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Proximal HCO3_ reabsorption is influenced by luminal HCO 3_ concentration and flow rate, extracellular fluid
volume, peritubular HCO3_ concentration, and PCO2, Cl_, K_, Ca2_, phosphate, parathyroid hormome, glucocorticoids,
_-adrenergic tone, and angiotensin II (4).
H_ secretion proceeds in the outer medullary collecting tubule, which is a unique segment that does not reabsorb Na _
or secrete K_ and the only function of which is the transport of H _. The medullary collecting tubule is lumenpositive, and H_ must be secreted against the electrochemical gradient via an electrogenic, Na _-independent process
modulated by the vacuolar H_-ATPase. H_ secretion is not inhibited by agents that block Na _ transport, but it is
influenced by aldosterone through a mechanism that is independent of Na _ delivery or reabsorption. The terminal
part, the inner medullary collecting duct, also plays an important role in distal acidification. The cellular process
involved in mediating H_ secretion appears to be similar to the process described in _-intercalated cells, but its
quantitative importance in overall renal H_ secretion remains to be determined. All segments of the collecting tubule
are very rich in cytosolic carbonic anhydrase II, but membranebound, luminal carbonic anhydrase IV is also present
in both outer and inner segments of the medullary collecting duct. The luminal CA IV seems to play an important
role for HCO3_ absorption in this segment.
Distal urinary acidification is influenced by blood pH and P CO2, distal Na_ transport and transepithelial potential
difference, aldosterone, and K_. Aldosterone influences distal acidification through several mechanisms. First, it
enhances Na_ transport in late distal and cortical collecting tubules and thereby increases the lumen-negative
potential difference across epithelium, so favoring both H _ and K_ secretion. This action is first mediated by
activation of preexisting epithelial Na _ channels (ENaC) and pumps (Na _,K_-ATPase) and subsequently mediated by
increasing the overall transport capacity of the renal tubular cells. Aldosterone seems to be responsible of the
specific localization of the ENaC in the apical membrane of principal cells of distal and cortical collecting tubules.
Both early regulatory and late anabolic-type actions depend on the transcriptional regulation exerted by
hormoneactivated mineralocorticoid receptors (MR). However, the regulatory pathways that link the transcriptional
action of aldosterone to these Na_ transport proteins is mediated by sgk (serum and glucocorticoid-regulated kinase)
and other regulatory proteins (7).
Aldosterone also enhances H_-ATPase activity in cortical and medullary collecting tubules, an effect that is
independent of plasma K_ levels. However, the stimulation of H _,K_- ATPase also observed in states of aldosterone
excess depends predominantly on the stimulus exerted by accompanying hypokalemia. Aldosterone also has an
effect on NH4 _ excretion by increasing NH3 synthesis, both as a direct action and as a consequence of simultaneous
changes in K_ homeostasis.
leaves the
growth is a prominent clinical feature in children. Rickets and osteomalacia are never observed unless
hypophosphatemia is present as occurs in the Fanconi syndrome. Nephrocalcinosis and urolithiasis are also
infrequent, even in situations in which hypercalciuria is present (16). Hypokalemia and related symptoms are also
restricted to cases with the Fanconi syndrome.
Proximal RTA (type 2) is caused by an impairment of HCO 3_ reabsorption in the proximal tubule and is
characterized by a decreased renal HCO3_ threshold, which is normally situated between 22 mmol/L in infants and
26 mmol/L in older children and aduts. Distal acidification mechanisms are intact; when plasma HCO 3_
concentration diminishes to sufficiently low levels, these patients may lower urine pH below 5.5 and excrete
adequate amounts of NH4_. However, when plasma HCO3_ concentration is normalized by administration of alkali,
the distal nephron is not capable of handling the large delivery of HCO 3_. As a consequence, the urine is highly
alkaline and contains a great fraction of the filtered load (_10 to 15%). This HCO 3_ wasting is a transient
phenomenon, and a steady state is again maintained when plasma HCO 3_ concentration stabilizes in the acidemic
range. It may occur as an isolated defect (e.g., mutations in the gene SLC4A4, encodingthe Na_/HCO3_ cotransporter
NBC-1) (17) or more commonly in association with generalized proximal tubular transport defects (e.g., in the
context of a dysfunctional Na_,K_ATP-ase system).
NBC-1, Na_-HCO3_ cotransporter; NHE-3, Na_-H_ exchanger; AE1, Cl_-HCO3_ exchanger; ENaC, epithelial Na_ channel; MC,
mineralocorticoid receptor.
HCO3
_ reabsorption
but, in contrast to a
NH4
_ excretion,
Renal
HCO3
_ reabsorption
_ 8 to 16 mmol/L) in a
and
Reabsorption
HCO3
_ Titration.
reabsorption of HCO3
_ is
of HCO3
_ and
The calculation of
Plasma HCO3
_-Urine
of the
permit
threshold is diminished.
HCO3
_ Excretion
_ Concentration.
at about 22
_.
However,
may proceed
is better uncovered
by examining HCO3
_ excretion
_ concentration
The measurement of
low; vice
syndrome)
b. in chronic interstitial nephropathies (obstructive uropathy, medullary cystic disease, drug-induced interstitial
nephritis,
renal transplant rejection, analgesic abuse nephropathy, AIDS nephropathy)
3. drug-induced hyperkalemia
a. impaired renin-aldosterone elaboration (cyclo-oxygenase inhibitors, converting enzyme inhibitors, heparin)
b. inhibitors of renal K_ secretion (potassium-retaining diuretics, trimethoprim, pentamidine, cyclosporin A)
c. altered K_ distribution (insulin antagonists, _-adrenergic antagonists, _-adrenergic agonists, digitalis,
succinylcholine)
J Am Soc Nephrol 13: 21602170, 2002 Renal Tubular Acidosis 2165
in patients with
a state of metabolic
_ excretion
a significant anionic
2K_
u_
Uosm/Posm
(1)
where K_
uand
K_
prepresent
are
_ concentration.
NDDDD
fractional K_ excretion N or I I I D D
Ca excretion N I I I N or D
citrate excretion N D D D N
In situation of normal acid-base equilibrium (after alkali loading)
fractional HCO3_ excretion _10 to 15% _5% _5 to 15% _5% _5 to 10%
U-B PCO2 _20 mmHg _20 mmHg _20 mmHg _20 mmHg _20 mmHg
Other tubular defects Often present Absent Absent Absent Absent
Nephrocalcinosis/lithiasis Absent Often present Often present Often present Absent
Bone involvement Often present Rarely present Rarely present Rarely present Absent
a
_ concentration
should not
the