Metabolic Alkalosis Pathogenesis, Diagnosis, and Treatment: Core Curriculum 2022

American Journal of Kidney Diseases, Journal Year: 2022, Volume and Issue: 80(4), P. 536 - 551

Published: May 5, 2022

Metabolic alkalosis is a widespread acid-base disturbance, especially in hospitalized patients. It characterized by the primary elevation of serum bicarbonate and arterial pH, along with compensatory increase Pco2 consequent to adaptive hypoventilation. The pathogenesis metabolic involves either loss fixed acid or net accumulation within extracellular fluid. may be via gastrointestinal tract kidney, whereas sources excess alkali oral parenteral intake. Severe critically ill patients—arterial blood pH 7.55 higher—is associated significantly increased mortality rate. kidney equipped sophisticated mechanisms avert generation persistence (maintenance) enhancing excretion. These include filtration as well decreased absorption enhanced secretion specialized transporters specific nephron segments. Factors that interfere these will impair ability eliminate bicarbonate, therefore promoting impairing correction alkalosis. factors volume contraction, low glomerular rate, potassium deficiency, hypochloremia, aldosterone excess, elevated carbon dioxide. Major clinical states are alkalosis, including vomiting, cortisol licorice ingestion, chloruretic diuretics, calcium genetic diseases such Bartter syndrome, Gitelman cystic fibrosis. In this installment AJKD Core Curriculum Nephrology, we review alkalosis; appraise precipitating events; discuss presentations, diagnoses, treatments FEATURE EDITORAsghar RastegarADVISORY BOARDUrsula C. BrewsterMichael ChoiAnn O'HareBiff F. PalmerThe aims give trainees nephrology strong knowledge base core topics specialty providing an overview topic citing key references, foundational literature led current approaches.IntroductionA gain from fluid fundamental (GI) kidney. Excess accumulate (HCO3−) administration lactate, acetate, citrate supplementation. GI directly coupled intracellular HCO3−, which then transported blood, thus increasing HCO3− concentration pH.The order maintain systemic status narrow physiological range. Any (generation phase) elicit series enhance excretion Thus, significant not persist so long kidney's remains intact irrespective source new HCO3−.The encompasses 2 distinct phases, maintenance, first conceptualized Seldin 1972 although there some overlap certain disease states. phase defined period manifested initial H+ (acid) chloride (Cl−) through (eg, vomiting) diuretics). maintenance refers when active has subsided subsiding (ie, vomiting diuretic usage stopped), but persists due impairment (recovery) follows achieved existing electrolyte deficits (hypokalemia hypochloremia) corrected inciting event (GI loss) treated. This Nephrology try incorporate gained on over last 6 decades into comprehensive description pathophysiology, diagnosis, treatment alkalosis.To better understand underlying facilitating generation, recovery detailed understanding pathways molecules regulating reabsorption tubules essential. issue discussed following section.Bicarbonate Absorption, Secretion, Generation Kidney: A Coordinated InteractionAcid Secretion Bicarbonate Reabsorption (Reclamation) Proximal TubuleApproximately 85% 90% filtered reabsorbed proximal tubule, remaining being absorbed thick ascending limb loop Henle, distal convoluted collecting ducts. tubule mediated lumen principally Na+/H+ exchanger 3 (NHE3) H+-transporting adenosine triphosphatase (H+-ATPase). Secreted reacts luminal rapidly dissociates dioxide (CO2) H2O, catalyzed membrane carbonic anhydrase (CAIV). CO2 enters cells where it converted cytosolic (CAII) before transportation basolateral Na+/HCO3− cotransporter (NBCe1). Figure 1 includes depiction role apical NHE3 H+-ATPase, NBCe1, CAIV CAII tubule.Bicarbonate Absorption Distal Nephron (Including Collecting Duct)The duct plays major homeostasis fine-tuning base. cortical comprises cell types: A-intercalated cells, secrete (acid); B-intercalated (base); principal absorb Na+ water ion (K+). primarily H+-ATPases (and H+/K+-ATPases), generating under control CAII. delivered exchange for Cl− Cl−/HCO3− anion protein (AE1).As opposed occur length medullary ducts, localized rarely found duct. Thanks mostly pendrin, Cl−. results H+-ATPase. types (CCD) their involved H+, transport shown 1.Ammoniagenesis Its Role New GenerationAmmonia (NH3) generated metabolism glutamine process ammoniagenesis (Fig 2). As weak base, NH3 acquires H2O yield NH4+ (ammonium) at physiologic pH. NH3/NH4+ secreted lumen, NH3, trapped (secreted H+-ATPase NHE3), NHE3, can function Na+/NH4+ exchanger. Enzymes responsible regulated indirectly K+). limb, interstitium Na+/K+/2Cl− (NKCC2). parallel secretion. Once intercalated H+/K+-ATPase). part dependent presence nonerythroid Rh protein, RhCG, present both connecting leads elimination duct, allowing tubule. By K+ pivotal NH4+/NH3 generation.Figure 2Schematic segments ammonium/ammonia transport. Ammonium (NH4+) Glutamine α-ketoglutarate eventually HCO3−) glutaminase glutamate dehydrogenase. H+-ATPase-mediated TAL (NKCC2; encoded SLC12A1) predominantly form NH4+. excreted urine its anion. generates (via metabolism), while excreting (ammonium chloride). returned NBCe1. Compared baseline state (A), hypokalemia (B) enhances stimulates activates AE1 induces expression activity nongastric H+/K+-ATPase downregulates HCO3−-secreting transporter pendrin cells. Bold arrows indicate activated molecules; thin denote inactive processes hypokalemia. Abbreviations: ADP, diphosphate; AE1, 1; AQP2, aquaporin 2; ATP, triphosphate; CAII, anhydrase; CCD, duct; DCT, tubule; ENaC, epithelial sodium channel; cotransporter; 3; NKCC, PCT, Pi, inorganic phosphate; TALH, Henle. Created BioRender.com.View Large Image ViewerDownload Hi-res image Download (PPT)Figure (PPT)Additional Readings➢Lee HW, Osis G, Harris AN, et al. NBCe1-A regulates ammonia basal conditions response acidosis. J Am Soc Nephrol. 2018;29(4):1182-1197.➢Moe OW, Preisig PA, Alpern RJ. Cellular model NaCl NaHCO3 absorption. Kidney Int. 1990;38(4):605-611.➢Soleimani M. multiple roles Nephrol Dial Transplant. 2015;30(8):1257-1266.➢Soleimani M, Burnham CE. Physiologic molecular aspects Na+:HCO3− health processes. 2000;57(2):371-378.➢Soleimani Rastegar A. Pathophysiology renal tubular acidosis: curriculum 2016. Dis. 2016;68(3):488-498.➢Weiner ID, Hamm LL. Molecular Annu Rev Physiol. 2007;69:317-340.Pathogenesis AlkalosisCase 1: 47-year-old man brought emergency department altered mental after unresponsive home his neighbors. Little known about medical history except few medications home, over-the-counter antacids ibuprofen. His neighbors indicated patient had heavy smoking noticed weight months. On arrival, pressure was 95/57 mm Hg, pulse rate 96 beats/min, he afebrile. oxygen saturation oximetry 92%. Basic chemistry laboratory testing showed Na+, 142 mEq/L; K+, 2.9 Cl−, 90 45 total calcium, 9.1 mg/dL; urea nitrogen (SUN), 38 creatinine (Scr), 1.7 mg/dL. An gas (ABG) revealed 7.48; Paco2, 52 Hg; Pao2, 70 Hg. service consulted workup management abnormalities.Question differential diagnosis should (select best answer):a)Excessive use inhibitor acetazolamideb)Ectopic corticotropin production possible lung malignancyc)Intake HCO3−-containing antacid heartburn setting pre-existing chronic (CKD)d)Gastric outlet obstruction vomitingFor answer question, see text.Box displays causes divided categories based intravascular status. sections gastric overuse prototypes depletion. We mineralocorticoid volume-depleted volume-expanded states.Box 1Etiologies Alkalosis1.Intravascular depletion hypochloremia.i.Gastric (HCl) loss: nasogastric drainageii.Renal wastinga.Loop diuretics furosemide, bumetanide, etc), thiazides hydrochlorothiazide)b.Inherited disorders: Batter syndrome; syndromeiii.Laxative overuseiv.Chloride-losing diarrhea (acquired inherited)v.Cystic fibrosisvi.Posthypercapnic statevii.High-volume ileostomy outputviii.Hypochloremia without depletion?2.Intravascular expansion depletioni.Primary aldosteronismii.Renin-secreting tumorsiii.Renal artery stenosis: unilateral bilateraliv.Pseudohyperaldosteronism apparent syndromea. Mutations MRb. HSD11B2: stimulation MRc. Altered 11-hydroxysteroid dehydrogenase type (excessive intake carbenoxolone, licorice, grapefruit)d. Primary deoxycorticosterone excess: deficiency 17α-hydroxylase 11β-hydroxylase genesv.Liddle syndrome: gain-of-function mutations ENaCvi.Cushing adrenal gland tumors ectopic (excess occupies MR; more potent cause hypokalemic than pituitary tumors)vii.Glucocorticoid-remediable aldosteronismAbbreviations: MR, receptor.Gastric AlkalosisVomiting tube suctioning lead acid-producing parietal cell. Parietal produce hydrochloric needed digestion 3. facilitated activity. extruded H+/K+-ATPase, (AE2), "generating" referred "alkaline tide." step vomiting. short-lived individual euvolemic, normochloremic, normokalemic. However, (as severe result (ECF) contraction hypochloremia direct HCl lumen. addition, resulting activate renin-angiotensin-aldosterone system (RAAS), wasting. Together critical ceased.Figure 3Schematic localization cytoplasmic (AE2; SLC4A2) Excessive addition blood. AE-2, NHE, (PPT)Diuretic-Induced AlkalosisInhibitors generate subsequent salt (NaCl) Thiazides (inhibitors Na+/Cl− [NCC]) mild contrast, (furosemide analogs) inhibition NKCC2. combination several sequential steps. starts wasting, activation renin-aldosterone (RAS). Next, wasting increases delivery Cl−) segments, channel (ENaC) (predominantly outer [ROMK]) H+/K+-ATPase) 4A ). amplified 4B), also effect duct.Figure 4Schematic mechanism Henle (A) With normal vascular volume, NKCC ENaC ROMK) offset mitigating impact homeostasis. When depletion, RAAS activated. aldosterone. inhibit molecules. Aldo, aldosterone; CaSR, calcium-sensing receptor; CFTR, fibrosis transmembrane conductance regulator; ion; NCC, NCX, sodium-calcium exchanger; RAAS, system; ROMK, TAL, limb; TRPV5, transient receptor potential vanilloid member 5. (PPT)Carbonic inhibitors (such acetazolamide) used patients congestive heart failure. they various disorders seizures, glaucoma, mountain sickness, idiopathic intracranial hypertension. They inhibiting nongap (hyperchloremic) case acidosis, Question 1, option (a) correct. Glucocorticoids high concentrations, like those production, bind leading urine, hypertension detected majority presents tachycardia suggestive (b) correct.Ingestion absorbable containing CO32− (carbonate) diminished impaired HCO3−. Absorbable medications, usually correct acidosis CKD hypotension makes (c) implausible 1.Many accompanied Vomiting large losses section 3). ECF RAS, hypochloremia. Vital signs (low depletion) alkalosis) fit category loss-induced acidosis; thus, (d).Question 2: Match each presentation:Clinical diagnosis:a)Overuse furosemideb)Ectopic malignancyc)Gastric vomitingPresentation:1)Blood pressure, 160/100 40 mEq/L2)Blood 4

Language: Английский

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Regulation Mechanisms and Maintenance Strategies of Stemness in Mesenchymal Stem Cells

Stem Cell Reviews and Reports, Journal Year: 2023, Volume and Issue: 20(2), P. 455 - 483

Published: Nov. 27, 2023

Language: Английский

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CYP51A1 drives resistance to pH-dependent cell death in pancreatic cancer

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 7, 2025

Disrupted pH homeostasis can precipitate cell death and represents a viable therapeutic target in oncological interventions. Here, we utilize mass spectrometry-based drug analysis, transcriptomic screens, lipid metabolomics to explore the metabolic mechanisms underlying pH-dependent death. We reveal CYP51A1, gene involved cholesterol synthesis, as key suppressor of alkalization-induced pancreatic cancer cells. Inducing intracellular alkalization by small molecule JTC801 leads decrease endoplasmic reticulum levels, subsequently activating SREBF2, transcription factor responsible for controlling expression genes biosynthesis. Specifically, SREBF2-driven upregulation CYP51A1 prevents accumulation within lysosomes, leading TMEM175-dependent lysosomal proton efflux, ultimately resulting inhibition In animal models, including xenografts, syngeneic orthotopic, patient-derived genetic or pharmacological enhances effectiveness suppressing tumors. These findings demonstrate role CYP51A1-dependent pathway inhibiting highlight its potential targetable vulnerability cancer. Previously, opioid analgesic JCT801 was reported induce via disruption authors investigate JCT801-induced death, identifying synthesis gene,

Language: Английский

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Mechanism of Hyperkalemia-Induced Metabolic Acidosis

Journal of the American Society of Nephrology, Journal Year: 2018, Volume and Issue: 29(5), P. 1411 - 1425

Published: Feb. 26, 2018

Background Hyperkalemia in association with metabolic acidosis that are out of proportion to changes glomerular filtration rate defines type 4 renal tubular (RTA), the most common RTA observed, but molecular mechanisms underlying associated incompletely understood. We sought determine whether hyperkalemia directly causes and, if so, through which this occurs. Methods studied a genetic model results from early distal convoluted tubule (DCT)–specific overexpression constitutively active Ste20/SPS1-related proline-alanine–rich kinase (DCT-CA-SPAK). Results DCT-CA-SPAK mice developed and suppressed ammonia excretion; however, titratable acid excretion urine pH were unchanged compared those wild-type mice. Abnormal decreased proximal expression ammonia-generating enzymes phosphate-dependent glutaminase phosphoenolpyruvate carboxykinase ammonia-recycling enzyme glutamine synthetase. These also had transporter family member Rhcg apical polarization H + -ATPase inner stripe outer medullary collecting duct. Correcting by treatment hydrochlorothiazide corrected acidosis, increased excretion, normalized ammoniagenic In mice, induction administration epithelial sodium channel blocker benzamil caused excretion. Conclusions decreases generation duct transport, leading impaired acidosis.

Language: Английский

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Mechanism for higher urine pH in normal women compared with men

AJP Renal Physiology, Journal Year: 2018, Volume and Issue: 314(4), P. F623 - F629

Published: Jan. 8, 2018

Regulation of acid-base metabolism maintains the pH body fluids within a tight range. Urine (UpH) is also regulated under normal conditions. Median 24-h urines ~6, but others have noted that UpH in women higher than men, which has been attributed to differences diet. If true, it would help explain fact calcium phosphate stones, form at urine pH, are much more common men. We studied 14 subjects (7 men and 7 women) fed identical meals Clinical Research Center. blood samples were collected during fasting after meals. (6.74 ± 0.11) exceeded (6.07 0.17) fed, not fasting, rose significantly with Serum total CO 2 net acid excretion fell zero period. In general linear model adjusted for age, sex, weight, gastrointestinal anion uptake was main predictor (3.9 0.6) (1.8 0.7) citrate, an absorbed by tract, state, fractional citrate The related greater absorption food anions raises UpH.

Language: Английский

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Renal Tubular Acidosis and Management Strategies: A Narrative Review

Advances in Therapy, Journal Year: 2020, Volume and Issue: 38(2), P. 949 - 968

Published: Dec. 26, 2020

Renal tubular acidosis (RTA) occurs when the kidneys are unable to maintain normal acid−base homeostasis because of defects in acid excretion or bicarbonate ion reabsorption. Using illustrative clinical cases, this review describes main types RTA observed practice and provides an overview their diagnosis treatment. The three major forms distal (type 1; characterized by impaired excretion), proximal 2; caused reabsorption filtered bicarbonate), hyperkalemic 4; abnormal potassium collecting duct). Type 3 is a rare form disease with features both RTA. Accurate plays important role optimal patient management. versus involves assessment urinary secretion, while RTA, selective aldosterone deficiency resistance its effects confirmed after exclusion other causes hyperkalemia. Treatment options include alkali therapy patients lowering serum concentrations through dietary modification potential new pharmacotherapies including newer binders.

Language: Английский

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Aggregation/dispersion transitions of T4 phage triggered by environmental ion availability

Journal of Nanobiotechnology, Journal Year: 2017, Volume and Issue: 15(1)

Published: April 24, 2017

Bacteriophage survives in at least two extremes of ionic environments: bacterial host (high ionic-cytosol) and that soil (low ionic-environmental water). The impact composition the micro- macro-environments has not so far been addressed phage biology.Here, we discovered a novel mechanism aggregation/disaggregation transitions by virions. When normal sodium levels media (150 mM) were lowered to 10 mM, advanced imaging scanning electron microscopy, atomic force microscopy dynamic light scattering all revealed formation viral packages, each containing 20-100 strength was returned from low high, aggregated state reversed dispersed state, change did substantially affect infectivity phage. By providing direct evidence, lowering ion below threshold 20 mM causes rapid aggregation while returning Na+ concentration values above this dispersion phage, identified biophysical aggregation.Our results implicate operation group behavior suggest new kind quorum sensing among its virions is mediated ions. Loss may act as trigger an evolutionary improve survival bacteriophage stimulating when outside host. Reversal also promising breakthrough biotechnological applications, since demonstrated here ability retain viable virion aggregates on standard micro-filters.

Language: Английский

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The ‘Achilles Heel’ of Metabolism in Renal Cell Carcinoma: Glutaminase Inhibition as a Rational Treatment Strategy

Kidney Cancer, Journal Year: 2019, Volume and Issue: 3(1), P. 15 - 29

Published: Jan. 25, 2019

An important hallmark of cancer is 'metabolic reprogramming' or the rewiring cellular metabolism to support rapid cell proliferation [1-5]. Metabolic reprogramming through oncometabolite-mediated transformation activation oncogenes in renal carcinoma (RCC) globally impacts energy production as well glucose and glutamine utilization RCC cells, which can promote dependence on supply growth [6, 7]. Novel inhibitors glutaminase, a key enzyme metabolism, target addiction viable treatment strategy metastatic (mRCC). Here, we review metabolic pathways how changes enable progression RCC. This overview provides scientific rationale for targeting this pathway patients with mRCC. We will summarize current understanding molecular mechanisms underlying anti-tumor efficacy glutaminase RCC, provide an clinical efforts mRCC, approaches identifying biomarkers patient stratification detecting therapeutic response early treated novel class anti-cancer drug. Ultimately, results ongoing trials demonstrate whether inhibition be worthy addition armamentarium drugs used

Language: Английский

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Biodegradable shape memory alloys: Progress and prospects

Biomaterials, Journal Year: 2021, Volume and Issue: 279, P. 121215 - 121215

Published: Oct. 28, 2021

Language: Английский

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Physiological aspects of pig kidney xenotransplantation and implications for management following transplant

Xenotransplantation, Journal Year: 2022, Volume and Issue: 29(3)

Published: March 16, 2022

Abstract Successful organ transplantation between species is now possible, using genetic modifications. This article aims to provide a comprehensive overview of the differences and similarities in kidney function humans, primates, pigs, preparation for pig‐allograft human xenotransplantation. The kidney, as principal defender body homeostasis, acts sensor, effector, regulator physiologic feedback systems. Considerations are made anticipated effects on each system when pig placed into recipient. Discussion topics include anatomy, global function, sodium water handling, hormone production response circulating hormones, acid–base balance, calcium phosphorus handling. Based available data, kidneys be compatible with physiology, despite few barriers.

Language: Английский

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