Pathogenesis and Management of Metabolic Acidosis and Alkalosis

Zeid J. Khitan

Joseph I. Shapiro

Acid-base disorders occur commonly in clinical medicine. Although the degree of acidosis or alkalosis that results is rarely life threatening, the careful evaluation of the acid-base status of the patient often provides insight into the underlying medical problem. Moreover, the pathophysiology and differential diagnosis of these disorders can be approached quite logically with a minimum of laboratory and clinical data. An effective approach to clinical acid-base disorders is accomplished most easily with a stepwise pathophysiologic approach.

Human acid-base homeostasis normally involves the tight regulation of CO₂ tension by respiratory excretion and plasma bicarbonate [HCO₃^–] concentration by renal HCO₃^– reabsorption and elimination of protons (H⁺) produced by metabolism. The pH of body fluids (which can be sampled easily) is determined by the CO₂ tension (in arterial blood, PaCO₂) and the [HCO₃^–]. Primary derangements of CO₂ tension are referred to as respiratory disturbances, whereas primary derangements of [HCO₃^–] are called metabolic disturbances (1).

In this chapter, we first review acid-base chemistry and physiology and then present a pathophysiologic approach to the diagnosis and management of metabolic acidosis and alkalosis.

Acid-Base Chemistry and Physiology

The chemistry of acids, bases, and buffers and the normal physiology of acid and bicarbonate excretion (2, 3) are described in detail in several excellent reviews and are summarized only briefly in this section.

BUFFERING

Clinical acid-base chemistry basically is the chemistry of buffers. For clinical purposes, we may define an acid as a chemical that donates an H⁺ and a base that accepts an H⁺. For any acid (HA), we can define its strength or tendency to donate H⁺ by its dissociation constant K according to the relationship:

If we rearrange this equation and apply a log transformation, we arrive at the familiar relationship:

Buffering refers to the ability of a solution containing a weak or poorly dissociated acid and its anion (a base) to resist change in pH when a strong acid (i.e., highly dissociated acid) or alkali is added. To illustrate this
important point, suppose 1 mL of 0.1 mol/L HCl is added to 9 mL of distilled water, the [H⁺] would increase from 10^-7 to 10^-2 mol/L. In other words, the pH would fall from 7.0 to 2.0. However, if we added 1 mL of 0.1 mol/L HCl to 9 mL of a 1 mol/L phosphate buffer (pK = 6.9) at pH 7.0, most of the dissociated H⁺ from HCl would combine with dibasic phosphate (HPO₄^2-) and only slightly change the ratio of dibasic to monobasic (H₂PO₄^–) phosphate. In fact, the pH would fall by only about 0.1 pH units. The addition of acid has been buffered by the phosphate dissolved in water. Another way to think about this is that the pH was stabilized by substances that bound the free H⁺ released by the HCl, in this case the phosphate. Such substances are called buffers (4).

Biochemical Determinants of pH

The bicarbonate buffer system is the most important buffer in the extracellular space in humans. Proteins and inorganic phosphate are less important buffers. Inorganic phosphate is probably the most important buffer in the intracellular space followed by bicarbonate and intracellular proteins. Although intracellular pH (pHi) is probably more important in predicting physiologic and clinical consequences than extracellular pH (5), it is difficult to measure in vivo without using sophisticated investigational techniques, such as ³¹P nuclear magnetic resonance (NMR) spectroscopy (6), laser scanning cytometry (7), and fluorescence lifetime imaging (8), which are not available for routine clinical applications. Therefore, our clinical efforts are focused on classifying disease states based on what is measurable, that is, extracellular pH. In particular, our attention focuses on the bicarbonate buffer system (2). We can assume that equilibrium conditions apply because there is abundant carbonic anhydrase in blood. Therefore, we can view the bicarbonate buffer system as the equilibrium reaction:

H₂CO₃ is defined by the partial pressure of CO₂ and the solubility of CO₂ in physiologic fluids, which is a constant S to all intents and purposes. We can therefore rearrange this equation as

which is attributed to Henderson in 1909.

Taking the antilog of both sides gives the following:

which is called the Henderson-Hasselbalch equation, first described by Hasselbalch in 1916. In blood at 37°C, the pK of the bicarbonate buffer system is 6.1 and the solubility coefficient for CO₂ is 0.03. Therefore, we can simplify our expression to

In the above equations, [HCO₃^–] is expressed in mM (or mEq/L) and PaCO₂ is expressed in torr (or mm Hg). Convenient expression allows us to view acid-base disorders as being attributable to the numerator of the ratio (metabolic processes), the denominator (respiratory processes), or both (mixed or complex acid-base disorders) (Fig. 3-1) (1).

Total Body Acid-Base Metabolism

A myriad of enzymatic reactions involve the loss or gain of protons that occurs with ongoing catabolism and anabolism. However, one simply has to examine the initial substrates and final products to understand whether acid or base is produced. To do this, it is helpful to think of acids and bases as “Lewis” acids and bases,
in other words, to consider acids as electron acceptors rather than proton donors. In concrete terms, acid is generated when a substrate is metabolized to something more anionic (e.g., glucose is metabolized to lactate through the Embden-Meyerhof glycolytic pathway). Conversely, if a substrate is metabolized to something more cationic (e.g., lactate is metabolized to CO₂ and H₂O via the tricarboxylic acid [TCA] cycle), then acid is consumed (9). Because of the importance of the bicarbonate buffer system in the overall acid-base homeostasis, we generally consider the addition of a proton as equivalent to the decrease in total body HCO₃^– and loss of a proton as a gain in HCO₃^– (9).

Figure 3-1 Modified Henderson-Hasselbalch equation, portraying the interacting effects of the primary acid-base disturbance and the secondary mechanisms on the pH.

This approach to understanding acid-base metabolism has led to its practical application in treating the acidosis of chronic renal failure with peritoneal dialysis. Although the lactate-based dialysate (generally at about 35 mM) has a pH of only 6.0, virtually all of the lactate is ionized; bicarbonate is generated and the acidosis is corrected via metabolism largely through the TCA cycle to CO₂ and H₂O (10).

Renal Acid Excretion

GENERAL CONSIDERATIONS

In adult men studied at sea level, the kidneys regulate the [HCO₃^–] at approximately 24 mM and the lungs control the PaCO₂ at about 38 torr, thus producing an arterial pH of approximately 7.42; for women, the corresponding values for [HCO₃^–], PaCO₂, and pH are 24 mM, 37 torr, and 7.43, respectively (11). The kidneys regulate plasma [HCO₃^–] and acid-base balance by reclaiming filtered HCO₃^– and generating new HCO₃^– to replace that lost internally in titrating metabolic acid and externally (e.g., from the gastrointestinal [GI] tract). A normal “Western diet” generates approximately 1 mmol of acid per kilogram of body weight per day. This
acid load must be excreted by the kidney to maintain acid-base homeostasis. The easiest way to understand the molecular processes involved in renal acid excretion is to separate renal acid-base handling itself into two functions: bicarbonate reabsorption and net acid excretion (NAE) (12).

RENAL CELLULAR MECHANISMS OF PROTON EXTRUSION

In recent years, our understanding of the renal cellular transport proteins that effect H⁺ extrusion has expanded significantly. We now know that in addition to the sodium-proton exchanger (Na⁺/H⁺ exchanger) that exchanges one H⁺ for one sodium molecule, the sodium phosphate symporter that transports one sodium with one monobasic phosphate molecule, and the vacuolar H⁺ ATPase that directly pumps H⁺ into the tubular lumen (13, 14, 15, 16, 17, 18, 19), other transport proteins may be of considerable importance. These other transport proteins include the family of chloride-bicarbonate symporters and exchangers, the “colonic” H⁺/K⁺ ATPase, and the Na⁺/K⁺ ATPase (20, 21, 22, 23). These transport proteins are expressed to different degrees in the different nephron segments depending on the function of the cell type within that nephron section.

On a more global basis, there is a tight link between acid secretion and the reclamation of filtered bicarbonate as well as the production of new bicarbonate by the kidney. For example, the reclamation of HCO₃^– filtered from the blood occurs when HCO₃^– formed inside the renal tubular cells by either H⁺ secretion or ammonium (NH₄⁺) synthesis is transported back into the blood via the basolateral Na⁺(HCO₃^–)₃ symporter (23) or a Cl^–/HCO₃^– antiporter (13, 24). Alternatively, bicarbonate can be secreted by certain cells of the collecting duct in exchange for chloride (25).

RENAL ACID-BASE METABOLISM

Base Reabsorption

When plasma is filtered at the glomerulus, HCO₃^– enters the tubule lumen. Mechanistically, each HCO₃^– that is reclaimed requires the epithelial secretion of one H⁺. This is accomplished largely by an Na⁺/H⁺ exchanger on the luminal membrane, although an electrogenic H⁺ ATPase also may be involved. On an organ physiology level, HCO₃^– reabsorption can be considered in terms of the plasma threshold (PT) for bicarbonate, that is, the plasma HCO₃^– concentration at which HCO₃^– begins to appear in the urine. In terms of the maximal net activity of tubular HCO₃^– reabsorption (also called T_max), assuming glomerular filtration rate (GFR) of 100 mL/min and a plasma [HCO₃^–] of 24 mM, the renal tubules must secrete about 2.4 mmol of H⁺ per minute to reclaim all of the filtered HCO₃^–. Therefore, HCO₃^– reclamation by the tubules involves a tremendous amount of H⁺ secretion. Bicarbonate reclamation is coupled tightly to sodium reabsorption and also is sensitive to a number of other influences. As the T_max for HCO₃^– increases, the PT for HCO₃^– increases. Conversely, decreases in T_max result in decreases in the PT. In particular, states of extracellular fluid (ECF) expansion and decreases in PCO₂ decrease the apparent T_max for HCO₃^–, whereas ECF contraction and increases in PCO₂ increase the apparent T_max for HCO₃^–. Parathyroid hormone (PTH) inhibits proximal tubule HCO₃^– reabsorption and lowers the apparent T_max and PT for HCO₃^–. Most (but not all) of this HCO₃^– reabsorption (about 85-90%) occurs in the proximal tubule (3).

Carbonic anhydrase that is present both intracellularly and on the tubular surface of the brush border of the proximal tubule allows the secreted H⁺ that combines with tubular fluid HCO₃^– to form H₂CO₃. This H₂CO₃ rapidly dissociates to form H₂O and CO₂ that can readily permeate proximal tubule cell membranes. Intracellularly, carbonic anhydrase catalyzes the formation of H₂CO₃ again, which subsequently dissociates into HCO₃^– and H⁺. Finally, HCO₃^– leaves the cell via several bicarbonate transport proteins, including the Na⁺(HCO₃^–)₃ symporter and the Cl^–/HCO₃^– exchanger (26). The secreted H⁺ also titrates citrate, another form of alkali (27). This process is shown schematically in Figure 3-2.

Net Acid Excretion

NAE is the net amount of H⁺ eliminated from the body. If we postulate that an excreted HCO₃^– molecule negates the value of an excreted H⁺, then we can consider NAE by the kidney to be the amount of H⁺ (both buffered and free) excreted in the urine minus the amount of HCO₃^– excreted in the urine. As discussed, H⁺ secretion into the tubule lumen mandates 1:1 stoichiometric HCO₃^– transport across the basolateral segment into the extracellular space; therefore, NAE represents the amount of new HCO₃^– generated by the kidneys and added to the body stores.

Figure 3-2 Schematic depicting proximal tubule HCO₃^– reclamation process. Two vehicles for apical H⁺ secretion: Na⁺/H⁺ exchanger (lightly shaded ellipse) and H⁺ ATPase (filled ellipse on apical side) are shown. Some basolateral ion pumps and exchangers, including the Na⁺/K⁺ ATPase (filled circle), Na⁺(HCO₃^–)₃ symporter (open circle), and HCO₃^–/Cl^– exchanger (lightly shaded ellipse), are also shown. The role of carbonic anhydrase (CA) both in the tubular cell and on the brush border in HCO₃^– reabsorption also is depicted.

NAE is accomplished primarily through elimination of titratable acid (which is mostly phosphate) and nontitratable acid (in the form of NH₄⁺) (12). These terms refer to clinical chemistry titration techniques by which known amounts of alkali were added to urine until a color change with a pH indicator (e.g., phenolphthalein) occurred. This color change occurred above the pK for the phosphate buffer system but below the pK for ammonia-ammonium (about 9). It must be stressed that the NAE is relatively insensitive to the urine pH. This concept is illustrated by the observation that addition of 1 mmol of HCl to 1 L of distilled water results in a pH of 3 (corresponding to an H⁺ concentration of 10^-3 mol/L). Therefore, in the extreme case (i.e., no buffers in the urine at all), extremely acidic urine (i.e., a very low pH) could eliminate very few protons from the body. There are several clinical settings discussed later in which acidic urine is elaborated, but NAE is insufficient. NAE requires the adequate function of both the proximal tubule to synthesize NH₄⁺ (which generates an HCO₃^– molecule) and the distal tubule and collecting tubules where H⁺ and NH₄⁺ secretion occur (26).

Proton secretion by the distal nephron involves the production of an electrogenic gradient that favors H⁺ secretion produced by removal of sodium from the luminal fluid and direct pumping of H⁺ into the tubular lumen. The latter is accomplished by the activities of vacuolar H⁺ ATPase and the H⁺/K⁺ ATPase in type A intercalated cells. Notably, chloride exchange with bicarbonate on the basolateral side of these distal tubular cells allows for proton secretion to be translated into bicarbonate addition to the blood. Finally, the epithelial membrane must not allow back leak of H⁺ or loss of the electrogenic gradient. Under normal circumstances, humans can elaborate a urine pH as low as 4.4, representing a 1,000:1 gradient of H⁺ between tubular fluid and cells. However, the excretion of NH₄⁺, which is discussed later, is of much greater importance in terms of NAE than is the level of urine pH achieved (28).

NAE is sensitive to a variety of factors, including the plasma K concentration (increases in plasma K decrease NH₄⁺ excretion, whereas decreases enhance H⁺ secretion by the distal nephron) and the effects of aldosterone. By stimulating the renin-angiotensin-aldosterone system, ECF contraction enhances distal acid secretion (29).

Ammonium Metabolism

The traditional view that NH₄⁺ excretion was determined by simple passive trapping of NH₄⁺ in the tubular lumen has been revised considerably. Recent studies have led to new insights into mechanisms of renal ammonia transport and metabolism (30). Although many of these proteins are primarily involved in the transport of H⁺ or K⁺, they also transport NH₄⁺ (31). The role of aquaporins and the identification of mammalian Rh glycoproteins (discussed below) are two new exciting areas of research in understanding ammonia transport in normal acid-base homeostasis (30). Importantly, proximal tubule cells deaminate glutamine to form alpha ketoglutarate (αKG) and NH₄⁺. Proximal tubule cells then secrete NH₄⁺ into the lumen, probably via substitution for an H⁺ using the luminal Na⁺/H⁺ antiporter. A key feature is that the further metabolism of αKG generates a new HCO₃^– molecule. Therefore, complete metabolism of each glutamine produces two NH₄⁺ and two HCO₃^– ions. Ammonium is later reabsorbed in the thick ascending limb of Henle (via substitution for K⁺ using the Na⁺/K⁺/2Cl^– cotransporter in the apical membrane), then across the basolateral membrane via the
sodium-hydrogen exchanger isoform 4 (NHE4) to the tubular interstitial space (32). This ultimately results in the increase in the medullary concentration of NH₄, which is highest in the inner medulla. This NH₄⁺ is then taken up by distal convoluted tubule and collecting duct cells, substituting for K⁺ using the basolateral Na⁺/K⁺ ATPase of the inner medullary collecting duct or as NH₃ (after losing H⁺) utilizing ammonia-specific transporters Rhesus Glycoproteins (Rhbg and Rhcg) along with a component of diffusive absorption. Collecting duct ammonia secretion involves parallel secretion of NH₃ utilizing Rhcg of the apical membrane or by its diffusive capacity along with cytosolic H⁺ generated by carbonic anhydrase II-mediated mechanism. H⁺ secretion across the apical membrane is primarily mediated by H⁺-ATPase and H⁺-K⁺ ATPase pumps. In the tubular lumen, H⁺ titrates luminal NH₃ to form NH₄⁺ and maintains low NH₃ concentration in the urinary space, which is necessary for continued NH₃ secretion (33). The net generation of any HCO₃^– from αKG metabolism is ultimately dependent on the excretion of NH₄⁺. This is because if this NH₄⁺ molecule is not excreted in the urine but rather is returned via the systemic circulation to the liver, it is used to form urea at the expense of generating an H⁺. Thus, the HCO₃^– molecule that was generated by the metabolism of the αKG will be neutralized, and no change in acid-base status will occur (30).

Difficulties in the routine clinical measurement of urinary NH₄⁺ concentrations have delayed our appreciation of its importance in net acid-base balance during pathophysiologic conditions including chronic metabolic acidosis or acid loads (31). However, recent observations by Batlle et al. (34) suggest that the urinary [NH₄⁺] may be inferred fairly accurately by calculations based on urinary electrolyte concentrations as is discussed subsequently.

Although the topic under discussion is “renal” acid-base metabolism, the liver may be significantly involved. Hepatic glutamine synthetase expression appears to be regulated by pH as well as protein ingestion (35, 36, 37). Perhaps more importantly, administration of amino acids via a parenteral rather than the enteral route often is accompanied by acid retention (38).

Clinical Approach to Acid-Base Disorders

Metabolic Acidosis

DEFINITIONS AND CAUSES

Metabolic acidosis is a systemic disorder characterized by a primary decrease in [HCO₃^–]. This may occur in three ways: (a) the addition of strong acid that is buffered by (i.e., consumes) HCO₃^–; (b) the loss of HCO₃^– from body fluids, usually through the GI tract or kidneys; and (c) the rapid addition to the ECF of nonbicarbonate solutions (dilutional acidosis). No organic anion is generated when HCO₃^– is lost or diluted. Reciprocal increases in the serum chloride concentration occur to preserve electroneutrality. Thus, these forms of metabolic acidosis generally are referred to as hyperchloremic or nonanion gap metabolic acidosis. When an organic acid consumes HCO₃^–, its organic anion is generated and may be retained in the ECF and serum. The serum chloride concentration does not increase with organic acidosis. An increase in the anion gap marks the existence and concentration of the organic anion (39).

DEFENSE OF SYSTEMIC pH DURING METABOLIC ACIDOSIS

Buffering

The hallmark of metabolic acidosis is a fall in plasma [HCO₃^–]. We stress that the fall in [HCO₃^–] always is mitigated by the participation of other buffers in both the ECF and the intracellular fluid (ICF). Roughly one-half of an administered acid load is buffered by nonbicarbonate buffers (40). Bone is an important buffer pool in states of chronic metabolic acidosis. In fact, the leaching of calcium from bone is one of the major deleterious effects of chronic metabolic acidosis (41, 42, 43).

Respiratory Compensation

A fall in PaCO₂ is a normal compensatory response with simple metabolic acidosis. The failure of this normal adaptive response is indicative of the presence of respiratory acidosis in the setting of a complex or mixed
acid-base disturbance. Conversely, an exaggerated fall in PaCO₂ producing a normal pH indicates the presence of respiratory alkalosis in the setting of a complex or mixed acid-base disturbance (44). The mechanism by which metabolic acidosis induces hypocapnia appears to be mediated in part by peripheral pH receptors in the carotid body, but mostly by central nervous system (CNS) pH receptors. This point is supported by the time course, specifically the temporal delay observed for respiratory compensation seen in experimental metabolic acidosis (45). The degree of chronic compensation varies from person to person; however, based on a large volume of clinical data, we can state with some confidence that the appropriate fall in PaCO₂ (in torr) should be 1 to 1.5 × the fall in [HCO₃^–] (in mM) (44). Oral acid loading in normal subjects produced a rapid fall in PCO₂ that reached a steady state after 30 minutes that was 0.85 times the fall in HCO₃^–, thus providing direct evidence for the rapid respiratory response to metabolic acidosis in humans (46).

Correction

The kidney provides the mechanism for the third line of defense to pH changes. However, this mechanism is rather slow compared to buffering (which begins immediately) and respiratory compensation (which begins within 15-30 minutes), since it takes up to 5 days to become maximal. NAE is increased in response to either metabolic acidosis (unless the kidney is the cause) or respiratory acidosis. This increase in NAE is largely NH₄⁺ excretion because titratable acid excretion is limited by the amount of excreted phosphate, which changes very little. Metabolic acidosis increases the processing of glutamine into NH₄⁺, which, in turn, leads to enhanced generation of HCO₃^–, by both transcriptional and translational regulations of key enzymes in this pathway (47). Chronic metabolic acidosis increases renal endothelin-1 activity that activates the NHE3 sodium-hydrogen ion antiporter on the proximal tubule brush border (48). Thus, both the generation of new HCO₃^– via the glutamine system and the enhancement of HCO₃^– reabsorption and titratable acid formation are stimulated. Of interest, the hypocapnia that occurs because of respiratory compensation actually limits renal correction in metabolic acidosis (49). Note that renal correction never corrects the pH to normal until the disorder causing HCO₃^– loss or acid generation is halted.

BIOCHEMICAL AND PHYSIOLOGIC EFFECTS OF METABOLIC ACIDOSIS

Mild degrees of acidemia generally are well tolerated, at least acutely, and even may afford some physiologic advantages, such as favorable oxygen delivery from hemoglobin. However, with marked acidemia, pH < 7.10, myocardial contractility is depressed and peripheral resistance falls (50, 51). These manifestations may be a result of the effect of acidosis to depress both vascular and myocardial responsiveness to catecholamines as well as innate myocardial contractility. Both myocardial β-adrenergic receptor density and physiologic responses to β agonists appear to be decreased by metabolic acidosis (52, 53).

Clearly, metabolic acidosis induces an intracellular acidosis in myocytes (48, 49). This intracellular acidosis in turn impairs contractile responses to normal or even elevated cytosolic calcium concentrations (54, 55). Alterations in troponin I-troponin C interactions mediated by low pH appear to shift the sensitivity of troponin C to calcium (56). Additionally, impairment of actin-myosin cross-bridge cycling caused by increases in the concentration of inorganic phosphate in the monovalent form may be involved in the decreased calcium sensitivity and contractile dysfunction seen with acidosis (57). The increase in monovalent inorganic phosphate results both from the acidic environment, which increases the ratio of monovalent to divalent inorganic phosphate, and from an impairment of myocardial energy production, which increases the total intracellular concentration of inorganic phosphate (58, 59). Metabolic acidosis and hypoxia appear to additively or synergistically impair myocardial function, a phenomenon consistent with the monovalent inorganic phosphate hypothesis (60). The vasodepressor effect of acidosis likely results from similar molecular mechanisms (61).

CLINICAL FEATURES

Clinically, one can observe an increase in ventilatory effort with even mild degrees of acidosis. With severe metabolic acidosis (e.g., pH < 7.20), respirations become extremely deep and rapid (Kussmaul). Mild degrees of acidosis do not appear to markedly impair hemodynamic stability, at least in subjects with otherwise normal cardiovascular function. However, severe metabolic acidosis may lead to hypotension, pulmonary edema, and, ultimately, ventricular standstill (50, 62, 63). Chronic metabolic acidosis, even if fairly mild, causes hypercalciuria and bone disease as bone buffering of acid leads to marked calcium losses from the bone because
of increases in prostaglandin E2 (PGE2) production (64). This aspect is extremely important in determining treatment of renal tubular acidosis (RTA) or the acidosis of chronic renal failure.

LABORATORY FINDINGS

Simple metabolic acidosis is characterized by a decrease in blood pH, [HCO₃^–], and PCO₂ (through compensation). Note that a failure to lower the PCO₂ by 1 to 1.5 × the fall in [HCO₃^–] indicates the coexistence of respiratory acidosis (44). The clinical implications of this are quite profound because this failure of compensation may signify impending severe respiratory failure. Serum electrolytes reveal a fall in [TCO₂]. Acidosis tends to shift potassium out of cells in a rather complex manner (65), and renal potassium excretion tends to increase in many states of metabolic acidosis. Normal or increased serum potassium in the face of decreased total body potassium stores occurs commonly in cases of metabolic acidosis (Chapter 5) (65). Some states of metabolic acidosis are characterized by the retention of an organic anion generated in concert with HCO₃^– consumption (organic acidosis), whereas others are not (hyperchloremic). The screening of plasma for such organic anions is not practical on a routine, immediate basis; thus, a calculation performed on the serum electrolytes called the serum anion gap (SAG) is employed (66).

Serum Anion Gap

The SAG is a concept used in acid-base pathophysiology to infer whether an organic or mineral acidosis is present. We use the routine venous blood serum electrolytes to calculate the SAG (58):

Here we use TCO₂ as an index of HCO₃^–. We define unmeasured cations (UCs) as cations that are not Na⁺ (e.g., K⁺, Mg²⁺, Ca²⁺) and unmeasured anions (UAs) as anions that are not Cl^– or HCO₃^– (e.g., SO₄^2-, H₂PO₄^–, HPO₄^2-, albumin, organic anions). Thus, electroneutrality demands that

where the UA and UC concentrations are expressed in mEq/L rather than mmol/L. Putting formulas (3.8) and (3.9) together, we see that

Normally, the SAG is about 9 (6-12 mEq/L). Although the SAG is used routinely in the differential diagnosis of metabolic acidosis, we stress that it is a relative rather than absolute indicator of the underlying pathophysiology. Note that the maintenance of stoichiometry (i.e., 1 mEq increase in anion gap for every 1 mmol decrease in HCO₃^–) depends on the clearance mechanisms for the anion as well as the myriad factors that influence HCO₃^– concentration. Therefore, some organic acidoses may manifest trivial or even no increase in the anion gap, whereas some hyperchloremic acidoses may have coincidental increases in the anion gap. This must be kept in mind when evaluating the differential diagnosis of metabolic acidosis. However, a major increase in the anion gap (e.g., SAG >26 mEq/L) always implies the existence of an organic acidosis (67).

If we look at the changes in the SAG and compare it to changes in HCO₃^– concentrations, additional insights can be made. This is often referred to as the “Delta gap” = Delta SAG – Delta Serum [HCO₃^–] or the “Delta-Delta.” It takes advantage of the assumption that with a pure organic metabolic acidosis, the fall in HCO₃^– and the increase in SAG should be equal (with the disclaimers stated above). Ergo, if the Delta gap is very positive (i.e., >6), it suggests that there must be another process generating alkali. Conversely, if the Delta gap is very negative (i.e., <-6), it suggests that there is another source of acid that does not result in an increase in SAG, ergo a concomitant nonanion gap metabolic alkalosis.

Urine Anion Gap

To address a different problem, urinary electrolytes have been used to estimate the quantity of NH₄⁺ in the urine, a measurement that has been difficult to develop into a routine clinical test. The concept is quite similar to that described for the SAG. In the urine, because of electroneutrality

When urine pH is <6, UA does not include appreciable amounts of HCO₃^–, but consists primarily of phosphate (H₂PO₄^– more than HPO₄^2-) and, to a lesser degree, sulfate (SO₄^2-) and organic anions. UC is made up mostly of NH₄⁺. Therefore, if we define the urinary anion gap (UAG) as

then we see that this is determined largely by the amount of NH₄⁺ in the urine that holds true in clinical studies of metabolic acidosis (34). In contrast to the SAG, which is useful in many settings of clinical acid-base diagnosis and therapy, the UAG has a very narrow clinical application in the differentiation of renal from nonrenal causes of nonanion gap metabolic acidosis (68).

DIFFERENTIAL DIAGNOSIS OF METABOLIC ACIDOSIS

The differential diagnosis of metabolic acidosis generally is approached clinically by using the SAG. Those acidosis states associated with retention of an organic anion are classified as increased anion gap or simply anion gap metabolic acidosis. Those acidosis states not associated with retention of an organic anion are classified as nonanion gap or hyperchloremic metabolic acidosis (66). These disorders are listed in Table 3-1.

CAUSES OF HYPERCHLOREMIC METABOLIC ACIDOSIS

Gastrointestinal Loss of HCO₃^–

Diarrhea

Diarrhea is the most common cause of hyperchloremic metabolic acidosis and always should be considered early in the differential diagnosis. The concentration of HCO₃^– in diarrheal fluid is generally greater than that of plasma. In the extreme case of cholera, patients may lose up to 20 L/day of fluid containing 30 to 50 mEq/L of HCO₃^– (69). However, hypovolemic shock likely will cause lactic acidosis and increase the anion gap in that situation. Ileostomy fluid is also rich in HCO₃^–, especially early after construction (70).

Table 3-1 Differential Diagnosis of Metabolic Acidosis

Normal Anion Gap (Hyperchloremic)	Increased Anion Gap (Organic)
Gastrointestinal Loss of HCO₃^–	Increased Acid Production
Diarrhea	Lactic acidosis
Intestinal fistula or drainage	Diabetic ketoacidosis
Anion exchange resins	Starvation
Ingestion of CaCl₂ or MgCl₂	Alcoholic ketoacidosis
Renal Loss of HCO₃^–	Inborn errors of metabolism
Renal tubular acidosis	Toxic alcohol ingestion
Carbonic anhydrase inhibitors	Salicylate intoxication
Hypoaldosteronism	Other intoxications
K-sparing diuretics	Failure of acid excretion
Miscellaneous	Acute renal failure
Recovery from ketoacidosis	Chronic renal failure
Dilutional acidosis	—
Addition of HCl	—
Parenteral alimentation	—
Sulfur ingestion	—

The diagnosis of diarrheal loss of HCO₃^–, however, may be difficult in the very young or very old (71). In the former case, the distinction between diarrhea and an underlying RTA is extremely important. The UAG may be very helpful in this setting. Patients with diarrhea as a cause of metabolic acidosis typically have a very negative UAG (i.e., urinary chloride exceeds the sum of urinary NA⁺ + K⁺ by >10 mEq/L) reflecting the presence of ample urinary NH₄⁺ concentrations, whereas patients with all forms of distal RTA have positive UAGs reflecting the inadequate urinary NH₄⁺ concentrations present (34).

Gastrointestinal Drainage and Fistulas

The succus entericus and pancreatic and biliary secretions are rich in HCO₃^– and poor in Cl^–. The succus entericus has a daily volume of 600 to 700 mL but may be increased in disease states. Biliary secretions amount to >1 L/day of fluid, with [HCO₃^–] approaching 60 mmol/L. Pancreatic secretion may exceed 2 L/day, with [HCO₃^–] approaching 120 mmol/L. Therefore, it is not surprising that GI drainage or fistulas could cause significant metabolic acidosis (72).

The technique of simultaneous kidney/pancreas transplant (SPK) has been used for the treatment of type I diabetic patients with end-stage renal disease (73). When urinary drainage of the HCO₃^–-rich exocrine secretions of the pancreatic allograft is employed rather than enteric drainage, this addition of pancreatic exocrine fluid causes urinary loss because the bladder cannot absorb the pancreatic secretion. Thus, SPK with urinary drainage is often associated with significant normal anion gap metabolic acidosis (74, 75). Many of these patients require sodium bicarbonate supplementation (as high as 100-150 mEq/day) on a chronic basis. The incidence of metabolic acidosis can be significantly lowered with enteric drainage compared to urinary drainage because the intestine can absorb the HCO₃^– (76).

Urinary Diversion to Bowel

Patients may require urinary diversion from normal egress through the bladder for a variety of reasons. Approaches to this include the creation of an ileal loop conduit or, less commonly, drainage of the ureters into the sigmoid colon (ureterosigmoidostomy) (77). Although metabolic acidosis can develop with both procedures, it is more severe with ureterosigmoidostomy. The pathophysiology for both situations is the bowel mucosal secretion of HCO₃^– in exchange for Cl^– during water reabsorption, which may lead to significant HCO₃^– losses in the GI tract effluent (72). Newer reconstructive procedures including ileal neobladders, which minimize the time of contact between urine and bowel mucosa, have been successful in limiting HCO₃^– loss (78).

Chloride-containing Anion Exchange Resins

Cholestyramine is a nonabsorbable anion exchange resin used to bind bile acids in the gut for a variety of purposes, including the treatment of obstructive liver disease as well as hypercholesterolemia and the management of acute diarrhea in children (79). However, this resin has some affinity for HCO₃^– and may exchange Cl^– for HCO₃^– across the bowel mucosa. In conditions of renal insufficiency where new HCO₃^– generation is impaired, in volume depletion or patients taking spironolactone, hyperchloremic metabolic acidosis has been reported (80).

Calcium or Magnesium Ingestion

The divalent cations, calcium or magnesium, are absorbed incompletely in the GI tract. If large amounts of these cations are ingested in soluble form (e.g., as the Cl₂ salts), then the unabsorbed Ca²⁺ or Mg²⁺ reacts with HCO₃^–, which has been exchanged across the mucosa for Cl^–, to form an insoluble salt. Thus, plasma HCO₃^– falls to a moderate degree (81).

Renal Loss of HCO₃^–

Renal Tubular Acidosis

RTA refers to a group of functional disorders characterized by impairment of renal HCO₃^– reabsorption and H⁺ excretion that is out of proportion to any reduction in GFR. In many cases, the RTAs exist in the presence of a completely normal GFR. Unfortunately, a nomenclature has evolved that confuses many experienced clinicians as well as trainees and students. We provide a pathophysiologic classification of these disorders
while referring to this nomenclature. RTAs can be divided into those characterized by disturbed distal nephron function (i.e., impaired NAE) and those caused by impaired proximal HCO₃^– reabsorption (82). Distal RTAs are divided into those associated with hypokalemia (83) and those associated with hyperkalemia, which may be further subdivided into RTA caused by hypoaldosteronism and RTA characterized by a general distal tubular defect (84).

Proximal Renal Tubular Acidosis

Proximal RTA, also called type II RTA, is an uncommon but very interesting disorder (85, 86). Basically, the acid-base disturbance is caused by impairment in proximal tubular reabsorption of HCO₃^–, the nephron site where 85% of HCO₃^– usually is reabsorbed. The delivery of HCO₃^–-rich fluid to distal nephron sites leads to substantial bicarbonaturia, when plasma levels of HCO₃^– are normal, as well as urinary losses of potassium and sodium. Thus, patients present with hypokalemia and hyperchloremic metabolic acidosis. When the plasma concentration of HCO₃^– is maintained at normal by administration of HCO₃^–, fractional HCO₃^– excretion (i.e., the fraction of filtered HCO₃^– that is excreted in the urine) exceeds 15%.

In physiologic terms, the apparent T_max and PT for HCO₃^– are significantly reduced in patients with proximal RTA. However, once a level of plasma HCO₃^– is achieved that is below the patient’s PT for HCO₃^–, renal acid handling is normal. In other words, NAE equals dietary and endogenous acid production rates and the subject comes into a steady state of acid-base balance, albeit at a moderately reduced plasma HCO₃^– concentration (and a mild reduction in systemic pH). Because a steady state in acid handling is achieved, patients with proximal RTA have less severe acidosis as well as less nephrocalcinosis (which results from bone calcium mobilization from acidosis) than patients with distal RTAs (see the following).

The problem with proximal HCO₃^– reabsorption may occur independently but more commonly coexists with other defects in proximal nephron function, such as decreased reabsorption of glucose, amino acids, phosphate, and uric acid. The term Fanconi syndrome is employed when general proximal nephron function is disturbed (87). Patients with full-blown Fanconi syndrome may have severe osteomalacia and malnutrition in addition to the mild metabolic acidosis associated with proximal RTA (88). Proximal RTA may occur as a primary disorder and present in infancy or may be acquired in the course of other diseases or as a result of exposure to substances toxic to this nephron segment. A list of causes of proximal RTA is shown in Table 3-2. Treatment of this condition is approached by addressing the underlying cause, but if this is ineffective, administration of large amounts of HCO₃^– (10-15 mmol/kg/day) and potassium to compensate for ongoing potassium losses in the urine caused by the bicarbonaturia is necessary. This is necessary to avoid growth retardation in children and osteopenia, which may be produced by even mild degrees of acidemia (89).

Table 3-2 Causes of Renal Tubular Acidosis

Proximal	Distal (Hypokalemic)	Distal (Hyperkalemic)
Primary	Primary	Hypoaldosteronism
Cystinosis	Hypercalcemia	Obstructive nephropathy
Wilson disease	Nephrocalcinosis	Sickle cell disease/trait
Lead toxicity	Multiple myeloma	Lupus erythematosus
Cadmium toxicity	Lupus erythematosus	Analgesic nephropathy
Mercury toxicity	Amphotericin B	Renal transplant rejection
Amyloidosis	Toluene	Cyclosporine toxicity
Multiple myeloma	Renal transplant rejection	Other interstitial disease
Nephrotic syndrome	Medullary sponge kidney	—
Medullary cystic disease	—	—
Outdated tetracycline	—	—
Injury from kidney preservation	—	—

Distal Renal Tubular Acidosis

The distal RTAs are characterized primarily by impaired NAE, which is due, at least in part, to impaired NH₄⁺ excretion. The central role of impaired NH₄⁺ excretion in this disorder is highlighted by a recent clinical study in which all patients with either hypokalemic distal RTA (also called type I or classic distal RTA) or hyperkalemic distal RTA (previously referred to as type IV RTA), caused by either hypoaldosteronism or a generalized tubular defect, had a positive UAG reflecting decreased NH₄⁺ excretion. How NH₄⁺ excretion is impaired in this diverse set of clinical disorders is still incompletely understood (84, 90).

Hypokalemic distal RTA has long been considered a disorder of the collecting duct in which the quantity of H⁺ secretion is inadequate to effect the necessary NAE for the subject to maintain acid-base balance. Clinically, patients with hypokalemic distal RTA present with hyperchloremic metabolic acidosis but are unable to acidify their urine (pH < 5.5 is commonly used) in response to an acid challenge. It must be stressed that the failure to acidify the urine does not fully explain the defect in NAE, which is primarily caused by an associated defect in NH₄⁺ excretion (91). However, the failure to acidify the urine under conditions of systemic acidosis historically has been considered the clinical hallmark of hypokalemic distal RTA. The physiologic mechanisms for this impaired acidification have been a topic of interest for some time and are summarized with clinical examples in Table 3-3. Basically, four mechanisms have been suggested for impaired acidification by the distal nephron: (a) back leak through a leaky epithelium; (b) pump failure, where the H⁺ ATPase cannot pump sufficient amounts of H⁺; (c) voltage defect, where a favorable transepithelial voltage cannot be generated (e.g., decreased sodium delivery to the distal nephron or decreased sodium reabsorption in the distal nephron); or (d) rate defect/NH₄⁺ defect, where urinary pH is reduced but NH₄⁺ excretion and NAE cannot be increased to normal amounts. Hypokalemic distal RTA appears to be caused by either back leak or pump failure. Patients may have an isolated defect in the H⁺/K⁺ ATPase or the vacuolar ATPase (92). Hyperkalemic distal RTAs are probably caused by either voltage defect or rate defect/NH₄⁺ defect (84).

A number of physiologic maneuvers have been used to examine these mechanisms clinically. The first and simplest test is that of a metered pH (i.e., using a pH meter rather than a dipstick) performed on urine collected under oil. If the subject is already acidemic (e.g., arterial pH < 7.35), then there is no need for ammonium chloride loading. In some cases, patients are able to maintain a normal plasma HCO₃^– concentration and systemic pH under most circumstances, but do not respond normally to increases in acid generation by increasing NAE. Recent studies have identified mutations in the vacuolar ATPase B1 subunit most likely responsible for this defect (93). This is called an incomplete distal RTA. If an incomplete distal RTA is suspected, ammonium chloride is administered to induce a mild case of metabolic acidosis. This test basically screens for back leak, pump failure, or voltage defects. An alternate method, the furosemide-fludrocortisone test, is a better-tolerated test for urine acidification (94). Furosemide increases distal Na⁺ delivery, and the mineralocorticoid fludrocortisone increases distal H⁺ secretion. Normal subjects will acidify urine to pH < 5.3 by 3 or 4 hours, whereas patients with distal RTA fail to do so. Infusion of sodium sulfate or sodium phosphate increases distal sodium delivery. The failure to lower urine pH after these maneuvers suggests pump failure or impaired voltage owing to inadequate distal sodium reabsorption. Another maneuver is to determine the urine to blood PCO₂ gradient when the patient has bicarbonaturia (urine [HCO₃^–] >100 mM) induced by HCO₃^– administration. Under conditions where bicarbonaturia is induced, H⁺ secreted into the collecting duct lumen will combine with HCO₃^– and form H₂CO₃. Because carbonic anhydrase is absent in the lumen of this segment (as well as the bladder), conversion to CO₂ and water is slow and occurs largely
in the urinary collecting system (i.e., renal pelvis, ureters, and urinary bladder), where the surface area for CO₂ absorption is small. This CO₂ essentially is trapped, and, when normalized for the blood PCO₂ (i.e., the difference between urine and blood), is a marker for the rate of distal H⁺ secretion. Patients with back leak or pump failure generally have a small difference between urine and blood PCO₂ (<20 torr).

Only gold members can continue reading. Log In or Register to continue