Brenner and Rector's The Kidney, 8th ed.

CHAPTER 14. Disorders of Acid-Base Balance

Thomas D. DuBose Jr.



Acid-Base Homeostasis, 505



Renal Regulation, 507



Systemic Response to Changes in Carbon Dioxide Tension, 508



Systemic Response to Addition of Nonvolatile Acids, 509



Systemic Response to Gain of Alkali, 511



Stepwise Approach to the Diagnosis of Acid-Base Disorders, 513



Respiratory Disorders, 517



Metabolic Disorders, 520

The appropriate diagnosis and management of acid-base disorders in acutely ill patients requires accurate and timely interpretation of the specific acid-base disorder. Appropriate interpretation requires simultaneous measurement of plasma electrolytes and arterial blood gases (ABGs), as well as an appreciation by the clinician of the physiologic adaptations and compensatory responses that occur with specific acid-base disturbances. In most circumstances, these compensatory responses can be predicted through an analysis of the prevailing disorder in a stepwise sequence.

The maintenance of systemic pH requires the integration of a number of physiologic mechanisms, including cellular and extracellular buffering and the compensatory actions of the kidneys and lungs.

This chapter reviews acid-base homeostasis as a consequence of acid-base chemistry and physiology but places major emphasis on the pathophysiologic basis, diagnosis, and management of clinical acid-base disorders. The diagnosis of acid-base disorders is reviewed in detail, with emphasis on a simple stepwise approach, founded on appreciation of the predictable compensatory responses to primary acid-base disturbances.


Acid-base homeostasis operates to maintain systemic arterial pH within a narrow range. Although the normal range for clinical laboratories is between 7.35 and 7.45 pH units, pH in vivo in an individual subject is maintained in a much more narrow range. This degree of tight regulation is accomplished through (1) chemical buffering in the extracellular fluid (ECF) and the intracellular fluid (ICF) and (2) regulatory responses that are under the control of the respiratory and renal systems. Those chemical buffers, respiration, and renal processes efficiently dispose of the physiologic daily load of carbonic acid (as volatile CO2) and nonvolatile acids and defend against the occasional addition of pathologic quantities of acid and alkali. Therefore, chemical buffers within the extracellular and intracellular compartments serve to blunt changes in pH that would occur with retention of either acids or bases. In addition, the control of CO2 tension (Pco2) by the central nervous system and respiratory system and the control of the plasma HCO3- by the kidneys constitute the regulatory processes that act in concert to stabilize the arterial pH.

The major buffer system in the body comprises a base (H+ acceptor), which is predominantly HCO3-, and an acid (H+ donor), which is predominantly carbonic acid (H2CO3):

(1)  H+ + HCO3- ⇔ H2CO3

Extracellular H+ concentration ([H+]e) throughout the body is constant in the steady state. The HCO3-/H2CO3 ratio is proportional to the ratio of all the other extracellular buffers (B-/HB) such as PO43- and plasma proteins:


The intracellular H+ concentration ([H+]i), or pHi, is also relatively stable, maintaining, under most circumstances, a fairly constant relationship to the extracellular H+ concentration. Both cellular ion exchange mechanisms and intracellular buffers (hemoglobin, tissue proteins, organophosphate complexes, and bone apatite) participate in the blunting of changes in both [H+]i and [H+]e. Extracellular and intracellular buffers provide the first line of defense against addition of acid or base to the body (see Mechanisms of pH Buffering, later).

The second line of defense is the respiratory system. Pulmonary participation in acid-base homeostasis relies on the excretion of CO2 by the lungs. The reaction is catalyzed by the enzyme carbonic anhydrase:


Large amounts of CO2 (10–12 mol/day) accumulate as metabolic end products of tissue metabolism. This CO2 load is transported in the blood to the lungs as hemoglobin-generated HCO3- and hemoglobin-bound carbamino groups.[1]


Conventionally, H+ concentration is expressed in two different ways, either directly as [H+] or indirectly as pH. The relationship between these two factors can be written in mathematically equivalent forms:

(5)  pH = -log10[H+]

(6)  [H+] (Eq/L) = 10-pH

When [H+] is expressed (for numeric convenience) in nanomoles per liter (nmol/L) or nanometers (nM), then

(7)  [H+] = 109–pH

Buffer Systems

Acid-base chemistry deals with molecular interactions that involve the transfer of H+. A large variety of molecules, both inorganic and organic, contain hydrogen atoms that can dissociate to yield H+. As defined classically, an acid is a molecular species that can function as an H+ donor; a base is a molecular species that can serve as an H+ acceptor. The relationship between an undissociated acid (HA) and its conjugate, disassociated base (A-) may be represented as

(8)  HA ⇔ H+ + A-

Besides the many inorganic and organic acid-base substances encountered in biologic systems, many protein molecules (e.g., hemoglobin) contain acidic groups that may dissociate, yielding a corresponding conjugate base.

Mechanisms of pH Buffering

Buffer systems are critical to the physiology and pathophysiology of acid-base homeostasis and, in their broadest definition, are systems that attenuate the pH change in a solution or tissue by reversibly combining with or releasing H+. Thus, the pH change of a solution during addition of acid or base equivalents, in the presence of a buffer system, is smaller than would have occurred if no buffer systems were present. The acid or base load can be extrinsic, such as during systemic acid or base infusion, or intrinsic, resulting from net generation of new acid or base equivalents that are added to the extracellular or intracellular space.

Chemical Equilibria of Physicochemical Buffer Systems

As an example of a physicochemical buffer pair, consider a neutral weak acid (HA) and its conjugate weak base (A-). Examples of such buffer pairs include acetic acid and acetate and the carboxyl groups on proteins. Another example of a physicochemical buffer pair is a neutral weak base (B) and its conjugate weak acid (BH+):

(9)  BH+ ⇔ B + H+

Examples of such buffer pairs are NH3 and NH4+ and the imidazole group in proteins. A rigorous analysis of the kinetics of reversible reactions in solution yields the law of mass action, which states that, at equilibrium (i.e., when the velocities of the forward and backward reactions are equal), the ratio of the concentration products of opposing reactions is a constant.



K′a and K′b are the equilibrium or dissociation constants for Equations 10 and 11, respectively.

Taking logarithms of both sides of Equations 10 and 11 and defining pK′a = -log10(K′a) and pK′b = -log10(K′b) yields



The dissociation constants K′a and K′b provide an estimate of the strength of the acid and base, respectively. From Equations 12 and 13, it can be seen that the buffer pairs are half dissociated at pH = pK′. In other words, pK′ of a buffer pair is defined as the pH at which 50% of the buffer pair exists as the weak acid (HA) and 50% as the anion (A-).

Chemical Equilibria for the Carbon Dioxide-Bicarbonate System

When CO2 is dissolved in water, H2CO3 is formed according to the reaction

(14)  CO2 + H2O ⇔ H2CO3

The rate of this reaction, in the absence of the enzyme carbonic anhydrase, is slow, with a half-time of about 8 seconds at 37°C. The major portion of CO2 remains as dissolved CO2; only about 1 part in 1000 forms H2CO3, a nonvolatile acid. Because H2CO3 is a weak acid, it dissociates to yield H+ and HCO3-.

(15)  H2CO3 ⇔ H+ + HCO3-

The concentration of dissolved CO2 is given by Henry's law:

(16)  [CO2]dis = αCO2Pco2

where αCO2 is the physical solubility coefficient for CO2, which has a value of 0.0301 mmol/L in most body fluids, including plasma. Because the concentration of H2CO3 is low and proportional to the concentration of dissolved CO2, Equations 14 and 15 can be combined and treated as a single reaction:

(17)  CO2 + H2O ⇔ H+ + HCO3-

The equilibrium constant for this reaction is given by


Defining K′ = K[H2O] as the apparent equilibrium constant and using Equation 17,


Taking logarithms of both sides of Equation 19 and recognizing that pK′ = -log10(K′), the familiar Henderson-Hasselbalch equation is derived:


Using pK′ = 6.1 in Equation 20, the Henderson equation is derived, which may be utilized in clinical interpretation of acid-base data:


The Physiologic Advantage of an Open Buffer System

The quantitative behavior of an open system buffer pair differs considerably from that in which the buffer pair is confined to a closed system. In an open system, the buffer pair may be envisioned as occurring in two separate but communicating compartments (internal and external). The external compartment provides an effective infinite reservoir of the uncharged buffer pair component, to which the barrier between the internal and the external compartments (e.g., plasma cell membrane, vascular capillary endothelium) is freely permeable.

Physiologically, the most important open system buffer is the CO2-HCO3- system. Adjustments in alveolar ventilation serve to maintain a constant Paco2:


The CO2-HCO3- buffer system has a pK′ of 6.1 and a base-to-acid ([HCO3-]/[H2CO3]) ratio of 20:1 at pH 7.4. Because buffer efficiency is greatest in the pH range near pKa′, it appears at first glance that the CO2-HCO3- system would not function as an effective buffer in the physiologic pH range. The potency and efficacy of the CO2-HCO3- buffer system are due largely to the augmentation of buffer capacity that accompanies operation in an open system. Because CO2 is freely diffusible across biologic barriers and cell membranes, its concentration in biologic fluids can be modulated rapidly through participation of the respiratory system. When acid (H+) is added to an HCO3--containing fluid, H+ combines with HCO3- to generate H2CO3, which, in the presence of the enzyme carbonic anhydrase, is rapidly dehydrated to CO2 (Equation 22). The CO2 produced can escape rapidly from the fluid and be excreted in the lung, preventing accumulation of CO2 concentrations in biologic fluids.

Regulation of Buffers

The plasma HCO3- concentration is protected by both metabolic and renal regulatory mechanisms. In addition, the pH of blood can be affected by respiratory adjustments in Paco2. Primary changes in Paco2 may result in acidosis or alkalosis, depending on whether CO2 is elevated above or depressed below the normal value: 40 mm Hg. Such disorders are termed respiratory acidosis and respiratory alkalosis, respectively. A primary change in the plasma HCO3-concentration owing to metabolic or renal factors results in commensurate changes in ventilation. The respiratory response to acidemia or alkalemia blunts the change in blood pH that would occur otherwise. Such respiratory alterations that adjust blood pH toward normal are referred to as secondary or compensatory alterations, because they occur in response to primary metabolic changes.

Human subjects are confronted, under most physiologic circumstances, with an acid challenge. “Acid production” in biologic systems is represented by the milliequivalents (mEq) of protons (H+) added to body fluids. Conversely, proton removal is equivalent to equimolar addition of base, OH- (generation of HCO3- from dissolved CO2). Metabolism generates a daily load of relatively strong acids (lactate, citrate, acetate, and pyruvate), which must be removed by other metabolic reactions. The oxidation of these organic acids in the Krebs cycle, for example, generates CO2, which must be excreted by the lungs. The oxidation of carbon-containing fuels produces as much as 16,000 to 20,000 mmol of CO2 gas daily. Nevertheless, the complete combustion of carbon involves the intermediate generation and metabolism of 2000 to 3000 mmol of relatively strong organic acids, such as lactic acids, tricarboxylic acids, keto acids, or other acids, depending on the type of fuel consumed. These organic acids do not accumulate in the body under most circumstances, with concentrations remaining in the low millimolar range. However, if production and consumption rates become mismatched, these organic acids can accumulate (e.g., lactic acid accumulation with strenuous exertion). Correspondingly, the HCO3- in the ECF will decline as the organic acid concentration increases. During recovery, the organic acids reenter metabolic pathways to CO2 production, removal of H+, and generation of HCO3-. Nevertheless, if the organic anions are excreted (e.g., ketonuria), these entities are no longer available for regeneration of HCO3-. The metabolism of some body constituents such as proteins, nucleic acids, and small fractions of lipids and certain carbohydrates generates specific organic acids that cannot be burned to CO2 (e.g., uric, oxalic, glucoronic, hippuric acids). In addition, the inorganic acids H2SO4 and H3PO4, derived respectively from sulfur-containing amino acids and organophosphates, must be excreted by the kidneys or the gastrointestinal tract.

In summary, in the steady state, as a result of the buffering power of the HCO3-/H2CO3 buffer system and its preeminence over other body buffer systems, addition or removal of H+ results in equimolar changes in the HCO3-concentration according to the relationship outlined in Equation 3. Moreover, because this buffer system is open to air, the concentration of CO2 remains essentially fixed. Therefore, the evidence for H+ addition or removal can be found in reciprocal changes in the numerator of the Henderson-Hasselbach equation (Equation 20), or the [HCO3-].

Integration of Regulatory Processes

Three physiologic processes militate against changes in the HCO3-/CO2 ratio: (1) metabolic regulation, (2) respiratory regulation, and (3) renal regulation. Metabolic regulation is of minor importance in terms of overall physiologic regulation of acid-base balance. Nevertheless, regulatory enzymes, whose activity may be pH sensitive, may catalyze metabolic reactions that either generate or consume organic acids. Such a process constitutes a negative feedback regulatory system. The best example is phosphofructokinase, the pivotal enzyme in the glycolytic pathway, the activity of which is inhibited by low pH and enhanced by high pH. Therefore, an increase in pHi accelerates glycolysis and generates pyruvate and lactate. It follows, therefore, that the generation of lactate in patients with lactic acidosis and the generation of keto acids in patients with ketoacidosis are impeded by acidemia.

Because, under most circumstances, CO2 excretion and CO2 production are matched, the usual steady-state Paco2 is maintained at 40 mm Hg. Underexcretion of CO2 produces hypercapnia, and overexcretion produces hypocapnia. Production and excretion are again matched but at a new steady-state Pco2. Therefore, the arterial Pco2 (Paco2) is regulated primarily by neurorespiratory factors and is not subject to regulation by the rate of metabolic CO2production. Hypercapnia is primarily the result of hypoventilation, not increased CO2 production. Increases or decreases in Pco2 represent derangements of control of neurorespiratory regulation or can result from compensatory changes in response to a primary alteration in the plasma HCO3- concentration.


Although temporary relief from changes in the pH of body fluids may be derived from chemical buffering or respiratory compensation, the ultimate defense against addition of nonvolatile acid or of alkali resides in the kidneys. The addition of a strong acid (HA) to the ECF titrates plasma HCO3-:

(23)  HA + NaHCO3 ⇔ NaA + H2O + CO2

The CO2 is expired by the lungs, and body HCO3- buffer stores are diminished. This process occurs constantly as endogenous metabolic acids are generated. To maintain a normal plasma HCO3- in the face of constant accession of metabolic acids, the kidneys must (1) conserve the HCO3- present in glomerular filtrate and (2) regenerate the HCO3- decomposed by reaction with metabolic acids (Equation 23). For more detail, see Chapter 7 .

The first process (HCO3- reclamation) is accomplished predominantly in the proximal tubule, with an additional contribution by the loop of Henle and a minor contribution by more distal nephron segments. Under most circumstances, the filtered load of HCO3- is absorbed almost completely, especially during an acid load. Nevertheless, when less acid is generated or if the plasma HCO3- concentration increases above the normal value of 25 mEq/L, HCO3- will be excreted efficiently into the urine. The second process, HCO3- regeneration, is represented by the renal output of acid or net acid excretion ( Fig. 14-1 ).



FIGURE 14-1  Synchrony of regulation of ammonium production (from glutamine [GLN] precursors, and excretion). Process allows generation of “new” HCO3- by the kidney. NH4+ excretion is regulated in response to changes in systemic acid-base and K+ balance. Segmental contributions include: proximal convoluted tubule, proximal straight tubule, thin descending limb, thick ascending limb, and medullary collecting duct. Up-regulated by acidosis and hypokalemia. Inhibited by hyperkalemia.



(24)  Net acid excretion = NH4+ + titratable acid - HCO3-

On balance, each milliequivalent of net acid excreted corresponds to 1 mEq of HCO3- returned to the ECF. This process of HCO3- regeneration is necessary to replace the HCO3- lost by the entry of fixed acids into the ECF or, less commonly, that HCO3- excreted in stool or urine. Because a typical North American diet generates fixed acids at 50 to 70 mEq/day, net acid excretion must be affected to maintain acid-base balance. Therefore, net acid excretion approximates 50 to 70 mEq/day. If acid production remained stable and unabated by net acid excretion, metabolic acidosis would ensue. Conversely, an increase in net acid excretion above the level of net acid production results in metabolic alkalosis.

Daily acid-base balance can be estimated, therefore, by subtracting net acid excretion plus any base absorbed from the gut from the amount of acid produced daily. The daily production of acid is represented by the amount of H2SO4and noncombustible organic acids generated. In other words, net acid production is represented by the milliequivalents of SO42- and organic acid anions (A-) excreted in the urine. It has been confirmed in patients ingesting an artificial diet that urinary [NH4+ + TA - HCO3] is equal to urinary [SO42- + organic A- + dietary phosphoester-derived H+].[1]


Generation of Respiratory Acidosis or Alkalosis: Acute Response

Intrinsic disturbances in the respiratory system can alter the relationship of CO2 production and excretion and give rise to abnormal values of Paco2. Some stimuli evoke a primary increase in ventilation, which lowers systemic Paco2. These stimuli include hypoxemia, fever, anxiety, central nervous system disease, acute cardiopulmonary processes, septicemia, liver failure, pregnancy, and drugs (e.g., salicylates).[2] Conversely, Paco2 increases if the respiratory system is depressed by suppression of the respiratory control center or of the respiratory apparatus itself (neuromuscular, parenchymal, and airway components).[3] In both kinds of acute respiratory disorders, CO2 is added to or subtracted from the body until the Paco2 assumes a new steady state so that pulmonary CO2 excretion equals CO2 production.

The accumulation or loss of CO2 causes changes in blood pH within minutes. The plasma HCO3- decreases slightly as the Paco2 is reduced in acute respiratory alkalosis and increases slightly in acute respiratory acidosis. [1] [2] [3] [4]The small changes in HCO3- concentration are due to buffering by nonbicarbonate buffers. [1] [2] [3] [4] The estimated change in blood HCO3- concentration is approximately equal to 0.1 mEq/L of [HCO3-] for each millimeter of mercury increase in Pco2 and 0.25 mEq/L for each millimeter of mercury decrease in PCO2[3]. Acute alterations in Pco2 in either direction within the physiologic range do not change the blood HCO3- concentration by more than a total of about 4 to 5 mEq/L from normal. Organic acid production, especially of lactic and citric acids, increases modestly during acute hypocapnia, decreasing the blood HCO3- concentration and blunting the respiratory response to metabolic alkalosis. [1] [2] [3] [4]

Chronic Response

Although the blood pH is relatively poorly defended during acute changes in Paco2, during chronic changes, the kidneys are recruited to excrete or retain HCO3- and return blood pH toward normal. The persistence of hypocapnia reduces renal bicarbonate absorption to achieve a further decrease in the plasma HCO3- concentration. Hypocapnia decreases renal HCO3- reabsorption[2] by inhibiting acidification in both the proximal[4] and the distal nephrons. The resulting decrease in plasma HCO3- concentration is equal to about 0.4 to 0.5 mEq/L for each millimeter of mercury decrease in Pco2[3]. Thus, the arterial pH falls toward but not completely back to normal.

Several hours to days are required for full expression of the renal response to chronic hypocapnia, [3] [4] which includes a reduction in the rate of H+ secretion, an increase in urine pH, a decrease in NH4+ and titratable acid excretion, and a modest bicarbonaturia (see Chapter 7 ). An increase in blood Cl- concentration occurs simultaneously by means of several mechanisms: a shift of Cl- out of red blood cells, ECF volume contraction, and enhanced Cl- reabsorption.

An overshoot in HCO3- generation and sustained reabsorption may occur on occasion so that blood pH may become alkaline with severe chronic hypercapnia (values ≤ 70 mm Hg). [3] [4] One example of this phenomenon is the increment in renal HCO3- generation caused by nocturnal CO2 retention in patients with obstructive sleep apnea. Both blood Pco2 and HCO3- concentration increase during the night. Later in the morning, alkalotic blood gas values are often obtained, because Paco2 has declined more rapidly than HCO3- concentration to values characteristic of wakefulness. In chronic hypercapnia, the blood HCO3- concentration increases about 0.25 to 0.50 mEq/L for each millimeter of mercury elevation in Paco2. [3] [4]

The increase in generation of HCO3- by the kidney during chronic hypercapnia takes several days for completion. The mechanism of HCO3- retention involves increased H+ secretion by both proximal and distal nephron segments, regardless of sodium bicarbonate or sodium chloride intake, mineralocorticoid levels, or K+ depletion. [1] [3] [4] [5]

Chronic hypercapnia results in sustained increases in renal cortical Pco2, and the increase in renal cortical Pco2 that occurs with chronic hypercapnia stimulates acidification. [4] [5] The increased Pco2 enhances distal H+ secretion so that increased NH4+ excretion occurs even with a low-salt diet or with hypoxemia. However, if hyperkalemia ensues or is present initially, the renal adaptation to chronic hypercapnia is blunted significantly. Hyperkalemia decreases NH4+ production and excretion even in the face of acidemia. [5] [6] The effect of an elevated Pco2 to augment tubule HCO3- reabsorption may also be mediated by hemodynamic changes, especially by systemic vasodilatation, so that a decreased effective ECF status is sensed by the kidney. Hypercapnia also decreases proximal sodium chloride reabsorption and causes a chloriuresis, which can further compromise ECF. [4] [5] If the hemodynamic alterations induced by hypercapnia are corrected, the direct influence of acute hypercapnia, to increase net renal HCO3- transport, is abated. Over time, an adaptation occurs in the proximal nephron: HCO3- reabsorption is stimulated after several days of hypercapnia.[7] The cellular mechanism by which chronic hypercapnia enhances H+ secretion by the distal nephron appears to involve an increase in the number of H+ pumps (H+-ATPase and H+,K+-ATPase) inserted into the apical membrane of proximal tubules and collecting ducts.[8]

In summary, although primary alterations in systemic Paco2 cause relatively marked changes in blood pH, renal homeostatic mechanisms allow the blood pH to return toward normal over a sufficient period. The renal response to chronic hypercapnia is manifest primarily by an increase in net acid excretion and HCO3- absorption, which is accomplished by augmented H+ secretion in both the proximal and the distal nephrons.


In addition to large quantities of CO2, the metabolic processes of the body produce a smaller quantity of nonvolatile acids. The lungs readily excrete CO2, and this process can respond rapidly to changes in production. In contrast, the kidneys must excrete nonvolatile acids through a much slower adaptive response. The time course of compensation for addition of acid or alkali to the body is displayed schematically in Figure 14-2 . The hypothetical completion of each process is plotted as a function of time and proceeds in the following sequence: (1) distribution and buffering in the ECF, (2) cellular buffering, (3) respiratory compensation, and (4) renal acid or base excretion.



FIGURE 14-2  Time course of acid-base compensatory mechanisms. In response to a metabolic acid or alkaline load, component approaches to completion of the distribution and extracellular buffering mechanisms, of cellular buffering events, and of respiratory and renal regulatory processes are presented as a function of time. ECF, extracellular fluid.



Sources of Endogenous Acids

Pathologically, acid loads may be derived from endogenous acid production (e.g., generation of keto acids and lactic acids) or loss of base (e.g., diarrhea) or from exogenous sources (e.g., ammonium chloride or toxin ingestion). Under normal physiologic circumstances, a daily input of acid derived from the diet and metabolism confronts the body. The net result of these processes amounts to about 1.0 mEq of new H+ per kilogram per day. [1] [4]

Sulfuric acid is formed when organic sulfur from methionine and cysteine residues of proteins are oxidized to SO42-. The metabolism of sulfur-containing amino acids is the primary source of acid in the usual Western diet, accounting for approximately 50%. The quantity of sulfuric acid generated is equal to the SO42- excreted in the urine.

Organic acids are derived from intermediary metabolites formed by partial combustion of dietary carbohydrates, fats, and proteins as well as from nucleic acids (uric acid). Organic acid generation contributes to net endogenous acid production when the conjugate bases are excreted in the urine as organic anions. If full oxidation of these acids can occur, however, H+ is reclaimed and eliminated as CO2 and water. The net amount of H+ added to the body from this source can be estimated by the amount of organic anions excreted in the urine.

Phosphoric acid can be derived from hydrolysis of PO43- esters in proteins and nucleic acids if it is not neutralized by mineral cations (e.g., Na+, K+, and Mg2+). The contribution of dietary phosphates to acid production is dependent on the kind of protein ingested. Some proteins generate phosphoric acid, whereas others generate only neutral phosphate salts. [1] [4] Hydrochloric acid is generated by metabolism of cationic amino acids (lysine, arginine, and some histidine residues) into neutral products. Other potential acid or base sources in the diet can be estimated from the amount of unidentified cations and anions ingested.

Potential sources of bases are also found in the diet (e.g., acetate, lactate, citrate) and can be absorbed to neutralize partially the H+ loads from the three sources just mentioned. These potential base equivalents may be estimated by subtracting the unmeasured anions in the stool (Na+ + K+ + Ca2+ + Mg2+ - Cl- - 1.8P) from those measured in the diet. The net base absorbed by the gastrointestinal tract is derived from the anion gap (AG) of the diet minus that of the stool. Acid production is partially offset by HCO3- produced when organic anions combine with H+ and are oxidized to CO2 and H2O or when dibasic phosphoesters combine with H+ during hydrolysis. The gastrointestinal tract may modify the amount of these potential bases reabsorbed under particular circumstances of acidosis or growth. It has been confirmed in patients ingesting an artificial diet that urinary [NH4+ + TA - HCO3] is equal to urinary [SO42- + organic A- + dietary phosphoester-derived H+]. [1] [4] [9]

In summary, dietary foodstuffs contain many sources of acids and bases. These can be estimated by the urinary excretion of SO42- and organic anions minus the unmeasured anions. The usual North American diet represents a daily source of acid generation for which the body must compensate constantly.

Hepatic and Renal Roles in Acid-Base Homeostasis

The generation of acid by protein catabolism is balanced by the generation of new HCO3- through renal NH4+ and titratable acid excretion. Hepatic protein catabolism, with the exception of sulfur- and PO43--containing amino acids, can be considered a neutral process. The products of these neutral reactions are HCO3- and NH4+ ( Fig. 14-3 ). Most of the NH4+ produced by metabolism of amino acids reacts with HCO3- or forms urea and, thus, has no impact on acid-base balance. A portion of this NH4+ is diverted to glutamine synthesis, the amount of which is regulated by pH. Acidemia promotes and alkalemia inhibits glutamine synthesis. Glutamine enters the circulation and reaches the kidney, where it is deaminated to form glutamate. Renal glutamine deamination results in NH4+ production and initiates a metabolic process that generates new HCO3- through α-ketoglutarate. Glutamine deamination in the kidney is also highly regulated by systemic pH, so that acidemia augments and alkalemia inhibits NH4+ and HCO3- production. The ultimate control, however, resides in the renal excretion of NH4+, because the NH4+ must be excreted to escape entry into the hepatic urea synthetic pool. Hepatic urea synthesis would negate the new HCO3- realized from α-ketoglutarate in the kidney. Hepatic regulation of NH4+ metabolic pathways appears to facilitate glutamine production when NH4+ excretion is stimulated by acidemia or, conversely, blunts glutamine production when excretion is inhibited by alkalemia.[9]



FIGURE 14-3  Hepatic and renal roles in NH4+ and acid balance. Virtually all NH4+ produced by metabolism of amino acids reacts with HCO3- to form urea, a process that has no impact on acid-base balance. A small fraction of this NH4+ is diverted to glutamine synthesis. This diversion is influenced by the local pH and acidemia-promoting and alkalemia-inhibiting glutamine synthesis. Glutamine circulates to the kidney, where it can be deaminated to form glutamate, initiating a process that eventually generates HCO3- through metabolism of α-ketoglutarate. If glutamine is not deaminated, it returns to the liver and is deaminated there to contribute to NH4+ to the urea synthetic pool.  (Adapted from Gennari FJ, Maddox DA: Renal regulation of acid-base homeostasis: Integrated response. In Seldin DW, Giebisch GH [eds]: The Kidney: Physiology and Pathophysiology, 3rd ed. New York, Lippincott Williams and Wilkins, 2000.)




Neurorespiratory Response to Acidemia

A critically important response to an acid load is the neurorespiratory control of ventilation. Although the precise mechanism for this response is debated, [1] [3] [4] [9] the prevailing view is that a fall in systemic arterial pH is sensed by the chemoreceptors that stimulate ventilation and, therefore, reduce Paco2. The fall in blood pH that would otherwise occur in uncompensated metabolic acidosis is, therefore, blunted. The pH is not restored to normal; however, Paco2 declines by an average of 1.25 mm Hg for each 1.0 mEq/L drop in HCO3- concentration. The appropriate Paco2 in steady-state metabolic acidosis can be estimated from the prevailing HCO3- concentration according to the expression[10]:

(25)  Paco2 = 1.5 [HCO3-] + 8 (±2 mm Hg)

It is convenient to remember that the predicted (or compensatory) Paco2 is also roughly equal to addition to the serum [HCO3-] of the number 15 (valid in pH range of 7.2–7.5). Because the Paco2 cannot fall below about 10 to 12 mm Hg, the blood pH is less well defended by respiration after very large reductions in the plasma HCO3- concentration ( Table 14-1 ).

TABLE 14-1   -- Acid-Base Abnormalities and Appropriate Compensatory Responses for Simple Disorders

Primary Acid-Base Disorders

Primary Defect

Effect on pH

Compensatory Response

Expected Range of Compensation

Limits of Compensation

Respiratory acidosis

Alveolar hypoventilation (↑ PCO2)

↑ Renal HCO3- reabsorption (HCO3- ↑)






Δ[HCO3-] = +1 mEq/L for each ↑ ΔPCO2 of 10 mm Hg

[HCO3-] = 38 mEq/L










Δ[HCO3-] = +4 mEq/L for each ↑ΔPCO2 of 10 mm Hg

[HCO3-] = 45 mEq/L

Respiratory alkalosis

Alveolar hyperventilation (↓ PCO2)

↓ Renal HCO3- reabsorption (HCO3- ↓)






Δ[HCO3-] = - 2 mEq/L for each ↓ ΔPCO2 of 10 mm Hg

[HCO3-] = 18 mEq/L










Δ[HCO3-] = - 5 mEq/L for each ↓ ΔPCO2 of 10 mm Hg

[HCO3-] = 15 mEq/L

Metabolic acidosis

Loss of HCO3- or gain of H+ (↓ HCO3-)

Alveolar hyperventilation to ↑ pulmonary CO2 excretion (↓ PCO2)



PCO2 = 1.5[HCO3-] + 8 ± 2



PCO2 = last 2 digits of pH × 100



PCO2 = 15 + [HCO3-]

PCO2 = 15 mm Hg

Metabolic alkalosis

Gain of HCO3- or loss of H+ (↑ HCO3-)

Alveolar hypoventilation to ↓ pulmonary CO2 excretion (↑ PCO2)



PCO2 = + 0.6 mm Hg for Δ[HCO3-] of 1 mEq/L



PCO2 = 15 + [HCO3-]

PCO2 = 55 mm Hg

Adapted from Bidani A, Tauzon DM, Heming TA: Regulation of whole body acid-base balance. In DuBose TD, Hamm LL (eds): Acid-Base and Electrolyte Disorders: A Companion to Brenner and Rector's The Kidney. Philadelphia, WB Saunders, 2002, pp 1–21.



Approximately 12 to 24 hours is required to achieve full respiratory compensation for metabolic acidosis (see Fig. 14-2 ).

Renal Excretion

As already discussed, the kidneys eliminate the acid that is produced daily by metabolism and diet and have the capacity to increase urinary net acid excretion (and, hence, HCO3- generation) in response to endogenous or exogenous acid loads. Renal excretion of acid is usually matched to the net production of metabolic and dietary acids, about 55 to 70 mEq/day, so little disturbance in systemic pH or HCO3- concentration occurs.

As an acid load is incurred, the kidneys respond to restore homeostasis by increasing NH4+ excretion (titratable acid excretion has limited capacity for regulation). With continued acid loading, renal net acid excretion increases over the course of 3 to 5 days (see Fig. 14-2 ) but does not quite achieve the level of acid production. Progressive positive acid balance ensues, buffered presumably by bone carbonate.

Thus, the renal response to an acid load requires (1) reclamation of the filtered HCO3- by the proximal tubule and (2) augmentation of NH4+ production and excretion by the distal nephron. In this way, the kidneys efficiently retain all filtered base and attempt to generate enough new base to restore the arterial pH toward normal.

In summary, acidosis enhances proximal HCO3- absorption, decreasing delivery of HCO3- out of the proximal tubule, and enhances distal acidification. Net acid excretion is increased by stimulation of NH4+ production and excretion. Hyperaldosteronism and the effect of nonreabsorbable anions can act synergistically to strengthen the renal defense to an acid challenge.


Whereas the major goal of the body in defense of an acid challenge is to conserve body buffer stores and to generate new base, the response to an alkali load is to eliminate base as rapidly as possible. The response is dependent on the same three responses outlined for defense of an acid challenge, namely, cellular buffering and distribution within the ECF, respiratory, and renal excretion.

Distribution and Cellular Buffering

Ninety-five percent of a base load in the form of HCO3- is distributed in the ECF within about 25 minutes [1] [4] [9] [11] (see Fig. 14-2 ). Simultaneously, the various processes of cellular buffering serve to dissipate this HCO3- load. Cellular buffering of the HCO3- load has a half-time of 3.3 hours. The apparent distribution volume for the administered HCO3- is inversely proportional to the preexisting plasma HCO3- concentration. A lesser fraction of base is buffered via cellular processes than occurs when a comparable amount of acid is administered (see Fig. 14-2 ). Two thirds of the administered HCO3- is retained in the ECF; a third is buffered in cells, principally by Na+/H+exchange, and a small amount is buffered by increased lactate production and Cl-/HCO3- exchange.[1] Modest hypokalemia as a result of K+ shifts into cells and is approximately equal to 0.4 to 0.5 mEq/L of K+ per 0.1 unit pH increase above 7.40.

In summary, the cellular defense against an alkaline load is somewhat less effective than the defense against an acid load. There is also poorer stabilization of intracellular pH in the alkaline than in the acid range. [1] [11]

Respiratory Compensation

The pulmonary response to an acute increase in HCO3- concentration is biphasic. Neutralization of sodium bicarbonate by buffers (H+ buffer-) results in CO2 liberation and an increase in Pco2:

(26)  Na+HCO3- + H+ buffer- ⇔ Na+ buffer- + H2CO3 ⇔H2O + CO2

The increased Pco2 stimulates ventilation acutely to return Pco2 toward normal. If the pulmonary system is compromised or the ventilation rate controlled artifically, increased CO2 production from infused sodium bicarbonate can lead to hazardous hypercapnia. [1] [4] [11]

About an hour after an abrupt increment in the HCO3- concentration, when the increased generation of CO2 subsides, stimulation of respiration is transformed into suppression of respiration, and Pco2 increases. This secondary hypercapnic response takes several hours and partially compensates for the elevated HCO3- concentration so that arterial pH is returned toward (although not completely to) normal (see Fig. 14-2 ).

The hypercapnic response to metabolic alkalosis is difficult to predict reliably. Attempts to substantiate a role for K+ deficiency in preventing hypoventilation have not been illuminating. [9] [11] [12] Moreover, studies of alkalotic patients taking diuretics demonstrate a predictable hypoventilatory response and cast doubt on a significant role of K+ deficiency to blunt alkalosis-induced hypoventilation.[11] Most studies have found that an increase in Pco2regularly occurs in response to alkalosis. The hypoventilatory response can lead to borderline or even frank hypoxemia in patients with chronic lung disease. [11] [12] In general, the increase in Paco2 can be predicted to equal 0.75 mm Hg per 1.0 mEq/L increase in plasma HCO3-; or more simply, add the value of 15 to the measured plasma [HCO3-][12] to predict the expected Paco2 (see Table 14-1 ).

Renal Excretion

With Extracellular Volume Expansion

Addition of sodium bicarbonate to the body results in prompt cellular buffering and respiratory compensation. However, as with an acid load, the kidneys have the ultimate responsibility for the disposal of base and restoration of base stores to normal. The renal response is more rapid with HCO3- addition than with acid ingestion (see Fig. 14-2 ). The speed and efficiency with which HCO3- can be excreted by the kidneys are such that it is difficult to render a patient with normal renal function more than mildly alkalotic on a chronic basis, even when as much as 24 mEq/kg/day of sodium bicarbonate is ingested for several weeks. [11] [12] A pulse base load is excreted almost entirely within 24 hours.

The proximal tubule is responsible principally for HCO3- excretion when the blood HCO3- concentration increases. Absolute proximal HCO3- reabsorption does not increase in proportion to HCO3- load in the rat kidney because of suppression of proximal acidification by alkalemia[5] so that HCO3- delivery to the distal nephron increases. The limited capacity of the distal nephron to secrete H+ can be overwhelmed easily, and bicarbonaturia increases progressively. NH4+ and titratable acid excretion are mitigated in response to the increasing urine pH. [5] [12]

Acute graded HCO3- loads that concomitantly increase ECF also function in human subjects to increase urinary HCO3- excretion progressively as plasma HCO3- concentration increases.[5] In summary, an acute base load is excreted entirely, and the blood HCO3- concentration is returned to normal within 12 to 24 hours because of depression of fractional proximal HCO3- reabsorption. In addition to suppression of reabsorption of the filtered HCO3-load, direct HCO3- secretion in the CCT has been proposed as another mechanism for mediating HCO3- disposal during metabolic alkalosis.[12]

The increased delivery of HCO3- out of the proximal tubule in response to an increased blood HCO3- concentration (and, hence, filtered HCO3- load) in the setting of ECF expansion facilitates HCO3- excretion and the return of blood pH toward normal. However, other factors may independently enhance distal H+ secretion sufficiently to prevent HCO3- excretion and thus counterbalance the suppressed fractional proximal HCO3- reabsorptive capacity. Under these circumstances, the alkalosis is maintained. For example, in the setting of primary hyperaldosteronism, despite the expanded ECF, a stable mild alkalotic condition persists in most experimental models owing to augmented collecting duct H+ secretion.[12] In such cases, concurrent hypokalemia facilitates the generation and maintenance of metabolic alkalosis by enhancing NH4+ production and excretion. [5] [12] Moreover, chronic hypokalemia dramatically enhances the abundance and functionality of the colonic H+,K+,-ATPase isoform in the medullary collecting tubule, thus increasing rather than decreasing bicarbonate absorption. [12] [13] [14] [15] Enhanced nonreabsorbable anion delivery, as with drug anions, also increases net collecting tubule H+ secretion by increasing the effective luminal negative potential difference or by suppressing HCO3- secretion in the cortical collecting duct (CCD).

With Extracellular Volume Contraction and Potassium Ion Deficiency

The renal response to an increase in plasma HCO3- concentration can be modified significantly in the presence of ECF contraction and K+ depletion. [15] [16] Because the volume of distribution of Cl- is approximately equal to ECF, the depletion of the ECF is roughly equivalent to the depletion of Cl-. The critical role of effective ECF and K+ stores in modifying net HCO3- reabsorption has been demonstrated in numerous experimental models.

Deficiency of both Cl- and K+ is common in metabolic alkalosis because of renal and/or gastrointestinal losses that occur concurrently with the generation of the alkalosis. [14] [16] With Cl- depletion alone, the normal bicarbonaturic response to an increase in plasma HCO3- is prevented and metabolic alkalosis can develop. K+ depletion, even without mineralocorticoid administration, can cause metabolic alkalosis in rats and humans. When Cl- and K+depletion coexist, severe metabolic alkalosis may develop in all species studied.

Two general mechanisms exist by which the bicarbonaturic response to hyperbicarbonatemia can be prevented by Cl- and/or K+ depletion: (1) As the plasma HCO3- concentration increases, there is a reciprocal fall in GFR. If the fall in glomerular filtration rate (GFR) were inversely proportional to the rise in the plasma HCO3- concentration, the filtered HCO3- load would not exceed the normal level. In this case, normal rates of proximal and distal HCO3-reabsorption would suffice to prevent bicarbonaturia. (2) Cl- deficiency or K+ deficiency increases overall renal HCO3- reabsorption in the setting of a normal GFR and high filtered HCO3- load. In this case, overall renal HCO3-reabsorption and, therefore, acidification would be increased. An increase in renal acidification might occur as a result of an increase in H+ secretion by the proximal or the distal nephron or by both nephron segments. [12] [13] [14]

The possibility that Cl- or K+ depletion might decrease GFR or increase proximal HCO3- reabsorption has been evaluated in experimental animals. That extracellular and plasma volume depletion decreases GFR is well described. GFR can also be decreased by K+ depletion in rats and dogs. The reduction in GFR by K+ depletion is assumed to be the result of increased production of the vasoconstrictors angiotensin II and thromboxane B2. [13] [15] These results, taken together, provide support for the first mechanism: that metabolic alkalosis can be maintained by a depression in GFR. [12] [13] [14] [15] [16]

The combination of an elevated and stable plasma HCO3- concentration, negligible urinary HCO3- excretion, and normal or only slightly depressed GFR suggests that renal HCO3- reabsorption is enhanced. An increase in renal acidification appears to be a major mechanism by which metabolic alkalosis is maintained in chronic models of this disorder. Animals with experimental forms of chronic metabolic alkalosis display increased HCO3- reabsorption in both the proximal and the distal tubules. The increase in HCO3- absorption in the proximal tubule is due, at least in part, to an increase in the delivered load of HCO3-. The augmented HCO3- absorption in distal nephron segments appears to be due to a primary increase in H+ secretion that is independent of the HCO3- load delivered. Recent studies have demonstrated clearly that chronic hypokalemia up-regulates “colonic” H+,K+-ATPase mRNA and protein expression in the renal medulla, concomitant with an increase in H+ secretion in the outer medullary collecting duct (OMCD) and IMCD. Chronic hypokalemia dramatically enhances the abundance and function of the colonic isoform of the H+,K+-ATPase in the medullary collecting tubule. Therefore, up-regulation of the H+,K+-ATPase by hypokalemia may be a significant factor in the maintenance of chronic metabolic alkalosis. [13] [17] [18]

The maintenance of a high plasma HCO3- concentration by the kidney can be repaired by repletion of Cl-.[19] The mechanism by which Cl- repairs metabolic alkalosis could include normalization of the low GFR that was induced by ECF repletion. In addition, Cl- repletion might result in a decrease in proximal HCO3- reabsorption, an increase in HCO3- secretion by the distal nephron, or other less well-defined mechanisms that favor enhanced Cl-reabsorption in preference to HCO3- reabsorption.

Repletion of K+ alone (without Cl- repletion) only partially corrects metabolic alkalosis. Indeed, several experimental studies have shown that Cl- repletion can repair the alkalosis despite persisting K+ deficiency. Full correction of metabolic alkalosis by Cl- but not K+ supplementation does not necessarily prove that K+ deficiency has no role in maintaining the alkalosis. In fact, in most studies of repair of hyperbicarbonatemia by Cl- repletion alone (without K+ repletion), normalization of blood pH occurred only after significant volume expansion occurred. There is complete agreement that, with simultaneous repair of K+ and Cl- deficiencies in metabolic alkalosis, correction of the alteration in renal HCO3- reabsorption ensues as a result of normalization of GFR, which allows increased HCO3--delivery from the proximal tubule and, thus, excretion of the excess HCO3-.

In summary, the physiologic response by the kidney to a base load associated with volume expansion is to excrete the base. Base is retained, however, if there is enhanced distal HCO3- reabsorption as a result of K+ and/or Cl-deficiency.

The four cardinal acid-base disorders reviewed thus far, and the predicted compensatory responses and their limits, are summarized in Table 14-1 .


Suspicion that an acid-base disorder exists is usually based on clinical judgment or on the finding of an abnormal blood pH, Paco2, or HCO3- concentration. Obviously, acid-base disorders require careful analysis of laboratory parameters along with the clinical processes occurring in the patient as revealed in the history and physical examination.

TABLE 14-2   -- Systematic Method for Diagnosis of Simple and Mixed Acid-Base Disorders



Obtain arterial blood gas and electrolyte panel simultaneously.



Compare the [HCO3-] measured on the electrolyte panel with the calculated value from the arterial blood gas. Because the latter is obtained by the Henderson-Hasselbach equation, agreement of two values rules out laboratory error or error due to time discrepancy between the drawing of blood gas and electrolytes.



Calculate the anion gap (correct for low albumin if necessary).



Appreciate the four major categories of high anion gap acidoses:






Lactic acid acidosis



Renal failure acidosis



Toxins and poisons



Appreciate the two major causes of non-anion gap acidoses:



Gastrointestinal loss of HCO3- Renal loss of HCO3-



Estimate the compensatory response for either PCO2 or HCO3- (see Table 14-1 )



Compare the ΔAG and the ΔHCO3- (see text).



Compare the Δ[Cl-] and the ΔNa+ (see text).




Step 1: Obtain Arterial Blood Gas and Electrolyte Values Simultaneously

To avoid errors in diagnosis, ABGs should be measured simultaneously with the plasma electrolyte panel in all patients with component acid-base abnormalities. This is necessary because changes in plasma HCO3-, Na+, K+, and Cl- do not allow precise diagnosis of specific acid-base disturbances. When obtaining ABGs, care should be taken to obtain the arterial blood sample without excessive heparin.

Step 2: Verify Acid-Base Laboratory Values

A careful analysis of the blood gas indices (pH, Paco2) should begin with a check to determine whether the concomitantly measured plasma HCO3- (total CO2 concentration from the electrolyte panel) is consistent. In the determination of ABGs by the clinical laboratory, both pH and Paco2 are measured, but the reported HCO3- concentration is calculated from the Henderson-Hasselbalch equation (Equation 20) by the blood gas analyzer. The calculated value for HCO3- or (total CO2) reported with the blood gas panel should be compared with the measured HCO3- concentration (total CO2) obtained on the electrolyte panel. The two values should agree within ± 2 to 3 mEq/L. If these values do not agree, the clinician should suspect that the samples were not obtained simultaneously or that a laboratory error is present. The stepwise analysis of all available laboratory values to determine whether the patient has a mixed or simple acid-base disturbance is emphasized in the following sections.

On occasion, it may be necessary to compute the third value (pH, Pco2, or HCO3-) when only two are available. From the Henderson equation, derived previously in this chapter (Equation 21), several caveats of clinical significance are apparent. First, the normal H+ concentration in blood is 40 nm (conveniently remembered as the last two digits of the normal blood pH, 7.40), and the corresponding H+ concentration at a pH of 7.00 is 100 nm. Second, the H+concentration increases by about 10 nm for each decrease in the blood pH of 0.10 unit (in the range 7.20–7.50). An acidotic patient with a pH of 7.30 (a reduction of 0.10 pH unit, or an increase of 10 nm H+ concentration to 50 nm) and a Pco2 of 25 mm Hg would have a HCO3- concentration of 12 mEq/L:

(27)  001086

Although the Henderson equation and H+ concentration have been suggested as the most physiologic way to portray acid-base equilibrium, the logarithmic transformation of the Henderson equation to the familiar Henderson-Hasselbalch equation is used more commonly (see Equation 20). This equation is useful because acidity is measured in the clinical laboratory as pH rather than H+ concentration.

Implicit in Equations 20 and 21 is the concept that the final pH, or H+ concentration, is determined by the ratio of HCO3- and Paco2, not by the absolute amount of either. Thus, a normal concentration of HCO3- does not necessarily mean that the pH is normal, neither does a normal Paco2 denote a normal pH. Conversely, a normal pH does not imply that either HCO3- or Paco2 is normal.

Step 3: Define the Limits of Compensation to Distinguish Simple from Mixed Acid-Base Disorders

After verifying the blood acid-base values by either the Henderson equation (Equation 21) or the Henderson-Hasselbalch equation (Equation 20), one can define the precise acid-base disorder. If the HCO3- concentration is low and the Cl- concentration is high, either chronic respiratory alkalosis or hyperchloremic metabolic acidosis is present. ABG determination serves to differentiate the two conditions. Although both have a decreased Paco2, the pH is high with a primary respiratory disorder and low in a metabolic disorder. Chronic respiratory acidosis and metabolic alkalosis are both associated with high HCO3- and low Cl- concentration in plasma. Again, a pH measurement distinguishes the two conditions. In many clinical situations, however, a mixture of acid-base disorders may exist. Diagnosis of these disturbances requires additional information and a more complex analysis of data.

A convenient, but not always reliable, approach is an acid-base map, such as the one displayed in Figure 14-4 , which defines the 95% confidence limits of simple acid-base disorders. [1] [4] [20] If the arterial acid-base values fall within one of the shaded bands in Figure 14-4 , one may assume that a simple acid-base disturbance is present, and a tentative diagnostic category can be assigned. Values that fall outside the shaded areas imply, but do not prove, that a mixed disorder exists.



FIGURE 14-4  Acid-base nomogram (map). Shaded areas represent the 95% confidence limits of the normal respiratory and metabolic compensations for primary acid-base disturbances.  Data falling outside the shaded areas denote a mixed disorder if a laboratory error is not present (see text).


The two broad types of acid-base disorders are metabolic and respiratory. Metabolic acidosis and alkalosis are disorders characterized by primary disturbances in the concentration of HCO3- in plasma (numerator of Equation 20), whereas respiratory disorders involve primarily alteration of Paco2 (denominator of Equation 20). The most commonly encountered clinical disturbances are simple acid-base disorders, that is, one of the four cardinal acid-base disturbances—metabolic acidosis, metabolic alkalosis, respiratory acidosis, or respiratory alkalosis—occurring in a pure or simple form. More complicated clinical situations, especially in severely ill patients, may give rise to mixed acid-base disturbances.[20] The possible combinations of mixed acid-base disturbances are outlined in Table 14-2 . To appreciate and recognize a mixed acid-base disturbance, it is important to understand the physiologic compensatory responses that occur in the simple acid-base disorders. Primary respiratory disturbances (denominator of Equation 20) invoke secondary metabolic responses (numerator of Equation 20), and primary metabolic disturbances evoke a predictable respiratory response (see Table 14-1 ). To illustrate, metabolic acidosis as a result of gain of endogenous acids (e.g., lactic acid or ketoacidosis) lowers the concentration of HCO3- in ECF and, thus, extracellular pH. As a result of acidemia, the medullary chemoreceptors are stimulated and invoke an increase in ventilation. As a result of the hypocapnic response, the ratio of HCO3- to Paco2 and the subsequent pH are returned toward, but not completely to, normal. The degree of compensation expected in a simple form of metabolic acidosis can be predicted from the relationship depicted in Equation 26. Thus, a patient with metabolic acidosis and a plasma HCO3- concentration of 12 mEq/L would be expected to have a Paco2 between 24 and 28 mm Hg. Values of Paco2 below 24 or greater than 28 mm Hg define a mixed metabolic-respiratory disturbance (metabolic acidosis and respiratory alkalosis or metabolic acidosis and respiratory acidosis, respectively). Therefore, by definition, mixed acid-base disturbances exceed the physiologic limits of compensation. Similar considerations are examined for each type of acid-base disturbance as these disorders are discussed in detail separately. It should be emphasized that compensation is a predictable physiologic consequence of the primary disturbance and does not represent a secondary acidosis or alkalosis (see Fig. 14-4 and Table 14-1 ). As emphasized in the following sections, the recognition of mixed disturbances demands of the alert physician consideration of additional clinical disorders that may require immediate attention or additional therapy.

Clinical and Laboratory Parameters in Acid-Base Disorders

For correct diagnosis of a simple or mixed acid-base disorder, it is imperative that a careful history is obtained. Patients with pneumonia, sepsis, or cardiac failure frequently have respiratory alkalosis, and patients with chronic obstructive pulmonary disease or a sedative drug overdose often display a respiratory acidosis. The patient's drug history assumes importance because patients taking loop or thiazide diuretics may have a metabolic alkalosis and patients receiving acetazolamide frequently have a metabolic acidosis. Physical findings are often helpful as well. Tetany may occur with alkalemia, cyanosis with respiratory acidosis, and volume contraction with metabolic alkalosis. The initial suspicion can then be supported or ruled out by laboratory data. Knowledge of the limits of compensation may be helpful in this regard. For example, the plasma HCO3- concentration rarely falls below 12 to 15 mEq/L as a result of compensation for a respiratory alkalosis and rarely exceeds 45 mEq/L as a result of compensation for respiratory acidosis.[20]

The plasma K+ value is often useful but should be considered only in conjunction with the knowledge of the HCO3- concentration and blood pH. It is generally appreciated that the serum K+ value can be altered by primary acid-base disturbances as a result of shifts of K+ either into the extracellular compartment or into the intracellular compartment. Metabolic acidosis leads to hyperkalemia as a result of cellular shifts whereby H+ is exchanged for K+ or Na+. It has been reported that for each decrease in blood pH of 0.10 pH unit, the K+ concentration should increase by 0.6 mEq/L. Thus, a patient with a pH of 7.20 would be expected to have a plasma K+ value of 5.2 mEq/L. However, considerable variation in this relationship has been reported in several conditions, especially diabetic ketoacidosis (DKA) and lactic acidosis, which are often associated with K+ depletion. The lack of correlation between the degree of acidemia and the plasma K+ level is a result of several factors, including the nature and cellular permeability of the accompanying anion, the magnitude of the osmotic diuresis, the level of renal function, and the degree of catabolism. It is important to appreciate that the relationship between arterial blood pH and plasma K+ is complex and, therefore, often variable. Nevertheless, the failure of a patient with severe metabolic acidosis to exhibit hyperkalemia or, conversely, the failure of a patient with severe metabolic alkalosis to exhibit hypokalemia suggests a significant derangement of body K+ homeostasis. Furthermore, the combination of a low plasma K+ and elevated HCO3- suggests metabolic alkalosis, whereas the combination of an elevated plasma K+ and low HCO3- suggests metabolic acidosis.

It is helpful to compare the serum Cl- concentration with the Na+ concentration. The serum Na+ concentration changes only as a result of changes in hydration. The Cl- concentration changes for two reasons: (1) changes in hydration and (2) changes in acid-base balance. Thus, changes in Cl- not reflected by proportional changes in Na+ suggest the presence of an acid-base disorder. For example, consider a patient with a history of vomiting, volume depletion, a Cl- concentration of 85 mEq/L, and a Na+ concentration of 130 mEq/L. In this case, both Na+ and Cl- are reduced, but the reduction in Cl- is proportionally greater (15% versus 7%). A disproportionate decrease in Cl-suggests metabolic alkalosis or respiratory acidosis, and a disproportionate increase in Cl- suggests metabolic acidosis or respiratory alkalosis.

Step 4: Calculate the Anion Gap

All evaluations of acid-base disorders should include a simple calculation of the AG. The AG is calculated from the serum electrolytes and is defined as:

(28)  AG = Na+ - (Cl- + HCO3-) = 10 ± 2 mEq/L

The AG represents the unmeasured anions normally present in plasma and unaccounted for by the serum electrolytes that are measured on the electrolyte panel. The unmeasured anions normally present in serum include anionic proteins (principally albumin and, to lesser extent, α and β globulins), PO43-, SO42-, and organic anions. When acid anions, such as acetoacetate and lactate, are produced endogenously in excess and accumulate in ECF, the AG increases above the normal value. This is referred to as a high anion gap acidosis. [20] [21] If it is assumed that the serum albumin is within the normal range, for each milliequivalent per liter increase in the AG, there should be an equal decrease in the plasma HCO3- concentration. Serum protein at 1 g/dL has a negative charge equivalence of approximately 1.7 to 2.4 mEq/L.[22] The contribution of other unmeasured anions includes PO43- (2 mEq/L), SO42-(1 mEq/L), and lactate and other organic anions (5 mEq/L).

An increase in the AG may be due to a decrease in unmeasured cations or an increase in unmeasured anions. Combined severe hypocalcemia and hypomagnesemia represent a decrease in the contribution of unmeasured cation (Table 14-3 ). In addition, the AG may increase secondary to an increase in anionic albumin, as a consequence of either an increased albumin concentration or alkalemia. [20] [21] The increased AG in severe alkalemia can be explained in part by the effect of alkaline pH on the electrical charge of albumin.

TABLE 14-3   -- The Anion Gap

Anion gap = Na+ - (Cl- + HCO3-) = 9 ± 3 mEq/L



Decreased anion gap



Increased cations (not Na+)



↑ Ca2+, Mg2+



↑ Li+



↑ IgG



Decreased anions (not Cl- or HCO3-)



↓ Albumin concentration hypoalbuminemia)[*]






Laboratory error









Increased anion gap



Increased anions (not Cl- or HCO3-)



↑ Albumin concentration






↑ Inorganic anions









↑ Organic anions















↑ Exogenously supplied anions












Ethylene glycol



Propylene glycol









Pyroglutamic acidosis



↑ Unidentified anions









Hyperosmolar, nonketotic states



Myoglobinuric acute renal failure



Decreased cations (not Na+)



↓ Ca2+, Mg2+



For each decline in albumin by 1 g/dL from normal (4.5 g/dL), anion gap decreases by 2.5 mEq/L.


A decrease in the AG can be generated by an increase in unmeasured cations or a decrease in the unmeasured anions (see Table 14-3 ). A decrease in the AG can result from (1) an increase in unmeasured cations (Ca2+, Mg2+, K+) or (2) the addition to the blood of abnormal cations, such as Li+ (Li+ intoxication) or cationic immunoglobulins (immunoglobulin G as in plasma cell dyscrasias). Because albumin is the major unmeasured anion, the AG will also decrease if the quantity of albumin is low (e.g., nephrotic syndrome, protein malnutrition).[22] In general, each decline in the serum albumin by 1 g/dL from the normal value of 4.5 g/dL decreases the AG by 2.5 mEq/L. Therefore, when hypoalbuminemia exists, it is possible to underestimate the AG and even miss an increased AG unless correction for the low albumin and its effect on the AG is taken into account. For example, in a patient with an albumin of 1.5 and an uncorrected AG of 10 mEq/L, the corrected AG would be 17.5 mEq/L.

Laboratory errors can create a falsely low AG. Hyperviscosity and hyperlipidemia lead to an underestimation of the true Na+ concentration, and bromide (Br-) intoxication causes an overestimation of the true Cl- concentration.[20]

In the presence of a normal serum albumin, elevation of unmeasured anions is usually due to addition to the blood of non-Cl--containing acids. Thus, in most clinical circumstances, a high AG indicates that a metabolic acidosis is present. The anions accompanying such acids include inorganic (PO43-, SO42-), organic (keto acids, lactate, uremic organic anions), exogenous (salicylate or ingested toxins with organic acid production), or unidentified anions.[20]When these non-Cl--containing acids are added to blood in excess of the rate of removal, HCO3- is titrated (consumed), and the accompanying anion is retained to balance the preexisting cationic (Na+) charge:

(29)  H+anion- + NaHCO3 ⇔ H2O + CO2 + Na+ anion-

The preexisting Cl- concentration is unchanged when the new acid anion is added to the blood. Therefore, the high AG acidoses exhibit normochloremia as well as a high gap. If the kidney does not excrete the anion, the magnitude of the decrement in HCO3- concentration will match the increment in the AG. If the retained anion can be metabolized to HCO3- directly or indirectly (e.g., ketones or lactate, after successful treatment), normal acid-base balance is restored as the AG returns toward the normal value. Alternatively, if the anion can be excreted, ECF contraction occurs, leading to renal sodium chloride retention. Cl- replaces the excreted anion, and hyperchloremic acidosis emerges as the anion is excreted and the AG disappears.

In summary, after the titration of HCO3-, the ability of the kidney to excrete the anion of an administered acid determines the type of acidosis that develops. If the anion is filtered and is nonreabsorbable (e.g., SO42-) ECF contraction, Cl- retention, and hyperchloremic acidosis with a normal AG develop (non-AG acidosis). Conversely, if the anion is poorly filtered (e.g., uremic anions) or is produced endogenously, filtered, and reabsorbed (e.g., lactate and other organic anions), no change in Cl- concentration occurs. The retained anion replaces the HCO3- lost when titrated by acid, creating a high-AG acidosis.

Superimposition of a High Anion Gap Acidosis on a Preexisting Acid-Base Disorder

By definition, a high AG acidosis has two identifying features: a low HCO3- concentration and an elevated AG. This means, therefore, that the elevated AG will remain evident even if another disorder coincides to modify the HCO3- concentration independently. Simultaneous metabolic acidosis of the high AG variety plus either metabolic alkalosis or chronic respiratory acidosis illustrates such a situation. The HCO3- concentration may be normal or even high in such a setting. However, the AG is normal, and the Cl- concentration is relatively depressed. Consider a patient with chronic obstructive pulmonary disease with a compensated respiratory acidosis (Paco2 of 65 mm Hg and HCO3- concentration of 40 mEq/L) in whom acute bronchopneumonia and respiratory decompensation develop. If this patient presents with an HCO3- concentration of 24 mEq/L, Na+ of 145 mEq/L, K+ of 4.8 mEq/L, and Cl-of 96 mEq/L, it would be incorrect to assume that this “normal” HCO3- concentration represents improvement in acid-base status toward normal. Indeed, the arterial pH would probably be low (≈7.1), as a result of a more serious degree of hypercapnia than observed previously (e.g., if the Pco2 increased from 65 to 80 mm Hg as a result of pneumonia). Even without blood gas measurements, prompt recognition that the AG was elevated to 25 mEq/L should suggest that a life-threatening lactic acidosis was superimposed on a preexisting chronic respiratory acidosis, necessitating immediate therapy.

Similarly, a normal arterial HCO3- concentration, Paco2, and pH do not ensure the absence of an acid-base disturbance. For example, an alcoholic who has been vomiting may develop a metabolic alkalosis with a pH of 7.55; HCO3-concentration of 40 mEq/L; Pco2 of 48 mm Hg; and Na+ of 135 mEq/L, Cl- of 80 mEq/L, and K+ of 2.8 mEq/L. If such a patient were then to develop a superimposed alcoholic ketoacidosis with a β-hydroxybutyrate concentration of 15 μM; the arterial pH would fall to 7.40, HCO3- concentration to 25 mEq/L, and Pco2 to 40 mm Hg. Although the blood gas values are normal, the AG (assuming no change in Na+, or Cl-) is elevated (25 mEq/L), indicating the existence of a mixed metabolic acid-base disorder (mixed metabolic alkalosis and metabolic acidosis). The combination of metabolic acidosis and metabolic alkalosis is not uncommon and is most easily recognized when the AG is elevated but the HCO3- concentration and pH are near normal (DAG > DHCO3-).

Mixed Acid-Base Disorders

Mixed acid-base disorders—defined as independently co-existing disorders, not merely compensatory responses—are often seen in patients in critical care units and can lead to dangerous extremes of pH. A patient with DKA (metabolic acidosis) may develop an independent respiratory problem, leading to respiratory acidosis or alkalosis. Patients with underlying pulmonary disease may not respond to metabolic acidosis with an appropriate ventilatory response because of insufficient respiratory reserve. Such imposition of respiratory acidosis on metabolic acidosis can lead to severe acidemia and a poor outcome. When metabolic acidosis and metabolic alkalosis coexist in the same patient, the pH may be normal or near normal. When the pH is normal, an elevated AG denotes the presence of a metabolic acidosis. A discrepancy in the ΔAG (prevailing minus normal AG) and the ΔHCO3- (normal minus prevailing HCO3-) indicates the presence of a mixed high gap acidosis—metabolic alkalosis (see example later). A diabetic patient with ketoacidosis may have renal dysfunction resulting in simultaneous metabolic acidosis. Patients who have ingested an overdose of drug combinations such as sedatives and salicylates may have mixed disturbances as a result of the acid-base response to the individual drugs (metabolic acidosis mixed with respiratory acidosis or respiratory alkalosis, respectively). Even more complex are triple acid-base disturbances. For example, patients with metabolic acidosis due to alcoholic ketoacidosis may develop metabolic alkalosis owing to vomiting and superimposed respiratory alkalosis owing to the hyperventilation of hepatic dysfunction or alcohol withdrawal. Conversely, when hyperchloremic acidosis and metabolic alkalosis occur concomitantly, the increase in Cl- is out of proportion to the change in HCO3- concentration (DCl- > ΔHCO3-).[20]

In summary, an AG exceeding that expected for a patient's albumin concentration and blood pH denotes the existence of either a simple high AG metabolic acidosis or a complex acid-base disorder in which an organic acidosis is superimposed on another acid-base disorder.

Step 5: Recognize Conditions Causing Acid-Base Abnormalities with High or Normal Anion Gap

Appreciation that the AG is elevated requires knowledge of the four causes of a high AG acidosis: (1) ketoacidosis, (2) lactic acid acidosis, (3) renal failure acidosis, and (4) toxin-induced metabolic acidosis ( Table 14-4 ). Accordingly, if the AG is normal in the face of metabolic acidosis, a hyperchloremic or non-AG acidosis exists. The specific causes of hyperchloremic acidosis that must be appreciated are outlined in a following section. Table 14-4displays the directional changes in pH, Pco2, and HCO3- for the four simple acid-base disorders. With this stepwise approach, in the next sections, the specific causes of the major types of acid-base disorders are reviewed in detail.

TABLE 14-4   -- Clinical Causes of High Anion Gap and Normal Anion Gap Acidosis



High anion gap acidosis






Diabetic ketoacidosis (acetoacetate)



Alcoholic ketoacidosis (β-hydroxybutyrate)



Starvation ketoacidosis



Lactic acid acidosis



L-Lactic acid acidosis (types A and B)



D-Lactic acid acidosis






Ethylene glycol



Methyl alcohol






Propylene glycol



Pyroglutamic acidosis



Normal anion gap acidosis



Gastrointestinal loss of HCO3- (negative urine anion gap)






Fistulae external



Renal loss of HCO3- or failure to excrete NH4+ (positive urine anion gap = low net acid excretion)



Proximal renal tubular acidosis (RTA)



Acetazolamide (or other carbonic anlydrase inhibitor)



Classic distal renal tubular acidosis (low serum K+)



Generalized distal renal tubular defect (high serum K+)






NH4Cl ingestion



Sulfur ingestion



Dilutional acidosis





Respiratory Acidosis

Respiratory acidosis occurs as the result of severe pulmonary disease, respiratory muscle fatigue, or depression in ventilatory control. The increase in Paco2 owing to reduced alveolar ventilation is the primary abnormality leading to acidemia. In acute respiratory acidosis, there is an immediate compensatory elevation (due to cellular buffering mechanisms) in HCO3-, which increases 1 mEq/L for every 10 mm Hg increase in Paco2. In chronic respiratory acidosis (>24 hr), renal adaption is achieved and the HCO3- increases by 4 mEq/L for every 10 mm Hg increase in Paco2. The serum bicarbonate will usually not increase above 38 mEq/L, however.

The clinical features of respiratory acidosis vary according to severity, duration, the underlying disease, and whether there is accompanying hypoxemia. A rapid increase in Paco2 may result in anxiety, dyspnea, confusion, psychosis, and hallucinations and may progress to coma. Lesser degrees of dysfunction in chronic hypercapnia include sleep disturbances, loss of memory, daytime somnolence, and personality changes. Coordination may be impaired, and motor disturbances such as tremor, myoclonic jerks, and asterixis may develop. The sensitivity of the cerebral vasculature to the vasodilating effects of CO2 can cause headaches and other signs that mimic increased intracranial pressure, such as papilledema, abnormal reflexes, and focal muscle weakness.

The causes of respiratory acidosis are displayed in Table 14-5 (right column). A reduction in ventilatory drive from depression of the respiratory center by a variety of drugs, injury, or disease can produce respiratory acidosis. Acutely, this may occur with general anesthetics, sedatives, β-adrenergic blockers, and head trauma. Chronic causes of respiratory center depression include sedatives, alcohol, intracranial tumors, and the syndromes of sleep-disordered breathing, including the primary alveolar and obesity-hypoventilation syndromes. Neuromuscular disorders involving abnormalities or disease in the motor neurons, neuromuscular junction, and skeletal muscle can cause hypoventilation. Although a number of diseases should be considered in the differential diagnosis, drugs and electrolyte disorders should always be ruled out. Mechanical ventilation when not properly adjusted and supervised may result in respiratory acidosis. This occurs if carbon dioxide production suddenly rises (because of fever, agitation, sepsis, or overfeeding) or if alveolar ventilation falls because of worsening pulmonary function. High levels of positive end-expiratory pressure in the presence of reduced cardiac output may cause hypercapnia as a result of large increases in alveolar dead space. Permissive hypercapnia has been utilized in the critical care setting with increasing frequency with the rationale of mitigating the barotrauma and volutrauma associated with high airways pressure and peak airways pressure in mechanically ventilated patients with respiratory distress syndrome. [23] [24]Acute hypercapnia of any cause can lead to severe acidemia, neurologic dysfunction, and death. However, when carbon dioxide levels are allowed to increase gradually, the resulting acidosis is less severe, and the elevation in arterial Pco2 is tolerated more readily. Although hypercapnia is not the goal of this approach, but secondary to the attempt to limit airway pressures, the arterial pH will decline, and the degree of acidemia may be called to the attention of the nephrologist intensivist. Furthermore, the magnitude of the acidemia associated with permissive hypercapnia may be augmented if superimposed on metabolic acidosis, such as lactic acid acidosis. This combination is not uncommon in the setting of the critical care unit. Bicarbonate therapy may be indicated with mixed metabolic acidosis-respiratory acidosis, but the goal of therapy with alkali is to not raise the bicarbonate and pH to normal. With low tidal volume ventilation, a reasonable therapeutic target for arterial pH is approximately 7.30.[23] Moreover, with hypercapnia in the range of 60 mm Hg, a larger amount of bicarbonate will be necessary to achieve this goal. Bicarbonate administration will further increase the Pco2, especially in patients on fixed rates of ventilation, and add to the magnitude of the hypercapnia. Use of a continuous bicarbonate infusion in this setting should be avoided if possible.

TABLE 14-5   -- Respiratory Acid-Base Disorders






Central nervous system stimulation






Anxiety, psychosis






Cerebrovascular accident



Meningitis, encephalitis









Hypoxemia or tissue hypoxia



High altitude, ↓ PaCO2



Pneumonia, pulmonary edema






Severe anemia



Drugs or hormones



Pregnancy, progesterone









Stimulation of chest receptors






Flail chest



Cardiac failure



Pulmonary embolism









Hepatic failure



Mechanical hyperventilation



Heat exposure



Recovery from metabolic acidosis









Drugs (anesthetics, morphine, sedatives)





















Emphysema/chronic obstructive



pulmonary disease









Adult respiratory distress syndrome






Mechanical ventilation






Permissive hypercapnia















Muscular dystrophies



Multiple sclerosis













Disease and obstruction of the airways, when severe or long-standing, causes respiratory acidosis. Acute hypercapnia follows sudden occlusion of the upper airway or the more generalized bronchospasm that occurs with severe asthma, anaphylaxis, and inhalational burn or toxin injury. Chronic hypercapnia and respiratory acidosis occur in end-stage obstructive lung disease.[3]

Restrictive disorders involving both the chest wall and the lungs can cause acute and chronic hypercapnia. Rapidly progressing restrictive processes in the lung can lead to respiratory acidosis because the high cost of breathing causes ventilatory muscle fatigue. Intrapulmonary and extrapulmonary restrictive defects present as chronic respiratory acidosis in their most advanced stages.

The diagnosis of respiratory acidosis requires, by definition, the measurement of arterial Paco2 and pH. Detailed history and physical examination often provide important diagnostic clues to the nature and duration of the acidosis. When a diagnosis of respiratory acidosis is made, its cause should be investigated. Pulmonary function studies, including spirometry, diffusing capacity for carbon monoxide, lung volumes, and arterial Paco2 and oxygen saturation usually provide adequate assessment of whether respiratory acidosis is secondary to lung disease. Workup for nonpulmonary causes should include a detailed drug history, measurement of hematocrit, and assessment of upper airway, chest wall, pleura, and neuromuscular function.[3]

The treatment of respiratory acidosis depends on its severity and rate of onset. Acute respiratory acidosis can be life-threatening, and measures to reverse the underlying cause should be simultaneous with restoration of adequate alveolar ventilation to relieve severe hypoxemia and acidemia. Temporarily, this may necessitate tracheal intubation and assisted mechanical ventilation. Oxygen should be carefully titrated in patients with severe chronic obstructive pulmonary disease and chronic CO2 retention who are breathing spontaneously. When oxygen is used injudiciously, these patients may experience progression of the respiratory acidosis. Aggressive and rapid correction of hypercapnia should be avoided because the falling Paco2 may provoke the same complications noted with acute respiratory alkalosis (i.e., cardiac arrhythmias, reduced cerebral perfusion, and seizures). It is advisable to lower the Paco2 gradually in chronic respiratory acidosis, aiming to restore the Paco2 to baseline levels while at the same time providing sufficient chloride and potassium to enhance the renal excretion of bicarbonate.[3]

Chronic respiratory acidosis is frequently difficult to correct, but general measures aimed at maximizing lung function with cessation of smoking, use of oxygen, bronchodilators, corticosteroids, diuretics, and physiotherapy can help some patients and can forestall further deterioration. The use of respiratory stimulants may prove useful in selected cases, particularly if the patient appears to have hypercapnia out of proportion to his or her level of lung function.

Respiratory Alkalosis

Alveolar hyperventilation decreases Paco2 and increases the HCO3-/Paco2 ratio, thus increasing pH (alkalemia). Nonbicarbonate cellular buffers respond by consuming HCO3-. Hypocapnia develops whenever a sufficiently strong ventilatory stimulus causes CO2 output in the lungs to exceed its metabolic production by tissues. Plasma pH and HCO3- concentration appear to vary proportionately with Paco2 over a range from 40 to 15 mm Hg. The relationship between arterial hydrogen ion concentration and Paco2 is about 0.7 nmol/L/mm Hg (or 0.01 pH unit/mm Hg) and that for plasma [HCO3-] is 0.2 mEq/L/mm Hg, or the [HCO3-] will decrease ≈2 mEq/L for each 10 mm Hg.[2]

Beyond 2 to 6 hours, sustained hypocapnia is further compensated by a decrease in renal ammonium and titrable acid excretion and a reduction in filtered HCO3- reabsorption. The full expression of renal adaptation may take several days and depends on a normal volume status and renal function. The kidneys appear to respond directly to the lowered Paco2 rather than the alkalemia per se. A 1 mm Hg fall in Paco2 causes a 0.4 to 0.5 mEq/L drop in HCO3- and a 0.3 nmol/L fall (or 0.003 unit rise in pH) in hydrogen ion concentration, or the [HCO3-] will decrease 4 mEq/L for each 10 mm Hg decrease in Paco2.[2]

The effects of respiratory alkalosis vary according to duration and severity but, in general, are primarily those of the underlying disease. A rapid decline in Paco2 may cause dizziness, mental confusion, and seizures, even in the absence of hypoxemia, as a consequence of reduced cerebral blood flow. The cardiovascular effects of acute hypocapnia in the awake human are generally minimal, but in the anesthetized or mechanically ventilated patient, cardiac output and blood pressure may fall because of the depressant effects of anesthesia and positive-pressure ventilation on heart rate, systemic resistance, and venous return. Cardiac rhythm disturbances may occur in patients with coronary artery disease as a result of changes in oxygen unloading by blood from a left shift in the hemoglobin-oxygen dissociation curve (Bohr effect). Acute respiratory alkalosis causes minor intracellular shifts of sodium, potassium, and phosphate and reduces serum-free calcium by increasing the protein-bound fraction. Hypocapnia-induced hypokalemia is usually minor.[2]

Respiratory alkalosis is the most common acid-base disturbance encountered in critically ill patients and, when severe, portends a poor prognosis. Many cardiopulmonary disorders manifest respiratory alkalosis in their early to intermediate stages. Hyperventilation usually results in hypocapnia. The finding of normocapnia and hypoxemia may herald the onset of rapid respiratory failure and should prompt an assessment to determine whether the patient is becoming fatigued. Respiratory alkalosis is a common occurrence during mechanical ventilation.

The causes of respiratory alkalosis are summarized in Table 14-5 (left column). The hyperventilation syndrome may mimic a number of serious conditions and be disabling. Paresthesias, circumoral numbness, chest wall tightness or pain, dizziness, inability to take an adequate breath, and rarely, tetany may be themselves sufficiently stressful to perpetuate a vicious circle. ABG analysis demonstrates an acute or chronic respiratory alkalosis, often with hypocapnia in the range of 15 to 30 mm Hg and no hypoxemia. Central nervous system diseases or injury can produce several patterns of hyperventilation with sustained arterial Paco2 levels of 20 to 30 mm Hg. Conditions such as hyperthyroidism, high caloric loads, and exercise raise the basal metabolic rate, but usually, ventilation rises in proportion so that ABGs are unchanged and respiratory alkalosis does not develop. Salicylates, the most common cause of drug-induced respiratory alkalosis, stimulate the medullary chemoreceptor directly. The methylxanthine drugs, theophylline and aminophylline, stimulate ventilation and increase the ventilatory response to carbon dioxide. High progesterone levels increase ventilation and decrease the arterial Paco2 by as much as 5 to 10 mm Hg. Thus, chronic respiratory alkalosis is an expected feature of pregnancy. Respiratory alkalosis is a prominent feature in liver failure, and its severity correlates well with the degree of hepatic insufficiency and mortality. Respiratory alkalosis is common in patients with gram-negative septicemia, and it is often an early finding, before fever, hypoxemia, and hypotension develop. It is presumed that some bacterial product or toxin acts as a respiratory center stimulant, but the precise mechanism remains unknown.

The diagnosis of respiratory alkalosis requires measurement of arterial pH and Paco2 (higher and lower than normal, respectively). The plasma potassium concentration is often reduced, and the serum chloride concentration increased. In the acute phase, respiratory alkalosis is not associated with increased renal bicarbonate excretion, but within hours, net acid excretion is reduced. In general, the bicarbonate concentration falls by 2.0 mEq/L for each 10 mm Hg decrease in Paco2. Chronic hypocapnia reduces the serum bicarbonate concentration by 5.0 mEq/L for each 10 mm Hg decrease in Paco2. It is unusual to observe a plasma bicarbonate concentration below 12 mEq/L as a result of a pure respiratory alkalosis.

When a diagnosis of hyperventilation or respiratory alkalosis is made, its cause should be investigated. The diagnosis of hyperventilation syndrome is made by exclusion. In difficult cases, it may be important to rule out other conditions such as pulmonary embolism, coronary artery disease, and hyperthyroidism.

The treatment of respiratory alkalosis is primarily directed toward alleviation of the underlying disorder. Because respiratory alkalosis is rarely life-threatening, direct measures to correct it will be unsuccessful if the stimulus remains unchecked. If respiratory alkalosis complicates ventilator management, changes in dead space, tidal volume, and frequency can minimize the hypocapnia. Patients with the hyperventilation syndrome may benefit from reassurance, rebreathing from a paper bag during symptomatic attacks, and attention to underlying psychologic stress. Antidepressants and sedatives are not recommended, although in a few patients, β-adrenergic blockers may help to ameliorate distressing peripheral manifestations of the hyperadrenergic state.


Metabolic Acidosis

Metabolic acidosis occurs as a result of a marked increase in endogenous production of acid (such as L-lactic acid and keto acids), loss of HCO3- or potential HCO3- salts (diarrhea or renal tubular acidosis [RTA]), or progressive accumulation of endogenous acids, when excretion is impaired because of renal insufficiency.[19]

The AG, when corrected for the prevailing albumin concentration (Equation 28), [20] [21] serves a useful role in the initial differentiation of the metabolic acidoses and should always be calculated. A metabolic acidosis with a normal AG (hyperchloremic, or non-AG acidosis) suggests that HCO3- has been effectively replaced by Cl-. Thus, the AG will not change.

In contrast, metabolic acidosis with a high AG (see Table 14-3 ) indicates addition of an acid other than hydrochloric acid or its equivalent to the ECF. If the attendant non-Cl- acid anion cannot be readily excreted and is retained after HCO3- titration, the anion replaces titrated HCO3- without disturbing the Cl- concentration (Equation 29). Hence, the acidosis is normochloremic and the AG increases. The relationship between the rate of addition to the blood of a non-Cl--containing acid, and the rate of excretion of the accompanying anion with secondary Cl- retention determines whether the resultant metabolic acidosis is expressed as a high AG or hyperchloremic variety. [19] [20]

Hyperchloremic (Normal Anion Gap) Metabolic Acidoses

The diverse clinical disorders that may result in a hyperchloremic metabolic acidosis are outlined in Table 14-6 . Because a reduced plasma HCO3- and elevated Cl- concentration may also occur in chronic respiratory alkalosis, it is important to confirm the acidemia by measuring arterial pH. Hyperchloremic metabolic acidosis occurs most often as a result of loss of HCO3- from the gastrointestinal tract or as a result of a renal acidification defect. The majority of disorders in this category can be reduced to two major causes: (1) loss of bicarbonate from the gastrointestinal tract (diarrhea) or from the kidney (proximal RTA) or (2) inappropriately low renal acid excretion (classic distal RTA [cDRTA], or renal failure). Hypokalemia may accompany both gastrointestinal loss of HCO3- and proximal and cDRTA. Therefore, the major challenge in distinguishing these causes is to be able to define whether the response of renal tubular function to the prevailing acidosis is appropriate (gastrointestinal origin) or inappropriate (renal origin).

TABLE 14-6   -- Differential Diagnosis of Hyperchloremic Metabolic Acidosis



Gastrointestinal bicarbonate loss






External pancreatic or small bowel drainage



Uterosigmoidostomy, jejunal loop






Calcium chloride (acidifying agent)



Magnesium sulfate (diarrhea)



Cholestyramine (bile acid diarrhea)



Renal acidosis






Proximal RTA (type II)



Distal (classic) RTA (type I)






Generalized distal nephron dysfunction (type IV RTA)



Mineralocorticoid deficiency



Mineralocorticoid resistance (PHA I—autosomal dominant)



Voltage defects (PHA I—autosomal recessive)






↓ Na+ delivery to distal nephron



Tubulointerstitial disease



Drug-induced hyperkalemia



Potassium-sparing diuretics (amiloride, triamterene, spironolactone)









ACE inhibitors and ARBs






Cyclosporine, tacrolimus






Early renal insufficiency






Acid loads (ammonium chloride, hyperalimentation)



Loss of potential bicarbonate: ketosis with ketone excretion



Dilution acidosis (rapid saline administration)






Cation exchange resins


ACE, angiotensin-converting enzyme; ARBs, angiotensin II receptor blockers; NSAIDs, nonsteroidal anti-inflammatory drugs; PHA, pseudohypoaldosteronism.




Diarrhea results in the loss of large quantities of HCO3- and HCO3- decomposed by reaction with organic acids. Because diarrheal stools contain a higher concentration of HCO3- and decomposed HCO3- than plasma, volume depletion and metabolic acidosis develop. Hypokalemia exists because large quantities of K+ are lost from stool and because volume depletion causes elaboration of renin and aldosterone, enhancing renal K+ secretion. Instead of an acid urine pH as might be logically anticipated with chronic diarrhea, a pH of 6.0 or more may be found. This occurs because chronic metabolic acidosis and hypokalemia increase renal NH4+ synthesis and excretion, thus providing more urinary buffer, accommodating an increase in urine pH. Therefore, the urine pH may not be less than 5.5. Nevertheless, metabolic acidosis caused by gastrointestinal losses with a high urine pH can be differentiated from RTA. Because urinary NH4+ excretion is typically low in RTA and high in patients with diarrhea, [5] [6] [25] the level of urinary NH4+ excretion (not usually measured by clinical laboratories) in metabolic acidosis can be assessed indirectly[6] by calculating the urine anion gap (UAG):

(30)  UAG = [Na+ + K+]u - [Cl-]u

where u denotes the urine concentration of these electrolytes. The rationale for using the UAG as a surrogate for ammonium excretion is that, in chronic metabolic acidosis, ammonium excretion should be elevated if renal tubular function is intact. Because ammonium is a cation, it should balance part of the negative charge of chloride in the previous expression. Therefore, the UAG should become progressively negative as the rate of ammonium excretion increases in response to acidosis or to acid loading. [6] [19] Because NH4+ can be assumed to be present if the sum of the major cations (Na+ + K+) is less than the sum of major anions in urine, a negative UAG (usually in the range of -20 to -50 mEq/L) provides evidence that sufficient NH4+ is present in the urine, as might obtain with an extrarenal origin of the hyperchloremic acidosis. Conversely, urine estimated to contain little or no NH4+ has more Na+ + K+ than Cl- (UAG is positive) [6] [19] [25] and would suggest a renal mechanism for the hyperchloremic acidosis, such as in cDRTA (with hypokalemia) or hypoaldosteronism with hyperkalemia. Note that this qualitative test is useful only in the differential diagnosis of a hyperchloremic metabolic acidosis. If the patient has ketonuria or drug anions in large quantity (penicillins or aspirin) in the urine, the test is not reliable.

In this situation, the urinary ammonium (UNH4+) may be estimated additionally from the measured urine osmolality (Uosm), urine [Na+ + K+], which will take into account the salts of *β-hydroxybutyrate and other keto acids, and urine urea and glucose (all expressed in mmol/L):

(31)  UNH4+ = 0.5 (Uosm - [2 (Na+ + K+)u + ureau + glucoseu]

Urinary ammonium concentrations of 75 mEq/L or more would be anticipated if renal tubular function is intact and the kidney is responding to the prevailing metabolic acidosis by increasing ammonium production and excretion. Conversely, values below 25 mEq/L denote inappropriately low urinary ammonium concentrations.

In addition to the UAG, the fractional excretion of Na+ may be helpful and would be expected to be low (<1%–2%) in patients with HCO3- loss from the gastrointestinal tract but usually exceeds 2% to 3% in RTA. [6] [25]

Gastrointestinal HCO3- loss, as well as proximal RTA (type 2) and cDRTA (type 1), results in ECF contraction and stimulation of the renin-aldosterone system, leading typically to hypokalemia. The serum K+ concentration, therefore, serves to distinguish these disorders with a low K+ from either generalized distal nephron dysfunction (e.g., type 4 RTA), in which the renin-aldosterone-distal nephron axis is abnormal and hyperkalemia exists, and the acidosis of glomerular insufficiency, in which normokalemia is the rule.

In addition to gastrointestinal tract HCO3- loss, external loss of pancreatic and biliary secretions can cause a hyperchloremic acidosis. Cholestyramine, calcium chloride, and magnesium sulfate ingestion can also result in a hyperchloremic metabolic acidosis (see Table 14-6 ), especially in patients with renal insufficiency. Coexistent L-lactic acidosis is common in severe diarrheal illnesses but will raise the AG.

Severe hyperchloremic metabolic acidosis with hypokalemia may occur on occasion in patients with ureteral diversion procedures. Because the ileum and the colon are both endowed with Cl-/HCO3- exchangers, when the Cl- from the urine enters the gut, the HCO3- concentration increases as a result of the exchange process.[19] Moreover, K+ secretion is stimulated, which, together with HCO3- loss, can result in a hyperchloremic hypokalemic metabolic acidosis. This defect is particularly common in patients with ureterosigmoidostomies and is more common with this type of diversion because of the prolonged transit time of urine caused by stasis in the colonic segment.

Dilutional acidosis, acidosis caused by exogenous acid loads and the posthypocapnic state, can usually be excluded by history. When isotonic saline is infused rapidly, particularly in patients with temporary or permanent renal functional impairment, the serum HCO3- declines reciprocally in relation to Cl-.[19] Addition of acid or acid equivalents to blood results in metabolic acidosis. Examples include infusion of arginine or lysine hydrochloride during parenteral hyperalimentation or ingestion of ammonium chloride. A similar situation may arise from endogenous addition of keto acids during recovery from ketoacidosis when the sodium salts of ketones may be excreted by the kidneys and lost as potential HCO3-.[26]

This sequence may also occur in mild, chronic ketoacidosis in which renal ketone excretion is high and may be accentuated by a defect in tubule ketone reabsorption.[27] The plasma ketone concentration is maintained at low levels. Continued titration of HCO3- with Cl- retention and excretion of potential base (ketones) may result in hyperchloremic acidosis. Metabolism of sulfur to sulfuric acid and excretion of SO42- with Cl- retention represents another example of a hyperchloremic acidosis resulting from increased acid loading and anion excretion.[26]

Loss of functioning renal parenchyma in progressive renal disease is known to be associated with metabolic acidosis. Typically, the acidosis is hyperchloremic when the GFR is between 20 and 50 mL/min but may convert to the typical high AG acidosis of uremia with more advanced renal failure, that is, when the GFR is less than 20.[28] It is generally assumed that such progression is observed more commonly in patients with tubulointerstitial forms of renal disease, but hyperchloremic metabolic acidosis can occur with advanced glomerular disease. The principal defect in acidification of advanced renal failure is that ammoniagenesis is reduced in proportion to the loss of functional renal mass. In addition, medullary NH4+ accumulation and trapping in the outer medullary collecting tubule may be impaired.[28] Because of adaptive increases in K+ secretion by the collecting duct and colon, the acidosis of chronic renal insufficiency is typically normokalemic.[28] Hyperchloremic metabolic acidosis associated with hyperkalemia is almost always associated with a generalized dysfunction of the distal nephron. [6] [25]However, K+-sparing diuretics, triamterene, pentamidine, cyclosporine, tacrolimus, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), β-blockers, and heparin may mimic or cause this disorder, resulting in hyperkalemia and a hyperchloremic acidosis. [6] [25] Such drugs should be discontinued before the diagnosis of a nonreversible, generalized defect of the distal nephron is considered. Drug-induced hyperkalemic metabolic acidosis almost always occurs in the face of renal functional impairment of some degree and is most common in patients prone to develop hyporeninemic hypoaldosteronism (e.g., diabetic nephropathy).

Disorders of Impaired Renal Bicarbonate Reclamation: Proximal Renal Tubular Acidosis


Because the first phase of acidification by the nephron involves reabsorption of the filtered HCO3-, 80% of the filtered HCO3- is normally returned to the blood by the proximal convoluted tubule.[5]

If the capacity of the proximal tubule is reduced, less of the filtered HCO3- is reabsorbed in this segment and more is delivered to the more distal segments. This increased HCO3- delivery overwhelms the limited capacity for bicarbonate reabsorption by the distal nephron, and bicarbonaturia ensues, net acid excretion ceases, and metabolic acidosis follows. Enhanced Cl- reabsorption, stimulated by ECF volume contraction, results in a hyperchloremic form of chronic metabolic acidosis. With progressive metabolic acidosis, the filtered HCO3- load declines progressively. As the plasma HCO3- concentration decreases, the absolute amount of HCO3- entering the distal nephron eventually reaches the low level approximating the distal HCO3- delivery in normal individuals (at the normal threshold). At this point, the quantity of HCO3- entering the distal nephron can be reabsorbed completely ( Fig. 14-5 ), and the urine pH declines. A new steady state in which acid excretion equals acid production then prevails. The serum HCO3- concentration usually reaches a nadir of 15 to 18 mEq/L, so that systemic acidosis is not progressive. Therefore, in proximal RTA, in the steady state, the serum HCO3- is low and the urine pH is acid (<5.5). With bicarbonate administration, the amount of bicarbonate in the urine increases FEHCO3- 10% to 15% and the urine pH becomes alkaline.[25]



FIGURE 14-5  Schematic representation of the single-nephron correlates of whole-kidney HCO3- titration curves (top) in normal subjects and in patients with proximal renal tubular acidosis (proximal RTA). The impact of these relationships on bicarbonaturia is displayed below the graph. Bicarbonate will not appear in the urine when reabsorption is complete at the plasma HCO3- concentration threshold, and distal H+ secretory processes are capable of reabsorbing the HCO3- delivered out of the proximal nephron. The relationship shows that the fractional proximal HCO3-reabsorptive capacity is reduced in patients with proximal RTA (50% versus the normal 80%), so the new steady state is achieved at the expense of systemic metabolic acidosis.



Pathogenesis of Proximal Renal Tubular Acidosis

Proximal RTA can present in two ways: one in which acidification is the only defective function and one in which there is a more generalized proximal tubule dysfunction. A proximal tubule defect involving only acidification is rare. Such a disorder would be assumed to involve a selective defect in the Na+/H+ antiporter, the H+-ATPase, or the Na+/HCO3-/CO32- symporter. Abnormalities of cell depolarization or abnormalities of the enzymes carbonic anhydrase II or IV could also cause a selective defect.[25]

In contradistinction to a selective defect, the majority of cases of proximal RTA fit into the category of generalized proximal tubule dysfunction with glycosuria, aminoaciduria, hypercitraturia, and phosphaturia, often referred to as the Fanconi syndrome. Numerous experimental studies in animal models demonstrate that the nephropathies associated with maleic acid and cystine involve disruption of active transcellular absorption of HCO3-, amino acids, and other solutes. Such a defect could be due to a generalized disorder of the Na+-coupled apical membrane transporters, a selective disorder of the basolateral Na+,K+-ATPase, or a specific metabolic disorder that lowers intracellular adenosine triphosphate (ATP) concentrations.

Development of the Fanconi syndrome by intracellular PO43- depletion has also been proposed in hereditary fructose intolerance, in which ingestion of fructose leads to accumulation of fructose 1-phosphate in the proximal tubule. Because these patients lack the enzyme fructose 1-phosphate aldolase, fructose 1-phosphate cannot be further metabolized and intracellular PO43- is sequestered in this form. The renal lesion is confined to the proximal tubule because this is the only segment in the kidney that possesses the enzyme fructokinase. Administration of large parenteral loads of fructose to rats leads to high intracellular concentrations of fructose 1-phosphate and low concentrations of ATP and guanosine triphosphate (GTP), as well as of total adenine nucleotides. Prior PO43- loading prevents reductions in intracellular ATP, total adenine nucleotides, and PO43-. [25] [29] Numerous investigators have noted an association between vitamin D deficiency and a proximal RTA with aminoaciduria and hyperphosphaturia. In these studies, correction of the vitamin D deficiency has allowed correction of the proximal tubule dysfunction.[25] Similar results have been obtained in patients with vitamin D-dependent and vitamin D-resistant rickets treated with dihydrotachysterol.[25] The mechanisms involved in the proximal tubule dysfunction are not yet clear.

Another model for isolated proximal tubule acidosis is inherited carbonic anhydrase deficiency. Sly and associates[30] have reported an inherited syndrome with osteopetrosis, cerebral calcification, and RTA caused by an inherited deficiency of carbonic anhydrase II. These patients may have combined proximal and distal RTA but have no other evidence for proximal tubule dysfunction and carbonic anhydrase IV is intact.[30] As already discussed, carbonic anhydrase II is present in the cytoplasm of renal cells, and thus, an acidification defect occurring in association with its deficiency is not unexpected. A defect of carbonic anhydrase IV (the membrane-bound form) has not been reported.

Clinical Spectrum

In general, proximal RTA is more common in children. The two most common causes of acquired proximal RTA in adults are multiple myeloma, in which increased excretion of immunoglobulin light chains injures the proximal tubule epithelium. The light chains that cause injury may have a biochemical characteristic in the variable domain that is resistant to degradation by proteases in lysosomes in proximal tubule cells. Accumulation of the variable domain fragments may be responsible for the impairment in tubular function. In contrast, idiopathic RTA, ifosfamide, lead intoxication, and cystinosis are more common causes in children. Certain chemotherapeutic agents (ifosfamide) also cause proximal RTA. Carbonic anhydrase inhibitors cause pure bicarbonate wasting but not the Fanconi syndrome, by contrast. A comprehensive list of the disorders associated with proximal RTA is displayed inTable 14-7 .[25] Some of the entries on this list are no longer seen and are of only historic interest. For example, application of sulfanilamide to the skin of patients with large surface area burns is no longer practiced in most centers. Sulfanilamide, a carbonic anhydrase inhibitor, is absorbed from burned skin. Pharmaceutical manufacturing techniques have improved, and outdated tetracycline is no longer associated with proximal RTA. Some of the agents or associated disorders on this list—such as ifosfamide, Sjögren's syndrome, renal transplantation, and amyloidosis—also appear as causes of distal RTA (see Table 14-7 ).

TABLE 14-7   -- Disorders with Dysfunction of Renal Acidification—Defective HCO3- Reclamation: Proximal Renal Tubular Acidosis



Selective (unassociated with Fanconi syndrome)






Transient (infants)



Idiopathic or genetic



Carbonic anhydrase deficiency, inhibition, or alteration












Mafenide acetate



Carbonic anhydrase II deficiency with osteopetrosis (Sly syndrome)



Generalized (associated with Fanconi syndrome)



Primary (without associated systemic disease)









Genetically transmitted systemic diseases






Lowe syndrome



Wilson syndrome









Hereditary fructose intolerance (during fructose ingestion)



Metachromatic leukodystrophy



Pyruvate carboxylase deficiency



Methylmalonic academia



Dysproteinemic states



Multiple myeloma



Monoclonal gammopathy



Secondary hyperparathyroidism with chronic hypocalcemia



Vitamin D deficiency or resistance



Vitamin D dependency



Drugs or toxins






Outdated tetracycline















Tubulointerstitial diseases



Sjögren syndrome



Medullary cystic disease



Renal transplantation



Other renal and miscellaneous diseases



Nephrotic syndrome






Paroxysmal nocturnal hemoglobinuria





The diagnosis of proximal RTA relies initially on the documentation of a chronic hyperchloremic metabolic acidosis. These patients generally present in the steady state with a chronic metabolic acidosis, an acid urine pH, and a low fractional excretion of HCO3-. With alkali therapy or slow infusion of sodium bicarbonate intravenously, when the plasma HCO3- increases above the threshold in these patients, bicarbonaturia ensues, and the urine becomes alkaline ( Fig. 14-6 ). By increasing the plasma bicarbonate concentration toward normal (18–20 mEq/L) with an intravenous infusion of sodium bicarbonate at a rate of 0.5 to 1.0 mEq/kg/hr, the urine pH, even if initially acid, will increase once the reabsorptive threshold for bicarbonate has been exceeded. Thus, the urine pH will exceed 7.5 and the fractional excretion of bicarbonate (FEHCO3-) will increase to 15 to 20 percent.



FIGURE 14-6  Type A intercalated cell of the collecting duct displaying five pathophysiologic defects that could result in classic distal RTA: (1) Defective H+-ATPase, (2) defective H+,K+-ATPase, (3) defective HCO3--Cl- exchanger, (4) H+ leak pathway, and (5) defective intracellular carbonic anhydrase (type 2).



The hyperchloremic metabolic acidosis is usually seen in association with hypokalemia. If bicarbonate administration has been high in an attempt to repair the acidosis, the bicarbonaturia will drive kaliuresis and the hypokalemia may be severe.[25] Patients with proximal tubule dysfunction exhibit intact distal nephron function (generate steep urine pH gradients and titrate luminal buffers) when the serum HCO3- concentration and, hence, distal HCO3-delivery are sufficiently reduced. A low HCO3- threshold exists. Below this plasma HCO3- concentration, distal acidification can compensate for defective proximal acidification, although at the expense of systemic metabolic acidosis. When the plasma HCO3- concentration is raised to normal values, a large fraction of the filtered HCO3- is inappropriately excreted because the limited reabsorptive capacity of the distal nephron cannot compensate for the reduced proximal nephron reabsorption.

Associated Characteristics

K+ excretion is typically high in patients with proximal RTA, especially during NaHCO3 administration.[25] Kaliuresis is promoted by the increased delivery of a relatively impermeant anion, HCO3-, to the distal nephron in the setting of secondary hyperaldosteronism, which is due to mild volume depletion. Therefore, correction of acidosis in such patients leads to an exaggeration of the kaliuresis and K+ deficiency.

If the acidification defect is part of a generalized proximal tubule dysfunction (Fanconi syndrome), such patients will have hypophosphatemia, hyperphosphaturia, hypouricemia, hyperuricosuria, glycosuria, aminoaciduria, hypercitraturia, hypercalciuria, and proteinuria.

Although Ca2+ excretion may be high in patients with proximal RTA, nephrocalcinosis and renal calculi are rare. This may be related to the high rate of citrate excretion in patients with proximal RTA compared with most patients with acidosis from other causes. Osteomalacia, rickets, abnormal gut Ca2+ and phosphorus absorption, and abnormal vitamin D metabolism in children are common, although not invariantly present. Adults tend to have osteopenia without pseudofractures.[25]

The proximal reabsorption of filtered low-molecular-weight proteins may also be abnormal in proximal RTA. Lysozymuria and increased urinary excretion of immunoglobulin light chains can occur.[25]


The magnitude of the bicarbonaturia (>10% of the filtered load) at a normal HCO3- concentration requires that large amounts of HCO3- be administered. At least 10 to 30 mEq/kg/day of HCO3- or its metabolic equivalent (citrate) is required to maintain plasma HCO3- concentration at normal levels. Correcting the HCO3- to near normal values (22–24 mEq/L) is desirable in children to preserve normal growth. Correction to this level is less desirable in adults. Large supplements of K+ are often necessary because of the kaliuresis induced by high distal HCO3- delivery when the plasma HCO3- concentration is normalized. Thiazides have proved useful in diminishing therapeutic requirements for HCO3- supplementation by causing ECF contraction to stimulate proximal absorption. However, K+ wasting continues to be a problem, often requiring the addition of a K+-sparing diuretic.[25] Vitamin D and PO43- may be supplemented and in some patients even improve the acidification defect. Fructose should be restricted in patients with fructose intolerance.[29]

Disorders of Impaired Net Acid Excretion with Hypokalemia: Classic Distal Renal Tubule Acidosis


The mechanisms involved in the pathogenesis of hypokalemic cDRTA have been more clearly elucidated by appreciation of the genetic and molecular bases of the inherited forms of this disease in the recent years. The observation that these patients tend to be hypokalemic (rather than hyperkalemic) demonstrates that generalized CCT dysfunction or aldosterone deficiency is not causative. Most studies suggest that the acquired or inherited forms of cDRTA are due to defects in the basolateral HCO3-/Cl- exchanger, or subunits of the H+-ATPase. Other examples include an abnormal leak pathway (e.g., amphoteriein B) [6] [19] [25] or abnormalities of the H+,K+-ATPase. Defects in either of these transport pathways or an increase in apical membrane permeability are displayed in Figure 14-6 , which depicts acid-base transporters of a type A intercalated cell in the medullary collecting duct and the possible abnormalities causing cDRTA. The classic feature of this entity is an inability to acidify the urine maximally (to <pH 5.5) in the face of systemic acidosis. [6] [25]

The pathogenesis of the acidification defect in most patients is evident by the response of the urine Pco2 to sodium bicarbonate infusion. When normal subjects are given large infusions of sodium bicarbonate to produce a high HCO3- excretion, distal nephron H+ secretion leads to the generation of a high Pco2 in the renal medulla and final urine.[31] The magnitude of the urinary Pco2 (often referred to as the urine minus blood Pco2 or U - B Pco2) can be used as an index of distal nephron H+ secretory capacity. [32] [33] The U - B Pco2 is generally subnormal in classic hypokalemic distal RTA, with the notable exception of amphotericin B-induced distal RTA, which remains as the most common example of the “gradient” defect. [31] [33] [34]

Inherited Defects in the Bicarbonate/Chlorine Ion Exchanger.

Recently, three groups have independently demonstrated an association between mutations in the AE-1 gene, which encodes the basolateral HCO3-/Cl- exchanger in the collecting duct, and the occurrence of autosomal dominant cDRTA (Example 3 in Fig. 14-6 ). [35] [36] [37] [38] Surprisingly, however, when these point mutations were expressed in vitro, abnormalities in HCO3-/Cl- exchange have not been observed. It was hypothesized that misdirection of the HCO3-/Cl- exchanger to the apical, rather than the basolateral, membrane might obtain in this disorder, resulting in impaired net H+ secretion. [36] [37] [39] For a more detailed discussion, the reader is referred to a recent review by Alper.[40]

Hydrogen Ion-Secretory Defects (Inherited and Acquired).

Alternatively, the rate of proton secretion could be affected by an abnormality in a specific transporter or mechanism involved in apical membrane proton extrusion. These include the apical H+-ATPase or the H+- K+-ATPase (seeFig. 14-6 ). Impairment of the H+-ATPase in cDRTA has been documented in both acquired and inherited disorders. Acquired defects of H+-ATPase have been demonstrated in renal biopsy specimens of patients with Sjögrens syndrome with evidence of classic hypokalemic distal RTA.[25] These biopsy specimens revealed an absence of H+-ATPase protein in the apical membrane of type A intercalated cells. Karet and colleagues[41] have described two different mutations in the ATP6B1 gene encoding the B1-subunit of the H+-ATPase. One defect is associated with sensorineural deafness (rd RTA 1), and the other with normal hearing (rd RTA 2).[42] The former recessive disorder is manifest in the first year of life as a failure to thrive, bilateral sensorineural hearing deficits, hyperchloremic, hypokalemic metabolic acidosis, severe nephrolithiasis, nehrocalcinosis, and osteodystrophy. Interestingly, the H+-ATPase is critical for maintaining pH in the cochlea and endolymph, and its loss in this disorder explains the loss of hearing as well as the renal tubule acidification defect. The latter defect is rare but is associated with normal hearing and has been localized to chromosome 7q 33-34. This group also identified the gene, ATP6N1B, which encodes an 840–amino acid novel kidney-specific isoform of ATP6N1A, the 116-kD noncatalytic accessory subunit of the proton pump. Through this work, they described a new kidney-specific proton pump accessory subunit that was highly expressed in proton-secreting cells in the distal nephron. [43] [44]

The genetic and molecular basis of distal RTA is outlined in Table 14-8 .

TABLE 14-8   -- Genetic and Molecular Bases of Distal Renal Tubular Acidoses

Classic distal RTA


 Autosomal dominant

Defect in AE-1 gene encodes for a single missense mutation (R589H) in the HCO3-/Cl- exchanger (band 3 protein)


Transporter may be misstargeted to apical membrane


Other missense mutations reported in some families (R589C and S613F)

Autosomal recessive

 With deafness

Mutations in ATP6B1, encoding B-subunit of the collecting duct apical H+-ATPase, maps to chromosome 7q33-34. Progressive sensorineural hearing loss (rd RTA1)

 With normal hearing

Linkage to segment of 7q33-34 distinct from ATP6N1B (rd RTA2)

 Carbonic anhydrase II deficiency

Defect in carbonic anhydrase II in RBC, bone, kidney

Endemic (Northeastern Thailand)

Possible abnormality in H+,K+-ATPase?


Reduced expression of H+-ATPase (Sjögren)

Generalized distal nephron Dysfunction


Pseudohypoaldosteronism type I


 Autosomal recessive

Missense mutation with loss of function of ENaC maps to chromosome 16p12.2-13.11 in six families and to 12p13.1-pter in five additional families

 Autosomal dominant

Heterozygous mutations of MLR; two frameshift mutations, two premature termination codons, and one splice donor mutation of the mineralocorticoid receptor gene (MLR)

Pseudohypoaldosteronism type II

WNK1 and WNK4 defect increases function of NCCT to increase NaCl absorption




Alternatively, abnormalities in the H+,K+-ATPase could result in both hypokalemia and metabolic acidosis. A role for H+,K+-ATPase involvement in cDRTA was suggested by the observation that chronic administration of vanadate in rats decreased H+,K+-ATPase activity and was associated with metabolic acidosis, hypokalemia, and an inappropriately alkaline urine.[45] In addition, an unusually high incidence of hypokalemic distal RTA (endemic RTA) has been observed in northeastern Thailand. To date, no genetic linkages between H+,K+-ATPase genes and inherited forms of cDRTA have been documented. Nevertheless, Schwartz and colleagues have presumed such an abnormality in an infant with severe metabolic acidosis and hypokalemia.[25]

Patients with impaired collecting duct H+ secretion and cDRTA also exhibit uniformly low excretory rates of NH4+ when the degree of systemic acidosis is taken into account. [5] [6] [25] Low NH4+ excretion equates with inappropriately low renal regeneration of HCO3-, indicating that the kidney is responsible for causing or perpetuating the chronic metabolic acidosis. Low NH4+ excretion in classic hypokalemic distal RTA occurs because of the failure to trap NH4+ in the medullary collecting duct as a result of higher than normal tubule fluid pH in this segment and loss of the disequilibrium pH (pH > 6.0).[46] The high urine pH indicates impaired H+ secretion.

In summary, hypokalemic distal RTA is characterized by inability to acidify the urine below pH 5.5. In some patients, this is attributable to an enhanced leakage pathway (amphotericin B lesion) or, in rare patients, without exposure to the antibiotic.[47] However, in most patients, the defect cannot be attributed to such a leak. In these patients, a decreased rate of distal H+ secretion is the likely mechanism. When the defect is a result of an abnormal H+-ATPase, hypokalemia occurs secondarily as a result of volume depletion-induced hyperreninemic hyperaldosteronism and acidosis that accompanies this disorder.

Clinical Spectrum and Associated Features

The hallmark of classic hypokalemic distal RTA has been the inability to acidify the urine appropriately during spontaneous or chemically induced metabolic acidosis. The defect in acidification by the collecting duct impairs NH4+and titratable acid excretion and results in positive acid balance, hyperchloremic metabolic acidosis, and volume depletion. [25] [48] [49] [50] Moreover, medullary interstitial disease, which commonly occurs in conjunction with distal RTA, may impair NH4+ excretion by interrupting the medullary countercurrent system for NH4+. [6] [25] [48] [49] Hypokalemia and hypercalciuria are typically present,[6] but proximal tubule reabsorptive function is preserved. The dissolution of bone, which may on occasion accompany distal RTA, appears to be the result of chronic positive acid balance that causes Ca2+, Mg2+, and PO43- wasting.[25] Because chronic metabolic acidosis also decreases renal production of citrate, [5] [6] [25] the resulting hypocitraturia in combination with hypercalciuria creates an environment favorable for urinary stone formation and nephrocalcinosis. Nephrocalcinosis appears to be a reliable marker for cDRTA, because nephrocalcinosis does not occur in proximal RTA or with generalized dysfunction of the nephron associated with hyperkalemia. [6] [25] Nephrocalcinosis probably aggravates further the reduction in net acid excretion by impairing the transfer of ammonia from the loop of Henle into the collecting duct. Pyelonephritis is a common complication of distal RTA, especially in the presence of nephrocalcinosis, and eradication of the causative organism may be difficult.[25] Distal RTA occurs frequently in patients with Sjögren's syndrome.[51]

The clinical spectrum of cDRTA is outlined in detail in Table 14-9 . [6] [25] [50]

TABLE 14-9   -- Disorders with Dysfunction of Renal Acidification—Selective Defect in Net Acid Excretion: Classic Distal Renal Tubular Acidosis









Autosomal dominant



AE 1 gene



Autosomal recessive



With deafness (rd RTA1 or ATP6B1 gene)



Without deafness (rd RTA2 or ATP6N1B)







Northeastern Thailand

Secondary to systemic disorders


Autoimmune diseases


 Hyperglobulinemic purpura

Fibrosing alveolitis


Chronic active hepatitis

 Sjögren syndrome

Primary biliary cirrhosis


Polyarthritis nodosa

 HIV nephropathy


Hypercalciuria and nephrocalcinosis


 Primary hyperparathyroidism

Vitamin D intoxication


Idiopathic hypercalciuria

 Medullary sponge kidney

Wilson disease

 Fabry disease

Hereditary fructose intolerance

 X-linked hypophosphatemia


Drug- and toxin-induced disease


 Amphotericin B




 Hepatic cirrhosis

Vanadate lithium


Classic analgesic nephropathy



Tubulointerstitial diseases


 Balkan nephropathy

Kidney transplantation

 Chronic pyelonephritis


 Obstructive uropathy

Jejunoileal bypass with hyperoxaluria

 Vesicoureteral reflux


Associated with genetically transmitted diseases


 Ehlers-Danlos syndrome

Hereditary elliptocytosis

 Sickle cell anemia

Marfan syndrome

 Medullary cystic disease

Jejunal bypass with hyperoxaluria

 Hereditary sensorineural deafness

Carnitine palmitoyltransferase

 Osteopetrosis with carbonic anhydrase II deficiency






Correction of chronic metabolic acidosis can usually be achieved in patients with cDRTA by administration of alkali in an amount sufficient to neutralize the production of metabolic acids derived from the diet.[25] In adult patients with distal RTA, this is may be equal to no more than 1 to 3 mEq/kg/day.[52] In growing children, endogenous acid production is usually between 2 and 3 mEq/kg/day but may, on occasion, exceed 5 mEq/kg/day. Larger amounts of bicarbonate must be administered to correct the acidosis and maintain normal growth. [6] [25] The various forms of alkali replacement are outlined in Table 14-10 .

TABLE 14-10   -- Forms of Alkali Replacement

Shohl solution


 Na+ citrate 500 mg

Each 1 mL contains 1 mEq sodium and is equivalent of 1 mEq of bicarbonate

 Citric acid 334 mg/5 mL

3.9 mEq/tablet (325 mg)

NaHCO3 tablets

7.8 mEq/tablet (650 mg)

Baking soda

60 mEq/tsp


25–50 mEq/tablet

Polycitra (K-Shohl solution)


 Na+ citrate 500 mg

Each 1 mL contains 1 mEq potassium and 1 mEq sodium and is equivalent to 2 mEq bicarbonate

 K+ citrate 550 mg

 Citric acid 334 mg/5 mL

Polycitra K crystals


 K+ citrate 3300 mg

Each packet contains 30 mEq potassium and is equivalent to 30 mEq bicarbonate

 Citric acid 1002 mg/packet

Urocit K tablets


 Potassium citrate

5 or 10 mEq/tablet




In adult patients with distal RTA, correction of acidosis with alkali therapy reduces urinary K+ excretion, and prevents hypokalemia and Na+ depletion.[25] Therefore, in most adult patients with distal RTA, K+ supplementation is not necessary. Frank wasting of K+ may occur in a minority of adult patients and in some children in association with secondary hyperaldosteronism despite correction of the acidosis by alkali therapy requiring K+ supplementation. If required, potassium can be administered as potassium bicarbonate (K-Lyte 25 or 50 mEq), potassium citrate (Urocit K), or polycitra (K-Shohls). [6] [25]

Maintenance of a normal serum bicarbonate with alkali therapy also raises urinary citrate, reduces urinary calcium, lowers the frequency of nephrolithiasis, and tends to correct bone disease and restore normal growth in children. [52] [53] Therefore, every attempt should be made to correct and maintain a near-normal serum [HCO3-] in all patients with cDRTA.

Severe hypokalemia with flaccid paralysis, metabolic acidosis, and hypocalcemia may occur in some patients under extreme circumstances and require immediate therapy. Because the hypokalemia may result in respiratory depression, increasing systemic pH with alkali therapy may worsen the hypokalemia. Therefore, immediate intravenous potassium replacement should be achieved prior to alkali administration.

Disorders of Impaired Net Acid Excretion with Hyperkalemia: Generalized Distal Nephron Dysfunction (Type 4 Renal Tubular Acidosis)

The coexistence of hyperkalemia and hyperchloremic acidosis suggests a generalized dysfunction in the cortical and medullary collecting tubules. In the differential diagnosis, it is important to evaluate the functional status of the renin-aldosterone system and of ECF volume. The specific disorders causing hyperkalemic hyperchloremic metabolic acidosis are outlined in detail in Table 14-11 . [6] [25]

TABLE 14-11   -- Disorders with Dysfunction of Renal Acidification: Generalized Abnormality of Distal Nephron with Hyperkalemia



Mineralocorticoid deficiency



Primary mineralocorticoid deficiency



Combined deficiency of aldosterone, desoxycorticosterone, and cortisol



Addison disease



Bilateral adrenalectomy



Bilateral adrenal destruction



Hemorrhage or carcinoma



Congenital enzymatic defects



21-Hydroxylase deficiency



3β-Hydroxydehydrogenase deficiency



Desmolase deficiency



Isolated (selective) aldosterone deficiency



Chronic idiopathic hypoaldosteronism



Heparin (low molecular weight or unfractionated) in critically ill patient



Familial hypoaldosteronism



Coricosterone methyloxidase deficiency, types 1 and 2



Primary zona glomerulosa defect



Transient hypoaldosteronism of infancy



Persistent hypotension and/or hypoxemia in critically ill patient



Angiotensin II-converting enzyme inhibition






Angiotensin-converting enzyme inhibitors (ACE-I) and AT1 receptor antagonists (ARB)



Secondary mineralocorticoid deficiency



Hyporeninemic hypoaldosteronism



Diabetic nephropathy



Tubulointerstitial nephropathies






Nonsteroidal anti-inflammatory agents



Acquired immunodeficiency syndrome



IgM monoclonal gammopathy



Mineralocorticoid resistance



PHA I—autosomal dominant (hMR defect)



Renal tubular dysfunction (voltage defect)



PHA I—autosomal recessive



PHA II—autosomal dominant



Drugs that interfere with Na+ channel function in CCT















Drugs that interfere with Na+, K+-ATPase in CCT



Cyclosporine, tacrolimus



Drugs that inhibit aldosterone effect on CCT






Disorders associated with tubulointerstitial nephritis and renal insufficiency



Lupus nephritis



Methicillin nephrotoxicity



Obstructive nephropathy



Kidney transplant rejection



Sickle cell disease



William syndrome with uric acid nephrolithiasis




The regulation of potassium excretion is primarily the result of regulation of potassium secretion, which responds to hyperkalemia, aldosterone, sodium delivery, and nonreabsorbable anions in the CCD. Therefore, a clinical estimate of K+ transfer into that segment could be helpful to recognize hyperkalemia of renal origin. An abnormally low fractional excretion of potassium or transtubular potassium gradient (TTKG) in the face of hyperkalemia defines hyperkalemia of renal origin. When the TTKG is low in a hyperkalemic patient (<8), it reveals that the collecting tubule is not responding appropriately to the prevailing hyperkalemia and that potassium secretion is impaired. In contrast, in hyperkalemia of nonrenal origin, the kidney should respond by increasing K+ secretion, as evidenced by a sharp increase in the TTKG. The TTKG assumes no significant net addition or absorption of K+ between the CCD and the final urine, that CCD tubular fluid osmolality is approximately the same as plasma osmolality, that “osmoles” are not extracted between CCD and final urine, and that plasma [K+] approximates peritubular fluid [K+]. Under certain clinical conditions, it is important to note that some or none of these assumptions may be entirely correct. With high urine flow rates, for example, the TTKG underestimates K+ secretory capacity in the hyperkalemic patient.

Hyperkalemia should also be regarded as an important mediator of the renal response to acid-base balance. Potassium status can affect distal nephron acidification by both direct and indirect mechanisms. First, the level of potassium in systemic blood is an important determinant of aldosterone elaboration, which is also an important determinant of distal H+ secretion. Chronic potassium deficiency was demonstrated in studies in our laboratory to stimulate ammonium production while chronic hyperkalemia suppressed ammoniagenesis. [54] [55] These changes in ammonium production may also affect medullary interstitial ammonium concentration and buffer availability.[55]Hyperkalemia has no effect on ammonium transport in the superficial proximal tubule but markedly impairs ammonium absorption in the thick ascending limb of henle's loop (TALH), reducing inner medullary concentrations of total ammonia and decreasing secretion of NH3 into the IMCD. The mechanism for impaired absorption of NH4+ in the TALH is competition between K+ and NH4+ for the K+ secretory site on the Na+-Cl--2K+ transporter. [56] [57]Hyperkalemia may also decrease entry of NH4+ into the medullary collecting duct through competition of NH4+ and K+ for the K+-secretory site on the basolateral membrane sodium pump ( Fig. 14-7 ).[57]



FIGURE 14-7  Relationship between NH4+ transport in the medullary thick ascending limb of Henle's loop (mTALH) and the terminal inner medullary collecting duct (tIMCD). This integrated process allows for both countercurrent multiplication of NH3 ↔ NH4+, achieving higher levels in the inner medulla, and facilitated entry of NH3/NH4+ into the tIMCD, bypassing the distal tubule and cortical collecting tubule (CCT), thus trapping NH4+ for excretion. The sites at which K+ competes with NH4+ transport are displayed to emphasize that hyperkalemia impairs NH4+production and transport.



In summary, hyperkalemia may have a dramatic impact on ammonium production and excretion ( Table 14-12 ). Chronic hyperkalemia decreases ammonium production in the proximal tubule and whole kidney, inhibits absorption of NH4+ in the medullary TALH (mTALH), reduces medullary interstitial concentrations of NH4+ and NH3, and decreases entry of NH4+ and NH3 into the medullary collecting duct. This same series of events leads, in the final analysis, to a marked reduction in urinary ammonium excretion (UAmV). The potential for development of a hyperchloremic metabolic acidosis is greatly augmented when a reduction in functional renal mass coexists (GFR < 60 mL/min) with hyperkalemia, or in the presence of aldosterone deficiency or resistance.

TABLE 14-12   -- Effects of Hyperkalemia on Ammonium Excretion

Decrease in ammonium production

Decrease in NH4- absorption thick ascending limb of henle

Decrease in interstitial NH4+ concentration

Impaired countercurrent multiplication

Decrease in NH3/NH4+ secretion into outer and inner medullary collecting ducts




Clinical Disorders

Generalized distal nephron dysfunction is manifest as a hyperchloremic, hyperkalemic metabolic acidosis in which urinary ammonium excretion is invariably depressed (positive UAG) and renal function often compromised. Although hyperchloremic metabolic acidosis and hyperkalemia occur with regularity in advanced renal insufficiency, patients selected because of severe hyperkalemia (>5.5 mEq/L) with, for example, diabetic nephropathy and tubulointerstitial disease have hyperkalemia that is disproportionate to the reduction in glomerular filtration rate. The TTKG and/or the FEK+ is usually low in patients with this disorder. In such patients, a unique dysfunction of potassium and acid secretion by the collecting tubule coexists and can be attributed to either mineralocorticoid deficiency, resistance to mineralocorticoid, or a specific type of renal tubular dysfunction (voltage defects). The clinical spectrum of generalized abnormalities in the distal nephron is summarized in Table 14-11 .

Primary Mineralocorticoid Deficiency

A number of factors modulate aldosterone secretion: angiotensin II, adrenocorticotropic hormone (ACTH), endothelin, dopamine, acetylcholine, epinephrine, plasma K+, and Mg2+. However, angiotensin II and plasma K+ remain the principal modulators of aldosterone production and secretion. Destruction of the adrenal cortex by hemorrhage, infection, invasion by tumors, or autoimmune processes results in Addison's disease. This causes combined glucocorticoid and mineralocorticoid deficiency and is recognized clinically by hypoglycemia, anorexia, weakness, hyperpigmentation, and a failure to respond to stress. These defects can occur in association with renal salt wasting and hyponatremia, hyperkalemia, and metabolic acidosis. The most common congenital adrenal defect in steroid biosynthesis is 21-hydroxylase deficiency, which is associated with salt wasting, hyperkalemia, and metabolic acidosis in a fraction of the patients. Causes of Addison's disease include tuberculosis, autoimmune adrenal failure, fungal infections, adrenal hemorrhage, metastasis, lymphoma, AIDS, amyloidosis, and drug toxicity (ketoconazole, fluconozole, phenytoin, rifampin, and barbiturates). These disorders are associated with low plasma aldosterone levels and high levels of plasma renin activity.[25] The metabolic acidosis of mineralocorticoid deficiency results from a decrease in hydrogen ion secretion in the collecting duct secondary to decreased H+-ATPase pump number and function. The hyperkalemia of mineralocorticoid deficiency decreases ammonium production and excretion.

Hyporeninemic Hypoaldosteronism

In contrast to patients with the primary adrenal disorder, patients in this group will exhibit low plasma renin activ-ity, are usually older (mean age 65 yr), and frequently have mild to moderate renal insufficiency (70%) and acidosis (50%) in association with chronic hyperkalemia in the range of 5.5 to 6.5 mEq/L ( Table 14-13 ).[25] Although the hyperkalemia may be asymptomatic, it is important to recognize that both the metabolic acidosis and the hyperkalemia are out of proportion to the level of reduction in GFR. The most frequently associated renal diseases are diabetic nephropathy and tubulointerstitial disease. Additional disorders associated with hyporeninemic hypoaldosteronism include tubulointerstitial nephritis, systemic lupus erythematosis, and HIV. For 80% to 85% of such patients, there is a reduction in plasma renin activity that cannot be stimulated by the usual physiologic maneuvers. Because approximately 30% of patients with hyporeninemic hypoaldosteronism are hypertensive, the finding of a low plasma renin in such patients suggests a volume-dependent form of hypertension with physiologic suppression of renin elaboration.

TABLE 14-13   -- Hyporeninemic Hypoaldosteronism: Typical Clinical Features

Mean age 65 yr



Asymptomatic hyperkalemia (75%)



Weakness (25%)



Arrhythymia (25%)

Hyperchloremic metabolic acidosis (>50%)

Renal insufficiency (70%)

Diabetes mellitus (50%)



Cardiac disorders



Arrhythmia (25%)



Hypertension (75%)



Congestive heart failure (50%)




Impaired ammonium excretion is the combined result of hyperkalemia, impaired ammoniagenesis, a reduction in nephron mass, reduced proton secretion, and impaired transport of ammonium by nephron segments in the inner medulla. [6] [25] [58] Hyperchloremic metabolic acidosis occurs in approximately 50% of patients with hyporeninemic hypoaldosteronism. Drugs, which may result in similar manifestations, are reviewed later.

Isolated Hypoaldosteronism in Critically Ill Patients

Isolated hypoaldosteronism, which may occur in critically ill patients, particularly in the setting of severe sepsis or cardiogenic shock, is manifest by markedly elevated ACTH and cortisol levels in concert with a decrease in aldosterone elaboration in response to angiotensin II. This may be secondary to selective inhibition of aldosterone synthase as a result of hypoxia or in response to cytokines such as tumor necrosis factor (TNF)-α or interleukin (IL)-1 or, alternatively, as a result of high circulating levels of atrial natriuretic peptide (ANP). [6] [25] [59] ANP, a powerful suppressor of aldosterone secretion, may be elevated in congestive heart failure (CHF), with atrial arrhythmias, in subclinical cardiac disease, and in volume expansion. The tendency to manifest the features of hypoaldosteronism, including hyperkalemia and metabolic acidosis, is often potentiated by the administration of potassium-sparing diuretics or potassium loads in parenteral nutrition solutions or as a result of heparin administration. The latter suppresses aldosterone synthesis in the critically ill patient ( Table 14-14 ).

TABLE 14-14   -- Isolated Hypoaldosteronism in the Critically Ill Patient

Elevated adrenocorticotropic hormone (ACTH) and cortisol levels in association with a decrease in aldosterone elaboration



Inhibition of aldosterone synthase












Atrial natriuretic peptide



Manifestations of hypoaldosteronism






Metabolic acidosis

Potentiated by K+-sparing diuretics, K+ loads in parenteral nutrition, or heparin




Resistance to Mineralocorticoid and Voltage Defects

Autosomal dominant pseudohypoaldosteronism type I (PHA) is the prototypical example of renal resistance to aldosterone action. This disorder, which is clinically less severe than the autosomal recessive form discussed later, is associated with hyperkalemia (which can be attributed to impaired potassium secretion), renal salt wasting, elevated levels of renin and aldosterone, and hypotension. Physiologic mineralocorticoid replacement therapy does not correct the hyperkalemia. The autosomal dominant disorder has been shown to be the result of a mutation in the intracellular mineralocorticoid receptor (hMR) in the collecting tubule.[60] Unlike the autosomal recessive disorder, this defect is not expressed in organs other than the kidney and becomes less severe with advancing age. Because the decrease in mineralocortoid reduces apical Na+ absorption and activity of the epithelial sodium channel (EnaC), transepithelial potential difference declines and K+ secretion is impaired.

The prototype for a “voltage” defect is autosomal recessive PHA I ( Fig. 14-8 ). This disorder is the result of a loss of function mutation of the gene that encodes one of the subunits of the a, b, or g subunit of the ENaC. [61] [62] [63] [64] [65] Children with this disorder have severe hyperkalemia and renal salt wasting because of impaired sodium absorption in principal cells of the CCT. In addition, the hyperchloremic metabolic acidosis may be severe and is associated with hypotension and marked elevations of plasma renin and aldosterone. These children also manifest vomiting, hyponatremia, failure to thrive, and respiratory distress. The latter is due to involvement of ENaC in the alveolus, preventing Na+ and water absorption in the lungs. [64] [66] Patients with this disease respond to a high salt intake and correction of the hyperkalemia. Unlike the autosomal dominant form, autosomal recessive PHA I persists throughout life.



FIGURE 14-8  Examples of “voltage” defects in the CCT causing abnormal Na+ transport (and K+ secretion) across the apical membrane of a principal cell: (1) the Na+ channel (ENaC) is blocked or occupied by amiloride, trimethoprim, or pentamidine or is inoperative (autosomal recessive PHA-I), and (2) inhibition of basolateral Na+,K+-ATPase activity by calcineurin-cyclosporine (CsA). As a consequence of impaired Na+ uptake, transepithelial K+ secretion is compromised, leading to hyperkalemia. The pathogenesis of metabolic acidosis, when present, is the result of the unfavorable voltage (which impairs H+ secretion by the type A intercalated cell, not shown) or the inhibition of NH4+ production and transport and the H+,K+-ATPase as a consequence of hyperkalemia.



A number of additional adult patients have been re-ported with a rare form of autosomal dominant low-renin hypertension, which is invariably associated with hyperkalemia, hyperchloremic metabolic acidosis, mild volume expansion, normal renal function, and low aldosterone levels. This syndrome has been designated familial hyperkalemic hypertension, but is also known as pseudohypoaldosteronism type II (PHA II),[67] or Gordon's syndrome. Lifton's group [68] [69] identified two genes causing PHA II. Both genes encode members of the WNK family of serine-threonine kinases. WNK1 and WNK4 localize to the CCT. WNK4 negatively regulates surface expression of the Na+-Cl- co-transporter in the connecting tubule (NCCT).[69] Loss of regulation of NCCT by WNK4 mutation appears to result in an increase in NCCT function, volume expansion, shunting of voltage, and therefore, reduced K+secretion in the CCT. [69] [70] [71] PHA II may be distinguished from selective hypoaldosteronism by the presence of normal renal function and hypertension, the absence of diabetes mellitus and salt wasting, and a kaliuretic response to mineralocorticoids. The acidosis in these patients is mild and can be accounted for by the magnitude of hyperkalemia; the acidosis and renal potassium excretion are resistant to mineralocorticoid administration. Thiazide diuretics consistently correct the hyperkalemia and metabolic acidosis, as well as the hypertension, plasma aldosterone, and plasma renin levels.

Secondary Renal Diseases Associated with Acquired Voltage Defects

In addition to the previous discussion on inherited voltage defects, Table 14-15 outlines a number of acquired renal disorders due to drugs or tubulointerstitial diseases, which are often associated with hyperkalemia.[25] Examples of the former include amiloride and the structurally related compounds, trimethoprim (TMP), and pentamidine. As discussed earlier, this explains the occurrence of hyperkalemic hyperchloremic acidosis in patients receiving higher doses of these agents. TMP and pentamidine occupy the Na+ channel, as does amiloride, causing hyperkalemia, which contributes to the acidosis. Additional drugs not related to amiloride include cyclooxygenase (COX)-2 inhibitors, cyclosporine, tacrolimus, and nonsteroidal anti-inflammatory durgs (NSAIDs). [72] [73] In these disorders, the frequency with which hyperkalemia is associated with metabolic acidosis and decreased net acid excretion as a result of impaired ammonium production or excretion cannot be presumed to be a result of the severity of impairment in renal function. Hyperkalemia which is out of proportion to the degree of renal insufficiency is typically observed with the nephropathies associated with sickle cell, HIV disease, systemic lupus erythematosis, obstructive uropathy; acute and chronic renal allograph rejection, hypoaldosteronism, multiple myeloma, and amyloidosis. [25] [74] Tubulointerstitial disease with hyperkalemia and hyperchloremic metabolic acidosis with or without salt wasting may be associated with analgesic abuse, sickle cell disease, ob-structive uropathy, nephrolithiasis, nephrocalcinosis, and hyperuricemia.[25]

TABLE 14-15   -- Causes of Drug-induced Hyperkalemia



Impaired renin-aldosterone elaboration/function



Cyclooxygenase inhibitors (NSAIDs)



β-Adrenergic antagonists






Converting-enzyme inhibitors and ARBs






Inhibitors of renal potassium secretion



Potassium-sparing diuretics (amiloride, triamterine)












Digitalis overdose






Altered potassium distribution



Insulin antagonists (somatostatin, diazoxide)



β-Adrenergic antagonists



α-Adrenergic agonists



Hypertonic solutions









Arginine hydrochloride, lysine hydrochloride




Hyperkalemic Distal Renal Tubular Acidosis

A generalized defect in CCD secretory function that results in hyperkalemic hyperchloremic metabolic acidosis has been delineated as hyperkalemic distal RTA because of the coexistence of an inability to acidify the urine (UpH > 5.5) during spontaneous acidosis or following an acid load and hyperkalemia. The hyperkalemia is the result of impaired renal K+ secretion and the TTKG or FEK+ is invariably lower than expected for hyperkalemia. Urine ammonium excretion is reduced, but aldosterone levels may be low, normal, or even increased. Hyperkalemic distal RTA may be observed in a wide variety of renal diseases including systemic lupus erythematosis, sickle cell disease, obstructive uropathy, transplantation, and amyloidosis. Drugs may be associated with a number of tubular defects that can be manifest as hyperkalemic distal RTA (see later). Hyperkalemic distal RTA can be distinguished from selective hypoaldosteronism because plasma renin and aldosterone levels are usually high or normal. Typically in selective hypoaldosteronism, the UpH is low and the defect in urinary acidification can be attributed to the decrease in ammonium excretion. In contrast with hypokalemic or cDRTA, patients with hyperkalemic distal RTA do not increase H+ or K+ excretion in response to nonreabsorbable anions (SO42-) or furosemide.

Drug-induced Renal Tubular Secretory Defects

Impaired Renin-Aldosterone Elaboration.

Drugs may impair renin or aldosterone elaboration or produce mineralocorticoid resistance and mimic the clinical manifestations of the acidification defect seen in the generalized form of distal RTA with hyperkalemia (see Table 14-15 ). COX inhibitors (NSAIDs or COX-2-I) can generate hyperkalemia and metabolic acidosis as a result of inhibition of renin release.[73] β-Adrenergic antagonists cause hyperkalemia as a result of altered potassium distribution and by interference with the renin-aldosterone system. Heparin impairs aldosterone synthesis as a result of direct toxicity to the zona glomerulosa and inhibition of aldosterone synthase. ACE inhibitors and ARBs interrupt the rennin-aldosterone system and result in hypoaldosteronism with hyperkalemia and acidosis, particularly in the patient with advanced renal insufficiency or in patients with a tendency to develop hyporeninemic hypoaldosteronism (diabetic nephropathy). The combination of potassium-sparing diuretics and ACE inhibitors should be avoided judiciously in diabetics.

Inhibitors of Potassium Secretion in the Collecting Duct.

Spironolactone acts as a competitive inhibitor of aldosterone and inhibits aldosterone biosynthesis. This drug may be a frequent cause of hyperkalemia and metabolic acidosis when administered to patients with significant renal insufficiency, in patients with advanced liver disease, or in patients unrecognized renal hemodynamic compromise. Similarly, amiloride and triamterine may be associated with hyperkalemia but through an entirely different mechanism. Both potassium-sparing diuretics occupy and thus block the apical Na+-selective channel (ENaC) in the collecting duct principal cell (see Fig. 14-8 ). Occupation of ENaC inhibits Na+ absorption and reduces the negative transepithelial voltage, which alters the driving force for K+ secretion. Amiloride is the prototype for a growing number of agents, including TMP and pentamidine, that act similarly to cause hyperkalemia, particularly in patients with AIDS. TMP and pentamidine are related structurally to amiloride and triamterene. The protonated forms of both TMP and pentamidine have been demonstrated by Kleyman and Ling[75] to inhibit ENaC in A6 distal nephron cells. This effect in A6 cells has been verified in rat late distal tubules perfused in vivo.[77] Hyperkalemia has been observed in 20% to 50% of HIV-infected patients receiving high-dose TMP-sulfamethoxazole (SMX) or TMP-dapsone for the treatment of opportunistic infections and as many as 100% of patients with AIDS-associated infections (Pneumocystis carinii) receiving pentamidine for more than 6 days.[77] The pathophysiologic basis of the hyperkalemia and metabolic acidosis from TMP is displayed in Table 14-16 . Because both TMP and pentamidine decrease the electrochemical driving force for both K+ and H+ secretion in the CCT, metabolic acidosis may accompany the hyperkalemia even in the absence of severe renal failure, adrenal insufficiency, tubulointerstitial disease, or hypoaldosteronism. Whereas it has been assumed that such a “voltage” defect could explain the decrease in H+ secretion, it is likely that, in addition, hyperkalemia plays a significant role in the development of metabolic acidosis by direct inhibition of ammonium production and excretion (see Fig. 14-7 and Table 14-12 ). Cyclosporine (CsA) or tacrolimus (FK 506) may be associated with hyperkalemia in the transplant recipient as a result of inhibition of the basolateral Na+,K+-ATPase, thereby decreasing intracellular [K+] and the transepithelial potential, which together decrease the driving force for K+ secretion (see Fig. 14-8 ).[73] It has been suggested that the specific mechanism of inhibition of the Na+ pump is through inhibition by these agents of calcineurin activity.[78] Either drug could also decrease the filtered load of K+ through hemodynamic mechanisms such as vasoconstriction, which decrease GFR and alter the filtration fraction.

TABLE 14-16   -- Hyperkalemic Hyperchloremic Metabolic Acidosis with Trimethoprim

Occurs in 20% of HIV patients on trimethoprin-sulfamethoxazole (TMP-SMX)

More prevalent with higher doses (>20 mg/kg/day)

Hyperkalemia most frequent complication

Seen in children and older HIV-negative patients on “conventional” doses


Etiology of metabolic acidosis

Voltage defect


Decreased ammonium production/excretion





In hyperkalemic hyperchloremic metabolic acidosis, documentation of the underlying disorder is necessary and therapy should be based on a precise diagnosis if possible. Of particular importance is a careful drug and dietary history. Contributing or precipitating factors should be considered, including low urine flow or decreased distal Na+ delivery, a rapid decline in GFR (especially in acute superimposed on chronic renal failure), hyperglycemia or hyperosmolality, and unsuspected sources of exogenous K+ intake.[25] The workup should include evaluation of the TTKG or the fractional excretion of potassium, an estimate of renal ammonium excretion (UAG, osmolar gap, and urine pH), and evaluation of plasma renin activity and aldosterone secretion. The latter may be obtained under stimulated conditions with dietary salt restriction and furosemide-induced volume depletion and the response of potassium excretion to furosemide and fludrocortisone.

The decision to treat is often based on the severity of the hyperkalemia. Reduction in serum potassium will often improve the metabolic acidosis by increasing ammonium excretion as potassium levels return to the normal range. Correction of hyperkalemia with sodium polystyrene can correct the metabolic acidosis as the serum potassium declines. [6] [25] Patients with combined glucocorticoid and mineralocorticoid deficiency should receive both adrenal steroids in replacement dosages. Additional measures may include laxatives, alkali therapy, or treatment with a loop diuretic to induce renal potassium and salt excretion ( Table 14-17 ). Volume depletion should be avoided unless the patient is volume overexpanded or hypertensive. Supraphysiologic doses of mineralocorticoids are rarely necessary and, if administered, should be done cautiously in combination with a loop diuretic to avoid volume overexpansion or aggravation of hypertension and to increase potassium excretion.[25] Infants with autosomal recessive or dominant PHA I should receive salt supplements in amounts sufficient to correct the volume depletion, hypotension, and other features of the syndrome and to allow normal growth. In contrast, patients with PHA II should receive thiazide diuretics along with dietary salt restriction. Although it may be prudent to discontinue drugs that are identified as the most likely cause of the hyperkalemia, this may not always be feasible in the patient with a life-threatening disorder, for example, during TMP-SMX or pentamidine therapy in the AIDS patient with Pneumocystis carinii pneumonia. Based on the previous analysis of the mechanism by which TMP and pentamidine cause hyperkalemia (voltage defect), it might also be reasoned that the delivery to the CCD of a poorly reabsorbed anion might improve the electrochemical driving force favoring K+ and H+ secretion. The combined use of acetazolamide along with sufficient sodium bicarbonate to deliver HCO3- to the CCT and thereby increase the negative transepithelial voltage could theoretically increase K+ and H+ secretion. Obviously with such an approach, aggravation of metabolic acidosis by excessive acetazolamide or insufficient NaHCO3 administration must be avoided.

TABLE 14-17   -- Treatment of Generalized Dysfunction of the Nephron with Hyperkalemia

Alkali therapy (Shohl solution or NaHCO3)

Loop diuretic (furosemide, bumetanide)

Sodium polystyrene sulfonate (Kayexalate)

Low-potassium diet



Fludrocortisone (0.1–0.3 mg/day)



Avoid in hypertension, volume expansion, heart failure



Combine with loop diuretic

Avoid drugs associated with hyperkalemia

In PHA I, add NaCl supplement




Distinguishing the Types of Renal Tubular Acidosis

The contrasting findings and diagnostic features of the three types of RTA discussed in this chapter are summarized in Table 14-18 :

TABLE 14-18   -- Contrasting Features and Diagnostic Studies in Renal Tubular Acidosis


Type of RTA



Classic Distal

Generalized Distal Dysfunction

Plasma [K+]




Urine pH with acidosis



<5.5 or >5.5

Urine net charge




Fanconi lesion




Fractional bicarbonate excretion









H+-ATPase defect



HCO3- -Cl-defect



Amphotericin B















Response to therapy

Least readily


Less readily

Associated features

Fanconi syndrome


Renal insufficiency


U-B PCO2, urine-blood CO2 tension.



See specific defects below.


Disorders of Impaired Net Acid Excretion and Impaired Bicarbonate Reclamation with normokalemia: Acidosis of Progressive Renal Failure

A reduction in functional renal mass by disease has long been known to be associated with acidosis.[28] The metabolic acidosis is initially hyperchloremic in nature (GFR in the range of 20-30 mL/min) but may convert to the normochloremic, high AG variety as renal insufficiency progresses and GFR falls below 15 mL/min. [28] [79]

The major defect in acidification is due to impaired net acid excretion. When the plasma HCO3- concentration is in the normal range, urine pH is relatively high (≥6.0), and net acid excretion is low. Unlike patients with distal RTA, patients with primary renal disease have a normal ability to lower the urine pH during acidosis.[28] The distal H+ secretory capacity is qualitatively normal and can be increased by buffer availability in the form of PO43- or by nonreabsorbable anions. Also in contrast to distal RTA, the U - B Pco2 gradient is normal in patients with reduced GFR, reflecting intact distal H+ secretory capacity.

The principal defect in net acid excretion in patients with reduced GFR is thus not an inability to secrete H+ in the distal nephron, but rather an inability to produce or to excrete NH4+. Consequently, the kidneys cannot quantitatively excrete all the metabolic acids produced daily, and metabolic acidosis supervenes.[28]

Although the acidosis of chronic progressive kidney disease is rarely severe, the argument can be made that the progressive dissolution of bone[28] and the impaired hydroxylation of 25-hydroxycholecalciferol by acidosis [28] [79]warrant treatment.

Moreover, chronic metabolic acidosis due to chronic progressive kidney disease prior to dialysis has other deleterious effects including: insulin resistance, suppression of the growth hormone/insulin-like growth factor (IGF)-1 cascade, increased levels of glucocorticoids, protein degradation, and muscle wasting. The latter is a result of activation of the ubiquitin-proteosome pathway. In general, it is accepted that alkali therapy helps to reverse these deleterious effects. An amount of alkali slightly in excess (1–2 mEq/kg/day) of dietary metabolic acid production usually restores acid-base equilibrium and prevents acid retention.[28] Fear of Na+ retention in chronic renal failure as a result of sodium bicarbonate administration appears ill founded. Unlike the case in sodium chloride therapy, patients with chronic renal disease retain administered sodium bicarbonate only as long as acidosis is present. Further sodium bicarbonate then exceeds the reabsorptive threshold and is excreted without causing an increase in weight or in blood pressure unless very large amounts are administered.

The clinical guidelines endorsed by the National Kidney Foundation (K/DOQI [Kidney disease outcomes quality initiative]) recommend monitoring of total CO2 in patients with chronic kidney disease (CKD) with a goal of maintaining the [HCO3-] above 22 mEq/L. Such therapy is based on the view that chronic metabolic acidosis has an adverse impact on muscle and bone metabolism.

Also of concern in chronic progressive kidney disease is the use of sevelamer hydrochloride, which has been shown in patients on chronic hemodialysis to result in significantly lower [HCO3-] compared with Ca2+-containing phosphate binders.[80] Although related to a lower intake of potential alkali, sevelamer may also provide an acid load.[81] Therefore, the clinician should be alert for changes in the [HCO3-] in the face of sevelamer treatment. A number of potential mechanisms exist for the acidosis associated with sevelamer. This agent binds monovalent phosphate in exchange for chloride in the gastrointestinal tract. For each molecule of monovalent phosphate bound, one molecule of HCl is liberated. Upon entry into the small intestine, exposure to pancreatic secretion of bicarbonate would result in the binding of bicarbonate by the polymer in exchange for chloride—much like the mechanism in chloride diarrhea. There may be other drug effects on bicarbonate in the colon as well.[82] As kidney disease progresses below a GFR of 15 mL/min, the non-AG acidosis typically evolves into the usual high AG acidosis of end-stage renal disease (see later).[80]

High Anion Gap Acidoses

The addition to the body of an acid load in which the attendant non-Cl- anion is not excreted rapidly results in the development of a high AG acidosis. The normochloremic acidosis is maintained as long as the anion that was part of the original acid load remains in the blood. AG acidosis is caused by the accumulation of organic acids. This may occur if the anion does not undergo glomerular filtration (e.g., uremic acid anions), if the anion is filtered but is readily reabsorbed, or if, because of alteration in metabolic pathways (ketoacidosis, L-lactic acidosis), the anion cannot be utilized. Theoretically, with a pure AG acidosis, the increment in the AG (DAG) above the normal value of 10 mEq/L should equal the decrease in bicarbonate concentration (DHCO3-) below the normal value of 25 mEq/L. When this relationship is considered, circumstances in which the increment in the AG exceeds the decrement in bicarbonate (DAG > DHCO3-) suggest the coexistence of a metabolic alkalosis. Such findings are not unusual when uremia leads to vomiting, for example.

Identification of the underlying cause of a high AG acidosis is facilitated by consideration of the clinical setting and associated laboratory values. The common causes are outlined in Table 14-19 and include: (1) lactic acid acidosis (e.g., L-lactic acidosis and d-lactic acidosis), (2) ketoacidosis (e.g., diabetic, alcoholic, and starvation ketoacidoses), (3) toxin- or poison-induced acidosis (e.g., ethylene glycol, methyl alcohol, or toluene poisoning), and (4) uremic acidosis. Initial screening to differentiate the high AG acidoses should include: (1) a history or other evidence of drug and toxin ingestion and ABG measurement to detect coexistent respiratory alkalosis (salicylates), (2) historical evidence of diabetes mellitus (DKA), (3) evidence of alcoholism or increased levels of β-hydroxybutyrate (alcoholic ketoacidosis), (4) observation for clinical signs of uremia and determination of the blood urea nitrogen and creatinine (uremic acidosis), (5) inspection of the urine for oxalate crystals (ethylene glycol), and finally, (6) recognition of the numerous settings in which lactic acid levels may be increased (hypotension, cardiac failure, ischemic bowel, intestinal obstruction and bacterial overgrowth, leukemia, cancer, and with certain drugs).

TABLE 14-19   -- Metabolic Acidosis with High Anion Gap

Conditions associated with type A lactic acidosis

Hypovolemic shock


Septic shock

Cardiogenic shock

 Low-output heart failure

 High-output heart failure

Regional hypoperfusion

Severe hypoxia

Severe asthma

Carbon monoxide poisoning

Severe anemia



Conditions associated with type B lactic acidosis



Liver disease



Diabetes mellitus



Catecholamine excess









Thiamine deficiency



Intracellular inorganic phosphate depletion



Intravenous fructose



Intravenous xylose



Intravenous sorbitol



Alcohols and other ingested compounds metabolized by alcohol












Ethylene glycol



Propylene glycol



Mitochondrial toxins



Salicylate intoxication



Cyanide poisoning



2,4-Dinitrophenol ingestion



Non-nucleoside antireverse transcriptase drugs



Other drugs









Inborn errors of metabolism



D-Lactic acidosis



Short-bowel syndrome



Ischemic bowel



Small bowel obstruction















Other toxins









Pyroglutamic acid

Uremia (late renal failure)




Lactic Acidosis


Lactic acid can exist in two forms: L-lactate and d-lactate. In mammals, only the levorotary form is a product of metabolism. d-Lactate can accumulate in humans as a byproduct of metabolism by bacteria, which accumulate and overgrow in the gastrointestinal tract with jejunal bypass or short bowel syndrome. Thus, d-lactic acid acidosis is a rare cause of a high AG acidosis. Hospital chemical laboratories measure routinely L-lactic acid levels, not d-lactic acid levels. Thus, most of the remarks that follow apply to L-lactic acid metabolism and acidosis except as noted. L-lactic acidosis is one of the most common forms of a high AG acidosis.

Although lactate metabolism bears a close relationship to that of pyruvate,[83] lactic acid is in a metabolic cul-de-sac with pyruvate as its only outlet. In most cells, the major metabolic pathway for pyruvate is oxidation in the mitochondria to acetyl coenzyme A by the enzyme pyruvate dehydrogenase within the mitochordria. The overall reaction is usually expressed as:

(32)  Pyruvate- + NADH ↔ lactate- + NAD + H+

Normally, this cytosolic reaction catalyzed by the enzyme lactate dehydrogenase (LDH) is close to equilibrium, so that the law of mass action applies and the equation is rearranged as:

(33)  001020

The lactate concentration is a function of the equilibrium constant (Keq), the pyruvate concentration, the cytosolic pH, and the intracellular redox state represented by the pyridine nucleotide concentration ratio [NADH]/[NAD+].[83]

After rearranging the mass action equation, the ratio of lactate concentration to pyruvate concentration may be expressed as

(34)  000965

Because Keq and intracellular H+ concentration are relatively constant, the normal lactate-to-pyruvate concentration ratio (1.0/0.1 mEq/L) is proportional to the NADH/NAD+ concentration ratio. The lactate-to-pyruvate ratio is regulated by the oxidation-reduction potential of the cell, therefore.

NADH/NAD+ is also involved in many other metabolic redox reactions.[83] Moreover, the steady-state concentrations of all these redox reactants are related to one another. Im-portant in considerations in acid-base pathophysiology are the redox pairs β-hydroxybutyrate-acetoacetate and ethanol-acetaldehyde. The ratio of the reduced to the oxidized forms of these molecules is thus a function of the cellular redox potential:


If the lactate concentration is high compared with that of pyruvate, NAD+ would be depleted, and the NADH/NAD+ ratio would increase. Likewise, all the other related redox ratios previously listed would be similarly affected; that is, both the β-hydroxybutyrate/acetoacetate and the ethanol-to-acetaldehyde ratios would increase. In clinical practice, these considerations are of practical importance. If lactate levels are increased as a result of lactic acidosis con-currently with ketone overproduction as a result of diabetic acidosis, the ketones exist primarily in the form of β-hydroxybutyrate. Tests for ketones that measure only acetoacetate (such as the nitroprusside reaction, e.g., Acetest tablets and reagent sticks), therefore, may be misleadingly low or even negative despite high total ketone concentra-tions. Similarly, high levels of alcohol plus ketones shift the redox ratio, so that the NADH/NAD+ ratio is increased. Again, ketones would then be principally in the form of β-hydroxybutyrate. This situation is commonly found in alcoholic ketoacidosis (AKA), in which qualitative ketone tests that are more sensitive to acetoacetate are frequently only trace positive or negative, despite markedly increased β-hydroxybutyrate levels.

The L-lactate concentration can be increased in two ways relative to the pyruvate concentration. First, when pyruvate production is increased at a constant intracellular pH and redox stage, the lactate concentration increases at a constant lactate-to-pyruvate ratio of 10. In contrast, states in which the production of lactate exceeds the ability to convert to pyruvate, so that the NADH/NAD+ redox ratio is increased, an increased L-lactate concentrations is observed, but with a lactate-to-pyruvate ratio greater than 10. This defines an excess lactate state.

Therefore, the concentration of lactate must be viewed in terms of cellular determinants (e.g., the intracellular pH and redox state) as well as the total body production and removal rates. Normally, the rates of lactate entry and exit from the blood are in balance, so that net lactate accumulation is zero. This dynamic aspect of lactate metabolism is termed the Cori cycle:


As can be envisioned by this relationship, either net overproduction of lactic acid from glucose by some tissues or underutilization by others results in net addition of L-lactic acid to the blood and lactic acid acidosis. However, ischemia accelerates both lactate production and decreases, simultaneously, lactate utilization.

The production of lactic acid has been estimated to be about 15 to 30 mEq/kg/day in normal humans.[28] This enormous quantity contrasts with total ECF buffer base stores of about 10 to 15 mEq/kg and with enhanced production can accumulate. The rate of lactic acid production can be increased with ischemia, seizures, extreme exercise, leukemia, and alkalosis.[83] The increase in production occurs principally through enhanced phosphofructokinase activity.

Decreased lactate consumption more commonly leads to L-lactic acidosis. The principal organs for lactate removal during rest are the liver and kidneys. Both the liver and the kidneys and perhaps muscle have the capacity for increased lactate removal under the stress of increased lactate loads.[83] Hepatic utilization of lactate can be impeded by several factors: poor perfusion of the liver; defective active transport of lactate into cells, or inadequate metabolic conversion of lactate into pyruvate because of altered intracellular pH, redox state, or enzyme activity. Examples of impaired hepatic lactate removal include primary diseases of the liver, enzymatic defects, tissue anoxia or ischemia, severe acidosis, altered redox states, as occurs with alcohol intoxication, fructose, or administration of nucleoside analog reverse transcriptase inhibitors (NRTIs) such as zidovudine and stavudine in patients with HIV infection [83] [84] [85] and biguanides such as phenformin or metformin. [83] [86] [87] Deaths have been reported due to refractory lactic acidosis secondary to thiamine deficiency in patients receiving parenteral nutrition formulations without thiamine.[88] Thiamine is a cofactor for pyruvate dehydrogenase that catalyzes the oxidative decarboxylation of pyruvate to acetyl coenzyme A under aerobic conditions. Pyruvate cannot be metabolized in this manner with thiamine deficiency, converting excess pyruvate to hydrogen ions and lactate.

The quantitative aspects of normal lactate production and consumption in the Cori cycle demonstrate how the development of lactic acidosis can be the most rapid and devastating form of metabolic acidosis. [83] [89]


Because lactic acid has a pKa of 3.8, lactic acid addition to the blood leads to a reduction in blood HCO3- concentration and an equivalent elevation in lactate concentration; which is associated with an increase in the AG. Lactate concentrations are mildly increased in various nonpathologic states (e.g., exercise), but the magnitude of the elevation is generally small. In practical terms, a lactate concentration greater than 4 mEq/L (normal is 1 mEq/L) is generally accepted as evidence that the metabolic acidosis is ascribable to net lactic acid accumulation.

Clinical Spectrum

In the classical classification of the L-lactic acidoses (see Table 14-19 ), type A L-lactic acidosis is due to tissue hypoperfusion or acute hypoxia, whereas type B L-lactic acidosis is associated with common diseases, drugs and toxins, and hereditary and miscellaneous disorders.[83]

Tissue underperfusion and acute underoxygenation at the tissue level (tissue hypoxia) are the most common causes of type A lactic acidosis. Severe arterial hypoxemia even in the absence of decreased perfusion can generate L-lactic acidosis. Inadequate cardiac output, of either the low-output or the high-output variety, is the usual pathogenetic factor. The prognosis is related directly to the increment in plasma L-lactate and the severity of the acidemia. [83] [87] [89]

Numerous medical conditions (without tissue hypoxia) predispose to type B L-lactic acidosis (see Table 14-19 ). Hepatic failure reduces hepatic lactate metabolism, and leukemia increases lactate production. Severe anemia, especially as a result of iron deficiency or methemoglobulinemia, may cause lactic acidosis. Among the most common causes of L-lactic acid acidosis is bowel ischemia and infarction in patients in the medical intensive care unit. Malignant cells produce more lactate than normal cells even under aerobic conditions. This phenomenon is magnified if the tumor expands rapidly and outstrips the blood supply. Therefore, exceptionally large tumors may be associated with severe L-lactic acid acidosis. Seizures, extreme exertion, heat stroke, and tumor lysis syndrome may all cause L-lactic acidosis.

Several drugs and toxins predispose to L-lactic acidosis (see Table 14-19 ). Of these, metformin and other biguanides (such as phenformin) are the most widely reported. [83] [86] [87] The occurrence of phenformin-induced lactic acidosis prompted the withdrawal of the drug from U.S. markets in 1977. Although much less frequent with metformin than with phenformin, metformin-induced lactic acidosis has been reported in association with volume depletion and with contrast dye administration. Fructose causes intracellular ATP depletion and lactate accumulation.[83] Inborn errors of metabolism may also cause lactic acidosis, primarily by blocking gluconeogenesis or by inhibiting the oxidation of pyruvate.[83] Carbon monoxide poisoning produces lactic acidosis frequently by reduction of the oxygen-carrying capacity of hemoglobin. Cyanide binds cytochrome a and a3 and blocks the flow of electrons to oxygen. Nucleoside analogs in patients with HIV infections can induce toxic effects on mitochondria by inhibiting DNA polymerase gamma. Hyperlactatemia is common with NRTI therapy, especially stavudine and zidovudine, but the serum L-lactate is usually only mildly elevated and compensated. [83] [84] [85] [90] Nevertheless, with severe concurrent illness, pronounced lactic acidosis may occur in association with hepatic steatosis. [83] [85] This combination carries a high mortality. Propylene glycol is used as a vehicle for intravenous medications and some cosmetics and is metabolized to lactic acid in the liver by alcohol dehydrogenase. The lactate is metabolized to pyruvic acid and shunted to the glycolytic pathway. Scattered case reports have described hyperosmolality with or without L-lactic acidosis when propylene glycol was used as a vehicle to deliver topical silver sulfadiazine cream, intravenous diazepam or lorazepam (in alcohol withdrawal), intravenous nitroglycerin, and etomidate. [91] [92] A prospective study of nine patients receiving high-dose lorezepam infusions[91] showed elevated plasma propylene levels and an elevated osmolar gap. Six of nine patients had moderate degrees of metabolic acidosis.[91]

Associated Clinical Features

Hyperventilation, abdominal pain, and disturbances in consciousness are frequently present, as are signs of inadequate cardiopulmonary function in type A L-lactic acidosis. Leukocytosis, hyperphosphatemia, hyperuricemia, and hyperaminoacidemia (especially alanine) are common, and hypoglycemia may occur.[83] Hyperkalemia may or may not accompany acute lactic acidosis.

Treatment of L-Lactic Acidosis

General Supportive Care.

The overall mortality in L-lactic acidosis is 60% to 70% but approaches 100% with coexisting hypotension.[83] Therapy for this condition has not advanced substantively for the last 2 decades. The basic principle and only effective form of therapy for L-lactic acidosis is that the underlying condition initiating the disruption in normal lactate metabolism must first be corrected. In type A L-lactic acidosis, cessation of acid production by improving tissue oxygenation, restoration of the circulating fluid volume, improvement or augmentation of cardiac function, resection of ischemic tissue, and amelioration of sepsis are necessary in many cases. Septic shock requires control of the underlying infection and volume resuscitation in hypovolomic shock. Hypothetically, interruption of the cytokine cascade may be advantageous but not yet applicable. High L-lactate levels portend a poor prognosis almost uniformly, and sodium bicarbonate is of little value. Vasoconstricting agents are problematic because they may potentiate the hypoperfused state. Dopamine is preferred to epinephrine if pressure support is required, but the vasodilator nitroprusside has been suggested because it may enhance cardiac output and hepatic and renal blood flow to augment lactate removal.[83] Nevertheless, nitroprusside therapy may result in cyanide toxicity and has no proven efficacy in the treatment of this disorder.

Alkali Therapy.

Alkali therapy is generally advocated for acute, severe acidemia (pH < 7.1) to improve inotropy and lactate utilization. However, in experimental models and clinical examples of lactic acidosis, it has been shown that NaHCO3therapy in large amounts can depress cardiac performance and exacerbate the acidemia. Parodoxically, bicarbonate therapy activates phosphofructokinase, thereby increasing lactate production. The use of alkali in states of moderate L-lactic acidemia is controversial, therefore, and it is generally agreed that attempts to normalize the pH or HCO3- concentration by intravenous NaHCO3 therapy is both potentially deleterious and practically impossible. Thus, raising the plasma HCO3- to approximately 15 to 17 mEq/L and the pH to 7.2 to 7.25 is a reasonable goal to improve tissue pH. Constant infusion of hypertonic bicarbonate has many disadvantages and is discouraged.

Fluid overload occurs rapidly with NaHCO3 administration because of the massive amounts required in some cases. In addition, central venoconstriction and decreased cardiac output are common. The accumulation of lactic acid may be relentless and may necessitate diuretics, ultrafiltration, or dialysis. Hemodialysis can simultaneously deliver HCO3-, remove lactate, remove excess ECF volume, and correct electrolyte abnormalities. The use of continuous renal replacement therapy as a means of lactate removal and simultaneous alkali addition is a promising adjunctive treatment in critically ill patients with L-lactic acidosis.

If the underlying cause of the L-lactic acidosis can be remedied, blood lactate will be reconverted to HCO3-. HCO3- derived from lactate conversion and any new HCO3- generated by renal mechanisms during acidosis and from exogenous alkali therapy are additive and may result in an overshoot alkalosis.

Other Agents.

Dichloroacetate, an activator of pyruvate dehydrogenase, was suggested in an uncontrolled study as a potentially useful therapeutic agent. In experimental L-lactic acidosis, dichloroacetate stimulated lactate consumption in muscle and, hence, decreased lactate production and improved survival. In nonacidotic diabetic patients, it successfully lowered lactate as well as glucose, lipid, and amino acid levels. Despite encouraging results of short-term clinical use in acute lactic acidosis, a prospective multicenter trial failed to substantiate any beneficial effect of dichloroacetate therapy.[93] The drug cannot be used chronically. Methylene blue was once advocated as a means of reversing the altered redox state to enhance lactate metabolism. There is no evidence from controlled studies supporting its use. THAM (0.3 M tromethamine) or other preparations of this type are not effective.[83] Tribonat, a mixture of THAM, acetate, NaHCO3, and phosphate, although apparently an effective clinical buffer, has shown no survival advantage in limited clinical trials.[94] Ringer's lactate and lactate-containing peritoneal dialysis solutions should be avoided.

d-Lactic Acidosis.

The manifestations of d-lactate acid acidosis are typically episodic encephalopathy and high AG acidosis in association with short bowel syndrome. Features include slurred speech, confusion, cognitive impairment, clumsiness, ataxia, hallucinations, and behavioral disturbances. d-Lactic acidosis has been described in patients with bowel obstruction, jejunal bypass, short bowel, or ischemic bowel disease. These disorders have in common ileus or stasis associated with overgrowth of flora in the gastrointestinal tract and is exacerbated by a high-carbohydrate diet.[83] d-Lactate, therefore, occurs when fermentation by colonic bacteria in the intestine accumulates and can be absorbed into the circulation. d-Lactate is not measured by the typical clinical laboratory that reports the L-isomer. The disorder should be suspected in patients with an unexplained AG acidosis and some of the typical features noted previously. While waiting for results of specific testing, the patient should be made NPO. Serum d-lactate levels of greater than 3 mmol/L confirm the diagnosis. Treatment with a low-carbohydrate diet and antibiotics (neomycin, vancomycin, or metronidazole) is often effective. [95] [96] [97] [98]


Diabetic Ketoacidosis

DKA is due to increased fatty acid metabolism and the accumulation of keto acids (acetoacetate and β-hydroxybutyrate) as a result of insulin deficiency or resistance in association with elevated glucagon levels. DKA is usually seen in insulin-dependent diabetes mellitus in association with cessation of insulin or an intercurrent illness, such as an infection, gastroenteritis, pancreatitis, or myocardial infarction, which increases insulin requirements temporarily and acutely. The accumulation of keto acids accounts for the increment in the AG, which is accompanied, most often, by evidence of hyperglycemia (glucose > 300 mg/dL). In comparison to patients with AKA, described later, DKA is associated with metabolic profiles characterized by a higher plasma glucose, lower β-hydroxybutyrate-to-acetoacetate and lactate-to-pyruvate ratios. [27] [98] [99]

Treatment of Diabetic Ketoacidosis.

Most, if not all, patients with DKA require correction of the volume depletion that almost invariably accompanies the osmotic diuresis and ketoacidosis. In general, it seems prudent to initiate therapy with intravenous isotonic saline at a rate of 1000 mL/hr, especially in the severely volume-depleted patient. When the pulse and blood pressure have stabilized and the corrected serum Na+ concentration is in the range 130 to 135 mEq/L, switch to 0.45% sodium chloride. Ringer lactate should be avoided. If the blood glucose level falls below 300 mg/dL, 0.45% sodium chloride with 5% dextrose should be administered. [27] [98]

Low-dose intravenous insulin therapy (0.1 U/kg/hr) smoothly corrects the biochemical abnormalities and minimizes hypoglycemia and hypokalemia. [27] [98] Usually, in the first hour, a loading dose of the same amount is given initially as a bolus intravenously. Intramuscular insulin is not effective in patients with volume depletion, which often occurs in ketoacidosis.

Total body K+ depletion is usually present, although the K+ level on admission may be elevated or normal. A normal or reduced K+ value on admission indicates severe K+ depletion and should be approached with caution. Administration of fluid, insulin, and alkali may cause the K+ level to plummet. When the urine output has been established, 20 mEq of potassium chloride should be administered in each liter of fluid as long as the K+ value is less than 4.0 mEq/L. Equal caution should be exercised in the presence of hyperkalemia, especially if the patient has renal insufficiency, because the usual therapy does not always correct hyperkalemia. Never administer potassium chloride empirically.

The young patient with a pure AG acidosis (DAG = DHCO3-) usually does not require exogenous alkali because the metabolic acidosis should be entirely reversible. Elderly patients, patients with severe high AG acidosis (pH < 7.15), or patients with a superimposed hyperchloremic component may receive small amounts of sodium bicarbonate by slow intravenous infusion (no more than 44-88 mEq in 60 min). Thirty minutes after this infusion is completed, ABGs should be repeated. Alkali administration can be repeated if the pH is 7.20 or less or if the patient exhibits a significant hyperchloremic component but is rarely necessary. The AG should be followed closely during therapy because it is expected to decline as ketones are cleared from plasma and herald an increase in plasma HCO3- as the acidosis is repaired. Therefore, it is not necessary to monitor blood ketone levels continuously. Hypokalemia and other complications of alkali therapy dramatically increase when amounts of sodium bicarbonate exceeding 400 mEq are administered. However, the effect of alkali therapy on arterial blood pH needs to be reassessed regularly, and the total administered kept at a minimum, if necessary. [27] [98] [99]

Routine administration of PO43- (usually as potassium phosphate) is not advised because of the potential for hyperphosphatemia and hypocalcemia. [27] [98] A significant propor-tion of patients with DKA have significant hyperphospha-temia before initiation of therapy. In the volume-depleted, malnourished patient, however, a normal or elevated PO43- concentration on admission may be followed by a rapid fall in plasma PO43- levels within 2 to 6 hours after initiation of therapy.

Alcoholic Ketoacidosis

Some chronic alcoholics, especially binge drinkers, who discontinue solid food intake while continuing alcohol consumption develop this form of ketoacidosis when alcohol ingestion is curtailed abruptly. [27] [98] [99] Usually the onset of vomiting and abdominal pain with dehydration leads to cessation of alcohol consumption before presentation to the hospital. [27] [99] The metabolic acidosis may be severe but is accompanied by only modestly deranged glucose levels, which are usually low but may be slightly elevated. [27] [99] Typically, insulin levels are low and levels of triglyceride, cortisol, glucagon, and growth hormone are increased. The net result of this deranged metabolic state leads to ketosis. The acidosis is primarily due to elevated ketone levels, which exist predominantly in the form of β-hydroxybutyrate because of the altered redox state induced by the metabolism of alcohol. Compared with patients with DKA, patients with AKA have lower plasma glucose concentrations and higher β-hydroxybutyrate-to-acetoacetate and lactate-to-pyruvate levels. [27] [99] This disorder is not rare and is underdiagnosed. The clinical presentation in AKA may be complex because a mixed disorder is often present and due to metabolic alkalosis (vomiting), respiratory alkalosis (alcoholic liver disease), lactic acid acidosis (hypoperfusion), and hyperchloremic acidosis (renal excretion of ketoacids). Finally, the osmolar gap is elevated if the blood alcohol level is elevated, but the differential should always include ethylene glycol and/or methanol intoxication.


Therapy includes intravenous glucose and saline administration, but insulin should be avoided. K+, PO43-, Mg2+, and vitamin supplementation (especially thiamine) are frequently necessary. Glucose in isotonic saline, not saline alone, is the mainstay of therapy. Because of superimposed starvation, patients with AKA often develop hypophosphatemia within 12 to 18 hours of admission. Treatment with glucose-containing intravenous fluids increases the risk for severe hypophosphatemia. Levels should be checked on admission and at 4, 6, 12, and 18 hours. Profound hypophosphatemia may provoke aspiration, platelet dysfunction, and rhabdomyolysis. Therefore, phosphate replacement should be provided promptly when indicated. Hypokalemia and hypomagnesemia are also common and should not be overlooked. [27] [99]

Starvation Ketoacidosis

Ketoacidosis occurs within the first 24 to 48 hours of fasting, is accentuated by exercise and pregnancy, and is rapidly reversible by glucose or insulin. Starvation-induced hypoinsulinemia and accentuated hepatic ketone production have been implicated pathogenetically. [27] [99] Fasting alone can in-crease ketoacid levels, although not usually above 10 mEq/L. High-protein, weight-loss diets typically cause mild ketosis but not ketoacidosis. Patients typically respond to glucose and saline infusion.

Drug- and Toxin-induced Acidosis


Intoxication by salicylates, although more common in children than in adults, may result in the development of a high AG metabolic acidosis, but the acid-base abnormality most commonly associated with salicylate intoxication in adults is respiratory alkalosis due to direct stimulation of the respiratory center by salicylates.[98] Adult patients with salicylate intoxication usually have pure respiratory alkalosis or mixed respiratory alkalosis-metabolic acidosis.[98] Metabolic acidosis occurs due to uncoupling of oxidative phosphorylation and enhances the transit of salicylates into the central nervous system. Only part of the increase in the AG is due to the increase in plasma salicylate concentration, because a toxic salicylate level of 100 mg/dL would account for an increase in the AG of only 7 mEq/L. High ketone concentrations have been reported to be present in as many as 40% of adult salicylate-intoxicated patients, sometimes as a result of salicylate-induced hypoglycemia.[100] L-Lactic acid production is also often increased, partly as a direct drug effect[98] and partly as a result of the decrease in Pco2 induced by salicylate. Proteinuria and pulmonary edema may occur.


General treatment should always consist of initial vigorous gastric lavage with isotonic saline followed by administration of activated charcoal per nasogastric tube. Treatment of the metabolic acidosis may be necessary because acidosis can enhance the entry of salicylate into the central nervous system. Alkali should be given cautiously and frank alkalemia should be avoided. Coexisting respiratory alkalosis can make this form of therapy hazardous. The renal excretion of salicylate is enhanced by an alkaline diuresis accomplished with intravenous NaHCO3. Caution is urged if the patient exhibits concomitant respiratory alkalosis with frank alkalemia because NaHCO3 may cause severe alkalosis and hypokalemia may result from alkalinization of the urine. To minimize the administration of NaHCO3, acetazolamide may be administered to the alkalemic patient, but this can cause acidosis and impair salicylate elimination. Hemodialysis may be necessary for severe poisoning, especially if renal failure coexists, is preferred with severe intoxication (>700 mg/L), and is superior to hemofiltration, which does not correct the acid-base abnormality. [98] [100]

Toxin-Induced Metabolic Acidoses

The Osmolar Gap in Toxin-induced Acidosis.

Under most physiologic conditions, Na+, urea, and glucose generate the osmotic pressure of blood. Serum osmolality is calculated according to the expression:

(37)  001026

The calculated and determined osmolalities should agree within 10 to 15 mOsm/kg. When the measured osmolality exceeds the calculated osmolality by more than 15 to 20 mOsm/kg, one of two circumstances prevails. First, the serum Na+ may be spuriously low, as occurs with hyperlipidemia or hyperproteinemia (pseudohyponatremia); or second, osmolytes other than sodium salts, glucose, or urea have accumulated in plasma. Examples include infused mannitol, radiocontrast media, or other solutes, including the alcohols, ethylene glycol, and acetone, that can increase the osmolality in plasma. In these examples, the difference between the osmolality calculated from Equation 37 and the measured osmolality is proportional to the concentration of the unmeasured solute. Such differences in these clinical circumstances have been referred to as the osmolar gap. With an appropriate clinical history and index of suspicion, the osmolar gap becomes a very reliable and helpful screening tool in toxin-associated high AG acidosis.


Ethanol, after absorption from the gastrointestinal tract, is oxidized to acetaldehyde, acetyl coenzyme A, and CO2. A blood ethanol level over 500 mg/dL is associated with high mortality. Acetaldehyde levels do not increase appreciably unless the load is exceptionally high or the acetaldehyde dehydrogenase step is inhibited by compounds such as disulfiram, insecticides, and sulfonylurea hypoglycemia agents. Such agents in the presence of ethanol result in severe toxicity. The association of ethanol with the development of AKA and lactic acidosis has been discussed in the previous section, but in general, ethanol intoxication does not cause a high AG acidosis.

Ethylene Glycol.

Ingestion of ethylene glycol, used in antifreeze, leads to a high AG metabolic acidosis in addition to severe central nervous system, cardiopulmonary, and renal damage. [98] [101] [102] The high AG is attributable to ethylene glycol metabolites, especially oxalic acid, glycolic acid, and other incompletely identified organic acids.[102] L-Lactic acid production also increases as a result of a toxic depression in the reaction rates of the citric acid cycle and altered intracellular redox state.[102] Recognizing oxalate crystals in the urine facilitates diagnosis, as does fluoresence of urine by a Wood's light if the ingested ethylene glycol contains a fluorescent vehicle. [101] [102] A disparity between the measured blood osmolality and that calculated (high osmolar gap) is often present. Treatment includes prompt institution of osmotic diuresis, thiamine and pyridoxine supplements, 4-methylpyrazole (fomepizole),[103] or ethyl alcohol and dialysis. [98] [101] [103] Ethanol or fomepizole should be given intravenously. Competitive inhibition of alcohol dehydrogenase with one of these agents is absolutely necessary in all patients to lessen toxicity because ethanol and fomepizole compete for metabolic conversion of ethylene glycol and alters the cellular redox state. Fomepizole (initiated as a loading dose of 7 mg/kg) offers the advantages of a predictable decline in ethylene glycol levels without the adverse effect of excessive obtundation, as seen with ethyl alcohol infusion. When these measures have been accomplished, hemodialysis should be initiated to remove the ethylene glycol metabolites. At this juncture the intravenous ethanol infusion should be increased to allow maintenance of the blood alcohol level in the range of 100 to 150 mg/dL or greater than 22 mmol/L.


Methanol (wood alcohol) ingestion causes metabolic acidosis in addition to severe optic nerve and central nervous system manifestations resulting from its metabolism to formic acid from formaldehyde. [98] [101] Lactic acids and keto acids as well as other unidentified organic acids may contribute to the acidosis. Because of the low molecular mass of methanol (32 Da), an osmolar gap is usually present. Therapy is generally similar to that for ethylene glycol intoxication, including general supportive measures, ethanol or fomepizole administration, and sometimes, hemodialysis.[103]

Isopropyl Alcohol.

Rubbing alcohol poisoning is usually the result of accidental oral ingestion or absorption through the skin. Although isopropyl alcohol is metabolized by the enzyme alcohol dehydrogenase, as are methanol and ethanol, isopropyl alcohol is not metabolized to a strong acid and does not elevate the AG. Isopropyl alcohol is metabolized to acetone, and the osmolar gap increases as the result of accumulation of both acetone and isopropyl alcohol. Despite a positive nitroprusside reaction from acetone, the AG, as well as the blood glucose, is typically normal, not elevated, and the plasma HCO3- is not depressed. Thus, isopropyl alcohol intoxication does not typically cause metabolic acidosis. Treatment is supportive, with attention to removal of unabsorbed alcohol from the gastrointestinal tract and administration of intravenous fluids. Hemodialysis is effective but not usually necessary. Although patients with significant isopropyl alcohol intoxication (blood levels > 100 mg/dL) may develop cardiovascular collapse and lactic acidosis, watchful waiting with a conservative approach (intravenous. fluids, electrolyte replacement, and tracheal intubation) is often sufficient. Very severe intoxication (>400 mg/dL) is an indication for hemodialysis.[98]


Intoxication with paraldehyde is now very rare, but is a result of acetic acid accumulation, the metabolic product of the drug from acetaldehyde and other organic acids.

Pyroglutamic Acidosis.

Pyroglutamic acid, or 5-oxoproline, is an intermediate in the γ-glutamyl cycle for the synthesis of glutathione. Acetaminophen ingestion can rarely deplete glutathione, resulting in increased formation of γ-glutamyl cysteine, which is metabolized to pyroglutamic acid.[104] Accumulation of this intermediate, first appreciated in the rare patient with congenital glutathione synthetase deficiency, has been observed recently in an acquired variety. Those patients observed thus far have severe high AG acidosis and alterations in mental status.[104] Many were septic and receiving full therapeutic doses of acetaminophen. All had elevated blood levels of pyroglutamic acid, which increased in proportion to the increase in the AG. It is conceivable that the heterozygote state for glutathione synthetase deficiency could predispose to proglutamic acidosis, because only a minority of critically ill patients on acetaminophen develop this newly appreciated form of metabolic acidosis.[104]


Advanced renal insufficiency eventually converts the hyperchloremic acidosis discussed earlier to a typical high AG acidosis.[28] Poor filtration plus continued reabsorption of poorly identified uremic organic anions contributes to the pathogenesis of this metabolic disturbance.

Classic uremic acidosis is characterized by a reduced rate of NH4+ production and excretion because of cumulative and significant loss of renal mass. [4] [5] [19] [28] Usually, acidosis does not occur until a major portion of the total functional nephron population (>75%) has been destroyed, because of the ability of surviving nephrons to increase ammoniagenesis. Eventually, however, there is a decrease in total renal ammonia excretion as renal mass is reduced to a level at which the GFR is 20 mL/min or less. PO43- balance is maintained as a result of both hyperparathyroidism, which decreases proximal PO43- absorption, and an increase in plasma PO43- as GFR declines. Protein restriction and the administration of phosphate biners reduce the availability of PO43-.

Treatment of Acidosis of Chronic Renal Failure.

The uremic acidosis of renal failure requires oral alkali replacement to maintain the HCO3- concentration above 20 mEq/L. This can be accomplished with relatively modest amounts of alkali (1.0–1.5 mEq/kg/day). Shohl solution or sodium bicarbonate tablets (325- or 650-mg tablets) are equally effective. It is assumed that alkali replacement serves to prevent the harmful effects of prolonged positive H+ balance, especially progressive catabolism of muscle and loss of bone. Because sodium citrate (Shohl solution) has been shown to enhance the absorption of aluminum from the gastrointestinal tract, it should never be administered to patients receiving aluminum-containing antacids because of the risk of aluminum intoxication. When hyperkalemia is present, furosemide (60–80 mg/day) should be added. An occasional patient may require chronic sodium polystyrene sulfonate (Kayexalate) therapy orally (15–30 g/day). The pure powder preparation is better tolerated long term than the commercially available syrup preparation and avoids sorbitol (which may cause bowel necrosis). The powder may be obtained from www.drugstore.com000672 (454 g for $246).

Metabolic Alkalosis

Diagnosis of Simple and Mixed Forms of Metabolic Alkalosis

Metabolic alkalosis is a primary acid-base disturbance that is manifest in the most pure or simple form as alkalemia (elevated arterial pH) and an increase in Paco2 as a result of compensatory alveolar hypoventilation. Metabolic alkalosis is one of the more common acid-base disturbances in hospitalized patients, and occurs as both a simple and a mixed disorder. [11] [104]

A patient with a high plasma HCO3- concentration and a low plasma Cl- concentration has either metabolic alkalosis or chronic respiratory acidosis. The arterial pH establishes the diagnosis, because it is increased in metabolic alkalosis and is typically decreased in respiratory acidosis. Modest increases in the Paco2 are expected in metabolic alkalosis. A combination of the two disorders is not unusual, because many patients with chronic obstructive lung disease are treated with diuretics, which promote ECF contraction, hypokalemia, and metabolic alkalosis. Metabolic alkalosis is also frequently observed not as a pure or simple acid-base disturbance, but in association with other disorders such as respiratory acidosis, respiratory alkalosis, and metabolic acidosis (mixed disorders). Mixed metabolic alkalosis-metabolic acidosis can be appreciated only if the accompanying metabolic acidosis is a high AG acidosis. The mixed disorder can be appreciated by comparison of the increment in the AG above the normal value of 10 mEq/L (DAG = Patient's AG - 10), with the decrement in the [HCO3-] below the normal value of 25 mEq/L (DHCO3- = 25 - Patient's HCO3-). A mixed metabolic alkalosis-high AG metabolic acidosis is recognized because the delta values are not similar. Often, there is no bicarbonate deficit, yet the AG is significantly elevated. Thus, in a patient with an AG of 20 but a near-normal bicarbonate, mixed metabolic alkalosis-metabolic acidosis should be considered. Common examples include renal failure acidosis (uremic) with vomiting or DKA with vomiting.

Respiratory compensation for metabolic alkalosis is less predictable than for metabolic acidosis. In general the anticipated Pco2 can be estimated by adding 15 to the patient's serum [HCO3-] in the range of HCO3- from 25 to 40 mEq/L. Further elevation in Pco2 is limited by hypoxemia and, to some extent, hypokalemia, which accompanies metabolic alkalosis with regularity. Nevertheless, if a patient has a Pco2 of only 40 mm Hg while the [HCO3-] is frankly elevated (e.g., 35 mEq/L) and the pH is in the alkalemic range, then respiratory compensation is inadequate and a mixed metabolic alkalosis-respiratory alkalosis exists.

In assessing a patient with metabolic alkalosis, two questions must be considered: (1) What is the source of alkali gain (or acid loss) that generated the alkalosis? (2) What renal mechanisms are operating to prevent excretion of excess HCO3-, thereby maintaining, rather than correcting, the alkalosis? In the following discussion, the entities responsible for generating alkalosis are discussed individually and reference is made to the mechanisms necessary to sustain the increase in blood HCO3- concentration in each case. The general mechanisms responsible for the maintenance of alkalosis have been discussed in detail earlier in this chapter, but are a result of the combined effects of chloride, ECF volume, and potassium depletion ( Fig. 14-9 ).



FIGURE 14-9  Pathophysiologic basis and approach to treatment of maintenance phase of chronic metabolic alkalosis. Paradoxical stimulation of bicarbonate absorption (H+ secretion) and NH4+ production and excretion is the combined result of Cl- deficiency, K+ deficiency, and secondary hyperaldosteronism. GFR, glomerular filtration rate.



Hypokalemia is an important participant in the maintenance phase of metabolic alkalosis and has selective effects on (1) H+ secretion and (2) ammonium excretion. The former is a result predominantly of stimulation of the H+,K+-ATPase in type A intercalated cells of the collecting duct. The latter is a direct result of enhanced ammoniagenesis and ammonium transport (proximal convoluted tubule, TALH, medullary collecting duct) in response to hypokalemia. Finally, hyperaldosteronism (primary or secondary) participates in sustaining the alkolosis by increasing activity of the H+,K+-ATPase in type A-IC cells as well as the ENaC and the Na+,K+-ATPase in principal cells in the collecting duct. The net result of the latter process is to stimulate K+ secretion through K+ selective channels in this same cell, thus maintaining the alkalosis.[105]

Under normal circumstances, the kidneys display an impressive capacity to excrete HCO3-. For HCO3- to be added to the ECF, HCO3- must be administered exogenously or retained in some manner. Thus, the development of metabolic alkalosis represents a failure of the kidneys to eliminate HCO3- at the normal capacity. The kidneys retain, rather than excrete, the excess alkali and maintain the alkalosis if one of several mechanisms is operative (see Fig. 14-9 ):



Cl- deficiency (ECF contraction) exists concurrently with K+ deficiency to decrease GFR and/or enhance proximal and distal HCO3- absorption. This combination of disorders evokes secondary hyperreninemic hyperaldosteronism and stimulates H+ secretion in the collecting duct and ammoniagenesis. Repair of the alkalosis may be accomplished by saline and K+ administration.



Hypermineralocorticoidism and hypokalemia are induced by autonomous factors unresponsive to increased ECF. The stimulation of distal H+ secretion is then sufficient to reabsorb the increased filtered HCO3- load and to overcome the decreased proximal HCO3- reabsorption caused by ECF expansion. Repair of the alkalosis in this case rests with removal of the excess autonomous mineralocorticoid; saline is ineffective.

The various causes of metabolic alkalosis are summarized in Table 14-20 . In attempting to establish the cause of metabolic alkalosis, it is necessary to assess the status of the ECF, blood pressure, serum K+, and renin-aldosterone system. For example, the presence of hypertension and hypokalemia in an alkalotic patient would suggest either some form of primary mineralocorticoid excess (see Table 14-20 ) or a hypertensive patient on diuretics. Low plasma renin activity and normal urinary Na+ and Cl- values in a patient not taking diuretics would also indicate a primary mineralocorticoid excess syndrome. The combination of hypokalemia and alkalosis in a normotensive, nonedematous patient can pose a difficult diagnostic problem. The possible causes to be considered include Bartter or Gitelman syndrome, Mg2+ deficiency, surreptitious vomiting, exogenous alkali, and diuretic ingestion. Urine electrolyte determinations and urine screening for diuretics are helpful diagnostic tools ( Table 14-21 ). If the urine is alkaline, with high values for Na+ and K+ concentrations but low values for Cl- concentration, the diagnosis is usually either active (continuous) vomiting (overt or surreptitious) or alkali ingestion. On the one hand, if the urine is relatively acid, with low concentrations of Na+, K+, and Cl-, the most likely possibilities are prior (discontinuous) vomiting, the posthypercapnic state, or prior diuretic ingestion. If, on the other hand, the urinary Na+, K+, and Cl- concentrations are not depressed, one must consider Mg2+ deficiency, Bartter or Gitelman syndrome, or current diuretic ingestion. In addition to a low serum Mg2+, in most patients, Gitelman syndrome is characterized by a low urine Ca2+. In contrast, the urine calcium is elevated in Bartter syndrome. The diagnostic approach to metabolic alkalosis is summarized in the flow diagram in Figure 14-10 .

TABLE 14-20   -- Causes of Metabolic Alkalosis



Exogenous HCO3- loads



Acute alkali administration



Milk-alkali syndrome



Effective ECV contraction, normotension, K+ deficiency, and secondary hyperreninemic hyperaldosteronism



Gastrointestinal origin






Gastric aspiration



Congenital chloridorrhea



Villous adenoma



Combined administration of sodium polystyrene sulfonate (Kayexalate and aluminum hydroxide)



Renal origin



Diuretics (especially thiazides and loop diuretics)



Edematous states



Posthypercapnic state






Recovery from lactic acidosis or ketoacidosis



Nonreabsorbable anions such as penicillin, carbenicillin



Mg2+ deficiency



K+ depletion



Bartter syndrome (loss of function mutations in TALH)



Gitelman syndrome (loss of function mutation in Na+-Cl-cotransporter)



Carbohydrate refeeding after starvation



ECV expansion, hypertension, K+ deficiency, and hypermineralocorticoidism



Associated with high renin



Renal artery stenosis



Accelerated hypertension



Renin-secreting tumor



Estrogen therapy



Associated with low renin



Primary aldosteronism












Glucocorticoid suppressible



Adrenal enzymatic defects



11β-Hydroxylase deficiency



17α-Hydroxylase deficiency



Cushing syndrome or disease



Ectopic corticotropin



Adrenal carcinoma



Adrenal adenoma



Primary pituitary












Chewer's tobacco



Lydia Pincham tablets



Gain of function mutation of ENaC with ECF volume expansion, hypertension, K+ deficiency, and hyporeninemic hypoaldosteronism



Liddle's syndrome




TABLE 14-21   -- Diagnosis of Metabolic Alkalosis

Saline-Responsive Alkalosis

Saline-Unresponsive Alkalosis

Low Urinary [Cl-] (<10 mEq/L)

High or Normal Urinary [Cl-] (>15–20 mEq/L)









Nasogastric aspiration



Diuretics (distant)






Villous adenoma



Bicarbonate therapy of organic acidosis



K+ deficiency






Liddle's syndrome






Primary aldosteronism



Cushing syndrome



Renal artery stenosis



Renal failure plus alkali therapy






Mg2+ deficiency



Severe K+ deficiency



Bartter syndrome



Gitelman syndrome



Diuretics (recent)






FIGURE 14-10  Diagnostic algorithm for metabolic alkalosis, based on the spot urine Cl- and K+ concentration. JGA, juxtaglomerular apparatus; HTN, hypertension.



Exogenous Bicarbonate Loads

Chronic administration of alkali to individuals with normal renal function results in minimal, if any, alkalosis. In patients with chronic renal insufficiency, however, overt alkalosis can develop after alkali administration, presumably because the capacity to excrete HCO3- is exceeded or because coexistent hemodynamic disturbances have caused enhanced fractional HCO3- reabsorption.

Bicarbonate and Bicarbonate-Precursor Administration

The propensity of patients with ECF contraction or renal disease plus alkali loads to develop alkalosis is exemplified by patients who receive oral or intravenous HCO3-, acetate loads in parenteral hyperalimentation solutions, sodium citrate loads (regional anticoagulation, transfusions, or infant formula), or antacids plus cation exchange resins. The use of trisodium citrate solution for anticoagulation regionally has been reported as a cause of metabolic alkalosis in patients on continuous renal replacement therapy. [106] [107] Citrate metabolism consumes a hydrogen ion and, thereby, generates HCO3- in liver and skeletal muscle. Dilute (0.1 N) HCl is often required for correction in this setting.[107] The risk for alkalosis, in my experience, is reduced when anticoagulant citrate dextrose formula A (ACD-A) is used because less bicarbonate is generated in comparison to hypertonic trisodium citrate administration.

Milk-Alkali Syndrome

Another cause is a long-standing history of excessive ingestion of milk and antacids. Milk-alkali syndrome is making a comeback because of the use of calcium supplementation (e.g., calcium carbonate) in women for osteoporosis treatment or prevention. Older women with poor dietary intake (“tea and toasters”) are especially prone. In Asia, betel nut chewing is a cause because the erosive nut is often wrapped in calcium hydroxide. Both hypercalcemia and vitamin D excess have been suggested to increase renal HCO3- reabsorption. Patients with these disorders are prone to develop nephrocalcinosis, renal insufficiency, and metabolic alkalosis.[105] Discontinuation of alkali ingestion or administration is usually sufficient to repair the alkalosis.

Normal Blood Pressure, Extracellular Volume Contraction, Potassium Depletion, and Hyperreninemic Hyperaldosteronism

Gastrointestinal Origin

Vomiting and Gastric Aspiration.

Gastrointestinal loss of H+ results in retention of HCO3- in the body fluids. Increased H+ loss through gastric secretions can be caused by vomiting for physical or psychiatric reasons, through nasogastric tube aspiration, or by a gastric fistula (see Table 14-20 ).[105]

The fluid and sodium chloride loss in vomitus or in nasogastric suction results in ECF contraction with an increase in plasma renin activity and aldosterone.[105] These factors decrease GFR and enhance the capacity of the renal tubule to reabsorb HCO3-.[11] During the active phase of vomiting, there is continued addition of HCO3- to plasma in exchange for Cl-. The plasma HCO3- concentration increases to a level that exceeds the reabsorptive capacity of the proximal tubule. The excess sodium bicarbonate enters the distal tubule, where, under the influence of the increased level of aldosterone, K+ and H+ secretion is stimulated. Because of ECF contraction and hypochloremia, the kidney avidly conserves Cl-. Consequently, in this disequilibrium state generated by active vomiting, the urine contains large quantities of Na+, K+, and HCO3- but has a low concentration of Cl-. On cessation of vomiting, the plasma HCO3- concentration falls to the HCO3- threshold, which is markedly elevated by the continued effects of ECF contraction, hypokalemia, and hyperaldosteronism. The alkalosis is maintained at a slightly lower level than during the phase of active vomiting, and the urine is now relatively acidic with low concentrations of Na+, HCO3-, and Cl-.

Correction of the ECF contraction with sodium chloride may be sufficient to reverse these events, with restoration of normal blood pH even without repair of K+ deficits.[11] Good clinical practice, however, dictates K+ repletion as well.

Congenital Chloridorrhea

This rare autosomal recessive disorder is associated with severe diarrhea, fecal acid loss, and HCO3- retention. The pathogenesis is due to loss of the normal ileal HCO3-/Cl- anion exchange mechanism so that Cl- cannot be reabsorbed. The parallel Na+/H+ ion exchanger remains functional, allowing Na+ to be reabsorbed and H+ to be secreted. Subsequently, net H+ and Cl- exit in the stool, causing Na+ and HCO3- retention in the ECF. [11] [105]Alkalosis results and is sustained by concomitant ECF contraction with hyperaldosteronism and K+ deficiency. Therapy consists of oral supplements of sodium and potassium chloride. The use of proton-pump inhibitors has been advanced as a means of reducing chloride secretion by the parietal cells and, thus, reducing the diarrhea.[108]

Villous Adenoma

Metabolic alkalosis has been described in cases of villous adenoma and is ascribed to high adenoma-derived K+ secretory rates. K+ and volume depletion likely cause the alkalosis, because colonic secretion is alkaline.

Renal Origin


Drugs that induce chloriuresis without bicarbonaturia, such as thiazides and loop diuretics (furosemide, bumetanide, and torsemide), acutely diminish the ECF space without altering the total body HCO3- content. The HCO3-concentration in the blood and ECF increases. The Pco2 does not increase commensurately, and a “contraction” alkalosis results.[105] The degree of alkalosis is usually small, however, because of cellular and non-HCO3- ECF buffering processes. [11] [105]

Administration of diuretics chronically tends to generate an alkalosis by increased distal salt delivery, so that both K+ and H+ secretion is stimulated. Diuretics, by blocking Cl- reabsorption in the distal tubule or by increasing H+pump activity, may also stimulate distal H+ secretion and increase net acid excretion. Maintenance of alkalosis is ensured by the persistence of ECF contraction, secondary hyperaldosteronism, K+ deficiency, enhanced ammonium production, stimulation of the H+,K+-ATPase, and the direct effect of the diuretic as long as diuretic administration continues. Repair of the alkalosis is achieved by providing Cl- to normalize the ECF deficit.

Edematous States

In diseases associated with edema formation (congestive heart failure, nephrotic syndrome, cirrhosis), effective ECF is diminished, although total ECF is increased. Common to these diseases is diminished renal plasma flow and GFR with limited distal Na+ delivery. Net acid excretion is usually normal, and alkalosis does not develop, even with an enhanced proximal HCO3- reabsorptive capacity. However, the distal H+ secretory mechanism is primed by hyperaldosteronism to excrete excessive net acid if GFR can be increased to enhance distal Na+ delivery or if K+ deficiency or diuretic administration supervenes.


Prolonged CO2 retention with chronic respiratory acidosis enhances renal HCO3- absorption and the generation of new HCO3- (increased net acid excretion). If the Pco2 is returned to normal, metabolic alkalosis, caused by the persistently elevated HCO3- concentration, emerges. Alkalosis develops immediately if the elevated Pco2 is abruptly returned toward normal by a change in mechanically controlled ventilation. There is a brisk bicarbonaturic response proportional to the change in Pco2. The accompanying cation is predominantly K+, especially if dietary potassium is not limited. Secondary hyperaldosteronism in states of chronic hypercapnia may be responsible for this pattern of response. Associated ECF contraction does not allow complete repair of the alkalosis by normalization of the Pco2 alone. Alkalosis persists until Cl- supplementation is provided. Enhanced proximal acidification as a result of conditioning induced by the previous hypercapnic state may also contribute to the maintenance of the posthypercapnic alkalosis.[5]

Bartter Syndrome

Both classic Bartter syndrome and the antenatal Bartter are inherited as autosomal recessive disorders and involve impaired TALH salt absorption, which results in salt wasting, volume depletion, and activation of the renin-angiotensin system.[109] These manifestations are the result of loss of function mutations of one of the genes that encode three transporters involved in vectorial NaCl absorption in the TALH. The most prevalent disorder is a mutation of the gene NKCC2 that encodes the bumetanide-sensitive Na+-2Cl-K+ cotransporter on the apical membrane. A second mutation has been discovered in the gene KCNJ1 which encodes the ATP-sensitive apical K+conductance channel (ROMK) that operates in parallel with the Na+-2Cl--K+ transporter to recycle K+. Both defects can be associated with classic Bartter syndrome. A third mutation of the CLCNKb gene encoding the voltage-gated basolateral chloride channel (ClC-Kb) is associated only with classic Bartter syndrome and is milder and rarely associated with nephrocalcinosis. All three defects have the same net effect, loss of Cl- transport in the TALH.[110]

Antenatal Bartter syndrome has been observed in consanguineous families in association with sensorineural deafness; a syndrome linked to chromosome 1p31. The responsible gene, BSND, encodes a subunit, barttin, that colocalizes with the CLC-Kb channel in the TALH and K-secreting epithelial cells in the inner ear. Barttin appears to be necessary for function of the voltage-gated chloride channel. Expression of ClC-Kb is lost when coexpressed with mutant barttins. Thus, mutations in BSND represent a fourth category of patients with Bartter syndrome.[109]

Such defects would predictably lead to ECF contraction, hyperreninemic hyperaldosteronism, and increased delivery of Na+ to the distal nephron and, thus, alkalosis and renal K+ wasting and hypokalemia. Secondary overproduction of prostaglandins, juxtaglomerular apparatus hypertrophy, and vascular pressor unresponsiveness would then ensue. Most patients have hypercalciuria and normal serum magnesium levels, which distinguishes this disorder from Gitelman syndrome.

Bartter syndrome is inherited as an autosomal recessive defect, and most patients studied with mutations in these genes have been homozygotes or compound heterozygotes for different mutations in one of these genes. A few patients with the clinical syndrome have no discernible mutation in any of these four genes. Plausible explanations include unrecognized mutations in other genes, a dominant-negative effect of a heterozygous mutation, or other mechanisms. Recently, two groups of investigators have reported features of Bartter syndrome in patients with autosomal dominant hypocalcemia and activating mutations in the calcium-sensing receptor (CaSR). Activation of the CaSR on the basolateral cell surface of the TALH inhibits function of ROMK. Thus, mutations in CaSR may represent a fifth gene associated with the Bartter syndrome.[90]

The pathophysiologic basis of the myriad manifestations of Bartter syndrome is displayed in Figure 14-11 . Historically, many of these features (e.g., elevated PGE2 and kallikreins), once considered potentially causative, are now realized to be secondary to the genetic defects in TALH solute transport.



FIGURE 14-11  Schematic representation of the pathogenesis of Bartter syndrome. The primary defect is impairment of solute reabsorption in the thick ascending limb of Henle's loop (TALH) as a result of an inherited loss of function mutation of NKCC2 (or BSC-1), ROMK, or ClCKB channel. These mutations impair the function of the Na+-2Cl--K+ transporter.



Distinction from surreptitious vomiting, diuretic administration, and laxative abuse is necessary to make the diagnosis of Bartter syndrome. The finding of a low urinary Cl- concentration is helpful in identifying the vomiting patient. The urinary Cl- concentration in Bartter syndrome would be expected to be normal or increased, rather than depressed.

The therapy of Bartter syndrome is generally focused on repair of the hypokalemia by inhibition of the renin-angiotensin-aldosterone or the prostaglandin-kinin system. K+ supplementation, Mg2+ repletion, propranolol, spironolactone, prostaglandin inhibitors, and ACE inhibitors have been used with limited success.

Gitelman Syndrome

Patients with Gitelman syndrome resemble the Bartter syndrome phenotype in that an autosomal recessive chloride-resistant metabolic alkalosis is associated with hypokalemia, a normal to low blood pressure, volume depletion with secondary hyperreninemic hyperaldosteronism, and juxtaglomerular hyperplasia. [110] [111] However, hypocalciuria and symptomatic hypomagnesemia are consistently useful in distinguishing Gitelman syndrome from Bartter syndrome on clinical grounds.[11] These unique features mimic the effect of chronic thiazide diuretic administration. A number of missense mutations in the gene SLC12A3, which encodes the thiazide-sensitive sodium-chloride cotransporter in the distal convoluted tubule, have been described and account for the clinical features including the classic finding of hypocalciuria.[112] However, it is not clear why these patients have pronounced hypomagnesemia. A recent study has demonstrated that peripheral blood mononuclear cells from patients with Gitelman syndrome express mutated NCCT mRNA. In a large consanguineous Bedouin family, missense mutations were noted in CLCNKb but the clinical features overlapped between Gitelman and Bartter syndrome.

Gitelman syndrome becomes symptomatic later in life and is associated with milder salt wasting than that occurring with the Bartter syndrome. A large study of adults with proven Gitelman syndrome and NCCT mutations showed that salt craving, nocturia, cramps, and fatigue were more common than in sex- and age-matched controls.[112] Women experienced exacerbation of symptoms during menses, and many had complicated pregnancies.

Treatment of Gitelman syndrome, as with Bartter syndrome, consists of liberal dietary sodium and potassium salts, but with the addition of magnesium supplementation in most patients. ACE inhibitors have been suggested as helpful in selected patients but may cause frank hypotension.

After Treatment of Lactic Acidosis or Ketoacidosis

When an underlying stimulus for the generation of lactic acid or keto acid is removed rapidly, as occurs with repair of circulatory insufficiency or with insulin, the lactate or ketones can be metabolized to yield an equivalent amount of HCO3-. Thus, the initial process of HCO3- titration that induced the metabolic acidosis is effectively reversed. In the oxidative metabolism of ketones or lactate, HCO3- is not directly produced; rather, H+ is consumed by metabolism of the organic anions, with the liberation of an equivalent amount of HCO3-. This process regenerates HCO3- if the organic acids can be metabolized to HCO3- before their renal excretion. Other sources of new HCO3-are additive with the original amount of HCO3- regenerated by organic anion metabolism to create a surfeit of HCO3-. Such sources include (1) new HCO3- added to the blood by the kidneys as a result of enhanced net acid excretion during the preexisting acidotic period and (2) alkali therapy during the treatment phase of the acidosis. The coexistence of acidosis-induced ECF contraction and K+ deficiency acts to sustain the alkalosis. [11] [105]

Nonreabsorbable Anions and Magnesium Ion Deficiency

Administration of large amounts of nonreabsorbable anions, such as penicillin or carbenicillin, can enhance distal acidification and K+ excretion by increasing the luminal potential difference attained[105] or possibly by allowing Na+ delivery to the CCT without Cl-, thus favoring H+ secretion without Cl--dependent HCO3- secretion.[105] Mg2+ deficiency also results in hypokalemic alkalosis by enhancing distal acidification through stimulation of renin and hence aldosterone secretion.

Potassium Ion Depletion

Pure K+ depletion causes metabolic alkalosis, although generally of only modest severity. One reason that the alkalosis is usually mild is that K+ depletion also causes positive sodium chloride balance with or without mineralocorticoid administration. The salt retention, in turn, antagonizes the degree of alkalemia. When access to salt as well as to K+ is restricted, more severe alkalosis develops. Activation of the renal H+,K+-ATPase in the collecting duct by chronic hypokalemia likely plays a role in maintenance of the alkalosis. Specifically, chronic hypokalemia has been shown to markedly increase the abundance of the colonic H+,K+-ATPase mRNA and protein in the OMCD. In animals, the alkalosis is maintained in part by reduction in GFR without a change in tubule HCO3- transport. In humans, the pathophysiologic basis of the alkalosis has not been well defined. Alkalosis associated with severe K+ depletion, however, is resistant to salt administration. Only repair of the K+ deficiency corrects the alkalosis.

Extracellular Volume Expansion, Hypertension, and Hypermineralocorticoidism (see Table 14-18 )

As previously discussed, mineralocorticoid administration increases net acid excretion and tends to create metabolic alkalosis. The degree of alkalosis is augmented by the simultaneous increase in K+ excretion leading to K+deficiency and hypokalemia. Salt intake for sufficient distal Na+ delivery is also a prerequisite for the development of both the hypokalemia and the alkalosis. Hypertension develops partly as a result of ECF expansion from salt retention. The alkalosis is not progressive and is generally mild. Volume expansion tends to antagonize the decrease in GFR and/or increase in tubule acidification induced by hypermineralocorticoidism and K+ deficiency.

Increased mineralocorticoid hormone levels may be the result of autonomous primary adrenal overproduction of mineralocorticoid or of secondary aldosterone release by primary renal overproduction of renin. In both examples, the normal feedback by ECF on net mineralocorticoid production is disrupted and volume retention results in hypertension. These disorders are considered in detail in Chapters 15 , 42 , and 43 .

High Renin

States associated with inappropriately high renin levels may be associated with hyperaldosteronism and alkalosis. Renin levels are elevated because of primary elaboration of renin or, secondarily, by diminished effective circulating blood volume. Total ECF may not be diminished. Examples of high-renin hypertension include renovascular, accelerated, and malignant hypertension. Estrogens increase renin substrate and, hence, angiotensin II formation. Primary tumor overproduction of renin is another rare cause of hyperreninemic hyperaldosterone-induced metabolic alkalosis.[105]

Low Renin

In these disorders, primary adrenal overproduction of mineralocorticoid suppresses renin elaboration. Hypertension occurs as the result of mineralocorticoid excess with volume overexpansion.

Primary Aldosteronism.

Tumor involvement (adenoma or, rarely, carcinoma) or hyperplasia of the adrenal gland is associated with aldosterone overproduction. Mineralocorticoid administration or excess production (primary aldosteronism of Cushing's syndrome and adrenal cortical enzyme defects) increases net acid excretion and may result in metabolic alkalosis, which may be worsened by associated K+ deficiency. ECF volume expansion from salt retention causes hypertension and antagonizes the reduction in GFR and/or increases tubule acidification induced by aldosterone and by K+ deficiency. The kaliuresis persists and causes continued K+ depletion with polydipsia, inability to concentrate the urine, and polyuria. Increased aldosterone levels may be the result of autonomous primary adrenal overproduction or of secondary aldosterone release due to renal overproduction of renin. In both situations, the normal feedback of ECF volume on net aldosterone production is disrupted, and hypertension from volume retention can result. The glucocorticoid-remediable form is an autosomal dominant form.

Glucocorticoid-Remediable Hyperaldosteronism.

This is an autosomal dominant form of hypertension, the features of which resemble those of primary aldosteronism (hypokalemic metabolic alkalosis and volume-dependent hypertension). In this disorder, however, glucocorticoid administration corrects the hypertension as well as the excessive excretion of 18-hydroxysteroid in the urine. Lifton has demonstrated that this disorder results from unequal crossing over between the two genes located in close proximity on chromosome 8.[113] This region contains the glucocorticoid-responsive promoter region of the gene encoding 11-b-hydroxylase (CYP11B1) where it is joined to the structural portion of the CYP11B2 gene encoding aldosterone synthase.[113] The chimeric gene produces excess amounts of aldosterone synthase, unresponsive to serum potassium or renin levels, but it is suppressed by glucocorticoid administration. Although a rare cause of primary aldosteronism, the syndrome is important to distinguish because treatment differs and it can be associated with severe hypertension, stroke, and accelerated hypertension during pregnancy.

Cushing Disease or Syndrome.

Abnormally high glucocorticoid production caused by adrenal adenoma or carcinoma or to ectopic corticotropin production causes metabolic alkalosis. The alkalosis may be ascribed to coexisting mineralocorticoid (deoxycorticosterone and corticosterone) hypersecretion. Alternatively, glucocorticoids may have the capability of enhancing net acid secretion and NH4+ production, which may be due to occupancy of cellular mineralocorticoid receptors.

Miscellaneous Conditions.

Ingestion of licorice, carbenoxolone, chewer's tobacco, or nasal spray can cause a typical pattern of hypermineralocorticoidism. These substances inhibit 11 β-hydroxysteroid dehydrogenase (which normally metabolizes cortisol to an inactive metabolite), so that cortisol is allowed to occupy type I renal mineralocorticoid receptors, mimicking aldosterone. Genetic apparent mineralocorticoid excess resembles excessive ingestion of licorice: volume expansion, low renin, low aldosterone levels, and a salt-sensitive form of hypertension, which may include metabolic alkalosis and hypokalemia. The hypertension responds to thiazides and spironolactone but without abnormal steroid products in the urine. Licorice and carbenoxolone contain glycyrrhetinnic acid, which inhibits 11 β-hydroxysteroid dehydrogenase. This enzyme is responsible for converting cortisol to cortisone, an essential step in protecting the mineralocorticoid receptor from cortisol, and protects normal subjects from exhibiting apparent mineralcorticoid excess. Without the renal-specific form of this enzyme, monogenic hypertension develops.

Liddle's Syndrome.

Liddle's syndrome is associated with severe hypertension presenting in childhood, accompanied by hypokalemic metabolic alkalosis. These features resemble primary hyperaldosteronism, but the renin and aldosterone levels are suppressed (pseudohyperaldosteronism).[113] The defect is constitutive activation of the ENaC at the apical membrane of principal cells in the CCD. Liddle originally described patients with low renin and low aldosterone levels that did not respond to spironolactone. The defect in Liddle's syndrome is inherited as an autosomal dominant form of monogenic hypertension and has been localized to chromosome 16q. Subsequently, this disorder has been attributed to an inherited abnormality in the gene that encodes the β- or the γ-subunit the renal ENaC. Either mutation results in deletion of the cytoplasmic tails of the β- or γ-subunits, respectively. The C-termini contain PY amino acid motifs that are highly conserved, and essentially all mutations in Liddle syndrome patients involve disruption or deletion of this motif. These PY motifs are important in regulating the number of sodium channels in the luminal membrane by binding to the WW domains of the Nedd4-like family of ubquitin-protein ligases.[114] Disruption of the PY motif dramatically increases the surface localization of ENaC complex, because these channels are not internalized or degraded (Nedd4 pathway), but remain activated on the cell surface.[114] Persistent Na+ absorption eventuates in volume expansion, hypertension, hypokalemia, and metabolic alkalosis.[113]

Symptoms and Treatment


Symptoms of metabolic alkalosis include changes in central and peripheral nervous system function similar to those in hypocalcemia: mental confusion, obtundation, and a predisposition to seizures, paresthesias, muscular cramping, and even tetany. Aggravation of arrhythmias and hypoxemia in chronic obstructive pulmonary disease is also a problem. Related electrolyte abnormalities including hypokalemia and hypophosphatemia are common, and patients may present with symptoms of these deficiencies.


The maintenance of metabolic alkalosis represents a failure of the kidney to excrete bicarbonate efficiently because of chloride or potassium deficiency or continuous mineralocorticoid elaboration or both. Treatment is primarily directed at correcting the underlying stimulus for HCO3- generation and to restore the ability of the kidney to excrete the excess bicarbonate. Assistance is gained in the diagnosis and treatment of metabolic alkalosis by paying attention to the urinary chloride, the arterial blood pressure, and the volume status of the patient (particularly the presence or absence of orthostasis) (see Fig. 14-10 ). Particularly helpful in the history is the presence or absence of vomiting, diuretic use, or alkali therapy. A high urine chloride and hypertension suggests that mineralocorticoid excess is present. If primary aldosteronism is present, correction of the underlying cause will reverse the alkalosis (adenoma, bilateral hyperplasia, Cushing's syndrome). Patients with bilateral adrenal hyperplasia may respond to spironolactone. Normotensive patients with a high urine chloride may have Bartter or Gitelman syndrome if diuretic use or vomiting can be excluded. A low urine chloride and relative hypotension suggests a chloride responsive metabolic alkalosis such as vomiting or nasogastric suction. [H+] loss by the stomach or kidneys can be mitigated by the use of proton-pump inhibitors or the discontinuation of diuretics. The second aspect of treatment is to remove the factors that sustain HCO3- reabsorption, such as ECF volume contraction or K+ deficiency. Although K+ deficits should be repaired, NaCl therapy is usually sufficient to reverse the alkalosis if ECF volume contraction is present, as indicated by a low urine [Cl-].

Patients with CHF or unexplained volume overexpansion represent special challenges in the critical care setting. Patients with a low urine chloride concentration, usually indicative of a “chloride-responsive” form of metabolic alkalosis, may not tolerate normal saline infusion. Renal HCO3- loss can be accelerated by administration of acetazolamide (250–500 mg intravenously), a carbonic anhydrase inhibitor, if associated conditions preclude infusion of saline (elevated pulmonary capillary wedge pressure, or evidence of CHF).[105] Acetazolamide is usually very effective in patients with adequate renal function, but can exacerbate urinary K+ losses. Dilute hydrochloric acid (0.1 N HCl) is also effective and must be infused centrally. It can cause hemolysis and may be difficult to titrate. If used, the goal should not be to restore the pH to normal, but to a pH of approximately 7.50. Hemodialysis against a dialysate low in [HCO3-] and high in [Cl-] can be effective when renal function is impaired. Patients receiving continuous renal replacement therapy in the intensive care unit typically develop metabolic alkalosis with high bicarbonate dialysate or when citrate regional anticoagulation is employed. Therapy should include reduction of alkali loads via dialysis by reducing the bicarbonate concentration in the dialysate, or if citrate is being used, by infusion of 0.1 N HCl postfiltration.


1. Bidani A, Tauzon DM, Heming TA: Regulation of whole body acid-base balance.   In: DuBose TD, Hamm LL, ed. Acid-Base and Electrolyte Disorders: A Com-panion to Brenner and Rector's The Kidney,  Philadelphia: WB Saunders; 2002:1-21.

2. Madias NE, Adrogue HJ: Respiratory alkalosis.   In: DuBose TD, Hamm LL, ed. Acid-Base and Electrolyte Disorders: A Companion to Brenner and Rector's The Kidney,  Philadelphia: WB Saunders; 2002:147-164.

3. Toews GB: Respiratory acidosis.   In: DuBose TD, Hamm LL, ed. Acid-Base and Electrolyte Disorders: A Companion to Brenner and Rector's The Kidney,  Philadelphia: WB Saunders; 2002:129-146.

4. Bidani A, DuBose Jr TD: Acid-base regulation: Cellular and whole body.   In: Arieff AI, DeFronzo RA, ed. Fluid, Electrolyte, and Acid Base Disorders,  2nd ed. New York: Churchill Livingstone; 1995:69.

5. Alpern RJ, Hamm LL: Urinary acidification.   In: DuBose TD, Hamm LL, ed. Acid-Base and Electrolyte Disorders: A Companion to Brenner and Rector's The Kidney,  Philadelphia: WB Saunders; 2002:23-40.

6. DuBose TD, McDonald GA: Renal tubular acidosis.   In: DuBose TD, Hamm LL, ed. Acid-Base and Electrolyte Disorders: A Companion to Brenner and Rector's The Kidney,  Philadelphia: WB Saunders; 2002:189-206.

7. Krapf R: Mechanisms of adaptation to chronic respiratory acidosis in the proximal tubule.  J Clin Invest  1989; 83:890-896.

8. Schwartz GJ, Al-Awqati Q: Carbon dioxide causes exocytosis of vesicles containing H+ pumps in isolated perfused proximal and collecting tubules.  J Clin Invest  1985; 75:1638-1644.

9. Gennari FJ, Maddox DA: Renal regulation of acid-base homeostasis: Integrated response.   In: Seldin DW, Giebisch G, ed. The Kidney: Physiology and Pathophysiology,  3rd ed. Philadelphia: Lippincott Williams and Wilkins; 2000:2015-2054.

10. Albert MS, Dell RB, Winters RW: Quantitative displacement of acid-base equilibrium in metabolic acidosis.  Ann Intern Med  1967; 66:312.

11. Galla JH: Metabolic alkalosis.   In: DuBose TD, Hamm LL, ed. Acid-Base and Electrolyte Disorders: A Companion to Brenner and Rector's The Kidney,  Philadelphia: WB Saunders; 2002:109-128.

12. DuBose TD: Metabolic alkalosis.   In: Greenberg A, ed. Primer on Kidney Diseases,  Philadelphia: Elsevier Saunders; 2005:90-96.

13. DuBose Jr TD, Codina J, Burges A, Pressley TA: Regulation of H+,K+-ATPase expression in kidney.  Am J Physiol  1995; 269:F500.

14. Wesson DE: Na/H exchange and H-K-ATPase increase distal tubule acidification in chronic alkalosis.  Kidney Int  1998; 53:945-951.

15. Wesson DE, Dolson GM: Endothelin-1 increases rat distal tubule acidification in vivo.  Am J Physiol  1997; 273:F586-F594.

16. Wesson DE: Combined K+ and Cl- repletion corrects augmented H+ secretion by distal tubules in chronic alkalosis.  Am J Physiol  1994; 266:F592-F603.

17. Guntupalli J, Onuigbo M, Wall SM, et al: Adaptation to low K+ media increases H+,K+-ATPase but not H+,K+-ATPase-mediated pHi recovery in OMCD1 cells.  Am J Physiol  1997; 273:C558-C571.

18. Wall SM, Mehta P, DuBose Jr TD: Dietary K+ restriction upregulates total and Sch- 28080-sensitive bicarbonate absorption in rat tIMCD.  Am J Physiol  1998; 275:F543-F549.

19. Krapf R, Alpern RJ, Seldin DW: Clinical syndromes of metabolic acidosis.   In: Seldin DW, Giebisch G, ed. The Kidney,  3rd ed. Philadelphia: Lippincott Williams and Wilkins; 2000:2055-2072.

20. Emmett M: Diagnosis of simple and mixed disorders.   In: DuBose TD, Hamm LL, ed. Acid-Base and Electrolyte Disorders: A Companion to Brenner and Rector's The Kidney,  Philadelphia: WB Saunders; 2002:41-54.

21. Oh MS, Carroll HJ: The anion gap.  N Engl J Med  1977; 297:814.

22. Feldman M, Soni N, Dickson B: Influence of hypoalbuminemia or hyperalbuminemia on the serum anion gap.  J Lab Clin Med  2005; 146:317-320.

23. Acute Respiratory Distress Syndrome Network : Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.  N Engl J Med  2000; 342:1301.

24. Slutsky AS, Tremblay LN: Multiple system organ failure. Is mechanical ventilation a contributing factor?.  Am J Respir Crit Care Med  1998; 157:1721-1725.

25. DuBose TD, Alpern RJ: Renal tubular acidosis.   In: Scriver CR, Beaudet AL, Sly WS, Valle D, ed. The Metabolic and Molecular Bases of Inherited Disease,  8th ed. New York: McGraw-Hill; 2001:4983-5021.

26. Wong KM, Chak WL, Cheung CY, et al: Hypokalemic metabolic acidosis attributed to cough mixture abuse.  Am J Kidney Dis  2001; 38:390.

27. Halperin M, Kamel KS, Cherny DZI: Ketoacidosis.   In: DuBose TD, Hamm LL, ed. Acid-Base and Electrolyte Disorders: A Companion to Brenner and Rector's The Kidney,  Philadelphia: WB Saunders; 2002:67-82.

28. Gautheir P, Simon EE, Lemann J: Acidosis of chronic renal failure.   In: DuBose TD, Hamm LL, ed. Acid-Base and Electrolyte Disorders: A Companion to Brenner and Rector's The Kidney,  Philadelphia: WB Saunders; 2002:207-216.

29. Morris Jr RC, Nigon K, Reed EB: Evidence that the severity of depletion of inorganic phosphate determines the severity of the disturbance of adenine nucleotide metabolism in the liver and renal cortex of the fructose-loaded rat.  J Clin Invest  1978; 61:209.

30. Sly WS, Whyte MP, Sundaram V, et al: Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification.  N Engl J Med  1985; 313:139.

31. Morris Jr RC: Renal tubular acidosis. Mechanisms, classification and implications.  N Engl J Med  1969; 281:1405.

32. DuBose Jr TD: Hydrogen ion secretion by the collecting duct as a determinant of the urine to blood Pco2 gradient in alkaline urine.  J Clin Invest  1982; 69:145.

33. DuBose Jr TD, Caflisch CR: Validation of the difference in urine and blood CO2 tension during bicarbonate loading as an index of distal nephron acidification in experimental models of distal renal tubular acidosis.  J Clin Invest  1985; 75:1116.

34. Batlle DC: Segmental characterization of defects in collecting tubule acidification.  Kidney Int  1986; 30:546-554.

35. Bruce LJ, Cope DL, Jones GK, et al: Familial distal renal tubular acidosis is associated with mutations in red cell anion exchanger (Band 3, AE1) gene.  J Clin Invest  1997; 100:1693.

36. Alper SL: Genetic diseases of acid-base transporters.  Annu Rev Physiol  2002; 64:899.

37. Karet FE, Gainza FJ, Gyory AZ, et al: Mutations in the chloride-bicarbonate exchanger gene AE1 cause autosomal dominant but not autosomal recessive distal renal tubular acidosis.  Proc Natl Acad Sci U S A  1998; 95:6337.

38. Jarolim P, Shayakul C, Prabakaran D, et al: Autosomal dominant distal renal tubular acidosis is associated in three families with heterozygosity for the R589H mutation in the AE1 (band 3) Cl-/HCO3- exchanger.  J Biol Chem  1998; 273:6380.

39. DuBose TD: Autosomal dominant distal renal tubular acidosis and the AE1 gene.  Am J Kidney Dis  1999; 33:1191-1197.

40. Alper SL: Molecular physiology of SLC4 anion exchangers.  Exp Physiol  2006; 91:153-161.

41. Karet FE, Finberg KE, Nelson RD, et al: Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness.  Nat Genet  1999; 21:84.

42. Karet FE, Finberg KE, Nayir A, et al: Localization of a gene for autosomal recessive distal renal tubular acidosis with normal hearing (rdRTA2) to 7q33-34.  Am J Hum Genet  1999; 65:1656.

43. Smith AN, Finberg KE, Wagner CA, et al: Molecular cloning and characterization of Atp6n1b.  J Biol Chem  2001; 276:42382.

44. Smith AN, Skaug J, Choate KA, et al: Mutations in Atp6n1b, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing.  Nat Genet  2000; 26:71.

45. Kaitwatcharachai C, Vasuvattakul S, Yenchitsomanuas P, et al: Distal renal tubular acidosis and high urine carbon dioxide tension in a patient with Southeast Asian ovalocytosis.  Am J Kidney Dis  1999; 33:1147-1152.

46. DuBose Jr TD, Lucci MS, Hogg RJ, et al: Comparison of acidification parameters in superficial and deep nephrons of the rat.  Am J Physiol  1983; 244:F497.

47. Bonilla-Felix M: Primary distal renal tubular acidosis as a result of a gradient defect.  Am J Kidney Dis  1996; 27:428.

48. DuBose Jr TD, Good DW: Role of the thick ascending limb and inner medullary collecting duct in the regulation of urinary acidification.  Semin Nephrol  1991; 11:120.

49. DuBose Jr TD, Good DW, Hamm LL, Wall SM: Ammonium transport in the kidney: New physiologic concepts and their clinical implications.  J Am Soc Nephrol  1991; 1:1193.

50. Laing CM, Toye AM, Capasso G, Unwin RJ: Renal tubular acidosis: Developments in our understanding of the molecular basis.  Int J Biochem Cell Biol  2005; 37:1151-1161.

51. Pessler F, Emery H, Dai L, et al: The spectrum of renal tubular acidosis in paediatric Sjogren syndrome.  Rheumatology  2006; 45:85-91.

52. Morris Jr RC, Sebastian A: Alkali therapy in renal tubular acidosis: Who needs it?.  J Am Soc Nephrol  2002; 13:2186-2188.

53. Wrong O, Henderson JE, Kaye M: Distal renal tubular acidosis: Alkali heals osteomalacia and increases net production of 1,25-dihydroxyvitamin D.  Nephron Physiol  2005; 101:72-76.

54. DuBose Jr TD, Good DW: Effects of chronic chloride depletion metabolic alkalosis on proximal tubule transport and renal production of ammonium.  Am J Physiol Renal Fluid Electrol Physiol  1995; 269:F508.

55. DuBose Jr TD, Good DW: Chronic hyperkalemia impairs ammonium transport and accumulation in the inner medulla of the rat.  J Clin Invest  1992; 90:1443.

56. Good DW: Ammonium transport by the thick ascending limb of Henle's loop.  Annu Rev Physiol  1994; 56:623.

57. Watts BA, Good DW: Effects of ammonium on intracellular pH in rat medullary thick ascending limb: Mechanisms of apical membrane NH4+ transport.  J Gen Physiol  1994; 103:917.

58. DuBose Jr TD, Caflisch CR: Effect of selective aldosterone deficiency on acidification in nephron segments of the rat inner medulla.  J Clin Invest  1988; 82:1624.

59. Antonipillai I, Wang Y, Horton R: Tumor necrosis factor and interleukin-1 may regulate renin secretion.  Endocrinology  1990; 126:273.

60. Geller DS, Rodriguez-Soriano J, Valla Boado A, et al: Mutations in the mineralocorticoid receptor gene cause autosomal dominant pseudohypoaldosteronism type 1.  Nat Genet  1998; 19:279.

61. Chang SS, Grunder S, Hanukoglu A, et al: Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalemic acidosis, pseudohypoaldosteronism type 1.  Nat Genet  1996; 12:248.

62. Grunder S, Firsou D, Chang SS, et al: A mutation causing pseudohypoaldosteronism type 1 identifies a conserved gyycine that is involved in the gating of the epithelial sodium channel.  EMBO J  1997; 16:899.

63. Viemann M, Peter M, Lopez-Siguero JP, et al: Evidence for genetic heterogeneity of pseudohypoaldosteronism type 1: Identification of a novel mutation in the human mineralocorticoid receptor in one sporadic case and no mutations in two autosomal dominant kindreds.  J Clin Endocrinol Metab  2001; 86:2056.

64. Adachi M, Tachibana K, Asakura Y, et al: Compound heterozygous mutations in the gamma subunit gene of ENaC (1627delG and 1570-1G->A) in one sporadic Japanese patient with a systemic form of pseudohypoaldosteronism type 1.  J Clin Endocrinol Metab  2001; 86:9.

65. Thomas CP, Zhou J, Liu KZ, et al: Systemic pseudohypoaldosteronism from deletion of the promoter region of the human beta epithelial Na+ channel subunit.  Am J Respir Cell Mol Biol  2002; 27:314-319.

66. Barker PM, Nguyen MS, Gatzy JT, et al: Role of gamma ENaC subunit in lung liquid clearance and electrolyte balance in newborn mice: Insights into perinatal adapation and pseudohypoaldosteronism.  J Clin Invest  1998; 102:1634.

67. Achard JM, Disse-Nicodem S, Fiquet-Kempf B, Jeunemaitre X: Phenotypic and genetic heterogeneity of familial hyperkalaemic hypertension (Gordon sydrome).  Clin Exp Pharmacol Physiol  2001; 28:1048.

68. Wilson FH, Disse-Nicodeme S, Choate KA, et al: Human hypertension caused by mutations in WNK kinases.  Science  2001; 293:1107-1112.

69. Wilson FH, Kahle KT, Sabath E, et al: Molecular pathogenesis of inherited hypertension with hyperkalemia: The Na-Cl cotransporter is inhibited by wild-type but not mutant WNK4.  Proc Natl Acad Sci U S A  2003; 100:680-684.

70. Kahle KT, Macgregor GG, Wilson FH, et al: Paracellular Cl- permeability is regulated by WNK4 kinase: Insight into normal physiology and hypertension.  Proc Natl Acad Sci U S A  2004; 101:14877-14882.

71. Kahle KT, Wilson FH, Leng Q, et al: WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion.  Nat Genet  2003; 35:372-376.

72. Braden GL, O'Shea MH, Mulhern JG, Germain MJ: Acute renal failure and hyperkalaemia associated with cyclooxygenase-2 inhibitors.  Nephrol Dial Transplant  2004; 19:1149-1153.

73. Caliskan Y, Kalayoglu-Besisik S, Sargin D, Ecder T: Cyclosporine-associated hyperkalemia: Report of four allogeneic blood stem-cell transplant cases.  Transplantation  2003; 75:1069-1072.

74. Caramelo C, Bello E, Ruiz E, et al: Hyperkalemia in patients infected with the human immunodeficiency virus: Iinvolvement of a systemic mechanism.  Kidney Int  1999; 56:198-205.

75. Schlanger LE, Kleyman TR, Ling BN: K+-Sparing diuretic actions of trimethoprim: Inhibition of Na+ channels in A6 distal nephron cells.  Kidney Int  1994; 45:1070-1076.

76. Kleyman TR, Roberts C, Ling BN: A mechanism for pentamidine-induced hyperkalemia: Inhibition of distal nephron sodium transport.  Ann Intern Med  1995; 122:103-106.

77. Valazquez H, Perazella MN, Wright FS, Ellison DH: Renal mechanisms of trimethoprim-induced hyerkalemia.  Ann Intern Med  1993; 19193:296-301.

78. Sands JM, McMahon SJ, Tumlin JA: Evidence that the inhibition of Na+/K+-ATPase activity by FK506 involves calcineurin.  Kidney Int  1994; 46:647-652.

79. Kraut JA, Kurtz I: Metabolic acidosis of CKD: Diagnosis, clinical characteristics, and treatment.  Am J Kidney Dis  2005; 45:978-993.

80. Qunibi WY, Hootkins RE, McDowell LL, et al: Treatment of hyperphosphatemia in hemodialysis patients: The Calcium Acetate Renagel Evaluation (CARE Study).  Kidney Int  2004; 65:1914-1926.

81. Sonikan MA, Pani IT, Iliopoulos AN, et al: Metabolic acidosis aggravation and hyperkalemia in hemodialysis patients treated by sevelamer hydrochloride.  Ren Fail  2005; 27:143-147.

82. Wrong O, Harland C: Sevelamer-induced acidosis.  Kidney Int  2005; 67:776-777.

83. Laski ME, Wesson DE: Lactic acidosis.   In: DuBose TD, Hamm LL, ed. Acid-Base and Electrolyte Disorders: A Companion to Brenner and Rector's The Kidney,  Philadelphia: WB Saunders; 2002:68-83.

84. John M, Mallal S: Hyperlactatemia syndromes in people with HIV infection.  Curr Opin Infect Dis  2002; 15:23.

85. Cote HC, Brumme ZL, Craig KJ, et al: Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients.  N Engl J Med  2002; 346:811.

86. Lalau JD, Race JM: Lactic acidosis in metformin therapy.  Drug  1999; 1:55.

87. Calabrese AT, Coley KC, DaPos SV, et al: Evaluation of prescribing practices: Risk of lactic acidosis with metformin therapy.  Arch Intern Med  2002; 162:434-437.

88. Romanski SA, McMahon MM: Metabolic acidosis and thiamine deficiency.  Mayo Clin Proc  1999; 74:259-263.

89. Luft FC: Lactic acidosis update for critical care clinicians.  J Am Soc Nephrol  2001; 12:S15.

90. Gerard Y, Maulin L, Yazdanpanah T, et al: Symptomatic hyperlactataemia: An emerging complication of antiretroviral therapy.  AIDS  2000; 14:2723-2730.

91. Wilson KC, Reardon C, Farber HW: Propylene glycol toxicity in a patient receiving intravenous diazepam.  N Engl J Med  2000; 343:815.

92. Arroliga AC, Shehab N, McCarthy K, Gonzales JP: Relationship of continuous infusion lorazepam to serum propylene glycol concentration in critically ill adults.  Crit Care Med  2004; 32:1709-1714.

93. Stacpoole PW, Wright EC, Baumgartner TG, et al: A controlled clinical trial of dichloroacetate for treatment of lactic acidosis in adults. The Dichloroacetate-Lactic Acidosis Study Group.  N Engl J Med  1992; 327:1564.

94. Bjerneroth G: Alkaline buffers for correction of metabolic acidosis during cardiopulmonary resuscitation with focus on Tribonat—A review.  Resuscitation  1998; 37:161-171.

95. Uchida H, Yamamoto H, Kisaki Y, et al: d-Lactic acidosis in short-bowel syndrome managed with antibiotics and probiotics.  J Pediatr Surg  2004; 39:634-636.

96. Jorens PG, Demey HE, Schepens PJ, et al: Unusual d-lactic acid acidosis from propylene glycol metabolism in overdose.  J Toxicol Clin Toxicol  2004; 42:163-169.

97. Lalive PH, Hadengue A, Mensi N, et al: Recurrent encephalopathy after small bowel resection. Implication of d-lactate.  Rev Neurol (Paris)  2001; 157:679.

98. Whitney GM, Szerlip HM: Acid-base disorders in the critical care setting.   In: DuBose TD, Hamm LL, ed. Acid-Base and Electrolyte Disorders: A Companion to Brenner and Rector's The Kidney,  Philadelphia: WB Saunders; 2002:165-187.

99. Umpierrez GE, DiGirolamo M, Tuvlin JA, et al: Differences in metabolic and hormonal milieu in diabetic- and alcohol-induced ketoacidosis.  J Crit Care  2000; 15:52.

100. Proudfoot AT, Krenzelok EP, Brent J, Vale JA: Does urine alkalinization increase salicylate elimination? If so, why?.  Toxicol Rev  2003; 22:129-136.

101. Sterns RH: Fluid, electrolyte, and acid-base disturbances.  Neph SAP  2003; 2:4-5.

102. Fraser AD: Clinical toxicologic implications of ethylene glycol and glycolic acid poisoning.  Ther Drug Monit  2002; 24:232-238.

103. Brent J, McMartin K, Phillips S, et al: Fomepizole for the treatment of methanol poisoning.  N Engl J Med  2001; 344:424-429.

104. Mizock BA, Belyaev S, Mecher C: Unexplained metabolic acidosis in critically ill patients: The role of pyroglutamic acid.  Intensive Care Med  2004; 30:502-505.

105. DuBose TD: Metabolic alkalosis.   In: Greenberg A, ed. Primer on Kidney Diseases,  Philadelphia: Elsevier Saunders; 2005:90-96.

106. Gupta M, Wadhwa NK, Bukovsky R: Regional citrate anticoagulation for continuous venovenous hemodiafiltration using calcium-containing dialysate.  Am J Kidney Dis  2004; 43:67-73.

107. Meier-Kriesche H, Gitomer J, Finkel K, DuBose T: Increased total to ionized calcium ratio during continuous venovenous hemodialysis with regional citrate anticoagulation.  Crit Care Med  2001; 29:748-752.

108. Aichbichler BW, Zerr CH, Santa Ana CA, et al: Proton-pump inhibition of gastric chloride secretion in congenital chloridorrhea.  N Engl J Med  1997; 336:106.

109. Simon DB, Karet FE, Rodriguez-Soriano J, et al: Genetic heterogeneity of Bartter's syndrome revealed by mutations in the K+ channel, ROMK.  Nat Genet  1996; 14:152-156.

110. Herbert SC, Gullans SR: The molecular basis of inherited hypokalemic alkalosis: Bartter's and Gitelman's syndromes.  Am J Physiol Renal Physiol  1996; 271:F957-F959.

111. Shaer AJ: Inherited primary renal tubular hypokalemic alkalosis: A review of Gitelman and Bartter syndromes.  Am J Med Sci  2001; 322:316-332.

112. Monkawa T, Kurihara I, Kobayashi K, et al: Novel mutations in thiazide-sensitive Na-Cl cotransporter gene of patients with Gitelman's syndrome.  J Am Soc Nephrol  2000; 11:65.

113. Toka HR, Luft FC: Monogenic forms of human hypertension.  Semin Nephrol  2002; 22:81.

114. Kamynina E, Staub O: Concerted action of ENaC, Nedd4-2, and Sgkl in transepithelial Na+ transport.  Am J Physiol Renal Physiol  2002; 283:F377.

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