Although temporary relief from changes in the pH of body fluids may be accomplished by chemical buffering or respiratory compensation, the ultimate defense against the addition of nonvolatile acid or alkali is the responsibility of the kidneys. The addition of a strong acid (HA) to the ECF titrates or consumes plasma HCO ₃ ⁻ :

The CO ₂ is expired by the lungs, and body HCO ₃ ⁻ buffer stores are diminished. This process occurs constantly as endogenous metabolic acids are generated. To maintain a normal plasma HCO ₃ ⁻ in the face of constant production of metabolic acids, predominantly as a result of dietary protein metabolism, the kidneys must 1. reabsorb virtually all of the HCO ₃ ⁻ present in glomerular filtrate and 2. regenerate the HCO ₃ ⁻ consumed by reaction with metabolic acids (see seventh equation earlier in “Renal Regulation”). The first process (HCO ₃ ⁻ reabsorption) is accomplished predominantly in the proximal tubule, with an additional contribution by the loop of Henle and a lesser, but critical, contribution by more distal nephron segments ( Fig. 15.1 ). Under most circumstances, the filtered load of HCO ₃ ⁻ is reabsorbed almost completely, especially during an acid load. “Acid production” in biologic systems is represented by the milliequivalents (mEq) of protons (H ⁺ ) added to body fluids. Ordinarily on a Western diet, especially animal-based proteins, there is a net daily endogenous acid load that consumes HCO ₃ ⁻ . Conversely, base addition to the extracellular fluid via the gastrointestinal tract is derived primarily from dietary fruits and vegetables. If less acid is generated or when, in the face of an alkali load, the plasma HCO ₃ ⁻ concentration increases above the normal value of 25 mEq/L, HCO ₃ ⁻ will be excreted into the urine. Therefore the kidney must efficiently excrete any excess in alkali added to the ECF, as well as regenerate the bicarbonate lost when net endogenous acid production is significant. The difference between endogenous acid production and the input of alkali absorbed by the gastrointestinal system (i.e., the difference in acid production and base generation) is known as net endogenous acid production . Since a Western diet is high in animal-based protein, net endogenous production is positive and consumes bicarbonate; therefore the kidney must regenerate the bicarbonate consumed by dietary protein intake.

HCO ₃ ⁻ reabsorption along the nephron.

The proximal tubule reabsorbs approximately 80% of the filtered HCO ₃ ⁻ . Substantial amounts are also reabsorbed in the thick ascending limb. The remaining amounts (∼5%) are reabsorbed in the collecting duct, which is critical for final regulation of acid excretion. The mechanisms are described in Chapter 9 , but the main apical transporters (Na-H exchange and H ⁺ -ATPase) are illustrated. Little HCO ₃ ⁻ (∼0%) remains in the final urine.

The process of HCO ₃ ⁻ regeneration is represented by the renal output of acid or net acid excretion :

The mechanisms of net acid excretion are discussed as follows but include two components: titratable acid (TA) and ammonium NH ₄ ⁺ ( Fig. 15.2 ). TA is the acid added to tubular fluid along the nephron to lower fluid pH to that of the final urine. The final pH of urine will depend on the amount of urinary buffer, principally phosphate, and the amount of acid added. TA can be measured by titrating urine (after removing ammonia) back to plasma pH or can be calculated using the urine and plasma pH and the buffer concentration (as a first approximation phosphate) and its pKa. NH ₄ ⁺ represents acid excretion since, as described in another chapter, for each NH ₄ ⁺ produced and excreted the carbon skeleton of glutamine from which it derives has been converted to HCO ₃ ⁻ ( Fig. 15.3 ).

Net acid excretion with typical Western diets, acid loading, and acidosis in chronic kidney disease (CKD).

Ammonium excretion has the capability for the most increase in acidosis and is the component most compromised in CKD. T.A., Urine titratable acidity.

From Gauthier P, Simon EE, Lemann J Jr. Acidosis of chronic renal failure. In: DuBose TD, Hamm LL, eds. Acid-Base and Electrolyte Disorders. Philadelphia: Saunders; 2002. pp. 207–216.

Synchrony of regulation of ammonium production (from glutamine [GLN] precursors, and excretion).

Process allows generation of “new” HCO ₃ ⁻ by the kidney. NH ₄ ⁺ excretion is regulated in response to changes in systemic acid-base and K ⁺ balance. Contributing segments include the proximal convoluted tubule, proximal straight tubule, thin descending limb, thick ascending limb, and medullary collecting duct. Upregulated by acidosis and hypokalemia. Inhibited by hyperkalemia.

On balance, each milliequivalent of net acid excreted corresponds to 1 mEq of HCO ₃ ⁻ returned to the ECF (i.e., regeneration of HCO ₃ ⁻ ). This process of HCO ₃ ⁻ regeneration is necessary to replace the HCO ₃ ⁻ lost by the endogenous acid entry into the ECF or, less commonly, the HCO ₃ ⁻ excreted in stool or urine. Because a typical Western diet, rich in animal-based proteins, generates fixed acids at 35 to 70 mEq/day, net acid excretion must approximate 35 to 70 mEq/day to match net acid production and avoid metabolic acidosis.

Pathologically, acid loads may be derived from endogenous acid production (e.g., generation of ketoacids 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 with an acid challenge. The net result of these processes amounts to the entry of about 0.5 to 1.0 mEq of new H ⁺ per kilogram per day into the ECF. ^,

Sulfuric acid is formed when organic sulfur from methionine and cysteine residues of proteins are oxidized to SO ₄ ² –. The metabolism of sulfur-containing amino acids is the primary source of acid in the usual Western diet, especially animal-derived proteins, accounting for approximately 50%. The quantity of sulfuric acid generated is equal to the SO ₄ ² – 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 CO ₂ and water. The net amount of H ⁺ added to the body from this source can be estimated by the quantity of organic anions excreted in the urine.

Phosphoric acid can be derived from hydrolysis of PO ₄ ^3– esters in proteins and nucleic acids if it is not neutralized by mineral cations (e.g., Na ⁺ , K ⁺ , and Mg ²⁺ ). 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. ^,

Potential sources of bases are also found in the diet (e.g., acetate, lactate, and citrate), primarily from fruits and vegetables, 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 ⁺ + Ca ²⁺ + Mg ²⁺ – Cl ^– – 1.8 P) from those measured in the diet. The net base absorbed by the gastrointestinal tract is derived from the AG of the diet minus that of the stool.

In summary, diets contain many sources of acids and bases. The usual North American diet, which is replete in animal-derived proteins, represents a daily source of acid generation for which the body must compensate constantly.

The generation of acid by protein catabolism is balanced by the generation of new HCO ₃ ⁻ through renal NH ₄ ⁺ and TA excretion (or, in sum, net acid excretion). Hepatic catabolism of proteins, with the exception of sulfur- and PO ₄ ^3– -containing amino acids, can be considered a neutral process. The products of these neutral reactions are HCO ₃ ⁻ and NH ₄ ⁺ . Most of the NH ₄ ⁺ produced by metabolism of amino acids reacts with HCO ₃ ⁻ and forms urea; thus it has no impact on acid-base balance. A portion of this NH ₄ ⁺ 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 initially; glutamate can also be deaminated, releasing another NH ₄ ⁺ and forming α-ketoglutarate. Renal glutamine deamination results in NH ₄ ⁺ production and initiates a metabolic process that generates new HCO ₃ ⁻ through α-ketoglutarate. Glutamine deamination in the kidney is also highly regulated by systemic pH, so acidemia augments and alkalemia inhibits NH ₄ ⁺ and HCO ₃ ⁻ production. The ultimate control, however, resides in the renal excretion of NH ₄ ⁺ because the NH ₄ ⁺ must be excreted to escape entry into the hepatic urea synthetic pool. Hepatic urea synthesis would negate the new HCO ₃ ⁻ realized from α-ketoglutarate in the kidney. Hepatic regulation of NH ₄ ⁺ metabolic pathways appears to facilitate glutamine production when NH ₄ ⁺ excretion is stimulated by acidemia or, conversely, blunts glutamine production when excretion is inhibited by alkalemia.

A critically important response to an acid load is the control of ventilation. A fall in systemic arterial pH is sensed by the chemoreceptors that stimulate ventilation and therefore reduce Pa co ₂ . The fall in blood pH that would otherwise occur in uncompensated metabolic acidosis is therefore blunted. The pH is not restored to normal; however, with normal lungs Pa co ₂ declines by an average of 1.25 mm Hg for each 1.0 mEq/L drop in HCO ₃ ⁻ concentration. The clinical features are hyperpnea (increased tidal volume) and tachypnea (increased respiratory rate), which is termed Kussmaul respiration. The appropriate Pa co ₂ in steady-state metabolic acidosis can be estimated from the prevailing HCO ₃ ⁻ concentration according to the following expression, commonly known as the Winter formula :

Other formulas to predict respiratory compensation are also available. Because the Pa co ₂ cannot fall below about 10 to 12 mm Hg, the blood pH is less well defended by respiration after large reductions in the plasma HCO ₃ ⁻ concentration ( Table 15.1 ). Approximately 12 to 24 hours is required to achieve full respiratory compensation for metabolic acidosis (see Fig. 15.4 ).

Conceptual illustration of time course of acid-base compensatory mechanisms in response to a metabolic acid load.

Component processes include rapid distribution and extracellular buffering mechanisms and cellular buffering events. But these most rapid mechanisms have limited capacity. Slower are respiratory and renal regulatory processes. ECF, Extracellular fluid.

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, HCO ₃ ⁻ generation) in response to endogenous or exogenous acid loads. Acidosis enhances proximal HCO ₃ ⁻ absorption, decreasing delivery of HCO ₃ ⁻ out of the proximal tubule, and enhances distal acidification. The enhanced distal acidification serves to reabsorb any remaining HCO ₃ ⁻ and facilitate TA excretion and NH ₄ ⁺ excretion. Increased HCO ₃ ⁻ reabsorption per se in the proximal tubule does not facilitate acid excretion since little HCO ₃ ⁻ is excreted into the urine even in normal circumstances. Net acid excretion is increased by stimulation of NH ₄ ⁺ production and excretion. Renal excretion of acid is usually matched to the net production of metabolic and dietary acids, often about 35 to 70 mEq/day, so little disturbance in systemic pH or HCO ₃ ⁻ concentration occurs.

As an acid load is incurred, the kidneys respond to restore balance primarily by increasing NH ₄ ⁺ excretion since TA excretion has limited capacity for upregulation ( Fig. 15.2 ). With continued acid loading, renal net acid excretion increases over the course of 3 to 5 days (see Fig. 15.4 ). Thus the renal response to an acid load requires 1. reabsorption of the filtered HCO ₃ ⁻ by the proximal tubule and 2. augmentation of NH ₄ ⁺ 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.

There is some controversy about whether the kidneys completely excrete higher than usual acid loads, particularly in patients with CKD. Certainly patients with reduced plasma HCO ₃ ⁻ have a chronic metabolic acidosis. But some patients with CKD and normal plasma HCO ₃ ⁻ levels may have positive acid balance (e.g., acid retention), perhaps buffered by bone carbonate and reflected in an acid renal interstitium. ^, There is also growing evidence (discussed more later) that not only does acidosis accelerate progression of CKD but that higher ammonium production and excretion may be harmful. On the other hand, in some studies higher urinary acid and ammonia excretion may be beneficial and/or be present in patients with slower progression. Both the mechanistic understandings and clinical implications are under active investigation. Whether and when to treat patients with CKD to correct acidosis is currently under consideration.

Ninety-five percent of a base load in the form of HCO ₃ ⁻ is distributed in the ECF within about 25 minutes ^{, , ,} (see Fig. 15.4 ). Cellular buffering over the next few hours 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. ^,

The pulmonary response to an acute increase in HCO ₃ ⁻ concentration is biphasic. Neutralization of sodium bicarbonate by buffers (H ⁺ buffer–) results in CO ₂ liberation and an increase in PCO ₂ :

A clinical corollary would be the acute increase in PCO ₂ observed in patients given intravenous NaHCO ₃ infusions. The increased PCO ₂ stimulates ventilation acutely to return PCO ₂ toward normal. If the pulmonary system is compromised or the ventilation rate is controlled artificially, increased CO ₂ production from infused sodium bicarbonate can lead to hazardous hypercapnia. ^{, ,}

About an hour after an abrupt increment in the HCO ₃ ⁻ concentration, when the increased generation of CO ₂ subsides, stimulation of respiration is transformed into suppression of respiration by elevated pH and PCO ₂ increases. This secondary hypercapnic response takes several hours and partially compensates for the elevated HCO ₃ ⁻ concentration so that arterial pH is returned toward (although not completely to) normal (see Fig. 15.4 ).

The hypercapnic response to metabolic alkalosis is more difficult to reliably predict than other acid-base disturbances. Most studies have found that an increase in PCO ₂ regularly occurs in response to alkalosis. The hypoventilatory response can lead to borderline or even frank hypoxemia in patients with chronic lung disease. In general, the increase in Pa co ₂ can be predicted to equal 0.75 mm Hg per 1.0 mEq/L increase in plasma HCO ₃ ⁻ ; or more simply, add the value of 15 to the measured plasma [HCO ₃ ⁻ ] to predict the expected Pa co ₂ (see Table 15.1 ).

For correct diagnosis of a simple or mixed acid-base disorder, it is imperative that a careful history be 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 respiratory acidosis. The clinical setting of an acid-base disorder may be much more revealing than complex formulas. The patient’s drug history assumes importance because patients taking loop or thiazide diuretics may have metabolic alkalosis and patients receiving acetazolamide frequently have 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 plasma K ⁺ value is often useful but should be considered only in conjunction with the HCO ₃ ⁻ 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 ⁺ into either the extracellular or intracellular compartment. Metabolic acidosis frequently leads to hyperkalemia. Some suggest 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 due to endogenous acid production, 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, the presence or absence of preexisting changes in K ⁺ homeostasis, 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 acidosis to exhibit hyperkalemia or, conversely, the failure of a patient with severe metabolic alkalosis to exhibit hypokalemia raises the possibility of a significant derangement of body K ⁺ homeostasis. The combination of a low plasma K ⁺ and elevated HCO ₃ ⁻ suggests metabolic alkalosis (or the action of aldosterone or the like, see later), whereas the combination of an elevated plasma K ⁺ and low HCO ₃ ⁻ suggests metabolic acidosis.

It is helpful to compare the serum Cl ⁻ concentration with the Na ⁺ concentration. In the absence of an exogenous source of concentrated sodium (e.g., hypertonic saline or NaHCO ₃ ), the serum Na ⁺ concentration changes only as a result of changes in hydration or total body water. 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% vs. 7%). A disproportionate decrease in Cl ⁻ suggests metabolic alkalosis or respiratory acidosis, and a disproportionate increase in Cl ⁻ suggests metabolic acidosis or respiratory alkalosis.

The four simple acid-base disorders and the predicted compensatory responses are summarized in Table 15.1 . The complete diagnosis including the possibility of complex mixed disturbances can best be determined by a stepwise approach (see Table 15.2 ).

For a complete diagnosis of acid-base disorders, one needs both an ABG and a simultaneous set of electrolytes. For a simple single disorder, the diagnosis is easy: If the pH is low, a respiratory acidosis (with high PCO ₂ and somewhat high HCO ₃ ⁻ ) or metabolic acidosis (with low HCO ₃ ⁻ and secondarily low PCO ₂ ) is present. The opposite situations occur with high pH. Or with electrolytes, if the HCO ₃ ⁻ concentration is low and the Cl ⁻ concentration is high, either chronic respiratory alkalosis or hyperchloremic metabolic acidosis is present. The ABG determination serves to differentiate the two conditions. Although both have a decreased Pa co ₂ , the pH is high with primary respiratory alkalosis and low in metabolic acidosis. Chronic respiratory acidosis and metabolic alkalosis are both associated with high HCO ₃ ⁻ and low Cl ⁻ concentration in plasma. Again, a pH measurement distinguishes the two conditions.

But neither ABG nor electrolytes alone can necessarily give a complete picture. For instance, an ABG alone may miss mixed disorders, which are only revealed by an analysis of the AG later discussion). While electrolyte abnormalities may suggest an acid-base disorder (e.g., high AG metabolic acidosis), the actual pH and the complete diagnosis with compensatory response require an ABG. Of note, the calculated value for HCO ₃ ⁻ or (or total CO ₂ ) reported with the ABG should be within ±2 mEq/L of the measured HCO ₃ ⁻ concentration (total CO ₂ ) obtained on the electrolyte panel. A greater difference may imply a laboratory error or nonsimultaneous measurements.

In many clinical situations, 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 Fig. 15.5 , which defines the 95% confidence limits of simple acid-base disorders. ^, If the arterial acid-base values fall within one of the blue bands in Fig. 15.3 , one may assume that a simple acid-base disturbance is present and a tentative diagnostic category can be assigned. There can be complex exceptions. Values that fall outside the blue areas imply but do not prove, that a mixed disorder exists.

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 HCO ₃ ⁻ in plasma, whereas respiratory disorders involve primarily alteration of Pa co ₂ . The most commonly encountered clinical disturbances are simple acid-base disorders (i.e., 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 .

To appreciate and recognize a mixed acid-base disturbance, it is important to understand the physiologic compensatory responses that occur in simple acid-base disorders. Primary respiratory disturbances invoke secondary metabolic responses and primary metabolic disturbances evoke a predictable respiratory response (see Table 15.1 and Fig. 15.3 ). These predictable compensations are defined as being part of the primary simple acid-base disorder. To illustrate, metabolic acidosis as a result of gain of endogenous acids (e.g., lactic acid or ketoacidosis) lowers the concentration of HCO ₃ ⁻ in the 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 HCO ₃ ⁻ to Pa co ₂ and the subsequent pH are returned toward, but not completely to, normal. Thus a patient with metabolic acidosis and a plasma HCO ₃ ⁻ concentration of 12 mEq/L would be expected to have a Pa co ₂ between 24 and 28 mm Hg. Values of Pa co ₂ below 24 or higher 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, an inappropriate compensation, too little or too much, identifies one form of a mixed acid-base disturbance.

Compensation is a predictable physiologic consequence of the primary disturbance and does not represent a secondary acidosis or alkalosis (see Fig. 15.5 and Table 15.1 ). The recognition of mixed disturbances may alert one to an additional clinical disorder that may require immediate attention or additional therapy (e.g., inadequate respiratory response to metabolic acidosis defining a respiratory acidosis).

The limits of compensation should also be recognized (see Table 15.1 ). For example, the plasma HCO ₃ ⁻ concentration rarely falls below 12 to 15 mEq/L as a result of compensation for respiratory alkalosis and rarely exceeds 45 mEq/L as a result of compensation for respiratory acidosis.

All evaluations of acid-base disorders should include a simple calculation of the AG since an elevated AG usually implies metabolic acidosis. The AG is calculated from the serum electrolytes and is defined as follows:

The AG represents the unmeasured anions normally present in plasma and unaccounted for by the serum electrolytes exclusive of K ⁺ that are measured on the electrolyte panel. Normal values for AG vary with the laboratory and analyte measurement techniques but in general have declined with more precise measurement of serum electrolytes by ion-selective electrodes. The normal value for AG ranges from 8 to 12 mEq/L, but the clinician should know the normal value for the AG in clinical laboratories used in their practice. Because of this range of normal values for the AG and for convenience, the following computations will use the value of 10 mEq/L as the “normal” AG. The unmeasured anions that contribute to this value are normally present in serum and include anionic proteins (principally albumin and, to lesser extent, α- and β-globulins), PO ₄ ^3– , SO ₄ ^2– , and organic anions. As already emphasized, interpretation of the AG requires either a normal serum albumin or correction of the AG to a normal plasma albumin. In general, reduction in the serum albumin level by 1 g/dL from the normal value of 4.5 g/dL decreases the AG by 2.5 mEq/L. 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 high AG acidosis. ^, Additionally, in a simple high AG metabolic acidosis, for each milliequivalent per liter increase in the corrected AG, there should be an equal decrease, measured as milliequivalent per liter, in the plasma HCO ₃ ⁻ concentration.

A number of conditions other than metabolic acidosis can occasionally change the AG up or down ( Table 15.3 ). 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 cations. In addition, the AG may increase secondary to an increase in anionic albumin, as a consequence of either an increased albumin concentration or alkalemia. ^, The increased AG in severe alkalemia can be explained in part by the effect of alkaline pH on the electrical charge of albumin.

A decrease in the AG can be generated by an increase in unmeasured cations or a decrease in unmeasured anions (see Table 15.3 ). A decrease in the AG can result from 1. an increase in unmeasured cations (Ca ²⁺ , Mg ²⁺ , 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, and capillary leak). With each decline in the serum albumin level by 1 g/dL from the normal value of 4.5 g/dL, the AG will decline by 2.5 mEq/L. 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 level of 1.5 g/dL and an uncorrected AG of 10 mEq/L, the “corrected” AG is 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.

In the presence of a normal serum albumin level, elevation of unmeasured anions is usually due to addition of non–Cl ⁻ -containing acid anion (e.g., lactate). Thus in most clinical circumstances, a high AG indicates that a metabolic acidosis is present. The anions accompanying such acids include inorganic (PO ₄ ³ –, SO ₄ ² –), organic (ketoacids, lactate, uremic organic anions), exogenous (salicylate or ingested toxins with organic acid production), or unidentified anions. 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 HCO ₃ ⁻ concentration will match the increment in the AG. If the retained anion can be metabolized to HCO ₃ ⁻ 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 is excreted, hyperchloremic acidosis may emerge as the anion is excreted and the AG disappears.

The presence of a significant elevation of the AG (unexplained by laboratory error or the unusual conditions noted) implies the presence of metabolic acidosis process whether or not acidemia (low pH) exists. For instance, a coexisting respiratory alkalosis or metabolic alkalosis could dominate the net pH even in the presence of a metabolic acidosis.

Utility of identifying an elevated AG derives from knowledge of the four causes of a high AG metabolic acidosis: 1. ketoacidosis, 2. lactic acidosis, 3. renal failure acidosis, and 4. toxin-induced metabolic acidosis ( Table 15.4 ). In contrast, 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 later section. Table 15.1 displays the directional changes in pH, PCO ₂ , and HCO ₃ ⁻ for the four simple acid-base disorders. With this stepwise approach, in subsequent sections, the specific causes of the major types of acid-base disorders are reviewed in detail.

By definition, a high AG acidosis has two identifying features: a low HCO ₃ ⁻ concentration and an elevated AG. The elevated AG will remain present even if another disorder coincides to modify the HCO ₃ ⁻ concentration independently. Simultaneous metabolic acidosis of the high AG variety plus either metabolic alkalosis or chronic respiratory acidosis is an example of such a situation. The resulting HCO ₃ ⁻ concentration may be normal or even high in such a setting. However, the AG will be high and the Cl ⁻ concentration relatively depressed. Consider a patient with chronic obstructive pulmonary disease with compensated respiratory acidosis (Pa co ₂ of 65 mm Hg and HCO ₃ ⁻ concentration of 40 mEq/L initially) in whom acute bronchopneumonia and respiratory decompensation develop. If this patient has an HCO ₃ ⁻ 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” HCO ₃ ⁻ concentration represents improvement in acid-base status toward normal. Indeed, the arterial pH would probably be low (7.19), as a result of a more serious degree of hypercapnia than observed previously (e.g., if the PCO ₂ 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 is superimposed on a preexisting chronic respiratory acidosis, which necessitates immediate therapy. In this example, the change in AG, frequently referred to as ΔAG, is computed as 25– 10, or patient’s calculated AG minus the normal AG, and is equal to 15 mEq/L.

Similarly, a normal arterial HCO ₃ ⁻ concentration, Pa co ₂ , and pH do not ensure the absence of an acid-base disturbance. For example, an alcoholic patient who has been vomiting may develop a metabolic alkalosis with a pH of 7.55, HCO ₃ ⁻ concentration of 40 mEq/L, PCO ₂ of 48 mm Hg, 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 (AKA) with a β-hydroxybutyrate concentration of 15 mmol/L, the arterial pH would fall to 7.40, HCO ₃ ⁻ concentration to 25 mEq/L, and PCO ₂ 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), and the ΔAG is 15 mEq/L, which indicates 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, as in this case, when the ΔAG is elevated, but the HCO ₃ ⁻ concentration and pH are near normal (ΔAG > ΔHCO ₃ ⁻ , or 15 vs. 0 mEq/L).

Although a variety of formulaic approaches have been proposed to compare the ΔAG and ΔHCO ₃ ⁻ , a conceptual approach as above with attention to the clinical ingredients is most useful. With an elevated AG, if the HCO ₃ ⁻ is higher than expected based on the ΔAG, then suspect a coexisting metabolic alkalosis or chronic respiratory acidosis (which also elevates the HCO ₃ ⁻ ). With an elevated AG, if the HCO ₃ ⁻ is lower than expected (or Cl ^– higher) based on the ΔAG, suspect a coexisting hyperchloremic metabolic acidosis or chronic respiratory alkalosis.

Mixed acid-base disorders—defined as independently coexisting disorders, not merely compensatory responses—are often seen in patients in critical care units and can lead to dangerous extremes of pH. 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. Note that failure of an appropriate ventilator response to metabolic acidosis represents a combined metabolic acidosis and respiratory acidosis. A patient with DKA (metabolic acidosis) may develop an independent respiratory problem, leading to respiratory acidosis or alkalosis. 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 of 10 mEq/L) and the ΔHCO ₃ ⁻ (normal, 25 mEq/L, minus prevailing HCO ₃ ⁻ ) indicates the presence of a mixed high gap acidosis–metabolic alkalosis (see example later).

Even more complex are triple acid-base disturbances. For example, patients with metabolic acidosis due to alcoholic ketoacidosis may develop metabolic alkalosis due to vomiting and superimposed respiratory alkalosis due 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 HCO ₃ ⁻ concentration (ΔCl ⁻ > ΔHCO ₃ ⁻ ).

In summary, an AG exceeding that expected for a patient’s albumin concentration (i.e., >10 mEq/L) 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.

Respiratory acidosis occurs as the result of severe pulmonary disease, respiratory muscle disorders, or depression in ventilatory control. An increase in Pa co ₂ owing to reduced alveolar ventilation is the primary abnormality leading to acidemia. In acute respiratory acidosis, there is an immediate small compensatory elevation in HCO ₃ ⁻ (due to cellular buffering mechanisms) of 1 mEq/L for every 10 mm Hg increase in Pa co ₂ . In chronic respiratory acidosis (>24 hours), renal adaptation is achieved and the HCO ₃ ⁻ increases by 4 mEq/L for every 10 mm Hg increase in Pa co ₂ . The serum bicarbonate concentration usually does not increase above 38 mEq/L, however.

Clinical features of respiratory acidosis vary according to the underlying disease, severity, duration, and presence or absence of accompanying hypoxemia. A rapid increase in Pa co ₂ may result in anxiety, dyspnea, confusion, psychosis, and hallucinations and may progress to coma. More subtle dysfunction in chronic hypercapnia may include sleep disturbances, loss of memory, daytime somnolence, and personality changes. Coordination may be impaired, and motor disturbances such as tremors, myoclonic jerks, and asterixis may develop. The sensitivity of the cerebral vasculature to the vasodilating effects of CO ₂ can cause headaches and other signs that mimic increased intracranial pressure, such as papilledema, abnormal reflexes, and focal muscle weakness.

Causes of respiratory acidosis are listed in Table 15.5 . A reduction in ventilatory drive from depression of the respiratory center by a variety of drugs, injuries, or disease can produce respiratory acidosis. Acutely, this may occur with general anesthetics, sedatives, narcotics, alcohol, 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 may result in respiratory acidosis when not properly adjusted and supervised or when complicated by barotrauma or displacement of the endotracheal tube. This occurs if carbon dioxide production rises (e.g., fever, agitation, sepsis, and 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 may be utilized in the critical care setting since lower tidal volumes may reduce the incidence of barotrauma associated with high airway pressure and peak airway pressures in mechanically ventilated patients with respiratory distress syndrome. Acute hypercapnia of any cause can lead to severe acidemia, neurologic dysfunction, and death. However, when CO ₂ levels are allowed to increase gradually, the resulting acidosis is less severe and the elevation in arterial PCO ₂ is tolerated more readily. Although the resulting hypercapnia is not the goal of this approach, but secondary to the attempt to limit airway pressures, the arterial pH will decline. The magnitude of the acidemia associated with permissive hypercapnia may be augmented if superimposed on metabolic acidosis, such as lactic acidosis. This combination is not uncommon in the critical care unit. Bicarbonate infusion may be indicated with mixed metabolic acidosis–respiratory acidosis, but the goal of therapy with alkali is to not increase the bicarbonate and pH to normal. With low tidal volume ventilation, a reasonable therapeutic target for arterial pH is approximately 7.25. 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 PCO ₂ , especially in patients with fixed rates of ventilation, and will add to the magnitude of the hypercapnia. Use of a continuous bicarbonate infusion in this setting may be necessary, but frequent monitoring of ABGs, electrolytes, and the volume status of the patient is necessary.

Disease and obstruction of the airways, when severe or long-standing, cause 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. Restrictive disorders involving either the chest wall or 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 Pa co ₂ 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. Chest radiography is an initial step. Pulmonary function studies including spirometry, diffusion capacity, lung volumes, and arterial Pa co ₂ 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. ^,

Treatment of respiratory acidosis depends on the underlying disease, severity, and rate of onset. Acute respiratory acidosis can be life-threatening, and measures to reverse the underlying cause should be undertaken simultaneously with restoration of adequate alveolar ventilation to relieve severe hypoxemia and acidemia. Temporarily, this may necessitate tracheal intubation and assisted mechanical ventilation. Oxygen levels should be carefully titrated in patients with severe chronic obstructive pulmonary disease and chronic CO ₂ retention who are breathing spontaneously. When oxygen is used injudiciously, these patients may experience progression of respiratory acidosis when ventilation is driven by oxygen pressure (Pa o ₂ ) and not the normal parameters of Pa co ₂ and pH. Aggressive and rapid correction of hypercapnia should be avoided because the falling Pa co ₂ 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 Pa co ₂ gradually in chronic respiratory acidosis, with the aim of restoring the Pa co ₂ to baseline levels while at the same time providing sufficient chloride and potassium to enhance the renal excretion of bicarbonate.

Chronic respiratory acidosis is frequently difficult to correct, but general measures aimed at maximizing lung function including cessation of smoking; use of oxygen, bronchodilators, corticosteroids, etc. and/or diuretics; and physiotherapy can help some patients and forestall further deterioration. Various respiratory stimulants used in the past are seldom used presently.

Alveolar hyperventilation decreases the Pa co ₂ and increases the HCO ₃ ⁻ /Pa co ₂ ratio, thus increasing pH (alkalemia). Nonbicarbonate cellular buffers respond by titrating HCO ₃ ⁻ down. Hypocapnia develops whenever a sufficiently strong ventilatory stimulus causes CO ₂ output in the lungs to exceed the metabolic production of CO ₂ by tissues. Plasma pH and HCO ₃ ⁻ concentration vary approximately proportionately with Pa co ₂ over a range from 40 to 15 mm Hg. The arterial [HCO ₃ ⁻ ] will decrease acutely approximately 2 mEq/L for each 10 mm Hg decrease in PCO ₂ . The relationship between pH and Pa co ₂ is about 0.01 pH unit/mm Hg.

Beyond 2 to 6 hours, sustained hypocapnia is further compensated by renal response, a decrease in renal ammonium and TA excretion, and a reduction in filtered HCO ₃ ⁻ reabsorption. The full expression of renal adaptation may take several days and depends on normal volume status and renal function. The kidneys appear to respond directly to the lowered Pa co ₂ rather than to the alkalemia per se, although both pH and PCO ₂ may be factors. With chronic respiratory alkalosis, a 1 mm Hg fall in Pa co ₂ causes a 0.4 to 0.5 mEq/L drop in HCO ₃ ⁻ and a 0.003 unit rise in pH, or the [HCO ₃ ⁻ ] will decrease 4 mEq/L for each 10 mm Hg decrease in Pa co ₂ . Chronic respiratory alkalosis is an exception to the general rule that physiologic compensation is never 100% efficient because some patients with this acid-base disorder may exhibit a normal arterial pH and are therefore fully compensated.

The effects of respiratory alkalosis vary according to its duration and severity and the underlying disease. Acute respiratory alkalosis causes intracellular shifts of sodium, potassium, and phosphate and reduces ionized calcium by increasing the protein-bound fraction of calcium based on the acute pH changes. A rapid decline in Pa co ₂ 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). Hypocapnia-induced hypokalemia is usually minor.

Respiratory alkalosis is among the most common acid-base disturbances in critically ill patients (often as a component of a mixed disorder) and, when severe, portends a poor prognosis. Many cardiopulmonary disorders manifest respiratory alkalosis in the early to intermediate stages. Hyperventilation usually results in hypocapnia. Respiratory alkalosis is a common occurrence during mechanical ventilation. In those with respiratory disorders or distress, the finding of normocapnia (particularly after prior hypocapnia) and increasing hypoxemia may herald the onset of rapid respiratory failure and should prompt an assessment to determine whether the patient is becoming fatigued.

The causes of respiratory alkalosis are summarized in Table 15.5 . Hyperventilation syndrome may mimic a number of serious conditions and may 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. CNS diseases or injury can produce several patterns of hyperventilation with sustained arterial Pa co ₂ levels of 20 to 30 mm Hg. 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 CO ₂ . High progesterone levels increase ventilation and decrease the arterial Pa co ₂ 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 Pa co ₂ (higher and lower than normal, respectively). The plasma K ⁺ concentration is often reduced, and the serum Cl– concentration increased. In the acute phase, respiratory alkalosis is not associated with increased renal HCO ₃ ⁻ excretion, but within hours, net acid excretion is reduced. In general, the HCO ₃ ⁻ concentration falls by 2.0 mEq/L for each 10 mm Hg decrease in Pa co ₂ acutely. Chronic hypocapnia reduces the serum bicarbonate concentration by 4 to 5 mEq/L for each 10 mm Hg decrease in Pa co ₂ . It is unusual to observe a plasma bicarbonate concentration below 12 mEq/L as a result of pure respiratory alkalosis. When a diagnosis of hyperventilation or respiratory alkalosis is made, the cause should be investigated. The diagnosis of hyperventilation syndrome is made by exclusion. In some cases, it may be important to rule out other conditions such as pulmonary embolism, coronary artery disease, pneumothorax, and hyperthyroidism.

The treatment of respiratory alkalosis is primarily directed toward alleviation of the underlying disorder. Respiratory alkalosis is rarely life-threatening. Direct measures to correct respiratory alkalosis will be unsuccessful if the underlying stimulus remains unchecked. If respiratory alkalosis complicates ventilator management, changes in dead space, tidal volume, and frequency can minimize the hypocapnia. Patients with hyperventilation syndrome may benefit from reassurance, rebreathing into a paper bag (with oxygenation monitoring) 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. The relationship of (and treatment of) recurrent hyperventilation syndrome and psychologic disorders and panic attacks can be explored.

Metabolic acidosis occurs mechanistically as a result of 1. a marked increase in endogenous production of acid (such as l -lactic acid and ketoacids) such that the ability of the kidneys to respond is exceeded, 2. loss of HCO ₃ ⁻ or potential HCO ₃ ⁻ salts (diarrhea or renal tubular acidosis [RTA]), or 3. inability of the kidneys to excrete acid, resulting in progressive accumulation of endogenous acids. However, empirically for diagnostic purposes, metabolic acidosis is frequently classified according to the AG: high AG metabolic acidosis or non-AG acidosis (or probably more appropriately, hyperchloremic metabolic acidosis). The AG, which can be corrected for the prevailing albumin concentration, serves a useful role in the diagnosis of metabolic acidoses and should always be considered. Metabolic acidosis with a normal AG (hyperchloremic or non-AG acidosis) suggests that HCO ₃ ⁻ has been effectively replaced by Cl ⁻ . Thus the AG does not change.

In contrast, a high AG usually indicates accumulation of an anion other than hydrochloric acid in the ECF. Metabolic acidosis with a high AG (see Table 15.3 ) reflects that an anion replaces titrated HCO ₃ ⁻ without disturbing the Cl ⁻ concentration. Hence the acidosis is normochloremic and the AG increases. In some cases, a disease process may cause an acidosis that is either hyperchloremic (non-AG) or high-AG; early CKD and diabetic ketoacidosis in well-hydrated persons are the best examples. The excretion rate of the accompanying anion (e.g., acetoacetate in ketoacidosis) is the determining factor in which type of acidosis is found in a given person. ^,

The diverse clinical disorders that may result in hyperchloremic or nongap metabolic acidosis are outlined in Table 15.6 . Because a reduced plasma HCO ₃ ⁻ and elevated Cl ⁻ concentration may also occur in chronic respiratory alkalosis, it is often important to confirm acidemia by measuring arterial pH. Normal AG metabolic acidosis occurs most often as a result of loss of HCO ₃ ⁻ from the gastrointestinal tract (diarrhea) or as a result of a renal acidification defect. The majority of disorders in this category can be attributed to one of 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 (classical distal RTA [cDRTA], type 4 RTA, or renal failure). Hypokalemia may accompany both gastrointestinal loss of HCO ₃ ⁻ and proximal RTA and cDRTA. Therefore a major challenge in some cases is distinguishing these causes to be able to determine whether the response of renal tubular function to the prevailing acidosis is appropriate (gastrointestinal origin) or inappropriate (renal origin).

Diarrhea results in the loss of large quantities of HCO ₃ ⁻ or potential HCO ₃ ⁻ (organic acid anions such as propionate and butyrate, which could be metabolized to HCO ₃ ⁻ ), and therefore metabolic acidosis frequently results. Volume depletion and hypokalemia often coexist due to sodium and K ⁺ losses. Hypokalemia is additionally from volume depletion causing secondary hyperaldosteronism, which enhances renal K ⁺ secretion by the collecting duct.

Although a low urine pH may be found with diarrhea, consistent with metabolic acidosis and appropriate renal response, in some cases a urine pH of 6.0 or more may be found. This occurs because chronic metabolic acidosis and hypokalemia increase renal NH ₄ ⁺ synthesis and excretion, which can increase urine pH. Therefore the urine pH, when 6.0 or higher, may erroneously suggest a renal cause of acidosis. Nevertheless, metabolic acidosis caused by gastrointestinal losses with a high urine pH can be differentiated from renal causes by measuring or estimating urinary NH4 ⁺ , as described later. Urinary NH ₄ ⁺ excretion is typically low in patients with renal causes of acidosis and high in patients with diarrhea. ^{, ,} Urine acidification and pH may also be low with marked volume depletion, which impairs delivery of distal sodium delivery, which in turn limits distal acidification.

The level of urinary NH ₄ ⁺ excretion (not usually measured by clinical laboratories) in metabolic acidosis can be assessed indirectly by calculating the urine anion gap (UAG) or urine osmolal gap. The UAG is:

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, assuming there is not a lot of HCO ₃ ⁻ in the urine as in alkaline urine. Therefore the UAG should become progressively negative as the rate of ammonium excretion increases in response to acidosis or to acid loading. ^, NH ₄ ⁺ can be assumed to be present if the sum of the major cations (Na ⁺ + K ⁺ ) is less than the concentration of Cl ⁻ in urine. A negative UAG (more than–20 mEq/L) implies that appropriate NH ₄ ⁺ is present in the urine with the acidosis, as might occur with an extrarenal origin of the hyperchloremic acidosis (e.g., diarrhea). Conversely, urine estimated to contain little or no NH ₄ ⁺ has more Na ⁺ + K ⁺ than Cl ⁻ (UAG is positive), which indicates 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 nongap metabolic acidosis. If the patient has ketonuria, drug anions (penicillins or aspirin), or toluene metabolites in the urine, the test is not reliable and should not be used.

The reliability and utility of the urine anion gap as a surrogate of urine ammonium excretion have been called into question. Theoretic concerns are that the urine AG should be dependent on dietary intake of Na, K, and Cl at steady state and therefore be predominantly dependent on dietary composition rather than acid excretion. Moreover, multiple observational studies have found no correlation between urine AG and urine ammonium concentration, mostly in healthy volunteers, kidney stone-formers, or patients with CKD. Importantly, though, no studies have reexamined whether urine anion gap can discriminate between RTA and extrarenal cause of acidosis (i.e., diarrhea).

The urinary ammonium (UNH ₄ ⁺ ) may also be estimated from calculation of the urine osmolal gap, which is the difference in measured urine osmolality (U _osm ), and the urine osmolality calculated from the urine [Na ⁺ + K ⁺ ] and the urine urea and glucose (all expressed in mmol/L):

Urinary ammonium concentrations of 75 mEq/L or more would be anticipated if renal tubular function is intact and the kidney is responding to a prevailing metabolic acidosis by increasing ammonium production and excretion. Conversely, values below 25 mEq/L in the presence of acidosis denote inappropriately low urinary ammonium concentrations. In addition to the UAG and osmolal gap, the fractional excretion of Na ⁺ may be helpful and would be expected to be low (<1% to 2%) in patients with HCO ₃ ⁻ loss from the gastrointestinal tract but usually exceeds 2% to 3% in patients with RTA. ^,

Gastrointestinal HCO ₃ ⁻ loss, as well as proximal RTA (type 2) and cDRTA (type 1), results in ECF contraction and stimulation of the renin-aldosterone system, which leads typically to hypokalemia. The serum K ⁺ concentration therefore serves to distinguish the previous disorders, which have 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, or the acidosis of progressive CKD, in which normokalemia or mild hyperkalemia is common (see later).

In addition to gastrointestinal tract HCO ₃ ⁻ loss, external loss of pancreatic and biliary secretions, as well as cholestyramine, calcium chloride, and magnesium sulfate ingestion, can all cause a nongap acidosis (see Table 15.6 ), especially in patients with renal insufficiency. Coexistent lactic acidosis is common in severe diarrheal illnesses and noted by an increase in the AG.

Severe nongap or hyperchloremic metabolic acidosis with hypokalemia may occur in patients with ureteral diversion procedures. Because the ileum and colon are both endowed with Cl ⁻ /HCO ₃ ⁻ exchangers, when the Cl– from the urine enters the gut, or pouch, the HCO ₃ ⁻ concentration increases as a result of the exchange process. Moreover, K ⁺ secretion is stimulated, which, together with HCO ₃ ⁻ 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 the history. When chloride-rich fluid such as isotonic saline is infused rapidly, particularly in patients with temporary or permanent renal functional impairment, the serum HCO ₃ ⁻ declines reciprocally in relation to Cl ⁻ , in part due to the dilutional effect of the fluid. This does not occur with the infusion of so-called balanced saline solutions such as lactated Ringer. Hyperchloremic acidosis can also be caused by administration of acid or acid equivalents such as infusion of arginine or lysine hydrochloride during parenteral hyperalimentation or ingestion of ammonium chloride.

Hyperchloremic metabolic acidosis may also occur in some settings of ketoacidosis. In mild, chronic ketoacidosis if GFR is maintained with adequate ECFV expansion and renal ketone excretion is high, the continued titration of HCO ₃ ⁻ with Cl ⁻ retention and excretion of potential base (ketones) may result in hyperchloremic acidosis. A similar situation could contribute to continued acidosis during recovery from typical high anion gap ketoacidosis when the sodium salts of ketones may be excreted and lost as potential HCO ₃ ⁻ . A similar mechanism for hyperchloremic acidosis in early CKD may occur with metabolism of sulfur to sulfuric acid and excretion of SO ₄ 2 ⁻ with Cl ^– retention.

Loss of functioning renal parenchyma in progressive kidney disease is known to be associated with metabolic acidosis. Typically, the acidosis is a hyperchloremic, nongap type 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 (i.e., when the GFR is <20 mL/min). It is generally assumed that such progression is observed more commonly in patients with tubulointerstitial forms of renal disease, but non-AG metabolic acidosis can also occur with advanced glomerular disease. The acidoses of CKD with an AG and hyperkalemic, hyperchloremic metabolic acidosis are discussed subsequently later. The principal defect in acidification of advanced kidney disease is that ammoniagenesis is reduced in proportion to the loss of functional renal mass. In addition, medullary NH ₄ ⁺ accumulation and trapping in the outer medullary collecting tubule may be impaired. Because of adaptive increases in K ⁺ secretion by the collecting duct and colon, the acidosis of chronic renal insufficiency is typically normokalemic.

Non-AG metabolic acidosis accompanied by hyperkalemia is almost always associated with a generalized dysfunction of the distal nephron. ^, However, K ⁺ -sparing diuretics (amiloride, triamterene), as well as pentamidine, cyclosporine, tacrolimus, nonsteroidal antiinflammatory drugs (NSAIDs), angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers (ARBs), β-blockers, and heparin may mimic or cause this disorder, resulting in hyperkalemia and a nongap metabolic acidosis. ^, Because hyperkalemia augments the development of acidosis by suppressing urinary net acid excretion, discontinuing these agents while reducing the serum K ⁺ allows ammonium production and excretion to increase, which will help repair the acidosis.

Proximal Renal Tubular Acidosis

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