Hyperbaric Oxygen Preconditioning Upregulates Heme OxyGenase-1 and Anti-Apoptotic Bcl-2 Protein Expression in Spontaneously Hypertensive Rats with Induced Postischemic Acute Kidney Injury.

Renal ischemia and reperfusion (I/R) injury is the most common cause of acute kidney injury (AKI). Pathogenesis of postischemic AKI involves hemodynamic changes, oxidative stress, inflammation process, calcium ion overloading, apoptosis and necrosis. Up to date, therapeutic approaches to treat AKI are extremely limited. Thus, the aim of this study was to evaluate the effects of hyperbaric oxygen (HBO) preconditioning on citoprotective enzyme, heme oxygenase-1 (HO-1), pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins expression, in postischemic AKI induced in normotensive Wistar and spontaneously hypertensive rats (SHR). The animals were randomly divided into six experimental groups: SHAM-operated Wistar rats (W-SHAM), Wistar rats with induced postischemic AKI (W-AKI) and Wistar group with HBO preconditioning before AKI induction (W-AKI + HBO). On the other hand, SHR rats were also divided into same three groups: SHR-SHAM, SHR-AKI and SHR-AKI + HBO. We demonstrated that HBO preconditioning upregulated HO-1 and anti-apoptotic Bcl-2 protein expression, in both Wistar and SH rats. In addition, HBO preconditioning improved glomerular filtration rate, supporting by significant increase in creatinine, urea and phosphate clearances in both rat strains. Considering our results, we can also say that even in hypertensive conditions, we can expect protective effects of HBO preconditioning in experimental model of AKI.

Persistent urinary phosphate wasting in a patient with metastatic breast cancer: What's your diagnosis?

Tumor-induced osteomalacia (TIO) can cause severe, persistent hypo-phosphatemia due to high fibroblast growth factor-23 (FGF-23) levels, which lead to uri-nary phosphate wasting. TIO is frequently encountered in association with mesenchy-mal tumors and responds well to resection of the primary malignancy. Rarely, TIO may be seen as a paraneoplastic phenomenon with solid organ malignancies where correction of biochemical abnormalities requires ongoing phosphorus replacement. We report a case of TIO in a patient with metastatic breast cancer complicated by increased parathyroid hormone release secondary to denosumab-induced hypocalcemia. The patient required intensive intravenous and oral phosphate supplementation in addition to vitamin D repletion. A high index of clinical suspicion can yield the correct diagnosis where TIO arises in the setting of a solid organ tumor and help the clinician appropriately manage these challenging cases.

Hypophosphatemic Hypovitaminosis D Induces Osteomalacia in the Adult Female Rat.

Osteomalacia is a bone-demineralizing disease of adulthood, often caused by hypovitaminosis D. Current animal models of the disease mimic osteomalacia as a consequence of gastric bypass or toxic exposure to metals, but a relevant model of diet-induced osteomalacia is lacking. For that purpose, 7-month-old female Sprague Dawley rats were randomly assigned into 2 weight-stratified groups and maintained for 4 months on synthetic diets containing negligible or normal levels of vitamin D. The dietary regimen resulted in vitamin D deficiency as measured by 25-hydroxyvitamin D serum levels; however, hypovitaminosis D per se did not affect biomarkers of calcium metabolism and bone turnover, nor did it result in increased osteoid. Thus, vitamin D depletion through the diet was found to be insufficient to induce an osteomalacia-like phenotype in the adult rat. After 4 months, the phosphate content of the vitamin D-depleted diet had decreased to 0.16% (calcium:phosphorus ratio of 5.85), resulting in an osteomalacic-like condition (trabecular osteoid surface/bone surface constituted 33%; CI, 26-40). The diet change also affected both metabolic and bone turnover biomarkers, including significantly suppressing serum fibroblast growth factor 23. Furthermore, decreased dietary phosphate in a vitamin D-depleted diet led to microarchitectural changes of trabecular and cortical bone, lower bone mass density, lower bone mass content and decreased bone strength, all indicating reduced bone quality. Taken together, our results show that osteomalacia can be induced in the adult female rat by depleting vitamin D and lowering phosphate content in the diet.

Differential Determinants of Tubular Phosphate Reabsorption: Insights on Renal Excretion of Phosphates in Kidney Disease.

We assessed the tubular reabsorption of phosphate (TRP) and maximal renal threshold for phosphate reabsorption to glomerular filtration rate (TmPi/GFR) and their determinants in 64 stages 2-4 chronic kidney disease (CKD) patients in order to define the early changes in phosphate metabolism in CKD. In multivariable analysis, TmPi/GFR correlates were estimated GFR (eGFR), intact parathyroid hormone (iPTH), and hemoglobin (R2 = 0.417), while TRP correlates were eGFR, iPTH, 24-h phosphaturia, and calcitriol (R2 = 0.72). This suggests that TmPi/GFR and TRP, respectively, assess hemoglobin-phosphate and bowel-kidney phosphate regulation axis. Iron supplementation based on TmPi/GFR or earlier phosphate restriction based on TRP should be investigated in view of modifying clinical outcomes in CKD.

[Infrequent and incremental dialysis: differences and definitions].

The purpose of this review is to give dignity at the Incremental Dialysis, which cannot be confused with the term and the therapeutic choice defined as Infrequent Dialysis. The Infrequent Dialysis is defined by each and every hemodialytic therapeutic choice like rhythms below thrice-weekly-hemodialytic treatments. Nonetheless, Infrequent Dialysis is a choice of replacement hemodialysis therapy with pays more special clinical attentions and nutritional monitoring and should also be accompanied by a slightly hypoproteic controlled nutrition. When talking about the Incremental Dialysis (CDDP) it is defined as a well-defined therapeutic program that requires a significant clinical attention. The CDDP begins with the pre-dialysis outpatient clinic in the short period of time when the patient passes, after a severe nutrition compliance assessment with a VFG of 5-10 mL / min / 1.73mq, from the conservative treatment to an hypoproteic diet composed of 0.6g/ Kg / day with or without essential amino acids and hyposaline diet supplemented by One-Weekly Dialysis. The Incremental Dialysis program is strictly tailored on the trend of Residual Renal Function (FRR). CDDP is a time variable therapeutic "bridge" that must provide a good metabolic status and a good quality of life of the treated patients. Recent studies have shown a lower mortality compared with thrice-weekly-dialysis and a neutral input/output balance of phosphorus pool due to the phosphaturia contribution compared to the thrice-weekly-patients who lose early their FRR. Further studies are needed to confirm the safety and validity of this therapeutic choice.

Does green tea consumption increase urinary oxalate excretion? Results of a prospective trial in healthy men.

OBJECTIVE: To investigate the impact of green tea on urinary oxalate excretion in healthy male volunteers. MATERIALS AND METHODS: The oxalate concentrations after different brewing times (2-60 min) of different qualities (2-8 g) of green tea were measured in in vitro experiment. In in vivo experiment, the effects on urine composition were assessed in 12 healthy men with an age of 24-29 years. Each subject was requested to collect two 24-h urine samples under normal dietary conditions. Green tea prepared from tea bags containing 2 g of tea leafs was consumed by the subjects for 7 consecutive days, and 24-h urine samples were collected and analyzed on days 6 and 7. After 3-week washout interval, all subjects consumed green tea containing 4 g of leaf tea for another 7 consecutive days. Two 24-h urine samples were collected on the last 2 days. Urine volume, pH, calcium, magnesium, sodium, phosphate, potassium, chloride, citrate, oxalate, urate and creatinine were measured. RESULTS: In the in vitro experiments, oxalate in solution increased with brewing time (p < 0.05) and tea quality (p < 0.05). In the in vivo experiment, 24-h urinary oxalate increased significantly (0.24 ± 0.09 mmol to 0.32 ± 0.13 mmol, p = 0.045) when tea was prepared from 2-g bags of green leaf tea. Consumption of green tea containing 4 g of leaf tea resulted in 24-h urinary oxalate increase (0.25 ± 0.25 mmol to 0.34 ± 0.22 mmol, p = 0.041). CONCLUSIONS: In vitro studies showed that there was a gradual increase in solution concentrations of oxalate that was associated with increased brewing time and increased quality of green tea. Studies in normal men showed that green tea consumption was associated with increased urinary exertion of oxalate.

Antiurolithic effect of olive oil in a mouse model of ethylene glycol-induced urolithiasis.

PURPOSE: At present, commercially available antiurolithic drugs have more adverse effects than potential therapeutic or preventive effects with chronic use. With this in mind, the present study was designed to assess the antiurolithic effect of olive oil in a mouse model of ethylene glycol (EG)-induced urolithiasis. MATERIALS AND METHODS: Adult albino mice were divided into 6 groups. Group I was fed the vehicle only. Group II was supplemented with 0.75% EG alone in drinking water during the experimental period to initiate deposition of calcium oxalate in kidneys, which leads to urolithiasis in animals. Groups III (olive oil control group) through V were fed olive oil orally at various doses during the experimental period. Group VI received cystone (750 mg/kg). Groups IV-VI additionally received 0.75% EG in drinking water ad libitum. SPSS ver.17.0 was used for statistical analysis. RESULTS: The study results showed significantly higher levels of serum urea, uric acid, and creatinine (p<0.05) in group II than in groups III-VI and I. Administration of olive oil at different doses restored the elevated serum parameters in groups IV and V compared with group II. Urine and kidney calcium, oxalate, and phosphate levels in groups IV-VI were significantly lower (p<0.05) than in animals with EG-induced urolithiasis (group II). Group V mice showed a significant restoration effect on serum as well as urine and kidney parameters compared with group II. CONCLUSIONS: Supplementation with olive oil (1.7 mL/kg body weight) reduced and prevented the growth of urinary stones, possibly by inhibiting renal tubular membrane damage due to peroxidative stress induced by hyperoxaluria.

Vitamin D deficiency is prevalent among idiopathic stone formers, but does correction pose any risk?

While vitamin D (vitD) deficiency is thought to contribute to poor health in a variety of ways and should be corrected, there is still concern about giving vitD supplements to patients with a history of nephrolithiasis. The aim is to study the prevalence of vitD deficiency and the effect on stone risk of cholecalciferol (vitD3) supplementation in a cohort of idiopathic stone formers (ISF). We screened for vitD deficiency and urinary measures of stone risk, comparing vitD deficient (serum 25-OH vitD ≤30 nmol/L; ≤12 ng/mL) with vitD insufficient (31-75 nmol/L; 13-30 ng/mL) or vitD replete (>75 nmol/L; >30 ng/mL); we investigated the effect of giving vitD3 (20,000 IU orally, weekly for 4 months) to 37 of the vitD deficients. Thirty-one percent (142/456) were vitD deficient, 57% (259/456) vitD insufficient, and the rest (12%) vitD replete (55/456). Comparison among the groups showed that baseline 24-h urinary measures related to stone risk expressed as concentration ratios over urine creatinine (Cr), such as U. Calcium/Cr, U. Oxalate/Cr, U. Citrate/Cr, and U. Uric acid/Cr were not significantly different. VitD3 supplementation did significantly increase serum 25-OH vitD levels and U. Phosphate/Cr ratios, as well as reduce serum parathyroid hormone (PTH) concentrations. Following vitD3 supplementation, there was an overall rise in 24-h urine calcium excretion, but it failed to reach statistical significance (p = 0.06). U. Calcium/Cr increased in 22 out of 37 patients (average increase +0.07 mmol/mmol), decreased in 14 (average decrease -0.13 mmol/mmol), and remained unchanged in 1; 6 out of 26 initially normocalciuric ISF developed hypercalciuria; and 6 out of 9 patients who became vitD replete were hypercalciuric after supplementation. It is appropriate to monitor urinary Ca excretion in vitD-supplemented stone formers, because it may reveal underlying hypercalciuria in some treated patients.

CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders.

CYP24A1 (hereafter referred to as CYP24) enzymatic activity is pivotal in the inactivation of vitamin D metabolites. Basal renal and extrarenal CYP24 is usually low but is highly induced by its substrate 1,25-dihydroxyvitamin D. Unbalanced high and/or long-lasting CYP24 expression has been proposed to underlie diseases like chronic kidney disease, cancers, and psoriasis that otherwise should favorably respond to supplemental vitamin D. Using genetically modified mice, we have shown that renal phosphate wasting hypophosphatemic states arising from high levels of fibroblast growth factor 23 (FGF23) are also associated with increased renal Cyp24 expression, suggesting that elevated CYP24 activity is pivotal to the pathophysiology of these disorders. We therefore crossed 2 mouse strains, each with distinct etiology for high levels of circulating FGF23, onto a Cyp24-null background. Specifically, we evaluated Cyp24 deficiency in Hyp mice, the murine homolog of X-linked dominant hypophosphatemic rickets, and transgenic mice that overexpress a mutant FGF23 (FGF23R176Q) that is associated with the autosomal dominant form of hypophosphatemic rickets. Loss of Cyp24 in these murine models of human disease resulted in near-complete recovery of rachitic/osteomalacic bony abnormalities in the absence of any improvement in the serum biochemical profile. Moreover, treatment of Hyp and FGF23R1760-transgenic mice with the CYP24 inhibitor CTA102 also ameliorated their rachitic bones. Our results link CYP24 activity to the pathophysiology of FGF23-dependent renal phosphate wasting states and implicate pharmacologic CYP24 inhibition as a therapeutic adjunct for their treatment.

Lipid-based nutrient supplements containing vitamins and minerals attenuate renal electrolyte loss in HIV/AIDS patients starting antiretroviral therapy: A randomized controlled trial in Zambia.

BACKGROUND & AIMS: Advanced HIV infection combined with undernutrition and antiretroviral therapy (ART) places HIV/AIDS patients at high risk of electrolyte abnormalities and increased morbidity and mortality. Here, in a sub-study of a large published randomized trial, we evaluated if nutritional supplements will help curtail renal electrolyte loss in HIV/AIDS patients starting ART. METHODS: 130 malnourished HIV-positive patients referred for ART received lipid-based nutrient supplements alone (LNS, n = 63) or together with vitamins and minerals (LNS-VM, n = 67). Serum and spot urine samples were collected and assayed for creatinine, potassium, magnesium and phosphate concentrations at baseline and after 12 weeks of ART, and fractional excretion and reabsorption were calculated using standard equations. RESULTS: Eighteen (28.6%) patients from the LNS and 16 (23.9%) from LNS-VM groups died, most during the referral interval before starting ART. Phosphate excretion at baseline, was high in both LNS (mean ± SD: 1.2 ± 0.6 mg/mg creatinine) and LNS-VM (1.1 ± 0.8 mg/mg creatinine) groups relative to normal physiological ranges. Phosphate excretion remained high in the LNS group (1.1 ± 0.41 mg/mg creatinine) but significantly decreased in the LNS-VM group (0.6 ± 0.28 mg/mg creatinine; p < 0.001) after 12 weeks of ART. This difference is probably explained by increased renal tubular reabsorption of phosphate in the LNS-VM group (88.3 ± 5.7%) compared to the LNS group (76.6 ± 8.9%). The fractional excretion of potassium (FEK) was not significantly different at baseline between the two groups (p = 0.69) but the values were above normal physiological ranges (i.e. >6.4%) reflecting renal potassium wasting. However, FEK was significantly lowered in the LNS-VM group (6.2 ± 3.4%) but not in the LNS group (12.8 ± 4.7%) after 12 weeks of ART (p < 0.001). Finally, the fractional excretion of magnesium was not significantly different between the two groups at baseline (p = 0.68) and remained unchanged within normal physiological ranges at 12 weeks of ART (p = 0.82) in both groups. CONCLUSIONS: The LNS-VM regimen appeared to offer protection against phosphate and potassium loss during HIV/AIDS treatment. This offers potential opportunities to improve care and support of poorly nourished HIV-infected patients in resource-limited settings. TRIAL REGISTRATION: www.pactr.org ID number: PACTR201106000300631.

Effect of magnesium dose on amount of pharmaceuticals in struvite recovered from urine.

Phosphorus (P) recovery was carried out through struvite precipitation from urines. Human urine, however, contains not only high nutrients for plants, such as P and nitrogen, but also pharmaceuticals and hormones. In this work, effects of magnesium (Mg) dose (in terms of Mg:P ratio) on P recovery efficiency and pharmaceutical amounts contained in struvite were investigated. Batch-scale experiments of synthetic and human urines revealed that struvite precipitation formed more X-shaped crystals with an increased molar ratio of Mg:P, while the amount of pharmaceuticals (tetracycline, demeclocycline, and oxytetracycline) in struvite decreased with an increased molar ratio of Mg:P. The lowest pharmaceutical amounts in struvite were found at the Mg:P ratio of 2:1 from both samples. Moreover, the maximum P recovery efficiency, quantity and purity of struvite were found in the range of 1.21 to 2:1. It indicated that the molar ratio of Mg:P has a significant impact on struvite precipitation in terms of pharmaceutical amounts in struvite; morphology, quantity and purity of struvite; and P recovery.

Bioavailability and Safety of Vitamin D3 from Pizza Baked with Fortified Mozzarella Cheese: A Randomized Controlled Trial.

PURPOSE: To assess the bioavailability and safety of vitamin D3 from fortified mozzarella cheese baked on pizza. METHODS: In a randomized, double-blind trial, 96 apparently healthy, ethnically diverse adults were randomized to consume 200 IU or 28 000 IU vitamin D3 fortified mozzarella cheese with pizza once weekly for a total of 8 weeks. Blood and urine samples were collected at baseline (week 1) and final (week 10) visits for serum 25-hydroxyvitamin D and other biochemical measures. The primary outcome compared serum 25-hydroxyvitamin D between groups at 10 weeks. The secondary outcome evaluated the safety of vitamin D dosing protocol as measured by serum and urine calcium, phosphate, creatinine, and serum parathyroid hormone (PTH). RESULTS: Serum 25-hydroxyvitamin D increased by 5.1 ± 11 nmol/L in the low-dose group (n = 47; P = 0.003), and by 73 ± 22 nmol/L in the high-dose group (n = 49; P < 0.0001). None of the subjects in either group developed any adverse events during the supplementation protocol. Serum PTH significantly decreased in the high-dose group only (P < 0.05). CONCLUSIONS: Vitamin D3 is safe and bioavailable from fortified mozzarella cheese baked on pizza.

[Management of hypophosphatemia: a case report]. / Le cas clinique du mois. Prise en charge d'une hypophosphatemia.

Hypophosphatemia is defined by a serum phosphate level lower than 0.8 mmol/l. If hypophosphatemia is chronically maintained, it is associated with muscular, osteous, neurological or cardio-respiratory disorders. We describe a patient with isolated hypophosphatemia, detail the mechanisms of phosphate homeostasis, and envisage the differential diagnosis of hypophosphatemia. Furthermore, we propose a sequential decisional algorithm based on basic biological tests and few complementary investigations. Treatment options are reviewed.

Life cycle comparison of centralized wastewater treatment and urine source separation with struvite precipitation: Focus on urine nutrient management.

Alternative approaches to wastewater management including urine source separation have the potential to simultaneously improve multiple aspects of wastewater treatment, including reduced use of potable water for waste conveyance and improved contaminant removal, especially nutrients. In order to pursue such radical changes, system-level evaluations of urine source separation in community contexts are required. The focus of this life cycle assessment (LCA) is managing nutrients from urine produced in a residential setting with urine source separation and struvite precipitation, as compared with a centralized wastewater treatment approach. The life cycle impacts evaluated in this study pertain to construction of the urine source separation system and operation of drinking water treatment, decentralized urine treatment, and centralized wastewater treatment. System boundaries include fertilizer offsets resulting from the production of urine based struvite fertilizer. As calculated by the Tool for the Reduction and Assessment of Chemical and Other Environmental Impacts (TRACI), urine source separation with MgO addition for subsequent struvite precipitation with high P recovery (Scenario B) has the smallest environmental cost relative to existing centralized wastewater treatment (Scenario A) and urine source separation with MgO and Na3PO4 addition for subsequent struvite precipitation with concurrent high P and N recovery (Scenario C). Preliminary economic evaluations show that the three urine management scenarios are relatively equal on a monetary basis (<13% difference). The impacts of each urine management scenario are most sensitive to the assumed urine composition, the selected urine storage time, and the assumed electricity required to treat influent urine and toilet water used to convey urine at the centralized wastewater treatment plant. The importance of full nutrient recovery from urine in combination with the substantial chemical inputs required for N recovery via struvite precipitation indicate the need for alternative methods of N recovery.

Chronic trimethyltin chloride exposure and the development of kidney stones in rats.

We recently reported that occupational exposure to trimethyltin (TMT) is a risk factor for developing kidney stones. To further examine the association between TMT exposure and the formation of kidney stones, we conducted a 180-day animal study and exposed the randomly grouped Sprague-Dawley (SD) rats to TMT in the drinking water at doses of 0, 8.2, 32.8 and 131.3 µg kg(-1) day(-1). Transient behavioral changes were observed in the high-dose group during the first 2 weeks of exposure. TMT exposure led to a significant dose-dependent inhibition of renal H(+)/K(+)-ATPase and an increase in urinary pH. In comparison to no kidney stones being identified in the control and the lowest dose group, 1 rat in the 32.8 µg kg(-1) day(-1) dose group and 3 out of 9 rats in the 131.3 µg kg(-1) day(-1) dose group were found to have stones in the kidney/urinary tract. Pathological analysis showed that more wide spread calcium disposition was observed in kidneys of rats with TMT exposure compared with the rats in the control group. However, X-ray diffraction (XRD) analysis found that the kidney stones were mainly composed of struvite with the formula: NH4MgPO4 6H2O, while calcium-containing components were also detected. Together, this study further demonstrates through animal studies that chronic exposure to a relatively low level of TMT induces nephrotoxicity and increases the risk for developing kidney stones.

Phosphorus recovery: minimization of amount of pharmaceuticals and improvement of purity in struvite recovered from hydrolysed urine.

Struvite (MgNH4PO4·6H2O) is normally used as a fertilizer in agriculture, where struvite crystallization from hydrolysed human urine is a simple and reliable method for phosphorus (P) recovery. Human urine, however, contains high amount of pharmaceuticals, which may cause health risk for applications. This research investigates the possibility of decreasing the amount of pharmaceuticals (tetracycline, demeclocycline and oxytetracycline) in struvite crystals recovered from synthetic and human urines by focusing on storage time, and of increasing the quality of struvite production. Urines were stored for different times up to 15 days prior to recovery of phosphorus by two steps, spontaneous precipitation and struvite crystallization. The morphology of spontaneous precipitates and struvite crystals was observed. Spontaneous precipitation removed around 17-24% of phosphate from synthetic and human urines, while pharmaceuticals were removed with a quite high amount at a short storage time (5 days) and this amount decreased with increasing the storage time (10 and 15 days). Urines with>70% remaining phosphates were re-used for struvite crystallization by adding extra magnesium. It was found that maximum P-recovery efficiency could be achieved from struvite crystallization at 5-day storage time, 70% and 68% of remaining P in the separated supernatant from synthetic and human urines, respectively, whereas less than 1% pharmaceuticals remained in the struvite crystals from both samples. This indicates that the procedure in this work is a good method for phosphorus recovery, in which high struvite purity (>99%) is obtained with low amount of pharmaceuticals.

Redefining normal bone and mineral clinical biochemistry reference intervals for healthy infants in Canada.

BACKGROUND: Few normative data exist for routine clinical chemistry in healthy term infants, that is, during a time of rapid development. Biochemical markers are significantly affected by these physiological changes and the lack of appropriate reference intervals may impede diagnostics in infants. OBJECTIVE: To define reference intervals for calcium, phosphate, creatinine, and alkaline phosphatase in infants from 1 to 12 months of age. DESIGN AND METHODS: This was an unblinded secondary analysis of 132 breastfeeding infants participating in a vitamin D3 supplementation trial (400-1600IU/d) followed prospectively until 1 year of age (NCT00381914). Serial non-fasting capillary and spot urine samples were collected for the measurement of plasma calcium, phosphate, creatinine, and alkaline phosphatase; urinary calcium, phosphate and creatinine (DxC600 Beckman Coulter); and whole-blood ionized calcium (ABL 725 Radiometer). All visits were conducted at McGill University in Montréal, Canada. RESULTS: All analytes changed significantly over time (p<0.05), but there was no effect of sex. From 1 to 12 months, values decreased for whole-blood ionized calcium; plasma calcium, phosphate, and alkaline phosphatase; and urinary calcium:creatinine. Plasma creatinine increased. For some analytes, particularly calcium and alkaline phosphatase, values were often above the 'typical' adult or older child reference limits. Smoothed centile curves (LMS method) were developed to fill existing gaps in normative data for these analytes. CONCLUSIONS: Most analytes showed a significant change from 1 to 12 months, confirming the need for age-specific reference values. These data can assist in the generation of new reference intervals for healthy term infants and ultimately improve the care of children.

The human response to acute enteral and parenteral phosphate loads.

The human response to acute phosphate (PO4) loading is poorly characterized, and it is unknown whether an intestinal phosphate sensor mechanism exists. Here, we characterized the human mineral and endocrine response to parenteral and duodenal acute phosphate loads. Healthy human participants underwent 36 hours of intravenous (IV; 1.15 [low dose] and 2.30 [high dose] mmol of PO4/kg per 24 hours) or duodenal (1.53 mmol of PO4/kg per 24 hours) neutral sodium PO4 loading. Control experiments used equimolar NaCl loads. Maximum PO4 urinary excretory responses occurred between 12 and 24 hours and were similar for low-dose IV and duodenal infusion. Hyperphosphatemic responses were also temporally and quantitatively similar for low-dose IV and duodenal PO4 infusion. Fractional renal PO4 clearance increased approximately 6-fold (high-dose IV group) and 4-fold (low-dose IV and duodenal groups), and significant reductions in plasma PO4 concentrations relative to peak values occurred by 36 hours, despite persistent PO4 loading. After cessation of loading, frank hypophosphatemia occurred. The earliest phosphaturic response occurred after plasma PO4 and parathyroid hormone concentrations increased. Plasma fibroblast growth factor-23 concentration increased after the onset of phosphaturia, followed by a decrease in plasma 1,25(OH)2D levels; α-Klotho levels did not change. Contrary to results in rodents, we found no evidence for intestinal-specific phosphaturic control mechanisms in humans. Complete urinary phosphate recovery in the IV loading groups provides evidence against any important extrarenal response to acute PO4 loads.

Effect of large doses of parenteral vitamin D on glycaemic control and calcium/phosphate metabolism in patients with stable type 2 diabetes mellitus: a randomised, placebo-controlled, prospective pilot study.

OBJECTIVE: Vitamin D (D3) status is reported to correlate negatively with insulin production and insulin sensitivity in patients with type 2 diabetes mellitus (T2DM). However, few placebo-controlled intervention data are available. We aimed to assess the effect of large doses of parenteral D3 on glycosylated haemoglobin (HbA(1c)) and estimates of insulin action (homeostasis model assessment insulin resistance: HOMA-IR) in patients with stable T2DM. MATERIALS AND METHODS: We performed a prospective, randomised, double-blind, placebo-controlled pilot study at a single university care setting in Switzerland. Fifty-five patients of both genders with T2DM of more than 10 years were enrolled and randomised to either 300,000 IU D3 or placebo, intramuscularly. The primary endpoint was the intergroup difference in HbA(1c) levels. Secondary endpoints were: changes in insulin sensitivity, albuminuria, calcium/phosphate metabolism, activity of the renin-aldosterone axis and changes in 24-hour ambulatory blood pressure values. RESULTS: After 6 months of D3 supply, there was a significant intergroup difference in the change in HbA(1c) levels (relative change [mean ± standard deviation] +2.9% ± 1.5% in the D3 group vs +6.9% ± 2.1% the in placebo group, p = 0.041) as HOMA-IR decreased by 12.8% ± 5.6% in the D3 group and increased by 10% ± 5.4% in the placebo group (intergroup difference, p = 0.032). Twenty-four-hour urinary albumin excretion decreased in the D3 group from 200 ± 41 to 126 ± 39, p = 0.021). There was no significant intergroup difference for the other secondary endpoints. CONCLUSIONS: D3 improved insulin sensitivity (based on HOMA-IR) and affected the course of HbA(1c) positively compared with placebo in patients with T2DM.

Metabonomics evaluation of urine from rats administered with phorate under long-term and low-level exposure by ultra-performance liquid chromatography-mass spectrometry.

The purpose of this study was to investigate the toxic effect of long-term and low-level exposure to phorate using a metabonomics approach based on ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Male Wistar rats were given phorate daily in drinking water at low doses of 0.05, 0.15 or 0.45 mg kg⁻¹ body weight (BW) for 24 weeks consecutively. Rats in the control group were given an equivalent volume of drinking water. Compared with the control group, serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin (TBIL), urea nitrogen (BUN) and creatinine (CR) were increased in the middle- and high-dose groups whereas albumin (ALB) and cholinesterase (CHE) were decreased. Urine metabonomics profiles were analyzed by UPLC-MS. Compared with the control group, 12 metabolites were significantly changed in phorate-treated groups. In the negative mode, metabolite intensities of uric acid, suberic acid and citric acid were significantly decreased in the middle- and high-dose groups, whereas indoxyl sulfic acid (indican) and cholic acid were increased. In the positive mode, uric acid, creatinine, kynurenic acid and xanthurenic acid were significantly decreased in the middle- and high-dose groups, but 7-methylguanine (N7G) was increased. In both negative and positive modes, diethylthiophosphate (DETP) was significantly increased, which was considered as a biomarker of exposure to phorate. In conclusion, long-term and low-level exposure to phorate can cause disturbances in energy-related metabolism, liver and kidney function, the antioxidant system, and DNA damage. Moreover, more information can be provided on the evaluation of toxicity of phorate using metabonomics combined with clinical chemistry.