REGULATION OF RENAL ACID SECRETION

A variety of physiological and pathophysiological stimuli can modulate renal H

+
secretion as well as NH
3
synthesis. Most of these factors produce coordinated changes in apical and basolateral acid-base
transport, as well as in NH
3
production.
Respiratory Acidosis Stimulates Renal H
+
Secretion
page 856
page 857
Table 38-5. THE EFFECTS OF CHRONIC ACIDOSIS ON PROXIMAL-TUBULE
FUNCTION
pH
o

pH
i

Protein kinase
C
Tyrosine kinase
pathways
Immediate early
genes

NHE3 NBC Na/Citrate cotransporter* Ammoniagenic

enzymes
* Enhanced Na citrate reabsorption is a defense against acidosis by conversion of citrate to
. The price paid is enhanced stone formation because luminal citrate reduces stones. Indeed, acidotic patients tend to get
calcium-containing kidney stones.
NBC, electrogenic Na/HCO
3
cotransporter; NH
3
, Na-H exchanger 3.
The four fundamental pH disturbances are respiratory acidosis and alkalosis, and metabolic acidosis and
alkalosis (see Fig. 27-11). In each case, the initial and almost instantaneous line of defense is the action of
buffers-both in the extracellular and intracellular compartments-to minimize the magnitude of the pH
changes (p. 634). However, restoring the pH to a value as close to "normal" as possible requires slower,
compensatory responses from the lungs or kidneys.
In respiratory acidosis, where the primary disturbance is an increase in arterial PCO
2
, the compensatory
response is an increase in renal H
+
secretion, which translates to increased production of new
Via
excretion. The opposite occurs in respiratory alkalosis. These changes in H
+
secretion tend to correct
the distorted
ratios that occur in primary respiratory acid-base derangements.
Respiratory acidosis stimulates H
+
secretion in at least two ways. First, an acute elevated PCO
2
directly
stimulates proximal-tubule cells to secrete H
+
, as shown by applying solutions in which it is possible to
change PCO
2
without altering basolateral pH or
. However, isolated changes in basolateral pH (i.e., without an accompanying change in
or PCO
2
), which also produce large changes in intracellular pH (pH
i
), have a negligible effect in the
short term. Thus, proximal-tubule cells seem to have a mechanism for sensing CO
2
. Second, chronic
respiratory acidosis leads to adaptive responses that upregulate acid-base transporters. For example,
activities of the apical Na-H exchanger and basolateral Na/HCO
3
cotransporter are elevated in membrane
vesicles that have been isolated from animals who were previously exposed to high PCO
2
levels. These
adaptive changes persist for some time, even after PCO
2
levels have returned to normal. Such a sustained
increase in transporter activity may help explain why, once H
+
secretion has adapted, reversing the original
respiratory acidosis may produce a rebound metabolic alkalosis. The Use of Out-of-Equilibrium
Solutions to Probe the Chemosensitivity of the Proximal Tubule
Metabolic Acidosis Stimulates Both Proximal H
+
Secretion and NH
3
Production
The first response to metabolic acidosis is increased alveolar ventilation, which blows off CO
2
(p. 723) and
thus corrects the distorted
ratio in a primary metabolic acidosis. The kidneys can also participate in the compensatory
response, assuming, of course, that the acidosis is not the consequence of renal pathology. An acute fall in
basolateral
stimulates proximal H
+
secretion, probably by enhancing
efflux from the proximal-tubule cell via the Na/HCO
3
cotransporter and also by reducing
backleak via tight junctions from interstitial fluid to tubule lumen.
In chronic metabolic acidosis, the adaptive responses of the proximal tubule are probably similar to those
outlined above for chronic respiratory acidosis. These include up-regulation of apical Na-H exchange and
electrogenic H
+
pumping, as well as basolateral Na/HCO
3
cotransport (Table 38-5). For example, when one
isolates brush border membranes from the renal cortex of animals who have been made chronically
acidotic, NHE3 activity is significantly increased. Therefore, the proximal-tubule cell adapts to chronic
acidosis, possibly by increasing the number of transporters. The up-regulation appears to involve activation
of PKC, a serine/threonine kinase (p. 102). In proximal-tubule cells, chronic intracellular acidosis also
stimulates a member of the Src family of receptor-associated tyrosine kinases (p. 111). Indeed, herbimycin,
a tyrosine-kinase inhibitor, blocks upregulation of NHE3 in chronic acidosis. Endothelin appears to be
essential for the upregulation of NHE3 in chronic metabolic acidosis.
The parallel activation of apical and basolateral transporters minimizes changes in pH
i
, while increasing
trans-epithelial
reabsorption. An important and still unresolved question concerns how tubule cells continue to
respond to a chronic acidosis even after the coordinated stimulation of apical and basolateral acid-base
transporters has returned pH
i
to normal.
In addition to the increased H
+
secretion, the other ingredient needed to produce new
is enhanced production. Together, the two increase
excretion. Indeed, the excretion of
into the urine increases markedly as a result of the adaptive response to chronic metabolic acidosis
(Fig. 38-7A). Thus, the ability to increase NH
3
synthesis is an important element in the kidney's defense
against acidotic challenges. Indeed, as a chronic metabolic acidosis develops, the kidneys progressively
excrete a larger fraction of urinary H
+
as
. As a consequence, the excretion of titratable acid becomes a progressively smaller fraction of total
acid excretion.
page 857
page 858
Figure 38-7 (A, Data from RF Pitts: Renal excretion of acid. Fed Proc 7:418-426, 1948. B, Data from Alpern RJ, Cogan MG, Rector FC: Effects
of extracellular fluid volume and plasma bicarbonate concentration on proximal acidification in the rat. J Clin Invest 71:736-746, 1983.)
The adaptive stimulation of NH
3
synthesis, which occurs in response to a fall in pH
i
, involves a stimulation
of both glutaminase and phosphoenolpyruvate carboxykinase (PEPCK). The stimulation of mitochondrial
glutaminase increases the conversion of glutamine to
and glutamate (see Fig. 38-5A). The stimulation of PEPCK enhances gluconeogenesis and thus the
conversion of -ketoglutarate (the product of glutamate deamination) to glucose.
Metabolic Alkalosis Reduces Proximal H
+
and, in the Cortical Collecting Tubule, May Even Provoke
Secretion
We can illustrate the response of the proximal tubule to metabolic alkalosis by considering an artificial
experimental maneuver. The upper curve in Figure 38-7B summarizes the results of experiments in which
investigators perfused single proximal tubules with solutions having progressively higher
concentrations, while maintaining
in the peritubular capillaries at a physiologic level. The rate of H
+
increases steeply up to a luminal
of approximately 45 mM, but levels off thereafter. The reason H
+
secretion increases with increased
luminal
is that the incremental
represents an additional buffer that helps keep luminal pH relatively alkaline in the vicinity of the apical
H
+
transporters.
The lower curve in Figure 38-7B shows the results from experiments that were similar, except that the
peritubular blood had a higher-than-physiological
; that is, there was a metabolic alkalosis on the basolateral side of the cells.
reabsorption is uniformly lower during alkalosis: for a given luminal
, the tubules secrete less H
+
. The likely explanation is that the increase in blood
(1) depresses the rate at which the Na/HCO
3
cotransporter moves
from cell to blood and (2) increases paracellular
backleak from interstitium to lumen.
So far, we have discussed the effect of metabolic alkalosis on H
+
secretion by the proximal tubule. In the
initial and cortical collecting tubule, metabolic alkalosis can cause the tubule to switch from secreting H
+
to
secreting
into the lumen. The intercalated cells in the ICT and CCT secrete H
+
, using an apical H
+
pump and
a basolateral Cl-HCO
3
exchanger (see Fig. 38-4D). Metabolic alkalosis, over a period of days, shifts the
intercalated-cell population, increasing the proportion of intercalated cells at the expense of cells.
Because cells have the opposite apical-versus-basolateral distribution of H
+
and
transporters, they secrete
into the lumen. Thus, the CCT now switches from net
reabsorption to net
secretion. Increased activity of intercalated cells may correct metabolic alkalosis by accelerating
Cl-HCO
3
exchange.
secretion can also exchange. be stimulated by increased luminal delivery of Cl
-
to the exchanger.
By Increasing
Delivery to the Tubules, an Increased Glomerular Filtration Rate Enhances
Reabsorption (Glomerulotubular Balance for
)
page 858
page 859
Increasing either luminal flow or luminal
significantly enhances
reabsorption, probably by raising effective
(and thus pH) in the microenvironment of H
+
transporters in the brush-border microvilli. Because a
high luminal pH stimulates the Na-H exchangers and H
+
pumps located in the microvilli of the proximal
tubule, increased flow translates to enhanced H
+
secretion. This flow-dependence, an example of
glomerulotubular (G-T) balance (p. 783), is important because it minimizes
loss, and thus the development of a metabolic acidosis, when GFR increases. Conversely, this G-T
balance of
reabsorption also prevents metabolic alkalosis when GFR decreases. The flow dependence of
reabsorption also accounts for the stimulation of H
+
transport that occurs after uninephrectomy (i.e.,
surgical removal of one kidney), when GFR in the remnant kidney rises in response to the loss of renal
tissue. Flow Dependence of HCO
-
3
Reabsorption
Volume Contraction Stimulates Renal H
+
Secretion by Increasing Levels of Angiotensin II, Aldosterone,
and Sympathetic Activity
As discussed in Chapter 39, a decrease in effective circulating volume stimulates Na
+
reabsorption by four
parallel pathways (p. 864), including activation of the renin-angiotensin-aldosterone axis (and thus an
increase in ANG II levels) and stimulation of renal sympathetic nerves (and thus the release of
norepinephrine). Both ANG II and norepinephrine stimulate Na-H exchange in the proximal tubule. Because
the proximal tubule couples Na
+
and H
+
transport, volume contraction not only increases Na
+
reabsorption
but H
+
secretion as well. Volume expansion has the opposite effect. On a longer time scale, volume
depletion also increases aldosterone levels, enhancing H
+
secretion in cortical and medullary collecting
ducts (see later). Thus, the regulation of effective circulating volume takes precedence over the regulation
of plasma pH.
Decreased dietary Na
+
intake increases apical Na-H exchange activity, even if one assesses the activity in
brush-border membrane vesicles removed from the animal. A high-Na
+
diet has the opposite effect.
Hypokalemia Increases Renal H
+
Secretion
As discussed on page 816, acid-base disturbances can cause changes in K
+
homeostasis. The opposite is
also true. Because a side effect of K
+
depletion is increased renal H
+
secretion, K
+
depletion is frequently
associated with metabolic alkalosis. Several lines of evidence indicate that, in the proximal tubule,
hypokalemia leads to a marked increase in apical Na-H exchange and basolateral Na/HCO
3
cotransport.
As in other cells, the pH of tubule cells falls during K
+
depletion (p. 652). The resulting chronic cell
acidification may lead to adaptive responses that activate Na-H exchange and electrogenic Na/HCO
3
cotransport, presumably by the same mechanisms that stimulate H
+
secretion in chronic acidosis (Table
38-5). In the proximal tubule, K
+
depletion also markedly increases NH
3
synthesis and
excretion, thus increasing urinary H
+
excretion as
. Finally, K
+
depletion stimulates apical K-H exchange in intercalated cells of the ICT and CCT (p.
824), enhancing H
+
secretion as a side effect of K
+
retention.
Just as hypokalemia can cause metabolic alkalosis, hyperkalemia is often associated with metabolic
acidosis. An important contributory factor may be reduced
excretion, perhaps because of lower synthesis in proximal-tubule cells and reduced
accumulation in the medullary interstitium. High luminal [K
+
] in the TAL may compromise
reabsorption because the K
+
competes with
for uptake by apical Na/K/Cl cotransporters and K
+
channels. Reduced
levels in the medullary interstitium provide less NH
3
for diffusion into the medullary collecting duct,
leading to less
excretion and thus to acidosis.
Both Glucocorticoids and Mineralocorticoids Stimulate Acid Secretion
Prolonged adrenal insufficiency (p. 786) leads to acid retention and, potentially, to life-threatening metabolic
acidosis. Both glucocorticoids and mineralocorticoids stimulate H
+
secretion, but at different sites along the
nephron.
Glucocorticoids (e.g., cortisol) enhance the activity of Na-H exchange in the proximal tubule and thus
stimulate H
+
secretion. In addition, they inhibit phosphate reabsorption, raising the luminal availability of
buffer anions for titration by secreted H
+
.
Mineralocorticoids (e.g., aldosterone) stimulate H
+
secretion by three coordinated mechanisms-one direct
and two indirect. First, mineralocorticoids directly stimulate H
+
secretion in the collecting tubules and ducts
by increasing the activity of the apical electrogenic H
+
pump and basolateral Cl-HCO
3
exchanger (see Fig.
38-4D). Second, mineralocorticoids indirectly stimulate H
+
secretion by enhancing Na
+
reabsorption in the
collecting ducts (p. 786), thus increasing the lumen-negative voltage. This increased negativity may
stimulate the apical electrogenic H
+
pump in intercalated cells to secrete acid. Third,
mineralocorticoids-particularly when administered for longer periods of time and accompanied by high Na
+
intake-cause K
+
depletion, indirectly increasing H
+
secretion (see previous section).
Diuretics Can Increase or Decrease H
+
Secretion, Depending on How They Affect Transepithelial Voltage,
Extracellular Fluid Volume, and Plasma [K
+
]
The effects of diuretics on renal H
+
secretion vary substantially from one diuretic to another, depending
both on the site and mechanism of action. From the point of view of acid-base balance, diuretics fall broadly
into two groups, those that promote the excretion of a relatively alkaline urine and those that have the
opposite effect. The Effect of Diuretics on Renal H
+
Excretion
To the first group belong carbonic-anhydrase inhibitors and K
+
-sparing diuretics. The CA inhibitors lead to
excretion of an alkaline urine by inhibiting H
+
secretion. Their greatest effect is in the proximal tubule, but
they also inhibit H
+
secretion by the TAL and DCT. K
+
-sparing diuretics-including amiloride, triamterene,
and the spironolactones-also alkalinize the urine. Both amiloride and triamterene inhibit the apical epithelial
Na
+
channels (ENaC) (p. 779) in the collecting tubules and ducts, thus hyperpolarizing the apical
membrane and making it more difficult for the electrogenic H
+
pump to secrete H
+
ions into the lumen.
Spironolactones decrease H
+
secretion by interfering with the action of aldosterone.
page 859
page 860
The second group of diuretics-which tend to increase urinary acid excretion and often induce
alkalosis-includes loop diuretics such as furosemide (which inhibits the apical Na/K/Cl cotransporter in the
TAL) and thiazide diuretics such as chlorthiazide (which inhibits the apical Na/Cl cotransporter in the
DCT). These diuretics act by three mechanisms. First, all cause some degree of volume contraction, and
thus lead to increased levels of ANG II and aldosterone (p. 866), both of which enhance H
+
secretion.
Second, these diuretics enhance Na
+
delivery to the collecting tubules and ducts, thus increasing the
elec-trogenic uptake of Na
+
, thus increasing the lumen-negative voltage, and thus enhancing H
+
secretion.
Third, this group of diuretics causes K
+
wasting; as discussed earlier, K
+
depletion enhances H
+
secretion.
References
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