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Acid-Base Balance and Regulation of PH: Chapter Objectives
Acid-Base Balance and Regulation of PH: Chapter Objectives
BALANCE AND
REGULATION OF pH
Chapter objectives
After studying this chapter you should be able to:
e Describe the mechanism for acid transport in the different nephron segments.
f Recognize the clinical and biochemical features of metabolic acidosis, list some
causes and give an approach to the differential diagnosis.
g Recognize metabolic alkalosis, list some causes, and explain the pathophysiology
of this disturbance during prolonged vomiting.
SYSTEMS OF THE BODY
4
Introduction Acid–base balance and regulation of
ACID–BASE BALANCE AND REGULATION OF pH
pH box 1
Just as the kidney is a critical organ in defending
the normal set points for extracellular fluid (ECF) A case of acidosis
volume, osmolality and potassium concentration, it
also plays a central role in the homeostasis of the Mrs Mary Loy is a 48-year-old woman of Chinese
plasma pH. While chemical buffering mechanisms background who has been sent by her family doctor
and respiratory elimination of carbon dioxide are to the Emergency Department because of his concern
important in immediate responses to disturbances in about her clinical condition and some biochemical
acid–base balance, it falls to the kidney to make long- results.
term adjustments in the rate of acid excretion which She had been complaining for some weeks of
allows the external balance with respect to hydrogen increasing lethargy, an extensive rash and ‘heavy
ion concentration to be maintained. This chapter will breathing’. She had been receiving treatment for
focus on the mechanisms whereby the kidney achieves 4 years for systemic lupus erythematosus (SLE), a
this role, and the origin of some disturbances of this multiorgan autoimmune condition for which a con-
system in disease. sultant rheumatologist had prescribed prednisone.
See box 1. However, Mrs Loy confessed to having discontinued
The clue in this case that there is a disturbance of this medication some 10 months earlier because she
acid–base metabolism is that the bicarbonate concen- was unhappy about its side effects.
tration, representing the base component of the prin- On examination she was febrile, unwell and had an
cipal physiological buffer system, is greatly reduced erythematous rash on her face and limbs. Her blood
below the normal range. This is consistent with acid pressure was 110/80, pulse rate 100 beats/min and
accumulation in the ECF, for which we must explore respiratory rate 20/min, the breathing being deep
both the cause and the consequences. and sighing. The referring doctor’s letter indicated
The key parameter involved in acid–base regulation that he had obtained a urinalysis result that morning
is the concentration of H+ in the ECF. The physiological showing: pH 7, blood +++ and protein ++.
set point for this parameter is 40 nmol/L, usually He had also obtained plasma biochemistry the pre-
expressed (using the negative base 10 logarithm) as the vious day, the results of which are as follows:
pH, which is normally 7.40. So important is homeosta- Sodium 135 mmol/L
sis of this parameter to the normal operation of meta- *Potassium 3.1 mmol/L
bolism and cellular function that pH is tightly regulated *Chloride 113 mmol/L
in the range 7.38–7.42, although a somewhat wider *Bicarbonate 13 mmol/L
range is compatible with life (7.0–7.8). Urea 8.0 mmol/L
Two forms of acid are generated as a result of normal Creatinine 0.09 mmol/L.
metabolic processes. Oxidative metabolism produces a
large amount of CO2 daily, and this so-called ‘volatile The family doctor is particularly concerned about the
acid’ is excreted through the lungs. Carbon dioxide low bicarbonate, which he interprets as a sign of acid
effectively acts as an acid in body fluids because of the build-up, and seeks full evaluation of her clinical and
following reactions: metabolic problem.
c.a.
(*Results outside the normal range; see Appendix.)
CO2 + H2O ∫ H2CO3 ∫ H+ + HCO3-
sodium. This process accounts for reabsorption of drogen phosphate (H2PO4-), which is excreted in the
some 85% of filtered bicarbonate, and operates at urine with sodium. This reaction has limited capacity
a high capacity but generates a low gradient of (removing up to 30 mmol of H+/day) and tends to
hydrogen ion concentration across the epithelium, proceed as the urine pH falls along the distal nephron
with the luminal pH falling only slightly from 7.4 at segments, typically from 7 down to 6 and below, the
the glomerulus to around 7.0 at the end of the proxi-
mal tubule. This is both because of the presence of
carbonic anhydrase in the luminal compartment and Late distal/collecting duct
because the epithelium is ‘leaky’ to hydrogen ions. Acid-secreting cell
Lumen Blood
secretion
NH3
synthesis
acid excretion
as NH4+
H+ Brainstem
accumulation pH pCO2
(hours)
blunts
plasma H+
HCO3- secretion
plasma
HCO3-
raised
(days) towards
normal
NH3
synthesis
acid excretion
as NH4+
Fig. 4.5
Mechanisms of renal and respiratory compensation for acid–base disturbances. The immediate action of
physicochemical buffers is omitted for clarity.
than would otherwise have occurred. A variety of extra- is not fully normalized, and never ‘overshoots’, as a
cellular and intracellular proteins provide a further result of respiratory compensation alone.
reserve of H+ binding sites, and a limited amount of
tissue phosphate also contributes some buffer capacity. Renal response
These reactions are essentially complete within a few Steady state correction of the acid–base disturbance
minutes of addition of acid to the body fluids, though requires the development over several days of an
further buffering occurs in bone and other tissues over increased capacity by the kidney to excrete the meta-
the ensuing hours and days. bolic acid load. This involves reabsorption of all filtered
bicarbonate, maximum titration of filtered buffers with
Respiratory response secreted H+, and increased intrarenal synthesis of
Despite initial buffering, the pH of the plasma will still ammonia, which combines with secreted hydrogen
fall somewhat during acidosis, and this acts as a potent ions in the luminal compartment and appears in the
stimulus to increase the ventilation rate via the activa- urine as large quantities of ammonium. The urine pH
tion of chemoreceptors within the brainstem (ventral falls to minimum levels (around 4.5) and the plasma
medulla) which respond to a fall in pH of the cere- bicarbonate, lowered initially by the reaction with
brospinal fluid. Clinically this manifests as a deep, added acid and subsequently by the hyperventilation
rapid breathing pattern (Kussmaul respiration). Over response, is elevated back up into the normal range. The
a matter of minutes to hours, this response drives the net result is a restoration of plasma pH to normal.
CO2 below normal, and thus serves to blunt the fall in
ECF pH by shifting the carbonic acid equilibrium reac- Before leaving the subject of renal acid secretion, a
tion (see Fig. 4.1). This respiratory response provides number of factors which have been identified as regu-
a medium-term compensation for the acidosis pro- lators of this process should be listed. The principal
duced by the metabolic disturbance. Note that while factors causing an increase in H+ secretion by the
54 the resulting plasma pH is brought up towards 7.40, it nephron include:
THE RENAL SYSTEM
4
Acid–base balance and regulation of Patterns of metabolic acidosis
‘Anion gap’=15
- 25
HCO3
Na+
145 +
K+ Cl- 105
+ - + -
H Cl gain H A gain
-
HCO3 loss
Metabolic
acidosis
Na+ Na+
145 + 145 +
K+ Cl- 115 K+ Cl- 105
Pattern A Pattern B
Normal anion gap Increased anion gap
Fig. 4.6
Patterns of metabolic acidosis. All figures are in mmol/L. AG, anion gap.
Table 4.3
Acid–base balance and regulation of Some causes of renal tubular acidosis (RTA)
pH box 3
Proximal RTA
The diagnosis Congenital (Fanconi syndrome, cystinosis, Wilson’s disease)
Paraproteinaemia (e.g. myeloma)
Mrs Loy’s electrolyte profile was examined and an Hyperparathyroidism
anion gap of 12 mmol/L was calculated (see original Drugs (carbonic anhydrase inhibitors)
biochemistry data). There was no history of gastroin- Distal RTA (‘classic’ type)
testinal disturbance and the urine pH was noted to Congenital
be inappropriately high at 7. An interim diagnosis of Hyperglobulinaemia
renal tubular acidosis was made. Autoimmune connective tissue diseases (e.g. systemic lupus
erythematosus)
Further investigation, directed toward defining the
Toxins and drugs (toluene, lithium, amphotericin)
immunological activity of her underlying connective
tissue disease, revealed that the levels of antinuclear Hyperkalaemic distal RTA
Hypoaldosteronism
antibodies (including antibodies to double-stranded Obstructive nephropathy
DNA) were elevated, and serum complement levels Renal transplant rejection
were low, consistent with activated SLE. In addition, Drugs (amiloride, spironolactone)
the urine contained many red cells and red cell casts
(see Chapter 7), and a large amount of protein. Renal
biopsy confirmed severe diffuse inflammation affect-
through later nephron segments. Plasma
ing the glomeruli as well as the tubulointerstitium.
bicarbonate falls, blood pH falls, and bicarbonate
A diagnosis of reactivated SLE was made, with the
appears in the urine.
complications of diffuse lupus nephritis (see Chapter
• In distal RTA, the defect is in the late distal tubule
7) and renal tubular acidosis. The distal tubular dys-
and collecting duct segments, where acid secretion
function in this setting reflects a disruptive effect of
is mediated by an H+-ATPase. In the classic form
the interstitial inflammatory changes on the trans-
of this disorder, the hydrogen pump itself is
port properties of the tubules.
probably defective. In other forms, such as that
induced by amphotericin (an antifungal antibiotic),
the impairment of net acid secretion results from
back-leak of hydrogen ions across an epithelium
• In proximal renal tubular acidosis (RTA), the
which is made abnormally permeable to these
defect lies in the mechanism normally present
ions.
within the proximal tubular epithelium for
reabsorbing bicarbonate (refer to Fig. 4.2). Thus, Some causes of proximal and distal RTA are given
either because of a specific defect in one of the in Table 4.3. Both proximal and distal RTA may be
components of the cellular acid secretory inherited as a primary defect, but a number of other
mechanism in this segment or because of non- conditions may produce secondary RTA in either
specific damage to, or malfunction of, the proximal segment. Notably, an alteration in proximal tubular
tubular epithelium as a whole, filtered bicarbonate function can be induced by high paraprotein levels
is incompletely reabsorbed. This results in a large as in myeloma, or by hyperparathyroidism, or by
flow of bicarbonate, together with sodium, the carbonic anhydrase inhibitor acetazolamide. Distal 57
SYSTEMS OF THE BODY
4
RTA, on the other hand, can be caused by conditions retention stabilizes, albeit at a reduced plasma bicar-
ACID–BASE BALANCE AND REGULATION OF pH
Lumen Blood
Principal cell
3Na+
Na+ ATP
Site of defect in
hyperkalaemic 2K+
distal RTA
K+
-
Cl
Intercalated cell
-
HCO3
Site of defect H+ -
in ‘classical’ ATP Cl
distal RTA
Fig. 4.7
Site of defect in two variants of
58 distal renal tubular acidosis (RTA).
THE RENAL SYSTEM
4
operation of the principal cell type in this tubular
Disturbances of acid–base balance:
Metabolic alkalosis
Acid–base balance and regulation of In this disorder there is a primary increase in the
pH box 4 plasma bicarbonate concentration and the plasma pH.
The causes fall into two groups according to whether
Treatment and outcome
there is associated contraction of the ECF volume
Mrs Loy’s treatment focused on the control of her or not.
underlying connective tissue disease. Immunosup- Hypovolaemic metabolic alkalosis is the commonest
pression using prednisone and cyclophosphamide was pattern, and includes disorders such as vomiting
initiated with a view to reducing the activity of her and gastric suction, in which acid-rich gastric
SLE. The metabolic acidosis and hypokalaemia were juices are lost from the body. Metabolic alkalosis
corrected initially with infusions, and later with associated with volume contraction also occurs during
oral supplements, of alkaline salts of sodium and treatment with most diuretics (other than carbonic
potassium. anhydrase inhibitors and potassium-sparing drugs).
Over the ensuing weeks her condition improved Here there is increased acid loss into the urine related
dramatically, with the fevers and rash subsiding, to the diuretic action on the tubules. The alkalosis
urinary protein and red cell excretion reduced, and associated with volume contraction is perpetuated by
plasma electrolyte profile reverted towards normal. secondary renal responses, described in more detail
Within several weeks it was possible to discontinue below.
her electrolyte and buffer therapy, and ongoing Normovolaemic (or hypervolaemic) metabolic alkalosis
management was directed towards long-term stabi- occurs when the primary disturbance provokes both
lization of the connective tissue disease. bicarbonate retention and a degree of volume expan-
sion. This most commonly occurs in corticosteroid 59
SYSTEMS OF THE BODY
4
excess states such as primary hyperaldosteronism alkali in the urine. Replacement of potassium helps
ACID–BASE BALANCE AND REGULATION OF pH
(Conn’s syndrome), Cushing’s syndrome and related correct the hypokalaemia and its consequences in the
disorders. Occasionally, overuse of antacid salts can kidney.
produce a similar pattern. The non-hypovolaemic forms of metabolic alkalo-
The homeostatic response to metabolic alkalosis sis, by way of contrast, are resistant to treatment
involves initial buffering of the rise in plasma bicar- with sodium chloride, but can usually be managed
bonate by titration of extracellular and intracellular by cessation of alkali therapy or correction of min-
buffers, including plasma proteins. Soon afterwards, eralocorticoid excess. The latter may involve either
the increased pH acts to inhibit ventilation through the adrenal gland surgery or blockade of mineralo-
medullary chemoreceptors, such that the pCO2 starts corticoid effect in the kidney by treatment with
to rise. Since, however, this is ultimately associated spironolactone.
with an unacceptable degree of hypoxia, the extent to
which this form of compensation occurs is limited,
such that the maximum pCO2 attained is rarely more
than 55 mmHg.
Vomiting
In the absence of counterbalancing stimuli, the
expected renal response to sustained metabolic alka-
losis would be to decrease tubular acid secretion,
Gastric loss of
inhibit bicarbonate reabsorption and excrete the ex-
cess bicarbonate into the urine. However, in the com-
monest form of metabolic alkalosis, that caused H+ (Cl-) Na+(Cl-)/H2O K+ (Cl-)
by sustained vomiting, this response is distorted by
other changes associated with the loss of gastric
fluid. As shown in Fig. 4.8, the loss of H+ initiates Hypovolaemia
the alkalosis (‘generation’ phase), which is actually
(Kidney)
worsened by the losses of sodium, water and potas- proximal aldosterone Hypokalaemia
sium (‘maintenance’ phase). The sodium losses are Na+HCO3-
associated with hypovolaemia, which triggers both reabsorption
proximal bicarbonate reabsorption and aldosterone distal NH3
H+ secretion synthesis
release, which stimulates distal acid secretion, thereby
aggravating the systemic alkalosis. Furthermore, the H+ excretion
hypokalaemia resulting from potassium loss (more
through the kidney than from gastric fluid) also stim-
Maintenance
ulates distal acid secretion and tubular ammonia
synthesis (see earlier), both of which enhance acid Generation
Metabolic
excretion and maintain the alkalosis. The net result alkalosis
is an inappropriately acid urine and a failure of the
kidney to effect long-term correction of the systemic Fig. 4.8
pH disturbance. Vomiting: generation and maintenance of metabolic
The cornerstone of management in hypovolaemic alkalosis. Note that the gastric loss of H+ is primarily
metabolic alkalosis states, exemplified by vomiting, responsible for generating the systemic alkalosis, while
is to provide adequate volume replacement as sodium the other mechanisms shown act through the kidney to
chloride (isotonic saline infusions), which switches maintain the alkalosis as long as sodium and potassium
off the volume-conserving mechanisms mentioned losses are uncorrected. Chloride is the deficient anion
above and allows the kidney to excrete the excess accompanying all cations shown.
Table 4.4
Summary of ‘simple’ acid–base disturbances
Self-assessment case study d What is the likely cause of the disturbance in this case?
e What would you expect the urine pH to be?
A consultation is requested on an 81-year-old man who has
been admitted to the hospital with an acute myocardial f What are the principles of treatment?
infarction (heart attack). There has been significant damage to g What would the effect of a bicarbonate infusion be on his
the left ventricle such that cardiac output is markedly reduced. plasma potassium concentration?
Furthermore, on day 5 after admission his course is
complicated by the development of acute ischaemia in the left Answers see page 146
leg, attributed to occlusion of a major leg artery following
embolization of a thrombus from the left ventricular cavity.
The patient’s plasma electrolyte results are as follows:
Self-assessment questions
Sodium 135 mmol/L
*Potassium 5.2 mmol/L b What would the effect on systemic acid–base balance be if a
Chloride 97 mmol/L patient were given long-term treatment with a carbonic
*Bicarbonate 14 mmol/L anhydrase inhibitor such as acetazolamide?
*Urea 14.0 mmol/L
c Where in the nephron is the steepest gradient of pH
*Creatinine 0.14 mmol/L.
between the plasma and the luminal fluid?
(*Values outside normal range; see Appendix.)
d Name three changes in the plasma which stimulate an
Arterial blood gas analysis reveal the following: pH 7.33, pCO2
increase in hydrogen ion secretion by the nephron.
29 mmHg, pO2 (breathing room air) 58 mmHg.
After studying this chapter you should be able to answer e Give three causes of a metabolic acidosis with a normal
the following questions: anion gap.
b What is the overall pattern of acid–base disturbance in this d Name three factors which perpetuate the systemic alkalosis
patient? which follows prolonged vomiting.
c What is the anion gap in this patient? Answers see page 146
61