Metabolic Acidosis Caused by a Deficit of NaHCO 3

Introduction

Metabolic acidosis could be caused by the gain of acids or the loss of sodium bicarbonate (NaHCO ₃ ). In this chapter, we focus on metabolic acidosis caused by the loss of NaHCO ₃ . In this type of metabolic acidosis, there are almost no new anions present in plasma; therefore, the anion gap in plasma (P _{Anion gap} ) is not increased, hence the term “nonanion gap” metabolic acidosis. Because the fall in the concentration of bicarbonate ( ${\text{HC}{\text{O}}_3}^{-}$ ) anions in plasma ( ${\text{P}}_{{\text{HCO}}_3}$ ) is matched by a rise in the concentration of chloride (Cl ⁻ ) ions in plasma (P _Cl ), this type of metabolic acidosis is also called hyperchloremic metabolic acidosis (HCMA).

There are two major groups of causes for this type of metabolic acidosis: direct and indirect loss of NaHCO ₃ . The direct loss of NaHCO ₃ may be via the gastrointestinal (GI) tract (e.g., patients with diarrhea) or via the urine in patients in the initial phase of a disease process that causes proximal renal tubular acidosis (pRTA). The indirect loss of NaHCO ₃ may be due to a low rate of excretion of ammonium ( ${\text{N}{\text{H}}_4}^{+}$ ) ions that is insufficient to match the daily rate of production of sulfuric acid (H ₂ SO ₄ ) from the metabolism of sulfur-containing amino acids (e.g., in patients with chronic renal failure or distal renal tubular acidosis [dRTA]). Indirect loss of NaHCO ₃ may also be due to the overproduction of an acid (e.g., hippuric acid formed during the metabolism of toluene) with the excretion of its conjugate base (hippurate anions) in the urine at a rate that exceeds the rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions (see Chapter 3 ).

Assessment of the rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions in the urine reveals the cause of HCMA. The rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions in adults who consume a typical Western diet is 20 to 40 mmol/day. In a patient with chronic metabolic acidosis and normal renal function, the expected rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions is ∼200 mmol/day (∼200 mmol ${\text{N}{\text{H}}_4}^{+}$ ions/g creatinine or ∼20 mmol ${\text{N}{\text{H}}_4}^{+}$ ions/mmol creatinine). If the rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions is low enough that it is not sufficient to generate enough new ${\text{HC}{\text{O}}_3}^{-}$ ions to replace that lost while titrating the H ⁺ ion load produced from usual dietary intake of sulfur-containing amino acids, the diagnostic category is renal tubular acidosis (RTA). In contrast, if the rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions is high, the cause of HCMA is a loss of NaHCO ₃ via the GI tract or the overproduction of an acid with the excretion of its anion in the urine at a higher rate than the rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions.

Objectives

• ▪

  To explain the pathophysiology of the disorders that lead to metabolic acidosis caused by a deficit of NaHCO ₃ .

• ▪

  To provide an approach to the diagnosis of metabolic acidosis caused by a deficit of NaHCO ₃ .

• ▪

  To discuss issues related to therapy with NaHCO ₃ in these patients.

Part A

Overview

Pathogenesis of metabolic acidosis caused by NaHCO ₃ loss

There are two ways to create a deficit of NaHCO ₃ while preserving electroneutrality ( Figure 4-1 ). First, the direct loss of NaHCO ₃ occurs when both Na ⁺ and ${\text{HC}{\text{O}}_3}^{-}$ ions are lost via one route (e.g., via the GI tract or in the urine). Second, the indirect loss of NaHCO ₃ . This occurs in two steps as follows:

• 1.

  Addition of an acid: The H ⁺ ions of the added acid react with ${\text{HC}{\text{O}}_3}^{-}$ ions, resulting in the formation of CO ₂ + H ₂ O; this CO ₂ is exhaled via the lungs. At this point, there is a deficit of ${\text{HC}{\text{O}}_3}^{-}$ anions together with an equivalent gain of new anions in the ECF compartment.

• 2.

  Excretion of the anions with Na ⁺ ions: The second step is the excretion of the anions in the urine with a cation other than H ⁺ or ${\text{N}{\text{H}}_4}^{+}$ ions (i.e., with Na ⁺ and/or K ⁺ ions). The net effect of steps 1 and 2 is the loss of NaHCO ₃ from the body.

A list of causes for an indirect loss of NaHCO ₃ is provided in Table 4-1 . Based on the rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions, there are two subgroups of disorders that cause metabolic acidosis due to the indirect loss of NaHCO ₃ :

• 1.

  Acid overproduction with a higher rate of excretion of the new anions than the rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions: In this subgroup, the major lesion is an overproduction of acids with a high rate of excretion of their anions in the urine. Even though the rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions is high, the rate of excretion of the new anions exceeds that of ${\text{N}{\text{H}}_4}^{+}$ ions; hence, some of these anions are excreted in the urine with Na ⁺ or K ⁺ ions. These new anions are excreted at a high rate either because they are secreted by the proximal convoluted tubule (PCT) (e.g., hippurate ⁻ anions produced from the metabolism of toluene in a glue sniffer) or because they are filtered and an appreciable quantity is not reabsorbed in the PCT (e.g., ketoacid anions early in the course of diabetic ketoacidosis).

• 2.

  Normal acid production but a low rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions: In this subgroup of patients, the rate of production of acids is not increased. Rather, the major defect is a low rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions ( low is defined as a rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions that is insufficient to generate enough new ${\text{HC}{\text{O}}_3}^{-}$ ions to dispose of the daily acid load produced in metabolism of sulfur-containing amino acids). Patients in this subgroup are heterogeneous with regard to the pathophysiology of their disorder; nevertheless, they are grouped together under the diagnostic category of RTA.

Part B

Conditions That Cause a Deficit of NaHCO ₃

The initial steps to define why a patient has metabolic acidosis without the accumulation of new anions in plasma (i.e., HCMA) are outlined in Flow Chart 4-1 . Assessing the rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions in the urine is key to determine the pathophysiology of the metabolic acidosis in these patients.

Direct loss of NaHCO ₃

In these conditions, both Na ⁺ and ${\text{HC}{\text{O}}_3}^{-}$ ions are lost via the same route. NaHCO ₃ may be lost via the GI tract (e.g., in a patient with diarrhea) or via the urine (e.g., in a patient in the initial phase of a disease state causing pRTA).

Loss of NaHCO ₃ in the Gastrointestinal Tract

There are two major sites where ${\text{HC}{\text{O}}_3}^{-}$ ions are added to the lumen of the GI tract and thus possibly two sites for its loss.

Secretion of ${\text{HC}{\text{O}}_3}^{-}$ ions by the pancreas

NaHCO ₃ is secreted by the pancreas. This process is stimulated by secretin, which is released by special enterocytes located in the duodenum in response to the H ⁺ ion load from the stomach. HCl secretion in the stomach (∼100 mmol/day) adds ${\text{HC}{\text{O}}_3}^{-}$ ions to the body. Because somewhat in excess of 100 mmol of NaHCO ₃ are secreted by the pancreas to ensure neutralization of this H ⁺ ion load, a modest net deficit of NaHCO ₃ may occur if most of this pancreatic secretion is lost. Therefore, a mild degree of metabolic acidosis may develop in these patients unless the duration of these losses is prolonged and/or there is another disorder that diminishes the rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions in the urine. Loss of pancreatic secretions may occur due to tube drainage, pancreatic or upper intestinal fistulae, or vomiting if the pyloric sphincter is patent as is the case in children and some adults. Fluid rich in NaHCO ₃ may also be retained in the lumen of the intestine (e.g., due to ileus), and hence metabolic acidosis may develop.

Secretion of ${\text{HC}{\text{O}}_3}^{-}$ ions by the late small intestine and the colon

Two luminal transport mechanisms are involved in this process: an Na ⁺ /H ⁺ exchanger (NHE) and a Cl ⁻ / ${\text{HC}{\text{O}}_3}^{-}$ anion exchanger (AE) ( Figure 4-2 ). Whether the net result is a loss of NaHCO ₃ depends on the rate of delivery of Na ⁺ and Cl ⁻ ions and the maximum transport capacity of each exchanger:

• 1.

  Low delivery of Na ⁺ and Cl ⁻ ions to the colon: In this setting, virtually all of the Na ⁺ and Cl ⁻ ions are reabsorbed while the secreted H ⁺ and ${\text{HC}{\text{O}}_3}^{-}$ ions are converted to CO ₂ + H ₂ O. There is no loss of NaHCO ₃ in this setting.

• 2.

  Very large delivery of Na ⁺ and Cl ⁻ ions to the colon: This may result in a loss of NaHCO ₃ or HCl depending on the maximum transport capacity of NHE and AE.

  • a.

    Loss of NaCl and NaHCO ₃ : Normally, the maximum transport capacity of NHE is less than that of AE because the rate of flux via NHE will be limited by the rise in the concentration of H ⁺ ions in the luminal fluid in the colon. The net effect of a large delivery of Na ⁺ and Cl ⁻ ions is to reabsorb as much NaCl as possible, but as more of the luminal Cl ⁻ ions are exchanged for ${\text{HC}{\text{O}}_3}^{-}$ ions than Na ⁺ ions are exchanged for H ⁺ ions, there will be a large loss of NaHCO ₃ in patients with severe diarrhea ( Figure 4-3 ). The composition of diarrheal fluid in a patient with cholera is shown in the margin note.

    Composition of Diarrheal Fluid in a Patient with Severe Diarrhea

    ${\text{HC}{\text{O}}_3}^{-}$	40-45 mmol/L
    Cl −	110-115 mmol/L
    K +	15 mmol/L
    Na +	140 mmol/L

    

  • b.

    Loss of NaCl and HCl: Some patients with diarrhea may not have a loss of NaHCO ₃ in their diarrheal fluid, and therefore do not develop metabolic acidosis. In fact, these patients may lose HCl in their diarrheal fluid, and therefore may develop metabolic alkalosis. The underlying defect is a decrease in the transport capacity of the Cl ⁻ / ${\text{HC}{\text{O}}_3}^{-}$ anion exchanger in the colon ( Figure 4-4 ). This was noted in patients with certain colonic adenomas and adenocarcinomas (hence, this AE is given the name downregulated in adenoma [DRA]). A low transport capacity of AE may also be due to an inborn error (e.g., patients with congenital chloridorrhea) or in certain inflammatory disorders that involve the colon (e.g., some patients with ulcerative colitis). In this setting, there is primarily a loss of NaCl in the diarrheal fluid. There may be also a loss of H ⁺ and Cl ⁻ ions in diarrheal the fluid, which results in the addition of ${\text{HC}{\text{O}}_3}^{-}$ ions to the body and the development of metabolic alkalosis. Because the colonic NHE cannot raise the concentration of H ⁺ ions in luminal fluid to higher than 0.1 mmol/L (or lower the pH below 4), the presence of H ⁺ ion acceptors in the luminal fluid in the colon are required to have an appreciable loss of HCl. The H ⁺ ion acceptors in this setting may be histidines in the proteins of bacteria in the lumen of the colon.

    

Treatment

One must first identify and treat emergencies that may be present on admission (e.g., hemodynamic instability) as well as anticipate and avoid those that might develop with therapy (e.g., hypokalemia). The volume of diarrheal fluid can be diminished by enhancing the reabsorption of NaCl that is secreted in the intestinal tract. This can be achieved by giving oral rehydration therapy, an oral solution that contain equimolar amounts of glucose and NaCl ( Figure 4-5 ). The design of this oral rehydration fluid takes advantage of the stoichiometry of the sodium-linked glucose transporter 1 (SLGT1), which mediates the absorption of glucose from the lumen of the small intestine to decrease the volume of diarrheal fluid. The stoichiometry of SLGT1 is that 2 mmol of Na ⁺ ions are absorbed per each mmol of glucose. One liter of oral rehydration solution contains 100 mmol of each Na ⁺ ions, Cl ⁻ ions, and glucose. The absorption of 100 mmol of glucose on SLGT1 leads to the absorption of 200 mmol of Na ⁺ ions. The source of the other 100 mmol of Na ⁺ ions is Na ⁺ ions that are secreted in the diarrheal fluid. Although it is not exactly known, it is possible that the negative luminal voltage created by the electrogenic absorption of Na ⁺ via SLGT1 provides the driving force for the paracellular reabsorption of 200 mmol of Cl ⁻ ions. In more modern versions of this solution, a form of alkali is added (e.g., by replacing 25 to 50 mEq of Cl ⁻ ions with citrate anions).

Part C

Diseases with Low Rate of Excretion of ${\text{N}{\text{H}}_4}^{+}$ Ions

Patients with metabolic acidosis of renal origin have a low rate of net acid excretion. There are three groups of disorders in this diagnostic category: first, pRTA; second, dRTA; and third, disorders with a very low GFR. From a pathophysiologic perspective, the renal defect results in a low rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions. pRTA is also characterized by a decreased capacity to reabsorb NaHCO ₃ .

Proximal renal tubular acidosis

The pathophysiology of metabolic acidosis in patients with pRTA has two components:

• 1.

  Decreased reabsorption of NaHCO ₃ in PCT:

  Although renal ${\text{HC}{\text{O}}_3}^{-}$ wasting and bicarbonaturia are present at the onset of disease, this is not a feature in the chronic steady state. In more detail, a decrease in the rate of H ⁺ ion secretion in the PCT diminishes the reabsorption of ${\text{HC}{\text{O}}_3}^{-}$ ions in the initial phase of the disease. As a result, delivery of ${\text{HC}{\text{O}}_3}^{-}$ ions to distal nephron segments exceeds their capacity to secrete H ⁺ ions, and ${\text{HC}{\text{O}}_3}^{-}$ ions are lost in the urine. As the ${\text{P}}_{{\text{HCO}}_3}$ falls, the filtered load of ${\text{HC}{\text{O}}_3}^{-}$ ions decreases until a point is reached where the capacity for H ⁺ ion secretion in the PCT and the distal nephron is sufficient to reclaim all the filtered load of ${\text{HC}{\text{O}}_3}^{-}$ ions. Thus, there is no further bicarbonaturia. In fact, the urine pH is characteristically low in patients with isolated pRTA ( Table 4-2 ). Bicarbonaturia with a urine pH close to 7.0 may be noted, however, during times of the alkaline tide because of the secretion of HCl in the stomach, causing the addition of ${\text{HC}{\text{O}}_3}^{-}$ ions to the ECF compartment and a transient rise in ${\text{P}}_{{\text{HCO}}_3}$ .

  TABLE 4-2

  Renal Handling of ${\text{HC}{\text{O}}_3}^{-}$ Ions in Patients with Proximal Renal Tubular Acidosis

  In all of the examples, the GFR is 180 L/day. The normal filtered load of ${\text{HC}{\text{O}}_3}^{-}$ ions is 4500 mmol/day ( ${\text{P}}_{{\text{HCO}}_3}$ 25 mmol/L × GFR 180 L/day). The lesion in patients with pRTA is a reduced H + ion secretion in PCT, and so the proximal reabsorption of ${\text{HC}{\text{O}}_3}^{-}$ ions falls. Because the distal nephron has a much lower capacity for H + ion secretion, only 900 mmol of ${\text{HC}{\text{O}}_3}^{-}$ per day (in this example) will be reabsorbed into the distal nephron, all the extra ${\text{HC}{\text{O}}_3}^{-}$ ions that are delivered to the distal nephron in excess of this amount will be excreted in the urine. As the filtered load of ${\text{HC}{\text{O}}_3}^{-}$ ions declines to the limits of the tubular reabsorption of ${\text{HC}{\text{O}}_3}^{-}$ ions, all the filtered load of ${\text{HC}{\text{O}}_3}^{-}$ ions is reabsorbed, there is no bicarbonaturia, and the urine pH is low in steady state.

  State	Filtered ${\text{HC}{\text{O}}_3}^{-}$ (mmol/day)	Proximal ${\text{HC}{\text{O}}_3}^{-}$ Reabsorption (mmol/day)	Distal ${\text{HC}{\text{O}}_3}^{-}$ Delivery (mmol/day)	${\text{HC}{\text{O}}_3}^{-}$ Excretion (mmol/day)
  Normal	4500	3600	900	<5
  Low H + Ion Secretion in the PCT
  Initial phase	4500	2700	1800	900
  Steady state	3600	2700	900	<5

• 2.

  A low rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions:

  The rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions is low in patients with pRTA despite the presence of chronic metabolic acidemia. This low rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions is due to an alkaline proximal cell pH (discussed later) in patients with the isolated form of pRTA and to a generalized PCT cell dysfunction in patients with the Fanconi syndrome type of disorder. A low rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions compared to control subjects was demonstrated in a study of patients with the familial form of isolated pRTA after NH ₄ Cl loading. In other patients with pRTA, a low rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions can be deduced from the absence of bicarbonaturia in the steady state of the disease. If the kidneys were able to generate the expected close to 200 mmol/day of ${\text{HC}{\text{O}}_3}^{-}$ ions in these patients, the capacity for ${\text{HC}{\text{O}}_3}^{-}$ ion reabsorption would be exceeded, and this should have resulted in bicarbonaturia, which is not present in the chronic steady state of the disease.

Clinical Subtypes of Proximal RTA

Hereditary Isolated Proximal RTA

Hereditary isolated pRTA has been described as an autosomal dominant disease, an autosomal recessive disease, or in some cases as a sporadic disease. Patients with isolated pRTA have both reduced capacity to reabsorb ${\text{HC}{\text{O}}_3}^{-}$ ions in their PCT and a low rate of excretion of ${\text{N}{\text{H}}_4}^{+}$ ions (see margin note). One possible explanation for this combination of defects is a more alkaline pH in PCT cells. This hypothesis could also explain the high rate of excretion of citrate observed in these patients. In more detail, the rate of excretion of citrate provides a “window” on the pH in PCT cells. An acidified PCT cell pH is associated with an enhanced reabsorption of citrate. Therefore, patients with metabolic acidemia have a very low rate of excretion of citrate. The sole exception to the previous statement is in patients with isolated pRTA who, despite metabolic acidemia, have a high rate of excretion of citrate. This may suggest that these patients have an alkaline PCT cell pH.

Hereditary Isolated Proximal RTA

• These findings are from studies in a single family from Costa Rica with hereditary autosomal dominant isolated pRTA.

• The molecular mechanism involved has not been identified.

Possible molecular lesions

There are three possible targets for a molecular lesion to cause isolated pRTA: the electrogenic sodium bicarbonate cotransporter 1 (NBCe1) at the basolateral membrane, the intracellular carbonic anhydrase II enzyme (CA _II ), and the sodium-hydrogen exchanger-3 (NHE-3) in the luminal membrane of the PCT cells. Only two of these three possible lesions have been demonstrated to be associated with pRTA ( Figure 4-6 ).

NBCe1 defect

${\text{HC}{\text{O}}_3}^{-}$ ions reabsorbed in the PCT exits the cell as an ion complex ( ${\text{Na}{\left[\text{HC}{\text{O}}_3\right]}_3}^{2-}$ ) which contains one Na ⁺ ion and three ${\text{HC}{\text{O}}_3}^{-}$ ions (or one ${\text{HC}{\text{O}}_3}^{-}$ ion and one ${\text{C}{\text{O}}_3}^{2-}$ ion), via NBCe1. Mutations in the gene encoding NBCe1 have been reported in children with the autosomal dominant hereditary isolated pRTA associated with ocular abnormalities. These mutations result in either a decreased maximum velocity (V _max ) or a lower affinity for ${\text{Na}{\left(\text{HC}{\text{O}}_3\right)}_3}^{2-}$ ion complex (higher K _m ) such that a higher concentration of ${\text{HC}{\text{O}}_3}^{-}$ ions (a more alkaline pH) in cells of the PCT are needed to export all ${\text{HC}{\text{O}}_3}^{-}$ ions that are reabsorbed.

Carbonic anhydrase II defect

H ⁺ ions that are secreted in the PCT are derived from the dissociation of H ₂ O in PCT cells. The OH ⁻ ions formed in PCT cells are removed as ${\text{HC}{\text{O}}_3}^{-}$ ions in a reaction that is catalyzed by the enzyme CA _II . Mutations involving CA _II lead to a more alkaline PCT cell pH because the OH ⁻ ion is a stronger base than the ${\text{HC}{\text{O}}_3}^{-}$ ion. Because CA _II is also present in cells of the late distal nephron segments, these patients develop a clinical picture of both pRTA and dRTA. CA _II is also involved in bone resorption. Hence, these patients may have dense bones (osteopetrosis) that are fragile, and therefore are at an and increased risk for bone fractures. They may also have cranial nerve compression due to excess bone, which can cause blindness, deafness, and/or facial paralysis.

NHE-3 defect

Although in theory a molecular defect in the NHE-3 could cause pRTA, mutations in the gene encoding this transporter have not been reported in patients with hereditary isolated pRTA. Perhaps the reason is that NHE-3 mediates the reabsorption of an amount of ${\text{HC}{\text{O}}_3}^{-}$ ions (∼3600 mmol/day), which is close to tenfold higher than the content of ${\text{HC}{\text{O}}_3}^{-}$ ions in the ECF compartment (∼375 mmol). Therefore, even a relatively moderate defect in its transport activity would lead to a profound degree of acidemia. In fact, when NHE-3 was knocked out in mice, virtually all of them died at an early age.

Distal Renal Tubular Acidosis