmenopausal hypercalciuric stone-forming women. Methods: BMD and intestinal calcium absorption were compared in 64 hypercalciuric and 42 normocalciuric calcium stone-forming women. Calcium absorption was assessed by using strontium as a surrogate marker for calcium. Strontium was administered to patients as an oral load, then measured in blood to calculate absorption after 60 minutes. Femoral and lumbar-spine BMD were measured by dual-energy x-ray absorptiometry. Results: Strontium absorption was significantly increased in hypercalciuric stone formers, whereas BMD z score was decreased in hypercalciuric patients at the lumbar spine, but not the femur. The increase in strontium absorption was detected in both postmenopausal (n 29) and premenopausal (n 35) hypercalciuric patients. The decrease in lumbar-spine BMD was confirmed in postmenopausal, but not premenopausal, hypercalciuric patients. Strontium absorption was greater in hypercalciuric patients with a lumbar-spine BMD z score of 2 or less (n 10) than in those with a score greater than 2( n 54). Multiple stepwise regression showed that lumbar-spine BMD was related negatively to intestinal strontium absorption and age in hypercalciuric patients. Conclusion: Results of the strontium absorption test suggest that the increase in calcium absorption is associated with a decrease in lumbar-spine BMD in hypercalciuric stone-forming women. Hypercalciuric stone-forming women with high calcium intestinal absorption denote a group of patients predisposed to loss of bone mass. Am J Kidney Dis 42:1177-1183. © 2003 by the National Kidney Foundation, Inc.

Background and aims Animal protein intake may cause an acid load that predisposes individuals to stones by influencing calcium and citrate excretion. These associations were not confirmed in recent studies. Therefore the present study was aimed to compare acid load of diet in stone formers and controls. Methods and results Participants to the study were 157 consecutive calcium stone formers and 144 controls. Diet was analyzed in these subjects using a software that evaluated nutrient intake from a three-day food intake diary. This software also estimated the potential renal acid load (PRAL, mEq/day). Twenty-four-hour urine excretion of ions and citrate was measured in stone formers. Stone former diet had lower intake of glucose, fructose, potassium and fiber and higher PRAL in comparison with controls. The multinomial logistic regression analysis showed that stone risk decreased in association with the middle and the highest tertiles of fiber intake and increased in association with the highest tertile of PRAL. The linear multiple regression analysis showed that calcium excretion was associated with the sodium excretion and that citrate excretion was associated with the PRAL and animal protein intake in stone formers. Conclusion Our findings suggest that stone formers may undergo a greater dietary acid load sustained by a low vegetable intake and base provision. Dietary acid load does not appear as the main determinant of calcium excretion, but may promote stone risk by decreasing citrate excretion. Sodium intake may predispose to stones by stimulating calcium excretion.

Aims: Two single-nucleotide polymorphisms (SNPs) at the calcium-sensing receptor (CASR) gene were previously associated with kidney stones in patients with primary hyperparathyroidism (PHPT): rs1501899, likely associated with a decrease in CASR expression, and Arg990Gly, causing a gain of CASR function. To evaluate the interaction of these two SNPs in the stone risk, we tested the association of stones with the genotype at both SNPs in PHPT patients and the association of rs1501899 with CASR expression as messenger RNA (mRNA) in human kidney samples.Methods and results: Two hundred and ninety-six PHPT patients were genotyped at the rs1501899 and Arg990Gly SNPs. Minor allele frequency at tested SNPs was higher in PHPT stone formers relative to non-stone forming patients. PHPT patients carrying one or two copies of the minor allele at both rs1501899 and Arg990Gly (n=16) had the maximal risk of stones (odds ratio, OR 8.3) and higher serum ionized calcium compared with homozygous patients for the wild-type allele at both SNPs. CASR expression as mRNA was measured by real time polymerase chain reaction (PCR) in normal kidney medulla samples from 109 subjects. CASR mRNA was significantly lower in medulla samples from homozygotes for the minor allele at rs1501899 than in subjects with other genotypes.Conclusions: We conclude that the simultaneous presence of the minor allele at rs1501899 and Arg990Gly may amplify the kidney stone risk in PHPT patients, despite their apparently opposite effects on CASR function in the kidney.

Background: The role of body composition (lean mass and fat mass) on urine chemistries and bone quality is still debated. Our aim was therefore to determine the effect of lean mass and fat mass on urine composition and bone mineral density (BMD) in a cohort of healthy females. Materials and methods: 78 female volunteers (mean age 46 +/- 6 years) were enrolled at the Stone Clinic of Parma University Hospital and subdued to 24-hour urine collection for lithogenic risk profile, DEXA, and 3-day dietary diary. We defined two mathematical indexes derived from body composition measurement (index of lean mass-ILM, and index of fat mass-IFM) and the cohort was split using the median value of each index, obtaining groups differing only for lean or fat mass. We then analyzed differences in urine composition, dietary intakes and BMD. Results: The women with high values of ILM had significantly higher excretion of creatinine (991 +/- 194 vs 1138 +/- 191 mg/day, p = 0.001), potassium (47 +/-+/- 13 vs 60 +/- 18 mEq/day, p < 0.001), phosphorus (520 +/- 174 vs 665 +/- 186 mg/day, p < 0.001), magnesium (66 +/- 20 vs 85 +/- 26 mg/day, p < 0.001), citrate (620 +/- 178 vs 807 +/- 323 mg/day, p = 0.002) and oxalate (21 +/- 7 vs 27 +/- 11 mg/day, p = 0.015) and a significantly better BMD values in limbs than other women with low values of ILM. The women with high values of IFM had similar urine composition to other women with low values of IFM, but significantly better BMD in axial sites. No differences in dietary habits were found in both analyses. Conclusions: Lean mass seems to significantly influence urine composition both in terms of lithogenesis promoters and inhibitors, while fat mass does not. Lean mass influences bone quality only in limb skeleton, while fat mass influences bone quality only in axial sites.

Background Obesity is a risk factor for nephrolithiasis (NL). According to an American study of a large cohort with a BMI >30, males increased the risk of NL of 30% and females of 200%. Moreover, diet plays an important role as NL risk factor, mainly in those western countries characterized by a large meet consume. This epidemiology study investigated the NL frequency in an obese Italian population, also considering the relation with metabolic syndrome and interaction with diet.

Genetic studies of calcium kidney stones evidenced the possible involvement of calcium-sensing receptor gene, vitamin D receptor gene and bicarbonate-sensitive adenylate cyclase gene, but it is uncertain which specific polymorphisms could be responsible. Thus, further studies are required to better assess the involvement of these or other genes and the interactions between different genes and between genes and environment. In addition to research in humans, the study of different strains of knock-out mice let us include the gene of phosphate reabsorption carrier NPT2, caveolin-1, protein NHERF-1, osteopontin and Tamm-Horsfall protein among the possible determinants. Further steps in the knowledge of calcium stone causes may be done using the instruments that the modern biotechnology and bioinformatics have made available to the researchers.

Objective: Familial hypocalciuric hypercalcemia (FHH) syndrome is a rare benign condition, inherited as an autosomal dominant trait, in which inactivating mutations of the calcium-sensing receptor (CASR) gene affects the body’s ability to regulate calcium homeostasis. Its outcome is featured by increased levels of serum calcium, moderate hypophosphatemia, and inadequately normal or elevated circulating parathyroid hormone levels. Affected patients are mostly asymptomatic and do not benefit from surgical resection of their mildly enlarged parathyroids. Design: We evaluated for hypercalcemia an Italian family that was identified via a young adult male proband referred to our center for parathyroidectomy. Methods: The patients and the family members were evaluated both biochemically and genetically as suspected FHH subjects. An in vitro functional study was performed by site-directed mutagenesis, and CASR activity was monitored by measuring intracellular calcium ([Ca 2C ]i). Results: The patient had a novel germline heterozygous CASR mutation (c.361_364GATT; p.D121del/fsX122). The mutation caused a premature stop codon at codon 122, exiting a truncated protein. The biochemical phenotype of all family members carrying the heterozygous deletion was concordant with classic FHH syndrome. Conclusions: Our findings confirm the role of CASR gene mutational analysis to offer a valuable addition for the recognition of FHH in hypercalcemic patients not yet characterized for a positive familial history of hypercalcemia, the only condition that identifies CASR gene mutations in hypercalcemia.

Nutrition experts, as well as specialists of different pathologies, are disclosing an ever increasing interest for protocols devoted to the welfare of patients and to prevention of nutrition related diseases. In fact, it is extensively acknowledged that nutrition plays a primary role in those complex diseases most widespread in the western countries like cardiovascular disease [1], cancer [2], Alzheimer's disease [3], diabetes [4], nephrolithiasis [5] etc. that account for over 60% of deaths world-wide. Even in our country, Italy, and in other South Europe's countries, until now protected by the Mediterranean diet, which in 2010 was awarded by UNESCO the human heritage status, the next generation will be the first with a life expectancy lower than of their parents, principally due to unhealthy eating habits and the obesity epidemic. To counteract this trend, in the last decade attention has been focused on the human nutrition field, with significant research topics being new molecules contrasting cholesterol accumulation in the arterial walls or capable of diminishing visceral fat [6], the role of bacterial microflora [7], the production of functional foods, studies on antioxidant properties of vitamins and polyphenols, etc. Moreover, beside knowledge acquired with traditional investigation techniques, the field of human nutrition can now avail itself of the new omics techniques that could give a significant contribute to mapping the interactions between genetics, nutrition and health [8]. In the area of Translational Medicine, we believe that the field of nutrition ought to be taken into greater account, as an interaction and mutual validation agency between basic and applied research, in order to generate advanced applications for diagnosis and therapy and to develop at the same time new instruments of investigation. We here propose a new section devoted to the rapid publication of research papers on all aspects of nutrition with applications in medicine and biotechnology. This section welcomes contributions that employ traditional clinical, metabolic and epidemiologic methods, but is also open to molecular and cell biology research applied to animal and human nutrition. Topics include: diet interactions in chronic diseases, gene-environment interactions, genes and cell metabolism, protein and aminoacid metabolism, lipid metabolism and diseases, carbohydrate metabolism and diseases, micronutrients and functional foods. Other topics relevant to nutrition will be appreciated as well.

Cardiovascular complications are the main cause of death in patients with chronic kidney disease (CKD). Among these complications, calcific arteriosclerosis and myocardial hypertrophy are the main predictors of cardiovascular morbidity and mortality. Epidemiological studies have shown their association with hyperparathyroidism, which has therefore been included among the non-traditional cardiovascular risk factors. Studies in laboratory animals have shown that PTH administration may induce calcific arteriosclerosis and myocardial hypertrophy. The former develops independently of hyperphosphatemia, but its mechanisms remain unknown. The latter is characterized by increased thickness of the myocardial fibers and especially the fibrous interstitium; its development is influenced by protein kinase C activation and the subsequent increase in cytosolic calcium as well as activation of intracellular signaling pathways inducing protein synthesis and proliferation. Different from these findings, in other studies PTH infusion was able to produce vasodilatation and to favor myocardial cell contraction and regeneration. These effects depend on protein kinase A activation. PTH may produce different and sometimes contradictory functional effects in the arteries and myocardium that are probably related to different experimental or clinical conditions. In patients with CKD and hyperparathyroidism, PTH may be considered a uremic toxin exerting its effects mainly by increasing cellular calcium. Thus, hyperparathyroidism is confirmed to be a target for the conservative therapy of CKD.

Background and objectiveSingle nucleotide polymorphisms (SNPs) of the calcium-sensing receptor (CASR) gene at the regulatory region were associated with idiopathic calcium nephrolithiasis. To confirm their association with nephrolithiasis, we tested patients with primary hyperparathyroidism (PHPT).DesignA genotype–phenotype association study.MethodsIn all, 332 PHPT patients and 453 healthy controls were genotyped for the rs7652589 (G>A) and rs1501899 (G>A) SNPs sited in the noncoding regulatory region of the CASR gene. Allele, haplotype, and diplotype distribution were compared between PHPT patients and controls, and in stone forming and stone-free PHPT patients.ResultsThe allele frequency at rs7652589 and rs1501899 SNPs was similar in PHPT patients and controls. The A minor alleles at these two SNPs were more frequent in stone forming (n=157) than in stone-free (n=175) PHPT patients (rs7652589: 36.9 vs 27.1%, P=0.007; rs1501899: 37.1 vs 26.4%, P=0.003). Accordingly, homozygous or heterozygous PHPT patients for the AA haplotype (n=174, AA/AA or AA/GG diplotype) had an increased stone risk (odds ratio 1.83, 95% confidence interval 1.2–2.9, P=0.008). Furthermore, these PHPT patients had higher serum concentrations of ionized calcium and parathyroid hormone (1.50±0.015 mmol/l and 183±12.2 pg/ml) than patients with the GG/GG diplotype (n=145, 1.47±0.011 mmol/l (P=0.04) and 150±11.4 pg/ml (P=0.049)). Using a logistic regression model, the increase in stone risk in PHPT patients was predicted by AA/AA or AA/GG diplotype, the highest tertile of serum ionized calcium values and the lowest tertile of age.ConclusionsPolymorphisms located in the regulatory region of the CASR gene may increase susceptibility of the PHPT patients to kidney stone production.

Calcium nephrolithiasis is one of the most prevalent uronephrologic disorders in the western countries. Studies in families and twins evidenced a genetic predisposition to calcium nephrolithiasis. Family-based or case–control studies of single-candidate genes evidenced the possible involvement of calcium-sensing receptor ( CASR ), vitamin D receptor ( VDR ), and osteopontin ( OPN ) gene polymorphisms in stone formation. The only high-throughput genome-wide association study identified claudin 14 ( CLDN14 ) gene as a possible major gene of nephrolithiasis. Specific phenotypes were related with these genes: CASR gene in normocitraturic patients, VDR gene in hypocitraturic patients with severe clinical course, and CLDN14 gene in hypercalciuric patients. The pathogenetic weight of these genes remains unclear, but an alteration of their expression may occur in stone formers. Technological skills, accurate clinical examination, and a detailed phenotype description are the basis to get new insight about the genetic basis of nephrolithiasis.

Previous studies have demonstrated a gain-of-function of the calcium-sensing receptor (CASR) gene R990G polymorphism. In this study, activation of the R990G CASR stably transfected in HEK-293 (HEK-990G) cells compared with that of the common variant (HEK-wild-type (WT)) by increasing concentrations of CaCl2 or calcimimetic R-568 caused significantly higher intracellular free calcium concentration ([Ca2+]i) and lower Ca-EC50. Moreover, the [Ca2+]i oscillation percentage was higher with a larger sinusoidal pattern in HEK-990G. R-568 induced a shift of the oscillatory events from 4 to 2 mmol/l extracellular calcium concentration in HEK-990G cells and increased the sinusoidal oscillation percentage in comparison with HEK-WT. Preincubation with thapsigargin or phospholipase C inhibitors completely prevented oscillations in both cell lines, consistent with the involvement of the inositol trisphosphate pathway, while protein kinase C inhibitor prevented oscillations in HEK-WT cells only. Finally, CaCl2 and R-568 caused a significant increase in p44/42 extracellular signaling-regulated kinase phosphorylation, with the mean Ca-EC50 values being significantly lower in HEK-990G. Our findings demonstrated that the 990G allele is associated with high sensitivity to R-568, which provided new evidence for differences in CASR signaling.

The effect of arachidonic acid (AA) on intracellular Ca 2+ concentration ([Ca 2+ ] i ) in human osteoblasts MG63 was studied. AA caused a concentration-dependent increase in [Ca 2+ ] i , mainly due to inward Ca 2+ transport from extracellular environment. Moreover, AA in Ca 2+ -free medium produced a small, transient increase of [Ca 2+ ] i , indicating that AA may also trigger Ca 2+ release from intracellular stores. Because the [Ca 2+ ] i response to AA was inhibited by the cyclooxygenase (COX) inhibitor indomethacin, we tested the effect of prostaglandins (PGs), products of COX pathway. PGs E1 and E2 caused an increase in [Ca 2+ ] i , which, however, was far lower than that obtained with AA. The [Ca 2+ ] i response to AA was not inhibited by nifedipine, suggesting that AA did not activate a voltage-dependent Ca 2+ channel. Our results indicate that AA could modulate [Ca 2+ ] i in MG63 human osteoblasts, where it may influence Ca 2+ transport across both plasma and endoplasmic membranes. Furthermore, they suggest that osteoblast activity may be modulated by AA.

Background: The aim of the present study was to investigate the interactions between the circulating concentrations of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and the mRNA concentration of its specific nuclear receptor in human leukocytes.Methods: We measured vitamin D receptor (VDR) mRNA extracted from leukocytes by use of TaqMan fluorescence analysis applied to the reverse transcription-PCR (RT-PCR) technique in 16 volunteers before and after calcitriol administration. VDR mRNA was also measured in leukocytes from calcium-stone-formers (37 hypercalciuric and 34 normocalciuric patients). The relationship between VDR mRNA concentrations and genetic VDR polymorphisms was analyzed in these patients.Results: Imprecision (CV) of RT-PCR was 1.3% within assay (n = 10) and 1.7% between assays (n = 4). Oral 1,25(OH)2D3 increased mean (SE) serum 1,25(OH)2D3 1.6 (0.3)-fold and VDR mRNA 1.6 (0.1)-fold 8 h after administration. The maximum VDR mRNA was reached 3.6 (1.3) h after 1,25(OH)2D3 ingestion. No differences in leukocyte VDR mRNA concentrations were found between normocalciuric and hypercalciuric stone-formers in the absence of stimulation. Finally, no association was found between VDR mRNA concentrations and genetic VDR polymorphisms in stone-formers.Conclusions: The TaqMan RT-PCR assay is a rapid and accurate method to measure VDR mRNA, and leukocytes are a useful model to study VDR and 1,25(OH)2D3 interactions. In humans, VDR mRNA is increased by agonist 1,25(OH)2D3, a finding resembling previously reported results obtained in cellular and animal models.

Recently, we have measured in erythrocytes a voltage-modulated and dihydropyridine-inhibited calcium influx. Since arachidonic acid and other polyunsaturated fatty acids influence the activities of most ion channels, we studied their effects on the erythrocyte Ca(2+) influx. It was measured on fresh erythrocytes, isolated from healthy donors, using the fluorescent dye Fura 2 as indicator of [Ca(2+)](i). AA (5-50 microM) and EPA (20-30 microM) stimulated a concentration-dependent increase in [Ca(2+)](i), deriving from extracellular calcium (1 mM), without affecting the intra- and extracellular pH and membrane voltage. The Ca(2+) influx rate varied from 0.5 to 3 nM Ca(2+)/s in the presence of AA and from 0.9 to 1.7 nM Ca(2+)/s with EPA. The Ca(2+) influx elicited by AA and EPA was not inhibited by dihydropyridines, while cyclooxygenase inhibitors were effective and PGE1 or PGE2 did not produce any effect. We conclude that AA could activate an erythrocyte voltage-independent Ca(2+) transport via an intermediate product of cyclooxygenase pathway; however, a direct interaction with the membrane lipid-protein cannot be excluded.

Calcium-sensing receptor (CaSR) is a plasma membrane protein that regulates tubular reabsorption of Ca. To establish its role in idiopathic hypercalciuria, the association of urinary Ca excretion with the polymorphisms of CASR gene has been studied in healthy subjects and in hypercalciuric and normocalciuric Ca stone formers. CASR exon 7 single nucleotide polymorphisms (SNP), G/T at codon 986, G/A at codon 990, and C/G at codon 1011, were evaluated by PCR amplification and direct sequencing in 97 normocalciuric stone formers, 134 hypercalciuric stone formers, and 101 normocalciuric healthy controls. Four haplotypes were defined on the basis of CASR gene SNP: haplotype 1 was characterized by the most frequent sequence; haplotypes 2, 3, or 4 by the presence of a single polymorphic variant at codon 986, 990, or 1011, respectively. The relative risk of hypercalciuria was calculated with multinomial logistic regression and was significantly increased only in individuals carrying haplotype 3 (Odds ratio, 13.0 [95% confidence interval, 1.7 to 99.4]). Accordingly, Ca excretion was higher in subjects bearing haplotype 3, whereas those bearing haplotype 2 showed a slight increase of plasma Ca concentration. Multiple regression analysis showed that haplotype 3 explained 4.1% of the total variance of Ca excretion and 12.6% of the variance explained by the variables considered in the study. In conclusion, CASR gene could be a component of the complex genetic background regulating Ca excretion. Arg990Gly polymorphism could facilitate activation of CaSR and increase Ca excretion and susceptibility to idiopathic hypercalciuria.

Nephrolithiasis is a very common disease with an increasing prevalence among industrialized populations. Kidney stone formation is a complex phenomenon, involving genetic and metabolic patterns, and nutrition can play an important role in this match both as a promoter or as a protective factor. To promote a deeper knowledge of such a challenging disease, clinicians and researchers have met in Rome, Italy, last March 2013, at the International Congress “Nephrolithiasis: a systemic disorder” to discuss patho-physiology and possible treatment of kidney stones. During the meeting, a whole session was dedicated to nutrition, seen both as a cause or a therapeutic tool for nephrolithiasis. Due to its etiopathogenesis, nephrolithiasis is also an ideal model for a nutrigenetics and nutrigenomics approach. Nutrigenomics and nutrigenetic respectively study the effects of a dietary treatment on gene expression and, on the other hand, the impact of an inherited trait on the response to a specific dietary treatment.

Urinary calcium is a determinant of bone mineral density in elderly men participating in the InCHIANTI study. Background It is generally acknowledged that calcium excretion is a determinant of bone mineral density. Since data confirming this hypothesis are not conclusive, the present study evaluates the relationship between calcium excretion and volumetric bone mineral density (vBMD) in a sample of general population mostly composed of elderly subjects. Methods This relationship was studied in 595 subjects in good health (M/F 302/293), selected from the InCHIANTI population, an epidemiologic survey on aging in Tuscany (Italy). Of these subjects, 432 (72.6%) were 65 years old or older. Trabecular and cortical apparent vBMDs were measured by peripheral quantitative computed tomography at right tibia and standardized to age and body mass index (BMI) in each gender (z-score). Results Men in the highest tertile of calcium excretion had significantly lower trabecular vBMD, and were more likely to have a trabecular z-score of -1 or less. These results were confirmed in men older than 64 years, but not in women and younger men. Sodium excretion and 25-hydroxycolecalciferol (25(OH)D) were greater in men and women in the highest tertile. No differences among tertiles were observed for cortical vBMD, circulating levels of interleukin-1β and interleukin-6, and intake of principal nutrients and calcium. The lower levels of vBMD z-score were confirmed in men in the highest tertile of calcium excretion, standardized to creatinine clearance, sodium excretion, plasma calcium, and logarithm of circulating 25(OH)D, and resulted to be associated with calcium excretion at multiple regression analysis in men. Conclusion High calcium excretion is associated with a decreased trabecular BMD in elderly men and may predispose men to trabecular bone loss.

Parathyroid tumors are almost invariably associated with parathormone (PTH) hypersecretion resulting in primary (PHPT) or secondary (SHPT) hyperparathyroidism. PHPT is the third most common endocrine disorder with a prevalence of 1-2% in post-menopausal women; SHPT is a major complication of chronic kidney failure, the prevalence of which is increasing. The calciumsensing receptor (CASR) is the key molecule regulating PTH synthesis and release from the parathyroid cells in response to changes in extracellular calcium concentrations. A potent calcimimetic, cinacalcet, has been developed in the last ten years and made available for medical treatment of both PHPT and SHPT. Cinacalcet has been demonstrated to be effective in inhibiting PTH secretion, though the drug fails to normalize PTH release, both in PHPT and SHPT patients with different degrees of disease severity, including patients with parathyroid carcinomas and with MEN1-related parathyroid tumors. Here we reviewed the molecular aspects of CASR target therapy and the effect of the CASR gene single nucleotide polymorphisms. Clinical data concerning the efficacy and safety of cinacalcet in controlling hyperparathyroidism are reported, focusing on the treatment of the different types of parathyroid tumors. Finally, limits of this target therapy are analyzed, pointing out the lack of efficacy in improving kidney and bone morbidities in PHPT and cardiovascular diseases in SHPT. Though cinacalcet is a target therapeutic option for parathyroid tumors, further approaches are warranted to fully control these metabolic disorders and the underlying tumors.

Idiopathic calcium nephrolithiasis is a multifactorial disease with a complex pathogenesis due to genetic and environmental factors. The importance of social and health effects of nephrolithiasis is further highlighted by the strong tendency to relapse of the disease. Long-term prospective studies show a peak of disease recurrence within 2–3 years since onset, 40-50% of patients have a recurrence after 5 years and more than 50-60% after 10 years. International nutritional studies demonstrated that nutritional habits are relevant in therapy and prevention approaches of nephrolithiasis. Water, right intake of calcium, low intake of sodium, high levels of urinary citrate are certainly important for the primary and secondary prevention of nephrolithiasis. In this review is discussed how the correction of nutritional mistakes can reduce the incidence of recurrent nephrolithiasis.

Background It is well established that nutritional habits are relevant in the prevention of Idiopathic Calcium Nephrolithiasis (ICN) and the Mediterranean diet is believed to be protective against nephrolithiasis and not only against cardiovascular events. A case-control study was performed to establish the nutritional habits of Italian ICN patients and the nutritional determinants of lithogenic risk in the considered population.

Background: Nephrolithiasis is more frequent and severe in obese patients from different western nations. This may be supported by higher calcium, urate, oxalate excretion in obese stone formers. Except these parameters, clinical characteristics of obese stone formers were not extensively explored. Aims: In the present paper we studied the relationship between obesity and its metabolic correlates and nephrolithiasis. Materials and methods: We studied 478 Caucasian subjects having BMI ≥25 kg/m 2 . The presence of nephrolithiasis, hypertension, diabetes mellitus and metabolic syndrome were noted. They underwent measurements of anthropometry (BMI and waist circumference, body composition), serum variables (fasting glucose, serum lipids and serum enzymes) and Mediterranean diet (MedDiet) nutritional questionnaire. Results: 45 (9.4%) participants were stone formers. Subjects with high serum concentrations of triglycerides (≥150 mg/dl), fasting glucose (> 100 mg/dl) and AST (>30 U/I in F or >40 U/I in M) were more frequent among stone formers than non-stone formers. Multinomial logistic regression confirmed that kidney stone production was associated with high fasting glucose (OR = 2.6, 95% CI 1.2-5.2, P = 0.011), AST (OR = 4.3, 95% CI 1.1-16.7, P = 0.033) and triglycerides (OR = 2.7, 95% CI 1.35.7, P = 0.01). MedDiet score was not different in stone formers and non-stone formers. However, stone formers had a lower consumption frequency of olive oil and nuts, and higher consumption frequency of wine compared with non-stone formers. Conclusions: Overweight and obese stone formers may have a defect in glucose metabolism and a potential liver damage. Some foods typical of Mediterranean diet may protect against nephrolithiasis.