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Background We aimed to describe the thiamine status in hospitalized hypervolemic heart failure (HF) and/or renal failure (RF) patients treated with furosemide and to investigate whether there was a difference in furosemide-related thiamine deficiency between patients with RF and HF. Methods Patients who were diagnosed as hypervolemia and treated with intravenous furosemide (at least 40 mg/day) were included in this prospective observational study. Whole blood thiamine concentrations were measured 3 times during hospital follow-up of patients. Results We evaluated 61 hospitalized hypervolemic patients, of which 22 (36%) were men and 39 (64%) were women, with a mean age of 69.00 ± 10.39 (45–90) years. The baseline and post–hospital admission days 2 and 4 mean thiamine levels were 51.71 ± 20.66 ng/ml, 47.64 ± 15.43 ng/ml and 43.78 ± 16.20 ng/ml, respectively. Thiamine levels of the hypervolemic patients decreased significantly during the hospital stay while furosemide treatment was continuing (p = 0.029). There was a significant decrease in thiamine levels in patients who had HF (p = 0.026) and also, thiamine was significantly lower in HF patients who had previously used oral furosemide before hospitalization. However, these findings were not present in patients with RF. Conclusions Thiamine substantially decreases in most hypervolemic patients receiving intravenous furosemide treatment during the hospital stay. Thiamine levels were significantly decreased with furosemide treatment in especially HF patients, but the decrease in thiamine levels did not detected at the same rate in RF patients. Diuretic-induced thiamine loss may be less likely in RF patients, probably due to a reduction in excretion.

Background Febuxostat is recommended for patients with chronic kidney disease (CKD) associated with hyperuricemia to lower the serum uric acid (sUA) concentration. However, it remains uncertain how this drug affects correlations between several laboratory parameters regarding glomerular filtration and renal tubular reabsorption of uric acid. Methods We enrolled 148 patients with CKD with hyperuricemia. Of them, 122 were treated with febuxostat, and 26 were treated without it. Clinical and laboratory parameters were recorded to calculate the estimated glomerular filtration rate (eGFR), fractional excretion of uric acid (FEUA), and the estimated 24-h urinary excretion of uric acid (eEUA). We retrospectively examined the correlations between those parameters to compare the patients treated with febuxostat to those without it. Results A significant inverse correlation between eGFR and FEUA was demonstrated in both patients treated with febuxostat and those without it. In patients treated with febuxostat, a significant inverse correlation was demonstrated between eGFR and sUA, whereas no significant correlation was demonstrated in those without it. There was a significant positive correlation between FEUA and eEUA in patients treated with febuxostat, whereas no significant correlation was revealed in those without it. Conclusions FEUA increased as eGFR declined in our study population. Febuxostat changed the correlation patterns between the clinical laboratory parameters. An additional administration of uricosuric agents would be helpful for further sUA lowering by increasing both FEUA and eEUA in patients treated with febuxostat.

The present study was carried out to evaluate the effect of dietary supplemental vitamin D3 on fibroblast growth factor 23 (FGF23) signals as well as phosphorus homeostasis and metabolism in laying hens. Fourteen 40-week-old Hy-Line Brown layers were randomly assigned into 2 treatments:1) vitamin D3 restriction group (n = 7) fed 0 IU/kg vitamin D3 diet, and 2) regular vitamin D3 group (n = 7) fed 1,600 IU/kg vitamin D3 diet. The study lasted for 21 d. Serum parameters, phosphorus and calcium excretion status, and tissue expressions of type II sodium-phosphate co-transporters (NPt2), FGF23 signals and vitamin D3 metabolic regulators were determined. Hens fed the vitamin D3 restricted diet had decreased serum phosphorus levels (by 31.3%, P = 0.028) when compared to those fed regular vitamin D3 diet. In response to the decreased serum phosphorus, the vitamin D3 restricted laying hens exhibited: 1) suppressed kidney expressions of 25-hydroxyvitamin D 1-α-hydroxylase (CYP27B1, by 52.8%, P = 0.036) and 1,25-dihydroxyvitamin D 24-hydroxylase (CYP24A1, by 99.4%, P = 0.032); 2) suppressed serum levels of FGF23 (by 14.6%, P = 0.048) and increased serum alkaline phosphatase level (by 414.1%, P = 0.012); 3) decreased calvaria mRNA expressions of fibroblast growth factor receptors (FGFR1, by 85.2%, P = 0.003, FGFR2, by 89.4%, P = 0.014, FGFR3, by 88.8%, P = 0.017, FGFR4, by 89.6%, P = 0.030); 4) decreased kidney mRNA expressions of FGFR1 (by 65.5%, P = 0.021), FGFR4 (by 66.0%, P = 0.050) and KLOTHO (by 68.8%, P = 0.038); 5) decreased kidney protein expression of type 2a sodium-phosphorus co-transporters (by 54.3%, P = 0.039); and 6) increased percent excreta calcium (by 26.9%, P = 0.002). In conclusion, the deprivation of dietary vitamin D3 decreased FGF23 signals in laying hens by reducing serum FGF23 level and suppressing calvaria and kidney mRNA expressions of FGF23 receptors.

Background: Vitexin is the main bioactive compound of hawthorn (Crataegus pinnatifida), a famous traditional Chinese medicine, and vitexin for injection is currently in phase I clinical trial in China. Objective: This investigation systematically evaluated the metabolism and toxicokinetics of vitexin in rats and dogs. Methods: Rats and beagle dogs were administrated different doses of vitexin, and then the plasma concentration, tissue distribution, excretion, metabolism, pharmacokinetics and plasma protein binding were investigated. Results : The elimination half-life (t1/2) values in rats after a single intravenous dose of 3, 15 and 75 mg/kg were estimated as 43.53±10.82, 22.86±4.23, and 21.17±8.64 min, and the values of the area under the plasma concentration-time curve (AUC0→∞) were 329.34±144.07, 974.79±177.27, and 5251.49±786.98 mg•min/L, respectively. The plasma protein binding rate in rats was determined as about 65% by equilibrium dialysis after 72 hr. After 24 hr of intravenous administration, 16.30%, 3.47% and 9.72% of the given dose were excreted in urine, feces and bile, respectively. The metabolites of the vitexin were hydrolyzed via deglycosylation. The pharmacokinetics of dogs after intravenous administration revealed t1/2, AUC0-∞ and mean residence time (MRT0-∞) values of 20.43±6.37 min, 227.96±26.68 mg•min/L and 17.12±4.33 min, respectively. The no-observed-adverse- effect level (NOAEL) was 50 mg/kg body weight/day. There was no significant accumulation effect at 8 or 20 mg/kg/day in dogs over 92 days of repeated administration. For the 50 mg/kg/- day dose group, the exposure (AUC, Cmax) decreased significantly with prolonged administration. This trend suggests that repeated administration accelerates vitexin metabolism. Conclusion: The absorption of vitexin following routine oral administration was very low. To improve the bioavailability of vitexin, the development of an injectable formulation would be a suitable alternative choice.

Polyuria is a common clinical condition characterized by a urine output that is inappropriately high (more than 3 L in 24 h) for the patient's blood pressure and plasma sodium levels. From a pathophysiological point of view, it is classified into two types: polyuria due to a greater excretion of solutes (urine osmolality300 mOsm/L) or due to an inability to increase solute concentration (urine osmolality150 mOsm/L). Sometimes both mechanisms can coexist (urine osmolality 150-300 mOsm/L). Polyuria is a diagnostic challenge and its proper treatment requires an evaluation of the medical record, determination of urine osmolality, estimation of free water clearance, use of water deprivation tests in aqueous polyuria, and measurement of electrolytes in blood and urine in the case of osmotic polyuria.

Introduction Hypouricemia may be caused by disorders leading to decreased UA production, oxidation of UA to allantoin by drugs or increased renal tubular loss of filtered UA, renal hypouricemia (RHUC). RHUC may be resulted from familial or acquired disorders. Familial RHUC cases are classified according to the gene affected as type 1 (SLC22A12 gene) and type 2 (SLC2A9). Clinical importance of RHUC entity is mainly determined by emerging of acute kidney injury (AKI) after strenuous exercise and urolithiasis. Case presentation Here, we report a case of RHUC with increased fractional excretion of uric acid value of more than 100%, serum uric acid level of nearly zero, and exercise-induced AKI episodes clinically and a new unpublished homozygous (biallelic) mutation of c.1419+2T>G (IVS11+2T>G) in the SLC2A9 gene genetically for the first time to our knowledge. Conclusion Clinicians should be aware of this rare entity defined as hereditary RHUC in order to provide long term renoprotection by advisements like simple precautions such as avoiding severe exercises.

In Morocco, the high consumption of dietary sodium increases the risk of non-communicable diseases (NCDs) and predisposes to cardiovascular diseases (CVDs) and hypertension. This study aims to assess the dietary sodium and potassium intake in a random sample of Moroccan adult students as a benchmark informing a national strategy for reducing salt intake. This cross-sectional study was conducted with 103 adults aged 18 to 25 years recruited in Casablanca. The 24-hour urinary excretion was used to measure the sodium and potassium. Creatinine excretion was used to validate the completeness of the urine collections. The average urinary sodium excretion was 3125.77 ± 121.99 mg/day, 13.5% consumed less than 5g/day, while 69% consumed more than 5 g/day of which 17.5% consumed more than twice the recommendations. For the average urinary potassium excretion was 1826.1 ± 61.2 mg/day, and more than 98% of the students consumed less than the adequate intake. The results of this pilot study show that the population studied has a high sodium intake and low potassium intake which does not meet World Health Organization (WHO) recommendations, which requires implementing an action plan to reduce salt.

Background: We assessed the extent to which urinary and fecal excretion of 14C-labeled drug material in animal ADME studies was predictive of human ADME studies. We compared observed plasma elimination half-lives for total drug-related radioactivity in humans to pre-study predictions, and we estimated the impact of any major differences on human dosimetry calculations. Methods: We included 34 human ADME studies with doses of 14C above 0.1 MBq. We calculated ratios of dosimetry input parameters (percentage fecal excretion in humans versus animals; observed half-life in humans versus predicted pre-study) and output parameters (effective dose post-study versus pre-study) and assessed their relationship. Results: A quantitative correlation assessment did not show a statistically significant correlation between the ratios of percentages of 14C excreted in feces and the ratios of dosimetry outcomes in the entire dataset, but a statistically significant correlation was found when assessing the studies that were based on ICRP 60/62 (n=19 studies; P=0.0028). There also appeared to be a correlation between the plasma half-life ratios and the ratios of dosimetry results. A quantitative correlation assessment showed that there was a statistically significant correlation between these ratios (P Conclusion: In all cases where the plasma elimination half-life for 14C in humans was found to be longer than the predicted value, the radiation burden was still within ICRP Category IIa. Containment of the actual radiation burden below the limit of 1.00 mSv appeared to be determined partly also by our choice to limit 14C doses to 3.7 MBq.

Purpose In a search for potentially modifiable factors to improve long-term outcome among kidney transplant recipients (KTR), we hypothesized that boron exposure is associated with improved long-term outcome in KTR. Methods We determined 24 h urinary boron excretion using inductively coupled plasma mass spectrometry as a measure of boron exposure in 693 stable KTR (57% male, mean age 53y), enrolled in the TransplantLines Food and Nutrition Biobank and Cohort Study. Dietary intake was assessed using validated food-frequency questionnaires. Results Linear regression analyses showed that dietary intake of fruit, wine and nuts were key determinants of boron excretion. In addition, boron excretion was negatively correlated with homocysteine and inflammatory parameters. In total, 73 (32%), 47 (20%) and 30 (13%) KTR died among the lowest, middle and highest tertiles of 24 h urinary boron excretion, respectively (Plog-rank P Conclusion Boron may be an overlooked target to improve long-term survival among KTR and potentially other patients, likely through pathways other than inflammation or the methionine-homocysteine cycle that were previously suggested. Interventional trials are warranted to confirm the potential of dietary boron supplementation in KTR and other patient populations.

OBJECTIVE This study evaluated urinary angiotensinogen in preeclampsia. METHODS Normal pregnant (n = 57) and preeclamptic patients (n = 31); Normal pregnant (n = 10) and preeclamptic rats (n = 10) were studied. Urinary angiotensinogen and plasma angiotensin II were assayed by enzyme-linked immunosorbent assay (ELISA). RESULTS Urinary angiotensinogen in preeclampsia patients (2.0 ± 1.1 ng/mg creatinine) was suppressed (*p

Objectives The present study was designed to determine the effect of dietary phosphorus restriction, independent of protein intake, on the urinary protein excretion in patients with proteinuria. Methods Seventy-one patients with proteinuria were enrolled in a parallel randomized controlled trial study. The patients were randomly allocated to receive either a recommended phosphorus-restricted diet (n = 36) or a recommended control diet (n = 35), for 8 weeks. A diet was designed and recommended to participants in a way that both trial groups would receive the same amount of energy and protein and the only significant difference between them was the amount of phosphorus intake. The study outcomes included the changes in spot urine protein-to-creatinine ratio, the changes in serum and urine levels of phosphorus, as well as the changes in estimated glomerular filtration rate (eGFR). Results The mean ± standard deviation of age, body mass index, and eGFR of the participants were 59 ± 14 years, 29 ± 5.5 kg/m2, and 56.1 ± 21.7 mL/min/1.73 m2, respectively. The amount of phosphorus intake decreased significantly in the phosphorus-restricted group compared to the control one (−709 vs. −369 mg/day; P Conclusions Although adherence to a phosphorus-restricted diet by patients with proteinuria led to a significant decrease in urinary protein excretion, this change was not significantly different from that of the control diet. Further studies with larger sample sizes and different designs will reveal more evidence for a link between phosphorus intake and proteinuria.

Background: While 25% of adult women in the world are hypertensive, the percentage of women, who cannot achieve blood pressure control despite taking medication, is 55.9 ± 1.5%. The aim of this study was to determine the prevalence and control rate of hypertension and to detect the factors affecting this situation in women in the 15-49 age group. Material and Methods: 700 women in the 15-49 age group were selected and a questionnaire was applied. Height, weight, and blood pressure were measured and spot urines were collected on the same day. 24-hour sodium excretion and daily salt intake were calculated using the Kawasaki method. Results: While 14.3% of the women were hypertensive, only 19% of them were able to achieve blood pressure control. Fifty eight percent of the hypertensive women use more than 15 g / day of salt and the estimated 24-hour urinary sodium excretion of these women was 311.6 ± 39.5 mmol / l. Hypertensive women using less than 5 g / day of salt were 0.3%. Salty foods consumed by the hypertensive women were pickles (55.6%), cheese (92.6%), olives (88.8%), vine leaves (71.6%), sujuk and Turkish pastrami (47.6%), and tomato paste (100%). Conclusions: In our study, participants were consuming large amounts of salt and there was a positive correlation between salt intake and blood pressure. Therefore, all efforts for sodium restriction are very important in the management of hypertension.

Tungsten is a naturally occurring transition element used in a broad range of applications. As a result of its extensive use, we are increasingly exposed to tungsten from our environment, including potable water, since tungsten can become bioaccessible in ground sources. The kidneys are particularly susceptible to tungsten exposure as this is the main site for tungsten excretion. In this study, we investigated the prolonged effects of tungsten on the kidneys and how this may impact injury and function. When mice were exposed to tungsten in their drinking water for 1 mo, kidney function had not significantly changed. Following 3-mo exposure, mice were presented with deterioration in kidney function as determined by serum and urine creatinine levels. During 3 mo of tungsten exposure, murine kidneys demonstrated significant increases in the myofibroblast marker α-smooth muscle actin (αSMA) and extracellular matrix products: fibronectin, collagen, and matricellular proteins. In addition, Masson’s trichrome and hematoxylin-eosin (H&E) staining revealed an increase in fibrotic tissue and vacuolization of tubular epithelial cells, respectively, from kidneys of tungsten-treated mice, indicative of renal injury. In vitro treatment of kidney fibroblasts with tungsten led to increased proliferation and upregulation of transforming growth factor β1 (TGFβ1), which was consistent with the appearance of fibroblast-to-myofibroblast transition (FMT) markers. Our data suggest that continuous exposure to tungsten impairs kidney function that may lead to the development of chronic kidney disease (CKD).

BACKGROUND Observational studies have linked pesticide exposure to various diseases, whereas organic food consumption has been associated with positive health outcomes. Organic farming standards prohibit the use of most pesticides, and organic food consumption may therefore reduce pesticide exposure. OBJECTIVES To determine the effects of diet (Western compared with Mediterranean) and food type (conventional compared with organic) and sex on urinary pesticide residue excretion (UPRE), as well as associations between specific diet components and UPRE. METHODS In this 2-wk, randomized dietary intervention trial, healthy adults were randomly allocated to an intervention (n = 13) or conventional (n = 14) group. Whereas participants in the intervention group consumed a Mediterranean diet (MedDiet) made entirely from organic foods, the conventional group consumed a MedDiet made entirely from conventional foods. Both groups consumed habitual Western diets made from conventional foods before and after the 2-wk intervention period. The primary outcome was UPRE. In addition, we assessed diet composition and pesticide residue profiles in foods eaten. Participants were aware of group assignment, but the study assessors were not. RESULTS During the intervention period, total UPRE was 91% lower with organic (mean 17 μg/d; 95% CI: 15, 19) than with conventional (mean 180 μg/d; 95% CI: 153, 208) food consumption (P

Purpose: We aimed to provide an extended analysis of the physiological handling of of the sodium burden induced by maintenance fluids. Materials and methods: We revisited two studies that demonstrated, in healthy volunteers and in surgical patients, that maintenance fluids with 154 mmol/L of sodium lead to a more positive fluid balance than a regimen containing 54 mmol/L. We report different unpublished data on the renal handling of the imposed sodium bur -dens with specific attention to the resulting fluid and sodium balances. Results: The kidneys adapt to the sodium-rich fluids not only by altering sodium excretion, but also by retaining extra free water by concentrating urine. Realigning urinary sodium excretion with an increased administration takes around one day in health and much longer in the clinical setting. This difference may be explained by the presence of hypovolemia-induced aldosterone secretion in the latter group. Non-osmotic storage of sodium limits an unrestrained fluid retention even when very high amounts of sodium are administered but fluid accu-mulation will inevitably be further prolonged. Conclusions: Sodium administration induced by sodium-rich maintenance fluids leads, especially in the clinical setting, to prolonged fluid retention when compared with a regimen that resembles a healthy dietary sodium in-take, even when kidney function is normal. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Context No consensus exists about the optimal duration of the low-iodine diet (LID) in the preparation of 131I therapy in differentiated thyroid cancer (DTC) patients. Objective This work aimed to investigate if a LID of 4 days is enough to achieve adequate iodine depletion in preparation for 131I therapy. In addition, the nutritional status of the LID was evaluated. Methods In this prospective study, 65 DTC patients treated at 2 university medical centers were included between 2018 and 2021. The patients collected 24-hour urine on days 4 and 7 of the LID and kept a food diary before and during the LID. The primary outcome was the difference between the 24-hour urinary iodine excretion (UIE) on both days. Results The median 24-hour UIE on days 4 and 7 of the LID were not significantly different (36.1 mcg [interquartile range, 25.4-51.2 mcg] and 36.5 mcg [interquartile range, 23.9-47.7 mcg], respectively, P = .43). On day 4 of the LID, 72.1% of the DTC patients were adequately prepared (24-hour UIE Conclusion The 24-hour UIE on day 4 of the LID did not differ from day 7, and therefore shortening the LID from 7 to 4 days seems justified to prepare DTC patients for 131I therapy in areas with sufficient iodine intake and may be beneficial to maintain a sufficient nutritional intake during DTC treatment.

Purpose of the research was to analyze the various options of postoperative analgesia in terms of their influence on the symptoms of surgical stress response in order to optimize the method of analgesia. Patients (n = 105) were divided into three groups depending on the method of postoperative analgesia. We have monitored the performance of the heart rate variability, the level of daily urine cortisol, as well as changes in the level of blood glucose. The study showed the activation of the regions of the autonomic nervous system in the control group was not significant. In group II, autonomic dysfunction with an increased tone of parasympathetic area has been detected. The use of TAP-block has been characterized by the activation of the regions of the autonomic nervous system. Postoperative hyperglycemia was observed in all groups. The highest rates were in the control group, in group II and III glucose level was lower. Indicators of urine cortisol excretion in the control group were 3 times higher than normal ones. In group II and III — 2.1 and 2.2 times higher, respectively. Increased excretion of daily cortisol indicates the presence of surgical stress in the postoperative period. The use of TAP-block in the postoperative period is characterized by the preservation of adaptive-compensatory reactions in response to surgical intervention, which has an obvious advantage over other methods of postoperative analgesia.

1. The metabolism and excretion of cetagliptin were investigated in healthy male subjects after a single oral dose of 100mg/50μCi [14C] cetagliptin.2. The mean concentration-time profile of cetagliptin was similar to that of total radioactivity in plasma after oral administration of [14C] cetagliptin in healthy male subjects. Cetagliptin was rapidly absorbed after oral administration. Unchanged cetagliptin was the most abundant radioactive component in all matrices investigated. Approximately 53.13% of plasma AUC of total radioactivity was accounted for by cetagliptin. Each metabolite plasma AUC was not higher than 2.93% of plasma AUC of total radioactivity. By 336 h after administration, 91.68% of the administered radioactivity was excreted, and the cumulative excretion in the urine and feces was 72.88% and 18.81%, respectively. The primary route of excretion of radioactivity was via the kidneys.3. Four metabolites were detected at trace levels, and it involved hydroxylated (M436-1 and M436-3), N- sulfate (M500), and N-carbamoyl glucuronic acid conjugates (M640B) of cetagliptin. These metabolites were detected also in plasma, urine, and feces at low levels, except that metabolite M640B was not detected in feces. All metabolites were observed with < 10% of parent compound systemic exposure after oral administration.

The objectives of this study are to evaluate the effects of (1) a potential interaction between supplement crude protein (CP) concentration and differing cow genotypes on milk production, (2) differing cow genotypes on milk production, and (3) decreasing the supplement CP concentration on milk production and N excretion during the main grazing season within a spring-calving herd. A 2 × 2 factorial arrangement experiment, with 2 feeding strategies [14%; n = 30 (lower CP; LCP) and 18%; n = 28 (higher CP; HCP) CP concentrate supplements] offered at varying levels according to pasture availability and days in milk (DIM) was conducted over the main grazing season from April 3 to September 3, 2019, at University College Dublin Lyons Farm. Cows were also grouped into 2 genotype groups: lower milk genotype; n = 30 [LM; milk kg predicted transmitting ability (PTA): 45 ± 68.6 (mean ± SD); fat kg PTA: 10 ± 4.9; and protein kg PTA: 7 ± 2.3] and higher milk genotype; n = 28 [HM; milk kg PTA: 203 ± 55.0; fat kg PTA: 13 ± 3.8; and protein kg PTA: 10 ± 2.4]. A total of 46 multiparous and 12 primiparous (total; 58) Holstein Friesian dairy cows were blocked on parity and balanced on DIM, body condition score, and Economic Breeding Index. Cows were offered a basal diet of grazed perennial ryegrass pasture. The N partitioning study took place from August 25 to 30, 2019 (187 ± 15.2 DIM). No interactions were observed for any milk production or milk composition parameter. No effect of supplement CP concentration was observed for any total accumulated milk production, daily milk production, or milk composition parameter measured. The HM cows had increased daily milk yield (+1.9 kg), fat and protein (+0.15 kg), and energy-corrected milk (+1.7 kg), compared with the LM cows. Furthermore, HM cows had decreased milk protein concentration (-0.1%) compared with LM cows. For the N partitioning study, cows offered LCP had increased pasture dry matter intake (PDMI; +0.9 kg/d), dietary N intake (+0.022 kg/d), feces N excretion (+0.016 kg/d), and decreased N partitioning to milk (-2%), and N utilization efficiency (-2.3%). In conclusion, offering cows LCP had no negative influence on milk production or milk composition over the main grazing season where high pasture quality was maintained. However, any potential negative effects of offering LCP on milk production may have been offset by the increased PDMI. Furthermore, offering cows LCP decreased N utilization efficiency due to the higher PDMI and feed N intake associated with cows on this treatment in our study.s.

Space travel burdens health by imposing considerable environmental stress associated with radioactivity and microgravity. In particular, gravity change predominantly impacts blood pressure and bone homeostasis, both of which are controlled mainly by the kidneys. Nuclear factor erythroid-2-related transcription factor 2 (Nrf2) plays essential roles in protecting the kidneys from various environmental stresses and injuries. To elucidate the effects of space travel on mammals in preparation for the upcoming space era, our study investigated the contribution of Nrf2 to kidney function in mice two days after their return from a 31-day stay in the International Space Station using Nrf2 knockout mice. Meaningfully, expression levels of genes regulating bone mineralization, blood pressure and lipid metabolism were found to be significantly altered in the kidneys after space travel in an Nrf2-independent manner. In particular, uridine diphosphate-glucuronosyltransferase 1A (Ugt1a) isoform genes were found to be expressed in an Nrf2-dependent manner and induced exclusively in the kidneys after return to Earth. Since spaceflight elevated the concentrations of fatty acids in the mouse plasma, we suggest that Ugt1a isoform expression in the kidneys was induced to promote glucuronidation of excessively accumulated lipids and excrete them into urine after the return from space. Thus, the kidneys were proven to play central roles in adaptation to gravity changes caused by going to and returning from space by controlling blood pressure and bone mineralization. Additionally, kidney Ugt1a isoform induction after space travel implies a significant role of the kidneys for space travelers in the excretion of excessive lipids.

Nalfurafine is a G-protein–biased KOR (kappa opioid receptor) agonist that produces analgesia and lacks central nervous system adverse effects. Here, we examined the cardiovascular and renal responses to intravenous and oral nalfurafine alone and in combination with furosemide, hydrochlorothiazide, or amiloride. We hypothesized that nalfurafine, given its distinct mechanism of vasopressin inhibition, would increase urine output to these diuretics and limit electrolyte loss. Following catheterization, conscious Sprague-Dawley rats received an isotonic saline infusion and were then administered an intravenous bolus of nalfurafine, a diuretic, or a combination. Mean arterial pressure, heart rate, and urine output were recorded for 90 minutes. In another study, rats were placed in metabolic cages and administered drug in an oral volume load. Hourly urine samples were then collected for 5 hours. Intravenous and oral nalfurafine produced a marked diuresis, antinatriuresis, antikaliuresis, and a decrease in mean arterial pressure. Compared with diuretic treatment alone, intravenous coadministration with nalfurafine significantly increased urine output to furosemide and hydrochlorothiazide and decreased sodium and potassium excretion. Notably, mean arterial pressure was reduced with nalfurafine/diuretic combination therapy compared to diuretics alone. Similarly, oral coadministration of nalfurafine significantly increased urine output to hydrochlorothiazide and decreased sodium and potassium excretion, whereas combination with furosemide only limited the amount of sodium excreted. Further, both intravenous and oral coadministration of nalfurafine enhanced the diuresis to amiloride and decreased sodium excretion. Together, these findings demonstrate that nalfurafine enhances the diuresis to standard-of-care diuretics without causing an excessive loss of electrolytes, offering a new approach to treat several cardiovascular conditions.

Potassium (K+) is the predominant intracellular cation in the body. The intracellular [K+] is 140–150 mEq/L; in blood it is 3.5–5 mEq/L. Serum contains a slightly higher concentration of K+ than plasma because K+ is released from red blood cells during clot formation. Maintenance of a high cellular concentration of K+ is necessary for several cellular functions, including growth, nucleic acid and protein synthesis, and regulation of cell volume, as well as pH and enzyme activation. In addition, a high intracellular concentration of K+ is essential to the maintenance of the resting membrane potential for cellular excitability and contraction. The high intracellular K+ concentration is maintained by the Na/K-ATPase located in the cell membranes of all animal cells. The activity of this enzyme is influenced by a variety of hormones. The kidney is the primary route for K+ excretion. In general, K+ excretion in the urine, called kaliuresis, parallels dietary intake. The other route for K+ excretion is the colon. Under conditions of decreased renal function, K+ excretion by the colon is enhanced.

Paeoniflorin-6'-O-benzene sulfonate (CP-25) is a novel ester derivative of paeoniflorin, which has been shown to have synergistic pharmacodynamic effects with leflunomide (LEF). To determine the effects of CP-25 on the pharmacokinetics of LEF in rats, we developed an UPLC-MS/MS-based method for the determination of levels of teriflunomide (TER, an active metabolite of LEF). This method was used to determine TER concentrations in the plasma, urine, feces, and bile, heart, liver, spleen, lung, kidney, intestinal, brain, and synovial tissues, and peripheral blood mononuclear cells (PBMCs) of rats in the control [LEF (10 mg/kg)] and combined [CP-25(50 mg/kg×7d) plus LEF (10 mg/kg)] groups. TER AUC, Tmax , MRT, t1/2α , and t1/2β were significantly lower and CL was significantly higher in the combined group than in the control group. Oral CP-25 administration in combination with LEF was found to promote TER excretion in urine, feces, and bile, and to reduce its contents in most tissues and organs, especially in the liver, which may reduce LEF-induced liver injury. CP-25 also increased TER exposure in the synovium and its absorption by PBMCs, and this could explain the synergistic effects of CP-25 and LEF.

Excretion of [14C]HR011303-derived radioactivity showed significant species difference. Urine (81.50% of dose) was the main excretion route in healthy male subjects, whereas feces (87.16% of dose) was the main excretion route in rats. To further elucidate the underlying cause for excretion species differences of HR011303, studies were conducted to uncover its metabolism and excretion mechanism. M5, a glucuronide metabolite of HR011303, is the main metabolite in humans and rats. Results of rat microsomes incubation study suggested that HR011303 was metabolized to M5 in the rat liver. According to previous studies, M5 is produced in both human liver and kidney microsomes. We found M5 in human liver can be transported to the blood by multidrug resistance-associated protein (MRP) 3 and then the majority of M5 can be hydrolyzed to HR011303. HR011303 enters the human kidney or liver through passive diffusion, whereas M5 is taken up through organic anion transporter (OAT) 3, organic anion-transporting polypeptide (OATP) 1B1, and OATP1B3. When HR011303 alone was present, it can be metabolized to M5 in both sandwich-cultured rat hepatocytes (SCRH) and sandwich-cultured human hepatocytes (SCHH) and excreted into bile as M5 in SCRH. Using transporter inhibitors in sandwich-cultured model and membrane vesicles that expressing MRP2 or Mrp2, we found M5 was substance of MRP2/Mrp2 and the bile efflux of M5 mainly mediated by MRP2/Mrp2. Considering the significant role of MRP3/Mrp3 and MRP2/Mrp2 in the excretion of glucuronides, the competition between them for M5 was possibly the determinant for the different excretion routes in humans and rats. Significance Statement Animal experiments are necessary to predict dosage and safety of candidate drugs prior to clinical trials. However, extrapolation results often differ from actual situation. For HR011303, excretory pathways exhibited a complete reversal, through urine in humans and feces in rats. Such phenomena have been observed in several drugs, but no in-depth studies have been conducted to date. In the present study, the excretion species differences of HR011303 can be explained by the competition for M5 between MRP2/Mrp2 and MRP3/Mrp3.

Western-style high-fat/high-sucrose diet (HFHSD) changes gut microbiota and bile acid (BA) profiles. Because gut microbiota and BAs could influence each other, the mechanism of changes in both by HFHSD is complicated and remains unclear. We first aimed to clarify the roles of BAs in the HFHSD-induced change of gut microbiota. Then, we studied the effects of the changed gut microbiota on BA composition and liver function. Male wild-type (WT) and human-like Cyp2a12/Cyp2c70 double knockout (DKO) mice derived from C57BL/6J were fed with normal chow or HFHSD for 4 weeks. Gut microbiomes were analyzed by fecal 16S ribosomal RNA gene sequencing, and BA composition was determined by liquid chromatography-tandem mass spectrometry. The DKO mice exhibited significantly reduced fecal BA concentration, lacked muricholic acids, and increased proportions of chenodeoxycholic and lithocholic acids. Despite the marked difference in the fecal BA composition, the profiles of gut microbiota in the two mouse models were quite similar. An HFHSD resulted in a significant increase in the BA pool and fecal BA excretion in WT mice but not in DKO mice. However, microbial composition in the two mouse models was drastically but similarly changed by the HFHSD. In addition, the HFHSD-induced change of gut microbiota inhibited BA deconjugation and 7α-dehydroxylation in both types of mice, which improved chronic liver injury observed in DKO mice. Conclusion: The HFHSD itself causes the change of gut microbiota due to HFHSD, and the altered composition or concentration of BAs by HFHSD is not the primary factor. On the contrary, the gut microbiota formed by HFHSD affects BA composition and ameliorates liver injury in the mouse model with human-like hydrophobic BA composition.

SGLTs are sodium glucose transporters found on the luminal membrane of the proximal tubule, where they reabsorb some 180 grams (one mole) of glucose from the glomerular filtrate each day. The natural glucoside phlorizin completely blocks glucose reabsorption. Oral SGLT2 inhibitors are rapidly absorbed into the blood stream where they remain in in the circulation for hours. On glomerular filtration, they bind specifically to SGLT2 in the luminal membrane of the early proximal tubule to reduce glucose reabsorption by 50-60%. Because of glucose excretion, these drugs lower plasma glucose and glycosylated hemoglobin levels in patients with type 2 diabetes mellitus. The drugs also protect against heart and renal failure. The aim of this review is to summarize what is currently known about the physiology of renal SGLTs and the pharmacology of SGLT drugs.

Background: Measurement of the 24-h urinary iodine concentration or urinary iodine excretion (UIE) is the gold standard to determine iodine status; however, this method is inconvenient. The use of salivary iodine could be a possible alternative since salivary glands express the sodium-iodine symporter.Objectives: We aimed to establish the correlation between the salivary iodine secretion and UIE, to evaluate the clinical applicability of the iodine saliva measurement.Methods: We collected 24-h urine and saliva samples from 40 participants >= 18 y: 20 healthy volunteers with no specific diet (group 1), 10 patients with differentiated thyroid cancer with a low dietary intake (

Epidemiological studies related to androgens and prostate cancer (PC) have focused on serum determination of testosterone, androstenedione (A4), and DHEA, with inconsistent results. Herein, we hypothesized that differences in androgen biosynthetic and metabolic pathways, rather than differences in specific androgen concentrations, are associated with prostatic carcinogenesis. Therefore, spot urine samples from 111 incident PC cases with Gleason score at diagnosis and 227 healthy population controls, were analyzed. Urinary androgen concentrations (nanograms/milligrams of creatinine) were determined by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS). Using a factor analysis, we identified three androgen urinary excretion patterns. In a subsample, we evaluated a modification effect of the androgen receptor (AR) CAG polymorphism. Pattern I, characterized by A4 and testosterone hydroxylated metabolites (11β-OHT; 2β-OHT; 15β-OHT; 2α-OHT; 6β-OHT), was associated with high PC odds among carriers of AR gene (CAG)>19 repeats (OR: 3.67 95% CI: 1.23–11.0; P for interaction= 0.009). Conversely, higher testosterone excretion (pattern III), was marginally associated with lower (OR: 0.35 95% CI: 0.12–1.00, P for trend= 0.08) poorly differentiated PC (Gleason ≥8). No clear association was observed with pattern II (DHEA; 16α and 16β-OHT). Our results were consistent with the previous evidence which suggests that the C11-oxy backdoor pathway is important for prostatic carcinogenesis. Androgen urine excretion analysis could be useful for PC diagnosis, treatment, and prognosis; however, further studies with a larger number of samples and the urinary determination of 11-ketoandrogens are necessary.

The increasing burden of heart failure (HF) and emerging knowledge regarding chloride as a prognostic marker in HF have increased the interest in the pathophysiology and interactions of chloride abnormalities with HF-related factors and treatments. Chloride is among the major electrolytes that play a unique role in fluid homeostasis and is associated with cardiorenal and neurohormonal systems. This review elucidates the role of chloride in the pathophysiology of HF, evaluates the effects of treatment on chloride (eg, diuretic agents cause higher urinary chloride excretion and consequently serum hypochloremia), and discusses recent evidence for the association between chloride levels and mortality.

The major transmembrane protein of the red blood cell, known as band 3, AE1, and SLC4A1, has two main functions: 1) catalysis of Cl−/[Formula: see text] exchange, one of the steps in CO2 excretion, and 2) anchoring the membrane skeleton. This review summarizes the 150-year history of research on red cell anion transport and band 3 as an experimental system for studying membrane protein structure and ion transport mechanisms. Important early findings were that red cell Cl− transport is a tightly coupled 1:1 exchange and band 3 is labeled by stilbenesulfonate derivatives that inhibit anion transport. Biochemical studies showed that the protein is dimeric or tetrameric (paired dimers) and that there is one stilbenedisulfonate binding site per subunit of the dimer. Transport kinetics and inhibitor characteristics supported the idea that the transporter acts by an alternating access mechanism with intrinsic asymmetry. The sequence of band 3 cDNA provided a framework for detailed study of protein topology and amino acid residues important for transport. The identification of genetic variants produced insights into the roles of band 3 in red cell abnormalities and distal renal tubular acidosis. The publication of the membrane domain crystal structure made it possible to propose concrete molecular models of transport. Future research directions include improving our understanding of the transport mechanism at the molecular level and of the integrative relationships among band 3, hemoglobin, carbonic anhydrase, and gradients (both transmembrane and subcellular) of [Formula: see text], Cl−, O2, CO2, pH, and nitric oxide (NO) metabolites during pulmonary and systemic capillary gas exchange.

Background: Acute Kidney Injury (AKI), a common disease of the urinary system, can be induced by high doses of gentamicin (GM). The renin-angiotensin system exerts a key role in the progression of the AKI since elevated intrarenal levels of Ang II, and ACE activity is found in this condition. However, it is unknown whether oral administration of angiotensin (Ang)-(1-7), a heptapeptide that evokes opposite effects of Ang II, may attenuate the renal injuries induced by gentamicin. Objectives: To evaluate the effects of Ang-(1-7) on GM-induced renal dysfunction in rats. Methods: AKI was induced by subcutaneous administration of GM (80 mg/Kg) for 5 days. Simultaneously, Ang-(1-7) included in hydroxypropyl β-cyclodextrin (HPβCD) was administered by gavage [46 μg/kg HPβCD + 30 μg/kg Ang-(1-7)]. At the end of the treatment period (sixth day), the rats were housed in metabolic cages for renal function evaluation. Thereafter, blood and kidney samples were collected. Results: Ang-(1-7) attenuated the increase of the plasmatic creatinine and proteinuria caused by GM but did not change the glomerular filtration rate nor tubular necrosis. Ang-(1-7) attenuated the increased urinary flow and the fractional excretion of H2O and potassium observed in GM rats but intensified the elevated excretion of sodium in these animals. Morphological analysis showed that Ang-(1-7) also reduced the tubular vacuolization in kidneys from GM rats. Conclusion: Ang-(1-7) promotes selective beneficial effects in renal injuries induced by GM.

Excess salt intake is viewed as a major contributor to hypertension and cardiovascular disease, and dietary salt restriction is broadly recommended by public health guidelines. However, individuals can have widely varying physiological responses to salt intake, and a tailored approach to evaluation and intervention may be needed. The traditional sodium related concepts are challenging to assess clinically for two reasons: (1) spot and 24‐hour urine sodium are frequently used to evaluate salt intake, but are more suitable for population study, and (2) some adverse effects of salt may be blood pressure‐independent. In recent years, previously unknown mechanisms of sodium absorption and storage have been discovered. This review will outline the limitations of current methods to assess sodium balance and discuss new potential evaluation methods and treatment targets.

Hyperoxaluria, one of the major risk factors for calcium oxalate urolithiasis and nephrocalcinosis, causes significant morbidity and mortality and should therefore be detected and treated as soon as possible. An early, consequent and adequate evaluation, but also a distinction between primary (PH) and secondary hyperoxaluria (SH) is therefore essential. We evaluated the usefulness of three consecutive 24-h urine collections under different diets [usual diet, (A), low oxalate diet, (B), high oxalate diet, (C)] to prove SH, or to find evidence of PH by changes in urinary oxalate excretion (Uox). We retrospectively analyzed results from 96 pediatric patients (47 females and 49 males, age 3–18 years) who presented with a history of nephrolithiasis, nephrocalcinosis and/or persistent hematuria in whom hyperoxaluria was found in an initial urine sample. The typical pattern of SH was found in 34 patients (mean Uox (A) 0.85 ± 0.29, (B) 0.54 ± 0.15 and (C) 0.95 ± 0.28 mmol/1.73m2/d). PH was suspected in 13 patients [(A) 1.21 ± 0.75; (B) 1.47 ± 0.51 and (C) 1.60 ± 0.82 mmol/1.73m2/d], but genetically proven only in 1/5 patients examined. No hyperoxaluria was found in 16 patients. Data were inconclusive in 33 patients. Urine collection under different diets is helpful to diagnose secondary hyperoxaluria and may provide evidence, that urinary oxalate excretion is normal. We have now established this procedure as our first diagnostic step before further, more extensive and more expensive evaluations are performed.

Spot determinations of the urine creatinine concentration are widely used as a substitute for 24-h urine collections. Expressed as the amount excreted per gram of creatinine, urine concentrations in a single-voided sample are often used to estimate 24-h excretion rates of protein, sodium, potassium, calcium, magnesium, urea and uric acid. These estimates are predicated on the assumption that daily creatinine excretion equals 1 g (and that a urine creatinine concentration of 100 mg/dL reflects a 1 L 24-h urine volume). Such estimates are invalid if the serum creatinine concentration is rising or falling. In addition, because creatinine excretion is determined by muscle mass, the assumption that 24-h urine creatinine excretion equals 1 g yields a misleading estimate at the extremes of age and body size. In this review, we evaluate seven equations for the accuracy of their estimates of urine volume based on urine creatinine concentrations in actual and idealized patients. None of the equations works well in patients who are morbidly obese or in patients with markedly decreased muscle mass. In other patients, estimates based on a reformulation of the Cockroft–Gault equation are reasonably accurate. A recent study based on this relationship found a high strength of correlation between estimated and measured urine output with chronic kidney disease (CKD) studied in the African American Study of Kidney Disease (AASK) trial and for the patients studied in the CKD Optimal Management with Binders and NictomidE (COMBINE) trial. However, the equation systematically underestimated urine output in the AASK trial. Hence, an intercept was added to account for the bias in the estimated output. A more rigorous equation derived from an ambulatory Swiss population, which includes body mass index and models the non-linear accelerated decline in creatinine excretion with age, could potentially be more accurate in overweight and elderly patients. In addition to extremes of body weight and muscle mass, decreased dietary intake or reduced hepatic synthesis of creatine, a precursor of creatinine or ingestion of creatine supplements will also result in inaccurate estimates. These limitations must be appreciated to rationally use predictive equations to estimate urine volume. If the baseline urine creatinine concentration is determined in a sample of known volume, subsequent urine creatinine concentrations will reveal actual urine output as well as the change in urine output. Given the constraints of the various estimating equations, a single baseline timed collection may be a more useful strategy for monitoring urine volume than entering anthropomorphic data into a calculator.

Cystinuria is the most common genetic cause of nephrolithiasis in children. It is considered a heritable aminoaciduria as the genetic defect affects the reabsorption of cystine and three other amino acids (ornithine, lysine, and arginine) in the renal proximal tubule. Patients affected by this condition have elevated excretion of cystine in the urine, and because of this amino acid's low solubility at normal urine pH, patients tend to form cystine calculi. To date, two genes have been identified as disease-causative: SLC3A1 and SLC7A9, encoding for the two subunits of the heterodimeric transporter. The clinical features of this condition are solely related to nephrolithiasis. The diagnosis is usually made during infancy or adolescence, but cases of late diagnosis are common. The goal of therapy is to reduce excretion and increase the solubility of cystine, through both modifications of dietary habits and pharmacological treatment. However, therapeutic interventions are not always sufficient, and patients often have to undergo several surgical procedures during their lives to treat recurrent nephrolithiasis. The goal of this literature review is to synthesize the available evidence on diagnosis and management of patients affected by cystinuria in order to provide physicians with a practical tool that can be used in daily clinical practice. This review also aims to shed some light on new therapy directions with the aim of ameliorating kidney outcomes while improving adherence to treatment and quality of life of cystinuric patients.

As one of the major polymethoxyflavones in citrus peels, sinensetin (Sin) has been reported to possess numerous bioactivities. However, its detailed in vivo metabolic fate has not been uncovered yet. In the present study, the possible metabolites of Sin were synthesized, and all five mono-demethylated metabolites were successfully identified via ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis in rats fed with 100 mg/(kg·bw) Sin. The excretion and pharmacokinetic studies were then carried out to quantitatively investigate their variation in content with time in urine, feces, and plasma samples. Results showed that 4'-demethylsinensetin, 6-demethylsinensetin, and 3'-demethylsinensetin were the three most abundant metabolites generated in the above-mentioned biological samples. In addition, the total amount of Sin with its metabolites showed a significantly higher content in urine than in feces, indicating that Sin may be easily absorbed in the small intestine.

Background and objective L-Ornithine phenylacetate is an intravenous formulation of the L-ornithine salt of phenylacetic acid under development for the treatment of hepatic encephalopathy. Very limited clinical data in patients are available, with a phase II study in target patients not designed for dose finding, to support phase III dose selection in a global development program. The objective of the present population pharmacokinetic modeling and simulation was to evaluate dose selection for target patient populations with a low body weight, ethnicity, and hepatic impairment in a global clinical study. Methods A population pharmacokinetic model was developed based on plasma concentrations of L-ornithine, phenylacetic acid, and phenylacetylglutamine data from four clinical trials in healthy subjects and patients with stable cirrhosis or hospitalized adult patients with liver cirrhosis and hepatic encephalopathy. A covariate analysis was conducted to identify source of variability to support dose selection for global clinical development of L-ornithine phenylacetate. Phenylacetylglutamine formation in the pharmacokinetic model also quantified pharmacodynamic effects measured by ammonia removal. Results Body weight and hepatic function were significant covariates determining phenylacetic acid exposure. After accounting for body weight, there was no difference between tested Caucasian and Asian populations in phenylacetic acid exposure. Renal dysfunction significantly reduced phenylacetylglutamine excretion. However, renal impairment had no impact on plasma phenylacetic acid and free ammonia levels. Exploratory modeling suggested that L-ornithine might enhance the removal of ammonia. Conclusions With a flat dosing algorithm, special consideration must be given to patients with a small body size (i.e., body weight ≤ 50 kg) and severe hepatic impairment.