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This goal of this study was to highlight the importance of minerals in the diet of fish for meeting micronutrient requirements in the human diet. First arsenic, calcium, cadmium, copper, iron, molybdenum, magnesium, manganese, sodium, phosphorus, potassium, selenium, and zinc concentrations of twelve commercially available tilapia samples were measured. The nutritional value of fillets in regard to their mineral content were assessed to establish potential health benefits or risks for consumers. The health benefit value of selenium was also calculated. Positive health benefit values indicate that tilapia fillets in the United States marketplace of this study do not pose health risks associated with mercury exposures. Selenium was the trace mineral of interest. After the market study, a seven-week fish feeding trial was conducted to study the influence of organic versus inorganic dietary selenium on Nile tilapia (Oreochromis niloticus). Fish were fed two different diets enriched with the same concentration (0.01g kg-1) of selenium in form of inorganic (sodium selenite) or organic (seleno-L-methionine) selenium in triplicate groups. There were no significant differences between growth and biometrics of fish fed different diets (p>0.05). At the end of trial twelve fish from each treatment were collected. Fillets of fish fed organic selenium had selenium concentrations of 0.55 ± 0.01 μg g-1 which were significantly (p<0.05) higher than fish fed inorganic selenium at levels of 0.22 ± 0.008 μg g-1 or fish samples from the marketplace with a selenium level of 0.2 ± 0.03 μg g-1. Fish fed organic selenium also had significantly higher (p<0.05) plasma and kidney selenium in comparison to fish fed inorganic selenium. No significant differences (p>0.05) were observed in glutathione peroxidase activities in either the plasma or liver of Nile tilapia in the different treatment groups. This study shows that organic selenium is a better option for production of Nile tilapia fillets rich in selenium. [ABSTRACT FROM AUTHOR]

Understanding the mechanisms of kidney stone formation, development patterns and associated pathological features are gaining importance due to an increase in the prevalence of the disease and diversity in the presentation of the stone composition. Based on the microstructural characteristics of kidney stones, it may be possible to explain the differences in the pathogenesis of pure and mixed types of stones. In this study, the microstructure and distribution of mineral components of kidney stones of different mineralogy (pure and mixed types) were analyzed. The intact stones removed from patients were investigated using synchrotron radiation X-ray computed microtomography (SR-μCT) and the tomography slice images were reconstructed representing the density and structure distribution at various elevation planes. Infrared (IR) spectroscopes, X-ray diffraction (XRD) and scanning electron microscopy (SEM) were used to confirm the bulk mineral composition in the thin section stones. Observations revealed differences in the micro-morphology of the kidney stones with similar composition in the internal 3-D structure. Calcium oxalate monohydrate stones showed well-organised layering patterns, while uric acid stones showed lower absorption signals with homogenous inner structure. Distinct mineral phases in the mixed types were identified based on the differential absorption rates. The 3-D quantitative analysis of internal porosity and spatial variation between nine different types of stones were compared. The diversity among the microstructure of similar and different types of stones shows that the stone formation is complex and may be governed by both physiological and micro-environmental factors. These factors may predispose a few towards crystal aggregation and stone growth, while, in others the crystals may not establish stable attachment and/or growth. [ABSTRACT FROM AUTHOR]

The effects of supplementation of arginine-silicate-inositol complex (ASI; 49.5–8.2–25 g/kg, respectively) to laying hens were investigated with respect to eggshell quality, calcium (Ca) balance, and expression of duodenal proteins related to Ca metabolism (calbindin and tight junction proteins). A total of 360 laying hens, 25 weeks old, were divided into 3 groups consisting of 6 replicate of cages, 20 birds per cage. The groups were fed a basal diet and the basal diet supplemented with 500 or 1000 mg ASI complex per kilogram for 90 days. Data were analyzed by ANCOVA using data during the first week of the adaptation period as covariates. As the ASI complex supplementation level increased, there were increases in feed intake (P < 0.0001), egg production (P < 0.001), egg weight (P < 0.0001) and eggshell weight (P < 0.001) weight, and shell thickness (P < 0.001) and decreases in feed conversion ratio and cracked egg percentage (P < 0.0001 for both). Concentrations of serum osteocalcin (P < 0.0001), vitamin D (P < 0.0001), calcium (P < 0.001), phosphorus (P < 0.001), and alkaline phosphatase (P < 0.008) as well as amounts of calcium retention (P < 0.0001) and eggshell calcium deposition (P < 0.001), and Ca balance (P < 0.0001) increased, whereas amount of calcium excretion (P < 0.001) decreased linearly in a dose-dependent manner. The ASI complex supplementation increased expressions of calcium transporters (calbindin-D28k, N sodium-calcium exchanger, plasma membrane calcium ATPase, and vitamin D receptor) and tight junction proteins (zonula occludens-1 and occludin) in the duodenum in a linear fashion (P < 0.0001 for all). In conclusion, provision of dietary ASI complex to laying hens during the peak laying period improved eggshell quality through improving calcium utilization as reflected by upregulation of genes related to the calcium metabolism. Further studies are needed to elucidate the contribution of each of the ASI complex ingredients. [ABSTRACT FROM AUTHOR]

Background: The role of mineral metabolism in mortality among dialysis patients has received increased attention, but some aspects remain unclear. The aim of the present study was to investigate the prognostic value of serum calcium and phosphate levels for all-cause mortality and cause-specific mortality in dialysis patients. Methods: Patients on hemodialysis and peritoneal dialysis were enrolled from a multicenter prospective cohort study in Korea (NCT00931970). The patients were divided into low, normal, and high groups according to their baseline serum calcium or phosphate levels. Cox proportional analysis and a proportional hazards model for the subdistribution of a competing risk were used to calculate hazard ratios (HRs) for the association of serum calcium and phosphate levels with all-cause and cause-specific mortality. Time-dependent values of calcium and phosphate were also evaluated to assess the effect of longitudinal change in mineral metabolism parameters on mortality types. Results: A total of 3,226 dialysis patients were followed up for a mean of 19.8 ± 8.2 months. Infection was the most common cause of death. Low serum phosphate was significantly associated with all-cause and infection-related death using time-dependent values (HR, 1.43 [95% confidence interval (CI), 1.06–1.93], P = 0.02, and HR, 1.66 [95% CI, 1.02–2.70], P = 0.04, respectively). Low serum phosphate was associated with significantly higher infection-related mortality, especially in patients older than 65 years or on dialysis more than one year or with serum albumin lower than 3.9 g/dL (HR, 2.06 [95% CI, 1.13–3.75], P = 0.02, HR, 2.19 [95% CI, 1.20–4.01], P = 0.01, and HR, 1.77 [95% CI, 1.00–3.13], P = 0.05, respectively). Multinomial logistic regression analysis results suggested that low serum albumin, creatinine, and body mass index correlated with low serum phosphate. Conclusions: Low serum phosphate in dialysis patients was an independent risk factor for infection-related death, especially in elderly patients. Persistently low serum phosphate might be a nutritional biomarker to predict increased susceptibility to infection and in turn worse outcomes in dialysis patients. [ABSTRACT FROM AUTHOR]

Introduction: Mounting evidence indicates that a disturbed Wnt–β-catenin signaling may be involved in the pathogenesis of chronic kidney disease-mineral and bone and mineral disorder (CKD-MBD). Data on the impact of CKD on circulating levels of the Wnt antagonists sclerostin and Dickkopf related protein 1 (DKK1) and the relationship with laboratory parameters of CKD-MBD are incomplete. Methods: We analyzed serum sclerostin and DKK1 in 308 patients across the stages of chronic kidney disease (kDOQI stage 1–2 n = 41; CKD stage 3 n = 54; CKD stage 4–5 n = 54; hemodialysis n = 100; peritoneal dialysis n = 59) as well as in 49 healthy controls. We investigated associations with demographics, renal function, parameters of mineral metabolism including 25(OH) vitamin D, 1,25(OH)2 vitamin D, biointact fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH), and bone turnover markers. Results: Serum sclerostin, but not DKK1, increases in more advanced stages of CKD and associates with PTH, phosphate, and 1,25(OH)2 vitamin D concentrations. Bone turnover markers are highest in hemodialysis patients presenting the combination of high PTH with low sclerostin level. Serum DKK1 levels are lower in CKD patients than in controls and are not associated with laboratory parameters of mineral metabolism. Interestingly, a direct association between DKK1 and platelet count was observed. Conclusion: In CKD, serum levels of the Wnt inhibitors DKK1 and sclerostin are unrelated, indicating different sites of origin and/ or different regulatory mechanisms. Sclerostin, as opposed to DKK1, may qualify as a biomarker of CKD-MBD, particularly in dialysis patients. DKK1 serum levels, remarkably, correlate almost uniquely with blood platelet counts. [ABSTRACT FROM AUTHOR]

To document the biochemical and pathologic features of vitamin D intoxication in lynx and to characterize mineral metabolism in healthy lynx, blood samples were obtained from 40 captive lynx that had been receiving excessive (approximately 30 times the recommended dose) vitamin D3 in the diet, and from 29 healthy free ranging lynx. Tissue samples (kidney, stomach, lung, heart and aorta) were collected from 13 captive lynx that died as a result of renal disease and from 3 controls. Vitamin D intoxication resulted in renal failure in most lynx (n = 28), and widespread extraskeletal calcification was most severe in the kidneys and less prominent in cardiovascular tissues. Blood minerals and calciotropic hormones in healthy lynx were similar to values reported in domestic cats except for calcitriol which was higher in healthy lynx. Changes in mineral metabolism after vitamin D intoxication included hypercalcemia (12.0 ± 0.3 mg/dL), hyperphosphatemia (6.3 ± 0.4 mg/dL), increased plasma calcidiol (381.5 ± 28.2 ng/mL) and decreased plasma parathyroid hormone (1.2 ± 0.7 pg/mL). Hypercalcemia and, particularly, hyperphosphatemia were of lower magnitude that what has been previously reported in the course of vitamin D intoxication in other species. However, extraskeletal calcifications were severe. The data suggest that lynx are sensitive to excessive vitamin D and extreme care should be taken when supplementing this vitamin in captive lynx diets. [ABSTRACT FROM AUTHOR]

Background: In vitro studies have shown inhibitory effects of magnesium (Mg) on phosphate-induced calcification of vascular smooth muscle cells, raising the possibility that maintaining a high Mg level may be useful for reducing cardiovascular risks of patients with hyperphosphatemia. We examined how serum Mg levels affect the association between serum phosphate levels and the risk of cardiovascular mortality in patients undergoing hemodialysis. Methods: A nationwide register-based cohort study was conducted using database of the Renal Data Registry of the Japanese Society for Dialysis Therapy in 2009. We identified 142,069 patients receiving in-center hemodialysis whose baseline serum Mg and phosphate levels were available. Study outcomes were one-year cardiovascular and all-cause mortality. Serum Mg levels were categorized into three groups (lower, <2.7 mg/dL; intermediate, ≥2.7, <3.1 mg/dL; and higher, ≥3.1 mg/dL). Results: During follow-up, 11,401 deaths occurred, out of which 4,751 (41.7%) were ascribed to cardiovascular disease. In multivariable analyses, an increase in serum phosphate levels elevated the risk of cardiovascular mortality in the lower- and intermediate-Mg groups, whereas no significant risk increment was observed in the higher-Mg group. Moreover, among patients with serum phosphate levels of ≥6.0 mg/dL, the cardiovascular mortality risk significantly decreased with increasing serum Mg levels (adjusted odds ratios [95% confidence intervals] of the lower-, intermediate-, and higher-Mg groups were 1.00 (reference), 0.81 [0.66–0.99], and 0.74 [0.56–0.97], respectively.). An interaction between Mg and phosphate on the risk of cardiovascular mortality was statistically significant (P = 0.03). Conclusion: Serum Mg levels significantly modified the mortality risk associated with hyperphosphatemia in patients undergoing hemodialysis. [ABSTRACT FROM AUTHOR]

Introduction: Activating calcium sensing receptor (CaSR) mutations cause autosomal dominant hypocalcemia (ADH) characterized by low serum calcium, inappropriately low PTH and relative hypercalciuria. Four activating CaSR mutations cause additional renal wasting of sodium, chloride and other salts, a condition called Bartter syndrome (BS) type 5. Until today there is no specific medical treatment for BS type 5 and ADH. We investigated the effects of different allosteric CaSR antagonists (calcilytics) on activating CaSR mutants. Methods: All 4 known mutations causing BS type 5 and five ADH mutations were expressed in HEK 293T cells and receptor signalling was studied by measurement of intracellular free calcium in response to extracellular calcium ([Ca2+]o). To investigate the effect of calcilytics, cells were stimulated with 3 mM [Ca2+]o in the presence or absence of NPS-2143, ATF936 or AXT914. Results: All BS type 5 and ADH mutants showed enhanced signalling activity to [Ca2+]o with left shifted dose response curves. In contrast to the amino alcohol NPS-2143, which was only partially effective, the quinazolinone calcilytics ATF936 and AXT914 significantly mitigated excessive cytosolic calcium signalling of all BS type 5 and ADH mutants studied. When these mutants were co-expressed with wild-type CaSR to approximate heterozygosity in patients, ATF936 and AXT914 were also effective on all mutants. Conclusion: The calcilytics ATF936 and AXT914 are capable of attenuating enhanced cytosolic calcium signalling activity of CaSR mutations causing BS type 5 and ADH. Quinazolinone calcilytics might therefore offer a novel treatment option for patients with activating CaSR mutations. [ABSTRACT FROM AUTHOR]

Background/Aims: The associations between phosphate, calcium, and intact parathyroid hormone (PTH) levels and composite cardiovascular end points have been studied. This study examined the associations of these markers with myocardial infarction (MI) and stroke separately. Methods: This is a longitudinal study on 65,849 hemodialysis patients from the Japan Renal Data Registry. Patients with prior events at baseline were excluded. Predictors were phosphate, albumin-corrected calcium, intact PTH, and calcium times phosphate product levels. Outcome was the first episode of MI or stroke during a 1-year observation period. Data were analyzed using multiple logistic regression analyses, adjusted for potential confounders. Results: There were 1,048, 651, and 2,089 events of incident MI, hemorrhagic, and ischemic stroke, respectively. Incident MI was associated with phosphate levels ≥6.5 mg/dL (odds ratio 1.49; confidence interval 1.23–1.80) compared with phosphate levels of 4.7–5.4 mg/dL and intact PTH levels>500 pg/mL (1.35; 1.03–1.79) compared with intact PTH levels of 151–300 pg/mL. Higher albumin-corrected calcium level was positively associated with MI (p = 0.04 by trend analysis). Hemorrhagic stroke was associated only with intact PTH levels>500 pg/mL (1.54; 1.10–2.17). Incident ischemic stroke had no association with phosphate, calcium, or intact PTH levels. The association of calcium times phosphate product with outcomes was essentially the same pattern as that of phosphate and outcomes. Conclusions: MI was associated with phosphate, calcium, and intact PTH levels, whereas hemorrhagic stroke was associated only with intact PTH. Ischemic stroke was not associated with any of them. The potential distinct beneficial effect on MI and stroke by managing bone and mineral disease should be investigated in future studies. [ABSTRACT FROM AUTHOR]

The alternative phosphate binder calcium acetate/magnesium carbonate (CaMg) effectively reduces hyperphosphatemia, the most important inducer of vascular calcification, in chronic renal failure (CRF). In this study, the effect of low dose CaMg on vascular calcification and possible effects of CaMg on bone turnover, a persistent clinical controversy, were evaluated in chronic renal failure rats. Adenine-induced CRF rats were treated daily with 185 mg/kg CaMg or vehicle for 5 weeks. The aortic calcium content and area% calcification were measured to evaluate the effect of CaMg. To study the effect of CaMg on bone remodeling, rats underwent 5/6th nephrectomy combined with either a normal phosphorus diet or a high phosphorus diet to differentiate between possible bone effects resulting from either CaMg-induced phosphate deficiency or a direct effect of Mg. Vehicle or CaMg was administered at doses of 185 and 375 mg/kg/day for 8 weeks. Bone histomorphometry was performed. Aortic calcium content was significantly reduced by 185 mg/kg/day CaMg. CaMg ameliorated features of hyperparathyroid bone disease. In CRF rats on a normal phosphorus diet, the highest CaMg dose caused an increase in osteoid area due to phosphate depletion. The high phosphorus diet combined with the highest CaMg dose prevented the phosphate depletion and thus the rise in osteoid area. CaMg had no effect on osteoblast/osteoclast or dynamic bone parameters, and did not alter bone Mg levels. CaMg at doses that reduce vascular calcification did not show any harmful effect on bone turnover. [ABSTRACT FROM AUTHOR]

Background: Due to the alarming increase in the incidence of thyroid cancer worldwide, more patients are receiving postoperative radioactive iodine (RAI) therapy and these patients are given a low-iodine diet along with levothyroxine withdrawal to induce a hypothyroid state to maximize the uptake of RAI by thyroid tissues. Recently, the reported cases of patients suffering from life-threatening severe hyponatremia following postoperative RAI therapy have increased. This study aimed to systematically assess risk factors for developing hyponatremia following RAI therapy in post-thyroidectomy patients. Methods: We reviewed the medical records of all thyroid cancer patients who underwent thyroidectomy and postoperative RAI therapy from July 2009 to February 2012. Demographic and biochemical parameters including serum sodium and thyroid function tests were assessed along with medication history. Results: A total of 2229 patients (47.0±11.0 years, female 76.3%) were enrolled in the analysis. Three hundred seven patients (13.8%) of all patients developed hyponatremia; 44 patients (2.0%) developed moderate to severe hyponatremia (serum Na+≤130 mEq/L) and another 263 (11.8%) patients showed mild hyponatremia (130 mEq/L

Increases in fibroblastic growth factor 23 (FGF23 or Fgf23) production by osteocytes result in hypophosphatemia and rickets in the Hyp mouse homologue of X-linked hypophosphatemia (XLH). Fibroblastic growth factor (FGF) signaling has been implicated in the pathogenesis of Hyp. Here, we conditionally deleted FGF receptor 1 (FGFR1 or Fgfr1) in osteocytes of Hyp mice to investigate the role of autocrine/paracrine FGFR signaling in regulating FGF23 production by osteocytes. Crossing dentin matrix protein 1 (Dmp1)-Cre;Fgfr1null/+ mice with female Hyp;Fgfr1flox/flox mice created Hyp and Fgfr1 (Fgfr1Dmp1-cKO)-null mice (Hyp;Fgfr1Dmp1-cKO) with a 70% decrease in bone Fgfr1 transcripts. Fgfr1Dmp1-cKO-null mice exhibited a 50% reduction in FGF23 expression in bone and 3-fold reduction in serum FGF23 concentrations, as well as reductions in sclerostin (Sost), phosphate regulating endopeptidase on X chromosome (PHEX or Phex), matrix extracellular phosphoglycoprotein (Mepe), and Dmp1 transcripts, but had no demonstrable alterations in phosphate or vitamin D homeostasis or skeletal morphology. Hyp mice had hypophosphatemia, reductions in 1,25(OH)2D levels, rickets/osteomalacia and elevated FGF2 expression in bone. Compared to Hyp mice, compound Hyp;Fgfr1Dmp1-cKO-null mice had significant improvement in rickets and osteomalacia in association with a decrease in serum FGF23 (3607 to 1099 pg/ml), an increase in serum phosphate (6.0 mg/dl to 9.3 mg/dl) and 1,25(OH)2D (121±23 to 192±34 pg/ml) levels, but only a 30% reduction in bone FGF23 mRNA expression. FGF23 promoter activity in osteoblasts was stimulated by FGFR1 activation and inhibited by overexpression of a dominant negative FGFR1(TK−), PLCγ and MAPK inhibitors. FGF2 also stimulated the translation of an FGF23 cDNA transfected into osteoblasts via a FGFR1 and PI3K/Akt-dependent mechanism. Thus, activation of autocrine/paracrine FGF pathways is involved in the pathogenesis of Hyp through FGFR1-dependent regulation of FGF23 by both transcriptional and post-transcriptional mechanisms. This may serve to link local bone metabolism with systemic phosphate and vitamin D homeostasis. [ABSTRACT FROM AUTHOR]

Background: Vitamin D repletion with high doses of vitamin D is often recommended to patients and healthy subjects. The safety, especially concerning changes in urinary calcium excretion is of great importance. Methods: In a double-blinded, placebo-controlled study in 40 healthy volunteers, we examined the changes in mineral metabolism during supplementation with 3000 IU of oral cholecalciferol daily during 4 months. Results: Both 25(OH)vitamin D and 1,25(OH)2vitamin D increased significantly in the active treated group as compared to the placebo group (186% versus 14% (P<0.001) and 28% versus – 8% (P<0.001)). No change was observed in urinary calcium excretion in the active group compared to the placebo group (P = 0.891). Fibroblast growth factor 23 increased significantly by 10% (P<0.018) in the active group. However, there was no difference in changes in FGF23 between treatment groups (P = 0.457). Conclusion: High dose cholecalciferol significantly increases 25(OH)vitamin D and 1,25(OH)2vitamin D levels compared to placebo. No changes in urinary calcium excretion or other measured components of the mineral metabolism were found between groups. Trial Registration: ClinicalTrials.gov NCT00952562. [ABSTRACT FROM AUTHOR]

Vascular mineralization contributes to the high cardiovascular morbidity and mortality in patients who suffer from chronic kidney disease and in individuals who have undergone solid organ transplantation. The immunosuppressive regimen used to treat these patients appears to have an impact on vascular alterations. The effect of 6-mercaptopurine (6-MP) on vascular calcification has not yet been determined. This study investigates the effect of 6-MP on vascular mineralization by the induction of trans-differentiation of rat vascular smooth muscle cells in vitro. 6-MP not only induces the expression of osteo-chondrocyte-like transcription factors and proteins but also activates alkaline phosphatase enzyme activity and produces calcium deposition in in vitro and ex vivo models. These processes are dependent on 6-MP-induced production of reactive oxygen species, intracellular activation of mitogen-activated kinases and phosphorylation of the transcription factor Cbfa1. Furthermore, the metabolic products of 6-MP, 6-thioguanine nucleotides and 6-methyl-thio-inosine monophosphate have major impacts on cellular calcification. These data provide evidence for a possible harmful effect of the immunosuppressive drug 6-MP in vascular diseases, such as arteriosclerosis. [ABSTRACT FROM AUTHOR]

Deranged calcium-phosphate metabolism contributes to the burden of morbidity and mortality in dialysis patients. This study aimed to assess the association of the phosphaturic hormone fibroblast growth factor 23 (FGF23) and soluble Klotho with all-cause mortality. We measured soluble Klotho and FGF23 levels at enrolment and two weeks later in 239 prevalent hemodialysis patients. The primary hypothesis was that low Klotho and high FGF23 are associated with increased mortality. The association between Klotho and atrial fibrillation (AF) at baseline was explored as secondary outcome. AF was defined as presence of paroxysmal, persistent or permanent AF. During a median follow-up of 924 days, 59 (25%) patients died from any cause. Lower Klotho levels were not associated with mortality in a multivariable adjusted analysis when examined either on a continuous scale (HR 1.25 per SD increase, 95% CI 0.84–1.86) or in tertiles, with tertile 1 as the reference category (HR for tertile two 0.65, 95% CI 0.26–1.64; HR for tertile three 2.18, 95% CI 0.91–2.23). Higher Klotho levels were associated with the absence of AF in a muItivariable logistic regression analysis (OR 0.66 per SD increase, 95% CI 0.41–1.00). Higher FGF23 levels were associated with mortality risk in a multivariable adjusted analysis when examined either on a continuous scale (HR 1.45 per SD increase, 95% CI 1.05–1.99) or in tertiles, with the tertile 1 as the reference category (HR for tertile two 1.63, 95% CI 0.64–4.14; HR for tertile three 3.91, 95% CI 1.28–12.20). FGF23 but not Klotho levels are associated with mortality in hemodialysis patients. Klotho may be protective against AF. [ABSTRACT FROM AUTHOR]

Lanthanum carbonate (LA) is an effective phosphate binder. Previous study showed the phosphate-binding potency of LA was twice that of calcium carbonate (CA). No study in which LA and CA were given at an equivalent phosphate-binding potency to rats or humans with chronic renal failure for a long period has been reported to date. The objective of this study was to compare the phosphate level in serum and urine and suppression of renal deterioration during long-term LA and CA treatment when they were given at an equivalent phosphate-binding potency in rats with adriamycin (ADR)-induced nephropathy. Rats were divided into three groups: an untreated group (ADR group), a CA-treated (ADR-CA) group and a LA-treated (ADR-LA) group. The daily oral dose of LA was 1.0 g/kg/day and CA was 2.0 g/kg/day for 24 weeks. The serum phosphate was lower in the ADR-CA or ADR-LA group than in the ADR group and significantly lower in the ADR-CA group than in the ADR group at each point, but there were no significant differences between the ADR and ADR-LA groups. The serum phosphate was also lower in the ADR-CA group than in the ADR-LA group, and there was significant difference at week 8. The urinary phosphate was significantly lower in the ADR-CA group than in the ADR or ADR-LA group at each point. The urinary phosphate was also lower in the ADR-LA group than in the ADR group at each point, and significant difference at week 8. There were no significant differences in the serum creatinine or blood urea nitrogen among the three groups. In conclusion, this study indicated the phosphate-binding potency of LA isn’t twice as strong as CA, and neither LA nor CA suppressed the progression of chronic renal failure in the serum creatinine and blood urea nitrogen, compared to the untreated group. [ABSTRACT FROM AUTHOR]

Context: PHEX or DMP1 mutations cause hypophosphatemic-rickets and altered energy metabolism. PHEX binds to DMP1-ASARM-motif to form a complex with α5β3 integrin that suppresses FGF23 expression. ASARM-peptides increase FGF23 by disrupting the PHEX-DMP1-Integrin complex. We used a 4.2 kDa peptide (SPR4) that binds to ASARM-peptide/motif to study the DMP1-PHEX interaction and to assess SPR4 for the treatment of energy metabolism defects in HYP and potentially other bone-mineral disorders. Design: Subcutaneously transplanted osmotic pumps were used to infuse SPR4-peptide or vehicle (VE) into wild-type mice (WT) and HYP-mice (PHEX mutation) for 4 weeks. Results: SPR4 partially corrected HYP mice hypophosphatemia and increased serum 1.25(OH)2D3. Serum FGF23 remained high and PTH was unaffected. WT-SPR4 mice developed hypophosphatemia and hypercalcemia with increased PTH, FGF23 and 1.25(OH)2D3. SPR4 increased GAPDH HYP-bone expression 60× and corrected HYP-mice hyperglycemia and hypoinsulinemia. HYP-VE serum uric-acid (UA) levels were reduced and SPR4 infusion suppressed UA levels in WT-mice but not HYP-mice. SPR4 altered leptin, adiponectin, and sympathetic-tone and increased the fat mass/weight ratio for HYP and WT mice. Expression of perlipin-2 a gene involved in obesity was reduced in HYP-VE and WT-SPR4 mice but increased in HYP-SPR4 mice. Also, increased expression of two genes that inhibit insulin-signaling, ENPP1 and ESP, occurred with HYP-VE mice. In contrast, SPR4 reduced expression of both ENPP1 and ESP in WT mice and suppressed ENPP1 in HYP mice. Increased expression of FAM20C and sclerostin occurred with HYP-VE mice. SPR4 suppressed expression of FAM20C and sclerostin in HYP and WT mice. Conclusions: ASARM peptides and motifs are physiological substrates for PHEX and modulate osteocyte PHEX-DMP1-α5β3-integrin interactions and thereby FGF23 expression. These interactions also provide a nexus that regulates bone and energy metabolism. SPR4 suppression of sclerostin and/or sequestration of ASARM-peptides improves energy metabolism and may have utility for treating familial rickets, osteoporosis, obesity and diabetes. [ABSTRACT FROM AUTHOR]

Intellectual disability and seizures are frequently associated with hypomagnesemia and have an important genetic component. However, to find the genetic origin of intellectual disability and seizures often remains challenging because of considerable genetic heterogeneity and clinical variability. In this study, we have identified new mutations in CNNM2 in five families suffering from mental retardation, seizures, and hypomagnesemia. For the first time, a recessive mode of inheritance of CNNM2 mutations was observed. Importantly, patients with recessive CNNM2 mutations suffer from brain malformations and severe intellectual disability. Additionally, three patients with moderate mental disability were shown to carry de novo heterozygous missense mutations in the CNNM2 gene. To elucidate the physiological role of CNNM2 and explain the pathomechanisms of disease, we studied CNNM2 function combining in vitro activity assays and the zebrafish knockdown model system. Using stable Mg2+ isotopes, we demonstrated that CNNM2 increases cellular Mg2+ uptake in HEK293 cells and that this process occurs through regulation of the Mg2+-permeable cation channel TRPM7. In contrast, cells expressing mutated CNNM2 proteins did not show increased Mg2+ uptake. Knockdown of cnnm2 isoforms in zebrafish resulted in disturbed brain development including neurodevelopmental impairments such as increased embryonic spontaneous contractions and weak touch-evoked escape behaviour, and reduced body Mg content, indicative of impaired renal Mg2+ absorption. These phenotypes were rescued by injection of mammalian wild-type Cnnm2 cRNA, whereas mammalian mutant Cnnm2 cRNA did not improve the zebrafish knockdown phenotypes. We therefore concluded that CNNM2 is fundamental for brain development, neurological functioning and Mg2+ homeostasis. By establishing the loss-of-function zebrafish model for CNNM2 genetic disease, we provide a unique system for testing therapeutic drugs targeting CNNM2 and for monitoring their effects on the brain and kidney phenotype. [ABSTRACT FROM AUTHOR]

Vitamin D (Vit D) deficiency is a common condition in chronic kidney disease (CKD) patients that negatively affects bone regeneration and fracture healing. Previous study has shown that timely healing of titanium implants is impaired in CKD. This study aimed to investigate the effect of Vit D supplementation on implant osseointegration in CKD mice. Uremia was induced by 5/6 nephrectomy in C57BL mice. Eight weeks after the second renal surgery, animals were given 1,25(OH)2D3 three times a week intraperitoneally for four weeks. Experimental titanium implants were inserted into the distal end of femurs two weeks later. Serum measurements confirmed decreased 1,25(OH)2D levels in CKD mice, which could be successfully corrected by Vit D injections. Moreover, the hyperparathyroidism observed in CKD mice was also corrected. X-ray examination and histological sections showed successful osseointegration in these mice. Histomorphometrical analysis revealed that the bone-implant contact (BIC) ratio and bone volume (BV/TV) around the implant were significantly increased in the Vit D-supplementation group. In addition, resistance of the implant, as measured by a push-in method, was significantly improved compared to that in the vehicle group. These results demonstrate that Vit D supplementation is an effective approach to improve the fixation of titanium implants in CKD. [ABSTRACT FROM AUTHOR]

Objective: Vitamin D and fibroblast growth factor-23 (FGF-23) are related with cardiovascular disorders. We have investigated the relationship of calcidiol (vitamin D metabolite) and FGF-23 plasma levels with the incidence of adverse outcomes in patients with coronary artery disease. Methods: Prospective follow-up study of 704 outpatients, attending the departments of Cardiology of four hospitals in Spain, 6–12 months after an acute coronary event. Baseline calcidiol, FGF-23, parathormone, and phosphate plasma levels were assessed. The outcome was the development of acute ischemic events (any acute coronary syndrome, stroke, or transient ischemic attack), heart failure, or death. Cox regression adjusted for the main confounders was performed. Results: Calcidiol levels showed a moderate-severe decrease in 57.3% of cases. Parathormone, FGF-23, and phosphate levels were increased in 30.0%, 11.5% and 0.9% of patients, respectively. Only 22.4% of patients had glomerular filtration rate<60 ml/min1.73 m2. After a mean follow-up was 2.15±0.99 years, 77 patients developed the outcome. Calcidiol (hazard ratio [HR] = 0.67; 95% confidence interval [CI] = 0.48–0.94; p = 0.021) and FGF-23 (HR = 1.13; 95% CI = 1.04–1.23; p = 0.005) plasma levels predicted independently the outcome. There was a significant interaction between calcidiol and FGF-23 levels (p = 0.025). When the population was divided according to FGF-23 levels, calcidiol still predicted the outcome independently in patients with FGF-23 levels higher than the median (HR = 0.50; 95% CI = 0.31–0.80; p = 0.003) but not in those with FGF-23 levels below this value (HR = 1.03; 95% CI = 0.62–1.71; p = 0.904). Conclusions: Abnormalities in mineral metabolism are frequent in patients with stable coronary artery disease. In this population, low calcidiol plasma levels predict an adverse prognosis in the presence of high FGF-23 levels. [ABSTRACT FROM AUTHOR]

Osteocytes express multiple genes involved in mineral metabolism including PHEX, FGF23, DMP1 and FAM20C. In Hyp mice, a murine model for X-linked hypophosphatemia (XLH), Phex deficiency results in the overproduction of FGF23 in osteocytes, which leads to hypophosphatemia and impaired vitamin D metabolism. In this study, to further clarify the abnormality in osteocytes of Hyp mice, we obtained detailed gene expression profiles in osteoblasts and osteocytes isolated from the long bones of 20-week-old Hyp mice and wild-type (WT) control mice. The expression of Fgf23, Dmp1, and Fam20c was higher in osteocytic cells than in osteoblastic cells in both genotypes, and was up-regulated in Hyp cells. Interestingly, the up-regulation of these genes in Hyp bones began before birth. On the other hand, the expression of Slc20a1 encoding the sodium/phosphate (Na+/Pi) co-transporter Pit1 was increased in osteoblasts and osteocytes from adult Hyp mice, but not in Hyp fetal bones. The direct effects of extracellular Pi and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on isolated osteoblastic and osteocytic cells were also investigated. Twenty-four-hour treatment with 10−8 M 1,25(OH)2D3 increased the expression of Fgf23 in WT osteoblastic cells but not in osteocytic cells. Dmp1 expression in osteocytic cells was increased due to the 24-hour treatment with 10 mM Pi and was suppressed by 10−8 M 1,25(OH)2D3 in WT osteocytic cells. We also found the up-regulation of the genes for FGF1, FGF2, their receptors, and Egr-1 which is a target of FGF signaling, in Hyp osteocytic cells, suggesting the activation of FGF/FGFR signaling. These results implicate the complex gene dysregulation in osteoblasts and osteocytes of Hyp mice, which might contribute to the pathogenesis. [ABSTRACT FROM AUTHOR]

Coronary artery calcification (CAC) is associated with increased mortality in patients on maintenance hemodialysis (MHD), but the pathogenesis of this condition is not well understood. We evaluated the relationship of CAC score (CACs) and variability in serum phosphorus in MHD patients. Seventy-seven adults on MHD at Huashan Hospital (Shanghai) were enrolled in July, 2010. CAC of all the patients were measured by computed tomography and CACs was calculated by the Agatston method at the entry of enrollment. Patients were divided into three categories according to their CACs (0∼10, 11∼400, and >400). Blood chemistry was recorded every 3 months from January 2008 to July 2010. Phosphorus variation was defined by the standard deviation (SD) or coefficient of variation (CV) and it was calculated from the past records. The ordinal multivariate logistic regression analysis was used to analyze the predictors of CAC. The mean patient age (± SD) was 61.7 years (±11.3) and 51% of patients were men. The mean CACs was 609.6 (±1062.9), the median CACs was 168.5, and 78% of patients had CACs more than 0. Multivariate analysis indicated that female gender (OR = 0.20, 95% CI = 0.07–0.55), age (OR = 2.31, 95% CI = 1.32–4.04), serum fibroblast growth factor 23 (OR = 2.25, 95% CI = 1.31–3.85), SD-phosphorus calculated from the most recent 6 measurements (OR = 2.12; 95% CI = 1.23–3.63), and CV-phosphorus calculated from the most recent 6 measurements (OR = 1.90, 95% CI = 1.16–3.11) were significantly and independently associated with CACs. These associations persisted for phosphorus variation calculated from past 7, 8, 9, 10, and 11 follow-up values. Variability of serum phosphorus may contribute significantly to CAC and keeping serum phosphorus stable may decrease coronary calcification and associated morbidity and mortality in MHD patients. [ABSTRACT FROM AUTHOR]

Oxalate toxicity is mediated through generation of reactive oxygen species (ROS) via a process that is partly dependent on mitochondrial dysfunction. Here, we investigated whether C-phycocyanin (CP) could protect against oxidative stress-mediated intracellular damage triggered by oxalate in MDCK cells. DCFDA, a fluorescence-based probe and hexanoyl-lysine adduct (HEL), an oxidative stress marker were used to investigate the effect of CP on oxalate-induced ROS production and membrane lipid peroxidation (LPO). The role of CP against oxalate-induced oxidative stress was studied by the evaluation of mitochondrial membrane potential by JC1 fluorescein staining, quantification of ATP synthesis and stress-induced MAP kinases (JNK/SAPK and ERK1/2). Our results revealed that oxalate-induced cells show markedly increased ROS levels and HEL protein expression that were significantly decreased following pre-treatment with CP. Further, JC1 staining showed that CP pre-treatment conferred significant protection from mitochondrial membrane permeability and increased ATP production in CP-treated cells than oxalate-alone-treated cells. In addition, CP treated cells significantly decreased the expression of phosphorylated JNK/SAPK and ERK1/2 as compared to oxalate-alone-treated cells. We concluded that CP could be used as a potential free radical-scavenging therapeutic strategy against oxidative stress-associated diseases including urolithiasis. [ABSTRACT FROM AUTHOR]

Oral phosphate loading and calcitriol stimulate Fibroblast growth factor 23 (FGF23) secretion, but the mechanisms underlying the stimulation of FGF23 remain to be studied. We compared the effect of intravenous phosphate loading with that of oral loading on FGF23 levels in normal and 5/6 nephrectomized uremic rats. Uremic rats (Nx) and sham-operated rats were fed a normal phosphate diet for 2 weeks and then divided into 3 groups: 1) with the same phosphate diet (NP), 2) with a high phosphate diet (HP), and 3) NP rats with intravenous phosphate infusion using a microinfusion pump (IV). Blood and urine were obtained 1 day (early phase) and 7 days (late phase) after the interventions. In the early and late phases, serum phosphate levels and fractional excretion of phosphate (FEP) were comparable in the HP and IV groups in both Sham and Nx rats. Serum phosphate levels in the HP and IV groups were equally and significantly higher than those in the NP group only in the late phase in Nx rats. In the early phase, FGF23 levels were comparable in the NP, HP, and IV groups, but were significantly higher in the HP and IV groups compared to the NP group in the late phase in Nx rats. 1α-hydroxylase and sodium dependent phosphate co-transporter 2a expression levels in the kidney in Nx rats were equally and significantly decreased in the HP and IV groups compared with the NP group, while 24-hydroxylase expression was equally and significantly increased. These results show that chronic intravenous phosphate loading increases bioactive FGF23, indicating that an alternative pathway for FGF23 regulation, in addition to the dietary route, may be present. This pathway is clearer under conditions produced by a kidney injury in which phosphate is easily overloaded. [ABSTRACT FROM AUTHOR]

Magnesium reduces vascular smooth muscle cell (VSMC) calcification in vitro but the mechanism has not been revealed so far. This work used only slightly increased magnesium levels and aimed at determining: a) whether inhibition of magnesium transport into the cell influences VSMC calcification, b) whether Wnt/β-catenin signaling, a key mediator of osteogenic differentiation, is modified by magnesium and c) whether magnesium can influence already established vascular calcification. Human VSMC incubated with high phosphate (3.3 mM) and moderately elevated magnesium (1.4 mM) significantly reduced VSMC calcification and expression of the osteogenic transcription factors Cbfa-1 and osterix, and up-regulated expression of the natural calcification inhibitors matrix Gla protein (MGP) and osteoprotegerin (OPG). The protective effects of magnesium on calcification and expression of osteogenic markers were no longer observed in VSMC cultured with an inhibitor of cellular magnesium transport (2-aminoethoxy-diphenylborate [2-APB]). High phosphate induced activation of Wnt/β-catenin pathway as demonstrated by the translocation of β-catenin into the nucleus, increased expression of the frizzled-3 gene, and downregulation of Dkk-1 gene, a specific antagonist of the Wnt/β-catenin signaling pathway. The addition of magnesium however inhibited phosphate-induced activation of Wnt/β-catenin signaling pathway. Furthermore, TRPM7 silencing using siRNA resulted in activation of Wnt/β-catenin signaling pathway. Additional experiments were performed to test the ability of magnesium to halt the progression of already established VSMC calcification in vitro. The delayed addition of magnesium decreased calcium content, down-regulated Cbfa-1 and osterix and up-regulated MGP and OPG, when compared with a control group. This effect was not observed when 2-APB was added. In conclusion, magnesium transport through the cell membrane is important to inhibit VSMC calcification in vitro. Inhibition of Wnt/β-catenin by magnesium is one potential intracellular mechanism by which this anti-calcifying effect is achieved. [ABSTRACT FROM AUTHOR]

Renal fibrosis plays an important role in the onset and progression of chronic kidney diseases (CKD). Although several mechanisms underlying renal fibrosis and candidate drugs for its treatment have been identified, the effect of iron chelator on renal fibrosis remains unclear. In the present study, we examined the effect of an iron chelator, deferoxamine (DFO), on renal fibrosis in mice with surgically induced unilateral ureter obstruction (UUO). Mice were divided into 4 groups: UUO with vehicle, UUO with DFO, sham with vehicle, and sham with DFO. One week after surgery, augmented renal tubulointerstitial fibrosis and the expression of collagen I, III, and IV increased in mice with UUO; these changes were suppressed by DFO treatment. Similarly, UUO-induced macrophage infiltration of renal interstitial tubules was reduced in UUO mice treated with DFO. UUO-induced expression of inflammatory cytokines and extracellular matrix proteins was abrogated by DFO treatment. DFO inhibited the activation of the transforming growth factor-β1 (TGF-β1)-Smad3 pathway in UUO mice. UUO-induced NADPH oxidase activity and p22phox expression were attenuated by DFO. In the kidneys of UUO mice, divalent metal transporter 1, ferroportin, and ferritin expression was higher and transferrin receptor expression was lower than in sham-operated mice. Increased renal iron content was observed in UUO mice, which was reduced by DFO treatment. These results suggest that iron reduction by DFO prevents renal tubulointerstitial fibrosis by regulating TGF-β-Smad signaling, oxidative stress, and inflammatory responses. [ABSTRACT FROM AUTHOR]

Background: Transforming growth factor-β (TGF-β) is a key cytokine during differentiation of mesenchymal stem cells (MSC) into vascular smooth muscle cells (VSMC). High phosphate induces a phenotypic transformation of vascular smooth muscle cells (VSMC) into osteogenic-like cells. This study was aimed to evaluate signaling pathways involved during VSMC differentiation of MSC in presence or not of high phosphate. Results: Our results showed that TGF-β induced nuclear translocation of Smad3 as well as the expression of vascular smooth muscle markers, such as smooth muscle alpha actin, SM22α, myocardin, and smooth muscle-myosin heavy chain. The addition of high phosphate to MSC promoted nuclear translocation of Smad1/5/8 and the activation of canonical Wnt/β-catenin in addition to an increase in BMP-2 expression, calcium deposition and alkaline phosphatase activity. The administration of TGF-β to MSC treated with high phosphate abolished all these effects by inhibiting canonical Wnt, BMP and TGF-β pathways. A similar outcome was observed in high phosphate-treated cells after the inhibition of canonical Wnt signaling with Dkk-1. Conversely, addition of both Wnt/β-catenin activators CHIR98014 and lithium chloride enhanced the effect of high phosphate on BMP-2, calcium deposition and alkaline phosphatase activity. Conclusions: Full VSMC differentiation induced by TGF-β may not be achieved when extracellular phosphate levels are high. Moreover, TGF-β prevents high phosphate-induced osteogenesis by decreasing the nuclear translocation of Smad 1/5/8 and avoiding the activation of Wnt/β-catenin pathway. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti-inflammatory drugs (NSAIDs) can produce adverse effects by inhibiting prostaglandin (PG) synthesis. A PGE1 analogue, misoprostol, is often utilized to alleviate NSAID-related gastrointestinal side effects. This study examined the effect of misoprostol on celecoxib renal toxicity. Additionally, the effects of these drugs on cardiovascular parameters were evaluated. Four randomized rat groups were orally gavaged for 9 days, two groups receiving vehicle and two groups receiving misoprostol (100 µg/kg) twice daily. Celecoxib (40 mg/kg) was co-administered once daily to one vehicle and one misoprostol group from days 3 to 9. Urine and blood samples were collected and blood pressure parameters were measured during the study period. Hearts and kidneys were harvested on final day. Day 2 urinary electrolyte samples revealed significant reductions in sodium excretion in misoprostol (0.12±0.05 µmol/min/100 g) and misoprostol+celecoxib groups (0.07±0.02 µmol/min/100 g). At day 3, all treatment groups showed significantly reduced sodium excretion. Potassium excretion diminished significantly in vehicle+celecoxib and misoprostol+celecoxib groups from day 3 onward. Urinary kidney injury molecule-1 levels were significantly increased in vehicle+celecoxib (0.65±0.02 vs. 0.35±0.07 ng/mL, p = 0.0002) and misoprostol+celecoxib (0.61±0.06 vs. 0.37±0.06 ng/mL, p = 0.0015) groups when compared to baseline; while plasma levels of cardiac troponin I increased significantly in vehicle+celecoxib (p = 0.0040) and misoprostol+misoprostol (p = 0.0078) groups when compared to vehicle+vehicle. Blood pressure parameters increased significantly in all misoprostol treated groups. Significant elevation in diastolic (p = 0.0071) and mean blood pressure (p = 0.0153) was noted in misoprostol+celecoxib compared to vehicle+celecoxib. All treatments produced significant tubular dilatation/necrosis compared to control. No significant myocardial changes were noticed; however, three animals presented with pericarditis. Kidney, heart, and plasma celecoxib levels revealed no significant change between vehicle+celecoxib and misoprostol+celecoxib. Concomitant misoprostol administration did not prevent celecoxib renal toxicity, and instead exacerbated renal side effects. Misoprostol did not alter plasma or tissue celecoxib concentrations suggesting no pharmacokinetic interaction between celecoxib and misoprostol. [ABSTRACT FROM AUTHOR]

Background: Observational data associate lower levels of serum vitamin D with coronary artery calcification, cardiovascular events and mortality. However, there is little interventional evidence demonstrating that moderate vitamin D deficiency plays a causative role in cardiovascular disease. This study examined the cardiovascular effects of dietary vitamin D deficiency and of vitamin D receptor agonist (paricalcitol) administration in apolipoprotein E knockout mice. Methods: Mice were fed atherogenic diets with normal vitamin D content (1.5IU/kg) or without vitamin D. Paricalcitol, or matched vehicle, was administered 3× weekly by intraperitoneal injection. Following 20 weeks of these interventions cardiovascular phenotype was characterized by histological assessment of aortic sinus atheroma, soluble markers, blood pressure and echocardiography. To place the cardiovascular assessments in the context of intervention effects on bone, structural changes at the tibia were assessed by microtomography. Results: Vitamin D deficient diet induced significant reductions in plasma vitamin D (p<0.001), trabecular bone volume (p<0.01) and bone mineral density (p<0.005). These changes were accompanied by an increase in calcification density (number of calcifications per mm2) of von Kossa-stained aortic sinus atheroma (461 versus 200, p<0.01). Paricalcitol administration suppressed parathyroid hormone (p<0.001), elevated plasma calcium phosphate product (p<0.005) and induced an increase in calcification density (472 versus 200, p<0.005) similar to that seen with vitamin D deficiency. Atheroma burden, blood pressure, metabolic profile and measures of left ventricular hypertrophy were unaffected by the interventions. Conclusion: Vitamin D deficiency, as well as excess, increases atherosclerotic calcification. This phenotype is induced before other measures of cardiovascular pathology associated clinically with vitamin D deficiency. Thus, maintenance of an optimal range of vitamin D signalling may be important for prevention of atherosclerotic calcification. [ABSTRACT FROM AUTHOR]

Background and Hypothesis: Even within accepted normal ranges, higher serum phosphorus, dietary phosphorus density, parathyroid hormone (PTH) and alkaline phosphatase (ALP) are independent predictors of cardiovascular mortality. Lower serum 25-hydroxy vitamin D (25(OH)D) also predicts adverse cardiovascular outcomes. We hypothesized that vascular dysfunction accompanying subtle disturbances of these bone metabolism parameters would result in associations with increased low grade albuminuria. Study Population and Measures: We examined participants in the National Health and Nutrition Examination Surveys 1999–2010 (N = 19,383) with estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m2 and without severe albuminuria (urine albumin:creatinine ratio (ACR) <300 mg/g). Albuminuria was quantified as ACR and fractional albumin excretion (FEalb). Results: Increasing quintiles of dietary phosphorus density, serum phosphorus and ALP were not associated with higher ACR or FEalb. The lowest versus highest quintile of 25(OH)D was associated with greater albuminuria, but not after adjustment for other covariates including cardiovascular risk factors. An association between the highest versus lowest quintile of bone-specific ALP and greater ACR persisted after covariate adjustment, but was not accompanied by an independent association with FEalb. Increasing quintiles of PTH demonstrated associations with both higher ACR and FEalb that were not abolished by adjusting for covariates including age, gender, race, body mass index, diabetes, blood pressure, history of cardiovascular disease, smoking, eGFR, 25(OH)D, season of measurement, lipids, hemoglobin and C-reactive protein. Adjusted increases in ACR and FEalb associated with the highest versus lowest quintile of PTH were 19% (95% confidence interval 7–28% p<0.001) and 17% (8–31% p = 0.001) respectively. Conclusion: In this population, of the bone mineral parameters associated with cardiovascular outcomes, only PTH is independently associated with ACR and FEalb. [ABSTRACT FROM AUTHOR]

: Chronic kidney disease (CKD) patients are at risk for developing new-onset diabetes mellitus (NODM) even after hemodialysis (HD) and peritoneal dialysis (PD) treatment. It is not clear if the incidence for NODM is different in CKD patients receiving HD and PD. This study compared the risk of NODM in PD patients and HD patients. Methods: All HD and PD patients in Taiwan Renal Registry Database from 1997 to 2005 were included and all patients were followed to December 31, 2008. The risk of NODM was analyzed in PD patients and propensity score matched HD patients using logistic regression for early type NODM (< = 6 months after dialysis) and Cox regression for late type NODM (>6 months after dialysis). Results: A total of 2548 PD patients and 10192 HD patients who had no diabetes on the initiation of dialysis were analyzed. The incidence for NODM was 3.7 per 100 patient/year for HD and 2.4 for PD patients. HD patients are more at risk for developing early type NODM (p<0.001) with an adjusted odds ratio of 1.41 [95% confidence interval (CI) 1.12–1.78)]. HD patients are more at risk for late type NODM (p<0.001) with an adjusted hazard ratio of 2.01 (95% CI: 1.77–2.29). Patient’s age was negatively associated with risk of early type of NODM (p<0.001) but positively associated with risk of late type NODM (p<0.001). Conclusions: Chronic kidney disease patients receiving hemodialysis are more at risk for developing new-onset diabetes mellitus compared to those receiving peritoneal dialysis. [ABSTRACT FROM AUTHOR]

Various bioactive peptides have been implicated in the homeostasis of organs and tissues. Adrenomedullin (AM) is a peptide with various bioactivities. AM-receptor, calcitonin-receptor-like receptor (CLR) associates with one of the subtypes of the accessory proteins, RAMPs. Among the RAMP subisoforms, only RAMP2 knockout mice (−/−) reproduce the phenotype of embryonic lethality of AM−/−, illustrating the importance of the AM-RAMP2-signaling system. Although AM and RAMP2 are abundantly expressed in kidney, their function there remains largely unknown. We used genetically modified mice to assess the pathophysiological functions of the AM-RAMP2 system. RAMP2+/− mice and their wild-type littermates were used in a streptozotocin (STZ)-induced renal injury model. The effect of STZ on glomeruli did not differ between the 2 types of mice. On the other hand, damage to the proximal urinary tubules was greater in RAMP2+/−. Tubular injury in RAMP2+/− was resistant to correction of blood glucose by insulin administration. We examined the effect of STZ on human renal proximal tubule epithelial cells (RPTECs), which express glucose transporter 2 (GLUT2), the glucose transporter that specifically takes up STZ. STZ activated the endoplasmic reticulum (ER) stress sensor protein kinase RNA-like endoplasmic reticulum kinase (PERK). AM suppressed PERK activation, its downstream signaling, and CCAAT/enhancer-binding homologous protein (CHOP)-induced cell death. We confirmed that the tubular damage was caused by ER stress-induced cell death using tunicamycin (TUN), which directly evokes ER stress. In RAMP2+/− kidneys, TUN caused severe injury with enhanced ER stress. In wild-type mice, TUN-induced tubular damage was reversed by AM administration. On the other hand, in RAMP2+/−, the rescue effect of exogenous AM was lost. These results indicate that the AM-RAMP2 system suppresses ER stress-induced tubule cell death, thereby exerting a protective effect on kidney. The AM-RAMP2 system thus has the potential to serve as a therapeutic target in kidney disease. [ABSTRACT FROM AUTHOR]

Renal α-Klotho (α-KL) plays a fundamental role as a co-receptor for fibroblast growth factor 23 (FGF23), a phosphaturic hormone and regulator of 1,25(OH)2 vitamin D3 (1,25VitD3). Disruption of FGF23-α-KL signaling is thought to be an early hallmark of chronic kidney disease (CKD) involving reduced renal α-KL expression and a reciprocal rise in serum FGF23. It remains unclear, however, whether the rise in FGF23 is related to the loss of renal α-KL. We evaluated α-KL expression in renal biopsy samples and measured levels of several parameters of mineral metabolism, as well as soluble α-KL (sKL), in serum and urinary samples from CKD patients (n = 236). We found that although renal α-KL levels were significantly reduced and serum FGF23 levels were significantly elevated in early and intermediate CKD, serum phosphate levels remained within the normal range. Multiple regression analysis showed that the increases in FGF23 were significantly associated with reduced renal function and elevated serum phosphate, but were not associated with loss of renal α-KL. Moreover, despite falling renal α-KL levels, the increase in FGF23 enhanced urinary fractional excretion of phosphate and reduced serum 1,25VitD3 levels in early and intermediate CKD, though not in advanced CKD. Serum sKL levels also fell significantly over the course of CKD, and renal α-KL was a significant independent determinant of sKL. These results demonstrate that FGF23 levels rise to compensate for renal failure-related phosphate retention in early and intermediate CKD. This enables FGF23-α-KL signaling and a neutral phosphate balance to be maintained despite the reduction in α-KL. In advanced CKD, however, renal α-KL declines further. This disrupts FGF23 signaling, and serum phosphate levels significantly increase, stimulating greater FGF23 secretion. Our results also suggest the serum sKL concentration may be a useful marker of renal α-KL expression levels. [ABSTRACT FROM AUTHOR]

Introduction: This study investigated the learning curve of a single-session retrograde intrarenal surgery (RIRS) in patients with mid-sized stones. Competence and trainee proficiency for RIRS was assessed using cumulative sum analysis (CUSUM). Materials and Methods: The study design and the use of patients' information stored in the hospital database were approved by the Institutional Review Board of our institution. A retrospective review was performed for 100 patients who underwent a single-session RIRS. Patients were included if the main stone had a maximal diameter between 10 and 30 mm. The presence of a residual stone was checked on postoperative day 1 and at one-month follow-up visit. Fragmentation efficacy was calculated “removed stone volume (mm3) divided by operative time (min)”. CUSUM analysis was used for monitoring change in fragmentation efficacy, and we tested whether or not acceptable surgical outcomes were achieved. Results: The mean age was 54.7±14.8 years. Serum creatinine level did not change significantly. Estimated GFR and hemoglobin were within normal limits postoperatively. The CUSUM curve tended to be flat until the 25th case and showed a rising pattern but declined again until the 56th case. After that point, the fragmentation efficacy reached a plateau. The acceptable level of fragmentation efficacy was 25 ml/min. Multivariate logistic regression analyses showed that stone-free rate was significantly lower for cases with multiple stones than those with a single stone (OR = 0.147, CI 0.032 – 0.674, P value  = 0.005) and for cases with higher number of sites (OR = 0.676, CI 0.517 – 0.882, P value  = 0.004). Conclusions: The statistical analysis of RIRS learning experience revealed that 56 cases were required for reaching a plateau in the learning curve. The number of stones and the number of sites were significant predictors for stone-free status. [ABSTRACT FROM AUTHOR]

The mitochondrial enzyme 25-hydroxyvitamin D 1α-hydroxylase, which is encoded by the CYP27B1 gene, converts 25OHD to the biological active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D). Renal 1α-hydroxylase activity is the principal determinant of the circulating 1,25(OH)2D concentration and enzyme activity is tightly regulated by several factors. Fibroblast growth factor-23 (FGF-23) decreases serum 1,25(OH)2D concentrations by suppressing CYP27B1 mRNA abundance in mice. In extra-renal tissues, 1α-hydroxylase is responsible for local 1,25(OH)2D synthesis, which has important paracrine actions, but whether FGF-23 regulates CYP27B1 gene expression in extra-renal tissues is unknown. We sought to determine whether FGF-23 regulates CYP27B1 transcription in the kidney and whether extra-renal tissues are target sites for FGF-23-induced suppression of CYP27B1. In HEK293 cells transfected with the human CYP27B1 promoter, FGF-23 suppressed promoter activity by 70%, and the suppressive effect was blocked by CI-1040, a specific inhibitor of extracellular signal regulated kinase 1/2. To examine CYP27B1 transcriptional activity in vivo, we crossed fgf-23 null mice with mice bearing the CYP27B1 promoter-driven luciferase transgene (1α-Luc). In the kidney of FGF-23 null/1α-Luc mice, CYP27B1 promoter activity was increased by 3-fold compared to that in wild-type/1α-Luc mice. Intraperitoneal injection of FGF-23 suppressed renal CYP27B1 promoter activity and protein expression by 26% and 60% respectively, and the suppressive effect was blocked by PD0325901, an ERK1/2 inhibitor. These findings provide evidence that FGF-23 suppresses CYP27B1 transcription in the kidney. Furthermore, we demonstrate that in FGF-23 null/1α-Luc mice, CYP27B1 promoter activity and mRNA abundance are increased in several extra-renal sites. In the heart of FGF-23 null/1α-Luc mice, CYP27B1 promoter activity and mRNA were 2- and 5-fold higher, respectively, than in control mice. We also observed a 3- to 10-fold increase in CYP27B1 mRNA abundance in the lung, spleen, aorta and testis of FGF-23 null/1α-Luc mice. Thus, we have identified novel extra-renal target sites for FGF-23-mediated regulation of CYP27B1. [ABSTRACT FROM AUTHOR]

p-Cresol is a by-product of the metabolism of aromatic aminoacid operated by resident intestinal bacteria. In patients with chronic kidney disease, the accumulation of p-cresol and of its metabolite p-cresyl-sulphate causes endothelial dysfunction and ultimately increases the cardiovascular risk of these patients. Therapeutic strategies to reduce plasma p-cresol levels are highly demanded but not available yet. Because it has been reported that the phosphate binder sevelamer sequesters p-cresol in vitro we hypothesized that it could do so also in peritoneal dialysis patients. To explore this hypothesis we measured total cresol plasma concentrations in 57 patients with end-stage renal disease on peritoneal dialysis, 29 receiving sevelamer for the treatment of hyperphosphatemia and 28 patients not assuming this drug. Among the patients not assuming sevelamer, 16 were treated with lanthanum whereas the remaining 12 received no drug because they were not hyperphosphatemic. Patients receiving sevelamer had plasma p-cresol and serum high sensitivity C-reactive protein concentrations significantly lower than those receiving lanthanum or no drug. Conversely, no difference was observed among the different groups either in residual glomerular filtration rate, total weekly dialysis dose, total clearance, urine volume, protein catabolic rate, serum albumin or serum phosphate levels. Multiple linear regression analysis showed that none of these variables predicted plasma p-cresol concentrations that, instead, negatively correlated with the use of sevelamer. These results suggest that sevelamer could be an effective strategy to lower p-cresol circulating levels in peritoneal dialysis patients in which it could also favorably affect cardiovascular risk because of its anti-inflammatory effect. [ABSTRACT FROM AUTHOR]

Background: Peritoneal calcification (PC) is a specific finding in patients undergoing peritoneal dialysis (PD), but its prevalence, risk factors, and impacts in PD patients remain unclear. The present study investigated these issues and provided information useful for the management of PC. Methods: The study included 183 PD patients. The severity of PC was determined using abdominal computed tomography (CT), and we summed up all scores from slices obtained from the diaphragm to the pelvic floor normalized to body surface area. We analyzed the associations between PC and demographic and clinical characteristics, and between PC and levels of biomarkers, including C-reactive protein (CRP), osteoprotegrin and fetuin-A. The determinants of PC were examined using multiple regression analysis. Results: Patients were categorized into group 1 (without PC, n = 133) and group 2 (with PC, n = 50). Group 2 patients showed different degrees of PC with a mean of 160±769 mm2/m2. Group 1 patients had higher fetuin-A levels than group 2 patients (861±309 vs. 760±210 µg/mL; p = 0.021). The independent risk factors for the presence of PC included male gender, previous peritonitis, and PD adequacy (KT/V). Further analysis performed in group 2 patients showed that the dosage of vitamin D, serum levels of CRP, and dialysate calcium load were the independent determinants of PC. However, the presence of PC did not affect patients’ technique survival, peritonitis incidence, or mortality in the mean follow up period of 28±12 months. Conclusions: The presence and severity of PC were associated with inflammation, peritoneal KT/V, and mineral metabolism. The impact of PC on the outcomes of PD patients requires further study with a longer follow-up. [ABSTRACT FROM AUTHOR]

Objective: The 7S domain of collagen type IV (P4NP_7S) assessed in plasma represents systemic collagen type IV formation. The objective of the study was to investigate the association of systemic collagen type IV formation with survival among patients undergoing hemodialysis. Methods: We performed an observational cohort study of 371 hemodialysis patients. Plasma P4NP_7S was analyzed using a specific enzyme-linked immunosorbent assay detecting the amino-terminal propeptide of type IV procollagen. Association between categories of plasma P4NP_7S concentrations and survival was initially assessed by Kaplan-Meier analysis, then in an adjusted Cox model. Results: For hemodialysis patients in the highest category of systemic collagen type IV formation, i.e. plasma P4NP_7S concentrations more than 775 pg/L, an increased risk for death was observed (highest P4NP_7S category vs all other categories, hazard ratio, 1.934; 95% confidence interval, 1.139 to 3.285). Survival analysis showed an increased risk of death in the highest P4NP_7S category compared to the other categories (Chi square 6.903; P = 0.032). Median survival was only 105 days in the highest P4NP_7S category whereas it was 629 days in the medium category, and 905 days in the lowest category. Multivariable-adjusted Cox regression showed increased odds for death with higher age and higher P4NP_7S categories. Systemic collagen type IV formation was associated with plasma concentrations of the collagen IV degradation product C4M (Spearman r = 0.764; P<0.0001) confirming extracellular matrix turnover. Conclusion: Among hemodialysis patients elevated systemic collagen type IV formation suggesting accelerating systemic fibrosis was associated with increased risk of death. [ABSTRACT FROM AUTHOR]

To investigate potential differences in stone composition with regard to the type of Primary Hyperoxaluria (PH), and in relation to the patient’s medical therapy (treatment naïve patients versus those on preventive medication) we examined twelve kidney stones from ten PH I and six stones from four PH III patients. Unfortunately, no PH II stones were available for analysis. The study on this set of stones indicates a more diverse composition of PH stones than previously reported and a potential dynamic response of morphology and composition of calculi to treatment with crystallization inhibitors (citrate, magnesium) in PH I. Stones formed by PH I patients under treatment are more compact and consist predominantly of calcium-oxalate monohydrate (COM, whewellite), while calcium-oxalate dihydrate (COD, weddellite) is only rarely present. In contrast, the single stone available from a treatment naïve PH I patient as well as stones from PH III patients prior to and under treatment with alkali citrate contained a wide size range of aggregated COD crystals. No significant effects of the treatment were noted in PH III stones. In disagreement with findings from previous studies, stones from patients with primary hyperoxaluria did not exclusively consist of COM. Progressive replacement of COD by small COM crystals could be caused by prolonged stone growth and residence times in the urinary tract, eventually resulting in complete replacement of calcium-oxalate dihydrate by the monohydrate form. The noted difference to the naïve PH I stone may reflect a reduced growth rate in response to treatment. This pilot study highlights the importance of detailed stone diagnostics and could be of therapeutic relevance in calcium-oxalates urolithiasis, provided that the effects of treatment can be reproduced in subsequent larger studies. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the impact of dietary calcium (Ca) and phosphorus (P), derived from bone meal, on the feline urine composition and the urinary pH, allowing a risk assessment for the formation of calcium oxalate (CaOx) uroliths in cats. Eight healthy adult cats received 3 canned diets, containing 12.2 (A), 18.5 (B) and 27.0 g Ca/kg dry matter (C) and 16.1 (A), 17.6 (B) and 21.1 g P/kg dry matter (C). Each diet was fed over 17 days. After a 7 dayś adaptation period, urine and faeces were collected over 2×4 days (with a two-day rest between), and blood samples were taken. Urinary and faecal minerals, urinary oxalate (Ox), the urinary pH and the concentrations of serum Ca, phosphate and parathyroid hormone (PTH) were analyzed. Moreover, the urine was microscopically examined for CaOx uroliths. The results demonstrated that increasing levels of dietary Ca led to decreased serum PTH and Ca and increased faecal Ca and P concentrations, but did not affect the urinary Ca or Ox concentrations or the urinary fasting pH. The urinary postprandial pH slightly increased when the diet C was compared to the diet B. No CaOx crystals were detected in the urine of the cats. In conclusion, urinary Ca excretion in cats seems to be widely independent of the dietary Ca levels when Ca is added as bone meal to a typical canned diet, implicating that raw materials with higher contents of bones are of subordinate importance as risk factors for the formation of urinary CaOx crystals. [ABSTRACT FROM AUTHOR]

Background and objectives: Secondary hyperparathyroidism (SHPT) in CKD is associated with an increased risk for mortality, but definitive data showing that parathormone control decreases mortality is still lacking. This study aimed to compare the mortality of patients with severe SHPT submitted to parathyroidectomy(PTX) with those who did not have access to surgery. Methods: This is a retrospective study in a cohort of 251 CKD patients with severe SHPT who were referred to a CKD-MBD Center for PTX from 2005 until 2012. Results: Most of our patients had indication of PTX, but only 49% of them had access to this surgical procedure. After a mean follow-up of 23 months, 72 patients had died. Non-survivors were older; more often had diabetes, lower serum 25 vitamin D and mostly had not been submitted to surgery. The relative risk of death was lower in the PTX patients (0.428; 95% CI, 0.28 to 0.67; p<0.0001). After adjustments, mortality risk was dependent on age (1.04; 95% CI, 1.01 to 1.07; p = 0.002), 25 vitamin D (0.43; 95% CI, 0.24 to 0.81; p = 0.006) and no access to PTX (4.13; 95% CI, 2.16 to 7.88; p<0.0001). Results remained the same in a second model using the PTX date as the study start date for the PTX group. Conclusions: Our data confirms the benefit of PTX on mortality in patients with severe SHPT. The high mortality encountered in our population is significant and urges the need to better treat these patients. [ABSTRACT FROM AUTHOR]

Background: In the same period as the increasing obesity epidemic, there has been an increased consumption of highly processed foods with a high salt content, and a few studies have suggested that a diet with a high salt content may be associated with obesity. Objective: To investigate the association between 24 h urinary sodium excretion and subsequent change in body weight (BW), waist circumference (WC), body fat (BF) and fat free mass (FFM) among adults. Design: A longitudinal population study based on the Danish part of the MONICA project, with examinations in 1987–1988 and 1993–1994. Complete information on 24 h urinary sodium excretion along with repeated measures of obesity, as well as on potential confounders, was obtained from 215 subjects. Linear regression was used to examine the association between sodium excretion, as a measure of salt consumption, and subsequent changes in BW, WC, BF and FFM, and further evaluated by restricted cubic splines. Stepwise adjustments were made for selected covariates. Results: Neither the crude nor the adjusted models showed any statistically significant associations between sodium excretion and change in BW or WC. Likewise, we found no significant association between sodium excretion and change in BF and FFM in the unadjusted models. However, after adjusting for potential baseline confounders and the concurrent BW change, we found a significant increase in BF of 0.24 kg (P = 0.015, CI: 0.05 to 0.43) per 100 mmol increase in 24 h urinary sodium excretion (equivalent to 6 g of salt), during the 6-year study period. Moreover, during the same period, we found a significant association with FFM of −0.21 kg (P = 0.041, CI: −0.40 to −0.01). Conclusions: These results suggest that a diet with a high salt content may have a negative influence on development in body composition by expanding BF and reducing FFM. [ABSTRACT FROM AUTHOR]

Peritonitis is a major complication of peritoneal dialysis (PD) being associated with hospitalization, catheter loss, technique failure, and increased mortality. Data on incidence rates and risk factors for peritonitis episodes vary between centers. In seven Austrian PD units clinical and laboratory data on each peritonitis episode were collected from all patients (n = 726) who performed PD between January 2000 and December 2009. The peritonitis incidence rate was 0.32 episodes/patient-year. In a multivariate analysis the risk of peritonitis was decreased by 57% in patients treated with oral active vitamin D (HR 0.43; 95% CI 0.28–0.64). Renal disease classified as “other or unknown” (HR 1.65; 95% CI 1.08–2.53) and serum albumin <3500 mg/dl (HR 1.49; 95% CI 1.04–2.15) were also associated with an increased risk of peritonitis. Albumin levels <3500 mg/dl (HR 1.89; 95% CI 1.13–3.17), age (HR 1.06 per year; 95% CI 1.03–1.09), and cardiomyopathy (HR 3.01; 95% CI 1.62–5.59) were associated with increased mortality, whereas treatment with oral active vitamin D was associated with a significantly lower risk of death (HR 0.46; 95% CI 0.27–0.81). In this retrospective multi-center study we identified several factors being related to increased risk of peritonitis in PD patients. Treatment with oral active vitamin D was identified as being independently associated with decreased risk of peritonitis, and decreased all-cause mortality in PD patients. [ABSTRACT FROM AUTHOR]

High plasma fibroblast growth factor-23 (FGF23) concentration predicts the risk of death and poor outcomes in patients with chronic kidney disease or chronic heart failure. We checked if FGF23 concentration could be modified in patients with end stage liver disease (ESLD) and predict mortality. We measured plasma FGF23 in 200 patients with ESLD registered on a liver transplant waiting list between January 2005 and October 2008. We found that median plasma FGF23 concentration was above normal values in 63% of the patients. Increased FGF23 concentration was not explained by its classical determinants: hyperphosphataemia, increased calcitriol concentration or decreased renal function. FGF23 concentration correlated with the MELD score, serum sodium concentration, and GFR. Forty-six patients died before being transplanted and 135 underwent liver transplantation. We analyzed the prognostic value of FGF23 levels. Mortality was significantly associated with FGF23 levels, the MELD score, serum sodium concentration and glomerular filtration rate. On multivariate analyses only FGF23 concentration was associated with mortality. FGF23 levels were independent of the cause of the liver disease. To determine if the damaged liver can produce FGF23 we measured plasma FGF23 concentration and liver FGF23 mRNA expression in control and diethyl-nitrosamine (DEN)-treated mice. FGF23 plasma levels increased with the apparition of liver lesions in DEN-treated mice and that FGF23 mRNA expression, which was undetectable in the liver of control mice, markedly increased with the development of liver lesions. The correlation between FGF23 plasma concentration and FGF23 mRNA expression in DEN-treated mice suggests that FGF23 production by the liver accounts for the increased plasma FGF23 concentration. In conclusion chronic liver lesions can induce expression of FGF23 mRNA leading to increased FGF23 concentration, which is associated with a higher mortality in patients on a liver-transplant waiting list. In these patients FGF23 concentration was the best predictor of mortality. [ABSTRACT FROM AUTHOR]

Pseudohypoaldosteronism type 1 (PHA1) is a rare inherited disease characterized by resistance to the actions of aldosterone. Mutations in the subunit genes (SCNN1A, SCNN1B, SCNN1G) of the epithelial sodium channel (ENaC) and the NR3C2 gene encoding the mineralocorticoid receptor, result in systemic PHA1 and renal PHA1 respectively. Common clinical manifestations of PHA1 include salt wasting, hyperkalaemia, metabolic acidosis and elevated plasma aldosterone levels in the neonatal period. In this study, we describe the clinical and biochemical manifestations in two Chinese patients with systemic PHA1. Sequence analysis of the SCNN1A gene revealed a compound heterozygous mutation (c.1311delG and c.1439+1G>C) in one patient and a homozygous mutation (c.814_815insG) in another patient, all three variants are novel. Further analysis of the splicing pattern in a minigene construct showed that the c.1439+1G>C mutation can lead to the retainment of intron 9 as the 5′-donor splice site disappears during post-transcriptional processing of mRNA. In conclusion, our study identified three novel SCNN1A gene mutations in two Chinese patients with systemic PHA1. [ABSTRACT FROM AUTHOR]

Purpose: To retrospectively assess the clinical utility in ureteroscopy (URS) planning of cumulative stone diameter (CSD), which does not account for stone width or depth, as a predictor of URS outcome and compare it with stone volume. Materials and Methods: Patients with renal stones treated at a single institute by flexible URS were retrospectively evaluated. To assess the clinical utility of CSD, relationships between stone-free (SF) status and stone burden (CSD and volume) were analyzed using the area under the receiver operating characteristics (AUROC) curve. To identify stone number impact on CSD, the AUROC of CSD divided by stone number was evaluated. Correlation coefficients of CSD and stone volume were also calculated for groups by stone number. Results: In cases with CSD <20.0 mm, CSD and stone volume revealed equal ability to predict SF status. In cases with CSD ≥20.0 mm, stone volume showed higher predictive ability. The ROC curves for cases with ≥4 stones showed that CSD was less predictive of SF status than stone volume. The correlation coefficients of CSD and stone volume by stone number were 0.922 for 1 stone, 0.900 for 2–3 stones, and 0.661 for ≥4 stones. Conclusions: In cases with CSD ≥20.0 mm or ≥4 stones, we should evaluate stone volume for a more predictive stone burden, and pretreatment non-contrast CT seems sufficient. In cases with CSD <20.0 mm or 1–3 stones, CSD was as valid a predictor of preoperative stone burden as stone volume, so preoperative kidney-ureter-bladder (KUB) films may be sufficient. [ABSTRACT FROM AUTHOR]

Patients with CKD have abnormal vascular remodeling that is a risk factor for cardiovascular disease. MicroRNAs (miRNAs) control mRNA expression intracellularly and are secreted into the circulation; three miRNAs (miR-125b, miR-145 and miR-155) are known to alter vascular smooth muscle cell (VSMC) proliferation and differentiation. We measured these vascular miRNAs in blood from 90 patients with CKD and found decreased circulating levels with progressive loss of eGFR by multivariate analyses. Expression of these vascular miRNAs miR-125b, miR-145, and miR-155 was decreased in the thoracic aorta in CKD rats compared to normal rats, with concordant changes in target genes of RUNX2, angiotensin II type I receptor (AT1R), and myocardin. Furthermore, the expression of miR-155 was negatively correlated with the quantity of calcification in the aorta, a process known to be preceded by vascular de-differentiation in these animals. We then examined the mechanisms of miRNA regulation in primary VSMC and found decreased expression of miR-125b, 145, and 155 in VSMC from rats with CKD compared to normal littermates but no alteration in DROSHA or DICER, indicating that the low levels of expression is not due to altered intracellular processing. Finally, overexpression of miR-155 in VSMC from CKD rats inhibited AT1R expression and decreased cellular proliferation supporting a direct effect of miR-155 on VSMC. In conclusion, we have found ex vivo and in vitro evidence for decreased expression of these vascular miRNA in CKD, suggesting that alterations in miRNAs may lead to the synthetic state of VSMC found in CKD. The decreased levels in the circulation may reflect decreased vascular release but more studies are needed to confirm this relationship. [ABSTRACT FROM AUTHOR]

Background: The role of the Model for End-Stage Liver Disease (MELD) score in predicting complications, such as Acute Kidney Injury (AKI), after orthotopic liver transplantation (OLT) has yet to be evaluated and serum creatinine may be too heavily weighted in the existing MELD formula, since it has many pitfalls in cirrhotic patients. Methods: Retrospective data of the perioperative period from consecutive adult OLTs performed from January to December 2009 were recorded. Univariate and multivariate analysis were performed to analyze the risk factors for AKI and mortality after OLT. Results: There were 114 OLTs performed in the study period, 22 (19,2%) were submitted to dialysis prior OLT and were excluded from the analysis for AKI. The median age was 52 years and 66% were male. Median creatinine value was 0.85mg/dL and MELD was 19. Fifty-two of the 92 patients (56,5%) developed AKI in the first 72 hours after OLT. The only independent risk factor for AKI was calculated MELD and when the components of the MELD score were analyzed, INR had a much stronger impact in predicting AKI then serum creatinine. Overall mortality rate was 32,5% and anesthesia duration was the only variable associated with higher mortality rate. Conclusions: Although MELD score seems to have a good performance in predicting AKI after OLT, serum creatinine had no impact on its prediction despite its importance on MELD calculation. Modifying the MELD score, which could include novel AKI biomarkers, may improve its prognostic accuracy and provide a better tool for public health planning. [ABSTRACT FROM AUTHOR]

Background: Hyperuricemia is now regarded as a risk factor for cardiovascular disease. Micro-albuminuria is associated with increased risk for cardiovascular disease and chronic kidney disease. We hypothesized that elevated serum uric acid (UA) is associated with development of micro-albuminuria in the general population. Methodology/Principal Findings: We conducted a community-based prospective cohort study. A total of 1862 subjects from southern Taiwan, all older than 40 years, were screened and 993 of these participants without micro-albuminuria were followed for 4 years. Urinary albumin-to-creatinine ratio was measured two times per year. A multiple linear regression model indicated that serum UA was independently associated with ln(ACR) after adjustment for 8 factors (age, sex, and 6 metabolic metrics) (β = 0.194, p<0.01). Logistic regression analysis indicated that each 1 mg/dL increase of UA was associated with a 1.42-fold increased risk of micro-albuminuria after adjustment for the same 8 factors (OR = 1.42, 95% CI: 1.27–1.59, p<0.01). A Cox regression model using subjects with serum UA less than 5 mg/dL as reference group indicated higher hazard ratios (HRs) only found in subjects with serum UA more than 7 mg/dL (HR = 3.54, 95% CI: 2.11–5.93, p<0.01) and not in subjects with serum UA of 5 to 7 mg/dL (HR = 1.30, 95% CI: 0.82–2.07, p = 0.15). Conclusion: Hyperuricemia is significantly associated with micro-albuminuria in middle-aged and elderly males and females from a general population in Taiwan. Elevated serum UA is an independent predictor for development of micro-albuminuria in this population. [ABSTRACT FROM AUTHOR]

The formation of fetuin-A-containing calciprotein particles (CPP) may facilitate the clearance of calcium phosphate nanocrystals from the extracellular fluid. These crystals may otherwise seed extra-osseous mineralization. Fetuin-A is a partially phosphorylated glycoprotein that plays a critical role in stabilizing these particles, inhibiting crystal growth and aggregation. CPP removal is thought to be predominantly mediated by cells of the reticuloendothelial system via type I and type II class A scavenger receptor (SR-AI/II). Naked calcium phosphate crystals are known to stimulate macrophages and other cell types in vitro, but little is known of the effect of CPP on these cells. We report here, for the first time, that CPP induce expression and secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-1β in murine RAW 264.7 macrophages. Importantly, however, CPP induced significantly lower cytokine secretion than hydroxyapatite (HAP) crystals of equivalent size and calcium content. Furthermore, CPP only had a modest effect on macrophage viability and apoptosis, even at very high levels, compared to HAP crystals, which were strongly pro-apoptotic at much lower levels. Fetuin-A phosphorylation was found to modulate the effect of CPP on cytokine secretion and apoptosis, but not uptake via SR-AI/II. Prolonged exposure of macrophages to CPP was found to result in up-regulated expression of SR-AI/II. CPP formation may help protect against some of the pro-inflammatory and harmful effects of calcium phosphate nanocrystals, perhaps representing a natural defense system for calcium mineral stress. However, in pathological states where production exceeds clearance capacity, these particles may still stimulate pro-inflammatory and pro-apoptotic cascades in macrophages, which may be important in the pathogenesis of vascular calcification. [ABSTRACT FROM AUTHOR]