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Bibliography on: Calcium Metabolism and Urinary Stones

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Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 30 Mar 2023 at 01:40 Created: 

Calcium Metabolism and Urinary Stones

Wikipedia: Calcium Metabolism — everybody knows that osteoporosis is a huge threat and that the best way to reduce the risk of osteoporosis is to take lots of dietary calcium supplements and vitamin D pills.

OK, exercise is good, too, but that can involve actually breaking a sweat — something that not everyone wants to do.

But, did you also know that hypercalciuria (too much secreted calcium in the urine) is associated with a significant increase in the risk for kidney stones? And, you can easily get hypercalciuria if you pop too many calcium-supplement pills. Hmmmm. Nice choice, break a hip or pass kidney stones... What to do? As with most things biological, reality lies somewhere in the trade-off zone. A quick look at the literature dealing with calciuria and kidney stones is one way to start.

Created with PubMed® Query: (calciuria OR "calcium metabolism") AND (urolith OR "kidney stone" OR "kidney stones" OR "bladder stones" OR stones) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2023-03-24

Osman O, Manzi S, Wasko MC, et al (2023)

Case report: disease mechanisms and medical management of calcium nephrolithiasis in rheumatologic diseases.

BMC urology, 23(1):42.

BACKGROUND: Nephrolithiasis as a feature of rheumatologic diseases is under recognized. Understanding presenting features, diagnostic testing is crucial to proper management.

CASE PRESENTATION: A 32 year old woman with a history of recurrent complicated nephrolithiasis presented to a rheumatologist for a several month history of fatigue, dry eyes, dry mouth, arthralgias. She had a positive double-stranded DNA, positive SSA and SSB antibodies. She was diagnosed with Systemic Lupus erythematosus (SLE) and Sjogren's syndrome and was started on mycophenalate mofetil. Of relevance was a visit to her local emergency room 4 years earlier with profound weakness with unexplained marked hypokalemia and a non-anion gap metabolic acidosis. Approximately one year after that episode she developed flank pain and nephrocalcinosis. She had multiple issues over the ensuing years with stones and infections on both sides. Interventions included extracorporeal shockwave lithotripsy as well as open lithotomy and eventual auto-transplantation of left kidney for recurrent ureteric stenosis. 24 h stone profile revealed marked hypocitraturia, normal urine calcium, normal urine oxalate and uric acid. She was treated with potassium citrate. Mycophenolate was eventually stopped due to recurrent urinary tract infections and she was started on Belimumab. Because of recurrent SLE flares, treatment was changed to Rituximab (every 6 months) with clinical and serologic improvement. Her kidney stone frequency gradually improved and no further interventions needed although she continued to require citrate repletion for hypocitraturia.

CONCLUSIONS: Nephrolithiasis can be a prominent and even presenting feature in Sjogrens syndrome as well as other rheumatologic diseases. Prompt recognition and understanding disease mechanisms is important for best therapeutic interventions for kidney stone prevention as well as treatment of underlying bone mineral disease.

RevDate: 2023-03-23

Musiał N, Bogucka A, Tretiakow D, et al (2023)

Proteomic analysis of sialoliths from calcified, lipid and mixed groups as a source of potential biomarkers of deposit formation in the salivary glands.

Clinical proteomics, 20(1):11.

Salivary stones, also known as sialoliths, are formed in a pathological situation in the salivary glands. So far, neither the mechanism of their formation nor the factors predisposing to their formation are known despite several hypotheses. While they do not directly threaten human life, they significantly deteriorate the patient's quality of life. Although this is not a typical research material, attempts are made to apply various analytical tools to characterise sialoliths and search for the biomarkers in their proteomes. In this work, we used mass spectrometry and SWATH-MS qualitative and quantitative analysis to investigate the composition and select proteins that may contribute to solid deposits in the salivary glands. Twenty sialoliths, previously characterized spectroscopically and divided into the following groups: calcified (CAL), lipid (LIP) and mixed (MIX), were used for the study. Proteins unique for each of the groups were found, including: for the CAL group among them, e.g. proteins from the S100 group (S100 A8/A12 and P), mucin 7 (MUC7), keratins (KRT1/2/4/5/13), elastase (ELANE) or stomatin (STOM); proteins for the LIP group-transthyretin (TTR), lactotransferrin (LTF), matrix Gla protein (MPG), submandibular gland androgen-regulated protein 3 (SMR3A); mixed stones had the fewest unique proteins. Bacterial proteins present in sialoliths have also been identified. The analysis of the results indicates the possible role of bacterial infections, disturbances in calcium metabolism and neutrophil extracellular traps (NETs) in the formation of sialoliths.

RevDate: 2023-03-14
CmpDate: 2023-03-14

Li Y, Lu X, Yu Z, et al (2023)

Meta-data analysis of kidney stone disease highlights ATP1A1 involvement in renal crystal formation.

Redox biology, 61:102648.

Nephrolithiasis is a complicated disease affected by various environmental and genetic factors. Crystal-cell adhesion is a critical initiation process during kidney stone formation. However, genes regulated by environmental and genetic factors in this process remain unclear. In the present study, we integrated the gene expression profile data and the whole-exome sequencing data of patients with calcium stones, and found that ATP1A1 might be a key susceptibility gene involved in calcium stone formation. The study showed that the T-allele of rs11540947 in the 5'-untranslated region of ATP1A1 was associated with a higher risk of nephrolithiasis and lower activity of a promoter of ATP1A1. Calcium oxalate crystal deposition decreased ATP1A1 expression in vitro and in vivo and was accompanied by the activation of the ATP1A1/Src/ROS/p38/JNK/NF-κB signaling pathway. However, the overexpression of ATP1A1 or treatment with pNaKtide, a specific inhibitor of the ATP1A1/Src complex, inhibited the ATP1A1/Src signal system and alleviated oxidative stress, inflammatory responses, apoptosis, crystal-cell adhesion, and stone formation. Moreover, the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine reversed ATP1A1 down-regulation induced by crystal deposition. In conclusion, this is the first study to show that ATP1A1, a gene modulated by environmental factors and genetic variations, plays an important role in renal crystal formation, suggesting that ATP1A1 may be a potential therapeutic target for treating calcium stones.

RevDate: 2023-02-28

Zittermann A, Trummer C, Theiler-Schwetz V, et al (2023)

Long-term supplementation with 3200 to 4000 IU of vitamin D daily and adverse events: a systematic review and meta-analysis of randomized controlled trials.

European journal of nutrition [Epub ahead of print].

PURPOSE: The upper tolerable intake level for vitamin D in the general population has been set at 4000 international units (IU) daily, but considerable uncertainty remains. We summarized reported harmful effects of a daily vitamin D supplement of 3200-4000 IU in trials lasting ≥ 6 months.

METHODS: We performed a systematic review and meta-analysis of randomized controlled trials in several databases and identified 22 trials reporting safety data. Parameters of calcium metabolism, falls, hospitalization, and mortality were assessed.

RESULTS: The selected trials comprised a total number of 12,952 participants. All trials used supplemental vitamin D3. The relative risk (RR) of hypercalcemia in the vitamin D vs. control arm was 2.21 (95%CI: 1.26-3.87; 10 studies), with a vitamin D-induced frequency of hypercalcemia of 4 cases per 1000 individuals. Subgroup analysis in trials with > 100 and ≤ 100 study participants revealed an RR of 2.63 (95%CI: 1.30-5.30; 7 studies) and 0.80 (95%CI: 0.24-2.62; 3 studies), respectively (Pinteraction = 0.06). Risks of falls and hospitalization were also significantly increased in the vitamin D arm with an RR of 1.25 (95%CI: 1.01-1.55; 4 studies) and 1.16 (95%CI: 1.01-1.33; 7 studies), respectively. Risks of hypercalciuria, kidney stones, and mortality did not differ significantly between study arms. Quality assessment revealed high risk of incomplete reporting of safety-related outcome data.

CONCLUSION: Supplemental vitamin D doses of 3200-4000 IU/d appear to increase the risk of hypercalcemia and some other adverse events in a small proportion of individuals, indicating that this dose is not completely safe. In future studies, rigorous reporting of safety-related outcomes is needed when using moderately high doses of vitamin D.

RevDate: 2023-02-15

Abdalbary M, Chishti E, Shakhashiro M, et al (2023)

Impact of urinary calcium excretion on kidney, bone, and cardiovascular systems in patients with bone biopsy proven osteoporosis: a longitudinal long-term follow-up study.

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA [Epub ahead of print].

UNLABELLED: The impact of urine calcium on kidney, bone, and cardiovascular systems in osteoporosis is not well-known. In this 7-year-follow-up study, high urine calcium did not affect kidney function but increased risk of kidney stones, while low urine calcium increased cardiovascular diseases. Maintaining normal urine calcium is beneficial for bone health.

PURPOSE: Hypercalciuria is common in patients with osteoporosis. However, the long-term effect of urinary calcium excretion (UCaE) on patients' health is not well-examined. The current study aims to assess the impact of UCaE on kidney, bone, and cardiovascular outcomes in patients with bone biopsy proven osteoporosis.

METHODS: Longitudinal study of all patients with osteoporosis who underwent bone biopsy and 24-h urine collection between 2008 and 2015 in the University of Kentucky. DXA scans, serum markers, kidney function, and cardiovascular events were recorded until last clinic visit in 2021. Exclusion criteria were secondary osteoporosis or conditions that might substantially impact UCaE. The significant results in univariate analysis were confirmed in multi-variable regression models involving clinically important covariates that might impact patients' outcomes.

RESULTS: Study included 230 patients with mean follow-up of 7.2 ± 2.9 years. The mean age was 61 years, and the mean eGFR at baseline was 85 ± 19 ml/min/1.73 m[2]. Low bone turnover (LBT) was present in 57% and high bone turnover (HBT) in 43% of patients. Hypercalciuria was found in one-third of patients with no difference between LTB and HTB. UCaE correlated positively with eGFR but did not affect the rate of eGFR decline over time. Higher UCaE predicted kidney stones development. We observed U-shaped effect of UCaE on bone health. Hypercalciuria predicted loss of BMD at all sites, but also hypocalciuria was associated with higher loss in total hip BMD. Upper limb fractures were the most observed fractures, and their incidence was higher in patients with hyper- or hypo-calciuria. Lower UCaE independently predicted development of major adverse cardiac events (MACE) and cardiovascular disease (CVD).

CONCLUSION: UCaE correlated with eGFR but it did not affect the change of eGFR over time. Patients with normal UCaE had lower incidence of upper limb fractures and less reduction in BMD. Low UCaE predicted MACE and CVD.

RevDate: 2023-01-23
CmpDate: 2023-01-23

Yuan S, Ibrahim IAA, R Ren (2023)

Anti-urolithiatic Activity of Daidzin in Ethylene Glycol-Induced Urolithiasis in Rats.

Applied biochemistry and biotechnology, 195(2):905-918.

Urolithiasis is a common urological disorder, which causes considerable morbidity in both genders at all age groups worldwide. Though treatment options such as diuretics and non-invasive techniques to disintegrate the deposits are available, but often they are found less effective in the clinics. In this work, we planned to investigate the ameliorative effects of daidzin against the ethylene glycol (EG)-induced urolithiasis in rats. The male albino rats were distributed into four groups (n = 6) as control (group I), urolithiasis induced by the administration of 0.75% EG (group II), urolithiasis induced rats treated with 50 mg/kg of daidzin (group III), and urolithiasis rats treated with standard drug 750 mg/kg of cystone (group IV). The urine volume, pH, and total protein in the urine were assessed. The activities of marker enzymes in both plasma and kidney tissues were analyzed using assay kits. The levels of kidney function markers such as calcium, oxalate, urea, creatinine, uric acid, magnesium, BUN, and phosphorous were estimated using assay kits. The status of antioxidants and inflammatory cytokines were also examined using kits. The renal tissues were examined by histopathological analysis. Our results revealed that the daidzin treatment effectively decreased the urine pH and protein level and increased the urine volume in the urolithiasis rats. Daidzin decreased the calcium, oxalate, uric acid, and urea, creatinine, and BUN levels and also improved the magnesium and phosphorus in the urolithiasis rats. The activities of AST, ALT, ALP, GGT, and LDH were effectively reduced by the daidzin in both serum and renal tissue. Daidzin also reduced the inflammatory marker and increased the antioxidant levels. Histopathology results also proved the therapeutic effects of daidzin. Together, our results displayed that daidzin is effective in the amelioration of EG-induced urolithiasis in rats.

RevDate: 2022-12-06

Zhang SY, Collingwood JD, Fujihashi A, et al (2022)

Incidence of Emergency Department Presentations of Symptomatic Stone Disease in Pediatric Patients: A Southeastern Study.

Cureus, 14(11):e30979.

Background The incidence of nephrolithiasis during childhood has increased significantly over recent decades. Some studies indicate a rapid rise in adolescents, particularly in African American women. This study serves to identify trends in symptomatic pediatric nephrolithiasis presentations to the emergency department (ED) as a result of increasing incidence and to determine associations between demographic variables at our single-site tertiary pediatric hospital in the Southeast United States. Methods After IRB approval, a review of the data provided by the Pediatric Health Information System, a pediatric database that includes clinical and resource utilization data for 51 of the largest children's hospitals in the nation, yielded 644 pediatric occurrences of nephrolithiasis at single-site emergency departments from 2006 to 2020. The percent change and average percent change in three-year intervals were calculated to establish a trend over time. A chi-square test of independence was performed to assess associations between race, gender, and age groups. Results A total of 780 stone occurrences and associated patient demographic data were reviewed for 644 children (364, 56.52% female) with median age of 183 ± 45.11 months (9-397 months). Of the 644 children, 79 (12.3%) were noted to have recurrent symptomatic nephrolithiasis, contributing to 136/780 stone events. There was a marked increase of 84.4% in confirmed pediatric nephrolithiasis occurrences over 15 years, with an average percent increase of 16.1% every three years. A Chi[2] test of independence was performed between gender and age group (>/< 10yr), gender and race, and race and age group. No expected cell frequencies were less than five. There is no statistically significant relationship between gender and age group, χ[2] (1, N=644) = 3.30, p=0.692. There is no significant association between race (Caucasian vs. non-Caucasian) and age group (>/< 10yr), χ[2] (1, N=644) = 0.393, p=0.531. There is a statistically significant relationship between gender and race (Caucasian vs. non-Caucasian), χ[2] (1, N=644) = 5.28, p=0.021. Caucasian females were more likely to present to our tertiary pediatric hospital's emergency department with nephrolithiasis than Caucasian males or non-Caucasian males or females. Additionally, our data reflected a greater percentage of symptomatic nephrolithiasis presentations occurred in the second decade of life (85.4% vs 14.3%, 552 vs 92 stone events). Conclusion Based on our data, there is a marked increase of 84.4% in pediatric nephrolithiasis occurrences from 2006 to 2020, with a mean increase of 16.1% every three years at our single-site tertiary referral pediatric hospital in the Southeast. Among demographic groups, white adolescent females have an increased risk of developing kidney stones.

RevDate: 2022-11-22
CmpDate: 2022-11-22

Dent EL, MJ Ryan (2022)

Fifty years of impact on treating bone disease: a commentary on Gasser et al.

Clinical science (London, England : 1979), 136(22):1657-1659.

The precise control of whole-body calcium is essential for the maintenance of normal physiological function. Disruptions in calcium homeostasis can lead to pathology including osteoporosis, kidney stone formation, and cardiac arrythmias. During the 1960s and early 1970s, a full understanding of calcium metabolism was still emerging. This commentary spotlights a seminal Clinical Science paper published in 1972 that significantly advanced the field and contributed to the eventual approval of bisphosphonate drugs commonly used to treat postmenopausal osteoporosis, cancer metastases, and other calcium disorders.

RevDate: 2022-11-18
CmpDate: 2022-11-16

Fan G, Baker MR, Terry LE, et al (2022)

Conformational motions and ligand-binding underlying gating and regulation in IP3R channel.

Nature communications, 13(1):6942.

Inositol-1,4,5-trisphosphate receptors (IP3Rs) are activated by IP3 and Ca[2+] and their gating is regulated by various intracellular messengers that finely tune the channel activity. Here, using single particle cryo-EM analysis we determined 3D structures of the nanodisc-reconstituted IP3R1 channel in two ligand-bound states. These structures provide unprecedented details governing binding of IP3, Ca[2+] and ATP, revealing conformational changes that couple ligand-binding to channel opening. Using a deep-learning approach and 3D variability analysis we extracted molecular motions of the key protein domains from cryo-EM density data. We find that IP3 binding relies upon intrinsic flexibility of the ARM2 domain in the tetrameric channel. Our results highlight a key role of dynamic side chains in regulating gating behavior of IP3R channels. This work represents a stepping-stone to developing mechanistic understanding of conformational pathways underlying ligand-binding, activation and regulation of the channel.

RevDate: 2022-10-19
CmpDate: 2022-10-17

Cabuzu D, Ramakrishnan SK, Moor MB, et al (2022)

Loss of Ecrg4 improves calcium oxalate nephropathy.

PloS one, 17(10):e0275972.

Kidney stone is one of the most frequent urinary tract diseases, affecting 10% of the population and displaying a high recurrence rate. Kidney stones are the result of salt supersaturation, including calcium and oxalate. We have previously identified Esophageal cancer-related gene 4 (Ecrg4) as being modulated by hypercalciuria. Ecrg4 was initially described as a tumor suppressor gene in the esophagus. Lately, it was shown to be involved as well in apoptosis, cell senescence, cell migration, inflammation and cell responsiveness to chemotherapy. To the best of our knowledge, nothing is known about ECRG4's function in the renal tissue and its relationship with calciuria. We hypothesized that the increased expression of Ecrg4 mRNA is triggered by hypercalciuria and might modulate intratubular calcium-oxalate precipitation. In this study, we have first (i) validated the increased Ecrg4 mRNA in several types of hypercalciuric mouse models, then (ii) described the Ecrg4 mRNA expression along the nephron and (iii) assessed ECRG4's putative role in calcium oxalate nephropathy. For this, Ecrg4 KO mice were challenged with a kidney stone-inducing diet, rich in calcium and oxalate precursor. Taken together, our study demonstrates that Ecrg4's expression is restricted mainly to the distal part of the nephron and that the Ecrg4 KO mice develop less signs of tubular obstruction and less calcium-oxalate deposits. This promotes Ecrg4 as a modulator of renal crystallization and may open the way to new therapeutic possibilities against calcium oxalate nephropathy.

RevDate: 2022-10-13
CmpDate: 2022-10-13

Xiao H, Qin G, B Fang (2022)

Nanoparticle-mediated delivery system alleviates the formation of infection stones by activating TRPV5.

General physiology and biophysics, 41(5):465-471.

Infection stones constitute a small but intractable group of diseases of urinary system. In this study, we explored the potential therapeutic effect of a small activation RNA, ds-320, encapsulated in chitosan (320-chitosan). Western blot analysis verified the downregulation of TRPV5 in patients and rat model of infection stones, as well as the stimulation of ds-320 on TRPV5 expression. MTT assay showed that chitosan-mediated delivery was less cytotoxic to ds-320 compared with liposome delivery. Further a modified invasion assay revealed an inhibitory effect of 320-chitosan on bacterial invasion into normal rat kidney epithelial NRK-52E cells. The establishment of infection stone model was performed by intravesical injection of 1×108 CFU of Proteus mirabilis. In animal experiments, no visible stones were obtained. The number of live bacteria and white blood cells in urine showed no difference among all infected rats at the time of sacrifice. However, we observed a decline in urine calcium and pH, suggesting the effect of acidification. Overall, our study provides evidence for the protective effect of 320-chitosan, for its ability to down-regulate urinary calcium, acidify urine, and inhibit bacteria from invading renal epithelial cells. Thus, it can be served as an important complementary therapy for infection stones.

RevDate: 2022-09-28
CmpDate: 2022-09-26

Mikhalchik E, Basyreva LY, Gusev SA, et al (2022)

Activation of Neutrophils by Mucin-Vaterite Microparticles.

International journal of molecular sciences, 23(18):.

Nano- and microparticles enter the body through the respiratory airways and the digestive system, or form as biominerals in the gall bladder, salivary glands, urinary bladder, kidney, or diabetic pancreas. Calcium, magnesium, and phosphate ions can precipitate from biological fluids in the presence of mucin as hybrid nanoparticles. Calcium carbonate nanocrystallites also trap mucin and are assembled into hybrid microparticles. Both mucin and calcium carbonate polymorphs (calcite, aragonite, and vaterite) are known to be components of such biominerals as gallstones which provoke inflammatory reactions. Our study was aimed at evaluation of neutrophil activation by hybrid vaterite-mucin microparticles (CCM). Vaterite microparticles (CC) and CCM were prepared under standard conditions. The diameter of CC and CCM was 3.3 ± 0.8 µm and 5.8 ± 0.7 µm, with ƺ-potentials of -1 ± 1 mV and -7 ± 1 mV, respectively. CC microparticles injured less than 2% of erythrocytes in 2 h at 1.5 mg mL[-1], and no hemolysis was detected with CCM; this let us exclude direct damage of cellular membranes by microparticles. Activation of neutrophils was analyzed by luminol- and lucigenin-dependent chemiluminescence (Lum-CL and Luc-CL), by cytokine gene expression (IL-6, IL-8, IL-10) and release (IL-1β, IL-6, IL-8, IL-10, TNF-α), and by light microscopy of stained smears. There was a 10-fold and higher increase in the amplitude of Lum-CL and Luc-CL after stimulation of neutrophils with CCM relative to CC. Adsorption of mucin onto prefabricated CC microparticles also contributed to activation of neutrophil CL, unlike mucin adsorption onto yeast cell walls (zymosan); adsorbed mucin partially suppressed zymosan-stimulated production of oxidants by neutrophils. Preliminary treatment of CCM with 0.1-10 mM NaOCl decreased subsequent activation of Lum-CL and Luc-CL of neutrophils depending on the used NaOCl concentration, presumably because of the surface mucin oxidation. Based on the results of ELISA, incubation of neutrophils with CCM downregulated IL-6 production but upregulated that of IL-8. IL-6 and IL-8 gene expression in neutrophils was not affected by CC or CCM according to RT[2]-PCR data, which means that post-translational regulation was involved. Light microscopy revealed adhesion of CC and CCM microparticles onto the neutrophils; CCM increased neutrophil aggregation with a tendency to form neutrophil extracellular traps (NETs). We came to the conclusion that the main features of neutrophil reaction to mucin-vaterite hybrid microparticles are increased oxidant production, cell aggregation, and NET-like structure formation, but without significant cytokine release (except for IL-8). This effect of mucin is not anion-specific since particles of powdered kidney stone (mainly calcium oxalate) in the present study or calcium phosphate nanowires in our previous report also activated Lum-CL and Luc-CL response of neutrophils after mucin sorption.

RevDate: 2022-10-18
CmpDate: 2022-09-26

Tarczewska A, Bielak K, Zoglowek A, et al (2022)

The Role of Intrinsically Disordered Proteins in Liquid-Liquid Phase Separation during Calcium Carbonate Biomineralization.

Biomolecules, 12(9):.

Some animal organs contain mineralized tissues. These so-called hard tissues are mostly deposits of calcium salts, usually in the form of calcium phosphate or calcium carbonate. Examples of this include fish otoliths and mammalian otoconia, which are found in the inner ear, and they are an essential part of the sensory system that maintains body balance. The composition of ear stones is quite well known, but the role of individual components in the nucleation and growth of these biominerals is enigmatic. It is sure that intrinsically disordered proteins (IDPs) play an important role in this aspect. They have an impact on the shape and size of otoliths. It seems probable that IDPs, with their inherent ability to phase separate, also play a role in nucleation processes. This review discusses the major theories on the mechanisms of biomineral nucleation with a focus on the importance of protein-driven liquid-liquid phase separation (LLPS). It also presents the current understanding of the role of IDPs in the formation of calcium carbonate biominerals and predicts their potential ability to drive LLPS.

RevDate: 2022-10-24
CmpDate: 2022-10-24

Ali FT, El-Azeem EMA, Hekal HFA, et al (2022)

Association of TRPV5, CASR, and CALCR genetic variants with kidney stone disease susceptibility in Egyptians through main effects and gene-gene interactions.

Urolithiasis, 50(6):701-710.

Kidney stone disease (KSD) represents an urgent medical problem because of increasing its prevalence. Several functional polymorphisms in genes involved in the renal handling of calcium were associated with KSD pathogenesis. Among those, the rs4236480 of transient receptor potential vanilloid member 5 (TRPV5) gene, the rs1801725 of calcium-sensing receptor (CASR) gene, and the rs1801197 of calcitonin receptor (CALCR) gene appear to be of great importance. Due to the scarce data on the Egyptians, this study aimed to evaluate the association of these candidate genetic variants with the risk of developing KSD in an Egyptian population. To do so, the biochemical parameters were measured along with the genotyping of the three polymorphisms using allelic discrimination assay in 134 KSD patients and 86 age and sex-matched healthy subjects. The results showed that the genotypic distributions and allelic frequencies of the studied variants were significantly different between cases and controls. The three polymorphisms increased the risk of KSD significantly under all the tested genetic models (OR ranges from 2.152 to 5.994), except for the recessive model of the CALCR rs1801197 polymorphism after Bonferroni correction. The gene-gene interaction analyzed by multifactor dimensionality reduction selected the three-locus combination as the best model associated with the susceptibility to KSD with OR 9.706. Further, synergistic interactions were identified between TRPV5 rs4236480 and CALCR rs1801197 variants and CASR rs1801725 and CALCR rs1801197 variants. In conclusion, the TRPV5 rs4236480, CASR rs1801725, and CALCR rs1801197 polymorphisms showed a significant association with the risk of KSD in the Egyptian population. Furthermore, their complex interactions might have an impact on the genetic susceptibility to develop KSD.

RevDate: 2022-10-24
CmpDate: 2022-10-24

Guimerà J, Martínez A, Bauza JL, et al (2022)

Effect of phytate on hypercalciuria secondary to bone resorption in patients with urinary stones: pilot study.

Urolithiasis, 50(6):685-690.

The objective is to evaluate the effect of phytate supplements on calciuria in patients with urinary stones and elevated bone resorption. The secondary objective is to analyze the therapeutic effect of phytate based on measurements of serum markers of bone resorption. This is a controlled randomized study included patients according to predefined inclusion and exclusion criteria, and randomized them into two groups. Patients in the phytate group received a 380 mg capsule of calcium-magnesium InsP6 (Salvat Laboratories[®]) every 24 h for 3 months and patients in the control group received no treatment. All included patients were male or female, 18-65 years old, had hypercalciuria (> 250 mg/24 h), had a ß-Crosslaps level greater than 0.4 ng/mL, and had bone densitometry results indicative of osteopenia or osteoporosis in the femur and/or spine. At study onset, calciuria was 321 ± 52 mg/24 h in the phytate group and 305 ± 57 mg/24 h in the control group (p > 0.05). At 3 months, calciuria was significantly lower in the phytate group than the control group (226 ± 45 mg/24 h vs. 304 ± 58 mg/24 h, p < 0.05). At study onset, the mean ß-CrossLaps level was 1.25 ± 0.72 ng/mL in the phytate group and 0.57 ± 0.13 ng/mL in the control group (p < 0.05). However, at 3 months, the ß-CrossLaps level was significantly lower in the phytate group than in the control group (0.57 ± 0.13 ng/mL vs. 0.77 ± 0.42 ng/mL, p < 0.05). Phytate reduced calciuria in patients with hypercalciuria secondary to bone resorption. The ß-CrossLaps assay was effective for evaluating the efficacy of phytate on hypercalciuria during follow-up.

RevDate: 2022-10-05
CmpDate: 2022-09-29

Chandran M, Yeh LTL, de Jong MC, et al (2022)

Cognitive deficits in primary hyperparathyroidism - what we know and what we do not know: A narrative review.

Reviews in endocrine & metabolic disorders, 23(5):1079-1087.

Classic symptoms of primary hyperparathyroidism (PHPT) are seen in approximately 20% of patients. While features such as kidney stones and skeletal disease are often highlighted as directly related to the disease, others can be even more prevalent. For example, cognitive dysfunction and reduced quality of life are common complaints in many patients, even among those who are classified as being asymptomatic. The pathophysiology of PHPT involves the impact of excess parathyroid hormone (PTH) on calcium metabolism. Referencing putative neurocognitive issues, many animal studies have illustrated the potential roles of PTH and PTH receptors in the brain. Functional imaging and pre-and post-parathyroidectomy studies have suggested a link between the neuronal impact of elevated PTH levels on specific functional aspects of the central nervous system, such as cognition. Confounding a direct role for PTH are hypercalcemia and vitamin D deficiency, both of which could conceivably alter CNS function in PHPT. The lack of strong evidence that parathyroidectomy improves cognition in patients with PHPT raises the question as to whether parathyroid surgery should be recommended on this basis alone. This narrative review summarizes the available literature on neurocognitive function in PHPT.

RevDate: 2022-07-26
CmpDate: 2022-07-26

Bhardwaj R, Bhardwaj A, Dhawan DK, et al (2022)

4-PBA rescues hyperoxaluria induced nephrolithiasis by modulating urinary glycoproteins: Cross talk between endoplasmic reticulum, calcium homeostasis and mitochondria.

Life sciences, 305:120786.

AIM: Urinary glycoproteins such as Tamm Horsfall Protein (THP) and Osteopontin (OPN) are well established key regulators of renal stone formation. Additionally, recent revelations have highlighted the influence of Endoplasmic Reticulum (ER) and mitochondria of crucial importance in nephrolithiasis. However, till date conclusive approach highlighting the influence of ER stress on urinary glycoproteins and chaperone in nephrolithiasis remains elusive. Therefore, the present study was focussed on deciphering the possible effect of 4-PBA mitigating ER stress on urinary glycoproteins and calnexin (chaperone) with emphasis on interlinking calcium homeostasis in hyperoxaluric rats.

MATERIAL AND METHODS: Post 9 days of treatment, animals were sacrificed, and renal tissues were investigated for urinary glycoproteins, calnexin, calcium homeostasis, ER environment, redox status, and mitochondrial linkage.

KEY FINDINGS: 4-PBA appreciably reversed the altered levels of THP, OPN, and calnexin observed along with curtailing the disrupted calcium homeostasis when assessed for SERCA activity and intra-cellular calcium levels. Additionally, significant improvement in the perturbed ER environment as verified by escalated ER stress markers, disturbed protein folding-aggregation-degradation (congo red assay) pathway, and redox status was found post 4-PBA intervention. Interestingly, linkage of ER stress and mitochondria was established under hyperoxaluric conditions when assessed for protein levels of VDAC1 and GRP75.

SIGNIFICANCE: 4-PBA treatment resulted in rectifying the repercussions of ER-mitochondrial caused distress when assessed for protein folding/aggregation/degradation events along with disturbed calcium homeostasis. The present study advocates the necessity to adopt a holistic vision towards hyperoxaluria with emphasis on glycoproteins and ER environment.

RevDate: 2022-10-15
CmpDate: 2022-08-23

Aliberti L, Gagliardi I, Gamberini MR, et al (2022)

Beta-thalassaemia major: Prevalence, risk factors and clinical consequences of hypercalciuria.

British journal of haematology, 198(5):903-911.

Regular transfusion and chelation therapy produces increased life expectancy in thalassaemic patients who may develop new complications. Since few data are available regarding hypercalciuria in β-thalassaemia major (TM), the aim of our study was to evaluate its prevalence, risk factors and clinical consequences. We enrolled 176 adult TM patients followed at the Center of Thalassemia of Ferrara. Hypercalciuria was defined by a calciuria of 4 mg/kg/day or more in a 24-h urine sample. Anamnestic, biochemical and radiological data were collected. Hypercalciuria prevalence was reported in 69.3% of patients (females 52.5%). Hypercalciuric (HC) patients used deferasirox (DFX) more often than normocalciuric (NC) patients (47.5% vs 29.6%; p < 0.05). In HC subjects plasma parathyroid hormone (PTH) (24.1 ± 10.4 vs 30.1 ± 13.2 pg/ml) and phosphate levels (3.6 ± 0.5 vs 3.8 ± 0.7 mg/dl) were lower, whereas serum calcium (9.6 ± 0.4 vs 9.4 ± 0.4 mg/dl) and urinary 24-h phosphaturia (0.9 ± 0.4 vs 0.6 ± 0.3 g/day) were higher as compared to NC patients (p < 0.05 for all comparisons). Supplementation with oral calcium and cholecalciferol was similar between the groups. A higher rate of kidney stones was present in HC (14.8%) versus NC patients (3.7%) (p < 0.05). Hypercalciuria is a frequent complication in adequately treated adult TM patients. Hypercalciuria prevalence is increased in DFX users whereas haemoglobin level or calcium supplements play no role. A significant proportion of HC patients developed kidney stones.

RevDate: 2022-11-13
CmpDate: 2022-05-19

Lee Y, Wiriyasermkul P, Kongpracha P, et al (2022)

Ca[2+]-mediated higher-order assembly of heterodimers in amino acid transport system b[0,+] biogenesis and cystinuria.

Nature communications, 13(1):2708.

Cystinuria is a genetic disorder characterized by overexcretion of dibasic amino acids and cystine, causing recurrent kidney stones and kidney failure. Mutations of the regulatory glycoprotein rBAT and the amino acid transporter b[0,+]AT, which constitute system b[0,+], are linked to type I and non-type I cystinuria respectively and they exhibit distinct phenotypes due to protein trafficking defects or catalytic inactivation. Here, using electron cryo-microscopy and biochemistry, we discover that Ca[2+] mediates higher-order assembly of system b[0,+]. Ca[2+] stabilizes the interface between two rBAT molecules, leading to super-dimerization of b[0,+]AT-rBAT, which in turn facilitates N-glycan maturation and protein trafficking. A cystinuria mutant T216M and mutations of the Ca[2+] site of rBAT cause the loss of higher-order assemblies, resulting in protein trapping at the ER and the loss of function. These results provide the molecular basis of system b[0,+] biogenesis and type I cystinuria and serve as a guide to develop new therapeutic strategies against it. More broadly, our findings reveal an unprecedented link between transporter oligomeric assembly and protein-trafficking diseases.

RevDate: 2022-10-11
CmpDate: 2022-10-11

Schlaht KM, Sas DJ, Davis DMR, et al (2022)

An investigation of metabolic disturbances, including urinary stone disease, hypothyroidism, and osteoporosis in basal cell nevus syndrome.

Pediatric dermatology, 39(5):713-717.

BACKGROUND/OBJECTIVES: Basal cell nevus syndrome (BCNS) is an autosomal dominant skin cancer predisposition syndrome associated with abnormal mineral metabolism, a risk factor for urinary stone disease (USD). However, no research investigating the association between BCNS and USD or other manifestations of abnormal mineral metabolism has been conducted. The objective of this study is to investigate the association between BCNS and conditions associated with disordered mineral metabolism including USD, hypothyroidism, and osteoporosis and compare them to prevalence in the general population to elucidate potential unknown manifestations of the condition.

METHODS: This retrospective study examined medical records of adult and pediatric patients with confirmed BCNS from the Mayo Clinic database from 1 January 1995 to 12 January 2020. Records were surveyed for evidence of USD and other comorbidities potentially related to BCNS. The studied cohort included 100 adult patients and 5 pediatric patients.

RESULTS: A total of 105 patients were included in this analysis, 10 of whom experienced confirmed USD, representing a prevalence of 10%. Six adult patients were identified with a diagnosis of osteoporosis, representing a prevalence of 6%. Thirteen adult patients were identified with a diagnosis of hypothyroidism, representing a prevalence of 13%.

CONCLUSIONS: This study identified a prevalence of USD in BCNS patients comparable to estimates of national prevalence, indicating that known abnormalities in mineral metabolism likely do not increase the incidence of USD in BCNS patients. Additional findings included increased prevalence of hypothyroidism and decreased prevalence of osteoporosis in the BCNS cohort compared to national averages.

RevDate: 2022-07-16

Tamma G, Di Mise A, Ranieri M, et al (2022)

Early Biomarkers of Altered Renal Function and Orthostatic Intolerance During 10-day Bedrest.

Frontiers in physiology, 13:858867.

Exposure to actual or simulated microgravity results in alterations of renal function, fluid redistribution, and bone loss, which is coupled to a rise of urinary calcium excretion. We provided evidence that high calcium delivery to the collecting duct reduces local Aquaporin 2 (AQP2)-mediated water reabsorption under vasopressin action, thus limiting the maximal urinary concentration to reduce calcium saturation. To investigate early renal adaptation into simulated microgravity, we investigated the effects of 10 days of strict bedrest in 10 healthy volunteers. We report here that 10 days of inactivity are associated with a transient, significant decrease (day 5) in vasopressin (copeptin) paralleled by a decrease in AQP2 excretion, consistent with an increased central volume to the heart, resulting in reduced water reabsorption. Moreover, bedrest caused a significant increase in calciuria secondary to bone demineralization paralleled by a decrease in PTH. Urinary osteopontin, a glycoprotein exerting a protective effect on stone formation, was significantly reduced during bedrest. Moreover, a significant increase in adrenomedullin (day 5), a peptide with vasodepressor properties, was observed at day 5, which may contribute to the known reduced orthostatic capacity post-bedrest. We conclude that renal function is altered in simulated microgravity and is associated with an early increase in the risk of stone formation and reduced orthostatic capacity post-bedrest within a few days of inactivity.

RevDate: 2022-10-15
CmpDate: 2022-07-14

Puliani G, Hasenmajer V, Simonelli I, et al (2022)

Safety and Efficacy of PTH 1-34 and 1-84 Therapy in Chronic Hypoparathyroidism: A Meta-Analysis of Prospective Trials.

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research, 37(7):1233-1250.

Hypoparathyroidism is the only endocrine deficiency for which hormone replacement therapy is not the standard of care. Although conventional treatments may control hypocalcaemia, other complications such as hyperphosphatemia, kidney stones, peripheral calcifications, and bone disease remain unmet needs. This meta-analysis (PROSPERO registration number CRD42019126881) aims to evaluate and compare the efficacy and safety of PTH1-34 and PTH1-84 in restoring calcium metabolism in chronic hypoparathyroidism. EMBASE, PubMed, and CENTRAL databases were searched for randomized clinical trials or prospective studies published between January 1996 and March 2021. English-language trials reporting data on replacement with PTH1-34 or PTH1-84 in chronic hypoparathyroidism were selected. Three authors extracted outcomes, one author performed quality control, all assessed the risk of biases. Overall, data from 25 studies on 588 patients were analyzed. PTH therapy had a neutral effect on calcium levels, while lowering serum phosphate (-0.21 mmol/L; 95% confidence interval [CI], -0.31 to -0.11 mmol/L; p < 0.001) and urinary calcium excretion (-1.21 mmol/24 h; 95% CI, -2.03 to -0.41 mmol/24 h; p = 0.003). Calcium phosphate product decreased under PTH1-84 therapy only. Both treatments enabled a significant reduction in calcium and calcitriol supplementation. PTH therapy increased bone turnover markers and lumbar spine mineral density. Quality of life improved and there was no difference in the safety profile between PTH and conventionally treated patients. Results for most outcomes were similar for the two treatments. Limitations of the study included considerable population overlap between the reports, incomplete data, and heterogeneity in the protocol design. In conclusion, the meta-analysis of data from the largest collection to date of hypoparathyroid patients shows that PTH therapy is safe, well-tolerated, and effective in normalizing serum phosphate and urinary calcium excretion, as well as enabling a reduction in calcium and vitamin D use and improving quality of life. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

RevDate: 2022-03-11

Esper PLG, Rodrigues FG, Melo TL, et al (2022)

Bone Density, Microarchitecture, and Estimated Strength in Stone Formers: A Cross-Sectional HR-pQCT Study.

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association pii:6547011 [Epub ahead of print].

BACKGROUND: Low areal bone mineral density (BMD), increased fracture risk, and altered bone remodelling have been described among stone formers (SF), but the magnitude of these findings differs by age, sex, menopausal status, and urinary calcium (uCa). This study aimed to investigate volumetric (v) BMD, bone microarchitecture and biomechanical properties by high-resolution peripheral quantitative computed tomography (HR-pQCT) and finite element analysis (FEA) in young SF, irrespective of calciuria, further distinguishing trabecular from cortical compartments.

METHODS: HR-pQCT/FEA was performed at distal tibia (DT) and radius (DR) in 106 SF (57 males/49 premenopausal females; median age, 37 years) and compared with 106 non-SF (NSF) retrieved from an existing database, matched for age, sex, and body mass index (BMI). Biochemical/hormonal serum and urinary parameters were obtained from SF.

RESULTS: SF exhibited significantly lower trabecular number (Tb.N), higher trabecular separation (Tb.Sp) than NSF at both anatomical sites and lower cortical porosity in DR. In a subgroup analysis separated by sex, female SF presented significantly lower Tb.vBMD, relative bone volume fraction (BV/TV) and Tb.N, and higher Tb.Sp than NSF at both sites, while male SF showed significantly lower stiffness and failure load. A multivariate analysis showed Tb.N to be independently associated with sex and BMI at both sites and with uCa at DR.

CONCLUSIONS: The present findings suggest that bone disease represents an early event among SF, associated at least in part with calcium excretion, and mainly characterized by trabecular bone microarchitecture impairment, especially among women, but with reduced bone strength parameters in men.

RevDate: 2022-04-08
CmpDate: 2022-04-08

Li LS, Zhu YP, Xia QD, et al (2022)

High-Calcium Microenvironment during the Development of Kidney Calculi Can Promote Phenotypic Transformation of NRK-52E Cells by Inhibiting the Expression of Stromal Interaction Molecule-1.

BioMed research international, 2022:2350198.

OBJECTIVE: To explore whether Stromal Interaction Molecule-1 (STIM1) participates in the phenotypic transformation of NRK-52E cells under high-calcium microenvironment.

MATERIALS AND METHODS: NRK-52E cells were treated with high concentration of calcium. The viability and apoptosis of cells were detected by CCK-8 (cell counting kit-8) and flow cytometry, respectively. The expression changes of phenotypic marker proteins (E-cadherin and OPN) and calcium channel proteins (STIMl and Orai1) in high-calcium environment were detected by western blotting and real-time quantitative polymerase chain reaction. The expression of STIMl protein in NRK-52E cells was upregulated and downregulated by plasmid-STIM1 and plasmid-shRNA-STIMl, respectively. The expressions of phenotypic marker proteins after upregulation or downregulation of STIMl were detected again. Besides, the intracellular calcium concentrations of NRK-52E cells in different treatments were detected by flow cytometry.

RESULTS: High-calcium microenvironment can promote the phenotypic transformation and the adhesion of calcium salts in NRK-52E cells and simultaneously suppress the expression of STIMl protein in NRK-52E cells. Downregulation of STIMl protein could also promote the phenotype transformation, while both the gene silence of matrix gla protein (MGP) and overexpression of STIMl showed reverse results.

CONCLUSION: STIMl protein plays an important role in promoting phenotypic transformation of NRK-52E cells in high-calcium microenvironment.

RevDate: 2022-08-15
CmpDate: 2022-08-15

Negri AL, EE Del Valle (2022)

Role of claudins in idiopathic hypercalciuria and renal lithiasis.

International urology and nephrology, 54(9):2197-2204.

Paracellular transport in the kidney is mediated by a family of proteins located in the tight junctions called claudins which confers its ionic selectivity. Claudin-2 is highly expressed in the proximal tubule and descending limb of Henle and mediate paracellular reabsorption of sodium and calcium cations. In the thick ascending limb of Henle (TALH) calcium is reabsorbed by a paracellular channel formed by Claudin-16 and-19. Claudin-16 mediates cationic permeability while Claudin-19 increases the cationic selectivity of Claudin-16 by blocking anionic permeability. On the other hand, Claudin 14, that is also located in TALH, inhibits the paracellular permeability of Claudin-16 to calcium. Recent wide genomic association analysis studies have detected four common synonymous variants (genetic polymorphisms of a single nucleotide, SNPs) at the locus of Claudin-14 gene that were significantly associated with the presence of renal lithiasis. Another study of wide genomic association and nephrolithiasis was carried out in the general population but including chromosome X, where claudin-2 gene is located. They detected nine SNPs that had a significant association with renal lithiasis risk. A greater knowledge of the paracellular pathway controlled by claudins and its regulation will allow us to develop future new treatments for idiopathic hypercalciuria and renal lithiasis.

RevDate: 2022-02-03
CmpDate: 2022-02-03

Flisiński M, Brymora A, Skoczylas-Makowska N, et al (2021)

Fructose-Rich Diet Is a Risk Factor for Metabolic Syndrome, Proximal Tubule Injury and Urolithiasis in Rats.

International journal of molecular sciences, 23(1):.

Excessive consumption of fructose (FR) leads to obesity, metabolic syndrome (MS) and insulin resistance, which are known risk factors for kidney stones. The epidemiological study has suggested the association between fructose consumption and urolithiasis, but the precise mechanism is still not well understood. Male Wistar rats were assigned for 8 weeks to three groups with different FR content in diet: RD (n = 5)-regular diet with a FR < 3%; F10 (n = 6)-regular diet with an addition of 10% Fr in drinking water; F60 (n = 5)-60% FR as a solid food. Serum concentration of FR, creatinine (Cr), insulin (Ins), triglycerides (Tg), homocysteine (HCS), uric acid (UA), calcium (Ca), phosphate (Pi), magnesium (Mg) and sodium (Na) were measured. Based on 24 h urine collection the following tests were performed: urine pH, proteinuria (PCR), excretion of N-Acetyl-(D)-Glucosaminidase (NAG), monocyte chemoattractant protein (MCP-1), uric acid (uUAEx), phosphate (uPiEx), calcium (uCaEx), magnesium (uMgEx) and sodium (uNaEx). The creatinine clearance (CrCl) was calculated. Calcium deposits in kidney sections were examined using hematoxylin and eosin (HE) and von Kossa stains. The rats on F10 and F60, as compared to the RD diet, showed a tendency for lower CrCl, higher HCS level and some features of MS as higher Ins and TG levels. Interestingly, F10 (fluid) versus F60 (solid) diet led to higher serum Ins levels. F10 and F60 versus RD demonstrated higher urinary excretion of MCP-1 and NAG which were suggestive for inflammatory injury of the proximal tubule. F10 and F60 as compared to RD showed significantly lower uUAEx, although there were no differences in clearance and fractional excretion of UA. F60 versus RD induced severe phosphaturia (>30×) and natriuria (4×) and mild calciuria. F10 versus RD induced calciuria (3×), phosphaturia (2×) and mild natriuria. Calcium phosphate stones within the tubules and interstitium were found only in rats on FR diet, respectively, in two rats from the F10 group and another two in the F60 group. The rats which developed stones were characterized by significantly higher serum insulin concentration and urinary excretion of calcium and magnesium. A fructose-rich diet may promote development of calcium stones due to proximal tubule injury and metabolic syndrome.

RevDate: 2022-02-25
CmpDate: 2021-12-31

Smirnova VI, Lebedev DG, Lapin SV, et al (2021)

[Analysis of urinary stone composition by infrared spectroscopy in the population of the European part of Russia].

Urologiia (Moscow, Russia : 1999).

INTRODUCTION: Urolithiasis is one of the most common urological diseases, which affect at least 3% of the population.

AIM: To study the epidemiology of urolithiasis in the European part of the Russian Federation and to determine the composition of urinary stones in order to understand the pathogenetic mechanisms of urinary stones formation.

MATERIALS AND METHODS: Urinary stone were obtained from 2888 patients with urolithiasis and the composition of kidney stones was analyzed using the method of infrared spectroscopy.

RESULTS: The predominance of oxalate stones was seen in kidney stones with mixed composition (83%) and the prevalence of uric acid stones (54%) was revealed in "pure" kidney stones. Urinary stones with a predominance of oxalates had significantly less impurities (12,4%) than stones with a predominance of uric acid, phosphates and carbonates with average amount of impurities more than 24%. Conslusion. The analysis of stone composition with a consideration of pathogenic factor showed that disorders of calcium metabolism in the population of the European part of the Russian Federation prevailed (88%).

RevDate: 2022-01-17
CmpDate: 2022-01-17

Stone MS, Martin BR, CM Weaver (2021)

Short-Term Supplemental Dietary Potassium from Potato and Potassium Gluconate: Effect on Calcium Retention and Urinary pH in Pre-Hypertensive-to-Hypertensive Adults.

Nutrients, 13(12):.

Potassium supplementation has been associated with reduced urinary calcium (Ca) excretion and increased Ca balance. Dietary interventions assessing the impact of potassium on bone are lacking. In this secondary analysis of a study designed primarily to determine blood pressure effects, we assessed the effects of potassium intake from potato sources and a potassium supplement on urinary Ca, urine pH, and Ca balance. Thirty men (n = 15) and women (n = 15) with a mean ± SD age and BMI of 48.2 ± 15 years and 31.4 ± 6.1 kg/m[2], respectively, were enrolled in a cross-over, randomized control feeding trial. Participants were assigned to a random order of four 16-day dietary potassium interventions including a basal diet (control) of 2300 mg/day (~60 mmol/day) of potassium, and three phases of an additional 1000 mg/day (3300 mg/day(~85 mmol/day) total) of potassium in the form of potatoes (baked, boiled, or pan-heated), French fries (FF), or a potassium (K)-gluconate supplement. Calcium intake for all diets was approximately 700-800 mg/day. Using a mixed model ANOVA there was a significantly lower urinary Ca excretion in the K-gluconate phase (96 ± 10 mg/day) compared to the control (115 ± 10 mg/day; p = 0.027) and potato (114 ± 10 mg/day; p = 0.033). In addition, there was a significant difference in urinary pH between the supplement and control phases (6.54 ± 0.16 vs. 6.08 ± 0.18; p = 0.0036). There were no significant differences in Ca retention. An increased potassium intake via K-gluconate supplementation may favorably influence urinary Ca excretion and urine pH. This trial was registered at ClinicalTrials.gov as NCT02697708.

RevDate: 2022-01-17
CmpDate: 2022-01-17

Bargagli M, Ferraro PM, Vittori M, et al (2021)

Calcium and Vitamin D Supplementation and Their Association with Kidney Stone Disease: A Narrative Review.

Nutrients, 13(12):.

Kidney stone disease is a multifactorial condition influenced by both genetic predisposition and environmental factors such as lifestyle and dietary habits. Although different monogenic polymorphisms have been proposed as playing a causal role for calcium nephrolithiasis, the prevalence of these mutations in the general population and their complete pathogenetic pathway is yet to be determined. General dietary advice for kidney stone formers includes elevated fluid intake, dietary restriction of sodium and animal proteins, avoidance of a low calcium diet, maintenance of a normal body mass index, and elevated intake of vegetables and fibers. Thus, balanced calcium consumption protects against the risk for kidney stones by reducing intestinal oxalate availability and its urinary excretion. However, calcium supplementation given between meals might increase urinary calcium excretion without the beneficial effect on oxalate. In kidney stone formers, circulating active vitamin D has been found to be increased, whereas higher plasma 25-hydroxycholecalciferol seems to be present only in hypercalciuric patients. The association between nutritional vitamin D supplements and the risk for stone formation is currently not completely understood. However, taken together, available evidence might suggest that vitamin D administration worsens the risk for stone formation in patients predisposed to hypercalciuria. In this review, we analyzed and discussed available literature on the effect of calcium and vitamin D supplementation on the risk for kidney stone formation.

RevDate: 2022-05-31
CmpDate: 2022-04-04

Xun Y, Zhou P, Yang Y, et al (2022)

Role of Nox4 in High Calcium-Induced Renal Oxidative Stress Damage and Crystal Deposition.

Antioxidants & redox signaling, 36(1-3):15-38.

Aims: We aimed at exploring the role of nicotinamide adenine dinucleotide phosphate oxidase subunit 4 (Nox4) in the regulation of hypercalciuria-induced renal oxidative damage and crystal depositions. Results: High calcium activated Nox4 expression through protein kinase C (PKC). Downregulation of Nox4 expression attenuated hypercalciuria-induced osteoblast-associated protein expression, oxidative stress injury, and crystal deposition in rat kidneys of 1,25-dihydroxyvitamin D3 (VitD) urolithiasis model. Further, calcium-induced activation of mitogen-activated protein kinase (MAPK), overexpression of osteoblast-associated protein, oxidative stress injury, apoptosis, and calcium salt deposition in normal rat kidney epithelial-like (NRK-52E) cells were reversed by downregulating Nox4 expression but were enhanced by upregulating Nox4 expression in vitro. Moreover, calcium-induced increases of osteoblast-associated protein expression were attenuated by the c-Jun-N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK) inhibitors. Innovation: Our results demonstrated the effect of Nox4 in the pathological process of kidney stones in in vitro and in vivo studies for the first time. Calcium aggravates renal oxidative stress injury and crystal deposition by activating the Nox4-related reactive oxygen species (ROS)-ERK/JNK pathway in the rat kidney. This study is expected to provide a new theoretical basis for the prevention and treatment of kidney stones. Conclusion: Nox4-derived ROS induced by calcium through PKC caused oxidative stress damage and apoptosis in renal tubular epithelial cells; in addition, Nox4-derived ROS induced by calcium mediated abnormal activation of the bone morphogenetic protein 2 (BMP2) signaling pathway through the MAPK signaling pathway, which induced renal tubular epithelial cells to transdifferentiate into osteoblast-like cells, resulting in the formation of a kidney stone. Antioxid. Redox Signal. 36, 15-38.

RevDate: 2022-08-19
CmpDate: 2022-01-12

van Rosendael AR, van den Hoogen IJ, Gianni U, et al (2021)

Association of Statin Treatment With Progression of Coronary Atherosclerotic Plaque Composition.

JAMA cardiology, 6(11):1257-1266.

IMPORTANCE: The density of atherosclerotic plaque forms the basis for categorizing calcified and noncalcified morphology of plaques.

OBJECTIVE: To assess whether alterations in plaque across a range of density measurements provide a more detailed understanding of atherosclerotic disease progression.

This cohort study enrolled 857 patients who underwent serial coronary computed tomography angiography 2 or more years apart and had quantitative measurements of coronary plaques throughout the entire coronary artery tree. The study was conducted from 2013 to 2016 at 13 sites in 7 countries.

MAIN OUTCOMES AND MEASURES: The main outcome was progression of plaque composition of individual coronary plaques. Six plaque composition types were defined on a voxel-level basis according to the plaque attenuation (expressed in Hounsfield units [HU]): low attenuation (-30 to 75 HU), fibro-fatty (76-130 HU), fibrous (131-350 HU), low-density calcium (351-700 HU), high-density calcium (701-1000 HU), and 1K (>1000 HU). The progression rates of these 6 compositional plaque types were evaluated according to the interaction between statin use and baseline plaque volume, adjusted for risk factors and time interval between scans. Plaque progression was also examined based on baseline calcium density. Analysis was performed among lesions matched at baseline and follow-up. Data analyses were conducted from August 2019 through March 2020.

RESULTS: In total, 2458 coronary lesions in 857 patients (mean [SD] age, 62.1 [8.7] years; 540 [63.0%] men; 548 [63.9%] received statin therapy) were included. Untreated coronary lesions increased in volume over time for all 6 compositional types. Statin therapy was associated with volume decreases in low-attenuation plaque (β, -0.02; 95% CI, -0.03 to -0.01; P = .001) and fibro-fatty plaque (β, -0.03; 95% CI, -0.04 to -0.02; P < .001) and greater progression of high-density calcium plaque (β, 0.02; 95% CI, 0.01-0.03; P < .001) and 1K plaque (β, 0.02; 95% CI, 0.01-0.03; P < .001). When analyses were restricted to lesions without low-attenuation plaque or fibro-fatty plaque at baseline, statin therapy was not associated with a change in overall calcified plaque volume (β, -0.03; 95% CI, -0.08 to 0.02; P = .24) but was associated with a transformation toward more dense calcium. Interaction analysis between baseline plaque volume and calcium density showed that more dense coronary calcium was associated with less plaque progression.

CONCLUSIONS AND RELEVANCE: The results suggest an association of statin use with greater rates of transformation of coronary atherosclerosis toward high-density calcium. A pattern of slower overall plaque progression was observed with increasing density. All findings support the concept of reduced atherosclerotic risk with increased densification of calcium.

RevDate: 2021-07-27
CmpDate: 2021-07-27

Grahl MVC, Uberti AF, Broll V, et al (2021)

Proteus mirabilis Urease: Unsuspected Non-Enzymatic Properties Relevant to Pathogenicity.

International journal of molecular sciences, 22(13):.

Infection by Proteus mirabilis causes urinary stones and catheter incrustation due to ammonia formed by urease (PMU), one of its virulence factors. Non-enzymatic properties, such as pro-inflammatory and neurotoxic activities, were previously reported for distinct ureases, including that of the gastric pathogen Helicobacter pylori. Here, PMU was assayed on isolated cells to evaluate its non-enzymatic properties. Purified PMU (nanomolar range) was tested in human (platelets, HEK293 and SH-SY5Y) cells, and in murine microglia (BV-2). PMU promoted platelet aggregation. It did not affect cellular viability and no ammonia was detected in the cultures' supernatants. PMU-treated HEK293 cells acquired a pro-inflammatory phenotype, producing reactive oxygen species (ROS) and cytokines IL-1β and TNF-α. SH-SY5Y cells stimulated with PMU showed high levels of intracellular Ca[2+] and ROS production, but unlike BV-2 cells, SH-SY5Y did not synthesize TNF-α and IL-1β. Texas Red-labeled PMU was found in the cytoplasm and in the nucleus of all cell types. Bioinformatic analysis revealed two bipartite nuclear localization sequences in PMU. We have shown that PMU, besides urinary stone formation, can potentially contribute in other ways to pathogenesis. Our data suggest that PMU triggers pro-inflammatory effects and may affect cells beyond the renal system, indicating a possible role in extra-urinary diseases.

RevDate: 2021-11-23
CmpDate: 2021-11-23

Kwiatkowska B, Bisiecka A, Pawelec Ł, et al (2021)

Differential diagnosis of a calcified cyst found in an 18th century female burial site at St. Nicholas Church cemetery (Libkovice, Czechia).

PloS one, 16(7):e0254173.

During archaeological excavations in burial sites, sometimes stoned organic objects are found, in addition to human remains. Those objects might be of a different origin, depending on various factors influencing members of a community (i.e. diseases, trauma), which provides information about their living conditions. The St. Nicholas Church archaeological site (Libkovice, Czechia) in the 18th century horizon of the cemetery, yielded a maturus-senilis female skeleton with a stone object in the left iliac fossa. This object was an oviform cyst-like rough structure, measuring 54 mm in length, 35 mm in maximum diameter and 0.2-0.7 mm shell thickness. Within the object there were small fetal bones (long bones, i.e. femur and two tibias, two scapulas, three ribs, vertebrae and other tiny bone fragments). Methods utilized to analyze the outer and inner surface morphology of the cyst and its inside, included: X-ray, CT imaging, SEM, histological staining and EDS. The EDS analysis revealed the presence of primarily oxygen, calcium and phosphorus in bone samples, and oxygen and silicon, in stone shell. Based on the length of the femur (20.2 mm) and tibia (16 mm) shafts, the fetal age was determined as being in the 15-18 week of pregnancy. The differential diagnosis was conducted, including for the three most probable cases: fetiform teratoma (FT), fetus-in-fetu (FIF) and lithopedion. The possibility of fetiform teratoma was discounted due to the presence of an anatomically correct spine, long bones and the proportions of the find. Although the low calcium content in the shell (2.3% atom mass), the lack of skull bones and the better developed lower limbs indicate fetus-in-fetu rather than lithopedion, the analyses results are unable to conclusively identify the object under one of these two categories since there are insufficient such cases in excavation material with which to draw comparison.

RevDate: 2022-06-12
CmpDate: 2022-04-12

Bargagli M, Moochhala S, Robertson WG, et al (2022)

Urinary metabolic profile and stone composition in kidney stone formers with and without heart disease.

Journal of nephrology, 35(3):851-857.

OBJECTIVE: Kidney stone disease seems to be associated with an increased risk of incident cardiovascular outcomes; the aim of this study is to identify differences in 24-h urine excretory profiles and stone composition among stone formers with and without cardiovascular disease (CVD).

METHODS: Data from patients attending the Department of Renal Medicine's metabolic stone clinic from 1995 to 2012 were reviewed. The sample was divided according to the presence or absence of CVD (myocardial infarction, angina, coronary revascularization, or surgery for calcified heart valves). Univariable and multivariable regression models, adjusted for age, sex, BMI, hypertension, diabetes, eGFR, plasma bicarbonate and potential renal acid load of foods were used to investigate differences across groups.

RESULTS: 1826 patients had available data for 24-h urine analysis. Among these, 108 (5.9%) had a history of CVD. Those with CVD were older, have higher prevalence of hypertension and diabetes and lower eGFR. Univariable analysis showed that patients with CVD had significantly lower 24-h urinary excretions for citrate (2.4 vs 2.6 mmol/24 h, p = 0.04), magnesium (3.9 vs 4.2 mmol/24 h, p = 0.03) and urinary pH (6.1 vs 6.2, p = 0.02). After adjustment for confounders, differences in urinary citrate and magnesium excretions remained significant. No differences in the probability of stone formation or stone compositions were found.

CONCLUSIONS: Stone formers with CVD have lower renal alkali excretion, possibly suggesting higher acid retention in stone formers with cardiovascular comorbidities. Randomized clinical trials including medications and a controlled diet design are needed to confirm the results presented here.

RevDate: 2021-06-01

Litvinova MM, Khafizov K, Korchagin VI, et al (2021)

Association of CASR, CALCR, and ORAI1 Genes Polymorphisms With the Calcium Urolithiasis Development in Russian Population.

Frontiers in genetics, 12:621049.

Kidney stone disease is an urgent medical and social problem. Genetic factors play an important role in the disease development. This study aims to establish an association between polymorphisms in genes coding for proteins involved in calcium metabolism and the development of calcium urolithiasis in Russian population. In this case-control study, we investigated 50 patients with calcium urolithiasis (experimental group) and 50 persons lacking signs of kidney stone disease (control group). For molecular genetic analysis we used a previously developed gene panel consisting of 33 polymorphisms in 15 genes involved in calcium metabolism: VDR, CASR, CALCR, OPN, MGP, PLAU, AQP1, DGKH, SLC34A1, CLDN14, TRPV6, KLOTHO, ORAI1, ALPL, and RGS14. High-throughput target sequencing was utilized to study the loci of interest. Odds ratios and 95% confidence intervals were used to estimate the association between each SNP and risk of urolithiasis development. Multifactor dimensionality reduction analysis was also carried out to analyze the gene-gene interaction. We found statistically significant (unadjusted p-value < 0.05) associations between calcium urolithiasis and the polymorphisms in the following genes: CASR rs1042636 (OR = 3.18 for allele A), CALCR rs1801197 (OR = 6.84 for allele A), and ORAI1 rs6486795 (OR = 2.25 for allele C). The maximum OR was shown for AA genotypes in loci rs1042636 (CASR) and rs1801197 (CALCR) (OR = 4.71, OR = 11.8, respectively). After adjustment by Benjamini-Hochberg FDR we found only CALCR (rs1801197) was significantly associated with the risk of calcium urolithiasis development. There was no relationship between recurrent course of the disease and family history of urolithiasis in investigated patients. Thus we found a statistically significant association of polymorphism rs1801197 (gene CALCR) with calcium urolithiasis in Russian population.

RevDate: 2022-03-22
CmpDate: 2022-03-22

Harmacek D, Blanchard A, Wuerzner G, et al (2022)

Acute decrease of urine calcium by amiloride in healthy volunteers under high-sodium diet.

Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 37(2):298-303.

BACKGROUND: Amiloride is a competitive blocker of the epithelial sodium (Na) channel in the renal collecting duct. It is a less potent diuretic than thiazides or loop diuretics, but is often used in association with its potassium (K)-sparing profile. Whether amiloride has a hypocalciuric effect similar to thiazides remains unclear. Animal studies and experiments on cell lines suggested that amiloride increases calcium (Ca) reabsorption in the distal nephron, but human studies are scarce.

METHODS: We performed a post hoc analysis of a study with 48 healthy males (mean ± standard deviation age, 23.2 ± 3.9 years) who were assigned to a high-Na/low-K diet for 7 days before receiving 20 mg of amiloride orally. Urinary excretions of electrolytes were measured at 3 and 6 h afterwards; we calculated the relative changes in urinary excretion rates after amiloride administration.

RESULTS: The high-Na/low-K diet led to an expected suppression of plasma renin and aldosterone. Amiloride showed a mild natriuretic effect associated with a decreased kaliuresis. Urinary Ca excretion dropped substantially (by 80%) 3 h after amiloride administration and remained low at the sixth hour. At the same time, fractional excretion of lithium decreased by a third, reflecting an increased proximal tubular reabsorption.

CONCLUSIONS: During a high-Na/low-K diet, amiloride had a strong acute hypocalciuric effect, most probably mediated by increased proximal Ca reabsorption, even though a distal effect cannot be excluded. Further studies should establish if chronic amiloride or combined amiloride/thiazide treatment may decrease calciuria more efficiently and be useful in preventing kidney stones.

RevDate: 2021-11-10
CmpDate: 2021-11-10

Gomes Coutinho AG, Pinheiro E, R Fernandez (2020)

The calcium sensing receptor modulates H[+]-ATPase activity in intercalated cells.

Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 71(6):.

Previous studies found that calcium sensing receptor (CaSR) it's expressed in intercalated cells of the collecting duct and that its activation by calcium in the luminal membrane promotes acidification of urine. Therefore, the aim of the study was to analyze the effects of CaSR stimulus on the biochemical activity of the vacuolar H[+]-ATPase in a cellular model of intercalated cells, MDCK-C11 cells. Biochemical activity of H[+]-ATPase was performed using cell homogenates and the inorganic phosphate released was determined by a colorimetric method. Changes in cytosolic ionized calcium ([Ca[2+]]i) were also determined using Fluo-4. A significant increase of vacuolar H[+]-ATPase activity was observed when the CaSR was stimulated with agonists such as Gd[3+] (300 μM), neomycin (200 μM) and by the calcimimetic R-568 (1 μM). This activity was also stimulated in a dose-dependent fashion by changes in extracellular Ca[2+] concentration ([Ca[2+]]o) between 10[-2] and 2 mM. The calciolytic NPS 2143 (150 nM) significantly reduced the vacuolar H[+]-ATPase activity observed with 2 mM [Ca[2+]]o. Inhibition of phospholipase C (PLC) activity with U73122 (5 x 10[-7] M) reversed the increase in pump activity observed in the presence of Gd[3+]. Activation of CaSR by the specific CaSR agonist R-568 produced a sustained rise of [Ca[2+]]i, an effect that disappears when extracellular calcium was removed in the presence of thapsigargin. In summary, CaSR stimulation induces an increase in the vacuolar H[+]-ATPase activity of MDCK-C11 cells, an effect that involves an increase in [Ca[2+]]i and require PLC activity. The consequent decrease in intratubular pH could lead to increase ionization of luminal calcium, potentially reducing the formation of calcium phosphate stones.

RevDate: 2021-10-18
CmpDate: 2021-04-07

Porhanov VA, Medvedev VL, Budanov AA, et al (2021)

[Determination of calcium metabolism markers concentration in patients with calcium oxalate nephrolithiasis].

Urologiia (Moscow, Russia : 1999).

UNLABELLED: THE AIM OF THE RESEARCH: to reveal the relationship of various markers of calcium metabolism (osteopontin (OPN), parathyroid hormone-related protein (PTHrP), vitamin D, parathyroid hormone (PTH)) on the course of urolithiasis (Urolithiasis) in patients with calcium oxalate nephrolithiasis.

MATERIALS AND METHODS: 100 people were examined, the following groups were included: group 1 - patients with calcium oxalate primary nephrolithiasis (n=41), group 2 - with calcium oxalate recurrent nephrolithiasis (n=39). Group 3 included conditionally healthy volunteers (n=20). The studies were carried out by the immunoenzymometric ELIZA and biochemical methods using appropriate test systems.

RESULTS: in patients with recurrent nephrolithiasis, the serum PTHrP level is 54.6 (25.4-78.2) pg / ml, which is 3.7 times higher than in conventionally healthy individuals; the level of osteopontin is more than 1.5 times higher and amounts to 1.820 (0.991-2.212) pg / ml. In the group of primary nephrolithiasis, the level of PTHrP is 2-2.5 times higher than in conventionally healthy people. In patients with primary nephrolithiasis, the blood calcium level does not correlate with the level of PTHrP in the blood (r=- 0.0173, p> 0.05), as in the group with recurrent nephrolithiasis (r=0.0223, p>0.05).

DISCUSSION: in patients with recurrent nephrolithiasis in the preoperative period, the serum levels of osteopontin and PTHrP in the blood serum were higher than in patients who were first diagnosed with urolithiasis, the data obtained can be used as a criterion for predicting the risk of recurrence of urolithiasis in the postoperative period. The blood calcium level does not have a statistically significant relationship with PTHrP, which allows us to assume that PTHrP has other mechanisms of influence on the development of urolithiasis, given the data obtained that the PTHrP level in patients with primary and recurrent nephrolithiasis is higher than in conditionally healthy people.

CONCLUSION: Determination of the level of PTHrP and osteopontin in patients with urolithiasis allows predicting the risk of recurrence of urolithiasis at the stage of primary calcium oxalate nephrolithiasis. Determination of the level of PTHrP makes it possible to predict the risks of developing urolithiasis in conventionally healthy individuals, which can be used for targeted prevention of an unfavorable course of urolithiasis by prescribing timely adequate rational therapy and correcting the patients diet. At the same time, no correlation was found between the level of PTHrP and the level of blood calcium in patients with calcium oxalate nephrolithiasis; therefore, further studies of the role of this protein in the pathogenesis of urolithiasis are needed.

RevDate: 2021-05-14
CmpDate: 2021-05-14

Liu CJ, Cheng CW, Tsai YS, et al (2021)

Crosstalk between Renal and Vascular Calcium Signaling: The Link between Nephrolithiasis and Vascular Calcification.

International journal of molecular sciences, 22(7):.

Calcium (Ca[2+]) is an important mediator of multicellular homeostasis and is involved in several diseases. The interplay among the kidney, bone, intestine, and parathyroid gland in Ca[2+] homeostasis is strictly modulated by numerous hormones and signaling pathways. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor, that is expressed in calcitropic tissues such as the parathyroid gland and the kidney, plays a pivotal role in Ca[2+] regulation. CaSR is important for renal Ca[2+], as a mutation in this receptor leads to hypercalciuria and calcium nephrolithiasis. In addition, CaSR is also widely expressed in the vascular system, including vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs) and participates in the process of vascular calcification. Aberrant Ca[2+] sensing by the kidney and VSMCs, owing to altered CaSR expression or function, is associated with the formation of nephrolithiasis and vascular calcification. Based on emerging epidemiological evidence, patients with nephrolithiasis have a higher risk of vascular calcification, but the exact mechanism linking the two conditions is unclear. However, a dysregulation in Ca[2+] homeostasis and dysfunction in CaSR might be the connection between the two. This review summarizes renal calcium handling and calcium signaling in the vascular system, with a special focus on the link between nephrolithiasis and vascular calcification.

RevDate: 2021-06-27
CmpDate: 2021-04-23

Awuah Boadi E, Shin S, Yeroushalmi S, et al (2021)

Modulation of Tubular pH by Acetazolamide in a Ca[2+] Transport Deficient Mice Facilitates Calcium Nephrolithiasis.

International journal of molecular sciences, 22(6):.

Proximal tubular (PT) acidosis, which alkalinizes the urinary filtrate, together with Ca[2+] supersaturation in PT can induce luminal calcium phosphate (CaP) crystal formation. While such CaP crystals are known to act as a nidus for CaP/calcium oxalate (CaOx) mixed stone formation, the regulation of PT luminal Ca[2+] concentration ([Ca[2+]]) under elevated pH and/or high [Ca[2+]] conditions are unknown. Since we found that transient receptor potential canonical 3 (TRPC3) knockout (KO; -/-) mice could produce mild hypercalciuria with CaP urine crystals, we alkalinized the tubular pH in TRPC3-/- mice by oral acetazolamide (0.08%) to develop mixed urinary crystals akin to clinical signs of calcium nephrolithiasis (CaNL). Our ratiometric (λ340/380) intracellular [Ca[2+]] measurements reveal that such alkalization not only upsurges Ca[2+] influx into PT cells, but the mode of Ca[2+] entry switches from receptor-operated to store-operated pathway. Electrophysiological experiments show enhanced bicarbonate related current activity in treated PT cells which may determine the stone-forming phenotypes (CaP or CaP/CaOx). Moreover, such alkalization promotes reactive oxygen species generation, and upregulation of calcification, inflammation, fibrosis, and apoptosis in PT cells, which were exacerbated in absence of TRPC3. Altogether, the pH-induced alteration of the Ca[2+] signaling signature in PT cells from TRPC3 ablated mice exacerbated the pathophysiology of mixed urinary stone formation, which may aid in uncovering the downstream mechanism of CaNL.

RevDate: 2022-05-09
CmpDate: 2022-05-09

Downie ML, RT Alexander (2022)

Molecular mechanisms altering tubular calcium reabsorption.

Pediatric nephrology (Berlin, Germany), 37(4):707-718.

The majority of calcium filtered by the glomerulus is reabsorbed along the nephron. Most is reabsorbed from the proximal tubule (> 60%) via a paracellular pathway composed of the tight junction proteins claudins-2 and -12, a process driven by sodium and consequently water reabsorption. The thick ascending limb reabsorbs the next greatest amount of calcium (20-25%), also by a paracellular pathway composed of claudins-16 and -19. This pathway is regulated by the CaSR, whose activity increases the expression of claudin-14, a protein that blocks paracellular calcium reabsorption. The fine tuning of urinary calcium excretion occurs in the distal convoluted and connecting tubule by a transcellular pathway composed of the apical calcium channel TRPV5, the calcium shuttling protein calbindin-D28K and the basolateral proteins PMCA1b and the sodium calcium exchanger, NCX. Not surprisingly, mutations in a subset of these genes cause monogenic disorders with hypercalciuria as a part of the phenotype. More commonly, "idiopathic" hypercalciuria is encountered clinically with genetic variations in CLDN14, the CASR and TRPV5 associating with kidney stones and increased urinary calcium excretion. An understanding of the molecular pathways conferring kidney tubular calcium reabsorption is employed in this review to help explain how dietary and medical interventions for this disorder lower urinary calcium excretion.

RevDate: 2021-06-28
CmpDate: 2021-06-28

de Carvalho JF, LP Churilov (2021)

Safety of megadose of vitamin D in patients with nephrolithiasis.

Nutrition (Burbank, Los Angeles County, Calif.), 87-88:111201.

OBJECTIVE: This article describes two patients with renal lithiasis who received a megadose of 25-hydroxy vitamin D (25[OH]D) and had a good outcome.

METHODS: The first case reports a 74-year-old man with a long-term history of renal lithiasis and about four episodes of renal crisis. He was treated once with extracorporeal shock wave lithotripsy. He also had a history of dyslipidemia, myocardial infarction, and stroke. Laboratory tests demonstrated 25(OH)D of 28 ng/mL (normal range (nr): >30 ng/mL), normal lipid levels, creatinine of 1.1 mg/dL, and homocysteine of 26.6 mcmol/L (nr: 5-15 mcmol/L); parathyroid hormone (PTH) was high at 67.3 pg/mL (nr: 10-65 pg/mL), serum total calcium was 8.6 mg/dL, 24-h urinary calcium was 139 mg/d (normal range 100-300 mg/d), and urinary sediment was normal. He received 50 000 IU per week of vitamin D for 3 mo, and 25(OH)D increased to 36.6 ng/mL. Urinary calcium was 142 mg/d, PTH was 46.7 pg/mL, and serum calcium was 9.6 mg/dL. No renal crisis was perceived. He asked for an alternative form of medication since he usually would forget to take drugs. Vitamin D in a single dose of 600 000 IU intramuscular was prescribed. He was asked to increase water intake to 2 to 3 L/d. After 3 mo his 25(OH)D was 75.0 ng/mL, serum calcium was 9.2 mg/dL, urinary calcium was 148 mg/d, and PTH was 38.7 pg/mL. He had no episodes of lithiasis renal crisis. Folic acid and methylcobalamin were added, and homocysteine normalized. At follow-up 3 y later, the patient was asymptomatic, cardiologic evaluation was stable without any other renal lithiasis crises, 25(OH)D continued to be normal at 62 ng/mL, and he received a megadose of vitamin D every 6 mo. Renal ultrasound revealed only microlithiasis. The second case reports a 52-year-old man with a long-term history of renal lithiasis experienced since he was 30 y old, with three renal crisis episodes. He was treated with an extracorporeal shock wave three times. Laboratory tests demonstrated 25(OH)D 18 ng/mL, normal biochemistry, total serum calcium of 10.2 mg/dL, 24-h urinary calcium of 154 mg/d, and normal urinary sediment. He received 50 000 IU per week of 25(OH)D for 3 mo, and 25(OH)D increased to 40.3 ng/mL. Urinary calcium was 167 mg/d, PTH was 35.3 pg/mL, and serum calcium was 10.1 mg/dL. No renal crisis was perceived. He asked for an alternative form of medication, and vitamin D in a single dose of 600 000 IU intramuscular was prescribed. He was asked to increase water intake to 2 to 3 L/d. After 3 mo, his 25(OH)D was 82.0 ng/mL, serum calcium was 9.6 mg/dL, urinary calcium was 175 mg/d, and PTH was 35.3 pg/mL. The renal ultrasound was unchanged. He had no episodes of lithiasis renal crisis. At follow-up 4 y later, the patient was asymptomatic without any other renal lithiasis crises, a renal ultrasound revealed a reduction of calculi size to microlithiasis, 25(OH)D continues normal, and he received a megadose of this vitamin every 4 mo.

CONCLUSION: To the best of our knowledge, this is the first description of a megadose of vitamin D used in patients with nephrolithiasis. Furthermore, this shows the safety of this strategy in patients without hypercalciuria.

RevDate: 2022-05-27
CmpDate: 2022-05-24

Kumar A, J Balbach (2022)

Inactivation of Parathyroid Hormone: Perspectives of Drug Discovery to Combating Hyperparathyroidism.

Current molecular pharmacology, 15(2):292-305.

Hormonal coordination is tightly regulated within the human body and thus regulates human physiology. The parathyroid hormone (PTH), a member of the endocrine system, regulates the calcium and phosphate level within the human body. Under non-physiological conditions, PTH levels get upregulated (hyperparathyroidism) or downregulated (hypoparathyroidism) due to external or internal factors. In case of hyperparathyroidism, elevated PTH stimulates cellular receptors present in the bones, kidneys, and intestines to increase the blood calcium level, leading to calcium deposition. This eventually causes various symptoms, including kidney stones. Currently, there is no known medication that directly targets PTH in order to suppress its function. Therefore, it is of great interest to find novel small molecules or any other means that can modulate PTH function. The molecular signaling of PTH starts by binding its N-terminus to the G-protein coupled PTH1/2 receptor. Therefore, any intervention that affects the N-terminus of PTH could be a lead candidate for treating hyperparathyroidism. As a proof-of-concept, there are various possibilities to inhibit molecular PTH function by (i) a small molecule, (ii) N-terminal PTH phosphorylation, (iii) fibril formation and (iv) residue-specific mutations. These modifications put PTH into an inactive state, which will be discussed in detail in this review article. We anticipate that exploring small molecules or other means that affect the N-terminus of PTH could be lead candidates in combating hyperparathyroidism.

RevDate: 2021-09-20
CmpDate: 2021-09-20

Yi F, Garrett T, Deisseroth K, et al (2021)

Septohippocampal transmission from parvalbumin-positive neurons features rapid recovery from synaptic depression.

Scientific reports, 11(1):2117.

Parvalbumin-containing projection neurons of the medial-septum-diagonal band of Broca ([Formula: see text]) are essential for hippocampal rhythms and learning operations yet are poorly understood at cellular and synaptic levels. We combined electrophysiological, optogenetic, and modeling approaches to investigate [Formula: see text] neuronal properties. [Formula: see text] neurons had intrinsic membrane properties distinct from acetylcholine- and somatostatin-containing MS-DBB subtypes. Viral expression of the fast-kinetic channelrhodopsin ChETA-YFP elicited action potentials to brief (1-2 ms) 470 nm light pulses. To investigate [Formula: see text] transmission, light pulses at 5-50 Hz frequencies generated trains of inhibitory postsynaptic currents (IPSCs) in CA1 stratum oriens interneurons. Using a similar approach, optogenetic activation of local hippocampal PV ([Formula: see text]) neurons generated trains of [Formula: see text]-mediated IPSCs in CA1 pyramidal neurons. Both synapse types exhibited short-term depression (STD) of IPSCs. However, relative to [Formula: see text] synapses, [Formula: see text] synapses possessed lower initial release probability, transiently resisted STD at gamma (20-50 Hz) frequencies, and recovered more rapidly from synaptic depression. Experimentally-constrained mathematical synapse models explored mechanistic differences. Relative to the [Formula: see text] model, the [Formula: see text] model exhibited higher sensitivity to calcium accumulation, permitting a faster rate of calcium-dependent recovery from STD. In conclusion, resistance of [Formula: see text] synapses to STD during short gamma bursts enables robust long-range GABAergic transmission from MS-DBB to hippocampus.

RevDate: 2021-12-14
CmpDate: 2021-12-03

Charles PY, Letavernier E, Périé S, et al (2021)

Effect of parathyroidectomy on renal stone recurrence.

Urolithiasis, 49(4):327-334.

Parathyroidectomy (PTX) is routinely performed in hypercalciuric renal stone patients with primary hyperparathyroidism (PHPT). However, some data indicate a persistent stone activity following PTX, raising the issue of the link between PHPT and stone disease. We performed an observational study on 30 renal stone patients diagnosed with PHPT. Patients were selected among 1448 hypercalciuric patients referred in our department for a diagnostic evaluation. Patients with no parathyroid surgery or any biological follow-up were excluded. Clinical and biological data (including 24-h urine collection and a calcium load test) were collected before and within 12 months following surgery. Stone recurrence was evaluated by direct phone contact (median 43 months). Comparison of biological data before and after surgery showed a significant decrease of ionized calcium and serum parathyroid hormone after PTX. All stones contained calcium-dependent species such as carbapatite, brushite or dihydrate calcium oxalate. Urine saturation indexes and calciuria significantly decreased after surgery (from 9.9 to 5.9 mmol/d, p < 0.0001), but a persistent hypercalciuria was detected in 47% of patients. The other stone risk factors including diuresis stayed similar. Stone activity that was increasing (from 0.20-0.30 to 0.50-0.75/year) the 2 years before PTX, significantly decreased after surgery [0.05-0.15/year (p < 0.001)]. PTX in calcium-dependent renal stone formers with PHPT significantly decreases both stone recurrence and urine saturation indexes. However, PTX unmasked an underlying renal stone disease related to idiopathic hypercalciuria in half of patients with a remaining stone activity, testifying the need for patient's follow-up to prevent stone recurrence.

RevDate: 2022-03-28
CmpDate: 2022-03-28

Keller EX, De Coninck V, Pietropaolo A, et al (2021)

Metabolic Evaluation: Place of the Calcium Load Test: How, When, For Whom, and Why?.

European urology focus, 7(1):26-30.

Most human urinary stones are calcium-based and are often associated with hypercalciuria. A simple test described in 1975 by Pak et al allows for pathogenic classification of hypercalciuria: the calcium load test (CLT). The CLT explores calcium homeostasis after a low-calcium diet and then a calcium load (typically oral administration of 1 g of elemental calcium). Only simple laboratory equipment is required. Inadequate calcium excretion after a calcium-free diet or a calcium load is suggestive of resorptive or absorptive hypercalciuria, respectively. The CLT is particularly valuable in diagnosing primary hyperparathyroidism, even in most early stages of this disease. PATIENT SUMMARY: Kidney stone formation can be linked to calcium metabolism. When high calcium levels are found in urine despite adequate diet changes, a calcium load test may help to understand the underlying mechanisms. Urine and blood levels are explored during a low-calcium diet phase, and after a calcium load phase in the test. The calcium load test is particularly advantageous for revealing abnormally high function of the parathyroid gland, which is called hyperparathyroidism.

RevDate: 2022-05-31
CmpDate: 2020-12-31

Litvinova MM, Filippova TV, Khafizov KF, et al (2020)

[A complicated case of calcium urolithiasis in a carrier of SLC7A9 gene mutation responsible for cystinuria].

Urologiia (Moscow, Russia : 1999).

The article describes a clinical case of kidney stone disease (KSD) in a child of 4 y.o. with calcium urolithiasis. Analysis of chemical content of the kidney stones revealed their calcium-oxalate composition. According to the results of clinical exome sequencing the patient found to be a heterozygous carrier of a pathogenic variant c.695A>G (p.Tyr232Cys) in the gene SLC7A9, attributable for an autosomal recessive form of cystinuria type B. Because of the uroliths calcium composition the patient was also genotyped for SNPs in 15 genes involved in calcium metabolism. Polymorphisms associated with increased risk of calcium urolithiasis were found in 8 of 15 tested genes. The findings could explain clinical features of the patient.

RevDate: 2021-12-04
CmpDate: 2021-06-28

Lanka P, Devana SK, Singh SK, et al (2021)

Klotho gene polymorphism in renal stone formers from Northwestern India.

Urolithiasis, 49(3):195-199.

Klotho gene is an important gene involved in calcium homeostasis, and polymorphisms of this gene may render the individual prone to renal stone formation. We evaluated G395A single nucleotide polymorphisms (SNPs) of Klotho gene at rs1207568 in renal stone patients of North India. This was a prospective study involving 150 patients of renal stone disease (aged 15-60 years) and 100 age- and sex-matched controls. The DNA was isolated and subjected to polymerase chain reaction (PCR) for identifying the G395A Klotho SNPs at rs1207568. Confronting two pair primers were used, and gel electrophoresis showing two bands at 175,252 bp was considered as GG genotype, three bands at 121,175 and 252 bp as GA and two bands at 121 and 252 bp as AA genotype. The association between genotype and cases was evaluated by using Chi-square test and logistic regression analysis. Cases and controls were well matched for age (40.65 vs 42.06, p = 0.063) and sex (p = 0.420). Significantly high proportion of patients with renal stones had GG genotype as compared to controls (odds ratio (OR) 2.37(1.39,4.03), p = 0.001). None of the participants (cases and controls) had homozygous recessive AA genotype. The risk of stone formation was significantly higher in the population carrying G allele {OR 1.94 (1.225-3.073), p 0.004}. Mean serum calcium was higher in stone formers with GG genotype as compared to those with GA genotype (9.16 mg/dl vs 8.91 mg/dl; p = 0.06). GG genotype of G396A Klotho gene SNPs is associated with renal stone formation. The G allele carrier is twice at risk of renal stone formation. The absence of AA genotype in north-western Indian population remains a curiosity.

RevDate: 2021-06-28
CmpDate: 2021-06-28

Stern JM, Burk RD, Asplin J, et al (2021)

Kidney stone formation and the gut microbiome are altered by antibiotics in genetic hypercalciuric stone-forming rats.

Urolithiasis, 49(3):185-193.

Antibiotics can alter the gut microbiome (GMB), which may be associated with stone disease. We sought to determine the effect that antibiotics have on the GMB, urine ion excretion and stone formation in genetic hypercalciuric stone-forming (GHS) rats. 116th generation GHS rats were fed a fixed amount of a normal calcium (1.2%) and phosphate (0.65%) diet, and divided into three groups (n = 10): control (CTL) diet, or supplemented with ciprofloxacin (Cipro, 5 mg/day) or Bactrim (250 mg/day). Urine and fecal pellets were collected over 6, 12 and 18 weeks. Fecal DNA was amplified across the 16S rRNA V4 region. At 18 weeks, kidney stone formation was visualized by Faxitron and blindly assessed by three investigators. After 18 weeks, urine calcium and oxalate decreased with Bactrim compared to CTL and Cipro. Urine pH increased with Bactrim compared to CTL and Cipro. Urine citrate increased with Cipro compared to CTL and decreased by half with Bactrim. Calcification increased with Bactrim compared to CTL and Cipro. Increased microbial diversity correlated with decreased urinary oxalate in all animals (R = - 0.46, p = 0.006). A potential microbial network emerged as significantly associated with shifts in urinary pH. Bactrim and Cipro differentially altered the GMB of GHS rats. The Bactrim group experienced a decrease in urine calcium, increased CaP supersaturation and increased calcification. The GMB is likely a contributing factor to changes in urine chemistry, supersaturation and stone risk. Further investigation is required to fully understand the association between antibiotics, the GMB and kidney stone formation.

RevDate: 2020-10-13

Aoun B, Sanjad S, Degheili JA, et al (2020)

Kidney and Metabolic Phenotypes in Glycogen Storage Disease Type-I Patients.

Frontiers in pediatrics, 8:591.

Patients and Methods: A retrospective chart review of 32 GSD- I patients, followed at the American University of Beirut Medical Center, between 2007 and 2018 was conducted. Diagnosis was confirmed by enzymatic and/or genetic studies. Clinical presentation, growth, and kidney outcome were assessed. All patients were evaluated for body mass index, blood parameters of metabolic control including uric acid, alanine, lactic acid, and triglycerides in blood. Kidney evaluation included creatinine clearance, microalbuminuria, citraturia, and calciuria as well as urine microalbumin/creatinine ratio. Results: Almost one third of GSD-I patients developed microalbuminuria. This was detected below 7 months of age in 36% of patients who required early treatment with ACEI with significant reduction in albuminuria. Kidney stones were present in 6% and were associated with hypercalciuria and hypocitraturia. Poor metabolic control reflected by hyperuricemia, lactic acidosis, and hyperalaninemia were noted only in patients who developed microalbuminuria. Conclusion: Glomerular injury may appear in early infancy in poorly controlled patients. Adequate metabolic control and ACEI therapy may improve kidney outcome in GSD I patients. Plasma alanine appears to be a promising and reliable marker reflecting metabolic control in GSD-I patients.

RevDate: 2022-07-16

Guo S, Chia W, Wang H, et al (2022)

Vitamin D receptor (VDR) contributes to the development of hypercalciuria by sensitizing VDR target genes to vitamin D in a genetic hypercalciuric stone-forming (GHS) rat model.

Genes & diseases, 9(3):797-806.

Human idiopathic hypercalciuria (IH) is the most common cause of calcium oxalate nephrolithiasis with perturbed calcium metabolism with increased bone resorption and decreased renal calcium reabsorption, which can be phenotype-copied in the genetic hypercalciuric stone-forming (GHS) rat model. We previously demonstrated that high VDR expression plays important roles in the development of hypercalciuria in the GHS rats. However, the underlying mechanism through which VDR impact hypercalciuria development remains to be fully understood. Here, we sought to determine how VDR regulated its target genes that are implicated in calcium homeostasis and potentially hypercalciuria. We found that VDR expression in the GHS rats was elevated in the calcium transporting tissues, as well as in the thymus and prostate, but not in lung, brain, heart, liver and spleen, when compared with control SD rats. Snail expression in the GHS rats was significantly downregulated in kidney, intestine, thymus and testis. Intraperitoneal injection of 1,25(OH)2D3 significantly upregulated the expression of renal calcium sensing receptor (CaSR), intestinal calcium transporters transient receptor potential vanilloid type 6 (TRPV6), and VDR in GHS rats, compared with that in control SD rats. ChIP assays revealed that VDR specifically bound to the proximal promoters of target genes, followed by histone H3 hyperacetylation or hypermethylation. Collectively, our results suggest that elevated VDR expression may contribute to the development of hypercalciuria by sensitizing VDR target genes to 1,25(OH)2D3 through histone modifications at their promoter regions in a genetic hypercalciuric stone-forming (GHS) rat model.

RevDate: 2021-03-24
CmpDate: 2021-03-24

Schapher M, Koch M, Weidner D, et al (2020)

Neutrophil Extracellular Traps Promote the Development and Growth of Human Salivary Stones.

Cells, 9(9):.

Salivary gland stones, or sialoliths, are the most common cause of the obstruction of salivary glands. The mechanism behind the formation of sialoliths has been elusive. Symptomatic sialolithiasis has a prevalence of 0.45% in the general population, is characterized by recurrent painful periprandial swelling of the affected gland, and often results in sialadenitis with the need for surgical intervention. Here, we show by the use of immunohistochemistry, immunofluorescence, computed tomography (CT) scans and reconstructions, special dye techniques, bacterial genotyping, and enzyme activity analyses that neutrophil extracellular traps (NETs) initiate the formation and growth of sialoliths in humans. The deposition of neutrophil granulocyte extracellular DNA around small crystals results in the dense aggregation of the latter, and the subsequent mineralization creates alternating layers of dense mineral, which are predominantly calcium salt deposits and DNA. The further agglomeration and appositional growth of these structures promotes the development of macroscopic sialoliths that finally occlude the efferent ducts of the salivary glands, causing clinical symptoms and salivary gland dysfunction. These findings provide an entirely novel insight into the mechanism of sialolithogenesis, in which an immune system-mediated response essentially participates in the physicochemical process of concrement formation and growth.

RevDate: 2021-04-05
CmpDate: 2021-04-05

Milart J, Lewicka A, Jobs K, et al (2020)

Effect of Vitamin D Treatment on Dynamics of Stones Formation in the Urinary Tract and Bone Density in Children with Idiopathic Hypercalciuria.

Nutrients, 12(9):.

Vitamin D supplementation in patients with urolithiasis and hypercalciuria is considered to be unsafe. We analyzed the impact of vitamin D supplementation on selected health status parameters in children with idiopathic hypercalciuria. The study included 36 children with urolithiasis resulting from excessive calcium excretion. The level of calcium and 25(OH)D (hydroxylated vitamin D - calcidiol) in serum, urinary calcium excretion and the presence of stones in urinary tract were assessed prospectively. Blood and urine samples were collected at the time when the patient was qualified for the study and every three months up to 24 month of vitamin D intake at a dose of 400 or 800 IU/day. At time zero and at 12, and 24 months of vitamin D supplementation, densitometry was performed. Supplementation with vitamin D caused a statistically significant increase in the concentration of 25(OH)D in serum. There were no significant changes in calcium concentration in serum, excretion of calcium in urine but also in bone density. There was no significant increase in the risk of formation or development of stones in the urinary tract. Supplementation with vitamin D (400-800 IU/day) in children with idiopathic hypercalciuria significantly increases 25(OH)D concentration, does not affect calciuria, but also does not improve bone density.

RevDate: 2021-07-12
CmpDate: 2021-07-12

Zhou Y, EE Lower (2020)

Balancing Altered Calcium Metabolism with Bone Health in Sarcoidosis.

Seminars in respiratory and critical care medicine, 41(5):618-625.

Abnormal calcium metabolism in sarcoidosis patients can lead to hypercalcemia, hypercalciuria, and kidney stones. Hypercalcemia in sarcoidosis is usually due to increased activity of 1α-hydroxylase in macrophages of pulmonary granulomata, resulting in low levels of 25-hydroxyvitamin D and high levels of calcitriol. Vitamin D supplementation may be dangerous for some sarcoidosis patients and is recommended only for those with decreased 25-hydroxyvitamin D and reduced or normal calcitriol level. Diagnosis, treatment of osteoporosis, and maintenance of bone health are complex issues for sarcoidosis patients. An approach to diagnosis and treatment of bone fragility is presented.

RevDate: 2022-01-14
CmpDate: 2020-10-13

Sinha D, Steyer B, Shahi PK, et al (2020)

Human iPSC Modeling Reveals Mutation-Specific Responses to Gene Therapy in a Genotypically Diverse Dominant Maculopathy.

American journal of human genetics, 107(2):278-292.

Dominantly inherited disorders are not typically considered to be therapeutic candidates for gene augmentation. Here, we utilized induced pluripotent stem cell-derived retinal pigment epithelium (iPSC-RPE) to test the potential of gene augmentation to treat Best disease, a dominant macular dystrophy caused by over 200 missense mutations in BEST1. Gene augmentation in iPSC-RPE fully restored BEST1 calcium-activated chloride channel activity and improved rhodopsin degradation in an iPSC-RPE model of recessive bestrophinopathy as well as in two models of dominant Best disease caused by different mutations in regions encoding ion-binding domains. A third dominant Best disease iPSC-RPE model did not respond to gene augmentation, but showed normalization of BEST1 channel activity following CRISPR-Cas9 editing of the mutant allele. We then subjected all three dominant Best disease iPSC-RPE models to gene editing, which produced premature stop codons specifically within the mutant BEST1 alleles. Single-cell profiling demonstrated no adverse perturbation of retinal pigment epithelium (RPE) transcriptional programs in any model, although off-target analysis detected a silent genomic alteration in one model. These results suggest that gene augmentation is a viable first-line approach for some individuals with dominant Best disease and that non-responders are candidates for alternate approaches such as gene editing. However, testing gene editing strategies for on-target efficiency and off-target events using personalized iPSC-RPE model systems is warranted. In summary, personalized iPSC-RPE models can be used to select among a growing list of gene therapy options to maximize safety and efficacy while minimizing time and cost. Similar scenarios likely exist for other genotypically diverse channelopathies, expanding the therapeutic landscape for affected individuals.

RevDate: 2022-04-15
CmpDate: 2020-12-16

Yifan Z, Benxiang N, Zheng X, et al (2020)

Ceftriaxone Calcium Crystals Induce Acute Kidney Injury by NLRP3-Mediated Inflammation and Oxidative Stress Injury.

Oxidative medicine and cellular longevity, 2020:6428498.

OBJECTIVE: To investigate the role of inflammatory reactions and oxidative stress injury in the mechanisms of ceftriaxone calcium crystal-induced acute kidney injury (AKI) both in vivo and in vitro.

METHODS: Male Sprague Dawley rats were randomly divided into five groups of ten each according to different concentrations of ceftriaxone and calcium. Based on the levels of serum creatinine (Scr) and blood urea nitrogen (BUN), the AKI group was chosen for the subsequent experiments. Kidney histological examination and immunohistochemistry were performed. The expression of NLRP3 and IL-1β protein and the concentrations of oxidative stress markers such as ROS, MDA, and H2O2 in kidney tissues were estimated. In parallel, HK-2 human renal proximal tubule cells were exposed to ceftriaxone calcium crystals. The mRNA expression levels of NLRP3 and IL-1β and the concentrations of oxidative stress markers were evaluated. Finally, cell viability and rat survival were also assessed.

RESULTS: The results showed that significantly increased Scr and BUN levels, consistent with morphological changes and kidney stones, were found in the rats that received the highest concentration of ceftriaxone (1000 mg/kg) combined with calcium (800 mg/kg). The activation of the NLRP3 inflammasome axis and the marked elevation of MDA, H2O2, and ROS levels were observed both in vivo and in vitro. High expression of Nrf2, HO-1, and NQO1 was also documented. In addition, cell apoptosis and rat mortality were promoted by ceftriaxone calcium crystals.

CONCLUSIONS: Notably, we found that ceftriaxone-induced urolithiasis was associated with a high risk of AKI and NLRP3-mediated inflammasome and oxidative stress injury were of major importance in the pathogenesis.

RevDate: 2021-12-04
CmpDate: 2021-08-19

Irzyniec T, Boryń M, Kasztalska J, et al (2020)

The effect of an oral sodium phosphate load on parathyroid hormone and fibroblast growth factor 23 secretion in normo- and hypercalciuric stone-forming patients.

Clinical nutrition (Edinburgh, Scotland), 39(12):3804-3812.

BACKGROUND & AIMS: Abnormalities of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) secretion may cause calcium-phosphate (Ca-P) metabolism disorders in nephrolithiasis. Post-phosphate-load alterations in serum Ca, P and PTH, phosphaturia and calciuria enable monitoring hormonal regulation of Ca-P homeostasis. Our study aimed to determine differences in: 1.selected Ca-P metabolism parameters between healthy and kidney-stone-forming individuals, 2.PTH and FGF23 secretion induced by sodium-phosphate-load(NaP-load) in patients with/without hypercalciuria, 3.secretion of Ca-P related hormones in patients with low and normal/high serum concentrations of 25-hydroxyvitamin D3 (25OHD3).

METHODS: Sodium phosphates NaH2PO4/Na2HPO4-100mmol were administered orally for five days in 19 hypercalciuric [urinary Ca(U-Ca) 6.5 ± 1.7 mmol/d]-HSF, 35 normocalciuric (2.5±1 mmol/d)-NSF stone-forming patients and 19 controls (U-Ca 2.5 ± 1.4 mmol/d)-CG. On days 1 and 5 PTH-,FGF23-,Ca-,P were determined before and after NaP-load. The areas under PTH, FGF23 curves (AUC) were calculated. U-Ca, urinary phosphate (U-P) and sodium (U-Na) were also determined.

RESULTS: Following NaP-load, patients and controls exhibited expected alterations in Ca-P homeostasis. Despite changes in phosphate and PTH, no differences in FGF23 concentrations were observed. Patients differed from controls in having higher AUCPTH, calciuria and natriuresis, taking longer for PTH and P to normalize and lack of correlation between AUCPTH and phosphaturia. Post-NaP-load hypocalciuric effect of PTH secretion in NSF was less pronounced than in CG. In the HSFs, the hypocalciuric effect was more pronounced than in NSFs, but insufficient to correct hypercalciuria. In all stone-formers with low 25OHD3 concentrations, the AUCFGF23 was significantly increased on first (1215 ± 605vs766 ± 315 p = 0.0457) and fifth days (1211 ± 641vs777 ± 299 p = 0.041) of NaP-load, compared to normal/high 25OHD3-patients. Hypercalciuric patients with low 25OHD3 concentrations had greater AUCPTH5 than those with normal/high 25OHD3 (1005 ± 401vs835 ± 220 p = 0.0341).

CONCLUSIONS: Compared to controls, kidney-stone-forming patients exhibited enhanced PTH secretion after NaP-load. The HSFs showed a more pronounced hypocalciuric effect than NSFs, but insufficient to correct hypercalciuria. In hypercalciuric stone-formers with low 25OHD3, FGF23 engagement in hyperphosphatemia reduction increased.

RevDate: 2021-03-15
CmpDate: 2021-03-15

Islam AK, Holt S, Reisch J, et al (2020)

What Predicts Recurrent Kidney Stone after Parathyroidectomy in Patients with Primary Hyperparathyroidism?.

Journal of the American College of Surgeons, 231(1):74-82.

BACKGROUND: Some, but not all, patients with primary hyperparathyroidism (PHPT) and kidney stone disease (KSD) are cured of their nephrolithiasis after parathyroidectomy. The goal of this study was to identify risk factors for recurrent KSD despite successful parathyroidectomy in known stone formers with PHPT.

STUDY DESIGN: We conducted a single-center retrospective review of patients presenting to urology clinic with KSD between January 2008 and July 2018, who were diagnosed with concurrent PHPT, and underwent definitive parathyroidectomy. Laboratory testing for serum calcium, PTH (parathyroid hormone), phosphorus and 25-OH-vitamin D, and 24-hour urine studies for volume, pH, calcium, citrate, oxalate, uric acid, sodium, and creatinine was performed pre- and post-parathyroidectomy. Stone recurrence was determined on routine diagnostic imaging or by symptomatic KSD.

RESULTS: Mean age at parathyroidectomy was 57 ± 14 years. Pre-parathyroidectomy, mean serum calcium, 24-hour urine calcium, and PTH were 10.6 ± 0.5 mg/dL, 378 ± 209 mg/day, and 114 ± 97 pg/mL, respectively. Twenty-six of 69 patients (38%) had multigland parathyroid disease. After parathyroidectomy, serum calcium and PTH levels normalized in 69 of 69 and 62 of 69 patients, respectively. However, 37 of 69 patients (54%) had persistent hypercalciuria postoperatively, and 16 of 69 (23%) had recurrent KSD, on average, 2.0 ± 1.6 years after parathyroidectomy. Patients with recurrent KSD post-parathyroidectomy were significantly younger compared with patients without recurrent KSD (51 ± 15 vs 60 ± 13 years, p = 0.02). In a logistic regression model, younger age remains a strong predictive factor for recurrent KSD.

CONCLUSIONS: Nearly one-quarter of PHPT patients with KSD who undergo successful parathyroidectomy present with recurrent KSD despite normalization of serum calcium, and more than half exhibit persistent calciuria. These patients were younger and may require closer monitoring for stone recurrence after successful parathyroidectomy. Further studies are needed to better identify the etiology of KSD post-parathyroidectomy.

RevDate: 2021-04-07
CmpDate: 2021-04-07

Kim OH, Booth CJ, Choi HS, et al (2020)

High-phytate/low-calcium diet is a risk factor for crystal nephropathies, renal phosphate wasting, and bone loss.

eLife, 9:.

Phosphate overload contributes to mineral bone disorders that are associated with crystal nephropathies. Phytate, the major form of phosphorus in plant seeds, is known as an indigestible and of negligible nutritional value in humans. However, the mechanism and adverse effects of high-phytate intake on Ca[2+] and phosphate absorption and homeostasis are unknown. Here, we show that excessive intake of phytate along with a low-Ca[2+] diet fed to rats contributed to the development of crystal nephropathies, renal phosphate wasting, and bone loss through tubular dysfunction secondary to dysregulation of intestinal calcium and phosphate absorption. Moreover, Ca[2+] supplementation alleviated the detrimental effects of excess dietary phytate on bone and kidney through excretion of undigested Ca[2+]-phytate, which prevented a vicious cycle of intestinal phosphate overload and renal phosphate wasting while improving intestinal Ca[2+] bioavailability. Thus, we demonstrate that phytate is digestible without a high-Ca[2+] diet and is a risk factor for phosphate overloading and for the development of crystal nephropathies and bone disease.

RevDate: 2021-10-26
CmpDate: 2021-01-29

Bayomy O, Zaheer S, Williams JS, et al (2020)

Disentangling the Relationships Between the Renin-Angiotensin-Aldosterone System, Calcium Physiology, and Risk for Kidney Stones.

The Journal of clinical endocrinology and metabolism, 105(6):1937-1946.

CONTEXT: Complex relationships between aldosterone and calcium homeostasis have been proposed.

OBJECTIVE: To disentangle the influence of aldosterone and intravascular volume on calcium physiology.

DESIGN: Patient-oriented and epidemiology studies.

SETTING: Clinical research center and nationwide cohorts.

PARTICIPANTS/INTERVENTIONS: Patient-oriented study (n = 18): Participants were evaluated after completing a sodium-restricted (RES) diet to contract intravascular volume and after a liberalized-sodium (LIB) diet to expand intravascular volume. Cross-sectional studies (n = 3755): the association between 24h urinary sodium and calcium excretion and risk for kidney stones was assessed.

RESULTS: Patient-oriented study: compared to a RES-diet, a LIB-diet suppressed renin activity (LIB: 0.3 [0.1, 0.4] vs. RES: 3.1 [1.7, 5.3] ng/mL/h; P < 0.001) and plasma aldosterone (LIB: 2.0 [2.0, 2.7] vs. RES: 20.0 [16.1, 31.0] vs. ng/dL; P < 0.001), but increased calciuria (LIB: 238.4 ± 112.3 vs. RES: 112.9 ± 60.8 mg/24hr; P < 0.0001) and decreased serum calcium (LIB: 8.9 ± 0.3 vs. RES: 9.8 ± 0.4 mg/dL; P < 0.0001). Epidemiology study: mean urinary calcium excretion was higher with greater urinary sodium excretion. Compared to a urinary sodium excretion of < 120 mEq/day, a urinary sodium excretion of ≥220 mEq/day was associated with a higher risk for having kidney stones in women (risk ratio = 1.79 [95% confidence interval 1.05, 3.04]) and men (risk ratio = 2.06 [95% confidence interval 1.27, 3.32]).

CONCLUSIONS: High dietary sodium intake suppresses aldosterone, decreases serum calcium, and increases calciuria and the risk for developing kidney stones. Our findings help disentangle the influences of volume from aldosterone on calcium homeostasis and provide support for the recommendation to restrict dietary sodium for kidney stone prevention.

RevDate: 2021-07-19
CmpDate: 2021-07-19

DeLeon C, Wang HH, Gunn J, et al (2020)

A novel GPER antagonist protects against the formation of estrogen-induced cholesterol gallstones in female mice.

Journal of lipid research, 61(5):767-777.

Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in ovariectomized mice fed a lithogenic diet for 8 weeks. At 32 μg/day/kg CIMBA, no gallstones are found, even in ovariectomized ERα ([-/-]) mice treated with 6 μg/day 17β-estradiol and fed the lithogenic diet for 8 weeks. In conclusion, CIMBA treatment protects against the formation of estrogen-induced cholesterol gallstones by inhibiting the GPER signaling pathway in female mice. CIMBA may thus be a new agent for effectively treating cholesterol gallstone disease in women.

RevDate: 2021-03-22
CmpDate: 2021-03-22

Xie J, Huang JS, Huang XJ, et al (2020)

Profiling the urinary microbiome in men with calcium-based kidney stones.

BMC microbiology, 20(1):41.

BACKGROUND: The dogma that urine is sterile in healthy individuals has been overturned by recent studies applying molecular-based methods. Mounting evidences indicate that dysbiosis of the urinary microbiota is associated with several urological diseases. In this study, we aimed to investigate the urinary microbiome of male patients with calcium-based kidney stones and compare it with those of healthy individuals.

RESULTS: The diversity of the urinary microbiota in kidney stone patients was significantly lower than that of healthy controls based on the Shannon and Simpson index (P < 0.001 for both indices). The urinary microbiota structure also significantly differed between kidney stone patients and healthy controls (ANOSIM, R = 0.11, P < 0.001). Differential representation of inflammation associated bacteria (e.g., Acinetobacter) and several enriched functional pathways were identified in the urine of kidney stones patients. Meanwhile, we found the species diversity, overall composition of microbiota and predicted functional pathways were similar between bladder urine and renal pelvis urine in kidney stone patients.

CONCLUSIONS: A marked dysbiosis of urinary microbiota in male patients with calcium-based kidney stones was observed, which may be helpful to interpret the association between bacteria and calcium-based kidney stones.

RevDate: 2022-01-20
CmpDate: 2022-01-20

Schulster ML, DS Goldfarb (2020)

Vitamin D and Kidney Stones.

Urology, 139:1-7.

This review explores the relationship between vitamin D supplementation and lithogenesis. A causal relationship has been assumed despite myriad studies demonstrating that therapeutic doses of vitamin D do not increase lithogenic risk. Select stone formers may be at increased risk for recurrence with vitamin D supplementation, possibly from CYP24A1 gene mutations. Additionally, the evidence for who is vitamin D deficient, and the benefits of supplementation in those not at risk for rickets, is sparse. Concerns may be avoidable as vitamin D screening appears unnecessary in most patients, and superior pharmacology is available which increases bone density, while decreasing stone formation.

RevDate: 2021-02-11
CmpDate: 2021-02-11

Yue L, Wang L, Du Y, et al (2020)

Type 3 Inositol 1,4,5-Trisphosphate Receptor is a Crucial Regulator of Calcium Dynamics Mediated by Endoplasmic Reticulum in HEK Cells.

Cells, 9(2):.

Being the largest the Ca[2+] store in mammalian cells, endoplasmic reticulum (ER)-mediated Ca[2+] signalling often involves both Ca[2+] release via inositol 1, 4, 5-trisphosphate receptors (IP3R) and store operated Ca[2+] entries (SOCE) through Ca[2+] release activated Ca[2+] (CRAC) channels on plasma membrane (PM). IP3Rs are functionally coupled with CRAC channels and other Ca[2+] handling proteins. However, it still remains less well defined as to whether IP3Rs could regulate ER-mediated Ca[2+] signals independent of their Ca[2+] releasing ability. To address this, we generated IP3Rs triple and double knockout human embryonic kidney (HEK) cell lines (IP3Rs-TKO, IP3Rs-DKO), and systemically examined ER Ca[2+] dynamics and CRAC channel activity in these cells. The results showed that the rate of ER Ca[2+] leakage and refilling, as well as SOCE were all significantly reduced in IP3Rs-TKO cells. And these TKO effects could be rescued by over-expression of IP3R3. Further, results showed that the diminished SOCE was caused by NEDD4L-mediated ubiquitination of Orai1 protein. Together, our findings indicate that IP3R3 is one crucial player in coordinating ER-mediated Ca[2+] signalling.

RevDate: 2020-02-20
CmpDate: 2020-02-20

Spivacow FR, Pailler M, P Martínez (2019)

[Idiopathic hypercalciuria: can the diuretics be avoided?].

Medicina, 79(6):477-482.

Idiopathic hypercalciuria is defined as calcium excretion greater than 220 and 300 mg/day in women and men respectively, or greater than 4 mg/kg body weight. In women with osteoporosis it is observed in 19% of cases, while in kidney stones cases varies between 50 and 70%. We selected 206 hypercalciuric patients from our database, with and without renal lithiasis, to whom a restricted diet had been indicated. We divided them, according to the response, into a dependent diet and an independent diet. We considered 122 patients with diagnosis of hypercalciuria diet dependent (105 women and 17 men), which were followed with dietary control (800 mg of calcium, around 1 g of animal proteins and < 100 mEq sodium a day). The appearance of stones, or the recurrence of stones, was not considered, nor was bone involvement. After an average of 17 months, everyone had their calciuria controlled and there were even 16 (13%) who, after 42 months of follow-up, continued to be normocalciuric only on a diet. We conclude that the division of the hypercalciurias is fundamental, according to their response to a restricted diet, in order to avoid or postpone the use of diuretics and its adverse effects, with an adequate management of the diet.

RevDate: 2021-10-22
CmpDate: 2020-08-03

Buchalski B, Wood KD, Challa A, et al (2020)

The effects of the inactivation of Hydroxyproline dehydrogenase on urinary oxalate and glycolate excretion in mouse models of primary hyperoxaluria.

Biochimica et biophysica acta. Molecular basis of disease, 1866(3):165633.

The major clinical manifestation of the Primary Hyperoxalurias (PH) is increased production of oxalate, as a consequence of genetic mutations that lead to aberrant glyoxylate and hydroxyproline metabolism. Hyperoxaluria can lead to the formation of calcium-oxalate kidney stones, nephrocalcinosis and renal failure. Current therapeutic approaches rely on organ transplants and more recently modifying the pathway of oxalate synthesis using siRNA therapy. We have recently reported that the metabolism of trans-4-hydroxy-L-proline (Hyp), an amino acid derived predominantly from collagen metabolism, is a significant source of oxalate production in individuals with PH2 and PH3. Thus, the first enzyme in the Hyp degradation pathway, hydroxyproline dehydrogenase (HYPDH), represents a promising therapeutic target for reducing endogenous oxalate production in these individuals. This is supported by the observation that individuals with inherited mutations in HYPDH (PRODH2 gene) have no pathological consequences. The creation of mouse models that do not express HYPDH will facilitate research evaluating HYPDH as a target. We describe the phenotype of the Prodh2 knock out mouse model and show that the lack of HYPDH in PH mouse models results in lower levels of urinary oxalate excretion, consistent with our previous metabolic tracer and siRNA-based knockdown studies. The double knockout mouse, Grhpr KO (PH2 model) and Prodh2 KO, prevented calcium-oxalate crystal deposition in the kidney, when placed on a 1% Hyp diet. These observations support the use of the Grhpr KO mice to screen HYPDH inhibitors in vivo. Altogether these data support HYPDH as an attractive therapeutic target for PH2 and PH3 patients.

RevDate: 2021-02-05
CmpDate: 2020-07-17

Beara-Lasic L, DS Goldfarb (2020)

Nephrolithiasis in women: how different from men?.

Current opinion in nephrology and hypertension, 29(2):201-206.

PURPOSE OF REVIEW: Men have more kidney stones compared with women; however, the difference is progressively decreasing. The reasons for higher prevalence of stones in men, as well as increasing prevalence in women, is a subject of ongoing speculation. In this review, we summarize the evidence of differences between men and women and expand on the speculative causes.

RECENT FINDINGS: Stone incidence is rising in women and adolescent girls. Stone disease is more heritable among men than women, and women demonstrate greater influence of the unique environment. Women under the age of 50 years who have been pregnant, have more than double the odds of kidney stones compared with those who have never been pregnant. Women are more burdened with obesity, bariatric surgery and dieting, all associated with increased stones. Women have higher urinary pH because of greater absorption of dietary organic anions leading to increased urinary citrate, compared with men, and they differ in tubular calcium handling.

SUMMARY: It is obvious that the cause of stones in men and women is complex and requires further study. Potential clues offered are in the change of the female environment, influencing increasing incidence in stones, particularly of younger women and female adolescents.

RevDate: 2021-03-04
CmpDate: 2021-03-04

De Ruysscher C, Pien L, Tailly T, et al (2020)

Risk factors for recurrent urolithiasis in children.

Journal of pediatric urology, 16(1):34.e1-34.e9.

PURPOSE: To identify risk factors associated with recurrent kidney stones in a paediatric cohort in a Belgian tertiary centre.

STUDY DESIGN AND METHODS: Medical records of children with the first episode of urolithiasis between 1998 and 2016, followed at Ghent University Hospital initially and at least one-year follow-up were retrospectively reviewed. Patient characteristics, past medical history, presenting symptoms, the results of laboratory investigations and the applied management strategy were analysed. The significant variables from the univariate analysis were integrated into a backward conditional multivariate model.

RESULTS: Ninety-seven children were included in the analysis, of which 33 (34%) presented with at least one episode of stone recurrence. In the univariate analysis, body mass index (BMI) > 85th percentile and asymptomatic stones at initial presentation were associated with 1.8 and 0.1 times lower risk of recurrent stones, respectively (p = 0.020, 95% confidence interval (CI):0.368-8.749 and p = 0.017, 95% CI:0.014-0.921). In contrast, immobilization resulted in a 10-times higher risk (p = 0.002, 95% CI:1.968-50.005) and the need for technical intervention was associated with a 3.2- times higher risk (p = 0.017, 95% CI:1.297-8.084) of developing recurrent stones. On multivariate analysis only BMI >85th percentile was associated with a 15 times lower risk of stone recurrence (p = 0.030, 95% CI:0.006-0.739).

DISCUSSION: A possible explanation of reduced risk in patients with a BMI > 85th percentile may lie in a different metabolic profile. Immobilization as a risk factor can be explained by calcium metabolism, which is influenced by immobilization due to fractures, paralysis or motor disability because it causes resorption of the skeleton resulting in elevated blood calcium levels. This study showed that patients who presented without symptoms when the stones first occurred were less likely to have recurring kidney stones compared with patients with symptoms at initial presentation. When technical intervention was needed, we believe this is partly due to a larger stone burden, however we could not find an evidence-based explanation. The institutional protocol, which allowed to create a database with a limited number of patients, was lost to follow-up. Despite the retrospective setting some data were missing. There might also be a bias because the patients were followed-up at a tertiary centre. Possibly, our conclusions cannot be generalized toward the entire paediatric population.

CONCLUSION: Of all the factors investigated in our cohort, BMI >85 th percentile and asymptomatic stones are associated with a lower risk of stone recurrence. Conversely, immobilized patients and those who require technical intervention at initial presentation may benefit from an intense follow-up after the first episode of urolithiasis.

RevDate: 2021-01-10
CmpDate: 2020-11-09

Chen WC, Chou WH, Chu HW, et al (2019)

The rs1256328 (ALPL) and rs12654812 (RGS14) Polymorphisms are Associated with Susceptibility to Calcium Nephrolithiasis in a Taiwanese population.

Scientific reports, 9(1):17296.

Nephrolithiasis is a common disease affecting almost all populations, with an increasing prevalence over the past decades. Previous studies revealed several functional polymorphisms associated with the pathogenesis of nephrolithiasis. However, data on Asian populations are limited. In this study, three candidate polymorphisms were selected from previous studies to investigate the correlations with nephrolithiasis in a Taiwanese population. In total, 454 nephrolithiasis patients were recruited from Kaohsiung Medical University Hospital, with SNP frequency for 1513 subjects of general population from the Taiwan Biobank (TWB) as a genotypic reference. Results revealed that subjects with minor TT genotype at rs1256328 (alkaline phosphatase, liver/bone/kidney (ALPL)) have higher susceptibility to nephrolithiasis (odds ratio (OR) = 2.03, p = 0.0013). In addition, subjects carrying the minor AA genotype at rs12654812 (regulator of G protein signaling 14 (RGS14)) have higher susceptibility to nephrolithiasis (OR = 1.91, p = 0.0017). Among nephrolithiasis patients, subjects with GG at rs7627468 (calcium-sensing receptor (CASR)) have lower pH level in urine (p = 0.0088). Importantly, rs7627468 is associated with the expressions of IQCB1 and EAF2. rs12654812 could influence the expression of RGS14 itself, MXD3, and FGFR4. In summary, this study successfully validated the genetic roles of rs1256328 and rs12654812 in human nephrolithiasis.

RevDate: 2022-05-31
CmpDate: 2020-03-10

Howles SA, Wiberg A, Goldsworthy M, et al (2019)

Genetic variants of calcium and vitamin D metabolism in kidney stone disease.

Nature communications, 10(1):5175.

Kidney stone disease (nephrolithiasis) is a major clinical and economic health burden with a heritability of ~45-60%. We present genome-wide association studies in British and Japanese populations and a trans-ethnic meta-analysis that include 12,123 cases and 417,378 controls, and identify 20 nephrolithiasis-associated loci, seven of which are previously unreported. A CYP24A1 locus is predicted to affect vitamin D metabolism and five loci, DGKD, DGKH, WDR72, GPIC1, and BCR, are predicted to influence calcium-sensing receptor (CaSR) signaling. In a validation cohort of only nephrolithiasis patients, the CYP24A1-associated locus correlates with serum calcium concentration and a number of nephrolithiasis episodes while the DGKD-associated locus correlates with urinary calcium excretion. In vitro, DGKD knockdown impairs CaSR-signal transduction, an effect rectified with the calcimimetic cinacalcet. Our findings indicate that studies of genotype-guided precision-medicine approaches, including withholding vitamin D supplementation and targeting vitamin D activation or CaSR-signaling pathways in patients with recurrent kidney stones, are warranted.

RevDate: 2020-09-23
CmpDate: 2020-09-23

Dong D, Hao Q, Zhang P, et al (2019)

Endoplasmic reticulum Ca2+ release causes Rieske iron-sulfur protein-mediated mitochondrial ROS generation in pulmonary artery smooth muscle cells.

Bioscience reports, 39(12):.

Mitochondrial reactive oxygen species (ROS) cause Ca2+ release from the endoplasmic reticulum (ER) via ryanodine receptors (RyRs) in pulmonary artery smooth muscle cells (PASMCs), playing an essential role in hypoxic pulmonary vasoconstriction (HPV). Here we tested a novel hypothesis that hypoxia-induced RyR-mediated Ca2+ release may, in turn, promote mitochondrial ROS generation contributing to hypoxic cellular responses in PASMCs. Our data reveal that application of caffeine to elevate intracellular Ca2+ concentration ([Ca2+]i) by activating RyRs results in a significant increase in ROS production in cytosol and mitochondria of PASMCs. Norepinephrine to increase [Ca2+]i due to the opening of inositol 1,4,5-triphosphate receptors (IP3Rs) produces similar effects. Exogenous Ca2+ significantly increases mitochondrial-derived ROS generation as well. Ru360 also inhibits the hypoxic ROS production. The RyR antagonist tetracaine or RyR2 gene knockout (KO) suppresses hypoxia-induced responses as well. Inhibition of mitochondrial Ca2+ uptake with Ru360 eliminates N- and Ca2+-induced responses. RISP KD abolishes the hypoxia-induced ROS production in mitochondria of PASMCs. Rieske iron-sulfur protein (RISP) gene knockdown (KD) blocks caffeine- or NE-induced ROS production. Taken together, these findings have further demonstrated that ER Ca2+ release causes mitochondrial Ca2+ uptake and RISP-mediated ROS production; this novel local ER/mitochondrion communication-elicited, Ca2+-mediated, RISP-dependent ROS production may play a significant role in hypoxic cellular responses in PASMCs.

RevDate: 2020-03-16
CmpDate: 2020-03-16

Yang A, Guo H, Fu M, et al (2019)

Inhibitive Effects of Huashi Pill on Formation of Renal Stones by Modulating Urine Biochemical Indexes and Osteopontin in Renal Stone Rat Models.

Medical science monitor : international medical journal of experimental and clinical research, 25:8335-8344.

BACKGROUND Renal stones are the accumulated or deposited crystals that form and appear in supersaturated urine. This study aimed to the investigate the therapeutic effects of Huashi Pill on clearance of renal stones. MATERIAL AND METHODS Sprague Dawley rats were divided into normal control, positive control, low-dosage Huashi Pill, medium-dosage Huashi Pill, and high-dosage Huashi Pill groups. A renal rat model was established by using ethylene glycol, ammonium chloride, and calcium gluconate. The urinary pH, urine protein, and uric acid levels, as well as the calcium, magnesium, and phosphorus levels were examined. The blood urea nitrogen (BUN) and creatinine (Cr) levels were also evaluated. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin (TBIL) levels were evaluated. Crystal formation and calcium deposits were examined using hematoxylin and eosin (H and E) staining and von Kossa staining, respectively. Osteopontin (OPN) expression was evaluated with quantitative real-time polymerase chain reaction assay and immunohistochemical assay. RESULTS A renal stone rat model was successfully established. Huashi Pill significantly improved water and food intake and enhanced pH value of urine (P<0.05). Huashi Pill significantly improved the liver functions by decreasing ALT and TBIL levels (P<0.05). Huashi Pill regulated the amounts of microelements. Huashi Pill significantly decreased the urine protein, uric acid, and Cr levels (P<0.05). Huashi Pill inhibited formation of stone crystals and reduced the insoluble calcium deposition. Huashi Pill significantly downregulated expression of OPN in the kidney tissues of renal rat models (P<0.05). CONCLUSIONS Huashi Pill inhibited stone formation by regulating urine biochemical indexes and reducing OPN expression in kidney tissue in a renal stone rat model.

RevDate: 2020-03-09
CmpDate: 2019-10-31

Qin J, Cai Z, Xing J, et al (2019)

Association between calcitonin receptor gene polymorphisms and calcium stone urolithiasis: A meta-analysis.

International braz j urol : official journal of the Brazilian Society of Urology, 45(5):901-909.

PURPOSE: It has been reported that calcitonin receptor (CALCR) gene polymorphisms might be associated with calcium stone urolithiasis. Owing to mixed and inconclusive results, we conducted a meta-analysis to summarize and clarify this association.

MATERIALS AND METHODS: A systematic search of studies on the association between CALCR gene polymorphisms and calcium stone urolithiasis susceptibility was conducted in databases.

RESULTS: Odds ratios and 95% confi dence intervals were used to pool the effect size. Five articles were included in our meta-analysis.

CONCLUSIONS: CALCR rs1801197 might be associated with increased risk of calcium stone urolithiasis. There is insufficient data to fully confirm the association between CALCR rs1042138 and calcium stone urolithiasis susceptibility. Well-designed studies with larger sample size and more subgroups are required to validate the risk identified in the current meta-analysis.

RevDate: 2020-08-13
CmpDate: 2020-08-13

Roche EC, Redmond EJ, Yap LC, et al (2019)

Seasonal Variation in the Frequency of Presentation with Acute Ureteral Colic and Its Association with Meteorologic Factors.

Journal of endourology, 33(12):1046-1050.

Introduction: A seasonal variation in the frequency of acute stone presentations has been observed in studies from the United States, Africa, and Asia. The increased incidence of acute stone presentations during periods of warm weather has been attributed to both the dehydrating effect of elevated temperatures and the vitamin D related increase in calciuria during periods of increased sunshine. The aim of this study is to establish whether the association between various meteorologic parameters and the frequency of acute stone presentations also exists in a European climate. Methods: All computed tomography kidneys, ureters and bladder scans performed by Emergency Departments within the Dublin Midland Hospital Group between June 2017 and September 2018 were identified from the national radiologic database. The date of scan in addition to stone parameters (site, size, and side) was recorded. These data were then correlated with weather recordings obtained from the Irish meteorologic office. Results: A total of 2441 patients were investigated for suspected renal colic during the study period of which 781 were confirmed to have ureteral stones. An increased frequency of acute stone presentations was observed during the summer months of both years (June, July, and August). Unexpectedly, the heat wave of summer 2018 was not associated with an increased frequency of nephrolithiasis compared with summer 2017. Conclusion: There is an increased frequency of acute nephrolithiasis during the summer months in Ireland. Health care services should be tailored to expect an increase in service needs during these periods of increased activity.

RevDate: 2021-01-10
CmpDate: 2020-09-18

Anglani F, Gianesello L, Beara-Lasic L, et al (2019)

Dent disease: A window into calcium and phosphate transport.

Journal of cellular and molecular medicine, 23(11):7132-7142.

This review examines calcium and phosphate transport in the kidney through the lens of the rare X-linked genetic disorder Dent disease. Dent disease type 1 (DD1) is caused by mutations in the CLCN5 gene encoding ClC-5, a Cl[-] /H[+] antiporter localized to early endosomes of the proximal tubule (PT). Phenotypic features commonly include low molecular weight proteinuria (LMWP), hypercalciuria, focal global sclerosis and chronic kidney disease; calcium nephrolithiasis, nephrocalcinosis and hypophosphatemic rickets are less commonly observed. Although it is not surprising that abnormal endosomal function and recycling in the PT could result in LMWP, it is less clear how ClC-5 dysfunction disturbs calcium and phosphate metabolism. It is known that the majority of calcium and phosphate transport occurs in PT cells, and PT endocytosis is essential for calcium and phosphorus reabsorption in this nephron segment. Evidence from ClC-5 KO models suggests that ClC-5 mediates parathormone endocytosis from tubular fluid. In addition, ClC-5 dysfunction alters expression of the sodium/proton exchanger NHE3 on the PT apical surface thus altering transcellular sodium movement and hence paracellular calcium reabsorption. A potential role for NHE3 dysfunction in the DD1 phenotype has never been investigated, either in DD models or in patients with DD1, even though patients with DD1 exhibit renal sodium and potassium wasting, especially when exposed to even a low dose of thiazide diuretic. Thus, insights from the rare disease DD1 may inform possible underlying mechanisms for the phenotype of hypercalciuria and idiopathic calcium stones.

RevDate: 2020-11-04
CmpDate: 2020-11-04

van der Wijst J, van Goor MK, Schreuder MF, et al (2019)

TRPV5 in renal tubular calcium handling and its potential relevance for nephrolithiasis.

Kidney international, 96(6):1283-1291.

Nephrolithiasis or renal stone disease is an increasingly common problem, and its relatively high recurrence rate demands better treatment options. The majority of patients with nephrolithiasis have stones that contain calcium (Ca[2+]), which develop upon "supersaturation" of the urine with insoluble Ca[2+] salts; hence processes that influence the delivery and renal handling of Ca[2+] may influence stone formation. Idiopathic hypercalciuria is indeed frequently observed in patients with kidney stones that contain Ca[2+]. Genetic screens of nephrolithiasis determinants have identified an increasing number of gene candidates, most of which are involved in renal Ca[2+] handling. This review provides an outline of the current knowledge regarding genetics of nephrolithiasis and will mainly focus on the epithelial Ca[2+] channel transient receptor potential vanilloid 5 (TRPV5), an important player in Ca[2+] homeostasis. Being a member of the TRP family of ion channels, TRPV5 is currently part of a revolution in structural biology. Recent technological breakthroughs in the cryo-electron microscopy field, combined with improvements in biochemical sample preparation, have resulted in high-resolution 3-dimensional structural models of integral membrane proteins, including TRPV5. These models currently are being used to explore the proteins' structure-function relationship, elucidate the molecular mechanisms of channel regulation, and study the putative effects of disease variants. Combined with other multidisciplinary approaches, this approach may open an avenue toward better understanding of the pathophysiological mechanisms involved in hypercalciuria and stone formation, and ultimately it may facilitate prevention of stone recurrence through the development of effective drugs.

RevDate: 2020-01-10
CmpDate: 2020-01-10

Schöfl C (2019)

[Update - Calcium Metabolism].

Deutsche medizinische Wochenschrift (1946), 144(16):1125-1132.

A finely balanced control system keeps the extracellular calcium concentration within narrow limits. Disorders of calcium metabolism are often based on altered parathormone levels. Symptoms are not always clear, sometimes they are even missing: the more it is important to know possible associated diseases. The author presents basics, current diagnostics and concrete therapy options. Central hormone for the regulation of the calcium balance is the parathyroid hormone. With decreasing calcium, PTH leads to an increase in extracellular free calcium concentration in three ways. The classic symptoms of pHPT (polyuria, polydipsia, "stone, leg, and stomach pain") are rare now, as the condition is diagnosed much earlier. Treatment of choice in all symptomatic patients with pHPT is surgery. FHH and pHPT are both characterized by hypercalcaemia and increased parathyroid hormone. The differential diagnosis of urinary calcium excretion, which is usually lower in FHH but normal or elevated in pHPT, is crucial. In primary hypoparathyroidism, parathyroid failure interferes with calcium homeostasis at a central location. Consequences are hypocalcaemia, hyperphosphatemia and lack of active vitamin D. Due to increased urinary calcium excretion, patients with ADH are at high risk for kidney stones, nephrocalcinosis and the development of renal insufficiency. Recently, rhPTH 1-84 has been available for the treatment of hypoparathyroidism. However, long-term data is still lacking to provide a safe indication, considering potential effects and side effects.

RevDate: 2020-10-01
CmpDate: 2020-01-15

Bejan CA, Lee DJ, Xu Y, et al (2019)

Performance of a Natural Language Processing Method to Extract Stone Composition From the Electronic Health Record.

Urology, 132:56-62.

OBJECTIVES: To demonstrate the utility of a natural language processing (NLP) algorithm for mining kidney stone composition in a large-scale electronic health records (EHR) repository.

METHODS: We developed StoneX, a pattern-matching method for extracting kidney stone composition information from clinical notes. We trained the extraction algorithm on manually annotated text mentions of calcium oxalate monohydrate, calcium oxalate dihydrate, hydroxyapatite, brushite, uric acid, and struvite stones. We employed StoneX to identify patients with kidney stone composition data and mine >125 million notes from our institutional EHR. Analyses performed on the extracted patients included stone type conversions over time, survival analysis from a second stone surgery, and disease associations by stone composition to validate the phenotyping method against known associations.

RESULTS: The NLP algorithm identified 45,235 text mentions corresponding to 11,585 patients. Overall, the system achieved positive predictive value >90% for calcium oxalate monohydrate, calcium oxalate dihydrate, hydroxyapatite, brushite, and struvite; except for uric acid (positive predictive value = 87.5%). Survival analysis from a second stone surgery showed statistically significant differences among stone types (P = .03). Several phenotype associations were found: uric acid-type 2 diabetes (odds ratio, OR = 2.69, 95% confidence intervals, CI = 1.91-3.79), struvite-neurogenic bladder (OR = 12.27, 95% CI = 4.33-34.79), struvite-urinary tract infection (OR = 7.36, 95% CI = 3.01-17.99), hydroxyapatite-pulmonary collapse (OR = 3.67, 95% CI = 2.10-6.42), hydroxyapatite-neurogenic bladder (OR = 5.23, 95% CI = 2.05-13.36), brushite-calcium metabolism disorder (OR = 4.59, 95% CI = 2.14-9.81), and brushite-hypercalcemia (OR = 4.09, 95% CI = 1.90-8.80).

CONCLUSION: NLP extraction of kidney stone composition from large-scale EHRs is feasible with high precision, enabling high-throughput epidemiological studies of kidney stone disease. These tools will enable high fidelity kidney stone research from the EHR.

RevDate: 2020-09-09
CmpDate: 2020-09-09

Anract J, Baures M, Barry Delongchamps N, et al (2019)

Microcalcifications, calcium-sensing receptor, and cancer.

Cell calcium, 82:102051.

Calcium stones and calculi are observed in numerous human tissues. They are the result of deposition of calcium salts and are due to high local calcium concentrations. Prostatic calculi are usually classified as endogenous or extrinsic stones. Endogenous stones are commonly caused by obstruction of the prostatic ducts around an enlarged prostate resulting from benign prostatic hyperplasia or from chronic inflammation. The latter occurs mainly around the urethra and is generally caused by reflux of urine into the prostate. Calcium concentrations higher than in the plasma at sites of infection may induce the chemotactic response that eventually leads to recruitment of inflammatory cells. The calcium sensing receptor (CaSR) may be crucial for this recruitment as its expression and activity are increased by cytokines such as IL-6 and high extracellular calcium concentrations, respectively. The links between calcium calculi, inflammation, calcium supplementation, and CaSR functions in prostate cancer patients will be discussed in this review.

RevDate: 2020-01-06
CmpDate: 2020-01-06

Sun XY, Zhang H, Liu J, et al (2019)

Repair activity and crystal adhesion inhibition of polysaccharides with different molecular weights from red algae Porphyra yezoensis against oxalate-induced oxidative damage in renal epithelial cells.

Food & function, 10(7):3851-3867.

Renal epithelial cell injury is a key step in inducing kidney stone formation. However, research on the role of cell repair in the prevention and treatment of kidney stones is limited. In this study, the repair effect of degraded Porphyra yezoensis polysaccharide (PYP) on oxidative stress-mediated intracellular damage triggered by oxalate in human kidney proximal tubular epithelial (HK-2) cells was investigated, and the influence of molecular weight (Mw) on the repair ability of PYP was elucidated. Polysaccharides with different Mws were prepared by degrading PYP with hydrogen peroxide. Four degraded fractions, namely, PYP1, PYP2, PYP3, and PYP4, were successfully obtained with Mws of 576.2, 49.54, 12.65, and 4.020 kDa, respectively. A damaged cell model was established using 2.6 mmol L-1 oxalate to injure HK-2 cells. Various Mws of PYPs were used to repair the damaged cells. The repair mechanism of PYPs against oxalate-induced oxidative stress was examined by evaluating cell proliferation and physiological function recovery. Our study revealed that PYPs increased the viability of oxalate-injured HK-2 cells and restored their morphological characteristics and cytoskeleton. PYPs reduced the levels of oxalate-mediated lactase dehydrogenase release, reactive oxygen species generation, and intracellular Ca2+, the loss of mitochondrial membrane potential, the number of cells arrested in S phase, the expression of 8-hydroxy-desoxyguanosine and poly ADP ribose polymerase, lysosomal damage, and the number of apoptotic cells. The PYP fraction with low Mw presented an increased repair activity against cellular damage induced by oxalate. The resistance of the repaired renal cells to crystal adhesion and aggregation was stronger than that of the damaged cells. PYPs might inhibit the formation of kidney stones by repairing damaged cells and inhibiting crystal adhesion and aggregation. We concluded that PYP with low Mw could be used as a potential therapeutic agent against renal stone formation and recurrence.

RevDate: 2021-12-04
CmpDate: 2020-10-28

Rose E, Lee D, Xiao E, et al (2019)

Endocrine regulation of MFS2 by branchless controls phosphate excretion and stone formation in Drosophila renal tubules.

Scientific reports, 9(1):8798.

How inorganic phosphate (Pi) homeostasis is regulated in Drosophila is currently unknown. We here identify MFS2 as a key Pi transporter in fly renal (Malpighian) tubules. Consistent with its role in Pi excretion, we found that dietary Pi induces MFS2 expression. This results in the formation of Malpighian calcium-Pi stones, while RNAi-mediated knockdown of MFS2 increases blood (hemolymph) Pi and decreases formation of Malpighian tubule stones in flies cultured on high Pi medium. Conversely, microinjection of adults with the phosphaturic human hormone fibroblast growth factor 23 (FGF23) induces tubule expression of MFS2 and decreases blood Pi. This action of FGF23 is blocked by genetic ablation of MFS2. Furthermore, genetic overexpression of the fly FGF branchless (bnl) in the tubules induces expression of MFS2 and increases Malpighian tubule stones suggesting that bnl is the endogenous phosphaturic hormone in adult flies. Finally, genetic ablation of MFS2 increased fly life span, suggesting that Malpighian tubule stones are a key element whereby high Pi diet reduces fly longevity previously reported by us. In conclusion, MFS2 mediates excretion of Pi in Drosophila, which is as in higher species under the hormonal control of FGF-signaling.

RevDate: 2021-12-04
CmpDate: 2019-09-11

Imani Rad H, Peeri H, Amani M, et al (2019)

Allicin prevents the formation of Proteus-induced urinary crystals and the blockage of catheter in a bladder model in vitro.

Microbial pathogenesis, 132:293-301.

Stone formation and catheter blockage are major complications of Proteus UTIs. In this study, we investigated the ability of allicin to inhibit P. mirabilis-induced struvite crystallization and catheter blockage using a synthetic bladder model. Struvite crystallization inhibition study was carried out using P. mirabilis lysate as urease enzyme source in synthetic urine (SU). Struvite productions were monitored by phase contrast light microscopy and measurements of pH, Mg[2+] and Ca[2+] precipitation and turbidity. A catheter blockage study was performed in a synthetic bladder model mimicking natural UTI in the presence of allicin at sub-MIC concentrations (MIC = 64 μg/ml). The results of crystallization study showed that allicin inhibited pH rise and consequently turbidity and precipitation of ions in a dose-dependent manner. The results of catheter blockage study showed that allicin at sub-MIC concentrations (2, 4, 8 μg/ml) significantly increased the time for catheter blockage to occur to 61, 74 and 92 h respectively compared to allicin-free control (48 h). In a similar way, the results showed that allicin delayed the increase of SU pH level in bladder model in a dose-dependent manner compared to allicin-free control. The results also showed that following the increase of allicin concentration, Mg[2+] and Ca[2+] deposition in catheters were much lower compared to allicin-free control, further confirmed by direct observation of the catheters' eyehole and cross sections. We conclude that allicin prevents the formation of Proteus-induced urinary crystals and the blockage of catheters by delaying pH increase and lowering Mg[2+] and Ca[2+] deposition in a dose-dependent manner.

RevDate: 2021-01-09
CmpDate: 2020-06-11

Ibeh CL, Yiu AJ, Kanaras YL, et al (2019)

Evidence for a regulated Ca[2+] entry in proximal tubular cells and its implication in calcium stone formation.

Journal of cell science, 132(9):.

Calcium phosphate (CaP) crystals, which begin to form in the early segments of the loop of Henle (LOH), are known to act as precursors for calcium stone formation. The proximal tubule (PT), which is just upstream of the LOH and is a major site for Ca[2+] reabsorption, could be a regulator of such CaP crystal formation. However, PT Ca[2+] reabsorption is mostly described as being paracellular. Here, we show the existence of a regulated transcellular Ca[2+] entry pathway in luminal membrane PT cells induced by Ca[2+]-sensing receptor (CSR, also known as CASR)-mediated activation of transient receptor potential canonical 3 (TRPC3) channels. In support of this idea, we found that both CSR and TRPC3 are physically and functionally coupled at the luminal membrane of PT cells. More importantly, TRPC3-deficient mice presented with a deficiency in PT Ca[2+] entry/transport, elevated urinary [Ca[2+]], microcalcifications in LOH and urine microcrystals formations. Taken together, these data suggest that a signaling complex comprising CSR and TRPC3 exists in the PT and can mediate transcellular Ca[2+] transport, which could be critical in maintaining the PT luminal [Ca[2+]] to mitigate formation of the CaP crystals in LOH and subsequent formation of calcium stones.

RevDate: 2022-10-19
CmpDate: 2020-01-29

Curry JN, ASL Yu (2019)

Paracellular calcium transport in the proximal tubule and the formation of kidney stones.

American journal of physiology. Renal physiology, 316(5):F966-F969.

The proximal tubule (PT) is responsible for the majority of calcium reabsorption by the kidney. Most PT calcium transport appears to be passive, although the molecular facilitators have not been well established. Emerging evidence supports a major role for PT calcium transport in idiopathic hypercalciuria and the development of kidney stones. This review will cover recent developments in our understanding of PT calcium transport and the role of the PT in kidney stone formation.

RevDate: 2021-08-27
CmpDate: 2020-01-06

Cairoli E, Eller-Vainicher C, Morlacchi LC, et al (2019)

Bone involvement in young adults with cystic fibrosis awaiting lung transplantation for end-stage respiratory failure.

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 30(6):1255-1263.

UNLABELLED: Patients with cystic fibrosis awaiting lung transplantation for end-stage respiratory failure have high prevalence of reduced bone mineral density and fragility fracture. Suboptimal 25-hydroxyvitamin D levels could significantly contribute to the development of cystic fibrosis-related bone disease.

INTRODUCTION: The assessment of the prevalence of cystic fibrosis-related bone disease (CFBD) and its associated risk factors in young adults with cystic fibrosis (CF) awaiting lung transplantation for end-stage respiratory failure.

METHODS: Clinical characteristics, bone mineral density (BMD), the parameters of calcium metabolism, including vitamin D (25OHVitD) levels, and the presence of fragility fractures were evaluated in 42 CF patients (24 females, age 34.0 ± 8.4 years) consecutively referred as lung transplant candidates.

RESULTS: Mean 25OHVitD levels (54.9 ± 26.2 nmol/L) were below the reference range and hypovitaminosis D (25OHVitD < 75 nmol/L) was found in 34 patients (81%) and daily calcium intakes (median 550 mg/day) were lower than recommended. A BMD below the expected range for age (Z-score of - 2.0 or lower) and at least one prevalent fragility fracture were found in 22 patients (52.4%) and 18 patients (45.2%), respectively. The coexistence of low BMD and the presence of fracture was observed in 13 patients (31.0%). In these patients, the prevalence of nephrolithiasis was higher than in the remaining ones (p = 0.046). The presence of kidney stones was associated with a worse bone status and with severe vitamin D deficiency. In the whole sample, femoral BMD Z-scores were directly correlated with albumin-adjusted calcium (p < 0.05) and 25OHVitD levels (p < 0.01).

CONCLUSIONS: Despite the improvement of CF care, CFBD is still highly prevalent in young adults awaiting lung transplantation for end-stage CF. Suboptimal 25OHVitD levels could significantly contribute to the development of CFBD. The presence of nephrolithiasis could be an additional warning about the need for a careful evaluation of bone health in CF patients.

RevDate: 2019-05-09
CmpDate: 2019-05-09

Filippova TV, Litvinova MM, Rudenko VI, et al (2018)

[Genetic factors for monogenic forms of calcium urolithiasis].

Urologiia (Moscow, Russia : 1999).

The article presents pooled results of domestic and international studies investigating genetic aspects of urolithiasis associated with impaired calcium metabolism. The review highlights the importance of early and accurate diagnosis of hereditary diseases associated with kidney stone formation. Of more than 80 currently known monogenic forms of urolithiasis, the authors provide the list of the most significant forms. Using such molecular genetic methods as NGS (next generation sequencing) allows accurate detection of the genetic cause of the disease, develop an individual approach the patients management and timely prevention of the disease among the relatives of the proband.

RevDate: 2020-08-28
CmpDate: 2020-08-28

Gombedza F, Evans S, Shin S, et al (2019)

Melamine promotes calcium crystal formation in three-dimensional microfluidic device.

Scientific reports, 9(1):875.

Melamine, which induces proximal tubular (PT) cell damage has a greater nephrotoxic effect when combined with cyanuric and uric acids; however, it is unknown whether such effect can stimulate calcium phosphate (CaP)/calcium oxalate (CaOx) stone formation. Here, we show that melamine acts as an inducer of CaP, CaOx and CaP + CaOx (mixed) crystal formations in a time and concentration-dependent manner by stabilizing those crystals and further co-aggregating with melamine. To explore the physiological relevance of such melamine-augmented calcium crystal formation, we used 2-dimensional (2D) and 3D microfluidic (MF) device, embedded with PT cells, which also resembled the effect of melamine-stimulated CaP, CaOx and mixed crystal formation. Significantly, addition of preformed CaP and/or CaOx crystal in the presence of melamine, further potentiated those crystal formations in 3D MFs, which helped the growth and aggregation of mixed crystals. Our data show that the mechanism of such predisposition of stone formation could be largely due to co-crystallization between melamine and CaP/CaOx and pronounced effect on induction of stone-forming pathway activation in 3D MF. Taken together, melamine-induced CaP and/or CaOx crystal formation ex-vivo will help us in understanding the larger role of melamine as an environmental toxicant in producing the pathology in similar cellular microenvironments.

RevDate: 2020-09-03
CmpDate: 2020-09-03

Pozdzik A, Maalouf N, Letavernier E, et al (2019)

Meeting report of the "Symposium on kidney stones and mineral metabolism: calcium kidney stones in 2017".

Journal of nephrology, 32(5):681-698.

A symposium on kidney stones and mineral metabolism held on December 2017 in Brussels, Belgium was the first international multidisciplinary conference of the International Collaborative Network on Kidney Stones and Mineral Metabolism. This meeting addressed epidemiology, underlying pathophysiological mechanisms, genetics, pathological, as well as clinical and research topics. The participants included clinicians and recognized experts in the field from Europe and the United States interacted closely during the symposium which promoted a chance to explore new frontiers in the field of kidney stone disease. This manuscript summarizes some of the major highlights of the meeting.

RevDate: 2020-03-09
CmpDate: 2019-03-19

Oliveira B, Unwin R, SB Walsh (2019)

Inherited proximal tubular disorders and nephrolithiasis.

Urolithiasis, 47(1):35-42.

The proximal tubule is responsible for reclaiming water, phosphates and amino acids from the tubular filtrate. There are genetic defects in both phosphate and amino acid transporters leading to nephrolithiasis. This review also explores genetic defects in regulators of phosphate and calcium transport in this nephron segment that lead to stone formation.

RevDate: 2020-01-28
CmpDate: 2020-01-28

Rimer JD, Sakhaee K, NM Maalouf (2019)

Citrate therapy for calcium phosphate stones.

Current opinion in nephrology and hypertension, 28(2):130-139.

PURPOSE OF REVIEW: Calcium phosphate (CaP) stones represent an increasingly encountered form of recurrent nephrolithiasis, but current prophylactic medical regimens are suboptimal. Although hypocitraturia is a well-described risk factor for CaP stones, strategies that enhance citrate excretion have not consistently been effective at reducing CaP saturation and stone recurrence. This review summarizes the role of citrate therapy in CaP nephrolithiasis.

RECENT FINDINGS: Citrate in urine inhibits CaP stone formation through multiple mechanisms, including the formation of soluble citrate-calcium complexes, and inhibition of CaP nucleation, crystal growth and crystal aggregation. Recent in-vitro studies demonstrate that citrate delays CaP crystal growth through distinct inhibitory mechanisms that depend on supersaturation and citrate concentration. The impact of pharmacological provision of citrate on CaP saturation depends on the accompanying cation: Potassium citrate imparts a significant alkali load that enhances citraturia and reduces calciuria, but could worsen urine pH elevation. Conversely, citric acid administration results in minimal citraturia and alteration in CaP saturation.

SUMMARY: Citrate, starting at very low urinary concentrations, can significantly retard CaP crystal growth in vitro through diverse mechanisms. Clinically, the net impact on CaP stone formation of providing an alkali load during pharmacological delivery of citrate into the urinary environment remains to be determined.

RevDate: 2020-09-28

Idrees N, Tabassum B, Abd Allah EF, et al (2018)

Groundwater contamination with cadmium concentrations in some West U.P. Regions, India.

Saudi journal of biological sciences, 25(7):1365-1368.

Water is considered a vital resource because it is necessary for all aspects of human and ecosystem survival. However, due to natural processes and anthropogenic activities, various pollutants have been added to the ground water system. Among these, heavy metals are some of the most serious pollutants. Cd, a toxic heavy metal used in Ni-Cd batteries, the colouration of plastic and various discarded electronic products released into the water system causes serious health issues. The chronic exposure to Cd produces a wide variety of acute and chronic effects in humans. Cd accumulates in the human body, especially in the kidneys, resulting in kidney damage (renal tubular damage), which is a critical health effect. Other effects of Cd exposure are disturbances in calcium metabolism, hypercalciuria and the formation of kidney stones. High exposure to Cd can lead to lung cancer and prostate cancer; hence, poor quality water that may result in Cd toxicity has become a global concern. Thus, the aim of this study is to determine the concentration of Cd in underground water sources in western U.P. regions. Water samples were acidified to 1% with nitric acid and then stored in double-capped polyethylene bottles for further analysis by an atomic absorption spectrophotometer. After comparing the data to the WHO (2011) permissible limit, the study revealed that the concentration of Cd was higher than the regulatory threshold; therefore, the underground water system is seriously affected by Cd toxicity.

RevDate: 2020-02-25
CmpDate: 2019-06-07

Tavasoli S, Taheri M, Taheri F, et al (2019)

Evaluating the associations between urinary excretion of magnesium and that of other components in calcium stone-forming patients.

International urology and nephrology, 51(2):279-284.

PURPOSE: Magnesium plays numerous vital roles in human's body. It is known as a protective factor in stone formation by binding to oxalate in the intestinal and urinary system, and decreasing its absorption and crystallization, respectively. Due to controversies about the association between the 24-h urine magnesium and other urine metabolites in different studies, this study was designed to find a clear answer to this question.

METHODS: In this retrospective cross-sectional study, data from 24-h urinalysis of the calcium stone-forming (CSF) patients were assessed. The correlation between 24-h urine (24-U) magnesium to creatinine ratio (Mg/Cr) with other 24-U metabolites to creatinine ratio was assessed, using Spearman correlation test. The association between 24-U magnesium and 24-U oxalate was also studied in a multivariate logistic regression model.

RESULTS: Among 965 patients, the level of Mg/Cr showed a direct association with all other 24-U metabolite to Cr ratio (p-value < 0.001 for all analyses). The result of multivariate regression analysis showed that the higher quartile of 24-U oxalate (> 47 mg/24 h) increased the odds of 24-U magnesium more than 75 mg/24 h (data median) (OR 1.89, 95% CI 1.14-3.13) comparing with the lower quartile of 24-U oxalate (≤ 26 mg/24 h).

CONCLUSIONS: In a routine dietary habit, since rich sources of magnesium contain a high amount of oxalate at the same time, it is not surprising that magnesium level in 24-h urinalysis showed a direct association with 24-h urine oxalate.

RevDate: 2020-02-25
CmpDate: 2019-03-19

Faller N, Dhayat NA, DG Fuster (2019)

Nephrolithiasis secondary to inherited defects in the thick ascending loop of henle and connecting tubules.

Urolithiasis, 47(1):43-56.

Twin and genealogy studies suggest a strong genetic component of nephrolithiasis. Likewise, urinary traits associated with renal stone formation were found to be highly heritable, even after adjustment for demographic, anthropometric and dietary covariates. Recent high-throughput sequencing projects of phenotypically well-defined cohorts of stone formers and large genome-wide association studies led to the discovery of many new genes associated with kidney stones. The spectrum ranges from infrequent but highly penetrant variants (mutations) causing mendelian forms of nephrolithiasis (monogenic traits) to common but phenotypically mild variants associated with nephrolithiasis (polygenic traits). About two-thirds of the genes currently known to be associated with nephrolithiasis code for membrane proteins or enzymes involved in renal tubular transport. The thick ascending limb of Henle and connecting tubules are of paramount importance for renal water and electrolyte handling, urinary concentration and maintenance of acid-base homeostasis. In most instances, pathogenic variants in genes involved in thick ascending limb of Henle and connecting tubule function result in phenotypically severe disease, frequently accompanied by nephrocalcinosis with progressive CKD and to a variable degree by nephrolithiasis. The aim of this article is to review the current knowledge on kidney stone disease associated with inherited defects in the thick ascending loop of Henle and the connecting tubules. We also highlight recent advances in the field of kidney stone genetics that have implications beyond rare disease, offering new insights into the most common type of kidney stone disease, i.e., idiopathic calcium stone disease.

RevDate: 2020-02-25
CmpDate: 2019-03-19

Vezzoli G, Macrina L, Magni G, et al (2019)

Calcium-sensing receptor: evidence and hypothesis for its role in nephrolithiasis.

Urolithiasis, 47(1):23-33.

Calcium-sensing receptor (CaSR) is a plasma-membrane G protein-coupled receptor activated by extracellular calcium and expressed in kidney tubular cells. It inhibits calcium reabsorption in the ascending limb and distal convoluted tubule when stimulated by the increase of serum calcium levels; therefore, these tubular segments are enabled by CaSR to play a substantial role in the regulation of serum calcium levels. In addition, CaSR increases water and proton excretion in the collecting duct and promotes phosphate reabsorption and citrate excretion in the proximal tubule. These CaSR activities form a network in which they are integrated to protect the kidney against the negative effects of high calcium concentrations and calcium precipitates in urine. Therefore, the CaSR gene has been considered as a candidate to explain calcium nephrolithiasis. Epidemiological studies observed that calcium nephrolithiasis was associated with polymorphisms of the CaSR gene regulatory region, rs6776158, located within the promoter-1, rs1501899 located in the intron 1, and rs7652589 in the 5'-untranslated region. These polymorphisms were found to reduce the transcriptional activity of promoter-1. Activating rs1042636 polymorphism located in exon 7 was associated with calcium nephrolithiasis and hypercalciuria. Genetic polymorphisms decreasing CaSR expression could predispose individuals to stones because they may impair CaSR protective effects against precipitation of calcium phosphate and oxalate. Activating polymorphisms rs1042636 could predispose to calcium stones by increasing calcium excretion. These findings suggest that CaSR may play a complex role in lithogenesis through different pathways having different relevance under different clinical conditions.

RevDate: 2019-04-05
CmpDate: 2019-03-05

David K, Moyson C, Vanderschueren D, et al (2019)

Long-term complications in patients with chronic hypoparathyroidism: a cross-sectional study.

European journal of endocrinology, 180(1):71-78.

Objective Chronic hypoparathyroidism and its treatment may lead to symptoms and complications affecting quality of life. We determined complications in chronic hypoparathyroid patients. Design Retrospective cross-sectional study of patients with chronic hypoparathyroidism treated with active vitamin D supplements in a tertiary care centre during the year 2015. Primary outcome parameters were history of kidney stones and seizures and presence of renal and cerebral calcifications on imaging. Secondary outcome parameters were current symptoms of paraesthesia/cramps, hospitalization due to hyper/hypocalcaemia and hypercalciuria. Subjects One hundred and seventy patients were included - 143 (84%) with post-surgical hypoparathyroidism (PSHP), 16 (9%) with non-surgical hypoparathyroidism (NSHP) and 11 (7%) with pseudo-hypoparathyroidism (PHP). Results History of kidney stones and seizures was present in 15 and 9% of patients, respectively. Renal and cerebral imaging was performed in 51 and 26% of the patients, with 22 and 25% of these patients having renal and cerebral calcifications respectively. Both history of seizures and cerebral calcifications were significantly more in NSHP and PHP than in PSHP patients. No association was observed between seizures and cerebral calcifications. Cramps/paraesthesia were present in 16%, and hospitalization related to hypocalcaemia was reported in 5% of the patients. Calciuria was screened in 47% at the time of consultation, and in 76% of the patients during the past 5 years. In 36% of these patients, calciuria was increased. Conclusions Patients with chronic hypoparathyroidism frequently develop ectopic calcifications. Non-surgical patients suffer more from seizures and cerebral calcifications than patients that developed hypoparathyroidism post surgery. There is a need for increased screening of long-term complications, according to the guidelines.

RevDate: 2018-12-21
CmpDate: 2018-12-21

Raynor WY, Al-Zaghal A, Werner TJ, et al (2018)

18F-NaF PET/CT in Prostatic Calculi.

Clinical nuclear medicine, 43(12):e484-e485.

Primary prostatic calculi commonly present asymptomatically in men over the age of 50 years. Individual calculi form when the secretory tube is blocked by inflammation, prostatic secretions, or corpora amylacea. Although small prostatic calculi have been described as a component of normal aging, increased prevalence of calculi has been associated with benign prostatic hyperplasia and prostatitis. We are presenting prostatic calcification in a 69-year-old man as incidentally detected on F-NaF PET/CT. Although previous publications have reported F-NaF uptake portraying calcification in soft tissue, these findings demonstrate a new domain in which to assess calcium metabolism using F-NaF PET/CT.

RevDate: 2019-12-30
CmpDate: 2019-12-30

Tanaka H, Imasato M, Yamazaki Y, et al (2018)

Claudin-3 regulates bile canalicular paracellular barrier and cholesterol gallstone core formation in mice.

Journal of hepatology, 69(6):1308-1316.

BACKGROUND & AIMS: Most cholesterol gallstones have a core consisting of inorganic and/or organic calcium salts, although the mechanisms of core formation are poorly understood. We examined whether the paracellular permeability of ions at hepatic tight junctions is involved in the core formation of cholesterol gallstones, with particular interest in the role of phosphate ion, a common food additive and preservative.

METHODS: We focused on claudin-3 (Cldn3), a paracellular barrier-forming tight junction protein whose expression in mouse liver decreases with age. Since Cldn3-knockout mice exhibited gallstone diseases, we used them to assess the causal relationship between paracellular phosphate ion permeability and the core formation of cholesterol gallstones.

RESULTS: In the liver of Cldn3-knockout mice, the paracellular phosphate ion permeability through hepatic tight junctions was significantly increased, resulting in calcium phosphate core formation. Cholesterol overdose caused cholesterol gallstone disease in these mice.

CONCLUSION: We revealed that in the hepatobiliary system, Cldn3 functions as a paracellular barrier for phosphate ions, to help maintain biliary ion homeostasis. We provide in vivo evidence that elevated phosphate ion concentrations play a major role in the lifestyle- and age-related risks of developing cholesterol gallstone disease under cholesterol overdose.

LAY SUMMARY: Herein, we reveal a new mechanism for cholesterol gallstone formation, in which increased paracellular phosphate ion permeability across hepatobiliary epithelia causes calcium phosphate core formation and cholesterol gallstones. Thus, altered phosphate ion metabolism under cholesterol overdose plays a major role in the lifestyle- and age-related risks of developing cholesterol gallstone disease.

RevDate: 2020-08-01
CmpDate: 2020-07-28

Wang L, Holmes RP, JB Peng (2019)

Modeling the structural and dynamical changes of the epithelial calcium channel TRPV5 caused by the A563T variation based on the structure of TRPV6.

Journal of biomolecular structure & dynamics, 37(13):3506-3512.

TRPV5, transient receptor potential cation channel vanilloid subfamily member 5, is an epithelial Ca[2+] channel that plays a key role in the active Ca[2+] reabsorption process in the kidney. A single nucleotide polymorphism (SNP) rs4252499 in the TRPV5 gene results in an A563T variation in the sixth transmembrane (TM) domain of TRPV5. Our previous study indicated that this variation increases the Ca[2+] transport function of TRPV5. To understand the molecular mechanism, a model of TRPV5 was established based on the newly deposited structure of TRPV6 that has 83.1% amino acid identity with TRPV5 in the modeled region. Computational simulations were performed to study the structural and dynamical differences between the TRPV5 variants with A563 and T563. Consistent with the TRPV1-based simulation, the results indicate that the A563T variation increases the contacts between residues 563 and V540, which is one residue away from the key residue D542 in the Ca[2+]-selective filter. The variation enhanced the stability of the secondary structure of the pore region, decreased the fluctuation of residues around residue 563, and reduced correlated and anti-correlated motion between monomers. Furthermore, the variation increases the pore radius at the selective filter. These findings were confirmed using simulations based on the recently determined structure of rabbit TRPV5. The simulation results provide an explanation for the observation of enhanced Ca[2+] influx in TRPV5 caused by the A563T variation. The A563T variation is an interesting example of how a residue distant from the Ca[2+]-selective filter influences the Ca[2+] transport function of the TRPV5 channel. Communicated by Ramaswamy H. Sarma.

RevDate: 2019-06-17
CmpDate: 2019-06-17

Ali SN, Dayarathna TK, Ali AN, et al (2018)

Drosophila melanogaster as a function-based high-throughput screening model for antinephrolithiasis agents in kidney stone patients.

Disease models & mechanisms, 11(11):.

Kidney stone disease involves the aggregation of stone-forming salts consequent to solute supersaturation in urine. The development of novel therapeutic agents for this predominantly metabolic and biochemical disorder have been hampered by the lack of a practical pre-clinical model amenable to drug screening. Here, Drosophila melanogaster, an emerging model for kidney stone disease research, was adapted as a high-throughput functional drug screening platform independent of the multifactorial nature of mammalian nephrolithiasis. Through functional screening, the therapeutic potential of a novel compound commonly known as arbutin that specifically binds to oxalate, a key component of kidney calculi, was identified. Through isothermal titration calorimetry, high-performance liquid chromatography and atomic force microscopy, arbutin was determined to interact with calcium and oxalate in both free and bound states, disrupting crystal lattice structure, growth and crystallization. When used to treat patient urine samples, arbutin significantly abrogated calculus formation in vivo and outperformed potassium citrate in low pH urine conditions, owing to its oxalate-centric mode of action. The discovery of this novel antilithogenic compound via D. melanogaster, independent of a mammalian model, brings greater recognition to this platform, for which metabolic features are primary outcomes, underscoring the power of D. melanogaster as a high-throughput drug screening platform in similar disorders. This is the first description of the use of D. melanogaster as the model system for a high-throughput chemical library screen. This article has an associated First Person interview with the first authors of the paper.

RevDate: 2019-03-07
CmpDate: 2019-03-07

Dos Santos PMC, Amaral D, Tararthuch AL, et al (2018)

Calcium-sensing receptor (CaSR) modulates vacuolar H[+]-ATPase activity in a cell model of proximal tubule.

Clinical and experimental nephrology, 22(6):1258-1265.

BACKGROUND: The calcium-sensing receptor (CaSR) is localized in the apical membrane of proximal tubules in close proximity to the transporters responsible for proton secretion. Therefore, the aim of the present study was to analyze the effects of CaSR stimulation on the biochemical activity of the vacuolar H[+]-ATPase in a cellular model of proximal tubule cells, OKP cells.

METHODS: Biochemical activity of H[+]-ATPase was performed using cell homogenates, and the inorganic phosphate released was determined by a colorimetric method. Changes in cytosolic ionized calcium [Ca[2+]]i were also determined using Fluo-4.

RESULTS: A significant increase of vacuolar H[+]-ATPase activity was observed when the CaSR was stimulated with agonists such as Gd[3+] (300 µM) and neomycin (200 µM). This activity was also stimulated in a dose-dependent fashion by changes in extracellular Ca[2+] (Ca[2+]o) between 10[-4] and 2 mM. Gd[3+] and neomycin produced a sustained rise of [Ca[2+]]i, an effect that disappears when extracellular calcium was removed in the presence of 0.1 µM thapsigargin. Inhibition of phospholipase C (PLC) activity with U73122 (5 × 10[-8] M) reduced the increase in [Ca[2+]]i induced by neomycin.

CONCLUSION: CaSR stimulation induces an increase in the vacuolar H[+]-ATPase activity of OKP cells, an effect that involves an increase in [Ca[2+]]i and require phospholipase C activity. The consequent decrease in intratubular pH could lead to increase ionization of luminal calcium, potentially enhancing its reabsorption in distal tubule segments and reducing the formation of calcium phosphate stones.

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RJR Experience and Expertise

Researcher

Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.

Educator

Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.

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Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.

Technologist

Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.

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While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.

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Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.

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Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.

Designer

Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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OK, this book I have not actually read. But it seems super relevant, it is from a reputable publisher, and the table of contents looks genuinely interesting. Given that I have personally had big kidney stones removed twice (once via percutaneous nephrolithotomy, the next time via shockwave lithotripsy) and that (a) I still have some stones in one kidney and (b) I have just been shown to have hypercalciuria, I guess it is time for me to put a book like this on my must-read list. And maybe it is also time to ditch the daily dose of calcium pills... R. Robbins

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