Acid Base Balance and Progression of Kidney Disease

Regulation Of Acid-Base Balance

The Concentration Of H⁺ In The Body Fluids Is Low Compared With That Of Other Ions. For example, Na⁺ is present at a concentration of some 3 million times greater than that of H⁺ ([Na⁺] = 140 Meq/L And [H⁺] = 40 Neq/L). Because Of The Low [H⁺] Of The Body Fluids, It Is Commonly Expressed As The Negative Logarithm Or Ph.

• Virtually All Cellular, Tissue, And Organ Processes Are Sensitive To Ph. Indeed, Life Cannot Exist Outside A Range Of Body Flid Ph From 6.8 To 7.8 (160 To 16 Neq/L Of H⁺). Each Day, Acid And Alkali Are Ingested
• In The Diet. Also, Cellular Metabolism Produces Several Substances That Have An Impact On The Ph Of Body Fluids. Without Appropriate Mechanisms
• To Deal With This Daily Acid And Alkali Load And Thereby Maintain Acid-Base Balance, Many Processes Necessary For Life Could Not Occur.
• This Chapter Reviews The Maintenance Of Whole-Body Acid-Base Balance. Although The Emphasis Is On The Role Of The Kidneys In This Process, The Roles Of The Lungs And Liver Also Are Considered.
• In Addition, The Impact Of Diet And Cellular Metabolism on acid-base balance is presented. Finally, disorders of acid-base balance are considered, primarily to illustrate the physiologic processes involved.
• Throughout this chapter, acid is defined as any substance that adds H⁺ to the body fluids, whereas alkali is defined as a substance that removes H⁺ from the body fluids.

HCO₃^– Buffer System

Bicarbonate (HCO₃^– ) is an important buffer of the extracellular fluid (ECF). With a normal plasma [HCO₃^– ] of 23 to 25 mEq/L and a volume of 14 L (for a person weighing 70 kg), the ECF potentially can buffer 350 mEq of H⁺. The HCO3-buffer system differs from the other buffer systems of the body (e.g., phosphate) because it is regulated by both the lungs and the kidneys. This situation is best appreciated by considering the following reaction

⇒ \(\mathrm{CO}_2+\mathrm{H}_2 \mathrm{O}+\stackrel{\text { slow }}{\longleftrightarrow} \mathrm{H}_2 \mathrm{CO}_3 \stackrel{\text { fast }}{\longleftrightarrow} \mathrm{H}^{+}+\mathrm{HCO}_3^{-}\)

• As indicated, the first reaction (hydration/dehydration of CO₂) is the rate-limiting step. This normally slow reaction is greatly accelerated in the presence of carbonic anhydrase.
• * The second reaction, the ionization of carbonic acid (H2CO₃^–) to H⁺ and HCO₃^– , is virtually instantaneous. The Henderson-Hasselbalch equation is used to quantitate how changes in CO2 and HCO₃^–affect pH:

⇒ \(\mathrm{pH}=\mathrm{pK}^{\prime}+\log \frac{\mathrm{HCO}_3^{-}}{\alpha \mathrm{PCO}_2}\) (8-2)

⇒ \(\mathrm{pH}=6.1+\log \frac{\mathrm{HCO}_3^{-}}{0.03 \mathrm{PcO}_2}\) (8-3)

In these equations, the amount of CO₂ is determined from the partial pressure of CO₂ (PCO₂) and its solubility ( α). For plasma at 37° C, α has a value of 0.03. Also, pKˈ is the negative logarithm of the overall dissociation constant for the reaction in equation 8-1 and has a value for plasma at 37° C of 6.1. Alternatively,

*Carbonic anhydrase actually catalyzes the following reaction: H₂O → H⁺ + OH− + CO₂ → HCO₃^– + H⁺ → H2CO3 the relationships among HCO₃^– , CO₂, and [H⁺] can be determined as follows:

⇒ \(\left[\mathrm{H}^{+}\right]=\frac{24 \times \mathrm{PCO}_2}{\left[\mathrm{HCO}_3^{-}\right]}\)

Inspection of equations 8-3 and 8-4 shows that the pH and the [H⁺] vary when either the [HCO₃^– ] or the PCO₂ is altered. Disturbances of acid-base balance that result from a change in the [HCO₃^– ] are termed metabolic acid-base disorders, whereas those that result from a change in the Pco2 are termed respiratory acid-base disorders.

These disorders are considered in more detail in a subsequent section. The kidneys are primarily responsible for regulating the [HCO₃^– ] of the ECF, whereas the lungs control the PCO₂.

Overview Of Acid-Base Balance

The diet of humans contains many constituents that are either acid or alkali. In addition, cellular metabolism produces acid and alkali. Finally, alkali is normally lost each day in the feces. As described later in this chapter, the net effect of these processes is the addition of acid to the body fluids.

• For acid-base balance to be maintained, the acid must be excreted from the body at a rate equivalent to its addition. If acid addition exceeds excretion, acidosis results. Conversely, if acid excretion exceeds addition, alkalosis results.
• As summarized in Figure 8-1, the major constituents of the diet are carbohydrates and fats. When tissue perfusion is adequate, CO₂ is available to tissues, and insulin is present at normal levels, carbohydrates, and fats are metabolized to CO₂ and H₂O.
• Daily, 15 to 20 moles of CO₂ are generated through this process. Normally, this large quantity of CO₂ is effectively eliminated from the body by the lungs. Therefore this metabolically derived CO₂ has no impact on acid-base balance. CO₂ usually is termed volatile acid, reflecting the fact that it has the potential to generate H⁺ after hydration with H2O (see equation 8-1).
• Acids not derived directly from the hydration of CO₂ are termed nonvolatile acids (e.g., lactic acid). The cellular metabolism of other dietary constituents also has an impact on acid-base balance. For example, cysteine and methionine, which are

FIGURE 8-1 n Overview of the role of the kidneys in acid-base balance. HA represents nonvolatile acids and is referred to as net endogenous acid production. HCO₃^– bicarbonate; NaA, sodium salt of nonvolatile acid; NaHCO3, sodium bicarbonate; RNAE, renal net acid excretion.

• sulfur-containing amino acids yield sulfuric acid when metabolized, whereas hydrochloric acid results from the metabolism of lysine, arginine, and histidine. A portion of this nonvolatile acid load is offset by the production of HCO₃^– through the metabolism of the amino acids aspartate and glutamate. On average, the metabolism of dietary amino acids yields net nonvolatile acid production.
• The metabolism of certain organic anions (e.g., citrate) results in the production of HCO₃^–, which offsets nonvolatile acid production to some degree. Overall, in persons who ingest a diet containing meat, acid production exceeds HCO₃^– production. In addition to the metabolically derived acids and alkalis, the foods ingested contain acid and alkalis.
• For example, the presence of phosphate (H₂PO^–4 ) in ingested food increases the dietary acid load. Finally, during digestion, some HCO₃^– is normally lost in the feces. This loss is equivalent to the addition of nonvolatile acid to the body. Together, dietary intake, cellular metabolism, and fecal HCO₃^–  loss result in the addition of approximately 1 mEq/kg body weight of nonvolatile acid to the body each day (50 to 100 mEq/day for most adults).
• This acid, referred to as net endogenous acid production (NEAP), results in an equivalent loss of HCO₃^– from the body that must be replaced. Importantly, the kidneys excrete acid and in that process generate HCO₃^–.
• When insulin levels are normal, carbohydrates and fats are completely metabolized to CO₂ + H₂O. However, if insulin levels are abnormally low (e.g., in persons with diabetes mellitus), the metabolism of carbohydrates leads to the production of several organic keto acids (e.g., β-hydroxybutyric acid).
• In the absence of adequate levels of O₂ (hypoxia), anaerobic metabolism by cells also can lead to the production of organic acids (e.g., lactic acid) rather than CO₂ + H ₂O. This phenomenon frequently occurs in healthy persons during vigorous exercise.
• Poor tissue perfusion, such as occurs with reduced cardiac output, also can lead to anaerobic metabolism by cells and thus to acidosis. In these conditions, the organic acids accumulate and the pH of the body fluids decreases (acidosis).
• Treatment (e.g., administration of insulin in the case of diabetes) or improved delivery of adequate levels of O₂ to the tissues (e.g., in the case of poor tissue perfusion) results in the metabolism of these organic acids to CO₂ + H₂O, which consumes H + and thereby helps correct the acid-base disorder.

Nonvolatile acids do not circulate throughout the body but are immediately neutralized by the HCO₃^–n the ECF: H₂SO₄ + 2NaHCO₃ ↔ Na₂SO₄ + 2CO₂ + 2H₂O (8-5) HCl + NaHCO₃ ↔ NaCl + CO₂ + H₂O (8-6) This neutralization process yields the Na+ salts of the strong acids and removes HCO₃^–from the ECF.

Thus HCO3 minimizes the effect of these strong acids on the pH of the ECF. As noted previously, the ECF contains approximately 350 mEq of HCCO₃^–. If this HCO₃^– was not replenished, the daily production of nonvolatile acids ( ≈70 mEq/day) would deplete the ECF of HCO−3 within 5 days. Systemic acid-base balance is maintained when renal net acid excretion (RNAE) equals NEAP.

Renal Net Acid Excretion

Under normal conditions, the kidneys excrete an amount of acid equal to NEAP and in so doing replenish the HCO₃^– that is lost by neutralization of the nonvolatile acids. In addition, the kidneys must prevent the loss of HCO₃^– in the urine.

• The latter task is quantitatively more important because the filtered load of HCO₃^– is approximately 4320 mEq/day (24 mEq/L × 180 L/day = 4320 mEq/day), compared with only 50 to 100 mEq/day needed to balance NEAP. Both the reabsorption of filtered HCO₃^– and the excretion of acid are accomplished by H⁺ secretion by the nephrons.
• Thus in a single day, the nephrons must secrete approximately 4390 mEq of H⁺ into the tubular fluid. Most of the secreted H⁺ serves to reabsorb the filtered load of HCO₃^–. Only 50 to 100 mEq of H⁺, an amount equivalent to nonvolatile acid production, is excreted in the urine. As a result of this acid excretion, the urine is normally acidic. The kidneys cannot excrete urine more acidic than pH 4.0 to 4.5.
• Even at a pH of 4.0, only 0.1 mEq/L of H⁺ can be excreted. Thus to excrete sufficient acid, the kidneys excrete H⁺ with urinary buffers such as inorganic phosphate (Pi).* Other constituents of the urine also can serve as buffers (e.g., creatinine), although their role is less important than that of Pi. Collectively, the various urinary buffers are termed titratable acid. This term is derived from the method by which these buffers are quantitated in the laboratory. Typically, alkali (OH−) is added to a urine sample to titrate its pH to that of plasma (i.e., 7.4).
• The amount of alkali added is equal to the H⁺ titrated by these urine buffers and is termed titratable acid. The excretion of H⁺ as a titratable acid is insufficient to balance NEAP. An additional and important mechanism by which the kidneys contribute to the maintenance of acid-base balance is through the synthesis and excretion of ammonium (NH4⁺).
• The mechanisms involved in this process are discussed in more detail later in this chapter. About the renal regulation of acid-base balance, each NH4⁺ excreted in the urine results in the return of one HCO₃^– to the systemic circulation, which replenishes the HCO₃^– lost during the neutralization of the nonvolatile acids.

Thus the production and excretion of NH4⁺, like the excretion of titratable acid, are equivalent to the excretion of acid by the kidneys. In brief, the kidneys contribute to acid-base homeostasis by reabsorbing the filtered load of HCO₃^– and excreting an amount of acid equivalent to NEAP. This overall process is termed RNAE, and it can be quantitated as follows:

where (UNH⁺ 4 × V˙ ) and (UTA × V˙ ) are the rates of excretion (mEq/day) of NH4⁺ and titratable acid and (UHCO₃^– × V˙ ) is the amount of HCO₃^– lost in the urine (equivalent to adding H⁺ to the body).† Again, maintenance of acid-base balance means that RNAE must equal NEAP. Under most conditions, very little HCO₃^– is excreted in the urine. Thus RNAE essentially reflects titratable acid and NH⁺ 4 excretion. Quantitatively, TA accounts for approximately one-third and NH4⁺ for two-thirds of RNAE.

Segmental reabsorption of bicarbonate (HCO₃^– ). The fraction of the filtered HCO₃^– reabsorbed by the various segments of the nephron is shown. Normally, the entire filtered HCO₃^– is reabsorbed, and little or no HCO₃^– appears in the urine. CCD, Cortical collecting duct; DT, distal tubule; IMCD, inner medullary collecting duct; PT, proximal tubule; TAL, thick ascending limb.

HCO₃^– Reabsorption Along The Nephron

As indicated by equation 8-7, RNAE is maximized when little or no HCO₃^– is excreted in the urine. Indeed, under most circumstances, very little HCO₃^– appears in the urine. Because HCO₃^–is freely filtered at the glomerulus, approximately 4320 mEq/day is delivered to the nephrons and is then reabsorbed.

• Summarizes the contribution of each nephron segment to the reabsorption of the filtered HCO₃^–. The proximal tubule reabsorbs the largest portion of the filtered load of HCO₃^– Figure 8-3 summarizes the primary transport processes involved.
• H⁺ secretion across the apical membrane of the cell occurs by both a Na+-H⁺ antiporter and H⁺–adenosine triphosphatase (H⁺-ATPase). The Na+-H⁺ antiporter (NHE3) is the predominant pathway for H⁺ secretion (accounts for approximately two-thirds of HCO₃^– reabsorption) and uses the lumen-to-cell [Na+] gradient to drive this process (i.e., secondary active secretion of H⁺).
• Within the cell, H⁺ and HCO₃^– are produced in a reaction catalyzed by carbonic anhydrase (CA-II). The H⁺ is secreted into the tubular fluid, whereas the HCO₃^– exits the cell across the basolateral membrane and returns to the peritubular blood. HCO₃^– movement out of the cell across the basolateral membrane is coupled to other ions. The majority of HCO₃^– exits

Cellular Mechanism For The Reabsorption Of Fitered Bicarbonate (HCO₃^– ) By Cells Of The Proximal Tubule. Carbonic Anhydrase (Ca) Also Is Expressed On The Basolateral Surface (Not Shown). Ae1, Anion Exchanger 1; Atp, Adenosine Triphosphate; H2co3, Carbonic Acid; Nbce1, Sodium Bicarbonate Symporter; Nhe3, Na+-H + Antiporter; V-Atpase, Vacuolar Adenosine Triphosphatase.

• through a symporter that couples the efflx of Na+ with 3HCO₃^– (sodium bicarbonate cotransporter, NBCe1). In addition, some of the HCO₃^–  may exit in exchange for Cl− (via a Cl−-HCO₃^–  antiporter; AE1). As noted in Figure 8-3, CA-IV also is present in the brush border of the proximal tubule cells.
• This enzyme catalyzes the dehydration of H₂CO₃  in the luminal fluid and thereby facilitates the reabsorption of HCO₃^–. CA-IV also is present in the basolateral membrane (not shown in Figure 8-3), where it may facilitate the exit of HCO₃^–  from the cell.
• The cellular mechanism for HCO₃^– reabsorption by the thick ascending limb of the loop of Henle is very similar to that in the proximal tubule. H⁺ is secreted by an Na⁺-H⁺ antiporter and a vacuolar H⁺– ATPase.
• As in the proximal tubule, the Na⁺-H⁺ antiporter is the predominant pathway for H⁺ secretion. HCO₃^–  exit from the cell involves both a Na+-HCO₃^–  symporter and a Cl−-HCO₃^–  antiporter. However, the isoforms for these transporters differ from those in the proximal tubule.
• The Na+-HCO₃^– symporter is electrically neutral, exchanging equal numbers of Na+ for HCO₃^–. The Cl−-HCO₃^–  antiporter is the anion exchanger 2. Recently, evidence has been obtained for the presence of a K+-HCO₃^–symporter in the basolateral membrane, which also may contribute to HCO₃^–  exit from the cell.
• The distal tubule* and collecting duct reabsorb the small amount of HCO₃^– that escapes reabsorption by the proximal tubule and loop of Henle. Figure 8-4 shows the cellular mechanism of HCO₃^– reabsorption by the collecting duct, where H⁺ secretion occurs through the intercalated cell
• Within the cell, H⁺ and HCO₃^– are produced by the hydration of CO₂; this reaction is catalyzed by carbonic anhydrase (CA-II). H⁺ is secreted into the tubular fluid by two mechanisms. The first mechanism involves an apical membrane vacuolar H⁺-ATPase.
• The second mechanism couples the secretion of H⁺ with the reabsorption of K+ through an H⁺-K+-ATPase similar to that found in the stomach. The HCO₃^–  exits the cell across the basolateral membrane in exchange for Cl− (through a Cl−-HCO₃^–  antiporter, anion exchanger-1) and enters the peritubular capillary blood. Cl− exit from the cell across the basolateral membrane occurs via a Cl− channel, and perhaps also via a K+-Cl− symporter (KCC4).
• A second population of intercalated cells within the collecting duct secretes HCO₃^– rather than H⁺ into the tubular fluid.† In these intercalated cells, in contrast to the intercalated cells previously described, the H⁺– ATPase is located in the basolateral membrane (and to some degree also in the apical membrane), and a Cl−- HCO₃^–  antiporter is located in the apical membrane (see Figure 8-4).
• The apical membrane Cl−-HCO₃^–  antiporter is different from the one found in the basolateral membrane of the H⁺-secreting intercalated cell and has been identified as pendrin. The activity of the HCO3-secreting intercalated cell is increased during metabolic alkalosis when the kidneys must excrete excess HCO₃^–. However, under normal conditions, H⁺ secretion predominates in the collecting duct.
• *Here and in the remainder of the chapter the focus is on the function of intercalated cells. The early portion of the distal tubule, which does not contain intercalated cells, also reabsorbs HCO₃^–.
• The cellular mechanism is similar to that already described for the thick ascending limb of Henle’s loop, although transporter isoforms may be different.

The HCO₃^–  -secreting intercalated cells are termed either type B (or β-intercalated cells), or simply non–type-A intercalated cells. The H⁺-secreting intercalated cells are termed type A (or α-intercalated cells).

Cellular Mechanisms For The Reabsorption And Secretion Of HCO₃^–  By Intercalated Cells Of The Collecting Duct. Cl− Also May Exit The Cell Across The Basolateral Membrane Via A K+-Cl− Symporter (Not Shown). Ae1, Anion Exchanger 1; Ca, Carbonic Anhydrase; HCO₃^–  , Bicarbonate; H2co3, Carbonic Acid; Hka, H +-K⁺–Adenosine Triphosphatase; V-Atpase, Vacuolar Adenosine Triphosphatase.

• The Apical Membrane Of Collecting Duct Cells Is Not Very Permeable To H⁺, And Thus The Ph Of The Tubular Flid Can Become Quite Acidic. Indeed, The Most Acidic Tubular Flid Along The Nephron (Ph = 4.0 To 4.5) Is Produced There.
• In Comparison, The Permeability Of The Proximal Tubule To H⁺ And HCO₃^–  Is Much Higher, And The Tubular Flid Ph Falls To Only 6.5 In This Segment. As Explained Later, The Ability Of The Collecting Duct To Lower The Ph Of The Tubular Flid Is Critically Important For The Excretion Of Urinary Titratable Acids And Nh4⁺

Regulation Of H⁺ Secretion

Several factors regulate the secretion of H⁺, and thus the reabsorption of HCO₃^–, by the cells of the nephron. From a physiologic perspective, the primary factor that regulates H⁺ secretion by the nephron is a change in systemic acid-base balance. Thus acidosis stimulates RNAE, whereas RNAE is reduced during alkalosis.

• The response of the kidneys to metabolic acidosis has been extensively studied and includes both immediate changes in the activity or number of transporters in the membrane, or both, and longer-term changes in the synthesis of transporters. For example, with metabolic acidosis, the pH of the cells of the nephron decreases.
• This decrease stimulates H⁺ secretion by multiple mechanisms, depending on the particular nephron segment. First, the decrease in intracellular pH creates a more favorable cell-to-tubular fluid H⁺ gradient and thereby makes the secretion of H⁺ across the apical membrane more energetically favorable. Second, the decrease in pH can lead to allosteric changes in transport proteins, thereby altering their kinetics.
• Lastly, transporters may be shuttled to the plasma membrane from intracellular vesicles. With long-term acidosis, the abundance of transporters is increased, either by increased transcription of appropriate transporter genes or by increased translation of transporter messenger ribonucleic acid.
• Although some of the effects just described may be attributable directly to the decrease in intracellular pH that occurs with metabolic acidosis, most of these changes in cellular H⁺ transport are mediated by hormones or other factors. Three known mediators of the renal response to acidosis are endothelin (ET-1), cortisol, and angiotensin-II.
• ET-1 is produced by endothelial and proximal tubule cells. With acidosis, ET-1 secretion is enhanced. In the proximal tubule, ET-1 stimulates the phosphorylation and subsequent insertion into the apical membrane of the Na+-H⁺ antiporter and insertion of the Na+-3HCO₃^–  symporter into the basolateral membrane.

ET-1 may mediate the response to acidosis in other nephron segments as well. With acidosis, the secretion of the glucocorticoid hormone cortisol by the adrenal cortex is stimulated. It, in turn, acts on the kidneys to increase the transcription of the Na+-H⁺ antiporter and Na+-3HCO₃^–  symporter genes in the proximal tubule. Angiotensin

• In response to metabolic acidosis, H + secretion along the nephron is increased. Several mechanisms responsible for the increase in H + secretion have been elucidated.
• For example, the intracellular acidification that occurs during metabolic acidosis has been reported to lead to allosteric changes in the Na+-H + antiporter (NHE3) in the proximal tubule, thereby increasing its transport kinetics. Transporters also are shuttled to the plasma membrane from intracellular vesicles.
• This mechanism occurs in both the intercalated cells of the collecting duct, where acidosis stimulates the exocytic insertion of H + adenosine triphosphatase (H +-ATPase) into the apical membrane, and in the proximal tubule, where apical membrane insertion of the Na⁺-H ⁺ antiporter and H ⁺-ATPase has been reported, as has an insertion of the Na+-3HCO₃^–  symporter (NBCe1) into the basolateral membrane.
• With long-term acidosis, the abundance of transporters is increased, either by increased transcription of appropriate transporter genes or by increased translation of transporter messenger ribonucleic acid. Examples of this phenomenon include NHE3 and NBCe1 in the proximal tubule and the H ⁺-ATPase and Cl −-HCO₃^– antiporter (anion exchanger 1) in the acid-secreting intercalated cells. Additionally, acidosis reduces the expression of pendrin in the HCO₃^– -secreting intercalated cells.

II increases with acidosis and stimulates H⁺ secretion by increasing the activity of the Na+-H⁺ antiporter throughout the nephron. In the proximal tubule, angiotensin II also stimulates ammonium production and its secretion into the tubular fluid, which, as described later in this chapter, is an important component of the kidneys’ response to acidosis.

• Acidosis also stimulates the secretion of parathyroid hormone. The increased levels of parathyroid hormone act on the proximal tubule to inhibit phosphate reabsorption (see Chapter 9). In so doing, more phosphate is delivered to the distal nephron, where it can serve as a urinary buffer and thus increase the capacity of the kidneys to excrete titratable acid. As noted, the response of the kidneys to alkalosis is less well characterized.
• RNAE is decreased, which occurs in part by increased HCO₃^–  excretion but also by a decrease in the excretion of ammonium and titratable acid. The signals that regulate this response are not well characterized.
• Cells in the kidney and many other organs express H + and HCO₃^–  receptors that play key roles in the adaptive response to changes in acid-base balance. For example, G protein-coupled receptors that are regulated by extracellular [H +] (i.e., they are inactive when the pH is >7.5 and maximally activated when the pH is 6.8) recently have been identified (OGR1, GPR4, and TDAG8).
• When activated by extracellular acidification, these receptors increase the production of cyclic adenosine monophosphate (via stimulation of adenylyl cyclase) and/or IP3 and diacylglycerol (via stimulation of phospholipase C), which regulate a variety of acid-base transporters.
• By contrast, Pyk2 is activated by intracellular acidification, and its activation in the proximal tubule increases H + secretion via the Na+-H + antiporter (NHE3) located in the apical membrane and HCO₃^–absorption via NBCe1 across the basolateral membrane.
• Two signaling enzymes, soluble adenylyl cyclase, and guanylyl cyclase–D, are regulated by changes in intracellular HCO₃^–. When activated, soluble adenylyl cyclase increases cyclic adenosine monophosphate production, which activates protein kinase A, an effect that increases the amount of H +-ATPase in the apical membrane of α-intercalated cells in the kidney collecting duct.

Other factors not necessarily related to the maintenance of acid-base balance can influence the secretion of H⁺ by the cells of the nephron. Because a significant H⁺ transporter in the nephron is the Na+-H⁺antiporter, factors that alter Na⁺ reabsorption can secondarily affect H⁺ secretion.

• For example, with volume contraction (negative Na+ balance), Na+ reabsorption by the nephron is increased (see Chapter 6), including reabsorption of Na+ via the Na+-H⁺ antiporter. As a result, H⁺ secretion is enhanced. This phenomenon occurs by several mechanisms. One mechanism involves the renin-angiotensin-aldosterone system, which is activated by volume contraction. Angiotensin
• II acts on the proximal tubule to stimulate the apical membrane Na⁺-H⁺ antiporter and the basolateral Na+-3HCO₃^–  symporter. This stimulatory effect includes increased activity of the transporters and insertion of transporters into the membrane.
• To a lesser degree, angiotensin II stimulates H⁺ secretion in the thick ascending limb of Henle’s loop and the early portion of the distal tubule, a process also mediated by the Na+-H+ antiporter. The primary action of aldosterone on the distal tubule and collecting duct is to stimulate Na+ reabsorption by principal cells (see Chapter 6).
• However, it also stimulates intercalated cells in these segments to secrete H⁺. This effect is both indirect and direct. By stimulating Na+ reabsorption by principal cells, aldosterone hyperpolarizes the transepithelial voltage (i.e., the lumen becomes more electrically negative). This change in transepithelial voltage then facilitates the secretion of H+ by the intercalated cells.
• In addition to this indirect effect, aldosterone (and angiotensin II) acts directly on intercalated cells to stimulate H⁺ secretion via the H⁺-ATPase. The precise mechanisms for this stimulatory effect are not fully understood. Another mechanism by which ECF volume contraction enhances H⁺ secretion (HCO₃^–  reabsorption) is through changes in peritubular capillary Starling forces.
• As described in Chapters 4 and 6, ECF volume contraction alters the peritubular capillary Starling forces such that overall proximal tubule reabsorption is enhanced. With this enhanced reabsorption, more of the filtered load of HCO₃^–   is reabsorbed.
• Potassium balance influences the secretion of H⁺ by the proximal tubule. H⁺ secretion is stimulated by hypokalemia and inhibited by hyperkalemia.
• It is thought that K+-induced changes in intracellular pH are responsible, at least in part, for this effect, with the cells being acidified by hypokalemia and alkalinized by hyperkalemia.

Hypokalemia also stimulates H⁺ secretion by the collecting duct, which occurs as a result of increased expression of the H⁺-K+-ATPase in intercalated cells.

Formation Of New HCO₃^–

As discussed previously, reabsorption of the filtered HCO₃^–  is important for maximizing RNAE. However, HCO₃^– reabsorption alone does not replenish

General scheme for the excretion of H + with non-bicarbonate (non-HCO₃^–  ) urinary buffers (titratable acid). The primary urinary buffer is phosphate (HPO−4 2). An H +-secreting intercalated cell is shown. For simplicity, only the H + adenosine triphosphatase (V-ATPase) is depicted. H + secretion by H +-K+- ATPase also titrates luminal buffers. AE1, anion exchanger 1; CA, carbonic anhydrase; V-ATPase, vacuolar adenosine triphosphatase.

• The HCO₃^– is lost during the buffering of the nonvolatile acids produced during metabolism. To maintain acid-base balance, the kidneys must replace this lost HCO₃^–  with new HCO₃^–.
• A portion of the new HCO₃^– is produced when urinary buffers (primarily Pi) are excreted as titratable acid. This process is illustrated in Figure 8-5. In the distal tubule and collecting duct, where the tubular fluid contains little or no HCO₃^– because of “upstream” reabsorption, H⁺ secreted into the tubular fluid combines with a urinary buffer.
• Thus H⁺ secretion results in the excretion of H⁺ with a buffer, and the HCO₃^–  produced in the cell from the hydration of CO₂ is added to the blood. The amount of Pi excreted each day and thus available to serve as a urinary buffer is not sufficient to allow adequate generation of new HCO₃^–
• However, as noted, increased excretion of Pi does occur with acidosis and therefore contributes to the kidneys’ response to the acidosis. Nevertheless, this amount of Pi is inadequate to allow the kidneys to excrete sufficient net acid.
• In comparison, NH4⁺ is produced by the kidneys, and its synthesis and subsequent excretion add HCO₃^–  to the ECF. In addition, the synthesis of NH4⁺ and the subsequent production of HCO₃^–  are regulated in response to the acid-base requirements of the body. Because of this process, NH ⁺ 4 excretion is critically involved in the formation of new HCO₃^–.
• NH + 4 is produced in the kidneys through the metabolism of glutamine. Essentially, the kidneys metabolize glutamine, excrete NH4⁺, and add HCO₃^– to the body.
• However, the formation of new HCO₃^– by this process depends on the kidneys’ ability to excrete NH ⁺ 4 in the urine. If NH4⁺ is not excreted in the urine but enters the systemic circulation instead, it is converted into urea by the liver.
• This conversion process generates H⁺, which is then buffered by HCO₃^–. Thus the production of urea from really generated NH4⁺ consumes HCO₃^– and negates the formation of HCO₃^– through the synthesis and excretion of NH4⁺ by the kidneys. However, normally, the kidneys excrete NH4⁺ in the urine and thereby produce new HCO₃^–
• The process by which the kidneys excrete NH4⁺ is complex. Figure 8-6 illustrates the essential features of this process. NH4⁺ is produced from glutamine in the cells of the proximal tubule, a process termed ammoniagenesis. Each glutamine molecule produces two molecules of NH ⁺ 4 and the divalent anion 2-oxoglutarate−2.

The metabolism of this anion ultimately provides two molecules of HCO₃^–.The HCO₃^– exits the cell across the basolateral membrane and enters the peritubular blood as new HCO₃^–. NH4⁺ exits the cell across the apical membrane and enters the tubular fluid. The primary mechanism for the secretion of NH ⁺ 4 into the tubular fluid involves the Na+-H⁺ antiporter, with NH4⁺ substituting for H⁺. In addition, NH3 can diffuse out of the

 

Production, transport, and excretion of ammonium (NH4⁺) by the nephron. Glutamine is metabolized to NH4⁺ and bicarbonate (HCO₃^–) in the proximal tubule. The NH4⁺ is secreted into the lumen, and the HCO₃^– enters the blood. The secreted NH4⁺ is reabsorbed in Henle’s loop primarily by the thick ascending limb and accumulates in the medullary interstitium, where it exists as both NH4⁺ and ammonia (NH 3) (pKa ≈9.0). NH4⁺ diffuses into the tubular fluid of the collecting duct via RhCG and RhBG (not shown), and H ⁺ secretion by the collecting duct leads to accumulation ofNH4⁺ in the lumen by the processes of nonionic diffusion and diffusion trapping. For each molecule of NH4⁺ excreted in the urine, a molecule of “new” HCO₃^– is added back to the extracellular fluid. CA, Carbonic anhydrase; V-ATPase, vacuolar adenosine triphosphatase.

• cell across the plasma membrane into the tubular fluid, where it is protonated to NH4⁺. A significant portion of the NH4⁺ secreted by the proximal tubule is reabsorbed by the loop of Henle. The thick ascending limb is the primary site of this NH ⁺ 4 reabsorption, with NH4⁺ substituting for K⁺ on the Na+-K⁺-2Cl− symporter.
• In addition, the lumen-positive transepithelial voltage in this segment drives the paracellular reabsorption of NH4⁺ (see Chapter 4). The NH⁺+ 4 reabsorbed by the thick ascending limb of the loop of Henle accumulates in the medullary interstitium, where it exists in chemical equilibrium with NH 3 (pK = 9.0).
• NH4⁺ is then secreted into the tubular fluid of the collecting duct. The mechanisms by which NH⁺ 4 is secreted by the collecting duct include (1) transport into intercalated cells by the Na+-K+-ATPase (NH4⁺ substituting for K⁺) and exit from the cell across the apical membrane of intercalated cells by the H⁺-K+- ATPase (NH4+ substituting for H⁺) and (2) the process of nonionic diffusion and diffusion trapping.
• Of these mechanisms for NH ⁺ 4 secretion, quantitatively the most important are nonionic diffusion and diffusion trapping. By this mechanism, NH3 diffuses from the medullary interstitium into the lumen of the collecting duct. As previously described, H⁺ secretion by the intercalated cells of the collecting duct acidifies the luminal fluid (a luminal fluid pH as low as 4.0 to 4.5 can be achieved).
• Consequently, NH3 diffusing from the medullary interstitium into the collecting duct lumen (nonionic diffusion) is protonated to NH4⁺ by the acidic tubular fluid. Because the collecting duct is less permeable to NH4⁺ than to NH3, NH4⁺ is trapped in the tubule lumen (diffusion trapping) and eliminated from the body in the urine.
• Ammonia diffusion across the collecting duct occurs via Rh glycoproteins.* Two Rh glycoproteins have been identified thus far in the kidney (RhBG and RhCG) and are localized to the distal tubule and collecting duct. RhBG is localized to the basolateral membrane, whereas RhCG is found in both the apical and basolateral membranes. Both RhBG and RhCG are expressed to a greater degree in intercalated cells versus principal cells.

H+ secretion by the collecting duct is critical for the excretion of NH⁺ 4. If collecting duct H⁺ secretion is inhibited, the NH4⁺ reabsorbed by the thick ascending limb of Henle’s loop is not excreted in the urine. Instead, it is returned to the systemic circulation, where, as described previously, it is converted to urea by the liver, consuming HCO₃^– in the process. Thus new HCO₃^– is produced during the metabolism of glutamine by cells of the proximal tubule. However, the overall process is not complete until the NH4⁺ is excreted (i.e., the production of urea from NH4⁺ by the liver is prevented). Thus NH4⁺ excretion in the urine can be used as a “marker” of glutamine metabolism in the proximal tubule. In the net, one new HCO₃^– is returned to the systemic circulation for each NH4⁺ excreted in the urine.

• Renal tubule acidosis (RTA) refers to conditions in which net acid excretion by the kidneys is impaired. Under these conditions, the kidneys are unable to excrete a sufficient amount of net acid (renal net acid excretion [RNAE]) to balance net endogenous acid production and acidosis results.
• RTA can be caused by a defect in H⁺ secretion in the proximal tubule (proximal RTA) or distal tubule (distal RTA) or by inadequate production and excretion ofNH4⁺. Proximal RTA can be caused by a variety of hereditary and acquired conditions (e.g., cystinosis, Fanconi syndrome, or administration of carbonic anhydrase inhibitors).
• The majority of cases of proximal RTA result from generalized tubule dysfunction rather than a selective defect in one of the proximal tubule acid-base transporters. However, autosomal recessive and autosomal dominant forms of proximal RTA have been identified. An autosomal recessive form of proximal RTA results from a mutation in the Na+-HCO₃^–symporter (NBCe1).
• Because this transporter also is expressed in the eye, these patients also have ocular abnormalities. Another autosomal recessive form of proximal RTA occurs in persons who lack carbonic anhydrase (CA-II). Because CA-II is required for normal distal acidification, this defect includes a distal RTA component as well. Finally, an autosomal dominant form of proximal RTA has been identified.
• However, the transporter involved has not been identified. Regardless of the cause, if H + secretion by the cells of the proximal tubule is impaired, there is decreased reabsorption of the filtered HCO₃^–. Consequently, HCO₃^–is lost in the urine, the plasma [HCO₃^– ] decreases, and acidosis ensues.
• Distal RTA also occurs in several hereditary and acquired conditions (e.g., medullary sponge kidney, certain drugs such as amphotericin B, and conditions secondary to urinary obstruction). Both autosomal dominant and autosomal recessive forms of distal RTA have been identified.
• An autosomal dominant form results from mutations in the gene coding for the Cl−-HCO₃^– antiporter (anion exchanger-1) in the basolateral membrane of the acid-secreting intercalated cell. Autosomal recessive forms are caused by mutations in various subunits of vacuolar [H ⁺]–adenosine triphosphatase (H ⁺– ATPase).
• In some patients with Sjögren syndrome, an autoimmune disease, distal RTA develops as a result of antibodies directed against H +-ATPase. Lastly, H + secretion by the distal tubule and the collecting duct may be normal, but the permeability of the cells to H + is increased. This effect occurs with the antifungal drug amphotericin B, the administration of which leads to the development of distal RTA.

Regardless of the cause of distal RTA, the ability to acidify the tubular fluid in the distal tubule and collecting duct is impaired. Consequently, titratable acid excretion is reduced, and nonionic diffusion and diffusion trapping of NH4⁺ are impaired. This situation, in turn, decreases RNAE, with the subsequent development of acidosis. Failure to produce and excrete sufficient quantities of NH4⁺ also can reduce net acid excretion by the kidneys. This situation occurs as a result of generalized dysfunction of the distal tubule and collecting duct with impaired H⁺, NH4⁺, and K⁺ secretion.

• Generalized distal nephron dysfunction is seen in persons with loss of function mutations in the Na+ channel (ENaC), which are inherited in an autosomal recessive pattern. An autosomal dominant form also is seen with loss of function mutations in the mineralocorticoid receptor.
• More commonly, NH4⁺ production and excretion are impaired in patients with hyporeninemic hypoaldosteronism. These patients typically have moderate degrees of renal failure with reduced levels of renin and, thus, aldosterone. As a result, distal tubule and collecting duct function is impaired.
• Finally, several drugs also can result in distal tubule and collecting duct dysfunction. These drugs block the Na⁺ channel (e.g., amiloride), block the production or action of angiotensin II (angiotensin-converting enzyme inhibitor, angiotensin I receptor blockers), or block the action of aldosterone (e.g., spironolactone).
• Regardless of the cause, the impaired function of the distal tubule and collecting duct results in the development of hyperkalemia, which in turn impairs ammonia genesis by the proximal tubule. H + secretion by the distal tubule and collecting duct and thus NH4⁺ secretion also are impaired by these drugs.
• Thus RNAE is less than net endogenous acid production, and metabolic acidosis develops. If the acidosis that results from any of these forms of RTA is severe, individuals must ingest alkali (e.g., baking soda or a solution containing citrate*) to maintain acid-base balance.
• In this way, the HCO₃^– lost each day in the buffering of nonvolatile acid is replenished by the extra HCO₃^– ingested in the diet. *One of the byproducts of citrate metabolism is HCO₃^–. Ingestion of drinks containing citrate often is more palatable to patients than ingesting baking soda.
• An important feature of the renal NH4⁺ system is that it can be regulated by systemic acid-base balance. As already noted, cortisol levels increase during acidosis and cortisol stimulates ammonia genesis (i.e., NH4⁺ production from glutamine).
• Angiotensin II also stimulates ammonia genesis and secretion of NH ⁺ 4 into the tubular fluid. The expression of RhCG in the distal tubule and collecting duct is increased with acidosis (in some species, expression of RhBG is also increased).
• Thus in response to acidosis, both NH ⁺ 4 production and excretion are stimulated. Because this response involves the synthesis of new enzymes, it requires several days for complete adaptation. Other factors can alter renal NH ⁺ 4 excretion. For example, the [K+] of the ECF alters NH4+ production.

Hyperkalemia inhibits NH4+ production, whereas hypokalemia stimulates NH4⁺ production. The mechanism by which plasma [K⁺] alters NH4⁺ production is not fully understood. Alterations in the plasma [K⁺] may change the intracellular pH of proximal tubule cells and in that way influence glutamine metabolism. By this mechanism, hyperkalemia would raise intracellular pH and thereby inhibit glutamine metabolism. The opposite would occur during hypokalemia.

Response To Acid-Base Disorders

The pH of the ECF is maintained within a very narrow range (7.35 to 7.45).* Inspection of equation 8-3 shows *For simplicity of presentation in this chapter, the value of 7.40 for body fluid pH is used as normal, even though the normal range is from 7.35 to 7.45. Similarly, the normal range for PCO₂ is 35 to 45 mm Hg. However, a PCO₂ of 40 mm Hg is used as the normal value. Finally, a value of 24 mEq/L is considered a normal ECF [HCO₃^–], even though the normal range is 22 to 28 mEq/L.

• The pH of the ECF varies when either the [HCO₃^– ] or PCO₂ is altered. As already noted, disturbances of acid-base balance that result from a change in the [HCO₃^– ] of the ECF are termed metabolic acid-base disorders, whereas those resulting from a change in the PCO₂ are termed respiratory acid-base disorders. The kidneys are primarily responsible for regulating the [HCO₃^– ], whereas the lungs regulate the PCO₂.
• When an acid-base disturbance develops, the body uses a series of mechanisms to defend against the change in the pH of the ECF. These defense mechanisms do not correct the acid-base disturbance but merely minimize the change in pH imposed by the disturbance. Restoration of the blood pH to its normal value requires correction of the underlying process or processes that produced the acid-base disorder.
• The body has three general mechanisms to compensate for or defend against, changes in body fluid pH produced by acid-base disturbances: (1) extracellular and intracellular buffering, (2) adjustments in blood PCO₂ by alterations in the ventilatory rate of the lungs, and (3) adjustments in the RNAE.

Extracellular and Intracellular Buffers

The first line of defense against acid-base disorders is extracellular and intracellular buffering. The response of the extracellular buffers is virtually instantaneous, whereas the response to intracellular buffering is slower and can take several minutes. Metabolic disorders that result from the addition of nonvolatile acid or alkali to the body fluids are buffered in both the extracellular and intracellular compartments.

• The HCO₃^– buffer system is the principal ECF buffer. When nonvolatile acid is added to the body fluids (or alkali is lost from the body), HCO₃^– is consumed during the process of neutralizing the acid load, and the [HCO₃^–] of the ECF is reduced.
• Conversely, when nonvolatile alkali is added to the body fluids (or acid is lost from the body), H⁺ is consumed, causing more HCO₃^– to be produced from the dissociation of H₂CO₃.

Consequently, the [HCO₃^–] increases. Although the HCO₃^– buffer system is the principal ECF buffer, Pi and plasma proteins provide additional extracellular buffering. The combined action of the ECF buffering processes for HCO₃^–, Pi, and plasma protein accounts for approximately 50% of the buffering of a nonvolatile acid load and 70% of that of a nonvolatile alkali load. The remainder of the buffering under these two conditions occurs intracellularly. Intracellular buffering involves the movement of H⁺ into cells (during buffering of nonvolatile acid) or the movement of H⁺ out of cells (during buffering of nonvolatile alkali).

• H⁺ is titrated inside the cell by HCO₃^–, Pi, and the histidine groups on proteins. Bone represents an additional source of extracellular buffering. With acidosis, buffering by bone results in its demineralization because Ca++ is released from bone as salts containing Ca++ bind H⁺ in exchange for Ca++. When respiratory acid-base disorders occur, the pH of body fluids changes as a result of alterations in the Pro 2.
• Virtually all buffering in respiratory acid-base disorders occurs intracellularly. When the PCO₂ rises (respiratory acidosis), CO₂ moves into the cell, where it combines with H₂O to form H₂CO₃. H₂CO₃ then dissociates to H⁺ and HCO₃^–. Some of the H⁺ is buffered by cellular protein, and HCO₃^–  exits the cell and raises the plasma [HCO₃^–  ].
• This process is reversed when the PCO₂ is reduced (respiratory alkalosis). Under this condition, the hydration reaction (H₂O + CO₂ ↔ H₂CO₃) is shifted to the left by the decrease in PaCO₂. As a result, the dissociation reaction (H₂CO₃  ↔ H + +HCO₃) also shifts to the left, thereby reducing the plasma [HCO₃^–  ].

Respiratory Compensation

The lungs are the second line of defense against acid-base disorders. As indicated by the Henderson-Hasselbalch equation (see equation 8-3), changes in the PCO₂ alter the blood pH; a rise decreases the pH, and a reduction increases the pH. The ventilatory rate determines the PCO₂

• Increased ventilation decreases PCO₂ whereas decreased ventilation increases it. The blood PCO₂ and pH are important regulators of the ventilatory rate. Chemoreceptors located in the brainstem (ventral surface of the medulla) and periphery (carotid and aortic bodies) sense changes in PCO₂ and [H⁺] and alter the ventilatory rate appropriately.
• Thus when metabolic acidosis occurs, a rise in the [H⁺] (decrease in pH) increases the ventilatory rate. Conversely, during metabolic alkalosis, a decreased [H⁺] (increase in pH) leads to a reduced ventilatory rate. With maximal hyperventilation, the PCO₂ can be reduced to approximately 10 mm Hg. Because hypoxia, a potent stimulator of ventilation,
• Metabolic acidosis can develop in patients with insulin-dependent diabetes (secondary to the production of keto acids) if insulin dosages are not adequate. As a compensatory response to this acidosis, deep and rapid breathing develops. This breathing pattern is termed Kussmaul respiration. With prolonged Kussmaul respiration, the muscles involved can become fatigued. When this muscle fatigue happens, respiratory compensation is impaired, and the acidosis can become more severe.
• Loss of gastric contents from the body (i.e., through vomiting or nasogastric suction) produces metabolic alkalosis as a result of the loss of HCl. If the loss of gastric fluid is significant, extracellular fluid volume contraction occurs. Under this condition, the kidneys cannot excrete sufficient quantities of HCO₃^–  to compensate for metabolic alkalosis.

Bicarbonate (HCO₃^–  ) is not excreted because the volume contraction enhances Na+ reabsorption by the proximal tubule and increases angiotensin II and aldosterone levels (see Chapter 6). These responses in turn limit HCO₃^–  excretion because a significant amount of Na+ reabsorption in the proximal tubule is coupled to H ⁺ secretion through the Na^+-H⁺ antiporter. As a result, HCO₃^–  reabsorption is increased because of the need to reduce Na+ excretion.

• In addition, the elevated aldosterone levels stimulate H + secretion by the distal tubule and collecting duct. Thus in persons who lose gastric contents, metabolic alkalosis and, paradoxically, acidic urine characteristically occur. Correction of the alkalosis occurs only when euvolemia is re-established.
• With the restoration of euvolemia, by the addition of sodium chloride (NaCl) with fluid (e.g., isotonic saline), HCO₃^–  reabsorption by the proximal tubule decreases, as does H ⁺ secretion by the distal tubule and collecting duct. As a result, HCO₃^–  excretion increases, and the plasma concentration of HCO₃^–  ([HCO₃^–  ]) returns to normal.
• Also develops with hypoventilation, and the degree to which the PCO₂ can be increased is limited. In an otherwise healthy person, hypoventilation cannot raise the PCO₂ above 60 mm Hg. The respiratory response to metabolic acid-base disturbances may be initiated within minutes but may require several hours to complete.

Renal Compensation

The third and final line of defense against acid-base disorders is the kidneys. In response to an alteration in the plasma pH and PCO₂, the kidneys make appropriate adjustments in the excretion of HCO₃^– and net acid.

• The renal response may require several days to reach completion because it takes hours to days to increase the synthesis and activity of key H⁺ and HCO₃^–  transporters and the proximal tubule enzymes involved in NH4⁺ production. In the case of acidosis (increased [H⁺] or PCO₂), the secretion of H⁺ by the nephron is stimulated, and the entire filtered load of HCO₃^–  is reabsorbed.
• Titratable acid excretion is increased, the production and excretion of NH ⁺ 4 are also stimulated, and thus RNAE is increased. The new HCO₃^–  generated during the process of net acid excretion is added to the body and the plasma [HCO₃^–  ] increases.
• When alkalosis exists (decreased [H⁺] or PCO₂), the secretion of H⁺ by the nephron is inhibited. As a result, HCO₃^–  reabsorption is reduced, as is the excretion of both titratable acid and NH⁺ 4.
• Thus RNAE is decreased and HCO₃^–  appears in the urine. Also, some HCO₃^–  is secreted into the urine by the HCO₃^– -secreting intercalated cells of the distal tubule and collecting duct. With enhanced excretion of HCO₃^–, the plasma [HCO₃^–  ] decreases.

Simple Acid-Base Disorders

Table 8-1 summarizes the primary alterations and the subsequent compensatory or defense mechanisms of the various simple acid-base disorders. In all acid-base disorders, the compensatory response does not correct the underlying disorder but simply reduces the magnitude of the change in pH. Correction of the acid-base disorder requires treatment of its cause.

Metabolic Acidosis

Metabolic acidosis is characterized by a decreased ECF [HCO₃^– ] and pH. It can develop through the addition of nonvolatile acid to the body (e.g., diabetic ketoacidosis), loss of nonvolatile alkali (e.g., HCO₃^–  loss caused by diarrhea), or failure of the kidneys to excrete sufficient net acid to replenish the HCO₃^–  used to neutralize nonvolatile acids (e.g., renal tubular acidosis and renal failure).

As previously described, the buffering of H⁺ occurs in both the ECF and intracellular fluid (ICF) compartments. When the pH falls, the respiratory centers are stimulated, and the ventilatory rate is increased (respiratory compensation). This process reduces the PCO₂, which further minimizes the decrease in plasma pH. In general, a decrease of 1.2 mm Hg occurs in the PCO₂ for every 1 mEq/L decrease in ECF [HCO₃^–  ]. Thus

 

Response Of The Nephron To Acidosis. Et-1, Endothelin; HCO₃^–, Bicarbonate; NH4⁺, Ammonium; Pi, Phosphate; Pth, Parathyroid Hormone; Rhcg & Rhbg, Rhesus Glycoproteins; Rnae, Renal Net Acid Excretion; Ta, Titratable Acid; V˙, Urine Flow Rate.

• if the [HCO₃^–  ] was reduced to 14 mEq/L from a normal value of 24 mEq/L, the expected decrease in PCO₂ would be 12 mm Hg and the measured Pco2 would decrease to 28 mm Hg (normal PCO₂= 40 mm Hg).
• Finally, in metabolic acidosis, RNAE is increased. This increase occurs through the elimination of all HCO₃^–  from the urine (enhanced reabsorption of filtered HCO₃^– ) and through increased titratable acid and NH + 4 excretion (enhanced production of new HCO₃^–  ).
• If the process that initiated the acid-base disturbance is corrected, the enhanced net acid excretion by the kidneys ultimately returns the pH and [HCO₃^– ] to normal. After correction of the pH, the ventilatory rate also returns to normal.

Metabolic Alkalosis

Metabolic alkalosis is characterized by an increased ECF [HCO₃^– ] and pH. It can occur through the addition of nonvolatile alkali to the body (e.g., ingestion of antacids), as a result of volume contraction (e.g., hemorrhage), or, more commonly, from the loss of nonvolatile acid (e.g., loss of gastric HCl because of prolonged vomiting). Buffering occurs predominantly in the ECF compartment and to a lesser degree in the ICF compartment. The increase in the pH inhibits the respiratory centers, the ventilatory rate is reduced, and thus the PCO₂ is

Table 8-1

Characteristics Of Simple Acid-Base Disorders

 

Elevated (respiratory compensation). With appropriate respiratory compensation, a 0.7 mm Hg increase in PCO₂ is expected for every 1 mEq/L rise in ECF [HCO₃^– ]. The renal compensatory response to metabolic alkalosis is to increase the excretion of HCO₃^–  by reducing its reabsorption along the nephron.

• Normally, this process occurs quite rapidly (within minutes to hours) and effectively. However, as already noted, when alkalosis occurs with ECF volume contraction (e.g., vomiting in which fluid loss occurs with H⁺ loss), HCO₃^–  is not excreted.
• In volume-depleted individuals, renal excretion of HCO₃^–  is impaired and alkalosis is corrected, only with the restoration of euvolemia. Enhanced renal excretion of HCO₃^–  eventually returns the pH and [HCO₃^– ] to normal, provided that the underlying cause of the initial acid-base disturbance is corrected. When the pH is corrected, the ventilatory rate also returns to normal.

Respiratory Acidosis

Respiratory acidosis is characterized by an elevated PCO₂ and reduced ECF pH. It results from decreased gas exchange across the alveoli as a result of either inadequate ventilation (e.g., drug-induced depression of the respiratory centers) or impaired gas diffusion (e.g., pulmonary edema, such as that which occurs in cardiovascular or lung disease). In contrast to metabolic acid-base disorders, buffering during respiratory acidosis occurs almost entirely in the ICF compartment.

• The increase in the PCO₂ and the decrease in pH stimulate both HCO₃^–  reabsorption by the nephron and titratable acid and NH ⁺ 4 excretion (renal compensation). Together, these responses increase RNAE and generate new HCO₃^–
• The renal compensatory response takes several days to develop fully. Consequently, respiratory acid-base disorders are commonly divided into acute and chronic phases. In the acute phase, the time for the renal compensatory response is not sufficient, and the body relies on ICF buffering to minimize the change in pH.
• During this phase, and because of the buffering, a 1 mEq/L increase in ECF [HCO₃^–  ] occurs for every 10 mm Hg rise in PCO₂. In the chronic phase, renal compensation occurs, and a 3.5 mEq/L increase in ECF [HCO₃^– ] occurs for each 10 mm Hg rise in PCO₂ Correction of the underlying disorder returns the PCO₂ to normal, and renal net acid excretion decreases to its initial level.

Respiratory Alkalosis

Respiratory alkalosis is characterized by a reduced PCO₂ and an increased ECF pH. It results from increased gas exchange in the lungs, usually caused by increased ventilation from stimulation of the respiratory centers (e.g., by drugs or disorders of the central nervous system).

• Hyperventilation also occurs at high altitudes and as a result of anxiety, pain, or fear. As noted, buffering is primarily in the ICF compartment. As with respiratory acidosis, respiratory alkalosis has both acute and chronic phases reflecting the time required for renal compensation to occur.
• In the acute phase of respiratory alkalosis, which reflects intracellular buffering, the ECF [HCO₃^–  ] decreases 2 mEq/L for every 10 mm Hg decrease in PCO₂. With renal compensation, the elevated pH and reduced PCO2 inhibit HCO₃^–  reabsorption by the nephron and reduce TA andNH4⁺ excretion.
• As a result of these two effects, net acid excretion is reduced. With complete renal compensation, an expected 5 mEq/L decrease in ECF [HCO₃^–  ] occurs for every 10 mm Hg reduction in PCO₂ Correction of the underlying disorder returns the PCO₂ to normal, and renal excretion of acid then increases to its initial level.

Analysis Of Acid-Base Disorders

The analysis of an acid-base disorder is directed at identifying the underlying cause so that appropriate therapy can be initiated. The patient’s medical history and associated physical findings often provide valuable clues about the nature and origin of an acid-base disorder. In addition, the analysis of an arterial blood sample is frequently required. Such an analysis is straightforward if approached systematically. For example, consider the following data: The acid-base disorder represented by these values, or any other set of values, can be determined using the following three-step approach.

• Examination of the pH: When the pH is considered first, the underlying disorder can be classified as either acidosis or alkalosis. The defense mechanisms of the body cannot correct an acid-base disorder by themselves. Thus even if the defense mechanisms are completely operative, the change in pH indicates the acid-base disorder. In the example provided, a pH of 7.35 indicates acidosis.
• Determination of metabolic versus respiratory disorder: Simple acid-base disorders are either metabolic or respiratory. To determine which disorder is present, the clinician must next examine the ECF [HCO₃^–  ] and PCO₂ As previously discussed, acidosis could be the result of a decrease in the [HCO₃^–  ] (metabolic) or an increase in the PCO₂ (respiratory).
• Alternatively, alkalosis could be the result of an increase in the ECF [HCO₃^–  ] (metabolic) or a decrease in the PCO₂ (respiratory). For the example provided, the ECF [HCO₃^– ] is reduced from normal (normal = 24 mEq/L), as is the PCO₂ (normal = 40 mm Hg). The disorder therefore must be metabolic acidosis; it cannot be a respiratory acidosis because the PCO₂ is reduced.
• Analysis of a compensatory response: Metabolic disorders result in compensatory changes in ventilation and thus in the PCO₂, whereas respiratory disorders result in compensatory changes in RNAE and thus in the ECF [HCO₃^–  ]. In an appropriately compensated metabolic acidosis, the PCO₂ is decreased, whereas it is elevated in compensated metabolic alkalosis. With respiratory acidosis, compensation results in an elevation of the [HCO₃^–  ]. Conversely, the ECF [HCO₃^–  ] is reduced in response to respiratory alkalosis. In this example, the PCO₂ is reduced from normal, and the magnitude of this reduction (10 mm Hg decrease in PCO₂ for an 8 mEq/L increase in ECF [HCO₃^–  ]) is as expected. Therefore acid-base disorder is a simple metabolic acidosis with appropriate respiratory compensation.
• If the appropriate compensatory response is not present, a mixed acid-base disorder should be suspected. Such a disorder reflects the presence of two or more underlying causes for the acid-base disturbance. A mixed disorder should be suspected when analysis of the arterial blood gas indicates that appropriate

 

Approach for the analysis of simple acid-base disorders. *If the compensatory response is not appropriate, a mixed acid-base disorder should be suspected. HCO₃^–, bicarbonate; PCO₂, partial pressure of carbon dioxide.

• compensation has not occurred. For example, consider the following data:
• When the three-step approach is followed, it is evident that the disturbance is an acidosis that has both a metabolic component (ECF [HCO₃^–  ] <24 mEq/L) and a respiratory component (PCO₂ >40 mm Hg).
• Thus this disorder is mixed. Mixed acid-base disorders can occur, for example, in a person who has a history of a chronic pulmonary disease such as emphysema (i.e., chronic respiratory acidosis) and who experiences an acute gastrointestinal illness with diarrhea.
• Because diarrhea fluid contains HCO₃^–, its loss from the body results in the development of metabolic acidosis. A mixed acid-base disorder also is indicated when a patient has abnormal PCO₂ and ECF [HCO₃^– ] values but the pH is normal. Such a condition can develop in a patient who has ingested a large quantity of aspirin.
• Salicylic acid (which is the active ingredient in aspirin) produces metabolic acidosis, and at the same time, it stimulates the respiratory centers, causing hyperventilation and respiratory alkalosis. Thus the patient has a reduced ECF [HCO₃^– ] and a reduced PCO₂. (Note: The PCO₂ is lower than would occur with normal respiratory compensation of metabolic acidosis.)