Chronic Acidosis Research Articles

Chronic Metabolic Acidosis Elicits Hypertension via Upregulation of Intrarenal Angiotensin II and Induction of Oxidative Stress

Chronic metabolic acidosis (CMA) can be a consequence of persistent hypertension but could potentially play a role in invoking hypertension. Currently, there is a scarcity of studies examining the outcome of induced chronic acidosis on blood pressure regulation. This study investigates CMA as a cause of hypertension. Chronic acidosis was induced in Sprague Dawley rats (100–150 g) by providing a weak acid solution of 0.28 M ammonium chloride (NH4Cl) in tap water for 8 weeks. To determine whether the rats were acidotic, blood pH was measured, while blood pressure (BP) was monitored by tail-cuff plethysmography weekly. Rats were divided into five groups: control, CMA, CMA ± spironolactone, captopril, and tempol. Serum sodium and potassium; renal interstitial fluid (for Angiotensin II concentration); and kidney proximal tubules (for Na+/K+ ATPase- α1 concentration) were analyzed. Reactive oxygen species (ROS) were detected in renal cortical homogenates using electron paramagnetic resonance (EPR). In the CMA rats, a sustained elevation in mean arterial pressure (MAP) associated with a significant decrease in blood pH was observed compared to that of control over the 8 weeks. A significant decrease in MAP was observed in acidotic rats treated with captopril/tempol, whereas spironolactone treatment caused no decrease in MAP as compared to that of the CMA group. The interstitial angiotensin II was increased in the CMA group but decreased in the CMA with captopril and tempol groups. In addition, the urinary sodium was decreased, and the serum sodium levels increased significantly in the CMA groups as compared to that of control. However, the acidotic groups with captopril and tempol showed reduced levels of serum sodium and an elevation in urinary sodium as compared to that of the CMA group. In addition, there was a significant increase in plasma renin and no change in plasma aldosterone in the CMA group with no significant differences in plasma renin or aldosterone observed during spironolactone, captopril, or tempol treatments. The increased expression of Na+/K+ ATPase-α1 in the CMA group suggests that active transport of Na+ to the blood could be causative of the observed hypertension. Furthermore, the EPR analysis confirmed an elevation in superoxide (O2-) radical levels in the CMA group, but the tempol/captopril treated acidotic groups showed less (O2-) compared to that of either the CMA group or control. Taken together, our data suggest that induction of CMA could potentially be causative of hypertension, while the mechanisms underlying the increased BP could be through the activation of intrarenal Ang II and induction of oxidative stress.

Citrate Supplementation Restores the Impaired Mineralisation Resulting from the Acidic Microenvironment: An In Vitro Study.

Chronic metabolic acidosis leads to bone-remodelling disorders based on excessive mineral matrix resorption and inhibition of bone formation, but also affects the homeostasis of citrate, which is an essential player in maintaining the acid–base balance and in driving the mineralisation process. This study aimed to investigate the impact of acidosis on the osteogenic properties of bone-forming cells and the effects of citrate supplementation in restoring the osteogenic features impaired by the acidic milieu. For this purpose, human mesenchymal stromal cells were cultured in an osteogenic medium and the extracellular matrix mineralisation was analysed at the micro- and nano-level, both in neutral and acidic conditions and after treatment with calcium citrate and potassium citrate. The acidic milieu significantly decreased the citrate release and hindered the organisation of the extracellular matrix, but the citrate supplementation increased collagen production and, particularly calcium citrate, promoted the mineralisation process. Moreover, the positive effect of citrate supplementation was observed also in the physiological microenvironment. This in vitro study proves that the mineral matrix organisation is influenced by citrate availability in the microenvironment surrounding bone-forming cells, thus providing a biological basis for using citrate-based supplements in the management of bone-remodelling disorders related to chronic low-grade acidosis.

A U-Shape Fibre-Optic pH Sensor Based on Hydrogen Bonding of Ethyl Cellulose With a Sol-Gel Matrix

Development of a biocompatible pH sensor is of importance in biomedical applications, particularly for in vivo measurement, providing necessary information for clinical diagnosis and treatment such as chronic wounds and foetal acidosis. Traditional pH-indicator based optical sensors have problems of dye-leaching and photobleaching that restrict their uses in long-term monitoring. In this work, a dye-free fibre optic pH sensor is proposed consisting of a U-shape multimode optical fibre coated with a hybrid organic-inorganic composite film. The film is formed by cross-linking ethyl cellulose with a silica matrix at an optimised ethyl cellulose/silica molar ratio of 0.0065 via weakly interacted hydrogen bonding. This bonding is affected by hydrogen concentration (i.e., pH) in a solution resulting in a morphological change of the polymer aggregation presented in the silica matrix leading to refractive index change of the film. The developed sensor shows a reversible response to pH from 4.5 to 12.5 and exhibits linear correlation between transmitted light power and pH with a limit of agreement (LoA) between the sensor and a commercial probe of ±0.2 pH. For a clinically important range of pH values between 6 and 8 the LoA is ±0.1 pH. The sensor has low cross-sensitivity to temperature as the maximum interpreted pH change attributed to the power change is 0.12 pH when the temperature changes from 21 °C to 39 °C. To demonstrate biomedical relevance, the sensor is used to monitor pH of human serum. An in-house cytotoxicity assay is conducted with mouse fibroblast cell revealing that the film is not cytotoxic.

Impact of High-Flow Nasal Cannula on Arterial Blood Gas Parameters in the Emergency Department.

Background: High-flow nasal cannula (HFNC) oxygen is becoming an integral part of respiratory failure management. Effects of HFNC on arterial blood gas (ABG) parameters especially partial carbon dioxide (PaCO2) require further investigation to provide insight into the efficacy and safety of the treatment.Methods: Acute respiratory failure patients with sequential ABG parameters before and after initiating HFNC between June 2015 and June 2017 were analyzed in a tertiary academic center. Patients' baseline characteristics were evaluated and sequential ABG changes were compared and subgrouped as chronic obstructive pulmonary disease (COPD), respiratory acidosis, hypercapnia, and high lactate.Results: A total of 120 patients were enrolled in the study. There was a significant difference between the mean partial pressure of oxygen in arterial blood (PaO2), lactate, and peripheral oxygen saturation (SpO2) values between sequential ABGs after HFNC (P <0.001). In the COPD group (n=32), there was a significant difference between initial ABG means of PaO2, lactate, and SpO2 values and sequential ABG means (p<0.001). Hypercapnic patients PaCO2 levels were significantly lower after HFNC (p<0.001), while in the COPD group there was no significant change in PaCO2 values (p=0.068).Conclusions: Treatment with HFNC produced improvement of blood gas parameters in subjects with acute respiratory failure in the emergency department (ED). These results suggest that HFNC can be used in hypercapnic patients as well as hypoxemic patients. Further randomized controlled studies required to establish the impact of HFNC in the ED.

A retrospective study on transabdominal ultrasound measurements of the rumen wall thickness to evaluate chronic rumen acidosis in beef cattle

BackgroundChronic and subacute rumen acidosis are economically important in the beef industry. The aim of this study was to evaluate the potential suitability of the transabdominal ultrasonographic examination of the ruminal wall to diagnose chronic rumen acidosis in beef cattle compared to direct measurement of ruminal pH, as a fast non-invasive tool to be used in field condition. Ultrasonographic examination of the rumen was conducted in 478 beef cattle before rumenocentesis (chronic rumen acidosis group = pH ≤ 5.8; healthy group = pH ≥ 5.9). Rumen wall ultrasound measurements included rumen wall thickness (RWT) and rumen mucosa and submucosa thickness (RMST).ResultsThe Analysis of Variance showed the high significant effect of the pH class for RWT and RMST (P < 0.001). Spearman RANK correlation analysis showed interaction between rumen pH and RWT (− 0.71; P < 0.0001) and RMST (− 0.75; P < 0.0001). A significant Spearman’s correlations were found between volatile fatty acids (VFA) and RWT and RMST.The differentiation efficiency of RWT between healthy and chronic rumen acidosis groups, as a result of the receiver operator curve (ROC) analysis, was quite good with an area under the receiver operator curve (AUROC) of 0.88: P < 0.0001; 95% CI: 0.83–0.98. Using a cut-off value of > 8.2 mm. The differentiation efficiency of RMST between healthy and chronic rumen acidosis groups, as a result of ROC curve analysis, was good with an AUROC of 0.90: p < 0.0001; 95% CI: 0.85–0.94. Using a cut-off value of > 5.3 mm.ConclusionsIn this study, the thickening of RWT and RMST is correlated with the changes of ruminal pH. Transabdominal rumen ultrasound has the potential to become a powerful diagnostic tool useful to identify fattening bulls affected by chronic rumen acidosis.

Kidney and Metabolic Phenotypes in Glycogen Storage Disease Type-I Patients.

Patients and Methods: A retrospective chart review of 32 GSD- I patients, followed at the American University of Beirut Medical Center, between 2007 and 2018 was conducted. Diagnosis was confirmed by enzymatic and/or genetic studies. Clinical presentation, growth, and kidney outcome were assessed. All patients were evaluated for body mass index, blood parameters of metabolic control including uric acid, alanine, lactic acid, and triglycerides in blood. Kidney evaluation included creatinine clearance, microalbuminuria, citraturia, and calciuria as well as urine microalbumin/creatinine ratio.Results: Almost one third of GSD-I patients developed microalbuminuria. This was detected below 7 months of age in 36% of patients who required early treatment with ACEI with significant reduction in albuminuria. Kidney stones were present in 6% and were associated with hypercalciuria and hypocitraturia. Poor metabolic control reflected by hyperuricemia, lactic acidosis, and hyperalaninemia were noted only in patients who developed microalbuminuria.Conclusion: Glomerular injury may appear in early infancy in poorly controlled patients. Adequate metabolic control and ACEI therapy may improve kidney outcome in GSD I patients. Plasma alanine appears to be a promising and reliable marker reflecting metabolic control in GSD-I patients.

The acidic tumor microenvironment drives a stem-like phenotype in melanoma cells

Acidosis characterizes the microenvironment of most solid tumors and is considered a new hallmark of cancer. It is mainly caused by both “aerobic” and “anaerobic” glycolysis of differently adapted cancer cells, with the final product lactic acid being responsible of the extracellular acidification. Many evidences underline the role of extracellular acidosis in tumor progression. Among the different findings, we demonstrated that acidosis-exposed cancer cells are characterized by an epithelial-to-mesenchymal transition phenotype with high invasive ability, high resistance to apoptosis, anchorage-independent growth, and drug therapy. Acidic melanoma cells over-express SOX2, which is crucial for the maintenance of their oxidative metabolism, and carbonic anhydrase IX, that correlates with poor prognosis of cancer patients. Considering these evidences, we realized that the profile outlined for acid cancer cells inevitably remind us the stemness profile. Therefore, we wondered whether extracellular acidosis might induce in cancer cells the acquisition of stem-like properties and contribute to the expansion of the cancer stem cell sub-population. We found that a chronic adaptation to acidosis stimulates in cancer cells the expression of stem-related markers, also providing a high in vitro/in vivo clonogenic and trans-differentiating ability. Moreover, we observed that the acidosis-induced stem-like phenotype of melanoma cells was reversible and related to the EMT induction. These findings help to characterize a further aspect of stem cell niche, contributing to the sustainment and expansion of cancer stem cell subpopulation. Thus, the usage of agents controlling tumor extracellular acidosis might acquire great importance in the clinic for the treatment of aggressive solid tumor.Key messages• Extracellular acidosis up-regulates EMT and stem-related markers in melanoma cells• Acidic medium up-regulates in vitro self-renewal capacity of melanoma cells• Chronic acidosis adaptation induces trans-differentiation ability in melanoma cells• Melanoma cells adapted to acidosis show higher tumor-initiating potential than control cells• Extracellular acidosis promotes a stem-like phenotype in prostate and colorectal carcinoma cells

Cancer Cell Acid Adaptation Gene Expression Response Is Correlated to Tumor-Specific Tissue Expression Profiles and Patient Survival.

The acidic pH of the tumor microenvironment plays a critical role in driving cancer development toward a more aggressive phenotype, but the underlying mechanisms are unclear. To this end, phenotypic and genotypic changes induced by adaptation of cancer cells to chronic acidosis have been studied. However, the generality of acid adaptation patterns across cell models and their correlation to the molecular phenotypes and aggressiveness of human cancers are essentially unknown. Here, we define an acid adaptation expression response shared across three cancer cell models, dominated by metabolic rewiring, extracellular matrix remodeling, and altered cell cycle regulation and DNA damage response. We find that many genes which are upregulated by acid adaptation are significantly correlated to patient survival, and more generally, that there are clear correlations between acid adaptation expression response and gene expression change between normal and tumor tissues, for a large subset of cancer patients. Our data support the notion that tumor microenvironment acidity is one of the key factors driving the selection of aggressive cancer cells in human patient tumors, yet it also induces a growth-limiting genotype that likely limits cancer cell growth until the cells are released from acidosis, for instance during invasion.

Observações clínicas, hematologia e características do fluido ruminal de bovinos de corte recebendo dieta "Max Beef" grão inteiro

Este estudo propôs caracterizar os efeitos da alimentação baseada na dieta do grão de milho inteiro na dinâmica de parâmetros clínicos e metabólitos bioquímicos de bovinos confinados. Foram utilizados 20 bovinos, sem raça definida, adultos, com peso médio de 300 kg, divididos em dois grupos experimentais. O grupo experimental (G1; n=15), composto por animais alimentado somente dieta “Max Beef” Grão Inteiro e o grupo controle (G2; n=5), composto por animais, alimentado com bagaço de cana e a dieta “Max Beef” Grão Inteiro, na proporção 30:70. Todos os animais foram submetidos às observações clínicas, colheita de sangue por venopunção jugular e fluido ruminal. Os animais do grupo G1 (Dieta “Max Beef” Grão Inteiro) apresentaram movimentos ruminais incompletos, timpania ruminal branda e diarreia com grãos de milho inteiro. Não foram registradas alterações hematológicas nem na concentração de fibrinogênio. Apresentaram menor valor de pH ruminal durante todo o período experimental, com comprometimento da população de infusórios, diminuição da prova de redução do azul de metileno e tempo de sedimentação e flotação ausente. Conclui-se que dietas para bovinos de corte contendo “Max Beef” Grão Inteiro provoca acidose crônica ruminal e compromete as características físico-químicas e microbiológicas do fluido ruminal.

Sodium bicarbonate to improve physical function in patients over 60 years with advanced chronic kidney disease: the BiCARB RCT.

Advanced chronic kidney disease is common in older people and is frequently accompanied by metabolic acidosis. Oral sodium bicarbonate is used to treat this acidosis, but evidence is lacking on whether or not this provides a net gain in health or quality of life for older people. The objectives were to determine whether or not oral bicarbonate therapy improves physical function, quality of life, markers of renal function, bone turnover and vascular health compared with placebo in older people with chronic kidney disease and mild acidosis; to assess the safety of oral bicarbonate; and to establish whether or not oral bicarbonate therapy is cost-effective in this setting. A parallel-group, double-blind, placebo-controlled randomised trial. The setting was nephrology and geriatric medicine outpatient departments in 27 UK hospitals. Participants were adults aged ≥ 60 years with advanced chronic kidney disease (glomerular filtration rate category 4 or 5, not on dialysis) with a serum bicarbonate concentration of < 22 mmol/l. Eligible participants were randomised 1 : 1 to oral sodium bicarbonate or matching placebo. Dosing started at 500 mg three times daily, increasing to 1 g three times daily if the serum bicarbonate concentration was < 22 mmol/l at 3 months. The primary outcome was the between-group difference in the Short Physical Performance Battery score at 12 months, adjusted for baseline. Other outcome measures included generic and disease-specific health-related quality of life, anthropometry, 6-minute walk speed, grip strength, renal function, markers of bone turnover, blood pressure and brain natriuretic peptide. All adverse events were recorded, including commencement of renal replacement therapy. For the health economic analysis, the incremental cost per quality-adjusted life-year was the main outcome. In total, 300 participants were randomised, 152 to bicarbonate and 148 to placebo. The mean age of participants was 74 years and 86 (29%) were female. Adherence to study medication was 73% in both groups. A total of 220 (73%) participants were assessed at the 12-month visit. No significant treatment effect was evident for the primary outcome of the between-group difference in the Short Physical Performance Battery score at 12 months (-0.4 points, 95% confidence interval -0.9 to 0.1 points; p = 0.15). No significant treatment benefit was seen for any of the secondary outcomes. Adverse events were more frequent in the bicarbonate arm (457 vs. 400). Time to commencement of renal replacement therapy was similar in both groups (hazard ratio 1.22, 95% confidence interval 0.74 to 2.02; p = 0.43). Health economic analysis showed higher costs and lower quality of life in the bicarbonate arm at 1 year, with additional costs of £564 (95% confidence interval £88 to £1154) and a quality-adjusted life-year difference of -0.05 (95% confidence interval -0.08 to -0.01); placebo dominated bicarbonate under all sensitivity analyses for incremental cost-effectiveness. The trial population was predominantly white and male, limiting generalisability. The increment in serum bicarbonate concentrations achieved was small and a benefit from larger doses of bicarbonate cannot be excluded. Oral sodium bicarbonate did not improve a range of health measures in people aged ≥ 60 years with chronic kidney disease category 4 or 5 and mild acidosis, and is unlikely to be cost-effective for use in the NHS in this patient group. Once other current trials of bicarbonate therapy in chronic kidney disease are complete, an individual participant meta-analysis would be helpful to determine which subgroups, if any, are more likely to benefit and which treatment regimens are more beneficial. Current Controlled Trials ISRCTN09486651 and EudraCT 2011-005271-16. The systematic review is registered as PROSPERO CRD42018112908. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 27. See the NIHR Journals Library website for further project information.

Clinical and cost-effectiveness of oral sodium bicarbonate therapy for older patients with chronic kidney disease and low-grade acidosis (BiCARB): a pragmatic randomised, double-blind, placebo-controlled trial

BackgroundChronic kidney disease with metabolic acidosis is common in older people, but the effectiveness of oral sodium bicarbonate therapy in this group is unclear. We tested whether oral sodium bicarbonate provides net health benefit for older people with advanced chronic kidney disease and serum bicarbonate concentrations < 22 mmol/L.MethodsPragmatic multicentre, parallel group, double-blind, placebo-controlled randomised trial. We recruited adults aged ≥ 60 years with estimated glomerular filtration rate of < 30 mL/min/1.73 m2, not receiving dialysis, with serum bicarbonate concentration < 22 mmol/L, from 27 nephrology and geriatric medicine departments in the UK. Participants received oral sodium bicarbonate (up to 3 g/day) or matching placebo given for up to 2 years, randomised in a 1:1 ratio. The primary outcome was between-group difference in the Short Physical Performance Battery (SPPB) at 12 months, adjusted for baseline values, analysed by intention to treat. Secondary outcomes included generic and disease-specific quality of life (EQ-5D and KDQoL tools), anthropometry, renal function, walk distance, blood pressure, bone and vascular health markers, and incremental cost per quality-adjusted life year gained.ResultsWe randomised 300 participants between May 2013 and February 2017, mean age 74 years, 86 (29%) female. At 12 months, 116/152 (76%) participants allocated to bicarbonate and 104/148 (70%) allocated to placebo were assessed; primary outcome data were available for 187 participants. We found no significant treatment effect for the SPPB: bicarbonate arm 8.3 (SD 2.5) points, placebo arm 8.8 (SD 2.2) and adjusted treatment effect − 0.4 (95% CI − 0.9 to 0.1, p = 0.15). We found no significant treatment effect for glomerular filtration rate (0.6 mL/min/1.73 m2, 95% CI − 0.8 to 2.0, p = 0.39). The bicarbonate arm showed higher costs and lower quality of life as measured by the EQ-5D-3L tool over 1 year (£564 [95% CI £88 to £1154]); placebo dominated bicarbonate under all sensitivity analyses. Adverse events were more frequent in those randomised to bicarbonate (457 versus 400).ConclusionsOral sodium bicarbonate did not improve physical function or renal function, increased adverse events and is unlikely to be cost-effective for use by the UK NHS for this patient group.Trial registrationEuropean Clinical Trials Database (2011-005271-16) and ISRCTN09486651; registered 17 February 2012.

Luminal Succinate and Acidosis: Effects on Blood Pressure

Succinate (Suc) is well known as a Krebs cycle intermediate but extracellular Suc has been associated with a variety of pathologic processes. A distinct GPCR receptor for Suc (Sucnr1) was identified in the kidney and some (but not all) studies have documented that Suc infusions increase blood pressure (BP) via paracrine signaling. Luminal Suc has been reported to activate Sucnr1, stimulate renin release and alter BP in certain circumstances.In the nephron, apical NaDC1 (Na+ dicarboxylate cotransporter) is located only in the proximal tubule, reabsorbs filtered citrate and Suc, and is upregulated in acidosis. Thus NaDC1’s regulation is important in preventing calcium stones and promoting acid‐base homeostasis via effects of citrate reabsorption but its role in BP regulation is not known. Our purpose was to explore the role of NaDC1, luminal Suc, and acidosis in BP regulation.To address these issues, we used NaDC1 KO and WT mice on normal diet or 72 hr acid diet (0.4 M HCl). In initial clearance (CL) studies, KO mice had increased urinary Suc and citrate but no statistical difference in BP even with the infusion of 1 mmol/kg Suc. Suc infused WT did not have increased BP in CL. Acid diet reduced urinary Suc in WT, but had no consistent effect on BP in either KO or WT in CL.Since recent reports suggested that Suc may affect BP exclusively during more active periods (nocturnal in mice), we additionally examined BP using telemetry (BP/T) for 24/7 monitoring. During 8 PM‐5 AM on a normal diet mean arterial pressure (MAP) was significantly higher in KO than in WT. Acidosis appeared to lessen these BP/T differences. As an example of this, Figure 1 shows MAP at selected time points in a 24 hour cycle, 8 AM, 9 PM, 5AM and 8AM.To determine whether Sucnr1 gene expression alterations could influence these results, droplet digital PCR (Bio Rad) was performed. Data are expressed as copy numbers of target gene in 1 ng PCR reaction. Thus with ddPCR we determined on normal diet, Sucnr1 expression levels in KO (1343.6 ± 51) are significantly increased from that in WT (1052.8 ± 50, p&lt; 0.007). Furthermore, on 72 hr acid diet the expression of Sucnr1 in KO (1039.6 ± 33) fell while in WT increased to 1148 ± 50, p &lt;0.006).In sum, on normal diet, Sucnr1 expression is significantly greater in NaDC1 KO vs WT and in chronic acidosis expression decreases in KO but increases in WT. On normal diet MAP in KO is significantly higher than in WT while acidosis diminishes these differences (by slightly lowering KO MAP but raising slightly WT MAP).These diverse findings illustrate that NaDC1 (and presumably luminal Suc) can regulate BP but that this regulation varies with time of day (or associated factors such as activity) and acidosis.Support or Funding InformationNIH, DCI PTRF, LA CaTSMAP differences in NaDC1 KO mice vs WT mice on a normal dietFigure 1

104 Oral Sodium Bicarbonate Therapy for Older Patients with Chronic Kidney Disease and Low-Grade Acidosis: The BiCARB Randomised Controlled Trial

Abstract Background Oral sodium bicarbonate is often used to treat metabolic acidosis in older people with advanced chronic kidney disease, but evidence is lacking on whether this provides a net gain in health or quality of life. Methods We conducted a multicentre, parallel group, double-blind, placebo-controlled randomised trial. Adults aged 60 years and over with category 4 or 5 chronic kidney disease, not on dialysis, with serum bicarbonate concentrations &amp;lt;22 mmol/L were recruited from 27 UK centres. Participants were randomised 1:1 to oral sodium bicarbonate or matching placebo. The primary outcome was the between-group difference in the Short Physical Performance Battery at 12 months, adjusted for baseline. Other key outcome measures included generic and disease-specific health-related quality of life, anthropometry, physical performance, renal function, adverse events including commencement of renal replacement therapy, and health economic analysis. Results We randomised 300 participants, mean age 74 years; 86 (29%) were female. Mean baseline estimated GFR was 19 ml/min/1.73m2. Study medication adherence was 73% in both groups. No significant treatment effect was evident for the primary outcome of the between-group difference in the Short Physical Performance Battery at 12 months (-0.4 points; 95% CI -0.9 to 0.1, p=0.15). No significant treatment benefit was seen for any of the secondary outcomes. Adverse events were more frequent in the bicarbonate arm (457 versus 400). Time to commencing renal replacement therapy was similar in both groups (HR 1.22, 95% CI 0.74 to 2.02, p=0.43). Health economic analysis showed lower quality of life and higher costs in the bicarbonate arm at one year (£1234 vs £807); placebo dominated bicarbonate under all sensitivity analyses for incremental cost-effectiveness. Conclusions Oral sodium bicarbonate did not improve a wide range of health measures in this trial, and is unlikely to be cost-effective for use in the UK NHS in this patient group.

Chronic Obstructive Pulmonary Disease and Respiratory Acidosis in the Intensive Care Unit

Chronic obstructive lung disease is a common and preventable disease. One of its pathophysiological consequences is the presence of carbon dioxide retention due to hypoventilation and ventilation/perfusion mismatch, which in consequence will cause a decrease in the acid/base status of the patient. Whenever a patient develops an acute exacerbation, acute respiratory hypercapnic failure will appear and the necessity of a hospital ward is a must. However, current guidelines exist to better identify these patients and make an accurate diagnosis by using clinical skills and laboratory data such as arterial blood gases. Once the patient is identified, rapid treatment will help to diminish the hospital length and the avoidance of intensive care unit. On the other hand, if there is the existence of comorbidities such as cardiac failure, gastroesophageal reflux disease, pulmonary embolism or depression, it is likely that the patient will be admitted to the intensive care unit with the requirement of intubation and mechanical ventilation.

Myasthenic crisis treated in a Chinese neurological intensive care unit: clinical features, mortality, outcomes, and predictors of survival

BackgroundMyasthenic crisis (MC) often requires admission to an intensive care unit (ICU).MethodsWe retrospectively investigated 113 consecutive patients with first MC admitted to the neurological ICU. Patients’ demographic, clinical and other characteristics were examined, as well as therapeutic interventions, mortality and functional outcome.ResultsMC patients at first onset admitted to neurological ICU had a mortality rate of 18.6%. PCO2 level before intubation and score on Myasthenia Gravis–Activities of Daily Living (MG-ADL) scale at MC onset correlated with duration of ventilation and length of ICU stay. Compared with patients with good functional outcome, patients with intermediate or poor functional outcome were older at first MC onset, had lower pH and PO2, and had higher PCO2 before intubation. Multivariate logistic analysis identified pre-intubation PCO2 level as an independent predictor of survival. Cox regression showed that age at first MC onset requiring ICU management was the factor which significantly influenced the mortality.ConclusionsOur results suggest that PCO2 before intubation and MG-ADL score at MC onset may be useful indicators of more severe disease likely to require extensive respiratory support and ICU management. Higher pre-intubation PCO2 indicates chronic respiratory acidosis that can increase risk of severe disability and death, especially in patients with older age at first MC onset.

Effects of Creatine Treatment on Jejunal Phenotypes in a Rat Model of Acidosis.

We investigated the effects of creatine treatment on jejunal phenotypes in a rat model of oxidative stress induced by acidosis. In particular, the activities of some antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase, and glutathione reductase), the level of lipid peroxidation, the expression of heat shock proteins (HSP70), and the expression of the major carriers of the cells (Na+/K+-ATPase, sodium-glucose Transporter 1—SGLT1, and glucose transporter 2—GLUT2) were measured under control and chronic acidosis conditions. Creatine did not affect the activity of antioxidant enzymes in either the control or acidosis groups, except for catalase, for which the activity was reduced in both conditions. Creatine did not change the lipid peroxidation level or HSP70 expression. Finally, creatine stimulated (Na+/K+)-ATPase expression under both control and chronic acidosis conditions. Chronic acidosis caused reductions in the expression levels of GLUT2 and SGLT1. GLUT2 reduction was abolished by creatine, while the presence of creatine did not induce any strengthening effect on the expression of SGLT1 in either the control or chronic acidosis groups. These results indicate that creatine has antioxidant properties that are realized through direct interaction of the molecule with reactive oxygen species. Moreover, the administration of creatine seems to determine a functional strengthening of the tissue, making it more resistant to acidosis.

Renal Adaptive Changes in Response to Chronic Metabolic or Respiratory Acidosis: Regulation of Expression of Acid‐base Transporters and Enzymes

Kidneys excrete acid loads mainly by generating and excreting total ammonia (NH3plus NH4+) and to a lesser extent titratable acids (TA). Urinary excretion of NH3/NH4+ and TAincreases significantly in acidosis. We made the assumption that this augmented urinary acid excretion (NH3/NH4+and TA) will differ depending on the type of acid‐load. To test this hypothesis, we conducted in‐vivo experiments on mice to measure urinary NH3/NH4+and TA under metabolic or respiratory acid loads and investigated expression of carbonic anhydrase and acid‐base transporters by Western analysis.We induced metabolic acidosis in 2 groups of mice: one group received an acid diet (AD) supplemented with 0.4N HCl (at 1mg/g of chow); a second group received drinking water fortified with NH4Cl (0.28M) and 1% sucrose (NH4+‐W); a control group received normal diet (ND). Our data showed that urinary NH4+(u‐NH4+) increased gradually in mice on AD or NH4–W diet compared to control (ND) and the increase in u‐NH4+was proportionally higher than that of TA. Unexpectedly, expression of the NH3/NH4+transporters, Rhbg and Rhcg, in both groups of acid‐loaded mice was not significantly different compared to mice on ND. An interesting finding, however, was that expression of CA‐IV was reduced in both acidosis groups. In mice on AD, RNAseq data showed that carbonic anhydrase‐II (CA‐II) was upregulated whereas pendrin (a Cl‐HCO3−exchanger) expression was downregulated.We induced chronic respiratory acidosis by placing mice for 3 days in special chambers where breathing gas mixtures were 8% CO2(balance 21% O2&amp; 71% N2). A control group breathed normal air. There were no significant changes in urinary excretion of TA in both hypercapnic or control groups. However, urinary NH4+in hypercapnic mice increased significantly after 24 hours and continued to gradually increase in days 2 and 3. In control mice, there was a small increase in urinary NH4+excretion in day 1 (p &lt; 0.05), probably caused by housing distress in metabolic cages, but leveled off in days 2 and 3. Western analysis showed that hypercapnia induced a marked increase in expression of Rhbg but only a moderate increase of Rhcg. Chronic hypercapnia increased expression of CA‐IV significantly but decreased expression of pendrin.In summary, we demonstrated that renal response to acidosis varies with the type of acid load. High CO2 acidosis downregulated pendrin even though plasma HCO3−is high. In metabolic acidosis, the increase in urinary NH4+is likely caused by increased ammoniagenesis, whereas upregulation of NH3/NH4+transporters is more evident in respiratory than in metabolic acidosis. These data show a link among chronic hypercapnia, NH4+excretion and expression of the NH3/NH4+transporters, Rhbg and Rhcg. These studies are important to understand the renal mechanisms of correcting respiratory and metabolic acidosis.Support or Funding InformationU54 GM104940 from NIH, VA Merit grant, NIH‐RO1, Carol Lavin Bernick grant and Tulane Bridge grantThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Chronic Acidosis and Oxidative Stress: Protective Effect of Creatine Oral Administration on Rat Jejunum

The protective effect of creatine supplementation on the jejunal epithelium of rats under conditions of oxidative stress induced by chronic acidosis was investigated. In particular, we measured the activities of the main antioxidant enzymes (superoxide dismutase, glutathione peroxidase, catalase, glutathione reductase), the level of lipid peroxidation, the expression of heat shock proteins (HSP70), and the expression of the major carriers of the cells (Na+/K+-ATPase, SGLT1 and GLUT2) in control and chronic acidosis conditions. Creatine did not affect the activity of antioxidant enzymes, nor in control, neither in acidosis, except for catalase, which activity was reduced in both conditions. Creatine did not change the level of lipid peroxidation and the expression of HSP70. Finally, creatine stimulated the expression of (Na+/K+)-ATPase both in control and in chronic acidosis. Chronic acidosis caused a reduction in the expression of GLUT2 and SGLT1. GLUT2 reduction was abolished by creatine, while the presence of creatine did not induce any strengthening effect on the expression of SGLT1, neither in control nor in chronic acidosis. These results indicate that creatine has antioxidant properties that would be realized through direct interaction of the molecule with reactive oxygen species. Moreover, the administration of creatine seems to determine a functional strengthening of the tissue making the tissue more resistant to acidosis.

Exopolyphosphatase of Mycobacterium Tuberculosis Might Limit the Growth of Bacteria Which Thrive in Inflamed and Injured Lung

Pulmonary tuberculosis resembles cystic fibrosis and other chronic inflammatory lung diseases in its ability to cause chronic tissue destruction, hypoxia, tissue acidosis, and leakage of blood into the surrounding milieu. Destructive and inflammatory changes of the lung in diseases such as cystic fibrosis support the increased growth of the commensal Prevotella, a bacterial commensal which requires polyphosphate and thrives under inflammatory conditions. Since the nutritional needs of Prevotella are in some ways mirrored by those of the pathogens Pseudomonas aeruginosa and Berkholderia cepacia, it is possible that Prevotella may serve as a marker for these destructive lung pathogens. The biochemical milieu of pulmonary tuberculosis resembles that of other chronic inflammatory lung diseases in its ability to cause inflammation, destruction, tissue acidosis, and bleeding, yet in pulmonary tuberculosis, contrary to expectation, Prevotella species are decreased rather than increased. It is hypothesized that the M. tuberculosis exopolyphosphatase may serve to reduce polyphosphates required by Prevotella species. Since the nutritional needs of P. aeruginosa and B. cepacia resemble those of Prevotella, it is reasonable to hypothesize that addition of exopolyphosphatase might also hamper the growth of these dangerous lung pathogens, as well.

Renal aspects of metabolic acid-base disorders in neonates.

Acid-base homeostasis is one of the most tightly regulated systems in the body. Maintaining the acid-base balance is particularly challenging for preterm infants and growing neonates. The kidney, which represents the crucial ultimate line of defense against disturbances of acid-base balance, undergoes a complex maturation process during the transition from a fetal to an extra-uterine environment. This review article summarizes the physiology of acid-base regulation by the immature human kidney and discusses disorders of acid-base balance, such as metabolic acidosis, respiratory acidosis, metabolic alkalosis, and respiratory alkalosis. In conditions of metabolic acidosis, the serum anion gap and the urinary anion gap can be useful tools to define the nature of the acidosis. Metabolic acidosis can reflect a decrease in glomerular filtration rate, or be the consequence of selective disorders of proximal or distal tubular function. Most tubulopathies associated with metabolic acidosis observed in neonates are primary, hereditary, isolated tubulopathies. Proximal renal tubular acidosis is characterized by bicarbonate wasting, while the distal types of renal tubular acidosis are secondary to distal acidification defects. All tubulopathies are associated with hypokalemia, with the exception of type 4 hyperkalemic distal renal tubular acidosis. The transporter defects in the various acid-base tubulopathies are now well defined. Treatment of the acidosis varies according to the site and mechanism of the defect. Chronic renal tubular acidosis or alkalosis severely impair growth and calcium metabolism. Early rational therapeutic intervention can prevent some of the consequences of the disorders and improves the prognosis.