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Renal Physiology

CJASN ePress. Published on November 23, 2015 as doi: 10.2215/CJN.07400715

Acid-Base Homeostasis
L. Lee Hamm,*† Nazih Nakhoul,*† and Kathleen S. Hering-Smith*†

Abstract
Acid-base homeostasis and pH regulation are critical for both normal physiology and cell metabolism and
function. The importance of this regulation is evidenced by a variety of physiologic derangements that occur when
plasma pH is either high or low. The kidneys have the predominant role in regulating the systemic bicarbonate
concentration and hence, the metabolic component of acid-base balance. This function of the kidneys has two
*Department of
components: reabsorption of virtually all of the filtered HCO32 and production of new bicarbonate to replace that Medicine, Section of
consumed by normal or pathologic acids. This production or generation of new HCO32 is done by net acid Nephrology, Tulane
excretion. Under normal conditions, approximately one-third to one-half of net acid excretion by the kidneys is in Hypertension and
the form of titratable acid. The other one-half to two-thirds is the excretion of ammonium. The capacity to Renal Center of
excrete ammonium under conditions of acid loads is quantitatively much greater than the capacity to increase Excellence, Tulane
University School of
titratable acid. Multiple, often redundant pathways and processes exist to regulate these renal functions. Medicine, New
Derangements in acid-base homeostasis, however, are common in clinical medicine and can often be related to Orleans, Louisiana;
the systems involved in acid-base transport in the kidneys. and †Medicine
Clin J Am Soc Nephrol 10: ccc–ccc, 2015. doi: 10.2215/CJN.07400715 Service, Southeast
Louisiana Veterans
Health Care System,
New Orleans,
Acid-base homeostasis and pH regulation are critical CO2 1 H2 O↔H2 CO3 ↔H 1 1 HCO32 (2) Louisiana
for both normal physiology and cell metabolism and
function. Normally, systemic acid-base balance is well This buffer system is physiologically most important Correspondence:
because of its quantitative capacity to buffer acid or al- Dr. L. Lee Hamm,
regulated with arterial pH between 7.36 and 7.44; Tulane University, 131
intracellular pH is usually approximately 7.2. For kali loads and because of the capacity for independent
South Robertson, Suite
instance, chronic metabolic acidosis can be associated regulation of HCO32 and PCO2 by the kidneys and 1500, 15th Floor, New
with decreased bone density, nephrolithiasis, muscle lungs, respectively. In fact, this latter aspect of in- Orleans, LA 70112.
wasting, and progression of CKD (1–3). On a cellular dependent regulation is the most powerful aspect of Email: Lhamm@
this system. Although the lungs and kidneys can tulane.edu
level, many essential cellular processes, metabolic en-
zymes, and transmembrane transport processes are compensate for disorders of the other, normal homeo-
highly pH sensitive. Although this review will address stasis requires that both CO2 and HCO32 be normal.
systemic pH regulation and the role of the kidneys, Disorders of CO2 are usually referred to as respiratory
individual cells also have a variety of mechanisms to disorders, and disorders of HCO32 or fixed acids are
regulate their intracellular pH (4). Overall concepts referred to as metabolic disorders.
will be emphasized rather than specific pathways or Arterial CO2 is predominantly regulated by alveolar
processes, which are well covered elsewhere; refer- ventilation after production in peripheral tissues; CO2
ences are selective. is often referred to as a gaseous acid, because its addi-
tion to aqueous solutions produces carbonic acid,
which then releases H1 and HCO32 (Equation 2 driven
Basic Concepts to the right). Plasma HCO32 is predominantly regu-
Intracellular and extracellular buffers are the most lated by renal acid-base handling, and it will be dis-
immediate mechanism of defense against changes in cussed extensively below. The kidneys reabsorb,
systemic pH. Bone and proteins constitute a sub- produce, and in some circumstances, excrete HCO32.
stantial proportion of these buffers. However, the Plasma HCO32 is normally consumed daily by dietary
most important buffer system is the HCO32 /CO2 acids and metabolic acids. As expressed by Equation 1,
buffer system. The Henderson–Hasselbach equation raising HCO 3 2 or lowering P CO2 will raise sys-
(Equation 1) describes the relationship of pH, bicar- temic pH, and lowering HCO32 or raising PCO2 will
bonate (HCO32), and PCO2: lower pH.
In physiologic systems, the addition of an acid and
HCO32 the loss of alkali are essentially equivalent; for instance,
pH56:1 1 log (1)
0:03 3 PCO2 as obvious in Equation 2, loss of HCO32 will pull the
equation to the right, producing more H1. A frequent
where HCO32 is in milliequivalents per liter and PCO2 example of this is the loss of HCO32 with diarrhea or
is in millimeters of mercury. Equation 2 represents the proximal renal tubular acidosis. Conversely, the phys-
reaction (water [H2O]): iologic addition of alkali and the loss of acid are

www.cjasn.org Vol 10 December, 2015 Copyright © 2015 by the American Society of Nephrology 1
2 Clinical Journal of the American Society of Nephrology

essentially equivalent. Therefore, the excretion of acid by Renal Control of Plasma HCO32
the kidneys is equivalent to the production of base or The kidneys have the predominant role of regulating the
HCO32; this point becomes important in considering below systemic HCO32 concentration and hence, the metabolic
how the kidneys produce more HCO32. component of acid-base balance. This function of the kid-
Typical high–animal protein Western diets and endoge- neys has two components: reabsorption of virtually all of
nous metabolism produce acid, typically on the order of the filtered HCO32 and production of new HCO32 to re-
1 mEq/kg body wt per day or approximately 70 mEq/d for a place that consumed by normal or pathologic acids. This
70-kg person. Phosphoric acid and sulfuric acid are signifi- production or generation of new HCO32 is done by net
cant products of this normal metabolism of dietary nutri- acid excretion. In other words, the kidneys make new
ents, such as proteins and phospholipids. To maintain HCO32 by excreting acid.
acid-base homeostasis, these nonvolatile acids must be ex- Because HCO32 is freely filtered at the glomerulus, approxi-
creted by the kidney. Other nonvolatile acids, such as keto- mately 4.5 mol HCO32 is normally filtered per day (HCO32
acids and lactic acids, are produced in pathologic concentration of 25 mM/L 3GFR of 0.120 L/min 31440
conditions. Nonvolatile acid loads (or loss of HCO32 , min/d). Virtually all of this filtered HCO32 is reabsorbed,
which is an equivalent process) in excess of the excretory with the urine normally essentially free of HCO32. Seventy
capacity of the kidneys cause metabolic acidosis. Of note, to eighty percent of this filtered HCO32 is reabsorbed in the
vegetarian diets with high fruit and vegetable content are proximal tubule; the rest is reabsorbed along more distal
not acid producing and may produce a net alkali load (5); segments of the nephron (Figure 1).
this may be an important consideration in the progression In addition to reabsorption of filtered HCO32, the kidneys
or treatment of CKD (6). Although the kidneys normally also produce additional HCO32 beyond that which has been
control plasma HCO32, a few other factors have been con- filtered at the glomerulus. This process occurs by the excre-
sidered. Endogenous acid production may be regulated, at tion of acid into urine. (As indicated above, the excretion of
least under certain circumstances (7); for instance, lactic acid acid is equivalent to the production of alkali.) The net acid
and ketoacid production are decreased by a low pH. Also, excretion of the kidneys is quantitatively equivalent to the
hepatic production of HCO32 in the metabolism of proteins amount of HCO32 generation by the kidneys. Generation of
and amino acids is altered by systemic acid-base balance. new HCO3 2 by the kidneys is usually approximately
Therefore, a role for hepatic contribution to the control of 1 mEq/kg body wt per day (or about 70 mEq/d) and re-
plasma HCO32 has been hypothesized (8). places that HCO32 that has been consumed by usual en-
dogenous acid production (also about 70 mEq/d) as
discussed above. During additional acid loads and in cer-
Respiratory Control of PCO2 tain pathologic conditions, the kidneys increase the amount
Alveolar ventilation normally eliminates approximately of acid excretion and the resulting new HCO32 generation.
15 mol CO2 per day produced from normal cellular oxida- Net acid excretion by the kidneys occurs by two processes:
tive metabolism and maintains arterial P CO2 around the excretion of titratable acid and the excretion of ammo-
40 mmHg. Normally, with increases (or decreases) in CO2 nium (NH41). Titratable acid refers to the excretion of pro-
production, alveolar ventilation increases (or decreases) to tons with urinary buffers. The capacity of the nephron to
maintain PCO2 and keep pH constant. Alveolar ventilation excrete acid as free protons is limited as illustrated by the
is controlled by chemoreceptor cells located in the medulla fact that the concentration of protons (H1), even at a urine
oblongata (and to a lesser extent, those in the carotid bodies), pH 4.5, is ,0.1 mEq. However, the availability of urine
which are sensitive to pH and PCO2 (4). Chemoreceptors re-
spond to a decrease in cerebral interstitial pH by increasing
ventilation and hence, lowering PCO2. Therefore, small in-
creases in plasma CO2, which decrease pH, will result in
stimulation of ventilation, which will normally rapidly re-
turn PCO2 toward normal. Metabolic acidosis and the result-
ing acidemia will also result in an increase in ventilation
(and lowering of PCO2) in response to decreases in cerebral
interstitial pH. However, in contrast to the rapid response to
changes in CO2, the response to nonvolatile acids or a
change in plasma HCO32 is slower, because the central che-
moreceptors are relatively insulated by the blood-brain bar-
rier. Hence, acute changes in plasma HCO32 have a slower
effect on cerebral interstitial pH and hence, stimulation of
central chemoreceptors. This likely accounts for the 12- to
24-hour delay in the maximal ventilatory response to meta-
bolic acid-base disturbances. The maximal ventilation re-
sponse cannot usually reduce PCO2 ,10–12 mmHg (9–12).
Decreases in ventilation may be limited because of a variety Figure 1. | Relative HCO32 transport along the nephron. Most of the
of clinical circumstances, such as lung disease, fluid over- filtered HCO32 is reabsorbed in the proximal tubule. Virtually no
load, and central nervous system derangements. Also, de- HCO32 remains in the final urine. CCD, cortical collecting duct; DT,
creases in PO2 may limit the extent to which decreased distal convoluted tubule; IMCD, inner medullary collecting duct; TAL,
ventilation can raise PCO2. thick ascending limb.
Clin J Am Soc Nephrol 10: ccc–ccc, December, 2015 Acid-Base Homeostasis, Hamm et al. 3

buffers (chiefly phosphate) results in the excretion of acid


coupled to these urine buffers (13). Under normal condi-
tions, approximately one-third to one-half of net acid excre-
tion by the kidneys is in the form of titratable acid. The other
one-half to two-thirds is the excretion of NH41. The mecha-
nism whereby the excretion of NH41 results in net acid
excretion will be discussed below. The capacity to excrete
NH41 under conditions of acid loads is quantitatively much
greater than the capacity to increase titratable acid (Figure 2)
(14,15). Net acid excretion in the urine is, therefore, calcu-
lated as

net acid excretion 5 titratable  acid


1 ammonium2 urinary  HCO32 (3)
Figure 3. | Schematic representation of HCO32 reabsorption in the
Loss of alkali in the urine in the form of HCO32 decreases proximal tubule. Most H1 secretion occurs through Na1/H1 ex-
the amount of net acid excretion or new HCO32 generation. change, although a component of an H1 pump is also present. Car-
Loss of organic anions, such as citrate, in the urine represents bonic anhydrase (CA), both intracellular and luminal, is important for
the loss of potential alkali or HCO32. However, in humans, the HCO32 reabsorption. HCO32 exits the cell by NBCe1-A.
loss of these organic anions is not usually quantitatively sig-
nificant in whole–body acid-base balance (15).
for the remaining portion of proximal tubule H1 secretion
and HCO32 reabsorption (17–19). This H1-ATPase shares
Proximal Tubule HCO32 Reabsorption most subunits with the distal tubule H1-ATPase described
The proximal tubule reabsorbs at least 70%–80% of the below.
approximately 4500 mEq/d filtered HCO32 . The proxi- In the lumen of the proximal tubule, the secreted H1
mal tubule, therefore, has a high capacity for HCO32 re- reacts with luminal HCO32 to generate CO2 and H2O,
absorption. The mechanisms of this reabsorption are which for the purposes here, can be considered to be freely
illustrated in Figure 3. Most (probably .70%) of this permeable across the proximal tubule and reabsorbed.
HCO32 reabsorption occurs by proton secretion at the This reaction in the lumen (Equation 2 going from right
apical membrane by sodium-hydrogen exchanger NHE3 to left) is relatively slow unless catalyzed, which occurs
(16) (Figure 3). This protein exchanges one Na1 ion for one normally, by carbonic anhydrase (CA; in this case, membrane-
H 1 ion, driven by the lumen to cell Na 1 gradient bound CAIV tethered in the lumen). There are multiple
(approximately 140 mEq/L in the lumen and 15–20 mEq/L isoforms of CA, but membrane-bound CAIV and cytosolic
in the cell). The low intracellular Na1 is maintained by CAII are most important in renal acid-base transport
the basolateral Na1 /K1 -ATPase. An apical H1 -ATPase (20,21). Mutations in CAII are known to cause a form of
and possibly, NHE8 under some circumstances account mixed proximal and distal renal tubular acidosis with
osteopetrosis (22).
The source of the H1 in the cells is the generation of H1
and HCO32 from CO2 and H2O (Equation 2) catalyzed in
the cell by intracellular CA, predominantly cytosolic CAII.
The HCO32 generated within the proximal tubule cell by
apical H1 secretion exits across the basolateral membrane.
Most of this HCO32 exit occurs by sodium HCO32 co-
transport, NBCe1-A, or SLC4A4 (23). The stoichiometry
and transported ionic species have been active areas of
investigation, but studies suggest that 3 HCO32 Eq or
1 HCO32 Eq and 1 CO322 Eq are transported with each
Na1; this electrogenic stoichiometry results in Na1 and
HCO32 being driven out of the cell by the cell–negative
membrane voltage. Mutations in this (NBC-e1) protein
cause proximal renal tubular acidosis (24). Chloride-
bicarbonate exchange may also be present on the basolateral
membrane of the proximal tubule but is not the main mech-
anism of HCO32 reabsorption.
The proximal tubule is a leaky epithelium on the basis of
its particular tight junction proteins and therefore, unable
to generate large transepithelial solute or electrical gradi-
ents; the minimal luminal pH and HCO32 obtained at the
end of the proximal tubule are approximately pH 6.5–6.8
Figure 2. | Relative urinary titratable acid and ammonia in adults on and 5 mM, respectively. The inability of the proximal tu-
a control or acid loading diet (with NH4Cl). Reference 15. bule to lower pH further may also result from the
4 Clinical Journal of the American Society of Nephrology

dependence on the Na1 gradient (140:15–20) driving the unchanged. As mentioned above and discussed more below,
H1 (pH) gradient. In the late proximal tubule, ongoing re- clinically, this relates to the association of metabolic alkalosis
absorption of the low concentrations of luminal HCO32 with both volume contraction and edematous states (be-
may be countered and balanced by passive backleak of cause these have decreased effective arterial volume). Vol-
plasma or peritubular HCO32 into the lumen; however, ume expansion can be associated with decreased plasma
continued Na1/H1 exchange activity will result in contin- HCO32 and metabolic acidosis, usually mild. An important
ued Na1 reabsorption. additional component of the change in net HCO32 reab-
sorption with volume overload is an increased backleak of
HCO32 into the tubule lumen. In contrast to the effects of
Regulation of HCO32 Reabsorption in the Proximal volume, increasing delivery of HCO32 to the proximal tu-
Tubule bule with constant extracellular volume results in a pro-
A number of processes regulate proximal tubule HCO32 portional increase in HCO32 reabsorption; this can be
reabsorption both acutely and chronically. Many of these conceptualized as an increase in delivery to a reabsorptive
regulatory processes function to maintain acid-base ho- system that is not saturated (i.e., below the transport Km,
meostasis and are seemingly quite redundant; this is true the Michaelis–Menten constant [the substrate concentration
in both the proximal and distal nephron segments. How- that gives half-maximal velocity of an enzymatic reaction and
ever, other processes overlap with volume or sodium reg- also, is used to model transport kinetics]).
ulatory processes, and the acid-base effects seem A variety of hormones, some as above, affect proximal
secondary and at times, dysfunctional for pH per se; for HCO32 reabsorption (32,33). Some of these hormones act
instance, during metabolic alkalosis induced by vomiting on a short-term basis (response in minutes to hours), and
and volume depletion, various hormones are activated others act over longer periods (days). On an acute basis, for
(catecholamines, angiotensin II, and aldosterone) that restore instance, adrenergic agonists and angiotensin II stimulate
volume status but secondarily maintain high plasma HCO32 HCO32 reabsorption (32). Parathyroid hormone acting
and alkalemia. through cAMP inhibits but hypercalcemia stimulates proxi-
To maintain or restore acid-base balance, the proximal mal HCO32 reabsorption. With these hormones and others,
tubule increases HCO32 reabsorption during acidemia or many studies have addressed the specific processes and sig-
acid loads and decreases HCO32 reabsorption during al- nal transduction events (32). With chronic acid loads or ac-
kalemia or alkali loads (such that HCO32 might be ex- idosis, intrarenal endothelin-1 acting through the endothelin
creted into the urine). Because this has been recently B receptor has been identified as a crucial element in the
reviewed in this series (18), only a few comments will be upregulation of Na1/H1 exchange (26,27). Glucocorticoids
made. The signals for these changes are often thought to also are important in the development of proximal HCO32
be pH per se, either intracellular or extracellular. A variety transport and may be important in the chronic response to
of pH sensors have also been proposed (25), most notably acidosis (34). In clinical circumstances, various regulatory
including nonreceptor tyrosine kinase Pyk2, endothelin B factors may interact and be simultaneously operative. The
receptor (activated by endogenous renal endothelin) net effect of these combined influences would vary depend-
(26,27), and CO2 activation of ErbB1/2, ERK, and the api- ing on the exact circumstance. For instance, in metabolic
cal angiotensin I receptor (28). More directly, decreased alkalosis, volume contraction (and the associated hormonal
intracellular pH will increase the availability of protons changes and frequent fall in GFR) and high filtered loads of
for H 1 secretion and also, allosterically enhance the HCO32 increase proximal tubule HCO32 reabsorption,
Na1/H1 exchanger (29). In addition to allosteric modula- whereas increases in peritubular HCO32 and increased in-
tion of acid-base transporters, acute acidosis will cause in- tracellular pH may be inhibiting HCO32 reabsorption—the
sertion of additional transport proteins into the apical net effect is maintenance of metabolic alkalosis until the
membrane, probably through the mechanisms immediately volume status is corrected.
above; this has been best studied for NHE3. Chronic aci- Despite the regulation mentioned above, changes in
dosis induces the production of additional transport pro- proximal HCO32 reabsorption may not be directly reflec-
teins by increased transcription and production of mRNA; ted in changes in whole–kidney net acid excretion or
this is activated through a variety of signal transduction urinary HCO 3 2 excretion, because additional HCO 3 2
processes that are still being actively investigated. Both api- reabsorption and acid secretion occur in the distal nephron.
cal transport proteins (e.g., NHE3) and basolateral trans- Also, because virtually all of filtered HCO32 is normally
porters (e.g., NBCe1-A) are often activated and increased in reabsorbed by the kidneys, increases in HCO32 reabsorption
abundance in parallel, although the specifics may vary (30). per se cannot compensate for increased systemic acid loads
Chronic potassium depletion also increases H1 secretion, This compensation can only occur with increased acid excre-
probably in response to changes in intracellular pH (31). In tion as titratable acids or NH41.
fact, hypokalemia has many effects on the kidney that par-
allel chronic acidosis, including effects on NH41 excretion
discussed below. Distal Tubule Acidification
Extracellular fluid volume status is also an important Several segments after the proximal tubule contribute
determinant of proximal HCO32 reabsorption. Decreasing substantially to acid-base homeostasis. First, the thick
extracellular causes increased reabsorption of not only so- ascending limb (TAL) reabsorbs a significant amount of
dium but also, HCO32 , both in large part through in- HCO32, approximately 15% of the filtered load, predomi-
creased Na-H exchange. Increases in volume status inhibit nantly through an apical Na1/H1 exchanger (35). TAL
reabsorption of sodium and HCO32, other factors being acid-base transport is regulated by a variety of factors
Clin J Am Soc Nephrol 10: ccc–ccc, December, 2015 Acid-Base Homeostasis, Hamm et al. 5

(e.g., Toll-like receptors, dietary salt, aldosterone, angio- remains under investigation. These have been recently re-
tensin II, etc. [36–38]), but the integrated role of the thick viewed in this series (39) (Figure 4).
limb acid-base transport in various acid-base disorders has Conceptually, H1 secretion in the type A ICs will result
not been well clarified. in HCO32 reabsorption in the presence of luminal HCO32
Beyond the TAL, the distal tubule compared with the but will acidify the urine and generate new HCO32 in the
proximal tubule has a limited capacity to secrete H1 and absence of luminal HCO32 (i.e., if virtually all of the fil-
thereby, reabsorb HCO32. During inhibition of proximal tu- tered HCO32 has been reabsorbed upstream). The mech-
bule HCO32 reabsorption, increased distal delivery of anism of this H1 secretion involves primarily an apical
HCO32 can overwhelm this limited reabsorptive capacity. H1-ATPase as illustrated in Figure 4. The apical H1-ATPase
However, the collecting tubule is able to generate a large is an electrogenic active pump (vacuolar ATPase) able to
transepithelial pH gradient (urine pH ,5 with blood pH secrete H1 down to a urine pH of approximately 4.5. This
approximately 7.4). This large pH gradient is achievable is a multisubunit ATPase resembling that in intracellular
because of the primary active pumps responsible for distal organelles. The subunits are in two domains: a V0 trans-
nephron H1 secretion (discussed below) and because of membrane domain and a V1 cytosolic domain. Mutations
the relative impermeability of the distal tubule to ions (i.e., a in certain subunits are a known cause of distal renal tubu-
tight epithelial membrane). The large pH gradient ensures lar acidosis (40). Regulation of this pump is primarily by
the generation of titratable acid and the entrapment of NH41. recycling between subapical vesicles and the plasma mem-
The limitation in HCO32 reabsorption is likely, in part, brane involving the actin cytoskeleton and microtubules
caused by the absence of luminal CA discussed below, but (41). Regulation may also be accomplished, in certain sit-
there may be other factors as well, such as a limited number uations by assembly or disassembly of the two domains
of H1 pumps. and phosphorylation of subunits. H1 secretion also oc-
The distal tubule beyond the TAL consists of several curs through another set of pump(s): apical H 1 /K 1
distinct morphologic and functional segments, including -ATPases. H1 /K1 -ATPases in the collecting duct include
the distal convoluted tubule, the connecting segment, and both the gastric form of H1 /K1 -ATPase and the colonic
several distinct collecting duct segments, each with several form of H1 /K1 -ATPase (42). On the basis of inhibitor
cell types. Although several of these cell types can secrete studies, there may also be a third type of H 1 /
H1, the CA–containing (and mitochondrial–rich) interca- K1 -ATPase in the collecting duct (43,44). These trans-
lated cells (ICs) are chiefly responsible for acid-base trans- porters likely contribute to urine acidification under nor-
port. There are at least three types of ICs: type A or a ICs, mal conditions but particularly during states of
which secrete H1; type B or b ICs, which secrete HCO32; potassium depletion (42,44).
and non–A, non–B ICs, with a range of function that Conceptually, HCO32 reabsorption (or new HCO32
generation) as in the proximal tubule is a two-part process:
secretion of H1 into the lumen and HCO32 exit from the
cell across the basolateral membrane. Therefore, to com-
plete the process of HCO32 reabsorption or new HCO32
generation, HCO32 produced in the cell from CO2 and
H2O exits across the basolateral membrane (Equation 2
as in the proximal tubule, with H 1 being secreted across
the apical membrane). In other words, the HCO32 gen-
erated intracellularly by any of these pumps exits the
basolateral membrane. This exit into the blood occurs
through a chloride-bicarbonate exchanger, a truncated version
of the anion exchanger 1 (AE1; band 3 protein), which is the
Cl2/ HCO32 exchanger in red blood cells that facilitates CO2
transport (45). This is an electroneutral exchanger
driven by the ion concentrations of chloride and HCO32.
Mutations in AE1 can also cause distal renal tubular acidosis
(40,46). Two other transporters SLC26a7 (a C12/HCO32 ex-
changer) and KCC4 (a KCl cotransporter) are also in the
basolateral membrane of some acid secreting cells in the
collecting duct and likely contribute to urine acidification
in certain conditions (47–49).
In the cortical collecting duct, in addition to HCO 3 2
reabsorption by type A ICs, simultaneous HCO32 secretion
occurs in separate cells, the type B ICs (39,50). This process
involves an apical chloride-bicarbonate exchanger and a
basolateral H1-ATPase (51). In animal studies, HCO32
secretion is stimulated by alkali loading and inhibited by
low luminal chloride. The basolateral H1-ATPase is the
Figure 4. | Schematic of H1 and HCO32 transport in the types A and B same pump as in the apical membrane of type A IC, but
intercalated cells (ICs) in the collecting tubule (details are in the text). AE, the apical Cl2/ HCO32 exchanger has been identified as
anion exchanger. pendrin, a protein first identified as being abnormal in
6 Clinical Journal of the American Society of Nephrology

some patients with hereditary deafness (39,52,53). The influenced by chloride concentration gradients between tu-
importance of HCO32 secretion in human pathophysio- bular lumen and peritubular blood; this may result both
logic circumstances is not well characterized but may be from voltage changes and by direct lumen to cell concentra-
important in the maintenance and/or repair of metabolic tion gradients driving pendrin and other transporters.
alkalosis. In addition to aldosterone, other hormones and receptors,
The type B ICs, non–A, non–B ICs, and pendrin have including angiotensin II and the calcium-sensing receptor,
now also been implicated in NaCl transport/balance and stimulate distal acidification (61). An important role for in-
hypertension (53). This involves transport of Cl 2 and trarenal endothelin has also been found (27,62,63).
HCO32 on pendrin and also, a sodium–driven chloride/ Remodeling of IC morphology, number (relative numbers
HCO32 exchanger (NDCBE or SLC4A8); Cl2 exits the cell of A, B, and non–A, non–B ICs), and distribution of various
on AE4 (54–57). transporters has also been characterized (64,65). The matrix
Cytosolic CA, CAII, is present in all ICs of the collecting protein hensin is a key mediator of this remodeling.
tubule, and it facilitates provision of H1 to be secreted into
the lumen and HCO32 to be released into the basolateral
aspect and blood. However, several segments of the distal Ammonia Excretion
nephron do not have luminal CA (i.e., CAIV). The implica- NH41 excretion represents the other major mechanism
tions of this are that, as H1 is secreted into the lumen, lumi- whereby the kidneys excrete acid (66). Of the net acid
nal pH may be below equilibrium pH, with pH, CO2, and excreted (or new HCO 3 2 generated) by the kidneys,
HCO32 only coming to equilibrium later downstream in the approximately one-half to two-thirds (approximately
final urine. Final urine PCO2 may, therefore, rise above blood 40–50 mmol/d) is because of NH 4 1 excretion in the
PCO2 (as H1 and HCO32 react and come to equilibrium with urine. Additionally, during acid loading or acidosis,
CO2) and be an index of distal nephron H1 secretion. NH41 excretion can increase several fold, in contrast to
a more limited increase in titratable acidity (15) (Figure 2).
Traditionally, NH41 excretion was viewed as the excretion
Regulation of Acid-Base Transporters in the Distal of protons in conjunction with a buffer (ammonia [NH3]):
Nephron
Regulation of distal nephron acid-base transport is H 11 NH3 ↔ NH41 (4)
crucial, because this is the final site of control of urine
composition. The distal tubule responds to systemic aci- However, NH3/NH41 is not an effective physiologic buffer,
dosis in a teleologically appropriate direction of increased because its pKa is too high (approximately 9.2), and most
H1 secretion and new HCO32 generation. As in the prox- of total ammonia (.98%) at physiologic pH is NH41 on
imal tubule, changes in intracellular pH and plasma PCO2 the basis of the pKa. Furthermore, NH41, not NH3, is
affect proton secretion in the distal nephron. A significant produced within the kidneys. However, total ammonia
portion of this increased H1 secretion is through insertion excretion in the urine does represent acid excretion (or the
of additional H1-ATPase by fusion of subapical vesicles production of new HCO32) when considered in conjunc-
(containing H 1 -ATPase) with the plasma membrane. tion with the metabolism of the deamidated carbon skele-
These processes are mediated, in part, by a variety of sig- ton of glutamine. Glutamine is the predominant precursor
nal transduction systems (cAMP, cGMP, and PLC/protein of NH3 in the kidney (Figure 5). Conceptually, the metab-
kinase C) (39,41). A role for soluble adenyl cyclase, G olism of the carbon skeleton of glutamine can result in the
protein–coupled receptor 4, and other mechanisms in sensing formation of one HCO32 formed for every NH41 excreted.
pH changes or acid-base loads has also been proposed in Other amino acids can also be used to some extent. The
type A ICs and previously discussed in this series (39,41). predominant enzymatic pathway for NH3 formation is
Although the response to acidosis begins with these fairly mitochondrial phosphate–dependent glutaminase in the
rapid changes, chronic acidosis leads to a variety of proximal tubule, which produces one NH41 and glutamate.
changes in mRNA and protein levels of various transporters. Glutamate dehydrogenase can then convert glutamate into
Potassium depletion also increases H1 secretion in the distal a-ketoglutarate and a second NH41 . The a-ketoglutarate
tubule, similar to changes in the proximal tubule. produced can be converted to glucose or completely me-
The electrogenic nature of the apical H1-ATPase makes tabolized to HCO32. Other pathways for NH3 production
this process sensitive to transepithelial voltage. Therefore, also exist but are thought to be less important. Other
an increased lumen–negative voltage (e.g., more Na1 re- nephron segments other than the proximal tubule can
absorption) will increase H1 secretion. Increased Na1 re- produce NH3 but not to the same extent, and the other
absorption, such as with increased mineralocorticoids, will, segments do not have the same significant adaptive in-
therefore, be accompanied by increased H1 secretion. In- creases in ammoniagenesis with sustained acidosis as the
terestingly, the cell voltages of ICs are strikingly different proximal tubule. A variety of conditions affect the renal
from most cells, including principal cells: first, although production of NH3, but the most important is that of acid-
there is little data, the cell-negative voltages as shown in base status. Chronic metabolic acidosis can increase NH3
Figure 4 are much less (less negative), and second, the cells production several fold in the kidneys. Potassium balance
are energized by the H1 pump rather than by Na-K-ATPase also alters NH3 production, such that hyperkalemia sup-
as in most cells (54,57,58). H1 secretion, including in the presses NH3 formation (and transport in both the proximal
medullary collecting tubule, is also directly stimulated by tubule and thick limb), and hypokalemia increases NH3
mineralocorticoids, not just by secondary electrical effects production by the kidneys. Each of these changes has
(59,60). Distal tubule acidification may be strongly clinical correlates in overall acid-base balance. A variety
Clin J Am Soc Nephrol 10: ccc–ccc, December, 2015 Acid-Base Homeostasis, Hamm et al. 7

Figure 5. | Schematic of ammonia (NH3) production in the proximal tubule. A proximal tubule cell is enlarged to show that glutamine (Gln) is
metabolized to ammonium (NH41) by phosphate-dependent glutaminase (PDG); through a series of steps, the carbon skeleton of glutamine
can be metabolized to HCO32. NH3 can enter the proximal tubule lumen by either NH3 diffusion or NH41 movement on the Na1-H1 ex-
changer. AA0, neutral amino acids; B*AT1, B-type neutral amino acids transporter; GDH, glutamate dehydrogenase; aKG, alfa keto-glutarate;
LAT2, L-type amino acids transporter-2; OAA, oxalo-acetate; PEP, phospho enol-pyruvate; PEPCK, phospho enol-pyruvate carboxy kinase;
TCA, XXX.

Figure 6. | Ammonium (NH41) transport along the nephron. In the thick ascending limb, NH41 is reabsorbed by the Na2 K2 2Cl trans-
porter. In the collecting duct, Rh proteins mediate ammonia (NH3)/NH41 transport. The numbers depict the percentages of urinary total
NH 3 at each site. Total NH 3 is concentrated in the medulla (details are in the text). Gln, glutamine; PDG, phosphate-dependent
glutaminase.
8 Clinical Journal of the American Society of Nephrology

of hormones (angiotensin II, prostaglandins, etc.) have circumstances, basolateral membrane), transports NH3
also been shown to alter NH3 production. The enzymatic into the lumen. Luminal NH3 is then titrated by secreted
and transporter changes that facilitate enhanced ammo- H1 to NH41 as described above.
niagenesis during acidosis have recently been reviewed in
this series (18).
The transport of the produced NH41 along the nephron Acid and Alkali Loads
and into the urine is a complex process that is still a topic With this background, what are the pathologic chal-
of intense study (Figure 6). Most of the NH41 produced is lenges to normal acid-base homeostasis? Table 1 provides a
excreted into the urine rather than added to the venous basic conceptual classification of pathophysiologic types of
blood; this is particularly true with acidosis—the propor- acid and alkali loads. This differs from the usual classifi-
tions into urine and blood are almost even in normal con- cations of acid-base disorders per se, which focus only on
ditions (13,67). Therefore, during acidosis, both total NH3 clinical diagnostic algorithms or dive deeper into mecha-
production and secretion into urine are increased. The nisms. Acid loads can be in the form of either CO2 or non-
overall picture of NH3/NH41 transport is summarized volatile acids. Both types of acid loads occur normally on a
as follows. In the proximal tubular, NH41 is produced daily basis and must be excreted. Primary ventilatory dis-
from glutamine as discussed above and then, secreted orders resulting in increased arterial PCO2 are referred to
into the lumen. This secretion occurs by both Na1/NH41 by the term respiratory acidosis. Nonvolatile acids, such
exchange on the Na1/H1 exchanger and NH3 diffusion as phosphoric acid and sulfuric acid, are also normal by-
across the apical membrane (68–70). Interestingly, the se- products of metabolism of dietary nutrients, proteins, and
cretion of NH41 across the apical membrane is augmented phospholipids. Nonvolatile acid loads in excess of the excre-
by angiotensin II (71). Whether the diffusion of NH3 across tory capacity of the kidneys produce conditions termed met-
the apical membrane of the proximal tubule is lipid-phase abolic acidosis. In other words, with normal acid loads or
diffusion as long thought or facilitated by certain gas some increased acid loads that develop slowly, the kidneys
channels has not been determined. In the loop of Henle, can adapt, increasing acid excretion by both titratable acid
NH41 ion is reabsorbed into the interstitium, where it and NH41 excretion, and maintain normal systemic acid-
accumulates in the medulla. In the TAL, NH41 is trans- base homeostasis and pH. With larger acid loads (or base
ported across the apical membrane predominantly on the losses; for example, through severe diarrhea), the kidneys
Na1 -K1 -2Cl cotransporter, with perhaps some entry on cannot keep up (i.e., cannot excrete sufficient acid into the
K1 channels (72). NH41 has a similar hydrated size as K1 urine), and metabolic acidosis ensues. Metabolic acidosis is
and therefore, can often be transported through many K1 reflected predominantly by lowering of plasma or systemic
pathways (73). Remarkably, the apical membrane of the HCO32. Also, the loss of alkali from the body is equivalent
TAL is virtually impermeable to NH3 in contrast to most to the addition of acid, and therefore, it represents metabolic
cell membranes (74). NH3 probably leaves the TAL cell acidosis; such loss of alkali might occur from excess stool
across the basolateral membrane by NH3 diffusion and HCO32 losses or loss of HCO32 in the urine.
NH41 movement by NHE4 (72). One fraction of this med- Alkali loads, in contrast to acid loads, are not the result of
ullary NH41 is secreted back into the late proximal tubule normal physiology in persons on most diets, which provide
as NH3 diffusion coupled to H1 secretion, and therefore, it net dietary acid. Alkali loads can be either respiratory or
is partially recycled. Another fraction of medullary NH41 metabolic. Primary increases in ventilation and lowering of
enters the lumen of the cortical and medullary collecting PCO2 are referred to as respiratory alkalosis. Metabolic al-
ducts and as such, bypasses the superficial/cortical distal kali loads can result from excess excretion of urinary acid,
segment of the nephron. A small fraction of interstitial loss of other acids (such as gastric acid), or administration
NH41 is shunted to the systemic circulation for eventual of exogenous alkali, and they can result in metabolic alka-
detoxification by the liver. losis. Metabolic alkalosis is reflected primarily by an in-
In the cortical and medullary collecting ducts, interstitial creased plasma or systemic HCO32.
NH3/NH41 is secreted into the lumen by several mecha- Usually, however, as briefly discussed below, such met-
nisms, most identified only in recent years. The classic abolic alkali loads can be quickly excreted, so that the
mechanism involves diffusion of medullary NH3 across focus in understanding metabolic alkalosis is more on
the basolateral and apical membranes into the lumen, the factors that maintain the high plasma HCO 32 and not
where secreted H1 titrates NH3 to NH41. Another fraction the original generation by alkali load (79). Clinically, the
of transcellular NH41 secretion involves the Na1-K1-ATPase factors that often maintain high plasma HCO32 include
that carries NH41 into the cell by substituting NH41 for extracellular volume and chloride depletion, which may
K1. NH41 can also be transported by H1-K1-ATPases in decrease GFR, increase proximal tubule HCO32 reabsorp-
the collecting duct. Another critical mechanism of NH3/ tion, and increase angiotensin and mineralocorticoids, po-
NH 41 transport is Rh proteins, specifically RhBG and tent stimuli for H1 secretion in the proximal and distal
RhCG. These were only identified as NH3/NH41 trans- tubules, respectively, as discussed above. The intermediar-
porters in recent years (75,76). These proteins function as ies in volume depletion include increased sympathetic ac-
NH3/NH41 transporters, clearly facilitating diffusion of tivity and increased catecholamines, angiotensin II, and
NH3 but also, probably including (at least for RhBG) elec- aldosterone, all of which increase H1 secretion, HCO32
trogenic transport of NH41 (77,78). RhBG is present in the reabsorption, and/or NH41 excretion as discussed above.
basolateral membrane of type A ICs and can transport The classic edematous disorders of congestive heart failure
NH41 and NH3 into the cell, whereas RhCG, present at and cirrhosis and some nephrotic syndrome also have ef-
the apical membrane of several cell types (and in some fective extracellular volume depletion because of low
Clin J Am Soc Nephrol 10: ccc–ccc, December, 2015 Acid-Base Homeostasis, Hamm et al. 9

Table 1. Acid and alkali loads

Acid loads
CO2: Respiratory acidosis
Nonvolatile acids: Metabolic acidosis
Exogenous acids (e.g., salicylate, methanol, and ethylene glycol)
Pathologic endogenous acids (e.g., ketoacids and lactic acid)
Decreased renal acid excretion (e.g., renal failure and distal renal tubular acidosis)
Loss of alkali, equivalent to acid load
Gastrointestinal losses (e.g., diarrhea)
Urine losses (e.g., proximal renal tubular acidosis)
Alkali loads
Excess CO2 exhalation: Respiratory alkalosis
Nonvolatile alkali: Metabolic alkalosis
Exogenous alkali (e.g., NaHCO3 administration)
Loss of acid, equivalent to alkali load
Gastrointestinal losses (e.g., gastric fluid)
Excess urine H1 losses and renal production of new HCO32 (most classic causes of metabolic alkalosis, including
chloride depletion metabolic alkalosis and mineralocorticoid excess)

cardiac output or arterial underfilling (80); these condi- sensors; a variety of proteins seem to serve some of this func-
tions, thus, have sodium and H2O retention but also, can tion, but no single sensor can be proposed (25).
have increased HCO32 reabsorption, H1 secretion, and/or Increased metabolic acid production or ingestion will
NH41 excretion caused by the factors discussed above. initially result in increased new HCO32 generation, such
Therefore, both volume depletion (e.g., vomiting and di- that plasma HCO32 does not change. With larger acid loads,
uretics) and edematous disorders (primarily heart failure the capacity of the kidneys to generate new HCO32 is over-
and cirrhosis) can and often are associated with metabolic whelmed, and plasma HCO32 decreases. Metabolic acid
alkalosis. Chloride depletion alone through a variety of loads or metabolic acidosis results in increased fractional
mechanisms may also maintain metabolic alkalosis. Excess proximal tubule HCO32 reabsorption, increases in distal
mineralocorticoids from any condition can also stimulate H1 secretion (resulting in lower urine pH), and increased
H1 secretion and maintain metabolic alkalosis. Potassium NH41 excretion. (However, the lower plasma HCO32 during
depletion contributes to the maintenance of metabolic alka- metabolic acidosis decreases filtered HCO32 and hence, de-
losis by stimulating continued H1 secretion. creases absolute proximal HCO32 reabsorption.) Increased
H1 excretion may result not only from adaptive changes in
response to systemic pH per se but also, secondary to in-
Compensation for Acid-Base Disorders creases in systemic glucocorticoids and mineralocorticoids
The mechanisms of physiologic responses to acid or base with chronic acidosis and potassium depletion. The adaptive
loads can be expected on the basis of the understanding of changes within the kidney include various factors discussed
the mechanisms of usual physiology described above. The in the sections above, including endogenous endothelin. The
predicted extent of clinical response, however, is on the increased H1 secretion can result in increased titratable acid
basis of empirical observations and not just mechanisms. On excretion up to 2- to 3-fold in certain situations. Urinary
the basis of the chemistry, acute changes in PCO2 alter plasma NH41 excretion (a result of both increased production and
HCO32 slightly, because nonbicarbonate body buffers are increased secretion of produced NH41) can increase several
titrated. With chronic changes in PCO2 (respiratory acid- fold (Figure 2). The maximum renal compensation for acid
base disorders), the kidneys respond to the change in pH loading requires 3–5 days. Metabolic acid loads sufficient to
by altering plasma HCO32 in a direction to lessen the change lower plasma pH result in increased ventilation, result-
in systemic pH through the mechanisms described above. ing in a decrease in P CO2 sufficient to raise the systemic
These changes within the kidney take several days for com- pH toward but not to normal. The full respiratory
pletion and in general, do not return systemic pH completely compensation requires 12–24 hours. Paradoxically, the
back to normal. With chronic hypocapnia and the resultant compensatory hypocapnia during metabolic acidosis
increase in systemic pH, decreases in reabsorption of HCO32 may actually decrease somewhat the renal response to
in the proximal tubule and distal tubule H1 secretion result metabolic acidosis (84).
in a fall in plasma HCO32; these changes can begin within a Metabolic alkali loads can normally be quickly elimi-
very few hours (81). With chronic hypercapnia, increased nated in the urine, because the filtration rate of HCO32 is
proximal and distal H1 secretion results in increased HCO32 high, and a small reduction in proximal tubule HCO32
reabsorption and increased production of new HCO32, result- reabsorption can result in spillage of HCO32 in the urine
ing in a higher level of plasma HCO32; most of the cell and and prompt correction of the metabolic alkalosis. Fre-
molecular mechanisms parallel the response to metabolic acid quently, however, in states of metabolic alkalosis, other
loads, where these have been studied (82). Increased NH41 factors prevent the excretion of HCO32 and maintain the
excretion is expected as well with chronic respiratory acidosis metabolic alkalosis as described above. Metabolic alkalosis
(83). With the ubiquitous changes that occur in response to also results in some hypoventilation and increase in PCO2
acidosis or acid loads, many investigators have looked for acid to compensate for the alkalemia.
10 Clinical Journal of the American Society of Nephrology

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