Metabolic Acidosis

Harold M. Szerlip
Metabolic acidosis describes a process in which nonvolatile
acids accumulate in the body. For practical purposes, this
can result from either the addition of protons or the loss
of base. The consequence of this process is a decline in the
major extracellular buffer, bicarbonate, and, if unopposed, a
decrease in extracellular pH. Depending on the existence and
the magnitude of other acid-base disturbances, however, the
extracellular pH may be low, normal, or even high. Normal
blood pH is between 7.36 and 7.44, corresponding to a
hydrogen ion concentration of 44 to 36 nmol/L.
Because the body tightly defends against changes in pH, a
decreased pH sensitizes both peripheral and central chemoreceptors,
which triggers an increase in minute ventilation.
This compensatory respiratory alkalosis helps offset a marked
fall in pH. Because increased ventilation is a compensatory
mechanism stimulated by the acidemia, it never returns the pH
to normal. The expected partial pressure of carbon dioxide
(pCO2) for any given degree of metabolic acidosis can be
estimated by adding 15 back to the bicarbonate,
pCO2 15 HCO3
or by using Winters’ formula: pCO2 = (1.5 × [HCO3]) + 8 } 2.
OVERVIEW OF ACID-BASE BALANCE
To maintain extracellular pH within the normal range, the
daily production of acid must be excreted from the body
(Fig. 13.1). The vast majority of acid production results from
the metabolism of dietary carbohydrates and fats. Complete
oxidation of these metabolic substrates produces CO2 and
water. The 15,000 mmoles of CO2 produced daily are efficiently
exhaled by the lungs and are therefore known as “volatile
acid.” As long as ventilatory function remains normal, this
volatile acid does not contribute to changes in acid-base
balance. Nonvolatile or fixed acids are produced by the
metabolism of sulfate-containing and phosphate-containing
amino acids. In addition, incomplete oxidation of fats and
carbohydrates results in the production of small quantities
of lactate and other organic anions, which when excreted in
the urine represent a loss of base. Individuals consuming a
typical meat-based diet produce approximately 1 mmol/kg/
day of hydrogen ions. Fecal excretion of a small amount of
base also contributes to total daily acid production.
The kidney is responsible not only for the excretion of
the daily production of fixed acid but also for the reclamation
of the filtered bicarbonate. Bicarbonate reclamation occurs
predominantly in the proximal tubule, mainly through the
Na+-H+ exchanger. Active transporters in the distal tubule
secrete hydrogen ion against a concentration gradient.
Although urinary pH can fall to as low as 4.5, if there were
no urinary buffers, this would account for very little acid
excretion. For example, to excrete 100 mmoles of H+ into
unbuffered urine at a minimum urine pH of 4.5 ([H+] =
32 mmol/L) would require a daily urine volume of 3000 L.
Fortunately, urinary phosphate and creatinine help buffer
these protons, allowing the kidney to excrete approximately
40% to 50% of the daily fixed acid load as titratable acid
(TA), so called because they are quantitated by titrating the
urine pH back to that of plasma, 7.4. In addition to TA, renal
excretion of acid is supported by ammoniagenesis. NH3 is
generated in the proximal tubule by the deamidation of
glutamine to glutamate, which is subsequently deaminated
to yield α-ketoglutarate. The enzymes responsible for these
reactions are upregulated by acidosis and hypokalemia.
Hyperkalemia, on the other hand, reduces ammoniagenesis.
NH3 builds up in the renal interstitium and passively diffuses
into the tubule lumen along the length of the collecting
duct, where it is trapped by H+ as ammonium (NH4
).
Under conditions of increased acid production, the normal
kidney can increase acid excretion primarily by augmenting
NH3 production. Renal acid excretion varies directly with
the rate of acid production. Net renal acid excretion (NAE)
is equal to the sum of TA and NH4
, minus any secreted
HCO3
−[NAE = (TA + NH4
) – HCO3
]. Thus the etiology of
a metabolic acidosis can be divided into four broad categories:
(1) overproduction of fixed acids, (2) increased extrarenal
loss of base, (3) decrease in the kidney’s ability to secrete
hydrogen ions, and (4) inability of the kidney to reclaim the
filtered bicarbonate (Fig. 13.2).
EVALUATION OF URINARY ACIDIFICATION
The cause of metabolic acidosis often is evident from the
clinical situation. However, because the kidney is responsible
for both the reclamation of filtered HCO3
−and the excretion
of the daily production of fixed acid, to evaluate a metabolic
acidosis it may be necessary to assess whether the kidney is
appropriately able to reabsorb HCO3
−, secrete H+ against
a gradient, and excrete NH4
(Table 13.1). The simplest
test is to measure the urine pH. Although urine pH can
be measured using a dipstick, the lack of precision of this
CHAPTER 13 — METABOLIC ACIDOSIS 131
technique prevents it from being useful in making clinical
decisions. Although it has been suggested that urine be collected
under oil and the pH measured, using a pH electrode
to prevent the loss of CO2, in fact when the urine pH is less
than 6.0, the amount of dissolved CO2 is minimal and the
use of oil is unnecessary. Under conditions of acid loading,
urine pH should be below 5.5. A pH of higher than 5.5 usually
reflects impaired distal hydrogen ion secretion. Measuring
the pH after challenging the patient with the loop diuretic
furosemide will increase the sensitivity of this test by providing
Na+ to the distal tubule for reabsorption. The reabsorption of
Na+ creates a negative electrical potential in the lumen and
enhances H+ secretion. It is important, however, to rule out
urinary infections with urea-splitting organisms, which will
increase pH. An elevated urine pH may also be misleading in
conditions associated with volume depletion and hypokalemia,
as can occur in diarrhea. In contradistinction to furosemide,
volume depletion with decreased sodium delivery to the distal
tubule impairs distal H+ secretion. Furthermore, hypokalemia,
by enhancing ammoniagenesis, raises the urine pH.
Because renal excretion of NH4
accounts for the majority of
acid excretion, measurement of urine NH4
provides important
information. Urinary NH4
excretion can be decreased by
a variety of mechanisms, including a primary decrease in
ammoniagenesis by the proximal tubule, as seen in chronic
kidney disease (CKD), or decreased trapping in the distal
tubule either secondary to decreased H+ secretion or an
increased delivery of HCO3
−, which will preferentially buffer
H+, making it unavailable to form NH4
. Although direct
measurement of NH4
is becoming more readily available
in clinical laboratories and is the gold standard, many
laboratories still do not perform this assay. An estimate of
NH4
excretion, however, is easily obtained by calculating the
urine anion gap (UAG) or urine osmole gap. If, as is usual,
the anion balancing the charge of the NH4
is Cl−, the UAG
[(Na+ + K+) − Cl−] should be negative because the chloride
is greater than the sum of Na+ and K+ (Fig. 13.3). Although
the measurement of the UAG in conditions of acid loading
is often reflective of NH4
excretion, the presence of anions
other than Cl− (such as keto anions or hippurate) makes it
a less reliable assessment of NH4
than the urine osmole gap
(see Fig. 13.3). The urine osmole gap is calculated as follows:
[measured urine osmolality − calculated urine osmolality],
where calculated urine osmolality is [2(Na+ + K+) + (urea
nitrogen/2.8) + (glucose/18)]. The osmole gap is made
up primarily of NH4
salts. Thus half of the gap represents
NH4
. An osmole gap of greater than 100 mmol/L signifies
normal NH4
excretion.
Another test of distal H+ ion secretory ability is measurement
of urine pCO2 during bicarbonate loading. Distal
delivery of HCO3
−in the presence of normal H+ secretory
capacity results in elevated pCO2 in the urine. When there
is a secretory defect, urine pCO2 does not increase. In this
case, accurate measurement of urine pCO2 requires that
the urine be collected under oil to prevent the loss of CO2
into the air.