RENAL TUBULAR ACIDOSIS
The kidneys play a key role in maintaining systemic pH near 7.4. The
renal tubular acidoses (RTAs) are a group of disorders in which systemic
acidosis occurs because the kidneys are unable either to excrete acid or to
conserve bicarbonate. In either case, the result is a variable degree of normal
anion gap metabolic acidosis accompanied by an abnormal serum potassium
concentration. The RTA subtypes are classified as proximal or distal (pRTA,
dRTA) based on which nephron segment is malfunctioning.
PROXIMAL RTA
The proximal tubule reabsorbs 80%
of the filtered bicarbonate (see Plate 3-21). Proximal tubular cells also
metabolize glutamine, a process that yields bicarbonate, which is reabsorbed,
and NH4+, which is secreted into the nascent urine.
Proximal RTA (pRTA), in which these
processes fail, usually occurs as a component of generalized proximal tubular
dysfunction (renal Fanconi syndrome). Most cases are acquired, reflecting
exposure to substances that interfere with proximal tubular function, such as myeloma
proteins or drugs (e.g., cytotoxic drugs or sodium valproate). In rarer cases,
generalized proximal dysfunction may result from inherited diseases, such as
cystinosis (see Plate 4-64). In even rarer cases, pRTA may be an isolated
phenomenon (i.e., otherwise normal proximal function), as seen in individuals
with recessively inherited defects in the basolateral NBC Na+/ HCO3- transporter.
Because the distal nephron can
recapture some of the bicarbonate that is not reabsorbed in the proximal
tubule, pRTA generally features a milder acidosis than dRTA. Indeed, once serum
bicarbonate levels decline to 15 mEq/L, reabsorption in the distal nephron can
fully compensate for the proximal dysfunction. At this point, bicarbonate
wasting ceases, urine pH decreases (often becoming acidic), and serum
bicarbonate concentrations stabilize. If patients are given an intravenous
infusion of sodium bicarbonate, however, bicarbonate wasting resumes (with a
fractional excretion of ≥15%) and the urine pH increases. This sequence
of events is diagnostic of proximal RTA.
In addition to acidosis, pRTA
features hypokalemia because the nonreabsorbed bicarbonate produces a negative
charge in the collecting duct lumen, promoting K+
secretion through ROM-K channels. If there is generalized proximal tubule
dysfunction, the increased distal Na+ load that reaches the
cortical collecting duct also produces a negative intraluminal charge as it is
reabsorbed. In addition, the increased urine flow through the distal tubule,
which results from proximal salt wasting, stimulates K+ secretion through flow- sensitive maxi-K channels.
Although acidosis and hypokalemia
are the hallmarks of pRTA, several additional abnormalities are often seen.
Patients with generalized proximal tubular dysfunction, for example, exhibit
salt wasting, polyuria, phosphaturia (and hypophosphatemia), glucosuria,
uricosuria (and hypouricemia), aminoaciduria, microalbuminuria, and low
molecular weight proteinuria (e.g., retinol binding protein or β2-microglobulin). Moreover, patients often
develop rickets or osteomalacia cia (depending on age) because of inefficient
renal activation of vitamin D. Meanwhile, patients with isolated pRTA, like
those with NBC transporter mutations, often have aberrant calcification within
the eyes (band keratopathy), cataracts, and mental retardation.
Proximal RTA is often difficult to
treat because the marked bicarbonaturia mandates that large quantities of
alkali be provided on a regular basis. Extensive bicarbonate supplementation,
however, often causes worsening hypokalemia, and thus potassium
supplements are often required as well. If there is generalized proximal
tubular dysfunction, vitamin D and phosphate supplements are also helpful.
DISTAL RTA
The collecting duct contains
principal cells and intercalated cells (ICs), with the latter responsible for acid
base handling. Within the IC population, at least two subtypes of cells have been
described: type A and type
B. Type A cells secrete protons and
reabsorb bicarbonate, whereas type B cells do the reverse. It is unclear if
type A and B cells are molecular mirror images or separate cell types; however,
the acid load in the average human diet dictates that the great majority of ICs
be type A.
Classic distal RTA (i.e., hypokalemic dRTA) reflects type A cell
dysfunction. Because there is inadequate secretion of protons, the kidneys are
unable to appropriately acidify urine in the setting of systemic metabolic
acidosis or following an acid load (e.g., with ammonium chloride). The urine
anion gap (urine Na+ + K+ - Cl-) is a useful tool for
confirming this defect; it will be positive in patients with metabolic acidosis
if there are low levels of urine NH4+, the major unmeasured cation, secondary to
impaired urine acidification.
In most cases classic dRTA is
acquired. Major causes include immunologic diseases (e.g., Sjögren syndrome)
and drugs (e.g., lithium, amphotericin). Rarely, classic distal RTA can occur
during pregnancy, although it typically resolves after delivery. Genetic causes
have also been reported, such as autosomal dominant (and, rarely, autosomal recessive)
mutations in the gene encoding AE1, as well as autosomal recessive mutations in
subunits of the apical proton pump.
No matter the cause, classic dRTA
generally features hypokalemia, at least in part because the lack of proton
secretion in the collecting duct increases the gradient for potassium
secretion. Nephrolithiasis and/or nephrocalcinosis are also common, since
calcium precipitation is favored by urine alkalinity, which results from
failure of proton secretion, and hypocitraturia, which results from the
increased citrate reabsorption that occurs in response to acidosis. Metabolic
bone disease (osteomalacia or rickets) may occur because of the effects of
acidosis on bone, even though calcium and phosphate levels are usually normal.
In patients with autosomal recessive dRTA, progressive and irreversible
bilateral sensorineural hearing loss is common, reflecting the functional
significance of the H+ pump in the cochlea.
Classic dRTA is treated with alkali
replacement. If treatment is not instituted early on, however, chronic kidney
disease may occur secondary to nephrocalcinosis or uncontrolled nephrolithiasis
with consequent obstruction. Of note, alkali treatment does not improve
deafness in patients with autosomal recessive disease because orally administered
alkali cannot access the inner ear compartment.
Hyperkalemic dRTA is chiefly a by-product of distal nephron
dysfunction secondary to aldosterone resistance or deficiency. Acidosis reflects
both the absence of aldosterone-induced proton secretion and the inhibitory
effects of hyperkalemia on ammoniagenesis.
Most cases are related to drugs or
to hyporeninemic hypoaldosteronism. The most commonly implicated drugs include
trimethoprim, cyclosporine, and ACE inhibitors. Trimethoprim acts as an
antagonist of the ENaC, whereas cyclosporine inhibits the basolateral Na+/K+ ATPase. Hyporeninemic hypoaldosteronism is most
often found in the context of renal insufficiency, especially that caused by
diabetes mellitus.
Hyperkalemic dRTA is treated by
withdrawing precipitating drugs and providing sodium bicarbonate.
Fludrocortisone and/or potassium-lowering drugs, such as oral resins, are also
helpful, since reducing serum potassium concentrations increases renal ammo-
niagenesis and ammonia excretion.
MIXED RTA
The entity of transient mixed
proximal/distal RTA arising just after birth is thought to mark a developmental
hiatus in distal nephron function, which normally continues to mature after
birth. Nontransient RTA with both proximal and distal tubular dysfunction does,
however, accompany one form of autosomal recessive osteopetrosis
(Guibaud-Vainsel syndrome or marble brain disease). Investigators have
identified loss of carbonic anhydrase 2, an enzyme expressed both throughout the
nephron and in osteoclasts, as the biochemical defect. The disease presents in
infancy, with major signs including thickened but brittle bones, short stature,
mental retardation, dental malocclusion, and visual impairment from optic nerve
com ression. Calcification of the basal ganglia may occur.
