-
Physiological Reports Sep 2022Acute pyelonephritis caused by uropathogenic E. coli (UPEC) can cause renal scarring and lead to development of chronic kidney disease. Prevention of kidney injury...
Acute pyelonephritis caused by uropathogenic E. coli (UPEC) can cause renal scarring and lead to development of chronic kidney disease. Prevention of kidney injury requires an understanding of host factors and/or UPEC adaptive responses that are permissive for UPEC colonization of the urinary tract. Although some studies have suggested urine acidification limits UPEC growth in culture, other studies have described acid-resistance mechanisms (AR) in E. coli such as the CadC/CadBA module that promotes adaptation to acid and nitrosative stress. Herein we confirm and extend our previous study by demonstrating that despite urine acidification, metabolic acidosis induced by dietary ammonium chloride (NH Cl-A) exacerbates cystitis and pyelonephritis in innate immune competent (C3H-HeN) mice characterized by: (1) markedly elevated UPEC burden and increased chemokine/cytokine and NOS2 mRNA expression, (2) accumulation of intravesicular debris noninvasively detected by Power Doppler Ultrasound (PDUS), and (3) collecting duct (CD) dysfunction that manifests as a urine concentration defect. Bladder debris and CD dysfunction were due to the inflammatory response, as neither was observed in Tlr4-deficient (C3H-HeJ) mice. The effect of NH Cl-A was unrelated to acidosis as dietary administration of hydrochloric acid (HCl-A) yielded a comparable acid-base status yet did not increase UPEC burden. NH Cl-A increased polyamines and decreased nitric oxide (NO) metabolites in urine indicating that excess dietary ammonium shifts arginine metabolism toward polyamines at the expense of NO synthesis. Furthermore, despite increased expression of NOS2, NO production post UPEC infection was attenuated in NH Cl-A mice compared to controls. Thus, in addition to induction of metabolic acidosis and urine acidification, excess dietary ammonium alters the polyamine:NO balance and thereby compromises NOS2-mediated innate immune defense.
Topics: Acidosis; Ammonium Chloride; Animals; Arginine; Chemokines; Cystitis; Cytokines; Escherichia coli Infections; Hydrochloric Acid; Mice; Mice, Inbred C3H; Nitric Oxide; Polyamines; Pyelonephritis; RNA, Messenger; Toll-Like Receptor 4; Urinary Tract Infections; Uropathogenic Escherichia coli
PubMed: 36151614
DOI: 10.14814/phy2.15471 -
International Journal of Cancer Apr 2023The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that...
The mechanisms linking tumor microenvironment acidosis to disease progression are not understood. Here, we used mammary, pancreatic, and colon cancer cells to show that adaptation to growth at an extracellular pH (pH ) mimicking acidic tumor niches is associated with upregulated net acid extrusion capacity and elevated intracellular pH at physiological pH , but not at acidic pH . Using metabolic profiling, shotgun lipidomics, imaging and biochemical analyses, we show that the acid adaptation-induced phenotype is characterized by a shift toward oxidative metabolism, increased lipid droplet-, triacylglycerol-, peroxisome content and mitochondrial hyperfusion. Peroxisome proliferator-activated receptor-α (PPARA, PPARα) expression and activity are upregulated, at least in part by increased fatty acid uptake. PPARα upregulates genes driving increased mitochondrial and peroxisomal mass and β-oxidation capacity, including mitochondrial lipid import proteins CPT1A, CPT2 and SLC25A20, electron transport chain components, peroxisomal proteins PEX11A and ACOX1, and thioredoxin-interacting protein (TXNIP), a negative regulator of glycolysis. This endows acid-adapted cancer cells with increased capacity for utilizing fatty acids for metabolic needs, while limiting glycolysis. As a consequence, the acid-adapted cells exhibit increased sensitivity to PPARα inhibition. We conclude that PPARα is a key upstream regulator of metabolic changes favoring cancer cell survival in acidic tumor niches.
Topics: Humans; Transcription Factors; Gene Expression Regulation; PPAR alpha; Fatty Acids; Neoplasms; Acidosis; Lipid Metabolism; Liver; Tumor Microenvironment
PubMed: 36533672
DOI: 10.1002/ijc.34404 -
PloS One 2023Bone disease is highly prevalent in patients with chronic kidney disease (CKD), leading to an increased risk of bone fractures. This is due in part to metabolic...
Bone disease is highly prevalent in patients with chronic kidney disease (CKD), leading to an increased risk of bone fractures. This is due in part to metabolic acid-induced bone dissolution. Bisphosphonates (BPPs) are a potential treatment for inhibiting bone dissolution; however, there are limited studies observing the use of BPPs on acidotic patients. We aimed to determine efficacy of BPPs on maintaining bone health and pH regulation in acid-exposed mice. Using a diet-induced murine model of metabolic acidosis, we examined bone structure, composition, and mechanics as well as blood gases for three groups: control, acidosis, and acidosis + bisphosphonates (acidosis+BPP). Acidosis was induced for 14 days and alendronate was administered every 3 days for the acidosis+BPP group. The administration of BPP had little to no effect on bone structure, mechanics, and composition of the acidosis bones. However, administration of BPP did cause the mice to develop more severe acidosis than the acidosis only group. Overall, we discovered that BPPs may exacerbate acidosis symptoms by inhibiting the release of buffering ions from bone. Therefore, we propose that BPP administration should be carefully considered for those with CKD and that alkali supplementation could help minimize acidifying effects.
Topics: Animals; Mice; Alendronate; Ammonium Chloride; Diphosphonates; Acidosis; Osteolysis; Renal Insufficiency, Chronic
PubMed: 37713420
DOI: 10.1371/journal.pone.0291649 -
Journal of Renal Nutrition : the... May 2023Studies have shown that low or high serum bicarbonate levels (reflecting metabolic acidosis or alkalosis) are associated with increased all-cause mortality rates in...
OBJECTIVE
Studies have shown that low or high serum bicarbonate levels (reflecting metabolic acidosis or alkalosis) are associated with increased all-cause mortality rates in moderate and advanced chronic kidney disease (CKD) cases. Correction of presumed acidosis using sodium bicarbonate, targeting serum levels around 22 mmol/L, has proven to be beneficial in delaying the progression of the disease and provided mortality benefit. A similar prognostic association may exist between uncorrected metabolic acidosis in chronic liver disease. Correcting it with sodium-containing salts may require more interventions due to increased sodium/fluid load. In patients with liver failure, a naturally alkalotic state, where sodium load is a concern, the impact of this intervention is unclear.
DESIGN
This study aims to generate proof of concept through a retrospective chart review in individuals with CKD-related metabolic acidosis and liver cirrhosis.
RESULT
Our analysis revealed a statistically significant association between the need for paracentesis and bicarbonate therapy. Our study has multiple drawbacks, including a retrospective chart review and limitation of data due to single-center patients.
CONCLUSION
We extrapolate that lowering bicarbonate targets in other clinical scenarios like liver failure, pregnancy, and cardiac failure may be prudent and will lead to a lower sodium load.
Topics: Humans; Bicarbonates; Retrospective Studies; Acidosis; Chronic Disease; Renal Insufficiency, Chronic; Sodium; Liver Diseases; Kidney; Liver Failure
PubMed: 36736470
DOI: 10.1053/j.jrn.2022.12.008 -
Critical Care and Resuscitation :... Sep 2020To help shape the design of a future double blind placebo-controlled randomised clinical trial of bicarbonate therapy for metabolic acidosis, based on opinions of... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To help shape the design of a future double blind placebo-controlled randomised clinical trial of bicarbonate therapy for metabolic acidosis, based on opinions of intensive care clinicians in Australia and New Zealand.
DESIGN
An online survey was designed, piloted and distributed electronically to members of the Australian and New Zealand Intensive Care Society Clinical Trials Group (ANZICS CTG) mailing list. The survey sought to collect information about choice of placebo, method of bicarbonate administration, and acid-base monitoring.
MAIN OUTCOME MEASURES
Responses to six questions in the following domains were sought: 1) solution to be used as placebo; 2) method of administration; 3) target of the intervention; 4) timing of arterial blood gases to monitor the intervention; 5) duration of therapy; and 6) rate of bolus therapy (if selected as the best option).
RESULTS
One in every eight ANZICS CTG members completed the survey (118/880, 13.4%). Compound sodium lactate was the preferred solution for placebo (54/118, 45.8%), and continuous infusion of bicarbonate (80/118, 67.8%) was the most frequently selected method of administration. A pH > 7.30 was the preferred target (50/118, 42.4%), while monitoring with arterial blood gas analysis every 2 hours until the target is reached and then every 4 hours was the most favoured option (40/118, 33.9%). The preferred duration of therapy was until the target is achieved (53/118, 44.9%).
CONCLUSIONS
This survey offers important insights into the preferences of Australian and New Zealand clinicians in regards to any future randomised controlled trial of bicarbonate therapy for metabolic acidosis in the critically ill.
Topics: Acidosis; Australia; Calcium; Critical Care; Critical Illness; Double-Blind Method; Humans; New Zealand; Sodium Bicarbonate; Surveys and Questionnaires; Treatment Outcome
PubMed: 32900336
DOI: 10.1016/S1441-2772(23)00397-6 -
Nutrients Feb 2022Increased dietary acid load has a negative impact on health, particularly when renal function is compromised. Fibroblast growth factor 23 (FGF23) is a bone-derived...
Increased dietary acid load has a negative impact on health, particularly when renal function is compromised. Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that is elevated during renal failure. The relationship between metabolic acidosis and FGF23 remains unclear. To investigate the effect of dietary acid load on circulating levels of FGF23, rats with normal renal function and with a graded reduction in renal mass (1/2 Nx and 5/6 Nx) received oral NH4Cl for 1 month. Acid intake resulted in a consistent decrease of plasma FGF23 concentrations in all study groups when compared with their non-acidotic control: 239.3 ± 13.5 vs. 295.0 ± 15.8 pg/mL (intact), 346.4 ± 19.7 vs. 522.6 ± 29.3 pg/mL (1/2 Nx) and 988.0 ± 125.5 vs. 2549.4 ± 469.7 pg/mL (5/6 Nx). Acidosis also decreased plasma PTH in all groups, 96.5 ± 22.3 vs. 107.3 ± 19.1 pg/mL, 113.1 ± 17.3 vs. 185.8 ± 22.2 pg/mL and 504.9 ± 75.7 vs. 1255.4 ± 181.1 pg/mL. FGF23 showed a strong positive correlation with PTH (r = 0.877, p < 0.0001) and further studies demonstrated that acidosis did not influence plasma FGF23 concentrations in parathyroidectomized rats, 190.0 ± 31.6 vs. 215 ± 25.6 pg/mL. In conclusion, plasma concentrations of FGF23 are consistently decreased in rats with metabolic acidosis secondary to increased acid intake, both in animals with intact renal function and with decreased renal function. The in vivo effect of metabolic acidosis on FGF23 appears to be related to the simultaneous decrease in PTH.
Topics: Acidosis; Animals; Bone and Bones; Calcium; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Rats
PubMed: 35268016
DOI: 10.3390/nu14051041 -
The Canadian Veterinary Journal = La... May 2023Primary objectives of this study were to determine presenting complaints, physical examination, clinicopathologic findings, and hospitalization time of dogs with...
OBJECTIVE
Primary objectives of this study were to determine presenting complaints, physical examination, clinicopathologic findings, and hospitalization time of dogs with spontaneous hypoadrenocorticism presenting with critical disease; and to compare those end points to dogs with a more stable presentation. Secondary objectives were to evaluate the shock index and to identify precipitating stressors.
ANIMALS
Eighty-four dogs at the Western College of Veterinary Medicine between 1998 and 2018 were included.
PROCEDURE
Data were retrieved from the medical records.
RESULTS
Collapse and depression were more common among critically ill dogs. Hyperlactatemia was rare despite a diagnosis of hypovolemic shock, and a shock index was ineffective in this patient subset. Isosthenuria, total hypocalcemia, and more severe acidosis were more common ( < 0.05) in critical dogs. Owner separation was the most common precipitating stressor.
CONCLUSION AND CLINICAL RELEVANCE
We concluded that the critical Addisonian dog has unique characteristics that may aid in early disease identification.
Topics: Dogs; Animals; Dog Diseases; Adrenal Insufficiency; Acidosis
PubMed: 37138712
DOI: No ID Found -
The Turkish Journal of Gastroenterology... Oct 2019Metabolic acidosis is a common complication in patients with cirrhosis at the intensive care units (ICUs) and associated with increased mortality. The aim of our...
BACKGROUND/AIMS
Metabolic acidosis is a common complication in patients with cirrhosis at the intensive care units (ICUs) and associated with increased mortality. The aim of our research was to explore the epidemiology and risk factors of metabolic acidosis in critically ill patients with cirrhosis.
MATERIALS AND METHODS
A total of 975 patients with cirrhosis were selected into our study, and all participants were followed up for at least 28 days. Cox regression model and machine-learning algorithm were used to identify the importance of different risk factors, respectively. Finally, an improved prognostic model as Model for End-stage Liver Disease and metabolic acidosis (MELD-MA) was developed.
RESULTS
Among the 975 patients with liver cirrhosis, 506 had metabolic acidosis, including 257 patients who had decompensated metabolic acidosis at ICU admission. The 28-day mortality was 41% (206/506) in patients with metabolic acidosis. Bilirubin (hazard ratio (HR): 1.023, 95% confidence interval (CI): 1.011-1.036), international normalized ratio (HR: 1.527, 95% CI: 1.332-1.750), pH (HR: 0.173, 95% CI: 0.047-0.640), BE-Lac (HR: 0.907, 95% CI: 0.868-0.948), and BE-Na (HR: 0.923, 95% CI: 0.859-0.991) were considered as independent prognostic parameters for 28-day mortality. MELD-NA had significantly higher discrimination (area under the receiver operating characteristic curve 0.79) than MELD and Child-Pugh score.
CONCLUSION
Critically ill patients with cirrhosis have a high mortality rate and poor prognosis because of the high prevalence of metabolic acidosis. Lactic acidosis is the worst prognosis of all types of metabolic acidosis. MELD-MA performs well on the short-term mortality assessment in critically ill patients with cirrhosis and metabolic acidosis.
Topics: Acidosis; Aged; Critical Illness; Female; Humans; Intensive Care Units; Liver Cirrhosis; Male; Middle Aged; Prognosis; Proportional Hazards Models; Risk Factors; Severity of Illness Index
PubMed: 31633484
DOI: 10.5152/tjg.2019.18813 -
Journal of Cerebral Blood Flow and... Apr 2022This study investigated trans-cerebral internal jugular venous-arterial bicarbonate ([HCO]) and carbon dioxide tension (PCO) exchange utilizing two separate...
This study investigated trans-cerebral internal jugular venous-arterial bicarbonate ([HCO]) and carbon dioxide tension (PCO) exchange utilizing two separate interventions to induce acidosis: 1) acute respiratory acidosis via elevations in arterial PCO (PaCO) (n = 39); and 2) metabolic acidosis via incremental cycling exercise to exhaustion (n = 24). During respiratory acidosis, arterial [HCO] by 0.15 ± 0.05 mmol ⋅ l per mmHg elevation in PaCO across a wide physiological range (35 to 60 mmHg PaCO; P < 0.001). The of the venous-arterial [HCO] and PCO differences with respiratory acidosis were both related to the hypercapnia-induced elevations in cerebral blood flow (CBF) (both P < 0.001; subset n = 27); thus, trans-cerebral [HCO] exchange (CBF × venous-arterial [HCO] difference) was reduced indicating a shift from net release toward net uptake of [HCO] (P = 0.004). Arterial [HCO] was by -0.48 ± 0.15 mmol ⋅ l per nmol ⋅ l increase in arterial [H] with exercise-induced acidosis (P < 0.001). There was no relationship between the venous-arterial [HCO] difference and arterial [H] with exercise-induced acidosis or CBF; therefore, trans-cerebral [HCO] exchange was unaltered throughout exercise when indexed against arterial [H] or pH (P = 0.933 and P = 0.896, respectively). These results indicate that increases and decreases in systemic [HCO] - during acute respiratory/exercise-induced metabolic acidosis, respectively - differentially affect cerebrovascular acid-base balance (via trans-cerebral [HCO] exchange).
Topics: Acid-Base Equilibrium; Acid-Base Imbalance; Acidosis; Acidosis, Respiratory; Bicarbonates; Carbon Dioxide; Humans; Hydrogen-Ion Concentration
PubMed: 34904461
DOI: 10.1177/0271678X211065924 -
Open Heart Oct 2021
Topics: Acidosis; Cardiovascular Diseases; Chronic Disease; Humans; Public Health; Severity of Illness Index
PubMed: 34702776
DOI: 10.1136/openhrt-2021-001730