CJASN ePress. Published on June 25, 2020 as doi: 10.2215/CJN.16041219 Metabolic Alkalosis A Brief Pathophysiologic Review Michael Emmett Abstract Metabolic alkalosis is a very commonly encountered acid-base disorder that may be generated by a variety of exogenous and/or endogenous, pathophysiologic mechanisms. Multiple mechanisms are also responsible for Divisions of Internal the persistence, or maintenance, of metabolic alkalosis. Understanding these generation and maintenance Medicine and mechanisms helps direct appropriate intervention and correction of this disorder. The framework utilized in Nephrology, Department of this review is based on the ECF volume-centered approach popularized by Donald Seldin and Floyd Rector in Medicine, Baylor the 1970s. Although many subsequent scientific discoveries have advanced our understanding of the University Medical pathophysiology of metabolic alkalosis, that framework continues to be a valuable and relatively Center at Dallas, straightforward diagnostic and therapeutic model. Dallas, Texas CJASN 15: ccc–ccc, 2020. doi: https://doi.org/10.2215/CJN.16041219 Correspondence: Dr. Michael Emmett, Department of Medicine, Baylor Introduction profile, or Gamblegram (Figure 2), shows why the 2 University Medical Metabolic alkalosis is a primary acid-base disorder increased [HCO3 ] must be accompanied by a re- Center at Dallas, 3500 that increases the serum bicarbonate concentration duction of [Cl2](independentof[Na1]), a reduction Gaston Avenue, Room 2 [HCO3 ] (this is usually approximated by its surro- of the [AG2], or both (7,8). In fact, metabolic alkaloses H-102, Dallas, TX 2 75246-2096. Email: gate the venous total [CO2]) above 30 meq/L (1), reproducibly increase the [AG ] to a small degree, 1 Michael.Emmett@ causing the arterial blood [H ]tofall,i.e., the arterial mostly owing to increased negative charge density of BSWHealth.org blood pH increases into the alkaline range (.7.45). plasma proteins (9,10). Therefore, the relative [Cl2] Metabolic alkalosis is a very common disorder, espe- decrease must be even greater. cially in ICU settings (2). The diagnostic criteria and a However, an identical electrolyte pattern, increased 2 2 pathophysiologic approach to differential diagnosis [HCO3 ] and reduced [Cl ], is also generated by and treatment on the basis of dissection of the etiology compensation for chronic respiratory acidosis. Clini- and dominant maintenance mechanisms are reviewed. cal assessment and arterial blood pH measurement will point toward the correct diagnosis—the blood pH is high-normal/overtly alkaline with metabolic alka- Respiratory Compensation losis and low-normal/overtly acid with chronic re- Uncomplicated metabolic alkalosis rapidly (minutes spiratory acidosis. Venous blood pH, although less to hours) generates hypoventilatory compensation definitive than arterial, can also differentiate these that elevates the pCO2. Compensation reduces the disorders—add 0.03 pH units to the venous pH to . arterial pH, but it generally remains 7.45. Although approximate the arterial pH (11). the magnitude of the hypoventilatory response is 2 proportional to the [HCO3 ] increase, the response is very variable (Figure 1) (3–6, M.A. Fallahzadeh, et al., Pathogenesis: Generation and Maintenance “ unpublished observations). Seldin and Rector published a classic review The Generation and Maintenance of Metabolic Alkalosis” in 1972 (12). Although many subsequent discoveries Serum Chloride Concentration and have expanded our understanding of the complex Metabolic Alkalosis systemic neurohormonal, kidney, cellular, and para- Hyper- or hypochloremia can reflect water/hydration cellular mechanisms participating in the development disorders, acid/base disorders, or both. When an and maintenance of this acid-base disorder, the 2 abnormal [Cl ] is secondary to a water/hydration Seldin/Rector extracellular fluid (ECF) volume- disorder, there is a proportional degree of hyper- or centered approach continues to be an extremely useful 2 hyponatremia. Thus the abnormal [Cl ]coexistswith and relatively easy-to-understand diagnostic and ther- 1 an abnormal [Na ] in a 1:1.4 ratio. This relationship is apeutic framework for the metabolic alkaloses. Some disrupted in acid-base disorders such as metabolic experts believe the “ECF volume-centered” approach 2 alkalosis. The elevated [HCO3 ] with metabolic should be replaced by a chloride-depletion model alkalosis is generally associated with a reciprocally and cite experimental animal models to support their 2 1 reduced [Cl ] independent of [Na ]. The electrolyte position (13–16). However, others challenge these www.cjasn.org Vol 15 November, 2020 Copyright © 2020 by the American Society of Nephrology 1 2 CJASN Figure 1. | Respiratory compensation for metabolic alkalosis. Simultaneous pCO2 and [HCO3] data points derived from a recent compre- hensive literature review showing the best-fit linear regression line (*M.A. Fallahzadeh, et al., unpublished observations). Also shown are several commonly published relationship equations with adjacent references. The following very simple and easy to remember and utilize relationship: 5 1 2 pCO2 [HCO3] 10 (dashed line), to be very similar to the best-fit regression line in the HCO3 range between 30 and 50 meq/L. If the [HCO3 ] exceeds 55 mmol/L, the pCO2 may increase markedly. This is likely because of the development of a coexisting respiratory muscle weakness generatedbyalmost inevitableseverehypokalemia.Therefore,respiratoryacidosis oftencomplicates extreme metabolic alkalosis. pCO2,partial pressure of carbon dioxide; 1 TORR, 133.32 Pascal (Pa). 2 experimental results and their interpretation (17,18). Normal HCO3 Reclamation, Regeneration, and Generation This review uses the traditional “ECF volume-centered” Nonvolatile acids are generated by metabolism of ingested classification. foods and oxidation of endogenous substrates. A typical Western European/American diet generates 80–100 meq/d of nonvolatile strong acids (mainly sulfuric, phosphoric, and 1 hydrochloric). These acids release H that mainly reacts 2 with HCO3 to form H2CO3, which rapidly dehydrates to 2 “ ” CO2 and H2O. Thus, serum [HCO3 ] falls and is replaced 2 22 by the anions of the generated strong acids, i.e.,Cl ,SO4 , 22 HPO4 , etc. Acid-base homeostasis is restored by the kidney, which filters and secretes the acid anions mainly 1 1 with Na , then the tubules reabsorb the Na in exchange 1 for H , and finally the anions are excreted together with an 1 equal quantity of H , in the form of titratable acid (largely 2 1 – 1 H2PO4 ) and NH4 . In this way, 80 100 meq of H are “buffered” and excreted in the urine and 80–100 meq of 2 HCO3 are regenerated and added back to the body fluids. However, before the kidney can secrete/excrete the daily required load of acid and thereby regenerate the decomposed 2 fi 2 fi HCO3 , all the ltered HCO3 must rst be reclaimed and returned to the body. About 85%–90% of the normal filtered 2 – HCO3 load (4000 4500 meq/d) is reclaimed by the proximal 1 1 tubules via H secretion. A large fraction of proximal Na reabsorption occurs via the Na-H exchanger 3 (NHE3) in the luminal membrane. This exchange is energized by Figure 2. | The three majorserumelectrolytes in a normal patient and basolateral membrane Na-K ATPase, which reduces in- a patient with metabolic alkalosis, visualized using a Gamblegram. 1 2 tracellular Na and generates a negative intracellular charge. Note, when the HCO3 concentration increases and the anion gap also increases slightly (this occurs with most forms of metabolic al- This creates a strong inward (lumen into cell) electrochemical 2 1 1 kalosis), then the [Cl ] must fall and the Cl:Na ratio must fall below its Na gradient. Additionally, ATP-energized H pumps in normal 1:1.4 ratio. the lumenal membrane contribute a smaller fraction (about CJASN 15: ccc–ccc, November, 2020 Metabolic Alkalosis, Emmett 3 Figure 3. | Proximal tubule: The major proximal tubule cellular and 2 luminal events that participate in HCO3 reclamation. Intracellular H2OcombineswithCO2 to generate H2CO3 that rapidly dissociates to 1 2 H and HCO3 ions. These reactions are catalyzed bythe cytoplasmic enzyme carbonic anhydrase II (CAII). Na-K ATPase in the basolateral 1 membrane creates a steep Na electrochemical gradient that ener- 1 1 1 gizes Na reabsorption via the Na -H antiporter exchanger (NHE3). 1 2 When H moves into the lumen, it reacts with filtered HCO3 to form H2CO3. The H2CO3 dehydrates to H2OandCO2, a reaction catalyzed by intraluminal carbonic anhydrase IV (CAIV) (tethered to the luminal membrane). Generated CO2 flows into the cell, largely via the aquaporin 1 2 channel. The HCO3 ions generated within the cells move into the peri- 1 2 tubular capillary, primarily via aNa -3HCO3 cotransporter (the elec- trogenic NBCe1-A transporter; a product of the Solute Carrier Family 4 1 Member A4 or SLC4A4 gene). The net effect of the secretion of one H 1 molecule and reabsorption of one Na molecule is the addition of one molecule of NaHCO3 to the extracellular fluid and the disappearance of one NaHCO3 molecule from the lumen. In addition, a smaller component Figure 4. | Principal cellsa and type A and type B intercalated cells 1 2 of proximal tubule H secretion (HCO3 reclamation) is accomplished via are located in the late distal convoluted tubule, the connecting tu- 1 aV-typeH -ATPase pump complex. About 85%–90% of the filtered bule, and cortical collecting duct. Principal cell transport is energized 1 1 NaHCO3 is reclaimed in the proximal tubule.