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 Metabolic Acidosis Metabolic acidosis is primary reduction in bicarbonate (HCO3−), typically with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low or slightly... read more 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 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 Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more 
.
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 Hypokalemia Hypokalemia is serum potassium concentration < 3.5 mEq/L (< 3.5 mmol/L) caused by a deficit in total body potassium stores or abnormal movement of potassium into cells. The most common... read more , 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 Urinary Calculi Urinary calculi are solid particles in the urinary system. They may cause pain, nausea, vomiting, hematuria, and, possibly, chills and fever due to secondary infection. Diagnosis is based on... read more 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 Kidney Transplantation Kidney transplantation is the most common type of solid organ transplantation. (See also Overview of Transplantation.) The primary indication for kidney transplantation is End-stage renal failure... read more , or various disorders:
Autoimmune disease with hypergammaglobulinemia, particularly Sjögren syndrome Sjögren Syndrome Sjögren syndrome is a relatively common chronic, autoimmune, systemic, inflammatory disorder of unknown cause. It is characterized by dryness of the mouth, eyes, and other mucous membranes ... read more
or rheumatoid arthritis Rheumatoid Arthritis (RA) Rheumatoid arthritis is a chronic systemic autoimmune disease that primarily involves the joints. Rheumatoid arthritis causes damage mediated by cytokines, chemokines, and metalloproteases.... read more 
Nephrocalcinosis
Drugs (mainly amphotericin B, ifosfamide, and lithium)
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:
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 Kidney Transplantation Kidney transplantation is the most common type of solid organ transplantation. (See also Overview of Transplantation.) The primary indication for kidney transplantation is End-stage renal failure... read more , heavy metal exposure Heavy Metal Nephropathy Exposure to heavy metals and other toxins can result in tubulointerstitial disorders. (See also Overview of Tubulointerstitial Diseases.) Heavy metals (eg, lead, cadmium, copper) and other toxins... read more , and other inherited diseases (eg, fructose intolerance, Wilson disease Wilson Disease Wilson disease results in accumulation of copper in the liver and other organs. Hepatic or neurologic symptoms develop. Diagnosis is based on a low serum ceruloplasmin level, high urinary excretion... read more 
, oculocerebrorenal syndrome [Lowe syndrome], cystinosis).
Type 4 (generalized) RTA
Type 4 results from aldosterone deficiency or unresponsiveness of the distal tubule to aldosterone. Because aldosterone triggers sodium resorption in exchange for potassium and hydrogen, there is reduced potassium excretion, causing hyperkalemia Hyperkalemia Hyperkalemia is a serum potassium concentration > 5.5 mEq/L (> 5.5 mmol/L), usually resulting from decreased renal potassium excretion or abnormal movement of potassium out of cells. There... read more and reduced acid excretion. Hyperkalemia may decrease ammonia excretion, contributing to metabolic acidosis Metabolic Acidosis Metabolic acidosis is primary reduction in bicarbonate (HCO3−), typically with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low or slightly... read more . 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:
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 Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more
, usually due to diabetic nephropathy Diabetic Nephropathy Diabetic nephropathy is glomerular sclerosis and fibrosis caused by the metabolic and hemodynamic changes of diabetes mellitus. It manifests as slowly progressive albuminuria with worsening... read more 
or chronic interstitial nephritisCongenital adrenal hyperplasia Overview of Congenital Adrenal Hyperplasia Congenital adrenal hyperplasia is a group of genetic disorders, each characterized by inadequate synthesis of cortisol, aldosterone, or both. In the most common forms, accumulated hormone precursors... read more , particularly 21-hydroxylase deficiency
Critical illness
Cyclosporine use
Heparin use (including low molecular weight heparins)
HIV nephropathy HIV-Associated Nephropathy HIV-associated nephropathy is characterized by clinical findings similar to those of focal segmental glomerulosclerosis and often biopsy features of collapsing glomerulopathy (a variant of focal... read more
(due, possibly in part, to infection with Mycobacterium avium complex or cytomegalovirus)Interstitial renal damage (eg, due to systemic lupus erythematosus, obstructive uropathy, or sickle cell disease)
Nonsteroidal anti-inflammatory drugs (NSAIDs)
Other drugs (eg, pentamidine, trimethoprim)
Potassium-sparing diuretics (eg, amiloride, eplerenone, spironolactone, triamterene)
Primary adrenal insufficiency
Volume expansion (eg, in acute glomerulonephritis or chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more
)
Symptoms and Signs of RTA
RTA is usually asymptomatic. Severe electrolyte disturbances are rare but can be life threatening.
Nephrolithiasis Urinary Calculi Urinary calculi are solid particles in the urinary system. They may cause pain, nausea, vomiting, hematuria, and, possibly, chills and fever due to secondary infection. Diagnosis is based on... read more and nephrocalcinosis are possible, particularly with type 1 RTA.
Signs of extracellular fluid 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 Hypokalemia Hypokalemia is serum potassium concentration < 3.5 mEq/L (< 3.5 mmol/L) caused by a deficit in total body potassium stores or abnormal movement of potassium into cells. The most common... read more , 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 Overview of Arrhythmias The normal heart beats in a regular, coordinated way because electrical impulses generated and spread by myocytes with unique electrical properties trigger a sequence of organized myocardial... read more 
or paralysis may develop if hyperkalemia is severe.
Diagnosis of RTA
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 Metabolic Acidosis Metabolic acidosis is primary reduction in bicarbonate (HCO3−), typically with compensatory reduction in carbon dioxide partial pressure (Pco2); pH may be markedly low or slightly... read more (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 Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more . Arterial blood gas (ABG) sampling is done to help confirm RTA and to exclude respiratory alkalosis as a cause of compensatory metabolic acidosis. Serum electrolytes, blood urea nitrogen (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 orally). Normal kidneys reduce urine pH to < 5.2 within 6 hours 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/hour [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, aldosterone concentration is low, and cortisol is normal.
Treatment of RTA
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 Hypokalemia Hypokalemia is serum potassium concentration < 3.5 mEq/L (< 3.5 mmol/L) caused by a deficit in total body potassium stores or abnormal movement of potassium into cells. The most common... read more is present or, because sodium increases calcium excretion, when calcium calculi are present.
Vitamin D (eg, ergocalciferol 800 IU orally once/day) and oral calcium supplements (elemental calcium 500 mg orally 3 times/day, eg, as calcium carbonate, 1250 mg orally 3 times/day) may also be needed to help reduce skeletal deformities resulting from osteomalacia or rickets Hypophosphatemic Rickets Hypophosphatemic rickets is a genetic disorder characterized by hypophosphatemia, defective intestinal absorption of calcium, and rickets or osteomalacia unresponsive to vitamin D. It is usually... read more .
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) orally every 6 hours. In children, the total daily dose may need to be as much as 2 mEq/kg (2 mmol/L) every 8 hours; 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] orally every 6 hours in adults or 2 to 4 mEq/kg [2 to 4 mmol/L] every 6 hours 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 orally twice/day 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 orally once or twice/day titrated to effect). Alkalinization is often unnecessary. A few patients need mineralocorticoid replacement therapy (fludrocortisone 0.1 to 0.2 mg orally once/day, often higher in hyporeninemic hypoaldosteronism); mineralocorticoid replacement should be used with caution because it may exacerbate underlying hypertension, heart failure, or edema.
Key Points
Renal tubular acidosis is 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.
RTA is usually due to abnormal aldosterone production or response (type 4), or less often, due to impaired hydrogen ion excretion (type 1) or impaired bicarbonate resorption (type 2).
Consider RTA if patients have metabolic acidosis with a normal anion gap or unexplained hyperkalemia
Check ABG and serum electrolytes, BUN, and creatinine, and urine pH.
Do other testing to confirm type of RTA (eg, acid load test for type 1, bicarbonate infusion for type 2).
Treat using alkali therapy and measures to correct low serum potassium in type 2 and sometimes type 1 RTA , and using potassium restriction or potassium-wasting diuretics in type 4 RTA; give other electrolytes as needed.
