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Home , Contraction alkalosis, Metabolic alkalosis, Respiratory compensation

CJASN ePress. Published on June 25, 2020 as doi: 10.2215/CJN.16041219

Metabolic A Brief Pathophysiologic Review

Michael Emmett

Abstract 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 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 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 . 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- 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 . 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 ; 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 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 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 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 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. primarily by electrogenic Na -K ATPase pumps in the basolateral 1 membrane. The resulting low intracellular [Na ] and negative in- 1 1 tracellular potential difference combine to create a large gradient 30%) of proximal H secretion. Each secreted H 1 2 for Na to move from the lumen into these cells. Flowoccurs mainly generates a HCO3 molecule that is added to the ECF and throughthe epithelialsodiumchannel(ENaC;whichiscomposedof 2 causes the disappearance of an HCO3 molecule from the a, b,andg subunits, each a product of a different gene). Inward flow 1 1 1 1 lumen. Major aspects of proximal tubule Na reabsorption/H of Na ions is more rapid than the sum of outward movement of K – 2 (mainly through the renal outer medullary potassium channel secretionareshowninFigure3.The10% 15% of HCO3 2 [ROMK])andinwardflowofCl (mainlyviatheparacellularspace). that escapes proximal reclamation is reclaimed in the 1 Therefore, the Na influx generates a negative potential difference distal tubules/collecting ducts, as shown in Figure 4. 1 2 (PDofabout240mv)inthelumen.ThesecretionofH bythetypeA After HCO3 has largely disappeared from the distal 2 1 intercalated cells initially reacts with HCO3 in the lumen, which tubules/collecting ducts, continued H secretion regen- 2 2 represents HCO3 reclamation. As the luminal pH falls, additional erates decomposed ECF HCO3 . If dietary and metabolic 1 22 secreted H combines with buffers such as HPO4 and NH3to acids have produced 80–100 meq/d of nonvolatile acids, 2 generate urine titratable acid and NH4 , which creates equimolar 1 2 then 80–100 meq/d of H must be excreted by the kidneys. quantitates of systemic HCO . See Figure 5 for a description of in- 2 1 3 This regenerates the HCO3 that reacted with H derived tercalated cell ion transport. from nonvolatile acids and thereby decomposed or “dis- ” 2 appeared. Also, any HCO3 lost in stool must be regerated. Figure 4 shows the major distal kidney transport mech- 2 fl fl 2 As HCO3 disappears from the tubular uid, the uid pH anisms for HCO3 reclamation, regeneration, and gener- falls. The minimum achievable urine pH is about 4.5, which 1 2 1 ation (all linked to H secretion) and also HCO3 secretion represents only 0.03 meq/L of free [H ]. Therefore, virtually 1 (by type B intercalated cells). the entire excreted H load must be bound to urine buffers: 22 2 HPO4 (titrated to H2PO4 ) represents most of the titratable 1 1 2 acid, and NH3 binds to H to form NH4 . These buffered Metabolic Alkalosis—Source of Excess HCO3 1 H charges are electrically balanced by acid anions such as Usually metabolic alkalosis indicates an accumulation 2 2 “ ” 2 2 SO4 and Cl in the urine. of excess HCO3 . The source of excess HCO3 can be 4 CJASN

Table 1. Metabolic alkalosis: Mechanisms of generation

Ingest and absorb or infuse NaHCO or NaHCO precursors (i.e., Na acetate, Na citrate, Na gluconate) 3 3 1 Distal renal tubule HCO3 generation through enhanced H secretion Generous delivery of NaCl (or other Na salts such as Na SO or Na penicillin) to distal tubules/collecting ducts, which are actively 1 2 4 reabsorbing Na 1 1 K depletion (shifting H into cells) Remove HCl from body (/nasogastric suction/chloride-rich diarrhea)

exogenous, endogenous, or both. Exogenous sources are coexist: (1) the kidney tubules/ducts beyond the early 1 1 2 1 Na or K HCO3 salts or salts of precursors (organic distal tubule are avidly reabsorbing Na (for example, anions such as lactate, acetate or citrate, which generate activity is high and (2)thedeliveryofsaltand 2 HCO3 when completely oxidized). These salts can be volume to these sites is relatively large. ingested/absorbed or infused (Table 1). Clinical examples of kidney bicarbonate overproduc- The two potential endogenous sources of large tion are: 2 amounts of HCO3 are (1) the stomach and (2)the 2 1 kidneys. Net endogenous HCO3 generation requires H 1. Primary (especially when a high-salt 2 removal from the body. HCO3 is generated when HCl is diet is ingested) and other mimics of primary hyper- 2 secreted into gastric lumen, but net HCO3 accumulation in aldosteronism (Table 2). the ECF requires the HCl to be lost externally, usually as a 2. Loop and/or and several inherited syn- result of vomiting and/or suction (see section on gas- dromes that have like manifestations (i.e.,Bartter tric alkalosis). and Gitelman syndromes). 1 1 1 Normally, kidney H excretion into the urine (as NH4 3. The infusion of Na salts of poorly absorbed anions (PO4, 2 1 and/or titratable acid) generates HCO3 to replace the SO4, penicillin, etc.)ifdistaltubuleNa reabsorption is 1 quantity decomposed by nonvolatile H derived from stimulated by mineralocorticoids and/or volume contrac- 2 dietary intake and metabolism and any HCO3 lost in tion (19,20). 2 alkaline stool. To the extent kidney HCO3 generation “ ” 2 2 exceeds this requirement, excess HCO3 is generated. Another endogenous source of HCO3 is the movement This generally occurs when the following conditions of K1 from within cells into the ECF. In response to

Table 2. The metabolic alkaloses

ECF volume contracted: urine chloride concentration <20 meq/L Gastric alkalosis: vomiting/nasogastric suction Chloride-rich diarrhea (congenital chloridorrhea) Status/postchronic hypercapnia (acute reversal of chronic ) Cystic fibrosis with major sweating Thiazide or loop diuretics after renal tubule diuretic effect has dissipated Some villous adenomas ECF volume expanded: urine chloride concentration >20 meq/L Primary hyperaldosteronism (unilateral adenoma/bilateral hyperplasia/glucocorticoid-sensitive hyperaldosteronism) Severe Cushing syndrome (especially because of ectopic ACTH) Exogenous mineralocorticoids Reduced 11-b (OH) steroid dehydrogenase activity Chronic licorice/carbenoxolone ingestion Congenital AME syndrome (11-b HSD type 2 inactivating mutation) -secreting tumors Some forms of congenital adrenal hyperplasia 11-b hydroxylase deficiency 17-a hydroxylase deficiency Liddle syndrome ECF volume contracted: but urine chloride concentration >20 meq/L (generally indicates a renal tubule reabsorptive defect) Thiazide or loop diuretics actively working (defective Na reabsorption in loop of Henle, -like lesion) (defective Na reabsorption at the thiazide-sensitive site) Metabolic alkalosis: other Severe potassium deficiency Milk (calcium) alkali syndrome NaHCO3 loads with markedly reduced GFR Refeeding after fasting

ECF, extracellular fluid; ACTH, adrenocorticotropic hormone; AME, apparent mineralocorticoid excess; HSD, hydroxysteroid dehydrogenases CJASN 15: ccc–ccc, November, 2020 Metabolic Alkalosis, Emmett 5

, K1 exit is partially balanced by movement of 1 2 Table 3. Metabolic alkalosis: Mechanisms of maintenance H into cells and this generates ECF HCO3 (21,22). ECF 2 [HCO3 ] can also increase when the ECF volume contracts fi 2 Increased proximal renal tubule HCO3 reclamation around a xed quantity of HCO3 (23) (see section on Extracellular fluid contraction 1 gastric alkalosis). K depletion Continuous or intermittent generation of new HCO3 In distal kidney tubules and collecting ducts Gastric HCl losses Maintenance of Metabolic Alkalosis Exogenous alkali fi The various mechanisms responsible for the maintanence Reduced HCO3 ltration: reduced GFR/kidney failure of metabolic alkalosis are shown in Table 3. If metabolic alkalosis develops and the GFR is not markedly reduced, correction of the alkalosis should be relatively straightfor- syndromes, including milk-alkali or calcium-alkali syn- fi 2 ward: merely excrete a large fraction of the ltered HCO3 drome (35) and bicarbonate ingestion or vomiting by (which should be supranormal because of the higher patients with severe kidney dysfunction (36). fi 2 2 serum/ ltered [HCO3 ]). A brisk HCO3 diuresis would 2 then reduce the [HCO3 ] and restore normal acid-base status. This obviously has not occurred when metabolic The Metabolic Alkaloses: Etiology on the Basis of ECF alkalosis persists. Why does the kidney not excrete 2 Volume Status HCO3 and rapidly restore normal acid-base status? The generation, maintenance, and resolution of “classic” The answer to this question varies, depending on the examples of metabolic alkalosis in each ECF volume status underlying cause, and the precise explanations continue category is described below. to be refined and debated. Normal individuals ingesting up to 1000 meq/d of fi ECF Volume Contracted NaHCO3 for several weeks are able to ef ciently excrete 2 Classic Example: Gastric Alkalosis. this load with a minimal increase in their serum [HCO3 ] (24). Consequently, when metabolic alkalosis develops and Generation. Gastric fluid osmolality is about 300 mosm/L 2 persists despite a relatively normal GFR, this indicates the with a [Cl ] of about 150 meq/L and total cations of about 2 1 kidney is reclaiming HCO3 at a supranormal rate. 150 meq/L. The [H ] typically varies between 40 and 1 1 Most patients with metabolic alkalosis have developed 140 meq/L, [K ] varies between 10 and 15 meq/L, and [Na ] 2 increased proximal HCO3 reabsorption. The major stim- makes up the balance (37). Secretion of HCl (via gastric type 1 1 ulatory factors responsible are reduced intravascular, or H /K ATPase) into the gastric lumen generates equimolar effective arterial, blood volume, and hypokalemia (12). addition of HCO3 to the ECF. Normally, gastric HCl secretion and chronic respiratory acidosis also does not produce metabolic alkalosis because the acid is not 2 increase proximal tubule HCO3 reabsorption, but these lost from the body. The HCl leaves the stomach and enters 1 2 disordersarenotrelevanttothecurrentdiscussion. the small bowel, where H is neutralized by HCO3 mainly Metabolic alkalosis is also usually associated with secreted by the pancreas (with a smaller component from 2 accelerated distal HCO3 reabsorption and generation. bile and intestinal epithelium). This generates CO2 and water. 1 2 1 fl Generous distal Na delivery, combined with avid distal The secretion of HCO3 adds H to the body uids. Because 1 2 Na reabsorption (for example, because of high aldoste- the quantity of HCO3 secreted into the small bowel equals the 1 rone levels) accelerates distal H1 and K1 secretion. This quantity of H delivered from the stomach, these two occurs, in part, because distal Na1 reabsorption, mainly via processes neutralize one another. However, removal of the the epithelial sodium channel (ENaC) in principal cells, gastric HCl from the body, by vomiting or tube suction, generates a lumen negative electric potential (potential prevents the HCl from reaching the small bowel. Conse- 2 difference [PD]5240 mv), which drives paracellular and quently, HCO3 is not secreted into the intestinal lumen so 2 2 transcellular anion (mostly Cl ) reabsorption and enhances that a gastric-derived HCO3 bolusisaddedtotheECF 2 the secretion of H1 and K1. Also, many neurohormonal and an equal quantity of Cl is removed from the body. 1 1 stimuli of distal Na1 absorption increase type A interca- Later in the development of gastric alkalosis, a K /H cell 2 lated cell activity (25) (Figure 4). shift also generates additional HCO3 (described below). 2 Figure 5 shows three types of intercalated cells. The type Maintenance. Initially, much of the HCO3 added to 2 2 fi BintercalatedcellsecretesHCO3 in exchange for Cl , the ECF (after vomiting or gastric suction) is ltered and and can therefore contribute to the correction of meta- excreted by the kidneys largely as NaHCO3. The loss of fl bolic alkalosis. However, generous distal delivery of gastric uid combines with kidney loss of NaHCO3 and Cl2 is required to enable this cell to secrete major fluid to generate ECF : GFR falls and 2 fl quantities of HCO3 . Recent studies show that interca- kidney salt and uid retention are stimulated. Distal delivery 1 2 lated cells also play an important role in NaCl reab- of Na and HCO3 , linked with secondary hyperaldosteron- – 2 sorption and volume regulation (25 31) (discussed in ism, increases the fraction of HCO3 excreted as KHCO3 (40). the legend for Figure 5). Hypokalemia shifts K1 out of, and H1 into, cells generating 2 fi When the GFR is markedly reduced, metabolic acidosis ECF HCO3 (21,22). The resulting intracellular acidi ca- 2 usually develops. However, occasionally, metabolic alka- tion of kidney tubule cells stimulates HCO3 reclamation 2 losis occurs and then the HCO3 load cannot be excreted and generation. Hypokalemia also reduces pendrin activ- because of the reduced GFR. Kidney dysfunction contrib- ity and type B intercalated cell density, which further 2 utes to the maintenance of metabolic alkalosis in several limits HCO3 secretion (30,31). 6 CJASN

1 ECF contraction generates proximal and distal Na 2 1 reabsorption and HCO3 reclamation. Distally, Na reabsorp- 1 1 1 tion increases H and K secretion. K depletion also increases 1 1 H secretion by type A intercalated cells via both H ATPase and H/K ATPase pumps (see Figures 3 and 4), and increases kidney NH3 generation and excretion (38,39). During the maintenance phase, the urine electrolyte fl fi 1 1 2 pattern uctuates. Generally, ltered Na ,K ,HCO3 , Cl2, and water are avidly reabsorbed, generating concen- trated, electrolyte-poor, and relatively acid (denoted as “paradoxical aciduria” because metabolic alkalosis exists) urine. However, intermittently (for example, immediately after loss of a large bolus of gastric fluid), the serum 2 [HCO3 ] acutely increases, and for a period of time, the fi 2 larger load of ltered HCO3 cannot be completely re- claimed despite the multiple stimulatory factors described 2 1 previously. When this occurs, the urine [HCO3 ], [Na ], [K1], and pH all temporarily increase. Subsequently, the 2 serum [HCO3 ] declines, the ECF volume contracts further, and filtered NaHCO3 is completely reclaimed. Urine electrolyte concentrations and pH again fall. However, it is important to note that throughout these cyclic variations, the urine [Cl2] remains low. Thus, a low urine [Cl2](,20 meq/L) generally indicates the kidney’s ongoing response to reduced ECF volume or intra-arterial blood volume. 2 Resolution. The factors responsible for kidney HCO3 retention are reversed by adequate ECF volume expansion (NaCl infusion) and KCl repletion. Adequate restoration of ECF volume is signified by rising urine [Cl2] and the 1 development of a NaHCO3 diuresis. K replacement moves K1 into, and H1 out of, cells into the ECF, 2 simultaneously reducing the [HCO3 ] and increasing in- tracellular pH. The urine electrolyte profiles discussed above presume relatively intact kidney tubule function and the absence of diuretic activity. The term “” has been used to describe several different disorders in which the ECF “ ” fi 2 contracts around a relatively xed quantity of HCO3 .

Figure 5. | Continued. bicarbonate chloride exchanger (NDBCE; a productoftheSoluteCarrierFamily4 MemberA8orSLC4A8 gene) in the Figure 5. | Intercalated cells: Three different intercalated cell types luminal membrane (see discussion below). Non–type A/non–type B have been identified: type A intercalated cells, type B intercalated intercalated cells: this is the third type of intercalated cell. Both a V-type 1 1 2 2 cells, and non–type A/non–type B intercalated cells. Each is rich in H ATPase, pumping H , and Pendrin, exchanging HCO3 for Cl , 2 carbonic anhydrase II and is capable of generating abundant HCO3 coexist in the lumen membrane. The anion exchanger AE4 (a product of 1 1 1 and H from H2CO3. Type A intercalated cells: H is secreted into the theSoluteCarrierFamily4 MemberA4orSLC4A4 gene) isa major Na /3 1 1 1 2 lumen mainly via V-type H ATPase and to a smaller extent via H -K HCO3 transporter in the basolateral membrane, moving these ions into 2 ATPase.The generated cytoplasmic HCO3 moves into theperitubular the peritubular capillary. Although intercalated cells were originally capillary in exchange for Cl2, via anion exchanger 1 (AE1; a product of identified as major kidney acid base–regulating cells, it is now clear that the Solute Carrier Family 4 Member 1 or SLC4A1 gene). This trans- these cells also play an important role in salt and volume regulation porter is also called the “erythrocyte membrane protein band 3” in red (32,33). The sodium-driven bicarbonate chloride exchanger (NDBCE) blood cells. Type B intercalated cells: H1 is secreted into the peri- in the luminal membrane of the type B intercalated cells is an elec- 1 1 2 tubular capillary by V-type H ATPase in the basolateral membrane trically neutral ion exchanger moving one Na and two HCO3 ions (thesame proton transporteras found in typeA intercalated cells, but in into the cell while moving one Cl2 into the lumen. The net effect of two 2 2 the opposite, or luminal, membrane). The HCO3 generated in this Pendrin cycles (two HCO3 ions enter the lumen in exchange for 2 cell is secreted into the lumen via an anion exchanger named Pendrin uptake of twoCl ions) and one NDBCE cycle (twoHCO3 ions and one (a product of the Solute Carrier Family 26 Member A4 or SLC26A4 Na1 ion enter the cell and one Cl2 ion enters the lumen) has the net 2 2 gene) that exchanges one HCO3 for one Cl . Pendrin is a distinct and effect of the reabsorption on one molecule of NaCl. These acid-base different exchanger than the AE1 in the type A cells that is present in the and salt reabsorption interactions of intercalated cells may explain 1 2 basolateral membrane. A Na /3HCO3 cotransporter AE4 (a product why some patients with Pendred syndrome, a genetic defect of Pen- of the Solute Carrier Family 4 Member A4 or SLC4A4 gene) is present drin, develop severe salt depletion and metabolic alkalosis when in the basolateral membrane. These cells also have the sodium-driven treated with thiazide diuretics (34). CJASN 15: ccc–ccc, November, 2020 Metabolic Alkalosis, Emmett 7

Although gastric alkalosis is an ECF volume-“contracted” Generation. Autonomous hyperaldosteronism increases condition and the ECF contraction contributes impor- distal Na1 reabsorption, expanding the ECF. This expansion tantly to both its pathogenesis and maintenance, the major raises the GFR and reduces proximal tubule salt and water 2 cause of the blood [HCO3 ] increase is not shrinkage of reabsorption. Generous distal salt and water delivery ensue. 2 the ECF per se, but rather generation of HCO3 owing This results in inappropriately high aldosterone activity to gastric HCl loss and cellular H1-K1 shifts (21–23,40). combining with generous distal tubule salt and water delivery. Conversely, although expansion of the ECF with NaCl does This combination represents pathophysiology and high rates 2 1 1 1 dilute the ECF [HCO3 ] to a small degree, its correcting action of Na reabsorption, and indirectly linked K and H 2 1 1 in these patients is mainly a result of kidney HCO3 excretion. secretion ensue. Excretion of K and H exceeds physiologic Reducing or stopping the loss of gastric HCl is of course requirements, generating hypokalemia and metabolic alkalo- critical for reversing the process at its initiation point. sis. The development of hypokalemia and K1 depletion fl 2 1 However, if the gastric uid losses cannot be stopped, then contribute importantly to HCO3 generation when K fl 1 1 reducing the gastric uid [HCl] concentration with an H2 shifts out of cells in exchange for H (22), and kidney H blocker or proton pump inhibitor can be helpful (41). secretion and ammonia excretion increases. Additionally, 2 Table 2 lists the most common forms of ECF volume- hypokalemia increases proximal tubule HCO3 reclaimation 2 contracted metabolic alkalosis. The urine [Cl ]istypically and H1/K1 ATPase activity in type A intercalated reduced to ,20 meq/L. cells (25,27). Maintenance Phase. Usually, expansion of the ECF 2 reduces proximal salt reabsorption and HCO3 reclama- ECF Volume Expanded tion and simultaneously reduces renin, angiotensin II, and 1 Classic Example: Primary Mineralocorticoid Excess aldosterone levels. Consequently, distal Na reabsorption 1 1 Syndromes. Primary hyperaldosteronism is a condition of and K and H secretion remain modest despite high autonomous, or inappropriately upregulated, aldosterone delivery rates. However, when autonomous aldosterone secretion. This generates ECF volume expansion, hyper- secretion combines with generous distal salt delivery, in- 1 1 tension, hypokalemia, and metabolic alkalosis. A unilateral appropriately high levels of distal Na reabsorption and K 1 1 adrenal adenoma secreting aldosterone is the prototypical and H excretion develop. As hypokalemia and K depletion 2 cause of this disorder, but many conditions can mimic the ensue, they contribute importantly to both additional HCO3 2 1 electrolyte and acid-base pathophysiology of primary hy- generation and kidney HCO3 reclamation via systemic K / 1 peraldosteronism (Table 2). H cell shifts and acidification of kidney tubule cells. Hypo- 1 1 ECF Volume Regulation of Renin and Aldosterone kalemia also increases H /K -ATPase activity in type A 1 (Normal Physiology). The reabsorption of Na in late distal intercalated cells (Figures 4 and 5) (25,27). Furthermore, tubules/collecting ducts is mainly accomplished by principal aldosterone also increases salt reabsorption via asequence cells (Figure 4) through ENaC pores in the luminal mem- of pendrin-related events (Figure 5) (28). During the branes. When these pores are open, the electrochemical maintenance phase of autonomous hyperaldosteronism, gradient favors reabsorption of Na1. This generates a lumen the urine reflect the patient’s salt intake. Thus, 2 negative electrical potential (240 mv) that drives both the urine [Cl ] will generally be .20 meq/L. chloride reabsorption and secretion of K1 and H1. Recovery Phase. Successful resection of an adrenal ECF volume contraction in normal individuals reduces aldosterone secreting adenoma generally reverses the the GFR and sharply increases the reabsorption of NaCl entire syndrome. However, if hypertension has existed and NaHCO3 in the proximal tubules. Volume contraction for a long period of time, it may persist because of also generates secondary hyperaldosteronism (high aldo- structural vascular pathology. In lieu of surgery, drugs sterone activity driven by high renin and angiotensin II that block the action of aldosterone can be very helpful. The activity). The result of these coordinated actions is that the physical and biochemical manifestations of primary hyper- potent aldosterone-driven stimulus to reabsorb Na1 in the aldosteronism can also be ameliorated by ingestion of a distal/collecting tubules is coordinated with increased very-low-salt diet, which reduces distal salt delivery, 1 1 proximal reabsorption, which sharply reduces distal salt blunting H and K loss. Conversely, the physical 1 fi and water delivery. Consequently, reduced Na delivery ndings and electrolyte abnormalities are exacerbated by a to aldosterone-sensitive sites blunts the magnitude of Na1 high-salt diet (42,43). Analagously, other mineralocorticoid reabsorption and the indirectly linked secretion of K1 and excess syndromes and mineralocorticoid excess-like syndromes H1. The opposite occurs in response to ECF volume can sometimes be reversed or cured at their source and/or expansion in normal individuals—the GFR increases, treated by blocking downstream pathophysiology. proximal salt and water reabsorption fall, and generous distal salt and water delivery ensues. Simultaneously, renin ECF Volume Contracted: Diuretic and angiotensin II and aldosterone levels fall. Now despite Diuretic-Like Etiologies generous distal salt and water delivery, low aldosterone Classic Example: Thiazide and/or Loop Diuretics. Thiazide levels downmodulate distal Na1 reabsorption, and indirectly and/or loop diuretics very frequently generate hypokale- linked K1 and H1 secretion. This describes the normal mia and metabolic alkalosis. Despite development of a reciprocal physiologic balance that exists between the mag- relatively contracted ECF, or effective arterial blood vol- nitude of distal delivery of salt and water and neuro- ume, the generation and maintenance mechanisms of this hormonal stimulation of distal Na1 reabsorption and K1 condition has many similarities to the ECF volume-expanded and H1 secretion. This exquisite reciprocal balance is condition of primary hyperaldosteronism (42). That is because disrupted by autonomous aldosterone secretion (12,42). increased distal salt and volume delivery (due to the diuretics) 8 CJASN

combine with activation of the renin angiotensin II- All three types of intercalated cells located in the distal aldosterone axis. tubule/collecting ducts not only play a major role in Generation. Inhibition of the Na/K/2Cl cotransporter acid/base regulation, but also participate in volume (NKCC2) in the thick limb of Henle by loop diuretics and/or regulation and NaCl balance (32,33). These cells may be inhibition of the neutral Na/Cl cotransporter (NCC) in the especially important in moderating the development of diluting segment by thiazide diuretics increases NaCl and metabolic alkalosis in patients receiving thiazide diuretics volume delivery to more distal sites. Diuretics also generally (34) (see Figure 5). increase renin, angiotensin II, and aldosterone levels, Diagnostic Approach. When the cause of metabolic generating a state of secondary hyperaldosteronism. In alkalosis is not readily apparent from the history and the absence of diuretics, secondary hyperaldosteronism is physical examination, then it is very helpful to categorize typically associated with reduced distal salt and volume the disorder on the basis of the patient’s kidney function 1 delivery, which limits the magnitude of distal Na and volume status. If the GFR is markedly reduced and 1 1 reabsorption (and thereby H and K secretion). How- major acidic gastrointestinal fluid losses do not exist, a ever, diuretics generate a state of secondary hyperaldoster- source of exogenous bicarbonate loading should be sought. 1 onism linked with generous distal tubule Na and volume If the GFR is not markedly reduced, then carefully assess 1 delivery. Therefore, enhanced distal Na reabsorption via volume status with history, physical examination, and a 2 2 principal cell ENaCs occurs together with generous distal spot urine [Cl ] measurement. A urine [Cl ] ,20 meq/L is 1 1 1 Na and volume delivery, accelerating distal H and K consistent with a reduced ECF or effective intra-arterial 2 secretion and generating metabolic alkalosis and hypoka- volume, whereas a urine [Cl ] .20 meq/L suggests an 2 lemia. Hypokalemia also generates additional ECF HCO3 expanded state. Consider the diagnoses in Table 2. 1 1 via cellular H /K exchange, which also stimulates distal However, recognize that diuretic-generated metabolic 1 H secretion. During periods of diuretic activity, urine alkaloses are characterized by cyclic changes in urine 1 2 2 [Na ] and [Cl ] are both high. However, diuretic action is [Cl ] as the diuretic effect waxes and wanes. In general, 2 generally intermittent, and periods of diuretic activity cycle widely varying urine [Cl ] changes indicate diuretic use with periods of inactivity and recovery. During the “off- (which some patients may deny). diuretic” phases, avid kidney salt reabsorption markedly Metabolic alkalosis is a very common disorder. This 1 reduces distal NaCl delivery, limiting principal cell Na brief review provides a diagnostic and therapeutic 1 1 reabsorption and distal K and H secretion. Now, urine framework using an ECF volume-oriented physiologic 2 1 [Cl ] and [Na ] fall to low levels, reflecting the relative approach to the generation, maintenance, and resolution 2 1 ECF-contracted state. Thus, the urine [Cl ] and [Na ] cycle of this disorder. Space limitations preclude in-depth up and down depending on the level of diuretic activity. In discussion of many fascinating clinical metabolic alkalosis contrast, diuretic-mimicking disorders such as Bartter and syndromes and a number of recent physiologic and path- Gitelman syndromes are characterized by persistent, high ophysiologic discoveries that enhance our understanding of 2 urine [Cl ] because they never develop an “off-diuretic- this disorder. like” period. Maintenance. Again, many similarities to the mainte- Disclosures nance mechanisms described for primary hyperaldoster- The author has nothing to disclose. onism exist. Hypokalemia increases both proximal and 1 1 distal tubule H and NH4 secretion. ECF and/or Funding effective intra-arterial volume is reduced, generating a None. neurohormonal cascade that increases proximal tubule 2 NaCl and HCO3 reclamation. Periods of diuretic activity References deliver salt and volume to distal segments that are 1. Kraut JA, Lew V, Madias NE: Re-evaluation of total CO2 con- responding to hyperaldosteronism. 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Publication date available at Sohet F, Wagner CA, Eladari D, Chambrey R: Renal b-intercalated www.cjasn.org.