Metabolic acidosis regulates RGS16 and G protein signaling in osteoblasts.

Chronic metabolic acidosis stimulates cell-mediated net Ca2+ efflux from bone mediated by increased osteoblastic cyclooxygenase 2, leading to prostaglandin E2-induced stimulation of receptor activator of NF-κB ligand-induced osteoclastic bone resorption. Ovarian cancer G protein-coupled receptor-1 (OGR1), an osteoblastic H+-sensing G protein-coupled receptor, is activated by acidosis and leads to increased bone resorption. As regulator of G protein signaling (RGS) proteins limit GPCR signaling, we tested whether RGS proteins themselves are regulated by metabolic acidosis. Primary osteoblasts were isolated from neonatal mouse calvariae and incubated in physiological neutral or acidic (MET) medium. Cells were collected, and RNA was extracted for real-time PCR analysis with mRNA levels normalized to ribosomal protein L13a. RGS1, RGS2, RGS3, RGS4, RGS10, RGS11, and RGS18 mRNA did not differ between MET and neutral medium; however, by 30 min, MET decreased RGS16, which persisted for 60 min and 3 h. Incubation of osteoblasts with the OGR1 inhibitor CuCl2 inhibited the MET-induced increase in RGS16 mRNA. Gallein, a specific inhibitor of Gßγ signaling, was used to determine if downstream signaling by the ßγ-subunit was critical for the response to acidosis. Gallein decreased net Ca2+ efflux from calvariae and cyclooxygenase 2 and receptor activator of NF-κB ligand gene expression from isolated osteoblasts. These results indicate that regulation of RGS16 plays an important role in modulating the response of the osteoblastic GPCR OGR1 to metabolic acidosis and subsequent stimulation of osteoclastic bone resorption.NEW & NOTEWORTHY The results presented in this study indicate that regulation of regulator of G protein signaling 16 and G protein signaling in the osteoblast plays an important role in modulating the response of osteoblastic ovarian cancer G protein-coupled receptor 1 (OGR1) to metabolic acidosis and the subsequent stimulation of osteoclastic bone resorption. Further characterization of the regulation of OGR1 in metabolic acidosis-induced bone resorption will help in understanding bone loss in acidotic patients with chronic kidney disease.

Exogenous ketosis increases blood and muscle oxygenation but not performance during exercise in hypoxia.

Available evidence indicates that elevated blood ketones are associated with improved hypoxic tolerance in rodents. From this perspective, we hypothesized that exogenous ketosis by oral intake of the ketone ester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE) may induce beneficial physiological effects during prolonged exercise in acute hypoxia. As we recently demonstrated KE to deplete blood bicarbonate, which per se may alter the physiological response to hypoxia, we evaluated the effect of KE both in the presence and absence of bicarbonate intake (BIC). Fourteen highly trained male cyclists performed a simulated cycling race (RACE) consisting of 3-h intermittent cycling (IMT180') followed by a 15-min time-trial (TT15') and an all-out sprint at 175% of lactate threshold (SPRINT). During RACE, fraction of inspired oxygen ([Formula: see text]) was gradually decreased from 18.6% to 14.5%. Before and during RACE, participants received either 1) 75 g of ketone ester (KE), 2) 300 mg/kg body mass bicarbonate (BIC), 3) KE + BIC, or 4) a control drink in addition to 60 g of carbohydrates/h in a randomized, crossover design. KE counteracted the hypoxia-induced drop in blood ([Formula: see text]) and muscle oxygenation by ∼3%. In contrast, BIC decreased [Formula: see text] by ∼2% without impacting muscle oxygenation. Performance during TT15' and SPRINT were similar between all conditions. In conclusion, KE slightly elevated the degree of blood and muscle oxygenation during prolonged exercise in moderate hypoxia without impacting exercise performance. Our data warrant to further investigate the potential of exogenous ketosis to improve muscular and cerebral oxygenation status, and exercise tolerance in extreme hypoxia.

Effect of Bicarbonate on Net Acid Excretion, Blood Pressure, and Metabolism in Patients With and Without CKD: The Acid Base Compensation in CKD Study.

RATIONALE & OBJECTIVE: Patients with CKD are at elevated risk of metabolic acidosis due to impaired net acid excretion (NAE). Identifying early markers of acidosis may guide prevention in chronic kidney disease (CKD). This study compared NAE in participants with and without CKD, as well as the NAE, blood pressure (BP), and metabolomic response to bicarbonate supplementation. STUDY DESIGN: Randomized order, cross-over study with controlled feeding. SETTING & PARTICIPANTS: Participants consisted of 8 patients with CKD (estimated glomerular filtration rate 30-59mL/min/1.73m2 or 60-70mL/min/1.73m2 with albuminuria) and 6 patients without CKD. All participants had baseline serum bicarbonate concentrations between 20 and 28 mEq/L; they did not have diabetes mellitus and did not use alkali supplements at baseline. INTERVENTION: Participants were fed a fixed-acid-load diet with bicarbonate supplementation (7 days) and with sodium chloride control (7 days) in a randomized order, cross-over fashion. OUTCOMES: Urine NAE, 24-hour ambulatory BP, and 24-hour urine and plasma metabolomic profiles were measured after each period. RESULTS: During the control period, mean NAE was 28.3±10.2 mEq/d overall without differences across groups (P=0.5). Urine pH, ammonium, and citrate were significantly lower in CKD than in non-CKD (P<0.05 for each). Bicarbonate supplementation reduced NAE and urine ammonium in the CKD group, increased urine pH in both groups (but more in patients with CKD than in those without), and increased; urine citrate in the CKD group (P< 0.2 for interaction for each). Metabolomic analysis revealed several urine organic anions were increased with bicarbonate in CKD, including 3-indoleacetate, citrate/isocitrate, and glutarate. BP was not significantly changed. LIMITATIONS: Small sample size and short feeding duration. CONCLUSIONS: Compared to patients without CKD, those with CKD had lower acid excretion in the form of ammonium but also lower base excretion such as citrate and other organic anions, a potential compensation to preserve acid-base homeostasis. In CKD, acid excretion decreased further, but base excretion (eg, citrate) increased in response to alkali. Urine citrate should be evaluated as an early and responsive marker of impaired acid-base homeostasis. FUNDING: National Institute of Diabetes and Digestive and Kidney Diseases and the Duke O'Brien Center for Kidney Research. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02427594.

Intradialytic acid-base changes and organic anion production during high versus low bicarbonate hemodialysis.

The use of high dialysate bicarbonate for hemodialysis in end-stage renal disease is associated with increased mortality, but potential physiological mediators are poorly understood. Alkalinization due to high dialysate bicarbonate may stimulate organic acid generation, which could lead to poor outcomes. Using measurements of ß-hydroxybutyrate (BHB) and lactate, we quantified organic anion (OA) balance in two single-arm studies comparing high and low bicarbonate prescriptions. In study 1 (n = 10), patients became alkalemic using 37 meq/L dialysate bicarbonate; in contrast, with the use of 27 meq/L dialysate, net bicarbonate loss occurred and blood bicarbonate decreased. Total OA losses were not higher with 37 meq/L dialysate bicarbonate (50.9 vs. 49.1 meq using 27 meq/L, P = 0.66); serum BHB increased in both treatments similarly (P = 0.27); and blood lactate was only slightly higher with the use of 37 meq/L dialysate (P = 0.048), differing by 0.2 meq/L at the end of hemodialysis. In study 2 (n = 7), patients achieved steady state on two bicarbonate prescriptions: they were significantly more acidemic when dialyzed against a 30 meq/L bicarbonate dialysate compared with 35 meq/L and, as in study 1, became alkalemic when dialyzed against the higher bicarbonate dialysate. OA losses were similar to those in study 1 and again did not differ between treatments (38.9 vs. 43.5 meq, P = 0.42). Finally, free fatty acid levels increased throughout hemodialysis and correlated with the change in serum BHB (r = 0.81, P < 0.001), implicating upregulation of lipolysis as the mechanism for increased ketone production. In conclusion, lowering dialysate bicarbonate does not meaningfully reduce organic acid generation during hemodialysis or modify organic anion losses into dialysate.

Enteric methane emission and digestion in dairy cows fed wheat or molasses.

The aim of this experiment was to measure enteric methane (CH4) emission and its relation with rumen digestion in dairy cows fed diets rich in 1 of the 2 carbohydrate sources, starch or sugar. The rations were based on late first-cut grass-clover silage supplemented with wheat (Wh), NaOH-treated wheat (Wh+NaOH), sugar beet molasses (Mo), or sugar beet molasses with addition of sodium bicarbonate (Mo+Bic). Wheat and molasses made up 35% of dry matter in the 2 diets with molasses and wheat, respectively. Four cows fitted with ruminal, duodenal, and ileal canulae were used in a 4 × 4 Latin square design. Nutrient digestibility was measured using chromium oxide and titanium oxide as flow markers, and emissions of CH4 and hydrogen were measured via open-circuit indirect calorimetry on 4 consecutive days. Data were analyzed using PROC MIXED of SAS (version 9.4; SAS Institute Inc., Cary, NC) with treatment and period as fixed effects and cow as random effect. Furthermore, orthogonal contrasts were calculated. The cows produced 32.5, 33.6, 36.2, and 35.1 L of CH4/kg of dry matter intake (DMI) on diets Wh, Wh+NaOH, Mo, and Mo+Bic, respectively. The emission of CH4 per day, per kilogram of DMI, and per kilogram of energy-corrected milk as well as daily hydrogen emission were higher on the Mo diet compared with the Wh diet. With the present inclusion of wheat and molasses in the diet, no effects of NaOH treatment of wheat or of sodium bicarbonate supplementation to the Mo diet could be demonstrated on CH4 emission expressed per kilogram of DMI or per kilogram of energy-corrected milk. The duodenal flow of starch was higher when wheat was treated with NaOH. Under the conditions in the present experiment, ruminal NDF digestibility was not affected by carbohydrate source, NaOH treatment of wheat, or bicarbonate supplementation. Total volatile fatty acid concentration in the rumen and the proportions of acetate and propionate were not affected by carbohydrate source, NaOH treatment of wheat, or bicarbonate supplementation. Likewise, we could not show any influence of diet on microbial protein synthesis or efficiency of microbial protein synthesis expressed as grams of microbial protein synthesis per kilogram of true rumen-digested organic matter. We concluded that CH4 emission was increased when wheat was replaced by molasses, whereas no effect of manipulating rumen fermentation by NaOH treatment of wheat or addition of bicarbonate to molasses could be found with a level of approximately 25% of dry matter from starch and sugar, respectively.

Effect of Bicarbonate-Buffered Dialysate on Ventricular Arrhythmias in Hemodialysis Patients.

BACKGROUND: The etiology of sudden cardiac death in patients with end-stage renal disease (ESRD) on hemodialysis (HD) is largely unknown, though there is evidence to suggest that metabolic alkalosis induced by HD with a high-bicarbonate dialysate/prescription may play a role. METHODS: We investigated the effects of metabolic alkalosis induced by HD with an acetate-containing bicarbonate-buffered dialysate on frequency of ventricular arrhythmia in 47 patients with ESRD on chronic HD using 48-h Holter monitoring in 3 phases: intra-HD, post-HD day 1, and post-HD day 2. Serum levels of bicarbonate, calcium, and potassium along with hemodynamics were measured pre-HD, post-HD, 20-h post-HD, and 44-h post-HD. Correlations were performed to verify the association between bicarbonate prescription and change in serum bicarbonate levels post-HD and to determine if the HD-induced change in serum bicarbonate level (metabolic alkalosis) had any direct association with ambient ventricular arrhythmia (premature ventricular contractions per hour) or indirect associations with ambient ventricular arrhythmia by affecting electrolytes or hemodynamics that are known to increase the risk of ventricular arrhythmia. RESULTS: Mean pre-HD serum bicarbonate level was 21.3 mEq/L. Dialysate bicarbonate prescription (mean of 36.4 mEq/L) correlated with changes in serum bicarbonate levels immediately post-HD 26.7 mEq/L (r = 0.46, p < 0.01), 20-h post-HD 25.2 mEq/L (r = 0.38), and 44-h post-HD 23.2 mEq/L (r = 0.35, p = 0.01). No statistically significant correlations were found between the post-HD change in serum bicarbonate levels (metabolic alkalosis) with ambient ventricular arrhythmia, changes in serum calcium, potassium, or hemodynamics in any phase. CONCLUSIONS: High-bicarbonate dialysate prescription is associated with metabolic alkalosis following the HD procedure. A mild metabolic alkalosis induced by HD with an acetate-containing bicarbonate-buffered dialysate solution had no direct association with ambient ventricular arrhythmia on Holter monitoring and was not associated with changes in hemodynamics or changes in serum total calcium or potassium levels. This study helps to provide guidance for the safe use of high bicarbonate dialysate/prescription in patients with ESRD on HD.

Lactation ketoacidosis: an easily missed diagnosis.

Ketoacidosis is uncommon in non-diabetic women, but occurs in the postpartum period as a rare complication of continuing to breastfeed during periods of acute illness. We report a case of a lactating woman who presented with severe symptomatic ketoacidosis in the early postpartum period. We also review the pathophysiology and management of lactation ketoacidosis.

Gastroenteritis in Children.

Acute gastroenteritis is defined as a diarrheal disease of rapid onset, with or without nausea, vomiting, fever, or abdominal pain. In the United States, acute gastroenteritis accounts for 1.5 million office visits, 200,000 hospitalizations, and 300 deaths in children each year. Evaluation of a child with acute gastroenteritis should include a recent history of fluid intake and output. Significant dehydration is unlikely if parents report no decrease in oral intake or urine output and no vomiting. The physical examination is the best way to evaluate hydration status. The four-item Clinical Dehydration Scale can be used to determine severity of dehydration based on physical examination findings. In children with mild illness, stool microbiological tests are not routinely needed when viral gastroenteritis is the likely diagnosis. Mild gastroenteritis in children can be managed at home. Oral rehydration therapy, such as providing half-strength apple juice followed by the child's preferred liquids, is the mainstay of treatment for mild dehydration and is as effective as intravenous rehydration for preventing hospitalization and return to the emergency department. Oral rehydration solutions are recommended for moderate dehydration. Ondansetron may be prescribed if needed to prevent vomiting and improve tolerance of oral rehydration solutions. Hospitalization and intravenous fluids are recommended for children who do not respond to oral rehydration therapy plus an antiemetic and patients with severe dehydration (i.e., signs of shock or more than 10% dehydration). Handwashing, breastfeeding, and rotavirus vaccination reduce the incidence of acute gastroenteritis in young children.

Changes in V-ATPase subunits of human urinary exosomes reflect the renal response to acute acid/alkali loading and the defects in distal renal tubular acidosis.

In the kidney, final urinary acidification is achieved by V-ATPases expressed in type A intercalated cells. The B1 subunit of the V-ATPase is required for maximal urinary acidification, while the role of the homologous B2 subunit is less clear. Here we examined the effect of acute acid/alkali loading in humans on B1 and B2 subunit abundance in urinary exosomes in normal individuals and of acid loading in patients with distal renal tubular acidosis (dRTA). Specificities of B1 and B2 subunit antibodies were verified by yeast heterologously expressing human B1 and B2 subunits, and murine wild-type and B1-deleted kidney lysates. Acute ammonium chloride loading elicited systemic acidemia, a drop in urinary pH, and increased urinary ammonium excretion. Nadir urinary pH was achieved at four to five hours, and exosomal B1 abundance was significantly increased at two through six hours after ammonium chloride loading. After acute equimolar sodium bicarbonate loading, blood and urinary pH rose rapidly, with a concomitant reduction of exosomal B1 abundance within two hours, which remained lower throughout the test. In contrast, no change in exosomal B2 abundance was found following acid or alkali loading. In patients with inherited or acquired distal RTA, the urinary B1 subunit was extremely low or undetectable and did not respond to acid loading in urine, whereas no change in B2 subunit was found. Thus, both B1 and B2 subunits of the V-ATPase are detectable in human urinary exosomes, and acid and alkali loading or distal RTA cause changes in the B1 but not B2 subunit abundance in urinary exosomes.

Pyruvate in reduced osmolarity oral rehydration salt corrected lactic acidosis in sever scald rats.

BACKGROUND: A novel pyruvate-based oral rehydration salt (Pyr-ORS) was demonstrated of superiority over bicarbonate- or citrate-based one to preserve organ function and correct lactic acidosis in rehydration of lethal shock in animals. This study further compared these effects between low-osmolar Pyr-ORS and equimolar citrate-based counterpart. METHODS: Eighty rats, using a fatal burn shock model, were randomized into four groups (two subgroups per group: n = 10): the sham group (group SR), Pyr-ORS group (group PR), WHO-ORS III group (group CR), and no rehydration group. ORS was delivered by manual gavage during 24 h following burns. Oral administration consisted of half of counted volume in the initial 8 h plus the rest in the later 16 h. Systemic hemodynamics, visceral organ surface blood flow, organ function, and metabolic acidosis were determined at 8 h and 24 h after burn. Another set of rats with identical surgical procedures without tests was observed for survival. RESULTS: Survival was markedly improved in the groups PR and CR; the former showed a higher survival rate than the latter at 24 h (40% versus 20%, P < 0.05). Systemic hemodynamics, visceral blood flow, and function of heart, liver, and kidney were greatly restored in group PR, compared with group CR (all P < 0.05). Hypoxic lactic acidosis was efficiently reversed in group PR, instead of group CR, (pH 7.36 versus 7.11, base excess 2.1 versus -9.1 mmol/L, lactate 4.28 versus 8.18 mmol/L; all P < 0.05) at 24 h after injury. CONCLUSIONS: Pyruvate was advantageous over citrate in low-osmolar ORS for protection of organs and survival; pyruvate, but not citrate, in the ORS corrected hypoxic lactic acidosis in rats subjected to lethal burn shock in 24 h.

HYDration and Bicarbonate to Prevent Acute Renal Injury After Endovascular Aneurysm Repair With Suprarenal Fixation: Pilot/Feasibility Randomised Controlled Study (HYDRA Pilot Trial).

OBJECTIVE/BACKGROUND: Up to 25% of patients undergoing elective endovascular aneurysm repair (EVAR) develop acute kidney injury (AKI), which is associated with short and long-term morbidity and mortality. There is no high quality randomised evidence regarding prevention of EVAR related AKI. METHODS: A novel AKI prevention strategy for EVAR was devised, based on best evidence and an expert consensus group. This included a bolus of high dose sodium bicarbonate (NaHCO3) immediately before EVAR (1 mL/kg of 8.4% NaHCO3) and standardised crystalloid based hydration pre- and post-EVAR. A pilot/feasibility randomised controlled trial (RCT) was performed in two centres to assess the safety of the intervention, potential impact on AKI prevention, and feasibility of a national RCT; the primary end point was the proportion of eligible patients recruited into the study. AKI was defined using "Kidney Disease Improving Global Outcomes" and "Acute Kidney Injury Network" criteria based on National Institute for Health and Clinical Excellence AKI recommendations, using serum creatinine and hourly urine output. RESULTS: Fifty-eight patients (84% of those screened; median age 75 years [range 57-89 years], 10% female) were randomised to receive the standardised intravenous hydration with (intervention) or without (control) NaHCO3. Groups were comparable in terms of AKI risk factors; 56 of 58 participants had a device with suprarenal fixation. Overall, 33% of patients in the control arm developed AKI versus 7% in the intervention arm (as treated analysis). None of the patients receiving NaHCO3 developed a serious intervention related adverse event; five patients did not attend their 30 day follow-up. CONCLUSION: Bolus high dose NaHCO3 and hydration is a promising EVAR related AKI prevention method. This trial has confirmed the feasibility of delivering a definitive large RCT to confirm the efficacy of this novel intervention, in preventing EVAR related AKI.

Effects of carbohydrate type or bicarbonate addition to grass silage-based diets on enteric methane emissions and milk fatty acid composition in dairy cows.

The aim of the study was to compare the effect of fiber- or starch-rich diets based on grass silage, supplemented or not with bicarbonate, on CH4 emissions and milk fatty acid (FA) profile in dairy cows. The experiment was conducted as a 4 × 4 Latin square design with a 2 × 2 factorial arrangement: carbohydrate type [starch- or fiber-rich diets with dietary starch level of 23.1 and 5.9% on a dry matter basis, respectively], without or with bicarbonate addition [0 and 1% of the dry matter intake, respectively]. Four multiparous lactating Holstein cows were fed 4 diets with 42% grass silage, 8% hay, and 50% concentrate in 4 consecutive 4-wk periods: (1) starch-rich diet, (2) starch-rich diet with bicarbonate, (3) fiber-rich diet, and (4) fiber-rich diet with bicarbonate. Intake and milk production were measured daily and milk composition was measured weekly; CH4 emission and total-tract digestibility were measured simultaneously (5 d, wk 4) when animals were in open-circuit respiration chambers. Sensors continuously monitored rumen pH (3 d, wk 4), and fermentation parameters were analyzed from rumen fluid samples taken before feeding (1 d, wk 3). Cows fed starch-rich diets had less CH4 emissions (on average, -18% in g/d; -15% in g/kg of dry matter intake; -19% in g/kg of milk) compared with fiber-rich diets. Carbohydrate type did not affect digestion of nutrients, except starch, which increased with starch-rich diets. The decrease in rumen protozoa number (-36%) and the shift in rumen fermentation toward propionate at the expense of butyrate for cows fed the starch-rich diets may be the main factor in reducing CH4 emissions. Milk of cows fed starch-rich diets had lower concentrations in trans-11 C18:1, sum of cis-C18, cis-9,trans-11 conjugated linoleic acid (CLA), and sum of CLA, along with greater concentration of some minor isomers of CLA and saturated FA in comparison to the fiber-rich diet. Bicarbonate addition did not influence CH4 emissions or nutrient digestibility regardless of the carbohydrate type in the diet. Rumen pH increased with bicarbonate addition, whereas other rumen parameters and milk FA composition were almost comparable between diets. Feeding dairy cows a starch-rich diet based on grass silage helps to limit the negative environmental effect of ruminants, but does not lead to greater milk nutritional value because milk saturated FA content is increased.

In vivo pH mapping of injured lungs using hyperpolarized [1-13 C]pyruvate.

PURPOSE: To optimize the production of hyperpolarized 13 C-bicarbonate from the decarboxylation of hyperpolarized [1-13 C]pyruvate and use it to image pH in the lungs and heart of rats with acute lung injury. METHODS: Two forms of catalysis are compared calorimetrically to maximize the rate of decarboxylation and rapidly produce hyperpolarized bicarbonate from pyruvate while minimizing signal loss. Rats are injured using an acute lung injury model combining ventilator-induced lung injury and acid aspiration. Carbon images are obtained from both healthy (n = 4) and injured (n = 4) rats using a slice-selective chemical shift imaging sequence with low flip angle. pH is calculated from the relative HCO3- and CO2 signals using the Henderson-Hasselbalch equation. RESULTS: It is demonstrated that base catalysis is more effective than metal-ion catalysis for this decarboxylation reaction. Bicarbonate polarizations up to 17.2% are achieved using the base-catalyzed reaction. A mean pH difference between lung and heart of 0.14 pH units is measured in the acute lung injury model. A significant pH difference between injured and uninjured lungs is also observed. CONCLUSION: It is demonstrated that hyperpolarized 13 C-bicarbonate can be efficiently produced from the base-catalyzed decarboxylation of pyruvate. This method is used to obtain the first regional pH image of the lungs and heart of an animal. Magn Reson Med 78:1121-1130, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

Increasing alkali supplementation decreases urinary nitrogen excretion when adjusted for same day nitrogen intake.

We examined whether escalating doses of potassium bicarbonate (KHCO3) supplements alter urinary nitrogen excretion expressed as a ratio to same day nitrogen intake (measure of muscle-protein breakdown). The ratio declined significantly from placebo to low to high dose of KHCO3 supplementation in older adults over 3 months, suggesting muscle-sparing. INTRODUCTION: Neutralization of dietary acid load with alkali supplementation (i.e., KHCO3) has been hypothesized to have muscle protein-sparing effects. In controlled feeding studies with fixed nitrogen (N) intake/day, 24-h urinary N excretion is a good marker of muscle breakdown. However, in studies with self-selected diets, changes in 24-h urinary N excretion can be influenced by shifts in N intake. METHODS: We evaluated changes in 24-h total urinary N excretion as a ratio of N excretion to concurrent N intake in 233 older men and women who participated in an 84-day KHCO3 supplementation randomized placebo-controlled trial. RESULTS: After adjustment for relevant cofactors, escalating doses of KHCO3 (1 mmol/kg/day [low] or 1.5 mmol/kg/day [high]) resulted in a progressive decline in urinary N excretion/N intake compared to placebo (overall P for trend = 0.042). The 84-day change in urinary N excretion/N intake in the high-dose KHCO3 group was statistically significantly lower compared to placebo (P = 0.012) but not compared to the low-dose KHCO3 group (P = 0.276). The 84-day change in urinary N excretion/N intake in the low-dose KHCO3 group did not differ significantly from placebo (P = 0.145). CONCLUSIONS: Urinary N excretion expressed as ratio to same day N intake declined steadily with increasing doses of KHCO3 supplementation from low 1 mmol/kg/day to high 1.5 mmol/kg/day, suggesting a nitrogen-sparing effect. Compared to urinary N excretion alone, this ratio could be a more reasonable measure of muscle protein metabolism in large-scale long-term human studies. TRIAL REGISTRATION: Clinicaltrials.gov NCT1475214.

Dialysate Composition for Hemodialysis: Changes and Changing Risk.

Dialysate composition is a critical aspect of the hemodialysis prescription. Despite this, trial data are almost entirely lacking to help guide the optimal dialysate composition. Often, the concentrations of key components are chosen intuitively, and dialysate composition may be determined by default based on dialysate manufacturer specifications or hemodialysis facility practices. In this review, we examine the current epidemiological evidence guiding selection of dialysate bicarbonate, calcium, magnesium, and potassium, and identify unresolved issues for which pragmatic clinical trials are needed.

Oral Bicarbonate Slows Decline of Residual Renal Function in Peritoneal Dialysis Patients.

BACKGROUND/AIMS: Metabolic acidosis is a common consequence of end-stage renal disease (ESRD) which may result in a substantial adverse outcome. The effect of oral bicarbonate on the preservation of residual renal function (RRF) in peritoneal dialysis (PD) patients has been rarely reported. METHODS: We randomly assigned 40 continuous ambulatory peritoneal dialysis (CAPD) patients to the oral bicarbonate group or placebo group at a 1: 1 ratio. All enrollments were followed for a duration of 104 weeks. We took residual creatinine clearance (CCr), a measure of residual renal function (RRF), as the primary outcome. Residual CCr was calculated as the average of urea and creatinine clearance from a 24-hour urine collection. RESULTS: Thirteen patients in the placebo group and 15 patients in the treatment group completed the 104 weeks of follow-up with a comparable dropout rate (placebo group: 35% vs treatment group: 25%). Compared with the placebo group, serum bicarbonate in treatment group was significantly increased at each time point, and oral bicarbonate resulted in a slower declining rate of residual CCr (F=5.113, p=0.031). Baseline residual CCr at enrollment also had a significant effect on residual CCr (F=168.779, P<0.001). Charlson Comorbidity Index which was adopted to calculate a comorbidity score had no significant effect on residual CCr loss (F=0.168, P=0.685). CONCLUSION: Oral bicarbonate may have a RRF preserving effect in CAPD patients, and a normal to high level of serum bicarbonate (≥24mmol/L) may be appropriate for RRF preservation.

Gastric Fluid Volume Change After Oral Rehydration Solution Intake in Morbidly Obese and Normal Controls: A Magnetic Resonance Imaging-Based Analysis.

BACKGROUND: Although preoperative fluid intake 2 hours before anesthesia is generally considered safe, there are concerns about delayed gastric emptying in obese subjects. In this study, the gastric fluid volume (GFV) change in morbidly obese subjects was investigated after ingesting an oral rehydration solution (ORS) and then compared with that in nonobese subjects. METHODS: GFV change over time after the ingestion of 500 mL of ORS containing 2.5% carbohydrate (OS-1) was measured in 10 morbidly obese subjects (body mass index [BMI], >35) scheduled for bariatric surgery and 10 nonobese (BMI, 19-24) using magnetic resonance imaging. After 9 hours of fasting, magnetic resonance imaging scans were performed at preingestion, 0 min (just after ingestion), and every 30 minutes up to 120 minutes. GFV values were compared between morbidly obese and control groups and also between preingestion and postingestion time points. RESULTS: The morbidly obese group had a significantly higher body weight and BMI than the control group (mean body weight and BMI in morbidly obese, 129.6 kg and 46.3 kg/m, respectively; control, 59.5 kg and 21.6 kg/m, respectively). GFV was significantly higher in the morbidly obese subjects compared with the control group at preingestion (73 ± 30.8 mL vs 31 ± 19.9 mL, P = .001) and at 0 minutes after ingestion (561 ± 30.8 mL vs 486 ± 42.8 mL; P < .001). GFV declined rapidly in both groups and reached fasting baseline levels by 120 minutes (morbidly obese, 50 ± 29.5 mL; control, 30 ± 11.6 mL). A significant correlation was observed between preingestion residual GFV and body weight (r = .66; P = .001). CONCLUSIONS: Morbidly obese subjects have a higher residual gastric volume after 9 hours of fasting compared with subjects with a normal BMI. However, no differences were observed in gastric emptying after ORS ingestion in the 2 populations, and GFVs reached baseline within 2 hours after ORS ingestion. Further studies are required to confirm whether the preoperative fasting and fluid management that are recommended for nonobese patients could also be applied to morbidly obese patients.

Three-Stream, Bicarbonate-Based Hemodialysis Solution Delivery System Revisited: With an Emphasis on Some Aspects of Acid-Base Principles.

Hemodialysis patients can acquire buffer base (i.e., bicarbonate and buffer base equivalents of certain organic anions) from the acid and base concentrates of a three-stream, dual-concentrate, bicarbonate-based, dialysis solution delivery machine. The differences between dialysis fluid concentrate systems containing acetic acid versus sodium diacetate in the amount of potential buffering power were reviewed. Any organic anion such as acetate, citrate, or lactate (unless when combined with hydrogen) delivered to the body has the potential of being converted to bicarbonate. The prescribing physician aware of the role that organic anions in the concentrates can play in providing buffering power to the final dialysis fluid, will have a better knowledge of the amount of bicarbonate and bicarbonate precursors delivered to the patient.

The dynamics of the metabolism of acetate and bicarbonate associated with use of hemodialysates in the ABChD trial: a phase IV, prospective, single center, single blind, randomized, cross-over, two week investigation.

BACKGROUND: In the United States, hemodialysis (HD) is generally performed via a bicarbonate dialysate. It is not known if small amounts of acid used in dialysate to buffer the bicarbonate can meaningfully contribute to overall buffering administered during HD. We aimed to investigate the metabolism of acetate with use of two different acid buffer concentrates and determine if it effects blood bicarbonate concentrations in HD patients. METHODS: The Acid-Base Composition with use of hemoDialysates (ABChD) trial was a Phase IV, prospective, single blind, randomized, cross-over, 2 week investigation of peridialytic dynamics of acetate and bicarbonate associated with use of acid buffer concentrates. Eleven prevalent HD patients participated from November 2014 to February 2015. Patients received two HD treatments, with NaturaLyte® and GranuFlo® acid concentrates containing 4 and 8 mEq/L of acetate, respectively. Dialysate order was chosen in a random fashion. The endpoint was to characterize the dynamics of acetate received and metabolized during hemodialysis, and how it effects overall bicarbonate concentrations in the blood and dialysate. Acetate and bicarbonate concentrations were assessed before, at 8 time points during, and 6 time points after the completion of HD. RESULTS: Data from 20 HD treatments for 11 patients (10 NaturaLyte® and 10 GranuFlo®) was analyzed. Cumulative trajectories of arterialized acetate were unique between NaturaLyte® and GranuFlo® (p = 0.003), yet individual time points demonstrated overlap without remarkable differences. Arterialized and venous blood bicarbonate concentrations were similar at HD initiation, but by 240 min into dialysis, mean arterialized bicarbonate concentrations were 30.2 (SD ± 4.16) mEq/L in GranuFlo® and 28.8 (SD ± 4.26) mEq/L in NaturaLyte®. Regardless of acid buffer concentrate, arterial blood bicarbonate was primarily dictated by the prescribed bicarbonate level. Subjects tolerated HD with both acid buffer concentrates without experiencing any related adverse events. CONCLUSIONS: A small fraction of acetate was delivered to HD patients with use of NaturaLyte® and GranuFlo® acid buffers; the majority of acetate received was observed to be rapidly metabolized and cleared from the circulation. Blood bicarbonate concentrations appear to be determined mainly by the prescribed concentration of bicarbonate. TRIAL REGISTRATION: This trial was registered on ClinicalTrials.gov on 11 Dec 2014 ( NCT02334267 ).

D-lactic acidosis - case report and review of the literature.

D-lactic acidosis is a rare complication that occurs mainly in patients with malabsorption due to a surgically altered gastrointestinal tract anatomy, namely in short bowel syndrome or after bariatric surgery. It is characterized by rapid development of neurological symptoms and severe metabolic acidosis, often with a high serum anion gap. Malabsorbed carbohydrates can be fermented by colonic microbiota capable of producing D-lactic acid. Routine clinical assessment of serum lactate covers only L-lactic acid; when clinical suspicion for D-lactic acidosis is high, special assays for D-lactic acid are called for. A serum level of more than 3 mmol/L of D-lactate confirms the diagnosis. Management includes correction of metabolic acidosis by intravenous bicarbonate, restriction of carbohydrates or fasting, and antibiotics to eliminate intestinal bacteria that produce D-lactic acid. We report a case of D-lactic acidosis in a patient with short bowel syndrome and review the pathophysiology of D-lactic acidosis with its biochemical and clinical features. D-lactic acidosis should be considered when patients with short bowel syndrome or other malabsorption syndromes due to an altered gastrointestinal tract anatomy present with metabolic acidosis and neurological symptoms that cannot be attributed to other causes. With the growing popularity of bariatric surgery, this metabolic derangement may be seen more frequently in the future.