Proteome-wide mendelian randomization identifies therapeutic targets for nephrolithiasis.

Kidney Stone Disease (KSD) constitutes a multifaceted disorder, emerging from a confluence of environmental and genetic determinants, and is characterized by a high frequency of occurrence and recurrence. Our objective is to elucidate potential causative proteins and identify prospective pharmacological targets within the context of KSD. This investigation harnessed the unparalleled breadth of plasma protein and KSD pooled genome-wide association study (GWAS) data, sourced from the United Kingdom Biobank Pharma Proteomics Project (UKBPPP) and the FinnGen database version R10. Through Mendelian randomization analysis, proteins exhibiting a causal influence on KSD were pinpointed. Subsequent co-localization analyses affirmed the stability of these findings, while enrichment analyses evaluated their potential for pharmacological intervention. Culminating the study, a phenome-wide association study (PheWAS) was executed, encompassing all phenotypes (2408 phenotypes) catalogued in the FinnGen database version R10. Our MR analysis identified a significant association between elevated plasma levels of proteins FKBPL, ITIH3, and SERPINC1 and increased risk of KSD based on genetic predictors. Conversely, proteins CACYBP, DAG1, ITIH1, and SEMA6C showed a protective effect against KSD, documented with statistical significance (PFDR<0.05). Co-localization analysis confirmed these seven proteins share genetic variants with KSD, signaling a shared genetic basis (PPH3 + PPH4 > 0.8). Enrichment analysis revealed key pathways including hyaluronan metabolism, collagen-rich extracellular matrix, and serine-type endopeptidase inhibition. Additionally, our PheWAS connected the associated proteins with 356 distinct diseases (PFDR<0.05), highlighting intricate disease interrelations. In conclusion, our research elucidated a causal nexus between seven plasma proteins and KSD, enriching our grasp of prospective therapeutic targets.

[Association between the triglyceride-glucose index and the incidence of nephrolithiasis in male individuals].

OBJECTIVE: To analyze the association between the triglyceride-glucose (TyG) index and the risk of nephrolithiasis across various demographic and clinical subgroups, aiming to enhance early diagnosis and treatment of nephrolithiasis and promote personalized care in diverse populations. METHODS: This cross-sectional study analyzed the medical records of 84 968 adults, stratified into three categories (low, middle, high) according to their TyG index scores. To evaluate the association between the TyG index and nephrolithiasis risk, multivariable Logistic regression models were employed, adjusting for potential confounders. Additionally, piecewise linear regression models were used to investigate the non-linear dynamics of the TyG index's relationship with nephrolithiasis risk. Subgroup analyses were performed to explore variations in the effects of the TyG index across different demographic and clinical populations. RESULTS: Increasing TyG index was associated with a higher risk of nephrolithiasis, rising from 4.36% in the low group to 8.96% in the high group (P < 0.001). In adjusted models, males in the middle and high TyG index categories demonstrated significantly elevated risks of nephrolithiasis, with odds ratios of 1.18 (95%CI: 1.07-1.31, P=0.002) and 1.29 (95%CI: 1.15-1.45, P < 0.001), respectively. Conversely, in females, the association was not statistically significant post-adjustment (OR=0.98, 95%CI: 0.82-1.16, P=0.778). Among males, for each unit increment in the TyG index below the critical threshold of 8.98, there was a notable 40% escalation in the risk of developing nephrolithiasis (OR=1.40, 95%CI: 1.24-1.58, P < 0.001). Surpassing this threshold, the TyG index no longer conferred a significant increase in risk (OR=0.91, 95%CI: 0.78-1.06, P=0.24). Subgroup analyses indicated that this association remained stable regardless of age, BMI, or hypertension status. CONCLUSION: The TyG index is positively associated with the risk of nephrolithiasis in males, demonstrating a nonlinear dose-response relationship that becomes especially pronounced at certain index levels. This biomarker could potentially serve as a valuable clinical tool for identifying males who are at a high risk of developing nephrolithiasis, thereby enabling targeted preventive strategies. Further research is urgently needed to explore the underlying mechanisms and to verify the applicability of these results across different populations.

Increased risk of nephrolithiasis: an emerging issue in children with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

PURPOSE: To investigate the incidence of nephrolithiasis in a cohort of children with congenital adrenal hyperplasia (CAH), and to study if there is an association with the metabolic control of the disease. METHODS: This study was designed as a multicenter 1 year-prospective study involving 52 subjects (35 males) with confirmed molecular diagnosis of CAH due to 21-hydroxylase deficiency (21-OHD). Each patient was evaluated at three different time-points: T0, T1 (+6 months of follow-up), T2 (+12 months of follow up). At each follow up visit, auxological data were collected, and adrenocorticotrophic hormone (ACTH), 17-hydroxyprogesterone (17-OHP), Δ4-androstenedione, dehydroepiandrosterone sulfate (DHEAS) serum levels, and urinary excretion of creatinine, calcium, oxalate and citrate were assayed. Moreover, a renal ultrasound was performed. RESULTS: The incidence of nephrolithiasis, assessed by ultrasound was 17.3% at T0, 13.5% at T1 and 11.5% at T2. At T0, one subject showed nephrocalcinosis. In the study population, a statistically significant difference was found for 17-OHP [T0: 11.1 (3.0-25.1) ng/mL; T1: 7.1 (1.8-19.9) ng/mL; T2: 5.9 (2.0-20.0) ng/mL, p < 0.005], and Δ4-androstenedione [T0: 0.9 (0.3-2.5) ng/mL; T1: 0.3 (0.3-1.1) ng/mL; T2: 0.5 (0.3-1.5) ng/mL, p < 0.005] which both decreased over the follow up time. No statistically significant difference among metabolic markers was found in the group of the subjects with nephrolithiasis, even if 17-OHP, DHEAS and Δ4-androstenedione levels showed a tendency towards a reduction from T0 to T2. Principal component analysis (PCA) was performed to study possible hidden patterns of associations/correlations between variables, and to assess the trend of them during the time. PCA revealed a decrease in the amount of the variables 17-OHP, Δ4-androstenedione, and ACTH that occurred during follow-up, which was also observed in subjects showing nephrolithiasis. CONCLUSIONS: our data demonstrated that children affected with 21-OHD can be at risk of developing nephrolithiasis. Additional studies are needed to clarify the pathogenesis and other possible risk factors for this condition, and to establish if regular screening of kidney ultrasound in these patients can be indicated.

Renal complications and quality of life in postsurgical hypoparathyroidism: a case-control study.

PURPOSE: Conventional therapy (calcium and activated vitamin D) does not restore calcium homeostasis in patients with chronic hypoparathyroidism (HypoPT) and is associated with renal complications and reduced quality of life (QoL). The aim of this study was to evaluate in a case-control, cross-sectional study, the rate of renal complications and QoL in two sex- and age-matched cohort of patients with differentiated thyroid cancer with (n = 89) and without (n = 89) chronic post-operative HypoPT (PoHypoPT) and their relationship with the biochemical control of the disease. METHODS: Serum and urinary parameters, renal ultrasound and QoL were assessed by SF-36 and WHO-5 questionnaires. RESULTS: Forty-three (48.3%) PoHypoPT patients reported symptoms of hypocalcemia. Twenty-six (29.2%) patients were at target for all 6 parameters, 46 (51.6%) for 5. The most frequently unmet targets were gender-specific 24-h urinary calcium (44.9%) and serum calcium (37.1%). Serum phosphate, magnesium and 25(OH)D were in the normal range in > 90% of patients. Renal calcifications were found in 26 (29.2%) patients, with no correlation with 24-h urinary calcium. eGFR did not differ between patients and controls. Conversely, patients had a significant higher rate of renal calcifications and a lower SF-36, but not WHO-5, scores. SF-36 scores did not differ between PoHypoPT patients who were, or not, hypocalcemic. CONCLUSIONS: Our study shows that the rate of renal calcifications was higher in patients with PoHypoPT than in those without. This finding, together with the reduced QoL and the presence of hypocalcemic symptoms in about half patients, underscores that the treatment of chronic HypoPT with conventional therapy is suboptimal.

Stones left unturned: Missed opportunities to diagnose primary hyperparathyroidism in patients with nephrolithiasis.

BACKGROUND: Nephrolithiasis is a sequela of primary hyperparathyroidism and an indication for parathyroidectomy. The prevalence of primary hyperparathyroidism in patients with nephrolithiasis is 3% to 5%; however, recent studies suggest that many hypercalcemic patients with nephrolithiasis never undergo workup for primary hyperparathyroidism. Our goal is to evaluate primary hyperparathyroidism screening rates at a tertiary academic health institution and identify opportunities to increase referral rates in patients presenting with nephrolithiasis. METHODS: We retrospectively reviewed 15,725 patients across an academic health system who presented with nephrolithiasis between 2012 and 2020. Calcium levels measured within 6 months of presentation were identified, and those with hypercalcemia (≥10.3 mg/dL) were reviewed if parathyroid hormone levels were measured. Patients with primary hyperparathyroidism were evaluated to see if they were referred to a specialist for treatment. RESULTS: Of 15,725 patients presenting with nephrolithiasis, 12,420 (79%) had calcium levels measured; 630 patients (4.0%) were hypercalcemic, and 207 (33%) had parathyroid hormone levels measured. Patients were more likely to have parathyroid hormone levels sent if they were older, had higher calcium levels, or presented to an outpatient clinic (P = .028, P = .002, P < .001). We identified 89 patients (0.6%) with primary hyperparathyroidism, of which only 35 (39%) were referred for treatment. CONCLUSION: The proportion of patients presenting with nephrolithiasis ultimately diagnosed with primary hyperparathyroidism was significantly lower than others have reported. Additionally, a substantial number of patients with nephrolithiasis did not have calcium and/or parathyroid hormone levels measured. These missed opportunities for diagnosis are critical as early definitive management of primary hyperparathyroidism can prevent recurrent nephrolithiasis and other primary hyperparathyroidism-related end organ effects.

Parathyroidectomy for nephrolithiasis in primary hyperparathyroidism: Beneficial but not a panacea.

BACKGROUND: Nephrolithiasis is a classic indication for parathyroidectomy in primary hyperparathyroidism patients; however, the effects of parathyroidectomy on nephrolithiasis recurrence are not well studied. The aim was to determine effect of parathyroidectomy on time to first nephrolithiasis recurrence and recurrence rate per patient-years. METHODS: A retrospective cohort study of patients diagnosed with primary hyperparathyroidism and at least one episode of nephrolithiasis was performed. The patients were divided into observation, presurgery, and postsurgery groups. Endpoints were time to first recurrence of nephrolithiasis and average recurrence rate per patient-years. RESULTS: The cohort was comprised of 1,252 patients. In addition, 334 (27%) patients underwent parathyroidectomy and 918 (73%) were observed. The surgical and nonsurgical groups differed significantly in age, sex, Charlson, calcium, and primary hyperparathyroidism level. Overall recurrence rate was 31.3%. The 5-, 10-, and 15-year recurrence-free survival rates were 74.4%, 56.3%, 49.5%, respectively (presurgery), 82.4%, 70.9%, 62.8%, respectively (postsurgery; P < .0001), and 86.3%, 77.7%, and 70.6%, respectively (observation). The presurgery group had an increased risk of first recurrence compared with the observation group (hazard ratio 1.89; 95% confidence interval, 1.44-2.47). The average recurrence rates among all surgical patients who recurred were 1 event per 4.3 patient-years presurgery versus 1 event per 6.7 patient-years postsurgery (P = .0001). CONCLUSION: Recurrent nephrolithiasis is a significant problem in patients with primary hyperparathyroidism. Parathyroidectomy prolongs the time to first recurrence and decreases the number of re-recurrences over time but does not eliminate recurrences. Observation may also be a reasonable approach in selected patients.

Evaluation for Primary Hyperparathyroidism in Patients Who Present With Nephrolithiasis.

BACKGROUND: The incidence of primary hyperparathyroidism (PHP) is likely underestimated. Nephrolithiasis may indicate PHP with indication for parathyroidectomy. We sought to determine the proportion of patients with an index diagnosis of nephrolithiasis that have serum calcium levels measured, parathyroid hormone (PTH) levels measured if hypercalcemic, and time to referral for definitive management if PHP is diagnosed. METHODS: A single-institution retrospective review was performed of adult patients presenting with nephrolithiasis between July 1, 2016 and December 31, 2018. Exclusion criteria included currently admitted patients, prior nephrolithiasis, congenital or acquired urinary tract anomalies, and patients on calciuretics. Records were assessed for serum calcium and PTH measurement, as well as referrals. Univariate statistical analysis was performed. RESULTS: Of 1782 patients with nephrolithiasis screened, 968 met inclusion criteria. Patients were 49.8% female, 88.9% white. Mean age was 53 y. Within this cohort, 620 (64.0%) patients had a calcium measured, with a mean elapsed time from presentation of 27 d (interquartile range [IQR] 0-8). Twelve patients (1.58%) with calcium measured were hypercalcemic and eight (66.7%) had PTH measured with a mean elapsed time from presentation of 183 d (IQR 72-310), all had elevated or non-suppressed PTH. Five (62.5%) were referred to surgeons with mean elapsed referral time of 270 d (IQR 95-492). CONCLUSIONS: Many with index nephrolithiasis are not assessed for hypercalcemia or hyperparathyroidism. Patients with serum calcium and PTH values indicating PHP diagnosis may have significant delay to parathyroidectomy. Targeted interventions with electronic health record alerts or automated reflex testing may improve care in this domain.

miR-155 facilitates calcium oxalate crystal-induced HK-2 cell injury via targeting PI3K associated autophagy.

Nephrolithiasis is one of the most common and highly recurrent diseases worldwide. Accumulating evidence revealed the elevated miR-155 levels both in serum and urine of nephrolithiasis patients. The aim of our research was to explore the role of miR-155 in CaOx-induced apoptosis in HK-2 cells. The expression levels of miR-155 in serum and renal tissues were quantified in 20 patients with nephrolithiasis using qRT-PCR assay. ELISA was performed to determine urinary levels of interleukin (IL)-1ß, IL-6 and tumor necrosis factor-alpha (TNF-α). Renal tubular cell model of CaOx nephrolithiasis was established to investigate the role and molelular mechanism of miR-155. Cell viability and apoptosis were assessed by MTT and flow cytometry, respectively. Immunofluoresent staining of LC3 autophagosome and western blotting were performed to evaluate the autophagic activity. Luciferase reporter assay was employed to verify the interaction between miR-155 and PI3KCA/Rheb. PI3K/Akt/mTOR signaling was further examined by western blotting. Serum and renal levels of miR-155 and inflammatory factors were significantly elevated in nephrolithiasis patients than in controls. CaOx treatment caused up-regulation of miR-155 and induced autophagy in renal tubular epithelial cells, while silencing miR-155 or inhibition of autophagy by 3-metheladenine (3-MA) ameliorated CaOx crystal-induced cell injury. PI3KCA and Rheb was identified as downstream targets of miR-155. Moreover, miR-155 activates autophagy and promotes cell injury through repressing PI3K/Akt/mTOR signaling pathway. Taken together, these findings demonstrated that miR-155 facilitates CaOx crystal-induced renal tubular epithelial cell injury via PI3K/Akt/mTOR-mediated autophagy, providing therapeutic targets for ameliorating cellular damage by CaOx crystals.

Hyperparathyroidism in patients over 75: Clinical characteristics and outcome. Is conservative treatment a safe alternative?

OBJECTIVE: With the current aging of the world's population, primary hyperparathyroidism (PHPT) is increasingly detected in the elderly. Yet data on the presentation and outcome of PHPT in this group are scarce. The objective was to describe a cohort of patients aged 75 years or more with PHPT observed in our endocrine clinic. STUDY DESIGN: A retrospective analysis of medical records in an endocrine clinic at a tertiary hospital. We evaluated 182 patients with PHPT, aged 75 years or more at their last follow-up, all diagnosed at age 65 or more. Laboratory data were compared at diagnosis and last follow-up. RESULTS: Mean age at diagnosis was 73 ± 4 years, last follow-up was at 83 ± 4 years, and mean follow-up was 11.3 ± 5.5 years. Osteoporosis, fractures, and nephrolithiasis were diagnosed in 114(63 %), 84(46 %), and 43(24 %) patients, respectively. Overall, 150 patients had an indication for surgery; of them, the 29 who underwent parathyroidectomy were younger than the non-operated patients and had higher rates of hypercalciuria. During the follow-up of the 141 patients who did not undergo operation, serum and urinary calcium levels significantly had decreased, and vitamin D level had increased at last visit (10.4 ± 0.5 mg/dl, 161 ± 70 mg/24 h, 69 ± 17 nmol/l, p < 0.01 respectively) compared with levels at diagnosis (10.6 ± 0.2 mg/dl, 223 ± 95 mg/24 h, 53 ± 15 nmol/l, respectively, p = 0.001). Overall, 38 of the 182 patients (20 %) died during follow-up; these patients were significantly older at diagnosis (76 ± 5 vs. 72 ± 4 years) but there were no differences in laboratory variables. CONCLUSIONS: While most patients had a formal indication for surgery, few underwent parathyroidectomy. Serum and urinary calcium significantly decreased during follow-up in patients who did not undergo surgery. Our data are reassuring and support at least the consideration of conservative treatment for these patients.

Targeting kidneys by superparamagnetic allopurinol loaded chitosan coated nanoparticles for the treatment of hyperuricemic nephrolithiasis.

PURPOSE: The major short coming of conventional therapy system is that they can't deliver the therapeutics specifically to a site within the body without producing nonspecific toxicity. Present research aimed at developing kidney targeted allopurinol (AP) loaded chitosan coated magnetic nanoparticles (A-MNPs) for the management of hyperuricemic nephropathy manifested in the form of nephrolithiasis. METHODS: The work includes preparation of magnetic nanoparticles by chemical co-precipitation method and evaluation of the prepared batches for particle size analysis, Transmission electron microscopy, entrapment efficiency, in-vitro release study etc. Further, FTIR spectroscopy, X-ray diffraction, Differential Scanning Calorimetry, Vibrational sample magnetometer (VSM) and in-vivo animal studies were also performed. RESULTS: VSM analysis demonstrates that the prepared nanoparticles exhibit superparamagnetic magnetic behaviour which was retained even after coating by chitosan. In-vivo studies of A-MNPs showed 19.07-fold increase in kidney uptake of AP as compared to serum post 2 h of administration in mice whereas no drug was detected in kidney and serum post 2 h administration of pure drug (free-form) indicating successful targeting to kidney as well as sustained release of AP from the formulated A-MNPs. The significant (p < 0.01) effectiveness of A-MNPs in management of hyperuricemic nephrolithiasis was observed through estimating pH and uric acid levels in urine and serum samples of mice. These findings were also confirmed by histological examination of isolated kidney samples. CONCLUSION: Present investigation signifies that a simple external magnetic field is enough for targeting allopurinol to kidneys by formulating A-MNPs which further offers an effective approach for management of hyperuricemic nephrolithiasis. Graphical Abstract.

Normocalcemic Primary Hyperparathyroidism in Adults Without a History of Nephrolithiasis or Fractures: A Prospective Study.

The prevalence and the diagnostic criterion of "normocalcemic" primary hyperparathyroidism (NPHPT) are still uncertain and there is no consensual definition. This prospective study evaluated the prevalence of NPHPT in 676 adults without a history of fractures or nephrolithiasis and who would be submitted to thyroidectomy, the impact of adopting different cut-off values for 25-hydroxyvitamin D and estimated glomerular filtration rate (eGFR), and the agreement between biochemical diagnosis and the surgical finding of altered parathyroid glands. NPHPT was diagnosed in patients with normal total and ionized calcium and elevated PTH (in 2 measurements) and without a known cause of secondary HPT, including eGFR<40 ml/min/1.73 m2 and 25-hydroxyvitamin D<20 ng/dl. The 4 parathyroid glands were fully explored in these patients. Forty-six patients (6.8%) had a laboratory diagnosis of NPHPT. Altered parathyroid glands were detected in only 4 patients, corresponding to 0.6% of all patients and to 8.7% of those with a biochemical diagnosis of NPHPT. The latter was confirmed in 0/174 men, 1/252 premenopausal women, and 3/250 postmenopausal women. Among the 42 patients with elevated PTH and without altered parathyroid glands, 25 had 25-hydroxyvitamin D between 20 and 30 ng/dl, 7 had eGFR between 40 and 60 ml/min/1.73 m2, and 9 had both. The prevalence of NPHPT was 0.74% in this adult population without a history of nephrolithiasis or fractures. The diagnostic criterion using eGFR>60 ml/min/1.73 m2 and 25-hydroxyvitamin D>30 ng/dl was more appropriate considering the agreement with the surgical finding of altered parathyroid glands.

Total serum magnesium in cats with chronic kidney disease with nephrolithiasis.

OBJECTIVES: Magnesium has been 'the forgotten ion' for many years. Over the past decade, however, the role of magnesium in essential physiological functions and several illness conditions have been elucidated. Nevertheless, the investigation of magnesium in cats with chronic kidney disease (CKD) and nephrolithiasis is yet to be determined. The purpose of this study was to investigate whether CKD cats with nephrolithiasis have changes in total serum magnesium concentrations, and whether magnesium disorders may be associated with other electrolyte disturbances, as well as with prognosis. We also aimed to evaluate whether total serum magnesium concentration differs between CKD cats with and without nephrolithiasis. METHODS: Total serum magnesium concentrations were assessed in 42 cats with CKD with stage 1-4 nephrolithiasis. The correlation between magnesium and other electrolytes, as well as Kaplan-Meier survival analysis, were performed. We also selected 14 control cats with CKD without nephrolithiasis age-matched with 14 cats with CKD with nephrolithiasis. RESULTS: Hypermagnesemia was observed in 16/42 (38.1%) and hypomagnesemia in 6/42 (14.3%) cats. Serum magnesium abnormalities were observed in cats of all stages, and marked hypermagnesemia was noted in cats with stage 4 CKD with nephrolithiasis (P <0.001). There was a negative correlation between total serum magnesium and ionized calcium (r = -0.64; P <0.01), and a positive correlation between total serum magnesium and serum phosphorus (r = 0.58, P = 0.01). Cats with CKD with nephrolithiasis and hypomagnesemia or hypermagnesemia had higher mortality than those with normal total serum magnesium concentration (P <0.01), regardless of CKD stage. There was no difference in total serum magnesium concentration between CKD cats with and without nephrolithiasis. CONCLUSIONS AND RELEVANCE: Cats with CKD with nephrolithiasis have magnesium abnormalities. Hypomagnesemia and hypermagnesemia were associated with an increase in mortality, and thus total serum magnesium abnormalities may be used as prognostic factors in these cases.

Is oxidized low-density lipoprotein the connection between atherosclerosis, cardiovascular risk and nephrolithiasis?

Nephrolithiasis is considered a systemic disease. A link has been established between nephrolithiasis, cardiovascular disease (CVD), the metabolic syndrome and atherosclerosis. A significant correlation has been found between the high levels of oxidized low-density lipoprotein (oxLDL) and CVD and atherosclerosis, including coronary and femoral artery disease. To the best of our knowledge, oxLDL has not been evaluated in patients with nephrolithiasis. This study aimed to evaluate serum levels of oxLDL, anti-oxLDL antibodies (oxLDL-ab) and other markers of atherosclerosis in patients with nephrolithiasis, according to the severity of the disease. The population sample consisted of 94 patients of 30-70 years of age with no symptoms of CVD who presented with renal calculi documented by ultrasonography, abdominal X-ray or computed tomography. The patients were divided into two groups: Group 1 (≥ 3 stones) and Group 2 (1-2 stones). A comparison control group was formed with 21 healthy individuals. Enzyme-linked immunosorbent assays were used to assess oxLDL and oxLDL-ab. Lipid peroxidation indexes were also analyzed. Median serum oxLDL values were higher in Groups 1 and 2 compared to the control group (≥ 3 stones, p = 0.02; 1-2 stones, p = 0.03). Median serum anti-oxLDL antibody levels were lower in the patients in Group 1 compared to the controls (p = 0.03). There was no significant difference in the oxLDL/oxLDL-ab ratio between patients and controls. These findings suggest that this may be the link between nephrolithiasis and the greater incidence of atherosclerosis and cardiovascular disease in patients with kidney stones.

Polymorphisms of the VDR gene in patients with nephrolithiasis in a Han Chinese population.

An association study between VDR gene polymorphisms and nephrolithiasis was conducted in different populations, but it is not yet known whether the association exists in the Han Chinese population. Here, we genotyped three SNPs (rs731236, rs7975232 and rs10735810) in the promoter region of the VDR gene by iMLDR genotyping assays in a large case-control cohort. The results demonstrated that there was no association found between the three SNPs (rs731236, rs7975232 and rs10735810) in the VDR gene and nephrolithiasis, whether in allele or genotype distribution. However, SNP rs10735810 was correlated with the level of serum calcium in control groups, but not in patient groups. In conclusion, considering the large sample size, we believe that the SNP rs10735810 allele A in the VDR gene promoter region may influence the level of serum calcium, but not influence the formation of nephrolithiasis in a Han Chinese population.

Untargeted lipidomics based on UPLC-QTOF-MS/MS and structural characterization reveals dramatic compositional changes in serum and renal lipids in mice with glyoxylate-induced nephrolithiasis.

Nephrolithiasis is a systemic metabolic disease with a worldwide incidence that is increasing yearly, as well as a high recurrence rate; however, this disease's pathogenesis has not been thoroughly elucidated to date. Several epidemiological studies have shown that the risk for developing kidney stones increases in people with dyslipidemia. To explore the mechanism of lipid-induced kidney stones, we established a mouse model for renal urolithiasis based on intraperitoneal injections of glyoxylate (120 mg/kg/d). Lipidomics based on ultra high performance liquid chromatography coupled with quadrupole-time of flight mass spectrometry (UPLC-QTOF-MS/MS) was performed to determine the changes in lipid metabolism in serum and kidneys. We screened 179 and 196 different lipid metabolites in the kidneys and serum, respectively, including fatty acyls, glycerophospholipids, sphingolipids, glycerolipids and prenol lipids. We found that polyunsaturated fatty acids, such as arachidonic acid, eicosapentaenoic acid, and docosahexoenoic acid, and ceramides and lysophosphocholines mediated inflammatory responses and that the oxidative stress induced by oleylethanolamine and glycerophosphoethanolamine plasmalogens is closely related to the development of kidney stones. These results provide strong evidence for the relationship between lipid metabolism and the development of kidney stones and suggest a clear direction for future research.

Can urine osteopontin levels, which may be correlated with nutrition intake and body composition, be used as a new biomarker in the diagnosis of nephrolithiasis?

BACKGROUND AND AIM: The nephrolithiasis has a multifactorial etiology resulting from the interaction of metabolic, genetic and environmental factors. Parameters such as nutrition and urinary osteopontin (OPN) level may affect kidney stone formation. The purpose of this study is to evaluate the correlation between urinary OPN level and kidney stone formation and effect of nutrition on OPN level in nephrolithiasis. MATERIALS AND METHODS: This study was conducted on 88 volunteers including 44 healthy individuals and 44 patients diagnosed with nephrolithiasis and aging between 20 and 65 years. Some serum parameters and urinary OPN levels of the individuals were analyzed. Several anthropometric measurements of the individuals were taken and calculated their body mass index. Additionally, 24-hour dietary recall and water intakes were recorded and the participants completed food-frequency questionnaire for the evaluation of their nutritional status. RESULTS: Urinary OPN (ng/mL) levels of patients were lower than that of control group (p<0.05). Dietary energy, carbohydrate, poly-unsaturated fatty acid (PUFA) and n-6 fatty acids intakes and urinary OPN levels of male patients were positively correlated (p<0.05). Additionally, there was a negative correlation between their urinary OPN (ng/mL) and serum creatinine (mg/dL) levels of female patients (p<0.05). Body weight, waist circumference, hip circumference and body muscle mass values of healthy males were positively correlated with their urinary OPN levels (p<0.05). CONCLUSIONS: Results of the study showed that low urinary OPN levels were correlated with increased kidney stone risk, and dietary habits can affect urinary OPN level.

Association between low bone mass and the serum RANKL and OPG in patients with nephrolithiasis.

BACKGROUND: Nephrolithiasis is a risk factor for Osteopenia and osteoporosis. Receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) regulate bone remodeling and osteoclastogenesis. This study aimed to evaluate the relation between serum OPG, RANKL concentration, and bone mineral density (BMD) in patients with kidney stone disease. METHODS: Forty-four nephrolithiasis patients with either low bone mass or normal BMD (considered control group) were enrolled in this study. BMD was measured at lumbar spine (L1-L4) and femoral neck by dual-energy X-ray absorptiometry (DEXA). The serum OPG and RANKL were determined using the ELISA method. RESULTS: The median levels of serum OPG were significantly higher in nephrolithiasis patients with low bone mass compared to the nephrolithiasis patients with normal BMD (3.9 pmol/l versus 3.1 pmol/l; P = 0.03), respectively. Negative correlation was detected between bone densities of femoral neck and OPG in patients with nephrolithiasis (r = -.0344, P = 0.02). CONCLUSION: The present study showed that high serum fasting OPG levels may be indicative of femoral neck BMD in patients with nephrolithiasis.

Metabolic syndrome contributes to renal injury mediated by hyperoxaluria in a murine model of nephrolithiasis.

Metabolic syndrome (MS) individuals have a higher risk of developing chronic kidney disease through unclear pathogenic mechanisms. MS has been also related with higher nephrolithiasis prevalence. To establish the influence of MS on renal function, we designed a murine model of combined metabolic syndrome and hyperoxaluria. Four groups of male Sprague-Dawley rats were established: (1) control group (n = 10) fed with standard chow; (2) stone former group (SF) (n = 10) fed with standard chow plus 0.75% ethylene glycol administered in the drinking water; (3) metabolic syndrome group (MS) (n = 10), fed with 60% fructose diet; (4) metabolic syndrome + stone former group (MS + SF) (n = 10), 60% fructose diet and 0.75% EG in the drinking water. MS group showed a significant injury to renal function when hyperoxaluria was induced. It was demonstrated by a significant decrease of creatinine clearance (p < 0.001), with higher tubular damage (34.3%, CI 95% 23.9-44.7, p < 0.001), produced by deposition of crystals, and increased tubular synthesis of osteopontin as a response to tubular damage. Induction of hyperoxaluria in rats with MS causes severe morphological alterations with a significant impairment of renal function. This impairment is not produced in rats without MS. Therefore, this model can be useful for the study of the influence of MS in stone formation.