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Hyperkalemia in association with metabolic acidosis that are out of proportion to changes in glomerular filtration rate defines type 4 renal tubular acidosis (RTA), the most common RTA observed, but the molecular mechanisms underlying the associated metabolic acidosis are incompletely understood. We sought to determine whether hyperkalemia directly causes metabolic acidosis and, if so, the mechanisms through which this occurs. We studied a genetic model of hyperkalemia that results from early distal convoluted tubule (DCT)-specific overexpression of constitutively active Ste20/SPS1-related proline-alanine-rich kinase (DCT-CA-SPAK). DCT-CA-SPAK mice developed hyperkalemia in association with metabolic acidosis and suppressed ammonia excretion; however, titratable acid excretion and urine pH were unchanged compared with those in wild-type mice. Abnormal ammonia excretion in DCT-CA-SPAK mice associated with decreased proximal tubule expression of the ammonia-generating enzymes phosphate-dependent glutaminase and phosphoenolpyruvate carboxykinase and overexpression of the ammonia-recycling enzyme glutamine synthetase. These mice also had decreased expression of the ammonia transporter family member Rhcg and decreased apical polarization of H-ATPase in the inner stripe of the outer medullary collecting duct. Correcting the hyperkalemia by treatment with hydrochlorothiazide corrected the metabolic acidosis, increased ammonia excretion, and normalized ammoniagenic enzyme and Rhcg expression in DCT-CA-SPAK mice. In wild-type mice, induction of hyperkalemia by administration of the epithelial sodium channel blocker benzamil caused hyperkalemia and suppressed ammonia excretion. Hyperkalemia decreases proximal tubule ammonia generation and collecting duct ammonia transport, leading to impaired ammonia excretion that causes metabolic acidosis.
Copyright © 2018 by the American Society of Nephrology.
Background - Previous works suggested that neutralizing intratumoral lactic acidosis combined with glucose deprivation may deliver an effective approach to control tumor. We did a pilot clinical investigation, including a nonrandomized (57 patients with large HCC) and a randomized controlled (20 patients with large HCC) study.
Methods - The patients were treated with transarterial chemoembolization (TACE) with or without bicarbonate local infusion into tumor.
Results - In the nonrandomized controlled study, geometric mean of viable tumor residues (VTR) in TACE with bicarbonate was 6.4-fold lower than that in TACE without bicarbonate (7.1% [95% CI: 4.6%–10.9%] vs 45.6% [28.9%–72.0%]; p<0.0001). This difference was recapitulated by a subsequent randomized controlled study. TACE combined with bicarbonate yielded a 100% objective response rate (ORR), whereas the ORR treated with TACE alone was 44.4% (nonrandomized) and 63.6% (randomized). The survival data suggested that bicarbonate may bring survival benefit.
Conclusions - Bicarbonate markedly enhances the anticancer activity of TACE.
Funding - Funded by National Natural Science Foundation of China.
Clinical trial number - ChiCTR-IOR-14005319.
In extremely low birth weight (ELBW) infants, levels of hypercapnia (Paco 2) > 60 mm Hg are considered a risk factor for severe intraventricular hemorrhage (IVH). Since cerebral vasoreactivity depends on arterial pH (apH) rather than Paco 2, we hypothesize that the role of mild-to-moderate hypercapnia (45-60 mm Hg) in the occurrence of severe IVH is modulated by the metabolic component of acid-base status. ELBW infants (n = 580, born < 28 wk gestation, and BW < 1,000 g) were separated into "high-base deficit (BD)" (n = 291) and "low-BD" (n = 289) groups if infants' median BD were > 4 mEq/L or ≤4 mEq/L, respectively. Rates of severe IVH were higher in "high-BD" (16%) than "low-BD" (9%) group. Although adjusted risk for severe IVH increased with higher Paco 2 and higher BD, apH was the sole predictor of severe IVH. In ELBW infants, higher degree of acidemia, rather than hypercapnia per se, during the first 48 hours of life, is associated with higher occurrences of severe IVH.
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Mitochondrial DNA (mtDNA) content is thought to remain stable over the preimplantation period of human embryogenesis that is, therefore, suggested to be entirely dependent on ooplasm mtDNA capital. We have explored the impact of two disease-causing mutations [m.3243A>G myopathy, encephalopathy, lactic acidosis and stroke-like syndrome (MELAS) and m.8344A>G myoclonic epilepsy associated with ragged-red fibers (MERRF)] on mtDNA amounts in human oocytes and day 4-5 preimplantation embryos. The mtDNA amount was stable in MERRF and control materials, whereas gradually increasing from the germinal vesicle of oogenesis to the blastocyst stage of embryogenesis in MELAS cells, MELAS embryos carrying ∼3-fold higher mtDNA amount than control embryos (P = 0.0003). A correlation between mtDNA copy numbers and mutant loads was observed in MELAS embryos (R(2) = 0.42, P < 0.0013), suggestive of a compensation for the respiratory chain defect resulting from high mutation levels. These results suggest that mtDNA can replicate in early embryos and emphasize the need for sufficient amount of wild-type mtDNA to sustain embryonic development in humans.
Metabolic adaptation to stress is a crucial yet poorly understood phenomenon, particularly in the central nervous system (CNS). The ability to identify essential metabolic events which predict neuronal fate in response to injury is critical to developing predictive markers of outcome, for interpreting CNS spectroscopic imaging, and for providing a richer understanding of the relevance of clinical indices of stress which are routinely collected. In this work, real-time multianalyte microphysiometry was used to dynamically assess multiple markers of aerobic and anaerobic respiration through simultaneous electrochemical measurement of extracellular glucose, lactate, oxygen, and acid. Pure neuronal cultures and mixed cultures of neurons and glia were compared following a 90 min exposure to aglycemia. This stress was cytotoxic to neurons yet resulted in no appreciable increase in cell death in age-matched mixed cultures. The metabolic profile of the cultures was similar in that aglycemia resulted in decreases in extracellular acidification and lactate release in both pure neurons and mixed cultures. However, oxygen consumption was only diminished in the neuron enriched cultures. The differences became more pronounced when cells were returned to glucose-containing media upon which extracellular acidification and oxygen consumption never returned to baseline in cells fated to die. Taken together, these data suggest that lactate release is not predictive of neuronal survival. Moreover, they reveal a previously unappreciated relationship of astrocytes in maintaining oxygen uptake and a correlation between metabolic recovery of neurons and extracellular acidification.
Nucleoside analogue reverse transcriptase inhibitors are an integral component of combination antiretroviral treatment regimens. However, their ability to inhibit polymerase-γ has been associated with several mitochondrial toxicities, including potentially life-threatening lactic acidosis. A total of 650 antiretroviral-naive adults (69% female) initiated combination antiretroviral therapy (cART) and were intensively screened for toxicities including lactic acidosis as part of a 3-year clinical trial in Botswana. Patients were categorized as no lactic acidosis symptoms, minor symptoms but lactate <4.4 mmol/liter, and symptoms with lactate ≥ 4.4 mmol/liter [moderate to severe symptomatic hyperlactatemia (SH) or lactic acidosis (LA)]. Of 650 participants 111 (17.1%) developed symptoms and/or laboratory results suggestive of lactic acidosis and had a serum lactate drawn; 97 (87.4%) of these were female. There were 20 events, 13 having SH and 7 with LA; all 20 (100%) were female (p<0.001). Cox proportional hazard analysis limited to the 451 females revealed that having a higher baseline BMI was predictive for the development of SH/LA [aHR=1.17 per one-unit increase (1.08-1.25), p<0.0001]. Ordered logistic regression performed among all 650 patients revealed that having a lower baseline hemoglobin [aOR=1.28 per one-unit decrease (1.1-1.49), p=0.002] and being randomized to d4T/3TC-based cART [aOR=1.76 relative to ZDV/3TC (1.03-3.01), p=0.04] were predictive of the symptoms and/or the development of SH/LA. cART-treated women in sub-Saharan Africa, especially those having higher body mass indices, should receive additional monitoring for SH/LA. Women presently receiving d4T/3TC-based cART in such settings also warrant more intensive monitoring.
Acid extruders in neurons prohibit intracellular pH from falling very far below normal. Our recent report suggests that the acid-extruding sodium/bicarbonate transporter NBCn1 (Slc4a7) in rat brain is upregulated by chronic metabolic acidosis. In this study, we examined whether the Na(+)-driven Cl/HCO(3) exchanger NDCBE (Slc4a8) is also upregulated by similar systemic acid loads. Immunoblot revealed NDCBE protein (130 kDa) expressed in a variety of rat brain regions. In the hippocampus, NDCBE was localized to CA1-CA4 pyramidal neurons and dentate gyrus granular neurons determined by immunoperoxidase immunohistochemistry. The staining was dispersed in cell bodies and dendrites. NDCBE protein expression was then compared between rats in chronic metabolic acidosis and control rats. Immunoblot of crude plasma membrane fractions from the hippocampus showed a slight increase in NDCBE in acidotic rats (p=0.05). However, the expression in CA3 pyramidal neurons was significantly increased, determined by immunohistochemistry and quantitative analysis. The increase was also observed in other neurons including entorhinal cortical neurons, posterior cortical neurons, and outer stellate cells in cerebellum. The staining in choroid plexus epithelia was unaffected by chronic metabolic acidosis. These data demonstrate that the Na(+)-driven Cl/HCO(3) exchanger NDCBE is upregulated by chronic acid loads in a cell-specific manner.
Copyright © 2010 Elsevier B.V. All rights reserved.
OBJECTIVE - To study the effect of subcutaneous administration of insulin glargine on the rate of resolution of acidosis and intravenous insulin infusion requirement in children with moderate and severe diabetic ketoacidosis (DKA).
STUDY DESIGN - Retrospective cohort study.
SETTING - Pediatric intensive care unit of a university-based children's hospital.
PATIENTS - Children with moderate to severe DKA admitted between March 2001 and February 2003.
RESULTS - The outcomes of children who received 0.3 units/kg of subcutaneous insulin glargine in the first 6 h of management in addition to the standard treatment (n=12) were compared with those of children who received standard treatment alone (n=59). Measured outcomes included dose of intravenous insulin required, duration of insulin infusion and acidosis correction time. The two groups were similar in demographics and severity of illness. The mean time for acidosis correction (venous pH>or=7.3) in the insulin glargine group was shorter than the standard therapy group (12.4+/-2.9 h and 17.1+/-6.2 h respectively, p<0.001). The insulin infusion time was shorter in the insulin glargine group (14.8+/-6.0 h vs 24.4+/-9.0 h, p<0.001). There was a trend towards shorter total hospital stay in the glargine group (3.2+/-1.0 days vs 3.72+/-1.06 days).
CONCLUSIONS - In our small series of children with moderate and severe DKA, supplementing with subcutaneous insulin glargine led to a faster resolution of acidosis without any adverse effects. This could potentially lead to a shorter need for insulin infusion and a shorter ICU length of stay.
Sites of inflammation are characterized by significant changes in metabolic activity. Shifts in energy supply and demand can result in diminished delivery and/or availability of oxygen, leading to inflammation-associated tissue hypoxia and metabolic acidosis. These shifts in tissue metabolism, as indicated by previous studies, are frequently associated with vasculitis and profound recruitment of inflammatory cell types, particularly myeloid cells such as neutrophils (PMN) and monocytes. Here, we review recent work addressing the influence of hypoxia on development of inflammatory lesions, with particular emphasis on molecular pathways regulated by hypoxia-inducible factor (HIF).