RESUMO
Metabolic transformation of cancer cells leads to the accumulation of lactate and significant acidification in the tumor microenvironment. Both lactate and acidosis have a well-documented impact on cancer progression and negative patient prognosis. Here, we report that cancer cells adapted to acidosis are significantly more sensitive to oxidative damage induced by hydrogen peroxide, high-dose ascorbate, and photodynamic therapy. Higher lactate concentrations abrogate the sensitization. Mechanistically, acidosis leads to a drop in antioxidant capacity caused by a compromised supply of nicotinamide adenine dinucleotide phosphate (NADPH) derived from glucose metabolism. However, lactate metabolism in the Krebs cycle restores NADPH supply and antioxidant capacity. CPI-613 (devimistat), an anticancer drug candidate, selectively eradicates the cells adapted to acidosis through inhibition of the Krebs cycle and induction of oxidative stress while completely abrogating the protective effect of lactate. Simultaneous cell treatment with tetracycline, an inhibitor of the mitochondrial proteosynthesis, further enhances the cytotoxic effect of CPI-613 under acidosis and in tumor spheroids. While there have been numerous attempts to treat cancer by neutralizing the pH of the tumor microenvironment, we alternatively suggest considering tumor acidosis as the Achilles' heel of cancer as it enables selective therapeutic induction of lethal oxidative stress.
Assuntos
Acidose/fisiopatologia , Caprilatos/farmacologia , Ciclo do Ácido Cítrico/efeitos dos fármacos , Glucose/metabolismo , Mitocôndrias/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Sulfetos/farmacologia , Microambiente Tumoral , Adaptação Fisiológica , Antineoplásicos/farmacologia , Metabolismo Energético , Glicólise , Humanos , Concentração de Íons de Hidrogênio , Ácido Láctico/metabolismo , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Neoplasias/metabolismo , Neoplasias/patologia , Estresse Oxidativo , Células Tumorais CultivadasRESUMO
Chronic kidney disease (CKD), defined as the presence of irreversible structural or functional kidney damages, increases the risk of poor outcomes due to its association with multiple complications, including altered mineral metabolism, anemia, metabolic acidosis, and increased cardiovascular events. The mainstay of treatments for CKD lies in the prevention of the development and progression of CKD as well as its complications. Due to the heterogeneous origins and the uncertainty in the pathogenesis of CKD, efficacious therapies for CKD remain challenging. In this review, we focus on the following four themes: first, a summary of the known factors that contribute to CKD development and progression, with an emphasis on avoiding acute kidney injury (AKI); second, an etiology-based treatment strategy for retarding CKD, including the approaches for the common and under-recognized ones; and third, the recommended approaches for ameliorating CKD complications, and the final section discusses the novel agents for counteracting CKD progression.
Assuntos
Injúria Renal Aguda/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Insuficiência Renal Crônica/terapia , Acidose/fisiopatologia , Injúria Renal Aguda/terapia , Anemia , Meios de Cultivo Condicionados , Complicações do Diabetes/fisiopatologia , Diabetes Mellitus/fisiopatologia , Progressão da Doença , Transição Epitelial-Mesenquimal , Taxa de Filtração Glomerular , Humanos , Hiperpotassemia , Hipertensão/fisiopatologia , Falência Renal Crônica/complicações , Células-Tronco Mesenquimais/metabolismo , Nefrolitíase/fisiopatologiaRESUMO
This case represents a rare fulminant course of fried-rice associated food poisoning in an immunocompetent person due to pre-formed exotoxin produced by Bacillus cereus, with severe manifestations of sepsis, including multi-organ (hepatic, renal, cardiac, respiratory and neurological) failure, shock, metabolic acidosis, rhabdomyolysis and coagulopathy. Despite maximal supportive measures (continuous renal replacement therapy, plasmapheresis, N-acetylcysteine infusion and blood products, and broad-spectrum antimicrobials) and input from a multidisciplinary team (consisting of infectious diseases, intensive care, gastroenterology, surgery, toxicology, immunology and haematology), mortality resulted. This case is the first to use whole genome sequencing techniques to confirm the toxigenic potential of B. cereus It has important implications for food preparation and storage, particularly given its occurrence in home isolation during the COVID-19 pandemic.
Assuntos
Bacillus cereus/genética , Exotoxinas/genética , Doenças Transmitidas por Alimentos/diagnóstico , Acetilcisteína/uso terapêutico , Acidose/fisiopatologia , Acidose/terapia , Adulto , Antiarrítmicos/uso terapêutico , Antibacterianos/uso terapêutico , Arritmias Cardíacas/fisiopatologia , Arritmias Cardíacas/terapia , Bacillus cereus/isolamento & purificação , Transtornos da Coagulação Sanguínea/fisiopatologia , Transtornos da Coagulação Sanguínea/terapia , Transfusão de Sangue , Encefalopatias , Terapia de Substituição Renal Contínua , Evolução Fatal , Feminino , Doenças Transmitidas por Alimentos/microbiologia , Doenças Transmitidas por Alimentos/fisiopatologia , Doenças Transmitidas por Alimentos/terapia , Sequestradores de Radicais Livres/uso terapêutico , Humanos , Imunocompetência , Falência Hepática/fisiopatologia , Falência Hepática/terapia , Insuficiência de Múltiplos Órgãos/fisiopatologia , Insuficiência de Múltiplos Órgãos/terapia , Plasmaferese , Insuficiência Renal/fisiopatologia , Insuficiência Renal/terapia , Rabdomiólise/fisiopatologia , Rabdomiólise/terapia , Sepse/fisiopatologia , Sepse/terapia , Choque/fisiopatologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Sequenciamento Completo do GenomaRESUMO
Dendritic cells (DCs) are the most powerful antigen-presenting cells known to date and play an important role in initiating and amplifying both innate and adaptive immune responses. Extracellular acidosis is an important hallmark of a variety of inflammatory processes and solid tumors. However, few studies have focused on the effect of extracellular acidosis on DCs and their functions. Cellular mechanical properties reflect the relationship between cell structure and function, including cytoskeleton (especially F-actin organization), membrane negative charges, membrane fluidity, and osmotic fragility. The study investigated the effects of extracellular acidosis on the DCs functions from the perspective of cellular migration and mechanical properties. The results showed that migration ability, F-actin contents, and membrane negative charges of DCs were reduced by extracellular acidosis no matter whether LPS stimulated its maturation or not. And these functions could not return to normal after removing acidic microenvironment, which revealed that the function impairment induced by extracellular acidosis might be irreversible. In addition, the proliferation capacity of stimulated allogeneic T cells was impaired by extracellular acidosis. Our results suggest extracellular acidosis may play an immunosuppressive role in DCs-mediated immune process.
Assuntos
Acidose/imunologia , Movimento Celular/imunologia , Microambiente Celular/imunologia , Citoesqueleto/imunologia , Células Dendríticas/imunologia , Fluidez de Membrana/imunologia , Fragilidade Osmótica/imunologia , Acidose/fisiopatologia , Animais , Proliferação de Células , Sobrevivência Celular/imunologia , Células Cultivadas , Células Dendríticas/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microscopia ConfocalRESUMO
INTRODUCTION: Triclopyr is a synthetic auxin-like herbicide. It is considered to have low toxicity and there are few reports of poisoning. We report two cases of life-threatening toxicity following ingestions of 250 mL of 50 g/L triclopyr co-formulated with diethylene glycol monoethyl ether (DEGEE). CASE REPORTS: A 79-year-old male with a background of hypertension and atrial fibrillation presented two hours after ingestion with sedation, a severe high anion gap metabolic acidosis, raised osmolar gap and an aspiration pneumonitis. He was ventilated and dialysed for 10 h with resolution of the acidaemia. He was discharged home on day 33. A 66-year-old male with a past history of alcoholism and hypertension presented following a collapse. He had sedation, a severe high anion gap metabolic acidosis with a raised osmolar gap, acute kidney injury and vasodilatory shock. He was ventilated and received dialysis for 43 h. He had poor neurological recovery and died on day 10. DISCUSSION: Ingestion of triclopyr formulations can produce life-threatening toxicity. In large poisonings of triclopyr co-formulated with DEGEE, a high anion gap metabolic acidosis appears to be due to the glycol ether solvent rather than triclopyr itself. Management should focus on good supportive care including dialysis for significant metabolic acidosis.
Assuntos
Acidose/induzido quimicamente , Etilenoglicóis/intoxicação , Glicolatos/intoxicação , Herbicidas/intoxicação , Solventes/intoxicação , Equilíbrio Ácido-Base/efeitos dos fármacos , Acidose/diagnóstico , Acidose/fisiopatologia , Idoso , Evolução Fatal , Humanos , Masculino , Diálise Renal , Resultado do TratamentoRESUMO
OBJECTIVES: As a vasodilator, nitric oxide is considered to play a significant role in the homeostatic regulation of renal hemodynamics. To test the hypothesis that a kidney graft is capable of producing nitric oxide immediately after renal transplant surgery, we examined the possibility that it positively affects local metabolic acidosis. MATERIALS AND METHODS: In kidney transplant recipients, we analyzed renal vein and central vein blood samples, which reflect local and systemic metabolic alterations, respectively. Samples were taken immediately after kidney recirculation (that is, the first blood passing through after clamps are released) and at 5, 15, and 30 minutes thereafter. Levels of nitric oxide metabolites (nitrites, nitrates, and their sum), malondialdehyde (an indicator of oxidative damages), and parameters of acid-base balance (pH level, actual excess base, hemoglobin, actual bicarbonate, partial pressure of carbon dioxide, partial pressure of oxygen) were analyzed. Living kidney donors (the recipients' parents) were controls. RESULTS: In renal vein samples, nitrates and the sum of nitrites and nitrates were significantly higher than that shown in control (P < .001) and central vein (P < .05) samples, suggesting an immediate increase in nitric oxide production in the transplanted organ. Metabolic acidosis occurred in both the renal and central vein, indicated by decreased pH and actual bicarbonate level as well as by negative actual base excess level. Only in the renal vein was an increased nitrite and nitrate associated with a reduction of negative actual excess base, thereby suggesting a decrease in anion formation. CONCLUSIONS: Transplanted kidneys increase nitric oxide production immediately after organ transplant surgery, which positively affects local metabolic acidosis. The mechanism for this effect is likely local circulation improvement.
Assuntos
Equilíbrio Ácido-Base , Acidose/prevenção & controle , Transplante de Rim , Rim/metabolismo , Rim/cirurgia , Óxido Nítrico/metabolismo , Acidose/sangue , Acidose/etiologia , Acidose/fisiopatologia , Adulto , Biomarcadores/sangue , Feminino , Humanos , Concentração de Íons de Hidrogênio , Rim/fisiopatologia , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Nitratos/sangue , Nitritos/sangue , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Amelioration of hyperchloremic acidosis (Cl-Ac), a common complication in chronic kidney disease (CKD), could preserve renal function in chronic kidney disease (CKD). However, the development of Cl-Ac in CKD has not been clarified yet. METHODS: The degree of Cl-Ac, which is indicated as the bicarbonate concentration decrease with serum chloride concentration increase (∆[HCO3-]Cl), was compared with the estimated glomerular filtration rate (eGFR) by using CKD patient records. RESULTS: In 307 records with metabolic acidosis, a spline curve obtained from the plot comparing ∆[HCO3-]Cl with eGFR showed that ∆[HCO3-]Cl did not change, increased, and decreased during eGFR decrease until 27, from 27 to 17.5, and from 17.5 mL/min/1.73 m2, respectively. CONCLUSION: By CKD progression, Cl-Ac progressed and regressed at the CKD stages G4 and G5, respectively. The regression would have reflected the shift of Cl-Ac to high anion gap acidosis.
Assuntos
Equilíbrio Ácido-Base , Acidose/etiologia , Cloretos/sangue , Taxa de Filtração Glomerular , Rim/fisiopatologia , Insuficiência Renal Crônica/complicações , Acidose/sangue , Acidose/diagnóstico , Acidose/fisiopatologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bicarbonatos/sangue , Biomarcadores/sangue , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Estudos RetrospectivosRESUMO
OBJECTIVE: In this study, we examined the effect of acute hyponatremia associated with vasopressin (AVP) on the responses of the isolated rat's MCAs and PAs to acidosis, nitric oxide donor (SNAP) and to endothelium-dependent vasodilator ATP. METHODS: The studies were performed on isolated, perfused and pressurized MCAs and PAs in control conditions and during AVP-associated hyponatremia. Hyponatremia was induced in vitro by lowering Na+ concentration from 144 to 121 mmol/L in intra- and extravascular fluid in the presence of AVP. RESULTS: Parenchymal arterioles showed greater response to an increase in H+ and K+ ions concentration and to ATP in comparison with MCAs in control normonatremic conditions. Both PAs and MCAs constricted in response to acute hyponatremia associated with AVP. Interestingly, disordered regulation of vascular tone was observed in PAs but not in MCAs. The abnormalities in the regulation comprised a significant reduction of PA response to acidosis and the absence of the response to the administration of SNAP or ATP. CONCLUSIONS: Arginine vasopressin-associated hyponatremia leads to constriction and dysregulation of PAs which may impair neurovascular coupling.
Assuntos
Arteríolas/fisiopatologia , Encéfalo/irrigação sanguínea , Encéfalo/fisiopatologia , Hiponatremia/fisiopatologia , Acidose/fisiopatologia , Doença Aguda , Trifosfato de Adenosina/farmacologia , Animais , Arginina Vasopressina/administração & dosagem , Arginina Vasopressina/fisiologia , Arteríolas/efeitos dos fármacos , Modelos Animais de Doenças , Humanos , Hiponatremia/etiologia , Técnicas In Vitro , Masculino , Artéria Cerebral Média/efeitos dos fármacos , Artéria Cerebral Média/fisiopatologia , Doadores de Óxido Nítrico/farmacologia , Ratos , Ratos Wistar , S-Nitroso-N-Acetilpenicilamina/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstrição/fisiologiaRESUMO
Multiple risk factors for operative mortality in the setting of acute type A aortic dissection (ATAAD) have been described. Recently, the combination of severe acidosis and malperfusion was found to significantly impact operative mortality following surgery for ATAAD and a treatment algorithm was proposed. The purpose of this study is to validate these findings in our institution. A retrospective chart review was performed for patients who underwent ATAAD repair between Feb 1997 and Jan 2018. Preoperative nadir pH, bicarbonate, base deficit, organ malperfusion, and other relevant parameters were collected. Multivariable logistic regression was performed to evaluate operative mortality. A total of 298 patients underwent ATAAD repair. The highest operative mortality (18/49; 37%) was noted in patients with severe acidosis (base deficit ≤ -10). There were 96 patients (32%) with malperfusion. In patients with abdominal malperfusion, this trend is even more pronounced. Multivariable logistic regression showed that severe acidosis is associated with higher operative mortality, odds ratio of 13.9 (Pâ¯=â¯0.001). The presence of diabetes and advanced age were also associated with higher operative mortality. These findings validate the previously reported findings that severe acidosis is a strong predictor of operative mortality, and risk increases with associated organ malperfusion. This supports the suggestion that base deficit, which is easily performed at the bedside, should be used clinically to predict operative mortality and should be collected in aortic dissection databases.
Assuntos
Acidose/mortalidade , Aneurisma Aórtico/cirurgia , Dissecção Aórtica/cirurgia , Técnicas de Apoio para a Decisão , Procedimentos Cirúrgicos Vasculares/mortalidade , Equilíbrio Ácido-Base , Acidose/diagnóstico , Acidose/fisiopatologia , Doença Aguda , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/mortalidade , Dissecção Aórtica/fisiopatologia , Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/mortalidade , Aneurisma Aórtico/fisiopatologia , Feminino , Hemodinâmica , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Resultado do Tratamento , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Adulto JovemRESUMO
Hypokalemia increases ammonia excretion and decreases K+ excretion. The present study examined the role of the proximal tubule protein NBCe1-A in these responses. We studied mice with Na+-bicarbonate cotransporter electrogenic, isoform 1, splice variant A (NBCe1-A) deletion [knockout (KO) mice] and their wild-type (WT) littermates were provided either K+ control or K+-free diet. We also used tissue sections to determine the effect of extracellular ammonia on NaCl cotransporter (NCC) phosphorylation. The K+-free diet significantly increased proximal tubule NBCe1-A and ammonia excretion in WT mice, and NBCe1-A deletion blunted the ammonia excretion response. NBCe1-A deletion inhibited the ammoniagenic/ammonia recycling enzyme response in the cortical proximal tubule (PT), where NBCe1-A is present in WT mice. In the outer medulla, where NBCe1-A is not present, the PT ammonia metabolism response was accentuated by NBCe1-A deletion. KO mice developed more severe hypokalemia and had greater urinary K+ excretion during the K+-free diet than did WT mice. This was associated with blunting of the hypokalemia-induced change in NCC phosphorylation. NBCe1-A KO mice have systemic metabolic acidosis, but experimentally induced metabolic acidosis did not alter NCC phosphorylation. Although KO mice have impaired ammonia metabolism, experiments in tissue sections showed that lack of ammonia does impair NCC phosphorylation. Finally, urinary aldosterone was greater in KO mice than in WT mice, but neither expression of epithelial Na+ channel α-, ß-, and γ-subunits nor of H+-K+-ATPase α1- or α2-subunits correlated with changes in urinary K+. We conclude that NBCe1-A is critical for the effect of diet-induced hypokalemia to increase cortical proximal tubule ammonia generation and for the expected decrease in urinary K+ excretion.
Assuntos
Amônia/urina , Hipopotassemia/metabolismo , Túbulos Renais Proximais/metabolismo , Potássio na Dieta/sangue , Eliminação Renal , Simportadores de Sódio-Bicarbonato/metabolismo , Acidose/genética , Acidose/metabolismo , Acidose/fisiopatologia , Aldosterona/urina , Animais , Biomarcadores/sangue , Biomarcadores/urina , Modelos Animais de Doenças , Canais Epiteliais de Sódio/metabolismo , Glutamato-Amônia Ligase/metabolismo , ATPase Trocadora de Hidrogênio-Potássio/genética , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Hipopotassemia/genética , Hipopotassemia/fisiopatologia , Túbulos Renais Proximais/fisiopatologia , Camundongos Knockout , Fosforilação , Simportadores de Sódio-Bicarbonato/deficiência , Simportadores de Sódio-Bicarbonato/genética , Membro 3 da Família 12 de Carreador de Soluto/metabolismoRESUMO
The information regarding fetal effects of acetazolamide use during pregnancy and lactation is sparse. We report the clinical and pharmacodynamic characteristics of maternal acetazolamide use and the timing of its effects on acid-base balance in three cases who presented with metabolic acidosis in the newborn period. We found that the infants' clinical status soon after birth was inconsistently correlated with maternal drug dose and concentrations of medication in maternal serum. However, there was low transfer of the drug in breast milk and its use did not affect clinical symptomatology. We also present a review of literature on this subject to help consolidate our current knowledge on this topic.
Assuntos
Acetazolamida , Acidose , Doenças do Recém-Nascido , Administração dos Cuidados ao Paciente/métodos , Complicações na Gravidez/tratamento farmacológico , Pseudotumor Cerebral/tratamento farmacológico , Acetazolamida/administração & dosagem , Acetazolamida/efeitos adversos , Acetazolamida/farmacocinética , Acidose/induzido quimicamente , Acidose/fisiopatologia , Acidose/terapia , Inibidores da Anidrase Carbônica/administração & dosagem , Inibidores da Anidrase Carbônica/efeitos adversos , Inibidores da Anidrase Carbônica/farmacocinética , Feminino , Humanos , Recém-Nascido , Doenças do Recém-Nascido/induzido quimicamente , Doenças do Recém-Nascido/fisiopatologia , Doenças do Recém-Nascido/terapia , Masculino , Troca Materno-Fetal , Leite Humano/química , GravidezRESUMO
OBJECTIVES: Normal saline is the most common crystalloid solution that is used in renal transplant surgery. In this study, our aim was to determine the effects of a combination of half saline and bicarbonate versus normal saline as a routine solution. MATERIALS AND METHODS: For this double-blind random-ized clinical trial, we enrolled 100 adult patients undergoing kidney transplant. Patients were divided into 2 groups: those who received normal saline and those who received half saline and bicarbonate infusion as fluid replacement therapy during renal transplant. All patients received about 40 mL/kg of crystalloids during surgery. Serial creatinine con-centrations (primary outcomes) were compared between groups at 1, 2, 3, and 7 days after surgery. Urine output (secondary outcome) was compared between groups at recovery and at 6 and 24 hours after surgery. In addition, base excess, chloride, and sodium levels were measured before and 6 hours after surgery. Each liter of half saline-bircarbonate, which is relatively isoosmotic to human plasma, was composed of 70 mEq bicarbonate, 77 mEq chloride, and 147 mEq sodium. RESULTS: Patients who received half saline-bicarbonate had significantly lower postoperative creatinine levels at all time points than patients who received normal saline (P = .019). Serum chloride and sodium levels (P = .001) were significantly higher and base excess (P = .007) was significantly lower in the normal saline group at 6 hours after transplant. At all time points, urine output levels were significantly higher in the half saline-bicarbonate group (P = .001). CONCLUSIONS: The use of half saline-bicarbonate was associated with better early graft function compared with normal saline in the first 7 days after transplant.
Assuntos
Acidose/prevenção & controle , Bicarbonatos/administração & dosagem , Hidratação , Cuidados Intraoperatórios , Transplante de Rim , Solução Salina/administração & dosagem , Equilíbrio Ácido-Base , Acidose/diagnóstico , Acidose/etiologia , Acidose/fisiopatologia , Adulto , Bicarbonatos/efeitos adversos , Biomarcadores/sangue , Creatinina/sangue , Método Duplo-Cego , Feminino , Hidratação/efeitos adversos , Humanos , Cuidados Intraoperatórios/efeitos adversos , Irã (Geográfico) , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Solução Salina/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Lung cancer diagnosis via imaging may be confounded by the presence of indolent infectious nodules in imaging studies. This issue is pervasive in the southwestern US where coccidioidomycosis (Valley Fever) is endemic. AcidoCEST MRI is a noninvasive imaging method that quantifies the extracellular pH (pHe) of tissues in vivo, allowing tumor acidosis to be used as a diagnostic biomarker. Using murine models of lung adenocarcinoma and coccidoidomycosis, we found that average lesion pHe differed significantly between tumors and granulomas. Our study shows that acidoCEST MRI is a promising tool for improving the specificity of lung cancer diagnosis.
Assuntos
Acidose/fisiopatologia , Adenocarcinoma de Pulmão/diagnóstico , Neoplasias Pulmonares/diagnóstico , Imageamento por Ressonância Magnética/métodos , Infecções do Sistema Genital/diagnóstico , Animais , Diagnóstico Diferencial , Espaço Extracelular/química , Feminino , Humanos , Concentração de Íons de Hidrogênio , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Brake oil is an automobile transmission fluid composed of a mixture of toxic alcohols such as ethylene glycols and glycol ethers. Both accidental and intentional ingestion cases have been reported and they can present with multisystem involvement. Life-threatening complications evolve from deleterious effects on cardiopulmonary and renal systems. Effects on neurological and gastrointestinal systems give rise to a multitude of complications although non-fatal in nature. The biochemical panel consists of a high concentration of ethylene glycol with severe metabolic acidosis, high anion gap, high osmolar gap, oxaluria, and hypocalcemia. The mainstay of treatment is enhanced elimination of ethylene glycol and its metabolites by hemodialysis, together with general supportive care, gastric decontamination, and vitamins such as thiamine and pyridoxine to minimize the adverse effects of intoxication. CASE PRESENTATION: A 26-year-old Sinhalese woman presented with reduced urine output, shortness of breath, reduced level of consciousness, abdominal pain, and vomiting with mild degree fever of 2 days' duration. She had bilateral lower limb edema, crepitations over bilateral lower lung fields, and right-sided lower motor type facial nerve palsy. Investigations showed severe metabolic acidosis with high anion gap and high osmolar gap. With regular hemodialysis she made a complete recovery after 3 months. CONCLUSION: Even without a clear history of poisoning, the presence of a high anion, high osmolar gap metabolic acidosis should prompt one to search for ethylene glycol ingestion. Uncommon manifestations like cranial neuropathies need to be examined and considered. Timely aggressive treatment leads to a better prognosis.
Assuntos
Acidose/induzido quimicamente , Etilenoglicol/intoxicação , Doenças do Nervo Facial/induzido quimicamente , Equilíbrio Ácido-Base , Acidose/fisiopatologia , Acidose/terapia , Adulto , Feminino , Humanos , Diálise Renal , Tentativa de SuicídioRESUMO
We have recently reported that type A intercalated cells of the collecting duct secrete Na+ by a mechanism coupling the basolateral type 1 Na+-K+-2Cl- cotransporter with apical type 2 H+-K+-ATPase (HKA2) functioning under its Na+/K+ exchange mode. The first aim of the present study was to evaluate whether this secretory pathway is a target of atrial natriuretic peptide (ANP). Despite hyperaldosteronemia, metabolic acidosis is not associated with Na+ retention. The second aim of the present study was to evaluate whether ANP-induced stimulation of Na+ secretion by type A intercalated cells might account for mineralocorticoid escape during metabolic acidosis. In Xenopus oocytes expressing HKA2, cGMP, the second messenger of ANP, increased the membrane expression, activity, and Na+-transporting rate of HKA2. Feeding mice with a NH4Cl-enriched diet increased urinary excretion of aldosterone and induced a transient Na+ retention that reversed within 3 days. At that time, expression of ANP mRNA in the collecting duct and urinary excretion of cGMP were increased. Reversion of Na+ retention was prevented by treatment with an inhibitor of ANP receptors and was absent in HKA2-null mice. In conclusion, paracrine stimulation of HKA2 by ANP is responsible for the escape of the Na+-retaining effect of aldosterone during metabolic acidosis.
Assuntos
Equilíbrio Ácido-Base , Acidose/enzimologia , Fator Natriurético Atrial/metabolismo , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Túbulos Renais Coletores/enzimologia , Sódio/urina , Acidose/genética , Acidose/fisiopatologia , Acidose/urina , Adaptação Fisiológica , Aldosterona/urina , Animais , GMP Cíclico/urina , Feminino , ATPase Trocadora de Hidrogênio-Potássio/deficiência , ATPase Trocadora de Hidrogênio-Potássio/genética , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos C57BL , Camundongos Knockout , Comunicação Parácrina , Ratos , Transdução de Sinais , Xenopus laevisRESUMO
BACKGROUND: Gap acidosis, a type of metabolic acidosis caused by titratable acid accumulation, participates in CKD progression. It was found at all the stages of chronic kidney disease (CKD), whereas the kidney was believed to preserve its ability to excrete titratable acid until renal function is impaired severely. METHODS: Serum concentrations of lactate (Lac) and the other usually unmeasured anions (OUA) were separately examined using 420 records of blood gas analysis performed simultaneously with serum chemistry at a general hospital. RESULTS: Between the records grouped by the CKD stage, Lac was generally higher in the early stages than the late stages (2.2 ± 1.1, 1.9 ± 1.7, 1.5 ± 1.3, and 1.2 ± 0.6 mmol/L in G1-2, G3, G4, and G5, respectively). While OUA was not significantly different between G1-2, G3, and G4 (1.3 ± 2.0, 2.5 ± 2.7, and 2.6 ± 2.2 mEq/L, respectively), it was higher in G5 (4.7 ± 2.3 mEq/L) than in G1-4 (P < 0.001). In G5, OUA generally increased as eGFR decreased, and OUA was 6.6 ± 1.9, 4.7 ± 2.1 and 3.6 ± 2.0 mEq/L in subgroups of eGFR < 5, 5-10, and 10-15 mL/min/1.73 m2, respectively (P ≤ 0.001). CONCLUSIONS: Gap acidosis except lactic acidosis developed and progressed during the CKD stage G5, while lactic acidosis developed in the CKD stages G1-4. Prevention of lactic acidosis by preserving peripheral perfusion in the early CKD stages could slow CKD progression.
Assuntos
Equilíbrio Ácido-Base , Acidose/fisiopatologia , Rim/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Acidose/sangue , Acidose/diagnóstico , Acidose Láctica/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Progressão da Doença , Feminino , Humanos , Ácido Láctico/sangue , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Estudos Retrospectivos , Fatores de RiscoRESUMO
Epithelial-to-mesenchymal transition (EMT) is an important process of tumor progression associated with increased metastatic potential. EMT can be activated by external triggers such as cytokines or metabolic parameters (e.g. hypoxia). Since extracellular acidosis is a common finding in tumors, the aim of the study is to analyze its impact on the expression of EMT markers in vitro and in vivo as well as the functional impact on cell adhesion. Therefore, three tumor and two normal epithelial cell lines were incubated for 24 h at pH 6.6 and the expression of EMT markers was studied. In addition, mRNA expression of transcription and metabolic factors related to EMT was measured as well as the functional impact on cell adhesion, either during acidic incubation or after priming cells in an acidic milieu. E-cadherin and N-cadherin were down-regulated in all tumor and normal cell lines studied, whereas vimentin expression increased in only two tumor and one normal cell line. Down-regulation of the cadherins was seen in total protein and to a lesser extent in surface protein. In vivo an increase in N-cadherin and vimentin expression was found. Acidosis up-regulated Twist1 and Acsl1 but down-regulated fumarate hydratase (Fh). Cell adhesion during acidic incubation decreased in AT1 prostate carcinoma cells whereas preceding acidic priming increased their subsequent adhesion. Low tumor pH is able to modulate the expression EMT-related proteins and by this may affect the stability of the tissue structure.
Assuntos
Acidose/fisiopatologia , Biomarcadores/metabolismo , Caderinas/metabolismo , Adesão Celular , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Vimentina/metabolismo , Animais , Caderinas/genética , Humanos , Masculino , Ratos , Vimentina/genéticaRESUMO
INTRODUCTION: Exercise can cause a decrease in serum ionized calcium (iCa) concentration, which stimulates parathyroid hormone (PTH) secretion and activates bone resorption. We postulated that dermal Ca loss during cycling exercise is the major determinant of the serum iCa, PTH, and bone resorption (C-terminal telopeptide of type 1 collagen [CTX]) responses. METHODS: To investigate this, women (n = 13) and men (n = 12) age 18 to 45 yr performed the same exercise bout under cool (18°C) and warm (26°C) conditions. Exercise was 60 min of cycling at ~75% of peak aerobic power. Sweat samples were obtained during exercise using a skin patch method, and blood samples were obtained before and during exercise and during 60 min of recovery. RESULTS: Sweat volume and estimated sweat Ca loss were 50% higher for the warm condition than the cool condition. Despite this, there were no differences between thermal conditions in the changes (mean, 95% confidence interval [95% CI]) in iCa (cool, -0.07 mg·dL; 95% CI, -0.16 to 0.03); warm, -0.07 mg·dL; 95% CI, -0.20 to 0.05), PTH (cool, 34.4 pg·mL; 95% CI, 23.6-45.2; warm: 35.8 pg·mL; 95% CI, 22.4-49.1), or CTX (cool, 0.11 ng·mL; 95% CI, 0.08-0.13; warm, 0.15 ng·mL; 95% CI, 0.11-0.18). Adjusting for exercise-related shifts in plasma volume revealed a marked decline in vascular iCa content in the first 15 min of exercise (cool, -0.85 mg·dL; 95% CI, -1.01 to -0.68; warm, -0.85 mg·dL; 95% CI, -1.05 to -0.66), before substantial sweat Ca loss had occurred. CONCLUSIONS: This indicates that dermal Ca loss was not the primary trigger for the increases in PTH and CTX during exercise. Further research is necessary to understand the causes and consequences of the disruption in Ca homeostasis during exercise and specifically the extravascular shift in iCa.
Assuntos
Cálcio/metabolismo , Exercício Físico/fisiologia , Hormônio Paratireóideo/sangue , Pele/metabolismo , Sudorese/fisiologia , Acidose/fisiopatologia , Adolescente , Adulto , Reabsorção Óssea/fisiopatologia , Cálcio/sangue , Colágeno Tipo I/sangue , Feminino , Frequência Cardíaca/fisiologia , Homeostase , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeos/sangue , Adulto JovemRESUMO
Lymph vessels counteract edema by transporting interstitial fluid from peripheral tissues to the large veins and serve as conduits for immune cells, cancer cells, and pathogens. Because edema during inflammation and malignancies is frequently associated with acidosis, we tested the hypothesis that acid-base disturbances affect human thoracic duct contractions. We studied, by isometric and isobaric myography, the contractile function of human thoracic duct segments harvested with written informed consent from patients undergoing esophageal cancer surgery. Human thoracic ducts produce complex contractile patterns consisting of tonic rises in tension (isometric myography) or decreases in diameter (isobaric myography) with superimposed phasic contractions. Active tone development decreases substantially (~90% at 30 vs. 7 mmHg) at elevated transmural pressure. Acidosis inhibits spontaneous as well as noradrenaline- and serotonin-induced phasic contractions of human thoracic ducts by 70-90% at extracellular pH 6.8 compared to 7.4 with less pronounced effects observed at pH 7.1. Mean tension responses to noradrenaline and serotonin - averaged over the entire period of agonist exposure - decrease by ~50% at extracellular pH 6.8. Elevating extracellular [K+ ] from the normal resting level around 4 mmol/L increases overall tension development but reduces phasic activity to a level that is no different between human thoracic duct segments investigated at normal and low extracellular pH. In conclusion, we show that extracellular acidosis inhibits human thoracic duct contractions with more pronounced effects on phasic than tonic contractions. We propose that reduced phasic activity of lymph vessels at low pH attenuates lymph propulsion and increases the risk of edema formation.
Assuntos
Acidose/fisiopatologia , Edema/fisiopatologia , Vasos Linfáticos/fisiopatologia , Contração Muscular , Músculo Liso/fisiopatologia , Tórax/fisiopatologia , Agonistas Adrenérgicos/farmacologia , Idoso , Epinefrina/farmacologia , Feminino , Humanos , Vasos Linfáticos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Tono Muscular , Músculo Liso/efeitos dos fármacos , Periodicidade , Serotonina/farmacologia , Agonistas do Receptor de Serotonina/farmacologia , Tórax/patologiaRESUMO
Background It is well known that after menopause women are exposed to a greater cardiovascular risk, but the intracellular modifications are not properly described. The sodium/proton exchanger (NHE) and the sodium/bicarbonate cotransporter (NBC) regulate the intracellular pH and, indirectly, the intracellular sodium concentration ([Na+]). There are 2 isoforms of NBC in the heart: the electrogenic (1Na+/2[Formula: see text]; NBCe1) and the electroneutral (1Na+/1[Formula: see text]; NBCn1). Because NHE and NBCn1 hyperactivity as well as the NBCe1 decreased activity have been associated with several cardiovascular pathologies, the aim of this study was to investigate the potential alterations of the alkalinizing transporters during the postmenopausal period. Methods and Results Three-month ovariectomized rats (OVX) were used. The NHE activity and protein expression are significantly increased in OVX. The NBCe1 activity is diminished, and the NBCn1 activity becomes predominant in OVX rats. p-Akt levels showed a significant diminution in OVX. Finally, NHE activity in platelets from OVX rats is also higher in comparison to sham rats, resulting in a potential biomarker of cardiovascular diseases. Conclusions Our results demonstrated for the first time that in the cardiac ventricular myocytes of OVX rats NHE and NBC isoforms are altered, probably because of the decreased level of p-Akt, compromising the ionic intracellular homeostasis.