Bicarbonate Supplement Restores Urinary Klotho Excretion in Chronic Kidney Disease: A Pilot Study.

OBJECTIVE: We tested the hypothesis that correcting acidosis may improve urinary Klotho excretion and serum α-Klotho. DESIGN: This is a prospective, interventional, nonrandomized, open-label trial study. In this study setting, metabolic acidosis is commonly observed during chronic kidney disease (CKD). We reported a positive relationship between serum bicarbonate (Sbicar) and serum α-Klotho in these patients. SUBJECTS: The study involved 20 patients with a known kidney disease referred for renal checkup. Inclusion criteria were age ≥ 18 years, CKD stage 3-5 non dialysis, Sbicar < 22 mmol/L, and not receiving bicarbonate supplementation. INTERVENTION: Patients were then prescribed 1 g of oral sodium bicarbonate 3 times per day for 4 weeks. MAIN OUTCOME MEASURE: Patients were evaluated at two and 4 weeks by blood and urine measurements. RESULTS: Mean serum Klotho was 615 ± 287 pg/mL, and mean serum Sbicar was 19.3 ± 1.7 mmol/L at baseline. Sbicar increased from baseline at two (23.9 ± 2.9 mmol/L, P < .001) and 4 weeks (23.4 ± 1.9 mmol/L, P < .001). There was no change in serum Klotho at two (630 ± 333 mmol/L) and 4 weeks (632 ± 285 mmol/L). By contrast, urine Klotho/creatinine ratio, which was very low at baseline (34.6 ± 31.6 pg/mmoL), increased by 320% at two weeks (P < .005) and by 280% at 4 weeks (P < .01). CONCLUSIONS: Correcting acidosis by oral administration of sodium bicarbonate rapidly increases the urine excretion of soluble α-Klotho in CKD patients. However, a 4-week bicarbonate treatment was not able to increase serum α-Klotho. A longer study may confirm this pilot observation and increase serum Klotho, which has been shown to exert a protective cardiovascular effect during CKD.

Insulin receptor-related receptor as an extracellular alkali sensor.

The insulin receptor-related receptor (IRR), an orphan receptor tyrosine kinase of the insulin receptor family, can be activated by alkaline media both in vitro and in vivo at pH >7.9. The alkali-sensing property of IRR is conserved in frog, mouse, and human. IRR activation is specific, dose-dependent and quickly reversible and demonstrates positive cooperativity. It also triggers receptor conformational changes and elicits intracellular signaling. The pH sensitivity of IRR is primarily defined by its L1F extracellular domains. IRR is predominantly expressed in organs that come in contact with mildly alkaline media. In particular, IRR is expressed in the cell subsets of the kidney that secrete bicarbonate into urine. Disruption of IRR in mice impairs the renal response to alkali loading attested by development of metabolic alkalosis and decreased urinary bicarbonate excretion in response to this challenge. We therefore postulate that IRR is an alkali sensor that functions in the kidney to manage metabolic bicarbonate excess.

Resposta em parâmetros sanguíneos e urinários de vacas leiteiras ao aumento no balanço cátion-aniônico da dieta / Response in blood and urinary parameters of dairy cows to the increase in dietary cation-anion balance

Estudou-se efeito de quatro níveis de dietas catiônicas sobre os parâmetros ácido-base do sangue e o pH urinário de vacas em lactação. Para a manipulação dos níveis do balanço cátion-amônico da dieta (BCAD), foram adicionadas diferentes concentrações de bicarbonato de sódio às dietas, obtendo-se os seguintes tratamentos: +150, +250, +400 e +500mEq/kg de matéria seca. O experimento foi realizado durante o verão, por um período total de 72 dias, utilizando-se oito vacas da raça Holandesa após o pico de lactação, distribuídas em quadrado latino (4x4), replicado, em que cada período teve duração de 18 dias. O pH urinário e o bicarbonato, o pH, o CO2 total e a pCO2 do sangue aumentaram linearmente (P<0,01) com o aumento do BCAD. As concentrações de sódio e potássio do sangue não foram modificadas (P>0,05) pelo BCAD. A concentração de cloro no sangue diminuiu linearmente (P<0,01) com o aumento do BCAD. O aumento do BCAD afetou o equilíbrio ácido-base das vacas, promovendo efeito alcalinogênico, o que poderia levar a diferenças significativas no desempenho do animal.

The effect of four levels of cationic diets on acid-basic parameters of blood and the urinary pH were studied in dairy cattle. In order tomanage the dietary cation-anion balance (DCAB) different concentrations of sodium bicarbonate were added to diets, obtaining the following treatments: +150, +250, +400, and +500mEq/kg dry matter. The experiment was performed during the summer, totalizing 72 days, using eight Holstein cows after the lactating peak, distributed in 4 x 4 replicated latin square, with 18 days in each period. The urinary pH and the blood parameters (bicarbonate, pH, total CO2, and pCO2) linearly increased (P<0.01) with the DCAB increase. The sodium and potassium concentrations in blood were not modified (P>0.05) by DCAB. The chloride concentration in blood linearly decreased (P<0.01) with the DCAB increase. The DCAB increase affected the acid-base status of cows, promoting an alkalinogenic effect, what could lead to significant differences on animal performance.

Development and in vitro testing of a new method of urine preparation for retrograde ejaculation; the Liverpool solution.

OBJECTIVE: To design a new method for oral preparation of urine for sperm retrieval after retrograde ejaculation (RE) and to test the motility of sperm exposed to prepared and unprepared urine. DESIGN: In vitro testing of urine conditions and sperm motility. SETTING: Assisted conception unit at a teaching hospital in the United Kingdom. PATIENT(S): Ten healthy volunteers to provide urine and sperm specimens from men attending the unit for semen analysis. INTERVENTION(S): Various solutions of sodium bicarbonate and sodium chloride were drunk by a single subject until a suitable regimen was achieved. This regimen (called the Liverpool solution) was then tested on 10 volunteers. Samples of sperm were then added to prepared urine, unprepared urine, and culture medium, and the motility was analyzed. MAIN OUTCOME MEASURE(S): Urinary pH and osmolarity, sperm motility. RESULT(S): Urine produced by the 10 volunteers had a mean pH of 7.47 (range, 7.23-7.79) and a mean osmolarity of 289 mOsmol/L (range, 225-412 mOsmol/L), similar to that of medium. The progressive motility of sperm exposed to the unprepared urine was reduced (42.4% of sperm in medium), whereas that in the prepared urine was similar to that in the control medium. CONCLUSION(S): Liverpool solution can be used in any unit treating couples with RE, and it is a noninvasive and inexpensive regimen that may optimize urine pH and osmolarity for sperm survival after RE.

Isolation of bicarbonate from equine urine for isotope ratio mass spectrometry.

Sodium bicarbonate administration to horses prior to competition in order to enhance the buffer capacity of the organism is considered as a doping offence. The analysis of the isotopic composition of urinary bicarbonate/CO(2) (TCO(2)) may help to identify an exogenous bicarbonate source, as technical sodium bicarbonate exhibits elevated delta(13)C values compared with urinary total carbon. The isolation of TCO(2) from 60 equine urine samples as BaCO(3) followed by an isotopic analysis shows a significant variability of delta(13)C for TCO(2) of more than 10 per thousand. The delta(13)C of total carbon and TCO(2) seem to reflect different proportions of C3 and C4 plant material in the diet. The isotopic analysis of different mixtures of technical NaHCO(3) and equine urine shows that TCO(2) can be easily isolated without major isotopic fractionation; however, attention has to be paid to the storage time of urine samples, as a shift of delta(13)C of TCO(2) to lower values may occur.

Effects of urine alkalization and activated charcoal on the pharmacokinetics of orally administered carprofen in dogs.

OBJECTIVE: To investigate the effects of oral administration of activated charcoal (AC) and urine alkalinization via oral administration of sodium bicarbonate on the pharmacokinetics of orally administered carprofen in dogs. ANIMALS: 6 neutered male Beagles. PROCEDURES: Each dog underwent 3 experiments (6-week interval between experiments). The dogs received a single dose of carprofen (16 mg/kg) orally at the beginning of each experiment; after 30 minutes, sodium bicarbonate (40 mg/kg, PO), AC solution (2.5 g/kg, PO), or no other treatments were administered. Plasma concentrations of unchanged carprofen were determined via high-performance liquid chromatography at intervals until 48 hours after carprofen administration. Data were analyzed by use of a Student paired t test or Wilcoxon matched-pairs rank test. RESULTS: Compared with the control treatment, administration of AC decreased plasma carprofen concentrations (mean +/- SD maximum concentration was 85.9 +/- 11.9 mg/L and 58.1 +/- 17.6 mg/L, and area under the time-concentration curve was 960 +/- 233 mg/L x h and 373 +/- 133 mg/L x h after control and AC treatment, respectively). The elimination half-life remained constant. Administration of sodium bicarbonate had no effect on plasma drug concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: After oral administration of carprofen in dogs, administration of AC effectively decreased maximum plasma carprofen concentration, compared with the control treatment, probably by decreasing carprofen absorption. Results suggest that AC can be used to reduce systemic carprofen absorption in dogs receiving an overdose of carprofen. Oral administration of 1 dose of sodium bicarbonate had no apparent impact on carprofen kinetics in dogs.

Use of [14C]-sodium bicarbonate/urea to measure physical activity induced increases in total energy expenditure in free-living healthy males.

The aim of this study was to evaluate the utility of the [(14)C]-sodium bicarbonate/urea technique to detect physical activity-induced increases in total energy expenditure in free-living healthy men. Thirteen healthy males aged 34.1 +/- 11.7 yrs with body mass index 24.1 +/- 3.1 kg/m(2) were studied on three separate occasions, during which [(14)C]-bicarbonate was infused over 48-hours and urine was collected during the second 24-hours. On three separate occasions and in random order, subjects either remained sedentary, or performed a bout of physical activity on an electro-magnetically braked cycle ergometer sufficient to increase energy expenditure by 7% or 11% above predicted sedentary total energy expenditure. Urine samples were analyzed to evaluate the amount of [(14)C]-bicarbonate incorporated into urinary urea, thereby reflecting the amount of CO(2) produced per day, and upon conversion, the number of kilojoules of energy expended in 24-hours. All 13 subjects successfully completed the two physical activity treatments and there were no adverse events. As measured by the [(14)C]-urea assay, mean total energy expenditure values were not significantly different between sedentary activity (17902 +/- 905 kJ/day), the physical activity treatment designed to increase TEE by 7% (17701 +/- 594 kJ/day) and the physical activity treatment designed to increase TEE by 11% (18538 +/- 485 kJ/day) (P=0.668). In conclusion, although the [(14)C]-sodium bicarbonate/urea technique was well tolerated and did not interfere with normal daily activities, it was not able to accurately measure physical activity-induced increases in EE in the range of 7-11% above predicted sedentary total energy expenditure.

Effects of calcium carbonate, magnesium oxide and sodium citrate bicarbonate health supplements on the urinary risk factors for kidney stone formation.

We describe a model to illustrate different chemical interactions that can occur in urine following ingestion of individual and combined health supplements. Two types of interactions are defined: synergism and addition. The model was applied to eight healthy males who participated in a study to investigate the chemical interactions between calcium carbonate, magnesium oxide and sodium citrate-bicarbonate health supplements on calcium oxalate urinary stone risk factors. Subjects ingested these components individually and in combination for 7 days. Twenty-four-hour urines were collected at baseline and during the final day of supplementation. These were analysed using standard laboratory techniques. Three different chemical interactions, all involving citrate, were identified: magnesium and citrate exerted a synergistic effect on lowering the relative superaturation (RS) of brushite; the same two components produced a synergistic effect on raising pH; finally, calcium and citrate exerted an additive effect on lowering the RS of uric acid. We propose that the novel approach described in this paper allows for the evaluation of individual, additive and synergistic interactions in the assessment of the efficacy of stone-risk reducing preparations.

Effects of sodium lactate on ventilation and acid-base balance in healthy humans.

Sodium lactate inhibits ventilation when infused in healthy human subjects. This effect has been attributed to lactate-induced metabolic alkalosis. In order to further delineate the mechanisms responsible for this depression of ventilation, healthy humans were infused with sodium lactate with or without acetazolamide. Sodium lactate increased blood pH from 7.37 +/- 0.02 to 7.47 +/- 0.01 and induced a sustained urinary excretion of bicarbonate. PO2 of arterialized blood decreased by 10.3 +/- 2.1 mmHg, indicating an inhibition of ventilation. Acetazolamide decreased lactate-induced alkalinisation of blood (pH after lactate + acetazolamide 7.42 +/- 0.02), but did not prevent the drop in PO2. Acetazolamide alone tended to stimulate ventilation, as indicated by an increase in PO2. These results indicate that sodium lactate inhibits ventilation independently of changes in systemic blood pH. Alkalinization of the cerebrospinal fluid, or other central effects of lactate, is probably responsible for this ventilatory depression.