Principles of Acid–Base Physiology

Acid Balance

• 1.

  Production of acids : H ⁺ ions are produced in a metabolic process when all of their products have a greater anionic charge than all of their substrates.

• 2.

  Buffering of H ⁺ ions : This should minimize H ⁺ ion binding to proteins in vital organs (i.e., the brain and the heart). To do so, H ⁺ ions must react with ${{\text{HCO}}_3}^{-}$ ions. The vast majority of ${{\text{HCO}}_3}^{-}$ ions in the body is in the interstitial and intracellular compartments of skeletal muscle. The key to achieving this function is to have a low PCO ₂ in the capillaries of skeletal muscle.

• 3.

  Kidneys add new ${{\mathrm{HCO}}_3}^{-}$ ions to the body : This occurs primarily when ${{\text{NH}}_4}^{+}$ ions are excreted in the urine.

Base Balance

• 1.

  Input of alkali : This occurs primarily when fruit and vegetables are ingested because they contain the K ⁺ salts of organic acids that are metabolized to yield ${{\text{HCO}}_3}^{-}$ anions.

• 2.

  Elimination of alkali : This is achieved in a two-step process: (1) the alkali load stimulates the production of endogenous organic acids (e.g., citric acid), the H ⁺ ions of which eliminate ${{\text{HCO}}_3}^{-}$ anions, and (2) the kidneys excrete organic anions (e.g., citrate anions) with K ⁺ ions in the urine.

  • ▪

    To emphasize that acid–base balance is achieved while maintaining the urine pH close to 6.0. This minimizes the risk of forming uric acid precipitate if the urine pH were acidic (pK = 5.3), or calcium phosphate precipitate if the urine pH were alkaline (pK = 6.8). In addition, eliminating alkali via the excretion of organic anions (e.g., citrate anions) lowers the concentration of ionized calcium in the urine.

H ⁺ ions and the regeneration of ATP

Three important steps constitute the metabolic process for the regeneration of ATP (called coupled oxidative phosphorylation ); this involves H ⁺ ions in a major way. First, the energy needed to perform biological work in the cytosol of cells (e,g., ion pumping by Na-K-ATPase) is provided when the terminal high-energy phosphate bond in ATP ^4- is hydrolyzed. This converts ATP ^4- to adenosine diphosphate (ADP ³⁻ ), divalent inorganic phosphate ( ${{\text{HPO}}_4}^{2-}$ ) ions, and H ⁺ ion. Second, ADP enters the mitochondria on the adenine nucleotide translocator, while ATP exits. ${{\text{HPO}}_4}^{2-}$ ions and H ⁺ ions enter mitochondria by a symporter. Third, oxidation of the reduced form nicotinamide adenine dinucleotide (NADH, H ⁺ ) produces nicotinamide adenine dinucleotide (NAD ⁺ ) and two electrons. This represents the first step in the electron transport chain. Flow of these electrons through coenzyme Q and ultimately cytochrome C releases the energy that is used to pump H ⁺ ions from the mitochondrial matrix through the inner mitochondrial membrane. This creates a very large electrical driving force (∼150 mV) and a smaller chemical driving force for H ⁺ ion re-entry. This energy is recaptured as H ⁺ ions flow through the H ⁺ ion channel portion of the H ⁺ -ATP synthase in the inner mitochondrial membrane, which is coupled (linked) to ATP ^4- regeneration provided that ADP ^3- and ${{\text{HPO}}_4}^{2-}$ are available inside these mitochondria ( Figure 1-1 ). Hence, availability of ADP in the mitochondria sets an upper limit on the rate of coupled oxidative phosphorylation (see margin note).

Production and removal of H ⁺ ions

To determine whether H ⁺ ions are produced or removed during metabolism, we use a “metabolic process” analysis. A metabolic process is made up of a series of metabolic pathways that carry out a specific function; these pathways may be located in more than one organ. To establish the balance for H ⁺ ions in a metabolic process, one needs only examine the valences of all of its substrates and products, while ignoring all intermediates (see Chapter 5 for more details). If the sum of all of these valences is equal, there is no net production or removal of H ⁺ ions. When the products of a metabolic process have a greater anionic charge than its substrates, H ⁺ ions are produced (e.g., incomplete oxidation of the major energy fuels, carbohydrates, and fats). Conversely, when the products of a metabolic process have a lesser anionic charge than its substrates, H ⁺ ions are removed.

About 85% of kilocalories consumed, in a typical Western diet, are in the form of carbohydrates and fat. There is no net production of H ⁺ ions when glucose and triglycerides are completely oxidized to CO ₂ + H ₂ O because the substrates and the end products of these metabolic processes are neutral compounds. There is a net H ⁺ ion load, however, when complete oxidation of these fuels does not occur. L-Lactic acid accumulates during hypoxia, because its rate of production from glycolysis far exceeds its rate of removal via oxidation and/or gluconeogenesis. Ketoacids are produced during states of a net lack of insulin if their rate of production from metabolism of free fatty acids (triglycerides) in the liver exceeds their rate of removal by the brain and the kidneys.

The metabolism of certain dietary constituents leads to the addition of H ⁺ ions (e.g., proteins) or ${{\text{HCO}}_3}^{-}$ ions (e.g., fruit and vegetables) to the body. A general overview of the components of the daily turnover of H ⁺ ions is illustrated in Figure 1-2 . Overall, one must examine balances for both acids and bases to have a true assessment of H ⁺ ion balance.

Acid Balance

Oxidation of two classes of amino acids (cationic amino acids [e.g., lysine, arginine] and sulfur-containing amino acids [e.g., cysteine, methionine]) yields an H ⁺ ion load ( Table 1-1 ). In contrast, H ⁺ ions are removed during the oxidation of anionic amino acids (e.g., glutamate, aspartate), because all the products of their oxidation are neutral compounds (urea, glucose, or CO ₂ + H ₂ O). Because the number of cationic and anionic amino acids is nearly equal in the amino acid mixture in beefsteak, the H ⁺ ion load that causes a deficit of ${{\text{HCO}}_3}^{-}$ ions is mainly from the metabolism of sulfur-containing amino acids that yield sulfuric acid (H ₂ SO ₄ ).

TABLE 1-1

H ⁺ Ion Formation or Removal in Metabolic Reactions

Reactions that yield H + ions (more net negative charge in products than in substrates)

Glucose → L-lactate – + H + (new L-lactate anions)

C 16 fatty acid → 4 ketoacid anions − + 4H + (new ketoacid anions)

Cysteine → urea + CO 2 + H 2 O + 2 H + + ${{\text{SO}}_4}^{2-}$ (new ${{\text{SO}}_4}^{2-}$ anions)

Lysine + → urea + CO 2 + H 2 O + H + (loss of cationic charge in lysine)

Reactions that remove H + ions (more net positive charge in products than in substrates)

L-Lactate – + H + → glucose (L-lactate anion removed)

Glutamate – → urea + CO 2 + H 2 O

Citrate 3− + 3 H + → CO 2 + H 2 O (citrate anion removed)

H + are neither produced nor removed in the following reactions

Glucose → glycogen or CO 2 + H 2 O (neutrals to neutrals)

Triglyceride → CO 2 + H 2 O (neutrals to neutrals)

Alanine → urea + glucose or CO 2 + H 2 O (neutrals to neutrals)

H ₂ SO ₄

H ⁺ ions cannot be eliminated by metabolism of ${{\text{SO}}_4}^{2-}$ anions to neutral end products (because no such pathway exists) or by being excreted bound to ${{\text{SO}}_4}^{2-}$ anions in the urine (because of the low affinity of ${{\text{SO}}_4}^{2-}$ anions for H ⁺ ions). Hence, these H ⁺ ions must be titrated initially with ${{\text{HCO}}_3}^{-}$ ions and, as a result, CO ₂ is formed. Acid balance is restored when these ${{\text{SO}}_4}^{2-}$ anions are excreted in the urine with an equivalent amount of ${{\text{NH}}_4}^{+}$ ions because new ${{\text{HCO}}_3}^{-}$ ions are generated in this process ( Figure 1-3 ).

Dietary phosphate

The source of phosphate in the diet consists primarily of intracellular organic phosphates (including energy storage compounds e.g., ATP ⁴⁻ and phosphocreatine ²⁻ in beefsteak, and nucleic acids [RNA, DNA]) and phospholipids, which are primarily in organ meat (e.g., liver). The accompanying cation for both forms of intracellular organic phosphates is primarily potassium (K ⁺ ) ions. The acid–base impact of the metabolic process involving phosphate depends on whether their metabolism resulted in the addition of the monovalent inorganic phosphate $({{\text{H}}_2{{\text{PO}}_4}^{-})}^{}$ or the divalent inorganic phosphate $\left({{\text{HPO}}_4}^{2-}\right)$ to the body. In more detail, if ${\text{H}}_2{{\text{PO}}_4}^{-}$ were added, because it has a pK of 6.8, close to one bound H ⁺ ion per ${\text{H}}_2{{\text{PO}}_4}^{-}$ is released in the body at normal blood pH values (7.40) ( Figure 1-4 ). These H ⁺ ions react with ${{\text{HCO}}_3}^{-}$ ions, creating a deficit of ${{\text{HCO}}_3}^{-}$ ions in the body. To achieve H ⁺ ion balance, new ${{\text{HCO}}_3}^{-}$ ions must be regenerated. This occurs in two steps: (1) the kidney converts CO ₂ + H ₂ O to H ⁺ ions + ${{\text{HCO}}_3}^{-}$ ions and (2) these H ⁺ are secreted and bind to filtered ${{\text{HPO}}_4}^{2-}$ anions. Thus, ${\text{H}}_2{{\text{PO}}_4}^{-}$ is excreted when the urine pH is in the usual range (i.e., ∼6), while ${{\text{HCO}}_3}^{-}$ ions are added to the body. Hence, elimination of H ⁺ ions produced during the metabolism of organic phosphates to ${\text{H}}_2{{\text{PO}}_4}^{-}$ does not require the excretion of ${{\text{NH}}_4}^{+}$ ions. There is no net loss or gain of ${{\text{HCO}}_3}^{-}$ ions in this process.

On the other hand, if ${{\text{HPO}}_4}^{2-}$ were added to the body, at a urine pH of ∼6, it will be excreted as ${\text{H}}_2{{\text{PO}}_4}^{-}$ . Hence, new ${{\text{HCO}}_3}^{-}$ ions are generated in this process. To maintain acid–base balance, one possible mechanism is increased production of endogenous organic acids in response to this alkali load. Their H ⁺ ions remove this ${{\text{HCO}}_3}^{-}$ ion load, while their conjugate bases are excreted in the urine as K ⁺ salts (see Figure 1-4 ).

Abbreviations

• OA ^– , organic anions

• PCT, proximal convoluted tubule

Renal Handling of Organic Anions

• Approximately 360 mEq of organic anions are filtered daily (glomerular filtration rate [GFR] of 180 L/day, concentration of OA ⁻ in plasma ∼2 mEq/L). Of these anions, 90% are reabsorbed and only ∼10% are excreted.

• An alkali load diminishes the reabsorption of organic anions such as citrate in the PCT, and hence increases their excretion in the urine to achieve base balance.

Urine Citrate as a Window on pH of the Proximal Tubule Cell

• A low pH in PCT cells increases the reabsorption of citrate; the urine becomes virtually citrate free.

• A higher pH in PCT cells diminishes the reabsorption of citrate and thereby increases its excretion rate.

Base Balance

All the emphasis so far has been on the production and removal of H ⁺ ions. The diet, however, also provides an alkali load that is produced during the metabolism of a variety of organic anions in fruit and vegetables ( Figure 1-5 ). Although it would have been nice from a bookkeeping point of view to have these ${{\text{HCO}}_3}^{-}$ ions titrate some of the H ⁺ ion load from H ₂ SO ₄ produced from metabolism of sulfur-containing amino acids, this occurs only to a minor extent. The advantage of not having the dietary alkali load titrate dietary acid load becomes evident when considered in the context of minimizing the risk of kidney stone formation.

Dietary organic anions are first converted to ${{\text{HCO}}_3}^{-}$ ions in the liver. This avoids having a potentially toxic anion enter the systemic circulation (e.g., citrate anions, which chelate ionized calcium in plasma). In response to the alkali load, a variety of organic acids (e.g., citric acid) are produced in the liver. The fate of their H ⁺ ions is similar: the removal by ${{\text{HCO}}_3}^{-}$ ions. To prevent the synthesis of ${{\text{HCO}}_3}^{-}$ ions at a later time, the conjugate bases of these organic acids are made into end products of metabolism by being excreted with K ⁺ ions in the urine (see margin note), and hence base balance is achieved. As discussed later, the pH of cells of the proximal convoluted tubule (PCT) plays an important role in determining the rate of excretion of citrate and other organic anions in the urine. In fact, the rate of excretion of citrate in the urine is thought to provide a window on pH in the cells of PCT (see margin note).

From an integrative physiology point of view, the elimination of dietary alkali in the form of organic anions has a number of advantages in terms of minimizing the risk of kidney stone formation. In more detail, it avoids the excretion of ${{\text{HCO}}_3}^{-}$ ions, and hence the likelihood of kidney stones that form when the urine pH is too high (e.g., CaHPO ₄ ). In addition, the elimination of this dietary alkali in the form of citrate anions lessens the likelihood of forming calcium-containing kidney stones because citrate anions chelate ionized calcium in the urine.

Bicarbonate Buffer System

Even though at plasma pH of 7.4, the BBS is very far displaced from its pK (pH ∼6.1) and hence is not an ideal chemical buffer, nevertheless it is the most important physiologic buffer. This is caused by the fact that it can remove H ⁺ ions without requiring a high H ⁺ ion concentration. As shown in Eqn 1 , a low PCO ₂ “pulls” the BBS reaction to the right. As a result, the concentration of H ⁺ ions falls, which decreases the binding of H ⁺ ions to proteins ( Figure 1-6 ). In addition, the BBS is capable of removing a large quantity of H ⁺ ions because there is a large amount of ${{\text{HCO}}_3}^{-}$ ions in the body, ≈750 mmol in a 70 kg adult (see margin note).