MEDSCAPE

TREATMENT PEDIATRIC TYPE 1 RTA

Bicarbonate Therapy
• serum bicarbonate level is only mildly to moderately depressed (>10-12 mEq/L), bicarbonate
replacement may not be necessary
• warranted in patients with a pH of less than 7.15
• Dosage:
o Older children: 2-5 mEq/kg IV infusion over 4-8 hr depending on the severity of acidosis as
judged by the lowering of total CO2 content, clinical condition and pH
o 0.25-2mEq/kg IV infusion can be considered for acidosis with a pH <7.0-7.2
• Calculating the amount of bicarbonate replacement necessary must take into account the effect of
non-bicarbonate buffers on exogenously administered bicarbonate. Multiply the desired increase in
plasma bicarbonate concentration by the apparent volume of distribution and weight. The
bicarbonate deficit can be calculated as follows:
(Desired Bicarbonate - Measured Bicarbonate) x Weight (kg) x 0.6

• The general recommendation is to replace only half of the total bicarbonate deficit during the first
few hours of therapy.
o Do not overestimate or overcorrect the bicarbonate deficit. Rapid infusion of bicarbonate and
overcorrection of the metabolic acidosis can lead to complications such as tetany, seizures, and
hypokalemia by worsening the preexisting hypocalcemia and hypokalemia.
o Doses of bicarbonate exceeding 1 mEq/kg per dose may lead to an alkaline overshoot. For each
0.1 increase in pH, oxygen availability may decrease by 10% because of the shift of the oxygen-
hemoglobin dissociation curve to the left.
o Rapid infusion of sodium bicarbonate to correct metabolic acidosis has led to paradoxical CNS
acidosis in animal studies. The cause is believed to be sodium bicarbonate dissociating into
carbon dioxide and water; carbon dioxide rapidly crosses the blood-brain barrier, but
bicarbonate does not, leading to CNS acidosis.

• Treatment of acute metabolic acidosis by alkali therapy is usually indicated to raise and maintain the
plasma pH to greater than 7.20.
• Parenteral forms of sodium bicarbonate are available as 4% (half strength) or 8% solutions. The
sodium load can be significant when multiple bolus doses are administered
• If hypernatremia is a concern, consider continuous infusion of sodium bicarbonate as part of the
maintenance intravenous solution. For example, 34 mEq/L of sodium bicarbonate can be added to a
0.22% sodium chloride solution to make up a 0.45% salt solution for maintenance intravenous
therapy.
• The use of sodium bicarbonate therapy in cases of diabetic ketoacidosis is controversial. A report by
Glaser et al stated that patients with diabetic ketoacidosis who were treated with sodium
bicarbonate were at increased risk for cerebral edema.
Tromethamine
• Tromethamine (also called THAM or tris [hydroxymethyl]-aminomethane) is a buffer that can be
used to treat acidosis when concerns exist regarding carbon dioxide accumulation from the
metabolism of administered sodium bicarbonate.
• is a buffering agent that increases pH without increasing levels of PaCO2. It may be used to correct
metabolic acidosis if sodium bicarbonate is contraindicated
• THAM increases serum bicarbonate predictably:
o THAM + H2CO3 → THAM-H + HCO3-
o H2CO3 → CO2 + H2O
• Standard IV dose of 0.3 M undiluted solution:
o 1-2 mmol/kg/dose (3.3-6.6 mL/kg/dose)
o Maximum rate = 1 mL/min
• Dose (mL) of 0.3 M undiluted solution:
o Weight (kg) x Base Deficit (mmol/L)
o Maximum Rate = 1 mL/min

Thiamine
Thiamine is an essential coenzyme that combines with ATP to form thiamine pyrophosphate. The dosage
forms include a parenteral injection (100 mg/mL) and tablets. Thiamine administration rapidly corrects
the clinical symptomatology in metabolic acidosis.

Patients with Lowe syndrome typically present in infancy with
cataracts, progressive growth failure, hypotonia, and Fanconi
syndrome. Significant proteinuria is common. Blindness and renal
insufficiency often develop. Characteristic behavioral abnormalities
are also seen, including tantrums, stubbornness, stereotypy (repetitive
behaviors), and obsessions. There is no specific therapy for the
renal disease or neurologic deficits. Cataract removal is generally
required.
CLINICAL MANIFESTATIONS OF PROXIMAL
RENAL TUBULAR ACIDOSIS AND
FANCONI SYNDROME
Patients with isolated, sporadic, or inherited pRTA present with growth
failure in the 1st yr of life. Additional symptoms can include polyuria,
dehydration (from sodium loss), anorexia, vomiting, constipation, and
hypotonia. Patients with primary Fanconi syndrome have additional
symptoms, secondary to phosphate wasting, such as rickets. Those with
systemic diseases present with additional signs and symptoms specific
to their underlying disease. A non–anion gap metabolic acidosis is
present. Urinalysis in patients with isolated pRTA is generally unre-
markable. The urine pH is acidic (<5.5) because distal acidification
mechanisms are intact in these patients. Urinary indices in patients
with Fanconi syndrome demonstrate varying degrees of phosphaturia,
aminoaciduria, glycosuria, uricosuria, and elevated urinary sodium or
potassium. Depending on the nature of the underlying disorder, labo-
ratory evidence of chronic renal insufficiency, including elevated
serum creatinine, may be present.
529.2  Distal (Type I) Renal Tubular Acidosis
Rajasree Sreedharan and Ellis D. Avner
PATHOGENESIS
Distal RTA can be sporadic or inherited. It can also occur as a compli-
cation of inherited or acquired diseases of the distal tubules. Primary
or secondary causes of distal RTA can result in damaged or impaired
functioning of one or more transporters or proteins involved in the
acidification process, including the H+/ATPase, the HCO3−/Cl− anion
exchangers, or the components of the aldosterone pathway. Because of
impaired hydrogen ion excretion, urine pH cannot be reduced to <5.5,
despite the presence of severe metabolic acidosis. Loss of sodium bicar-
bonate distally, owing to lack of H+ to bind to in the tubular lumen (see
Fig. 529-1), results in increased chloride absorption and hyperchlore-
mia. Inability to secrete H+ is compensated by increased K+ secretion
distally, leading to hypokalemia. Hypercalciuria is usually present and
can lead to nephrocalcinosis or nephrolithiasis. Chronic metabolic
acidosis also impairs urinary citrate excretion. Hypocitraturia further
increases the risk of calcium deposition in the tubules. Bone disease is
common, resulting from mobilization of organic components from
bone to serve as buffers to chronic acidosis.
CLINICAL MANIFESTATIONS
Distal RTA shares features with those of pRTA, including non–anion
gap metabolic acidosis and growth failure; distinguishing features of
distal RTA include nephrocalcinosis and hypercalciuria. The phos-
phate and massive bicarbonate wasting characteristic of pRTA is gener-
ally absent. Table 529-1 lists the causes of primary and secondary distal
RTA. Although inherited forms are rare, 3 specific inherited forms of
distal RTA have been identified, including an autosomal recessive form
associated with sensorineural deafness.
Medullary sponge kidney is a relatively rare sporadic disorder in
children, although not uncommon in adults. It is characterized by
cystic dilation of the terminal portions of the collecting ducts as they
enter the renal pyramids. Ultrasonographically, patients often have
medullary nephrocalcinosis. Although patients with this condition
typically maintain normal renal function through adulthood, compli-
cations include nephrolithiasis, pyelonephritis, hyposthenuria (inabil-
ity to concentrate urine), and distal RTA. Associations of medullary
Chapter 529  ◆  Renal Tubular Acidosis  2531
sponge kidney with Beckwith-Wiedemann syndrome or hemihyper-
trophy have been reported.
529.3  Hyperkalemic (Type IV) Renal
Tubular Acidosis
Rajasree Sreedharan and Ellis D. Avner
PATHOGENESIS
Type IV RTA occurs as the result of impaired aldosterone production
(hypoaldosteronism) or impaired renal responsiveness to aldosterone
(pseudohypoaldosteronism). Acidosis results because aldosterone has
a direct effect on the H+/ATPase responsible for hydrogen secretion.
In addition, aldosterone is a potent stimulant for potassium secretion
in the collecting tubule; consequently, lack of aldosterone results in
hyperkalemia. This further affects acid–base status by inhibiting
ammoniagenesis and, thus, H+ excretion. Aldosterone deficiency typi-
cally occurs as a result of adrenal gland disorders such as Addison
disease or some forms of congenital adrenal hyperplasia. In children,
aldosterone unresponsiveness is a more common cause of type IV
RTA. This can occur transiently, during an episode of acute pyelone-
phritis or acute urinary obstruction, or chronically, particularly in
infants and children with a history of obstructive uropathy. The latter
patients can have significant hyperkalemia, even in instances when
renal function is normal or only mildly impaired. Rare examples of
inherited forms of type IV RTA have been identified.
CLINICAL MANIFESTATIONS
Patients with type IV RTA can present with growth failure in the first
few years of life. Polyuria and dehydration (from salt wasting) are
common. Rarely, patients (especially those with pseudohypoaldoste-
ronism type 1) present with life-threatening hyperkalemia. Patients
with obstructive uropathies can present acutely with signs and symp-
toms of pyelonephritis, such as fever, vomiting, and foul-smelling
urine. Laboratory tests reveal a hyperkalemic non–anion gap meta-
bolic acidosis. Urine may be alkaline or acidic. Elevated urinary
sodium levels with inappropriately low urinary potassium levels reflect
the absence of aldosterone effect.
DIAGNOSTIC APPROACH TO RENAL
TUBULAR ACIDOSIS
The first step in the evaluation of a patient with suspected RTA is
to confirm the presence of a normal anion gap metabolic acidosis,
identify electrolyte abnormalities, assess renal function, and rule
out other causes of bicarbonate loss such as diarrhea (see Chapter
55). Metabolic acidosis associated with diarrheal dehydration is
extremely common, and acidosis generally improves with correction
of volume depletion. Patients with protracted diarrhea can deplete
their total-body bicarbonate stores and can have persistent acidosis
despite apparent restoration of volume status. In instances where
a patient has a recent history of severe diarrhea, full evaluation
for RTA should be delayed for several days to permit adequate
time for reconstitution of total-body bicarbonate stores. If acidosis
persists beyond a few days in this setting, additional studies are
indicated.
Serum electrolytes, blood urea nitrogen, calcium, phosphorus, cre-
atinine, and pH should be obtained by venous puncture. Traumatic
blood draws (such as heel-stick specimens), small volumes of blood in
“adult-size” specimen collection tubes, or prolonged specimen trans-
port time at room temperature can lead to falsely low bicarbonate
levels, often in association with an elevated serum potassium value.
True hyperkalemic acidosis is consistent with type IV RTA, whereas
the finding of normal or low potassium suggests type I or II. The blood
anion gap should be calculated using the formula [Na+] − [Cl− +
HCO3−]. Values of <12 demonstrate the absence of an anion gap. Values
of >20 indicate the presence of an anion gap. If such an anion gap is
found, then other diagnoses (lactic acidosis, inborn errors of
2532  Part XXIII  ◆  Nephrology

bicarbonate levels can be maintained in the normal range. Patients with

systemic illness and Fanconi syndrome can have ongoing morbidity
LT kidney long with growth failure, rickets, and signs and symptoms related to their
underlying disease.

Bibliography is available at Expert Consult.

529.4  Rickets Associated with Renal

Tubular Acidosis
Russell W. Chesney

Rickets may be present in primary RTA, particularly in type II or

Figure 529-2 Ultrasound examination of a child with distal RTA
demonstrating medullary nephrocalcinosis.
metabolism, ingested toxins) should be investigated. If tachypnea is
noted, evaluation of an arterial blood gas might help to rule out the
possibility of a mixed acid-base disorder primarily involving respira-
tory and metabolic components. A detailed history, with particular
attention to growth and development, recent or recurrent diarrheal
illnesses, and a family history of mental retardation, failure to thrive,
end-stage renal disease, infant deaths, or miscarriages is essential.
Physical examination should determine growth parameters and
volume status as well as the presence of any dysmorphic features sug-
gesting an underlying syndrome.
Once the presence of a non–anion gap metabolic acidosis is con-
firmed, urine pH can help distinguish distal from proximal causes. A
urine pH <5.5 in the presence of acidosis suggests pRTA, whereas
patients with distal RTA typically have a urine pH >6.0. The urine
anion gap ([urine Na+ + urine K+] − urine Cl−) is sometimes calculated
to confirm the diagnosis of distal RTA. A positive gap suggests a defi-
ciency of ammoniagenesis and, thus, the possibility of a distal RTA. A
negative gap is consistent with proximal tubule bicarbonate wasting
(gastrointestinal bicarbonate wasting). A urinalysis should also be
obtained to determine the presence of glycosuria, proteinuria, or
hematuria, suggesting more global tubular damage or dysfunction.
Random or 24 hr urine calcium and creatinine measurements will
identify hypercalciuria. Renal ultrasonography should be performed
to identify underlying structural abnormalities such as obstructive
uropathies as well as to determine the presence of nephrocalcinosis
(Fig. 529-2).
pRTA. Hypophosphatemia and phosphaturia are common in the renal
tubular acidoses, which are also characterized by hyperchloremic met-
abolic acidosis, various degrees of bicarbonaturia, and, often, hyper-
calciuria and hyperkaluria. Bone demineralization without overt
rickets usually is detected in type I and distal RTA. This metabolic bone
disease may be characterized by bone pain, growth retardation, osteo-
penia, and, occasionally, pathologic fractures. Although acute meta-
bolic acidosis in vitamin D–deficient animals can impair the conversion
of 25-hydroxyvitamin D (25[OH]D) to 1,25-dihydroxyvitamin D
(1,25[OH]2D), resulting in reduced levels of this active metabolite, the
circulating levels of 1,25(OH)2D in patients with either type of RTA
are generally normal. If patients with RTA have chronic renal insuffi-
ciency, serum 1,25(OH)2D levels are reduced in relation to the degree
of renal impairment.
Bone demineralization in distal RTA probably relates to dissolution
of bone because the calcium carbonate in bone serves as a buffer
against the metabolic acidosis due to the hydrogen ions retained by
patients with RTA.
Administration of sufficient bicarbonate to reverse acidosis reverses
bone dissolution and the hypercalciuria that is common in distal RTA.
Proximal RTA is treated with both bicarbonate and oral phosphate
supplements to heal rickets. Doses of phosphate similar to those used
in familial hypophosphatemia or Fanconi syndrome may be indicated.
Vitamin D is required to offset the secondary hyperparathyroidism
that complicates oral phosphate therapy. Following therapy, growth in
patients with type II (proximal) RTA is greater than in patients with
primary Fanconi syndrome. In addition, “double osteomalacia” may be
evident when patients with either type of RTA also have vitamin D
deficiency.

TREATMENT AND PROGNOSIS

The mainstay of therapy in all forms of RTA is bicarbonate replace-
ment. Patients with pRTA often require large quantities of bicarbonate,
up to 20 mEq/kg/24 hr, in the form of sodium bicarbonate or sodium
citrate solution (Bicitra or Shohl solution). The base requirement for
distal RTAs is generally in the range of 2-4 mEq/kg/24 hr, although
patients’ requirements can vary. Patients with Fanconi syndrome
usually require phosphate supplementation. Patients with distal
RTA should be monitored for the development of hypercalciuria.
Those with symptomatic hypercalciuria (recurrent episodes of gross
hematuria), nephrocalcinosis, or nephrolithiasis can require thiazide
diuretics to decrease urine calcium excretion. Patients with type IV
RTA can require chronic treatment for hyperkalemia with sodium-
potassium exchange resin (Kayexalate).
Prognosis of RTA depends to a large part on the nature of any exist-
ing underlying disease. Patients with treated isolated proximal or distal
RTA generally demonstrate improvement in growth, provided serum