Acid-Base Disorders: Clinical Evaluation and Management

By Alluru S. Reddi

This book provides a concise yet comprehensive overview of acid-base disorders. Each chapter reviews an acid-base disorder, covering pathophysiology, evaluation, and management of the disorder. The chapters also include clinical cases and a Q&A section, based on scenarios and questions that clinicians regularly encounter when treating patients with these disorders. The book concludes with two chapters on acid-based disorders in special patient populations, including critically ill patients, pregnant patients, and surgical patients. 
Written by an expert in the field, Acid-Base Disorders: Clinical Evaluation and Management is a state-of-the-art resource that should assist clinicians and practitioners in managing patients with acid-base disorders. 

• Language: English
• Publisher: Springer
• Release date: Oct 31, 2019
• ISBN: 9783030288952

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© Springer Nature Switzerland AG 2020

A. S. ReddiAcid-Base Disordershttps://doi.org/10.1007/978-3-030-28895-2_1

1. Introduction to Acid–Base

Alluru S. Reddi¹ 

(1)

Professor of Medicine, Department of Medicine, Chief, Division of Nephrology and Hypertension, Rutgers New Jersey Medical School, Newark, NJ, USA

Keywords

Arterial blood gas (ABG)Blood gas analyzer (BGA)pHpO2 pCO2 HCO3 –

The arterial blood gas (ABG) determination is an important laboratory test in the evaluation of oxygenation and acid–base status of the body. This ABG test is most frequently done in the emergency department and critical care units. Also, this test is a valuable tool during operative procedures. When an ABG is ordered, four important values are reported: pH, partial pressure of oxygen (pO2), partial pressure of carbon dioxide (pCO2), and bicarbonate (HCO3 −). Base excess (BE) is also reported (see Chap. 3), which is used by some clinicians. The percent saturation of hemoglobin with oxygen in the arterial blood (SaO2) is done by either direct measurement using CO-oximetry or estimated from pO2. Only some blood gas analyzers are equipped with CO-oximeter for measurement of SaO2 directly, and other laboratories report calculated value. Mean SaO2 is 98%.

Technique of ABG Measurement

After collection of either arterial or venous blood, it is introduced into the blood gas analyzer (BGA) . The BGA aspirates the blood into a measuring chamber which contains ion-specific electrodes for pH, pO2, and pCO2. The pH is measured by two electrodes: a pH-measuring electrode and a reference electrode. The reference electrode contains a saturated solution of KCl, and the current flow compares the voltage of the unknown blood with a reference voltage, and the difference in voltage is displayed on a voltmeter calibrated in pH units.

pO2 is measured with Clark electrode or polarographic electrode. O2 diffuses across polypropylene membrane through the electrode immersed in phosphate buffer. O2 then reacts with water in the buffer and generates voltage (current) that is proportional to the number of O2 molecules in the solution. The current is measured and expressed as pO2.

The pCO2 electrode is a modified pH electrode with a silicone or Teflon rubber CO2 semipermeable membrane covering the tip of the electrode. The electrode is bathed in a solution containing NaHCO3. The CO2 diffuses from the blood across the semipermeable membrane, and the reaction between CO2 and water generates free H+ in proportion to the pCO2

A brief description of each of these components of ABG is described below.

pH

pH is measured by a specific pH electrode, and it indicates either acidity or alkalinity of blood. Actually the pH is an indirect measurement of hydrogen ion concentration (abbreviated as [H+]).The normal [H+] in the extracellular fluid is about 40 nmol/L or 40 nEq/L (range 38–42 nmol/L), which is precisely regulated by an interplay between body buffers, lungs, and kidneys. Since many functions of the cell are dependent on the optimum [H+], it is extremely important to maintain [H+] in blood ~ 40 nmol/L. Any deviation from this [H+] results either in acidemia ([H+] >40 nmol/L) or alkalemia ([H+] <40 nmol/L). The [H+] in blood is so low that it is not measured routinely. However, the [H+] is measured as pH, which is expressed as:

$$ pH=-\log\ \left[{\mathrm{H}}^{+}\right] $$

(1.1)

Thus, pH is defined as the negative logarithm of the [H+]. An inverse relationship exists between pH and [H+]. In other words, as the pH increases, the [H+] decreases and vice versa (Table 1.1). Cells cannot function at a pH below 6.8 and above 7.8. The normal arterial pH ranges from 7.38 to 7.42, which translates to a [H+] of 38–42 nmol/L. Mean pH is 7.40.

Table 1.1

Relationship between pH and [H+]

pO2

pO2 refers to the partial pressure of oxygen (tension) dissolved in blood. As mentioned, it is measured specifically by a pO2 electrode. The mean value of pO2 in a normal young man is approximately 97 mmHg at sea level. Various formulas have been developed to predict approximate values of pO2 in individuals of varying ages. Clinically, however, it is cumbersome to use these formulas on daily basis. One suggested way of estimating approximate pO2 is to assume 100 mmHg in a 10-year-old child and a decrease of 5 mmHg for every 10 years up to 90 years of age. For example, a 20-year-old man will have a pO2 of 95 mmHg, and it is 60 mmHg for a 90-year-old man.

pCO2

pCO2 indicates the partial pressure of carbon dioxide (tension) dissolved in blood. It reflects alveolar ventilation and represents respiratory component of ABG. The normal values range from 35 to 46 mmHg with a mean value of 40 mmHg.

HCO3 −

HCO3 − represents the bicarbonate concentration ([HCO3 −]) of the blood sample that is sent for the analysis of ABG. It is not a measured value but calculated from Henderson–Hasselbalch equation (see Chap. 2). This calculated [HCO3 −] is lower by 1–2 mEq/L than the [HCO3 −] from chemistry panel, which is measured as total CO2. Total CO2 comprises three components: HCO3 −, dissolved CO2, and carbonic acid. For this reason, total CO2 concentration is higher than the calculated HCO3−. Total CO2, calculated HCO3 −, and base excess (see Chap. 3) are indicators of metabolic components of ABG.

Normal ABG Values

Mean and range values of normal ABG are shown in Table 1.2.

Table 1.2

Mean and range values of normal ABG

BE base excess, SaO2 saturation of hemoglobin with oxygen

Arterial vs. Venous Blood Sample for ABG

Arterial blood is used most of the time to evaluate an acid–base disorder. However, venous blood samples can be used because there is insignificant difference in ABG values between these two samples (Table 1.3).

Table 1.3

Differences between arterial and venous blood samples

Although there is not much difference between the two samples in normal individuals, significant difference can be observed in pathological conditions. For example, large arteriovenous difference can be found in a patient with decreased cardiac output and on mechanical ventilation. In such a patient, the arterial pCO2 remains normal, but central venous pCO2 may be extremely elevated, as more CO2 is added to the perfusing tissue. In low cardiac output states, an arterial ABG is useful in assessing pulmonary gas exchange, and central venous ABG is useful in assessing pH and tissue oxygenation.

Primary Acid–Base Disorders

As stated above, a change in plasma [HCO3 −] results in a metabolic acid–base disturbance, whereas a change in arterial pCO2 results in a respiratory acid–base disorder. Clinically, four primary acid–base disorders can be recognized: (1) metabolic acidosis , (2) metabolic alkalosis , (3) respiratory acidosis , and (4) respiratory alkalosis . Changes in pH, HCO3 −, and pCO2 for each primary acid–base disorder are shown in Table 1.4. In addition, the respiratory acid–base disorders are classified into either acute or chronic based on the buffering mechanism. Buffering for acute disorder is complete in minutes to few hours, whereas for chronic disorder complete buffering takes a few days (see Chap. 2). Systemic disorders cause primary acid–base disorders, and the resultant pH changes are minimized by appropriate secondary physiologic response, as shown in Table 1.5.

Table 1.4

Primary acid–base disturbances

↑ increase ↓ decrease

Table 1.5

Primary acid–base disturbances and their secondary response

Secondary Physiologic Response (or Compensation)

It is a physiologic process that minimizes changes in pH or [H+] brought about by a primary change. In clinical practice, the term compensation rather than secondary physiologic response is usually used. Two types of compensatory responses (secondary physiologic responses) are involved: respiratory and renal. In a metabolic acid–base disorder, the compensatory response is respiratory. For example, in metabolic acidosis, the primary change is a decrease in plasma [HCO3 −] and an increase in [H+]. The compensatory response is a decrease in pCO2 due to hyperventilation. This decrease in pCO2 limits the rise in [H+], and thus the pH is returned to normal. The observed hyperventilation represents the normal physiologic response to an increase in [H+]. Conversely, hypoventilation is an appropriate physiological response to metabolic alkalosis. In a respiratory acid–base disorder, the compensatory response is renal. In respiratory acidosis, the primary change is an increase in pCO2 and a decrease in pH or an increase in [H+]. The renal compensation increases the plasma [HCO3 −] with a resultant increase in pH close to normal. Six rules of thumb were introduced to calculate the extent of compensatory response to the primary acid–base disorder (see Table 1.5).

Factors Influencing ABG

Factors such as collection of blood, time to collection of blood and its transportation to the laboratory, and temperature will influence the ABG results. Arterial blood should be collected under anaerobic conditions without air bubbles. Air bubbles give high pO2, and the blood samples should be placed in ice immediately. At 4 °C, ABG values remain stable for 2–4 h. Another reason for immediate determination of ABG is to prevent continuous metabolism occurring in white blood cells (WBCs) and reticulocytes. During metabolism, O2 is consumed and CO2 is generated. As a result, a decrease in pO2 and an increase in pCO2 up to 5 mmHg can occur. Because of an increase in pCO2, blood pH may be lower by 0.05 units. ABG should be determined immediately in patients with high WBC count (>12,000) because of high consumption of O2 during metabolism in these cells.

Too much anticoagulant such as heparin may lower pH, pO2, and pCO2. Citrate may decrease pH.

Changes in body temperature affect ABG results. In the ABG analyzer, the samples are read at a temperature of 37⁰ C. Deviations from this temperature, either decrease or increase, result in changes in pH, pO2, and pCO2. Table 1.6 shows temperature-corrected values for a normal ABG.

Table 1.6

Effect of temperature on ABG

Suggested Reading

Adrogué HJ, Madias NE. Measurement of acid-base status. In: Gennari FJ, Adrogué HJ, Galla JH, Madias NE, editors. Acid-base disorders and their treatment. Boca Raton: Taylor & Francis; 2005. p. 775–88.

Ashwood ER, Kost G, Kenny M. Temperature correction of blood-gas and pH measurements. Clin Chem. 1983;29:1877–85.

Byrne AL, Bennett M, Chatterji R, et al. Peripheral venous and arterial blood gas analysis in adults: are they comparable? A systemic review and meta-analysis. Respirology. 2014;19:168–75.

Hasan A. Handbook of blood gas/acid-base interpretation. London: Springer; 2013.

Kelly A-M. Review article: can venous blood gas analysis replace arterial in emergency medical care. Emerg Med Australia. 2010;22:493–8.

Malley WJ. Clinical blood gases. Application and noninvasive alternatives. Philadelphia: WB Saunders; 1990.

Neufeld O, Smith JR, Goldman SL. Arterial oxygen tension in relation to age in hospitalized patients. J Am Geriatr Soc. 1973;XXI:4–9.

© Springer Nature Switzerland AG 2020

A. S. ReddiAcid-Base Disordershttps://doi.org/10.1007/978-3-030-28895-2_2

2. Basic Acid–Base Chemistry and Physiology

Alluru S. Reddi¹ 

(1)

Professor of Medicine, Department of Medicine, Chief, Division of Nephrology and Hypertension, Rutgers New Jersey Medical School, Newark, NJ, USA

Keywords

Endogenous acidsEndogenous basesBuffersProximal tubuleHenleʼs loopDistal tubeCollecting duct

As discussed in Chap. 1, the acid–base physiology deals with the maintenance of normal hydrogen ion concentration ([H+]) and pH in body fluids and is precisely regulated by an interplay between body buffers, lungs, and kidneys. In everyday life, the blood pH is under constant threat by endogenous acid and base loads. If not removed, these loads can cause severe disturbances in blood pH and thus impair cellular function. However, three important regulatory systems prevent changes in pH and thus maintain blood pH in the normal range. These protective systems, as stated, are buffers, lungs, and kidneys.

Production of Endogenous Acids and Bases

An acid is a proton donor, whereas a base is a proton acceptor. Under physiological conditions, the diet is a major contributor to endogenous acid and base production.

Endogenous Acids

The oxidation of dietary carbohydrates, fats, and amino acids yields CO2. About 15,000 mmol of CO2 are produced by cellular metabolism daily. This CO2 combines with water in the blood to form carbonic acid (H2CO3):

$$ {CO}_2+{\mathrm{H}}_2\mathrm{O}\overset{CA}{\leftrightarrow }{\mathrm{H}}_2{CO}_3\leftrightarrow {\mathrm{H}}^{+}+{HCO_3}^{-}. $$

(2.1)

This reaction is catalyzed by carbonic anhydrase (CA), an enzyme present in tissues and red blood cells but absent in plasma. When H2CO3 dissociates into CO2 and H2O (a process called dehydration), the CO2 is eliminated by the lungs. For this reason, H2CO3 is called a volatile acid . In addition to volatile acid, the body also generates nonvolatile (fixed) acids from cellular metabolism. These nonvolatile acids are produced from sulfur-containing amino acids (i.e., cysteine and methionine) and phosphoproteins. The acids produced are sulfuric acid and phosphoric acid, respectively. Other sources of endogenous nonvolatile acids include glucose, which yields lactic and pyruvic acids; triglycerides, which yield acetoacetic and β-hydroxybutyric acids (ketoacids); and nucleoproteins, which yield uric acid. Hydrochloric acid is also formed from the metabolism of cationic amino acids (i.e., lysine, arginine, and histidine). Sulfuric acid accounts for 50% of all acids produced. A typical North American diet produces 1 mmol/kg/day of endogenous nonvolatile acid. Under certain conditions, acids are produced from sources other than the diet. For example, starvation produces ketoacids, which can accumulate in the blood. Similarly, strenuous exercise generates lactic acid. Drugs such as corticosteroids cause endogenous acid production by enhancing catabolism of muscle proteins.

Endogenous Bases

Endogenous base (HCO3 −) is generated from anionic amino acids (glutamate and aspartate) in the diet. Also, citrate or lactate generated during metabolism of carbohydrate yields HCO3 −. Vegetarian diets contain high amounts of anionic amino acids and small amounts of sulfur and phosphate-containing proteins. Therefore, these diets generate more base than acid. In general, the production of acid exceeds that of base in a person ingesting a typical North American diet. Table 2.1 summarizes endogenous sources of acids and bases in normal individuals.

Table 2.1

Sources of acid and alkali production

Maintenance of Normal pH

Buffers

All acids that are produced must be removed from the body in order to maintain normal blood pH. Although the kidneys eliminate most of these acids, it takes hours to days to complete the process. Buffers (both cellular and extracellular) are the first line of defense against wide fluctuations in pH. The most important buffer in blood is bicarbonate/carbon dioxide (HCO3 −/CO2). Other buffer systems are disodium phosphate/monosodium phosphate (Na2HPO4 ²−/NaH2PO4 −) and plasma proteins. In addition, erythrocytes contain the important hemoglobin (Hb) system, reduced Hb (HHb−) and oxyhemoglobin (HbO2 ²−). Bones also participate in buffering. The HCO3 −/CO2 system provides the first line of defense in protecting pH. Its role as a buffer can be described by incorporating this system into the Henderson–Hasselbalch equation as follows:

$$ pH= pKa+\log \frac{\left[{HCO_3}^{-}\right]}{\left[{\mathrm{H}}_2{CO}_3\right]}. $$

(2.2)

Although H2CO3 cannot be measured directly, its concentration can be estimated from the partial pressure of CO2 (pCO2) and the solubility coefficient (α) of CO2 at known temperature and pH. At normal temperature of 37 °C and pH of 7.4, the pCO2 is 40 mmHg, α is 0.03, and pKa is 6.1. The Henderson–Hasselbalch equation can be appropriately written as:

$$ pH=6.1+\log \frac{\left[{HCO_3}^{-}\right]}{0.03+{pCO}_2}. $$

(2.3)

Normal plasma [HCO3 −] is 24 mEq/L. Therefore,

$$ {\displaystyle \begin{array}{l} pH=6.1+\log \frac{24}{0.03\times 40}\\ {} pH=6.1+\log \frac{24}{1.2}=6.1+\log \frac{20}{1}\\ {} pH=6.1+1.3=7.4\end{array}} $$

(2.4)

It should be noted from the Henderson–Hasselbalch equation that the pH of a solution is determined by the pKa and the ratio of [HCO3 −] to pCO2, and not by their absolute values. Thus, because the kidneys regulate the [HCO3 −] and the lungs pCO2, the kidneys and lungs determine the pH of extracellular fluids.

Phosphate buffers are effective in regulating intracellular pH more efficiently than extracellular pH. Their increased effectiveness intracellularly is due to their higher concentrations inside the cell. Also, the pKa of this system is 6.8, which is close to the intracellular pH.

Plasma proteins contain several ionizable groups in their amino acids that buffer either acids or bases. For example, the imidazole groups of histidine and the N-terminal amino groups have pKa that are close to extracellular pH and thus function as effective buffers. In blood, hemoglobin is an important protein buffer because of its abundance in red blood cells.

Extracellular buffering to an acid load is complete within 30 min. Subsequent buffering occurs intracellularly and takes several hours to complete. Most of this intracellular buffering occurs in bone. Bone becomes an important source of buffering acid load acutely by an uptake of H+ in exchange for Na+, K+, and bone minerals. These bone minerals rescue the HCO3 −/CO2 system in severe acidosis.

It is apparent from the Henderson–Hasselbalch Eq. 2.2 that any change either in [HCO3 −] or pCO2 can cause a change in blood pH. The acid–base disturbance that results from a change in plasma [HCO3 −] is termed a metabolic acid–base disorder whereas that due to a change in pCO2 is called a respiratory acid–base disorder.

Lungs

After buffers, the lungs are the second line of defense against pH disturbance. In a normal individual, pCO2 is maintained around 40 mmHg. This pCO2 is achieved by expelling the CO2 that is produced by cellular metabolism through the lungs. Any disturbance in the elimination of CO2 may cause a change in blood pH. Thus, alveolar ventilation maintains normal pCO2 to prevent an acute change in pH. Alveolar ventilation is controlled by chemoreceptors located centrally in the medulla and peripherally in the carotid body and aortic arch. Blood [H+] and pCO2 are important regulators of alveolar ventilation. The chemoreceptors sense the changes in [H+] or pCO2 and alter alveolar ventilatory rate. For example, an increase in [H+], i.e., a decrease in pH, stimulates ventilatory rate and decreases pCO2. These responses, in turn, raise pH (see Eq. 2.3). Conversely, a decrease in [H+] or an increase in pH depresses alveolar ventilation and causes retention of pCO2 so that the pH is returned to near normal. An increase in pCO2 stimulates ventilatory rate, whereas a decrease depresses the ventilatory rate. The respiratory response to changes in [H+] takes several hours to complete.

Kidneys

As stated earlier, 1 mmol/kg/day of fixed acid is produced from the diet. If not removed, this acid is retained and plasma [HCO3 −] decreases. The result is metabolic acidosis. In a healthy individual, metabolic acidosis does not occur because the kidneys excrete the acid load and maintain plasma [HCO3 −] around 24 mEq/L. The maintenance of [HCO3 −] is achieved by three renal mechanisms:

1.

Reabsorption of filtered HCO3−

2.

Generation of new HCO3− by titratable acid (TA) excretion

3.

Formation of HCO3− from generation of NH4+

Reabsorption of Filtered HCO3 −

HCO3 − is freely filtered at the glomerulus. The daily filtered load (plasma concentration × glomerular filtration rate) of HCO3 − is 4320 mEq (24 mEq/L × 180 L/day = 4320 mEq/day). Almost all of this HCO3 − is reabsorbed by the tubular segments of the nephron, and urinary excretion is negligible (< 3 mEq). HCO3 − reabsorption by various segments of the nephron can be summarized as follows:

Proximal tubule: 80%.

Loop of Henle: 10%.

Distal tubule: 6%.

Collecting duct: 4%.

Proximal Tubule

As stated earlier, the proximal tubule has a high capacity for HCO3 − reabsorption. This reabsorption occurs because of H+ secretion into the tubular lumen via the Na/H exchanger isoform 3 (NHE3), as shown in Fig. 2.1. Another transporter, called H-ATPase, is also responsible for transport of some protons into the lumen (see Fig. 2.1). The H+ combines with the filtered HCO3 − to form H2CO3. The apical membrane is rich in carbonic anhydrase IV, which splits H2CO3 into H2O and CO2. The CO2 diffuses into the cell where it is hydrated to form H2CO3 in the presence of carbonic anhydrase II. H2CO3 is dehydrated to form H+ and HCO3 −. H+ are subsequently secreted into the lumen via the Na/H exchanger and H-ATPase to start the cycle again.

../images/480755_1_En_2_Chapter/480755_1_En_2_Fig1_HTML.png

Fig. 2.1

Schematic representation of H+ secretion and HCO3 − reabsorption in the proximal tubule cell. CA II carbonic anhydrase II; CA IV carbonic anhydrase IV

HCO3 − exit across the basolateral membrane occurs via an Na/HCO3 cotransporter, in which two to three HCO3 − ions are transported for each Na+ ion. Another mechanism occurs through the Cl/HCO3 antiporter, in which one HCO3 − is exchanged for one Cl−. Both the energy and electrochemical gradient for H+ secretion and HCO3 − exit are provided by the Na/K-ATPase pump located in the basolateral membrane (not shown in Fig. 2.1).

Loop of Henle

Most HCO3 − reabsorption occurs in the thick ascending Henleʼs loop . The mechanisms for H+ secretion into the lumen and HCO3 − exit across the basolateral membrane appear to be similar to those described for the proximal tubule.

Distal Tubule

For the purpose of understanding HCO3 − reabsorption, it is helpful to divide the distal tubule into three distinct segments: (1) distal convoluted tubule, (2) connecting tubule, and (3) cortical collecting duct. Very little is known about H+ secretion and HCO3 − reabsorption in the distal convoluted tubule. This tubule consists of only one cell type, which contains H-ATPase in its apical membrane. The other two segments of the distal tubule consist of principal cells and intercalated cells. The latter cells are responsible for acid–base transport. The intercalated cells in the cortical collecting duct are of three types: type A, type B, and type C cells. Type A intercalated cells contain H-ATPase and K/H exchanger in the apical membrane. H+ that is formed inside the cell from dehydration of H2CO3 is secreted into the lumen by these transporters (Fig. 2.2). HCO3 − exit is facilitated by the Cl/HCO3 exchanger.

../images/480755_1_En_2_Chapter/480755_1_En_2_Fig2_HTML.png

Fig. 2.2

Cellular model for H+ secretion and HCO3 − reabsorption in type A intercalated cell of the cortical collecting duct. CA II carbonic anhydrase II; broken arrow represents a conductance channel

In contrast, type B intercalated cells secrete HCO3 − into the lumen (Fig. 2.3). These cells possess pendrin, a Cl/HCO3 exchanger, in the apical membrane and H-ATPase in the basolateral membrane. HCO3 − secretion is stimulated by alkali loading and inhibited by depletion of luminal Cl−.

../images/480755_1_En_2_Chapter/480755_1_En_2_Fig3_HTML.png

Fig. 2.3

Cellular model for HCO3 − secretion and H+ reabsorption in type B intercalated cell of the cortical collecting duct. CA II carbonic anhydrase II; broken arrow represents a conductance channel

Type C (formerly non A, non B) cells express H-ATPase and pendrin (Cl/HCO3 exchanger) in the apical membrane. These cells also participate in HCO3 − handling.

Collecting Duct

The collecting duct includes the cortical portion and outer and inner medullary portions. The cellular mechanisms of HCO3 − reabsorption in the cortical collecting duct have been discussed in the previous paragraph. The intercalated cells of the outer medullary and inner medullary collecting duct reabsorb HCO3 − and secrete protons similar to the type A cell mechanisms (see Fig. 2.2). The cells of outer medullary and inner medullary collecting duct do not secrete HCO3 − into the lumen.

Regulation of HCO3− Reabsorption

A number of factors influence HCO3− reabsorption both in the proximal tubule and distal segments of the nephron. These factors are summarized in Tables 2.2 and 2.3. Since the Na/H antiporter is the major mechanism for H+ secretion, any factor that enhances or inhibits this antiporter stimulates or decreases HCO3 − reabsorption.

Table 2.2

Factors affecting HCO3 − reabsorption (or H+ secretion) by the proximal tubule

↑ increase ↓ decrease

Table 2.3

Factors affecting HCO3− reabsorption by the distal tubule

↑ increase ↓ decrease

Aldosterone plays an important role in HCO3 − reabsorption and H+ secretion by the intercalated (type A) cell. It also stimulates Na+ reabsorption by the principal cell. As a result of this Na+ reabsorption, the lumen becomes electrically negative, which promotes H+ secretion. Aldosterone seems to have little effect on HCO3 − reabsorption in the proximal tubule.

Generation of New HCO3 − from Excretion of Titratable Acid

Generally, one HCO3 − ion is reclaimed for each H+ that is secreted into the lumen. This mechanism alone does not replenish the HCO3 − lost in buffering the daily acid load. Additional HCO3 − has to be generated. How does the new HCO3 − form? The answer is as follows: whenever an H+ is secreted into the tubule, it combines with the filtered HCO3 − or with two important urinary buffers, namely, HPO4 ²− and NH3, to form H2PO4 − and NH4 +, respectively. For each H+ that combines with HPO4 ²−, one new HCO3 − is formed