Renal Tubular Acidosis

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, MD, Texas Tech University

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Renal tubular acidosis (RTA) is acidosis and electrolyte disturbances due to

impaired renal hydrogen ion excretion (type 1), impaired bicarbonate resorption
(type 2), or abnormal aldosterone production or response (type 4). (Type 3 is
extremely rare and is not discussed.) Patients may be asymptomatic, display
symptoms and signs of electrolyte derangements, or progress to chronic kidney
disease. Diagnosis is based on characteristic changes in urine pH and electrolytes
in response to provocative testing. Treatment corrects pH and electrolyte
imbalances using alkaline agents, electrolytes, and, rarely, drugs.

RTA defines a class of disorders in which excretion of hydrogen ions or reabsorption of filtered
bicarbonate is impaired, leading to a chronic metabolic acidosis with a normal anion gap.
Hyperchloremia is usually present, and secondary derangements may involve other electrolytes,
such as potassium (frequently) and calcium (rarely—see table Some Features of Different Types of
Renal Tubular Acidosis*).
Chronic RTA is often associated with structural damage to renal tubules and may progress
to chronic kidney disease.
Type 1 (distal) RTA
Type 1 is impairment in hydrogen ion secretion in the distal tubule, resulting in a persistently high
urine pH (>5.5) and systemic acidosis. Plasma bicarbonate is frequently <15 mEq/L (15 mmol/L),
and hypokalemia, hypercalciuria, and decreased citrate excretion are often present. Hypercalciuria
is the primary abnormality in some familial cases, with calcium-induced tubulointerstitial damage
causing distal RTA. Nephrocalcinosis and nephrolithiasis are possible complications of
hypercalciuria and hypocitraturia if urine is relatively alkaline.
This syndrome is rare. Sporadic cases occur most often in adults and may be primary (nearly always
in women) or secondary. Familial cases usually first manifest in childhood and are most often
autosomal dominant. Secondary type 1 RTA may result from drugs, kidney transplantation, or
various disorders:
• Autoimmune disease with hypergammaglobulinemia, particularly Sjögren syndrome or RA
• Kidney transplantation
• Nephrocalcinosis

• Medullary sponge kidney

• Chronic obstructive uropathy
• Drugs (mainly amphotericin B, ifosfamide, and lithium)
• Cirrhosis
• Sickle cell anemia
Potassium level may be high in patients with chronic obstructive uropathy or sickle cell anemia.

Type 2 (proximal) RTA

Type 2 is impairment in bicarbonate resorption in the proximal tubules, producing a urine pH > 7 if
plasma bicarbonate concentration is normal, and a urine pH < 5.5 if plasma bicarbonate
concentration is already depleted as a result of ongoing losses.
This syndrome may occur as part of a generalized dysfunction of proximal tubules and patients can
have increased urinary excretion of glucose, uric acid, phosphate, amino acids, citrate, calcium,
potassium, and protein. Osteomalacia or osteopenia (including rickets in children) may develop.
Mechanisms may include hypercalciuria, hyperphosphaturia, alterations in vitamin D metabolism,
and secondary hyperparathyroidism.

Type 2 RTA is very rare and most often occurs in patients who have one of the following:

• Fanconi syndrome
• Light chain nephropathy due to multiple myeloma
• Various drug exposures (usually acetazolamide, sulfonamides, ifosfamide,
outdated tetracycline, or streptozocin)
It sometimes has other etiologies, including vitamin D deficiency, chronic hypocalcemia with
secondary hyperparathyroidism, kidney transplantation, heavy metal exposure, and other inherited
diseases (eg, fructose intolerance, Wilson disease, oculocerebrorenal syndrome [Lowe syndrome],
cystinosis).

Type 4 (generalized) RTA

Type 4 results from aldosterone deficiency or unresponsiveness of the distal tubule to aldosterone.
Because aldosteronetriggers sodium resorption in exchange for potassium and hydrogen, there is
reduced potassium excretion, causing hyperkalemia and reduced acid excretion. Hyperkalemia may
decrease ammonia excretion, contributing to metabolic acidosis. Urine pH is usually appropriate
for serum pH (usually < 5.5 when there is serum acidosis). Plasma bicarbonate is usually > 17
mEq/L (17 mmol/L). This disorder is the most common type of RTA. It typically occurs sporadically
secondary to impairment in the renin- aldosterone-renal tubule axis (hyporeninemic
hypoaldosteronism), which occurs in patients with the following:
• Diabetic nephropathy
• Chronic interstitial nephritis
Other factors that can contribute to type 4 RTA include the following:

• ACE inhibitor use

• Aldosterone synthase type I or II deficiency

• Angiotensin II receptor blocker use

• Chronic kidney disease, usually due to diabetic nephropathy or chronic interstitial nephritis
• Congenital adrenal hyperplasia, particularly 21-hydroxylase deficiency
• Critical illness

• Cyclosporine use
• Heparin use (including low molecular weight heparins)
 • HIV nephropathy (due, possibly in part, to infection with Mycobacterium avium complex or
cytomegalovirus)
• Interstitial renal damage (eg, due to SLE, obstructive uropathy, or sickle cell disease)

• Potassium-sparing diuretics (eg, amiloride, eplerenone, spironolactone, triamterene)

• NSAID use

• Obstructive uropathy
• Other drugs (eg, pentamidine, trimethoprim)
• Primary adrenal insufficiency

• Pseudohypoaldosteronism (type I or II)

• Volume expansion (eg, in acute glomerulonephritis or chronic kidney disease)

Symptoms and Signs

RTA is usually asymptomatic. Severe electrolyte disturbances are rare but can be life threatening.

Nephrolithiasis and nephrocalcinosis are possible, particularly with type 1 RTA.

Signs of ECF volume depletion may develop from urinary water loss accompanying electrolyte
excretion in type 2 RTA.

People with type 1 or type 2 RTA may show symptoms and signs of hypokalemia, including muscle
weakness, hyporeflexia, and paralysis. Bony involvement (eg, bone pain and osteomalacia in adults
and rickets in children) may occur in type 2 and sometimes in type 1 RTA.
Type 4 RTA is usually asymptomatic with only mild acidosis, but cardiac arrhythmias or paralysis
may develop if hyperkalemia is severe.

Diagnosis
• Suspected in patients with metabolic acidosis with normal anion gap or with unexplained
hyperkalemia

• Serum and urine pH, electrolyte levels, and osmolalities

• Often, testing after stimulation (eg, with ammonium chloride, bicarbonate, or a loop
diuretic)

RTA is suspected in any patient with unexplained metabolic acidosis (low plasma bicarbonate and
low blood pH) with normal anion gap. Type 4 RTA should be suspected in patients who have
persistent hyperkalemia with no obvious cause, such as potassium supplements, potassium-
sparing diuretics, or chronic kidney disease. ABG sampling is done to help confirm RTA and to
exclude respiratory alkalosis as a cause of compensatory metabolic acidosis. Serum electrolytes,
BUN, creatinine, and urine pH are measured in all patients. Further tests and sometimes
provocative tests are done, depending on which type of RTA is suspected:
• Type 1 RTA is confirmed by a urine pH that remains > 5.5 during systemic acidosis. The
acidosis may occur spontaneously or be induced by an acid load test (administration of
ammonium chloride 100 mg/kg po). Normal kidneys reduce urine pH to < 5.2 within 6 h of
acidosis.
• Type 2 RTA is diagnosed by measurement of the urine pH and fractional bicarbonate
excretion during a bicarbonate infusion (sodium bicarbonate 0.5 to 1.0 mEq/kg/h [0.5 to 1.0
mmol/L] IV). In type 2, urine pH rises above 7.5, and the fractional excretion of bicarbonate
is > 15%. Because IV bicarbonate can contribute to hypokalemia, potassium supplements
should be given in adequate amounts before infusion.
• Type 4 RTA is confirmed by a history of a condition that could be associated with type 4
RTA, chronically elevated potassium, and normal or mildly decreased bicarbonate. In most
cases plasma renin activity is low, aldosteroneconcentration is low, and cortisol is normal.

Treatment
• Varies by type

• Often alkali therapy

• Treatment of concomitant abnormalities related to potassium, calcium, and phosphate

metabolism

Treatment consists of correction of pH and electrolyte balance with alkali therapy. Failure to treat
RTA in children slows growth.

Alkaline agents such as sodium bicarbonate, potassium bicarbonate, or sodium citrate help achieve
a relatively normal plasma bicarbonate concentration (22 to 24 mEq/L [22 to 24 mmol/L]).
Potassium citrate can be substituted when persistent hypokalemia is present or, because sodium
increases calcium excretion, when calcium calculi are present.
Vitamin D (eg, ergocalciferol 800 IU po once/day) and oral calcium supplements (elemental
calcium 500 mg po tid, eg, as calcium carbonate, 1250 mg po tid) may also be needed to help
reduce skeletal deformities resulting from osteomalacia or rickets.

Type 1 RTA
Adults are given sodium bicarbonate or sodium citrate 0.25 to 0.5 mEq/kg (0.25 to 0.5 mmol/L) po
q 6 h. In children, the total daily dose may need to be as much as 2 mEq/kg (2 mmol/L) q 8 h; this
dose can be adjusted as the child grows. Potassium supplementation is usually not required when
the dehydration and secondary aldosteronism are corrected with bicarbonate therapy.
Type 2 RTA
Plasma bicarbonate cannot be restored to the normal range, but bicarbonate replacement should
exceed the acid load of the diet (eg, sodium bicarbonate 1 mEq/kg [1 mmol/L] po q 6 h in adults
or 2 to 4 mEq/kg [2 to 4 mmol/L] q 6 h in children) to maintain serum bicarbonate at about 22 to
24 mEq/L (22 to 24 mmol/L) because lower levels risk growth disturbance. However, excess
bicarbonate replacement increases potassium bicarbonate losses in the urine. Thus, citrate salts
can be substituted for sodium bicarbonate and may be better tolerated.
Potassium supplements or potassium citrate may be required in patients who become
hypokalemic when given sodium bicarbonate but is not recommended in patients with normal or
high serum potassium levels. In difficult cases, treatment with low-dose hydrochlorothiazide 25 mg
po bid may stimulate proximal tubule transport functions. In cases of generalized proximal tubule
disorder, hypophosphatemia and bone disorders are treated with phosphate and vitamin D
supplementation to normalize the plasma phosphate concentration.

Type 4 RTA
Hyperkalemia is treated with volume expansion, dietary potassium restriction, and potassium-
wasting diuretics (eg, furosemide 20 to 40 mg po once/day or bid titrated to effect). Alkalinization
is often unnecessary. A few patients need mineralocorticoid replacement therapy
(fludrocortisone 0.1 to 0.2 mg po once/day, often higher in hyporeninemic hypoaldosteronism);
mineralocorticoid replacement should be used with caution because it may exacerbate underlying
hypertension, heart failure, or edema.