AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

This article covers the pathophysiology and causes of hyperchloremic metabolic acidoses, in particular the renal tubular acidoses (RTAs). It also addresses approaches to the diagnosis and management of these disorders. See also Metabolic Acidosis.

A low plasma bicarbonate concentration represents, by definition, metabolic acidosis, which may be primary or secondary to a respiratory alkalosis. Primary metabolic acidoses can occur as a result of a marked increase in endogenous acid production (eg, lactic or keto acids), loss of bicarbonate stores through diarrhea or renal tubular wasting, or progressive accumulation of endogenous acids when excretion is impaired by renal insufficiency.

The initial differentiation of metabolic acidosis should involve a determination of the anion gap (AG). This is usually defined as AG = (Na⁺) - [(HCO₃^- + Cl^-)], in which Na⁺ is sodium concentration, HCO₃^- is bicarbonate concentration, and Cl^- is chloride concentration; all concentrations are in mmol/L. It represents the difference between unmeasured cations and anions. This difference is due to the presence of anions in the plasma that are not routinely measured.

An increased AG is associated with renal failure, ketoacidosis, lactic acidosis, and ingestion of various toxins; it can usually be easily identified by evaluating routine plasma chemistry results and from the clinical picture. A normal AG acidosis is characterized by a lowered bicarbonate concentration, which (in the presence of a normal sodium concentration) is counterbalanced by an equivalent increase in plasma chloride concentration. For this reason, it is also known as hyperchloremic metabolic acidosis.

This finding suggests that HCO₃^- has been effectively replaced by Cl^- and arises from one of the following conditions:

• Bicarbonate loss from body fluids through the GI tract or kidneys, with subsequent chloride retention
• Defective renal acidification with failure to excrete normal quantities of metabolically produced acid (The conjugate base is excreted as the sodium salt and sodium chloride is retained.)
• Addition of hydrochloric acid to body fluids
• Addition or generation of another acid with rapid titration of bicarbonate and rapid renal excretion of the accompanying anion and replacement by chloride
• Rapid dilution of the plasma bicarbonate by saline

Pathophysiology

Gastrointestinal

Diarrhea is the most common cause of external loss of alkali resulting in metabolic acidosis. Biliary, pancreatic, and duodenal secretions are alkaline and are capable of neutralizing the acidity of gastric secretions. In normal situations, a luminal Na⁺/H⁺ exchanger in the jejunal mucosa effectively results in sodium bicarbonate (NaHCO₃) reabsorption, and the 100 mL of stool excreted daily has very small amounts of bicarbonate.

The development of diarrheal states and increased stool volume (potentially several L/d) may cause a daily loss of several hundred millimoles of bicarbonate. Some of this loss may not occur as bicarbonate loss itself; instead, intestinal flora produce organic acids that titrate bicarbonate, resulting in loss of organic anions in the stool stoichiometrically equivalent to the titrated bicarbonate. Because diarrheal stools have a higher bicarbonate concentration than plasma, the net result is a metabolic acidosis with volume depletion.

Other GI conditions associated with external losses of fluids may lead to large alkali losses. These include enteric fistulas and drainage of biliary, pancreatic, and enteric secretions; ileus secondary to intestinal obstruction, in which up to several liters of alkaline fluid may accumulate within the intestinal lumen; and villous adenomas that secrete fluid with a high bicarbonate content.

Renal

The kidneys maintain acid-base balance by bicarbonate reclamation and acid excretion. Most conditions that affect the kidneys cause a proportionate simultaneous loss of glomerular and tubular function. Loss of glomerular function results in the retention of many products of metabolism, including the anions of various organic and inorganic acids and urea. Loss of tubular function prevents the kidneys from excreting hydrogen ions and thereby causes metabolic acidosis. The development of azotemia, anion retention, and acidosis is defined as uremic acidosis. The term hyperchloremic acidosis (ie, RTA) refers to a diverse group of tubular disorders, uncoupled from glomerular damage, characterized by impairment of urinary acidification without urea and anion retention. These disorders can be divided into 2 general categories, proximal (type II) and distal (types I and IV).

Proximal renal tubular acidosis (type II [bicarbonate-wasting acidosis])

The proximal tubule is the major site for reabsorption of filtered bicarbonate. In proximal RTA (pRTA), bicarbonate reabsorption is defective. pRTA rarely occurs as an isolated defect of bicarbonate transport and is usually associated with multiple proximal tubule transport defects; therefore, urinary loss of glucose, amino acids, phosphate, uric acid, and other organic anions such as citrate can also occur (Fanconi syndrome).

A distinctive feature of type II pRTA is that it is nonprogressing, and when the serum bicarbonate is reduced to approximately 15 mEq/L, a new transport maximum is established and the proximal tubule is able to reabsorb all of the filtered bicarbonate. A fractional excretion of bicarbonate greater than 15% when the plasma bicarbonate is normal after bicarbonate loading is diagnostic of pRTA. In contrast, the fractional excretion of bicarbonate in low and normal bicarbonate levels is always less than 5% in distal RTA (dRTA). Another feature of pRTA is that the urine pH can be lowered to less than 5.5 with acid loading.

The pathogenic mechanisms responsible for the tubular defect in persons with pRTA are not completely understood. Defective pump secretion or function, namely the proton pump ([H⁺ adenosine triphosphatase [ATPase]), the Na⁺/H⁺ antiporter, and the basolateral membrane Na⁺/K⁺ ATPase, impair bicarbonate reabsorption. Deficiency of carbonic anhydrase (CA) in the brush-border membrane or its inhibition also results in bicarbonate wasting. Finally, structural damage to the luminal membrane with increased bicarbonate influx or a failure of generated bicarbonate to exit is a proposed mechanism that does not currently have strong experimental backing.

Distal renal tubular acidosis

The distal nephron, primarily the collecting duct, is the site at which urine pH reaches its lowest values. Inadequate acid secretion and excretion produce a systemic acidosis. A metabolic acidosis occurring secondary to decreased renal acid secretion in the absence of marked decreases in the glomerular filtration rate and characterized by a normal AG is due to diseases that are usually grouped under the term dRTA. These are further classified into hypokalemic (type I) and hyperkalemic (type IV) RTA. Until the 1970s, dRTA was thought to be a single disorder caused by an inability to maintain a steep H⁺ gradient across the distal nephron, either as a failure to excrete H⁺ or as a result of increased back-diffusion of H⁺ through an abnormally permeable distal nephron. Structural damage to the nephron from a variety of sources has been shown to result in different pathogenic mechanisms.

Excretion of urinary ammonium (NH4⁺) accounts for the largest portion of the kidneys' response to the accumulation of metabolic acids. Patients with dRTA are unable to excrete ammonium in amounts adequate to keep pace with a normal rate of acid production. In some forms of the syndrome, maximally acidic urine can be formed, indicating the ability to establish a maximal H⁺ gradient. However, despite the maximally acidic urine, the total amount of ammonium excretion is low. In other forms, urine pH cannot reach maximal acidity despite systemic acidemia, indicating low H⁺ secretion in the collecting duct.

In the presence of systemic acidemia, a low rate of urinary ammonium secretion is related either to decreased production of ammonia by the cells of the proximal convoluted tubule or to failure to accumulate ammonium in the distal convoluted tubule and excrete it in the urine. Decreased ammonium production is observed in hyperkalemic types of dRTA, also known as type IV RTA, because hyperkalemia causes an intracellular alkalosis with resultant impairment of ammonium generation and excretion. Acid secretion is thus reduced because of the deficiency of urinary buffers. This type of acidosis is also observed in early renal failure, due to a reduction in renal mass and decreased ammonium production in the remaining proximal tubular cells.

• Hypokalemic (classic) distal renal tubular acidosis (type I): In hypokalemic dRTA, also known as classic RTA or type I RTA, the deficiency is secondary to 2 main pathophysiological mechanisms, (1) a secretory defect and (2) a permeability defect.
• • When a secretory defect predominates, the decreased secretion of protons fails to maximally decrease the urinary pH. A decrease in the formation of titratable acidity and in ammonium trapping and secretion results in systemic acidosis. The mechanism of the hypokalemia is unclear, but hypotheses include (1) increased leakage of K⁺ into the lumen, (2) volume contraction due to urinary sodium loss and resulting in aldosterone stimulation that increases potassium losses, and (3) decreased proximal K⁺ reabsorption due to acidemia and hypocapnia.
  • When a permeability defect predominates, the collecting-duct proton pump functions normally but the high intratubular concentration of H⁺ dissipates due to abnormal permeability of the tubular epithelium.
• Hyperkalemic distal renal tubular acidosis (type IV): The pathogenesis of hyperkalemic dRTA, the most common RTA, is ascribed to 2 mechanisms, (1) a voltage defect or (2) a rate defect due to aldosterone deficiency or resistance.
• • The voltage-related type is more rare and is thought to be caused by inadequate negative intratubular potential at the cortical collecting duct. This, in turn, causes inadequate secretion of protons and potassium, with decreased trapping and excretion of ammonium and decreased excretion of potassium. Inadequate voltage generation may be secondary to several factors, including (1) administration of certain drugs, such as amiloride; (2) structural defects that inhibit active sodium reabsorption, such as sickle cell nephropathy; (3) severe limitation of sodium reabsorption in the distal tubule because of proximal sodium avidity, secondary to diseases such as cirrhosis; and (4) increased epithelial permeability to chloride, causing increased reabsorption and preventing the negative voltage linked to sodium reabsorption.
  • The more common form of hyperkalemic dRTA is due to aldosterone resistance or deficiency. Postulated mechanisms include (1) destruction of juxtaglomerular cells; (2) decreased sympathetic denervation of the juxtaglomerular apparatus; (3) decreased production of prostacyclin, causing a decrease in renin-aldosterone production; (4) primary hypoaldosteronism; and (5) secondary hypoaldosteronism from the long-term use of heparin. Aldosterone increases Na⁺ absorption and the negative intratubular potential. It also increases luminal membrane permeability to potassium and stimulates basolateral Na⁺/K⁺/ATPase, causing increased urinary potassium losses. Because aldosterone also directly stimulates the proton pump, aldosterone deficiency or resistance would be expected to cause hyperkalemia and acidosis. Another major factor in decreasing net acid excretion is the inhibition of ammoniagenesis due to hyperkalemia.
  • Incomplete distal renal tubular acidosis is another clinically important entity. It is considered a variant/milder form of type I RTA, in which the plasma bicarbonate concentration is normal, but there is a defect in tubular acid secretion. However, daily net acid excretion is maintained by increased ammoniagenesis. Hypercalciuria and hypocitraturia are present, so there is a propensity to nephrolithiasis and nephrocalcinosis. Most of the cases are those of idiopathic calcium phosphate stone formers, relatives of individuals with RTA or with unexplained osteoporosis. Any idiopathic stone former should be evaluated (by NH4Cl infusion).
  • See Hyporeninemic Hypoaldosteronism.

Miscellaneous

The administration of calcium chloride or cholestyramine (cationic resin that is given as chloride salt) may cause acidosis because of the formation of calcium carbonate or the bicarbonate salt of cholestyramine in the lumen of the intestine, which is then eliminated in the stool. Ureteral-GI connections, such as ureterosigmoidostomy for urinary diversion, also cause a potentially severe acidosis in virtually all patients. This acidosis results from the retention of urinary ammonium across the colonic mucosa and from the stool losses of bicarbonate. Because of this complication, ileal conduits have now largely replaced the procedure. However, hyperchloremic metabolic acidosis still occurs in approximately 10% of patients with ileal conduits, especially if obstruction is present.

The occurrence of metabolic acidosis with a normal AG is common in the late phase of diabetic ketoacidosis. This results from urinary loss of ketoanions with sodium and potassium. This external loss is equivalent to a loss of potential bicarbonate because each ketoanion, if retained and metabolized, would consume a proton and generate a new molecule of bicarbonate.

Infusion of large volumes of solutions containing sodium chloride and no alkali can cause a hyperchloremic metabolic acidosis. This is due to a dilution of the preexisting bicarbonate and to decreased renal bicarbonate reabsorption as a result of volume expansion.

In patients with a chronic respiratory alkalosis, renal acid secretion is decreased but endogenous acid production and chloride reabsorption are normal, resulting in a decreased plasma bicarbonate concentration and elevated chloride concentration. When the hypocapnia is repaired, the return of the PCO₂ to normal unveils a metabolic acidosis.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

Metabolic acidosis, per se, has no specific symptoms and signs; however, it can produce symptoms and signs from changes in pulmonary, cardiovascular, neurologic, and musculoskeletal function. Patients may report dyspnea upon exertion or, in severe cases, at rest.

Physical

Although metabolic acidosis has no specific symptoms and signs, changes in pulmonary, cardiovascular, neurologic, and musculoskeletal function may produce signs.

• General neurologic
• • If the acidosis is marked and of acute onset, the patient may report headache, lack of energy, nausea, and vomiting.
  • Neurologic abnormalities such as mental confusion progressing to stupor, when observed, are not usually secondary to the acidosis but are the cause of the acidosis itself.
  • In general, neurologic abnormalities are less common in persons with metabolic acidosis than in persons with respiratory acidosis.
• Pulmonary
• • An increase in minute ventilation of up to 4- to- 8-fold may occur in persons with respiratory compensation.
  • Tachypnea or hyperpnea (affecting the depth more than the rate of ventilation) may be the only clue to an underlying acidotic state.
• Cardiovascular
• • Effects on the cardiovascular system include direct impairment of myocardial contraction (especially at a pH <7.2), tachycardia, and increased risk of ventricular fibrillation or heart failure with pulmonary edema.
  • In advanced stages, overt cardiovascular collapse may occur from impaired catecholamine release.
• Musculoskeletal
• • Chronic acidemia, as is observed in RTA, can lead to a variety of skeletal problems. This is probably due in part to the release of calcium and phosphate during bone buffering of the excess protons. Decreased tubular absorption of calcium secondary to acidemia, especially in dRTA, leads to a negative calcium balance.
  • Clinical consequences include osteomalacia (leading to impaired growth in children), osteitis fibrosa (from secondary hyperparathyroidism), rickets (in children), and osteomalacia or osteopenia (in adults).
• Genitourinary
• • An important complication of chronic renal tubular acidosis (mainly distal, type I) is nephrocalcinosis and urolithiasis. A number of pathophysiological alterations contribute to stone formation.
    • Buffering of the chronic acid load by the bone, causing bone dissolution and promoting hypercalciuria
    • Diminution of renal tubular calcium reabsorption, further aggravating the hypercalcuria
    • Hypocitraturia because of avid citrate reabsorption by the proximal tubule
    • High urinary pH, causing insolubility of calcium phosphate and promoting its precipitation
  • In contrast, stone disease is rare with type 2 RTA because of the difference in its pathogenesis. Since the fall in plasma HCO₃ is nonprogressive, after the renal HCO₃ threshold is reached, there is complete absorption of luminal HCO₃. At this point, the urine pH is acid, since urine is devoid of HCO₃ and there is no defect in distal proton secretion. The daily acid load is thus excreted by the collecting duct, obviating the need for bone buffering. Also, citrate usually escapes proximal reabsorption (along with other solutes) and promotes calcium phosphate solubility.

Causes

• GI bicarbonate loss
• • Diarrhea may be caused by external pancreatic, biliary, or small bowel drainage; an ileus; a ureterosigmoidostomy; a jejunal loop; or an ileal loop, which may result in persons with hyperchloremic metabolic acidosis.
  • Drugs that increase GI bicarbonate loss include calcium chloride, magnesium sulfate, and cholestyramine.
• Proximal renal tubular acidosis
• • Causes of proximal tubular bicarbonate wasting are numerous. A selective defect (eg, isolated bicarbonate wasting) can occur as a primary disorder (with no obvious associated disease) that can be genetically transmitted or occur in transient form in infants.
  • Alterations in CA activity through drugs such as acetazolamide, sulfanilamide, and mafenide acetate produce bicarbonate wasting. Osteopetrosis with CA II deficiency and genetically transmitted and idiopathic CA deficiency also fall into the selective defect category. A generalized proximal tubule defect associated with multiple dysfunctions of the proximal tubule can also occur as a primary disorder in sporadic and genetically transmitted forms. It also occurs in association with genetically transmitted systemic diseases, including Wilson disease, cystinosis and tyrosinemia, Lowe syndrome, hereditary fructose intolerance, pyruvate carboxylase deficiency, metachromatic leukodystrophy, and methylmalonic acidemia.
  • pRTA is also observed in conditions associated with chronic hypocalcemia and secondary hyperparathyroidism, such as vitamin D deficiency or vitamin D resistance. Dysproteinemic states, such as multiple myeloma and monoclonal gammopathy, are also associated with pRTA.
  • Drugs or toxins that can induce pRTA include streptozotocin, lead, mercury, arginine, valproic acid, gentamicin, ifosfamide, and outdated tetracycline.
  • Renal tubulointerstitial conditions that are associated with pRTA include renal transplantation, Sjögren syndrome, and medullary cystic disease. Other renal causes include nephrotic syndrome and amyloidosis.
  • Paroxysmal nocturnal hemoglobinuria and hyperparathyroidism can also cause pRTA.
  • A summary of the causes of pRTA (type II) is as follows:
    • Primary - Familial or sporadic
    • Dysproteinemic states - Multiple myeloma (both pRTA and dRTA), amyloidosis (both pRTA and dRTA), light chain disease, cryoglobulinemia, monoclonal gammopathy
    • CA-related conditions - Osteopetrosis (anhydrase II deficiency), acetazolamide, mafenide
    • Drug or toxic nephropathy - Lead, cadmium, mercury, streptozotocin, outdated tetracycline, ifosfamide (both pRTA and dRTA)
    • Hereditary disorders - Cystinosis, galactosemia, Wilson disease, hereditary fructose intolerance, glycogen storage disease type I, tyrosinemia, Lowe syndrome
    • Interstitial renal conditions - Sjögren syndrome, medullary cystic disease (both pRTA and dRTA), Balkan nephropathy, renal transplant rejection (both pRTA and dRTA)
    • Miscellaneous - Paroxysmal nocturnal hemoglobinuria, malignancy, nephrotic syndrome, chronic renal vein thrombosis
• Hypokalemic (classic) distal renal tubular acidosis (type I)
• • Primary dRTA has been described in both sporadic and genetically transmitted forms. Autoimmune disorders such as hypergammaglobulinemia, cryoglobulinemia, Sjögren syndrome, thyroiditis, pulmonary fibrosis, chronic active hepatitis, primary biliary cirrhosis, systemic lupus erythematosus, and vasculitis can be associated with dRTA. dRTA can be secondary to genetically transmitted systemic diseases, including Ehlers-Danlos syndrome, hereditary elliptocytosis, sickle cell disease, Marfan syndrome, CA I deficiency or alteration, medullary cystic disease, and neuroaxonal dystrophy.
  • Disorders associated with nephrocalcinosis that cause hypokalemic dRTA include primary or familial hyperparathyroidism, vitamin D intoxication, milk-alkali syndrome, hyperthyroidism, idiopathic hypercalciuria, hereditary fructose intolerance, Fabry disease, and Wilson disease.
  • Drugs or toxins that can cause dRTA include amphotericin B, toluene, nonsteroidal anti-inflammatory drugs, lithium, and cyclamate.
  • Renal tubulointerstitial conditions associated with dRTA include chronic pyelonephritis, obstructive uropathy, renal transplantation, leprosy, and hyperoxaluria.
  • A summary of the causes of dRTA (type I) is as follows:
    • Primary - Idiopathic, isolated, sporadic
    • Tubulointerstitial conditions - Renal transplantation, chronic pyelonephritis, obstructive uropathy, leprosy
    • Genetic - Familial, Marfan syndrome, Wilson disease, Ehlers-Danlos syndrome, medullary cystic disease (dRTA and pRTA), osteopetrosis
    • Conditions associated with nephrocalcinosis - Hyperoxaluria, primary hypercalciuria, hyperthyroidism, primary hyperparathyroidism, vitamin D intoxication, milk-alkali syndrome, medullary sponge kidney
    • Autoimmune disorders - Chronic active hepatitis, primary biliary cirrhosis, Sjögren syndrome (dRTA and pRTA), systemic lupus erythematosus, autoimmune thyroiditis, pulmonary fibrosis, vasculitis
    • Drugs and toxicity - Amphotericin B, analgesics, lithium, toluene, ifosfamide (dRTA and pRTA)
    • Hypergammaglobulinemic states - Myeloma (both dRTA and pRTA), amyloidosis (dRTA and pRTA), cryoglobulinemia
    • Miscellaneous - Hepatic cirrhosis, AIDS (possibly)
• Hyperkalemic distal renal tubular acidosis (type IV)
• • Deficiency of or resistance to aldosterone is the most common cause of hyperkalemic dRTA. Deficiency of aldosterone with glucocorticoid deficiency is associated with Addison disease, bilateral adrenalectomy, and enzymatic defects (eg, 21-hydroxylase deficiency, 3 beta-ol-dehydrogenase deficiency, desmolase deficiency). Isolated aldosterone deficiency can be secondary to states of deficient renin secretion, including diabetic nephropathy, tubulointerstitial renal disease, nonsteroidal anti-inflammatory drug use, beta-adrenergic blocker use, AIDS, and renal transplantation.
  • Isolated aldosterone deficiency can also be observed secondary to heparin use; in corticosterone methyl oxidase deficiency, a genetically transmitted disorder; and in a transient infantile form.
  • Angiotensin1-converting enzyme inhibition, either endogenously or through ACE inhibitors such as captopril, and the newer angiotensin AT1 receptor blockers can cause hyperkalemic dRTA.
  • Resistance to aldosterone secretion is observed in pseudohypoaldosteronism, childhood forms of obstructive uropathy, cyclosporine nephrotoxicity, renal transplantation, and the use of spironolactone.
  • Voltage-mediated defects that cause hyperkalemic dRTA can be observed in obstructive uropathy; sickle cell disease; and the use of lithium, triamterene, amiloride, trimethoprim, or pentamidine.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Nonanion gap metabolic acidosis
Renal tubular acidosis

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The initial evaluation of a person with hyperchloremic acidosis should include a complete history and physical examination.
• Metabolic acidosis due to loss of intestinal secretions, medications, or exogenous acid intake is usually apparent from the history. An exception is diarrhea due to laxative abuse, for which the history is difficult to obtain. When this condition is suggested because of hypokalemia and a normal AG metabolic acidosis, it may be confirmed by findings of low sodium concentration in the urine from volume contraction, positive test results for stool phenolphthalein, or high fecal magnesium levels.
• Loss of intestinal secretions as the cause of acidosis may be confirmed by measuring the pH and AG ([Na⁺] + [K⁺] - [Cl^-]) of the volume lost; an alkaline pH and elevated AG suggest bicarbonate loss.
• If the cause of acidosis is not apparent from the history and physical examination findings, the next step is to determine whether hyperchloremic acidosis is present. Urinary ammonium excretion and urine pH can be used to define the etiology of the disorder:
• Urinary ammonium excretion (urine AG; urine net charge) is inferred from the urine AG, also known as the urine net charge, when direct measurement of ammonium is not possible.
• • The urine net charge is defined as follows: U_NA⁺ + U_K⁺ – U _Cl^- in which U_NA⁺ is urinary concentration of sodium, U_K⁺ is urinary concentration of potassium, and U_Cl^- is urinary concentration of chloride. The urinary net charge and ammonium excretion have a linear relationship. When excretion of Cl^- exceeds that of Na⁺ and K⁺, the urinary net charge is negative, and the assumption is that a substantial concentration of ammonium is present in the urine, which would be the case in metabolic acidosis of nonrenal origin. Conversely, in both hypokalemic and hyperkalemic dRTA, the urine concentration of ammonium is insufficient, excretion of Na⁺ and K⁺ exceed that of Cl^-, and the urinary net charge is positive.
  • This method has potential pitfalls. A negative urine AG is also observed in patients whose acidosis is due to nonrenal causes but in whom maximal acidification fails because of decreased presentation of sodium to the distal nephron. In these cases, the urinary sodium concentration is very low. Urinary excretion of ketoanions secondary to systemic ketoacidosis can cause a positive AG despite adequate ammonium excretion. Thus, ketonuria should also be excluded in cases of metabolic acidosis in which the etiology is uncertain enough to warrant calculation of the urine AG. The urine net charge is also less useful when large amounts of bicarbonate are present in the urine (pH >6).
• Urine pH tends to be increased in the presence of large amounts of ammonia in the urine.
• • An inability to lower the urine pH to less than 5.5 despite systemic acidemia was formerly considered the hallmark of dRTA. Given that a lower pH implies increased excretion of acid if the concentration of urinary buffers stays constant, an inability to decrease urine pH was interpreted as signifying decreased excretion of urine acid. Although this is true in many cases, it is not in all cases.
  • The presence of large amounts of ammonia in the urine, which typically occurs with chronic metabolic acidosis, tends to increase the urine pH. In hyperkalemic dRTA, urine pH can be maximally acidic. Decreased acid excretion is due to other concurrent defects, mainly decreased production of ammonia.
  • In patients with normal AG acidosis due to diarrhea, the pH can be greater than 5.5. This is because volume contraction results in decreased availability of Na⁺ for reabsorption in the collecting duct, lessening the negative intratubular potential and, thus, the rate of proton secretion.
  • Infection with urea-splitting organisms can also cause elevated urinary pH and may lead to an incorrect diagnosis of RTA.
  • The urine AG is calculated using the following formula: U_AG = U_NA⁺ + U_K⁺ – U _Cl^-.
  • Na⁺ + K⁺ + unmeasured cations = Cl^- + unmeasured anions. In the absence of ketonuria and bicarbonaturia, there are no significant unmeasured anions in the urine. The principal unmeasured cation is NH₄ and when present in substantial concentration is evident by a negative AG. U_AG is thus a measure of the urinary concentration of NH₄.
  • Urine pH and urine AG values in patients with RTA are as follows:
    • dRTA - Urine pH greater than 5.3, urine AG positive
    • pRTA - Urine pH usually less than 5.3, urine AG variable
    • dRTA type IV - Urine pH less than 5.3, urine AG positive
    • Renal failure - Urine pH less than 5.3, urine AG positive
    • Diarrhea - Urine pH variable, urine AG negative

Other Tests

• Acid-loading tests
• • The most common acid-loading test uses ammonium chloride. This test consists of the oral administration of 0.1 g/kg (1.9 mEq/kg) of ammonium chloride to induce metabolic acidosis. Urine is collected hourly 2-8 hours after administration, and urinary pH is tested. Failure to acidify urine below a pH of 5.5 supports the diagnosis of dRTA or incomplete dRTA, in which systemic acidosis is absent.
  • Urine pH would decrease normally in pRTA and hypoaldosteronism. In the setting of a preexisting acidosis, administration of an acidifying agent is unnecessary and potentially harmful.
  • Calcium chloride and arginine hydrochloride can also be used to induce systemic acidosis, with interpretation of results the same as for the ammonium chloride test.
• Urine PCO₂ test
• • The urine PCO₂ during alkaline diuresis reflects the rate of proton secretion in the distal tubule. In an alkaline diuresis induced by infusions of NaHCO₃, the intratubular pH is high, and this results in a high rate of proton secretion. Because of the high concentration of bicarbonate in the urine, large quantities of carbonic acid form. The carbonic acid dehydrates and forms water and carbon dioxide, thus raising the urine PCO₂.
  • In healthy individuals undergoing a bicarbonate diuresis, the urine PCO₂ should rise to above 70 mm Hg. In patients with secretory defects, ie, the inability to secrete protons in the collecting duct, the urine PCO₂ fails to rise above 55 mm Hg. In patients with permeability defects, the carbon dioxide tension rises normally because of the normal proton-pump function and because the H⁺ gradient does not favor the back-diffusion of protons under conditions of alkaline diuresis. Normal results are also observed in hypoaldosteronism RTA and reversible voltage-dependent defects.
  • The test is performed by infusing a quantity of NaHCO₃ sufficient to raise plasma bicarbonate to greater than 30 mEq/L and urine pH to higher than 7. This can be accomplished with intravenous or oral NaHCO₃. With the intravenous route, 7.5% NaHCO₃ is infused at a rate of 1-2 mL/min for 2 hours, with hourly samples taken for the duration of the test. The infusion is stopped when the pH from at least 3 urine collections is greater than 7.8. With the oral route, 200 mEq of NaHCO₃ is given in divided doses the evening prior to testing, and overnight dehydration is necessary.
  • An important disadvantage of this test is that false-positive results can occur in persons with concentration defects because urine bicarbonate concentrations are lower and lead to less carbon dioxide generated. This is significant because concentration defects are common in persons with dRTA and are a consistent finding in persons with chronic renal failure.
  • Contraindications to the test are other sodium-retaining states and congestive heart failure.
• Sodium sulfate and furosemide test
• • In healthy individuals, administering a sodium salt of a nonreabsorbable anion in the presence of a sodium-avid state results in negative intratubular potential and thus increased proton and potassium secretion. In patients with either secretory or voltage defects, the urine will not become maximally acidic. The test is performed by restricting salt to less than 1 g/d Na⁺ for 3 days and orally administering 1 mg of fludrocortisone in the evening 12 hours before the sodium sulfate infusion in order to ensure a sodium-avid state. The following morning, 500 mL of 4% sodium sulfate is administered intravenously over 1 hour. Urine pH, potassium excretion, and net acid excretion should be obtained.
  • A normal response does not necessarily rule out an acidification defect because a normal response can be observed in patients with hyperkalemic dRTA and those with reversible voltage-dependent defects, as with lithium. False-positive results can occur when the infusion is too rapid or when sodium avidity is absent because inadequate preparation or aldosterone resistance causes a bicarbonate-losing osmotic diuresis, thus raising the urine pH.
  • Because sodium sulfate is not commercially available, this method is largely limited to research settings. A more practical method involves orally administering 1 mg fludrocortisone the evening before testing and then giving 1 mg/kg of oral or intravenous furosemide the following morning. Evidence suggests furosemide enhances distal acidification by increasing distal sodium delivery, and results should be interpreted in the same manner as for the sodium sulfate test.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Treatment of GI causes of hyperchloremic acidosis is aimed at the underlying cause and includes (1) administration of saline solutions to repair the volume losses and (2) early administration of potassium.
  • Treatment of acidosis with bicarbonate-containing solutions is accompanied by potassium replacement to avoid severe hypokalemia, with its possible associated cardiac arrhythmias and muscular paralysis due to the introduction of potassium into the cells.
  • Patients with chronic acidosis secondary to diarrhea benefit from long-term therapy with sodium and potassium citrate solutions.
• For hyperchloremic acidosis (ie, RTA), once an underlying disease entity has been identified, specific therapy is needed to control the primary problem. Therapy for the hyperchloremic acidosis itself is still needed. Depending on the type of RTA, the goals of therapy are to decrease the rate of progressive renal insufficiency by preventing nephrocalcinosis and nephrolithiasis; to neutralize metabolic bone disease; and, in children, to improve growth.
• In cases of pRTA, multitherapy with large quantities of alkali, vitamin D, and potassium supplementation is required.
• • The usual range of bicarbonate administration is 5-15 mEq/kg/d, and the administration must be accompanied or preceded by the administration of large amounts of potassium.
  • pRTA can be difficult to treat because alkali administration results in prompt and marked bicarbonaturia and potassium wasting.
  • The use of diuretics to induce extracellular volume depletion that enhances proximal tubular bicarbonate reabsorption can be effective but is usually accompanied by worsening of the hypokalemia. Thus, diuretics must be used with caution, and they require additional potassium or the addition of potassium-sparing agents.
• In hypokalemic dRTA, treatment consists of long-term alkali administration in amounts sufficient to counterbalance endogenous acid production and any bicarbonaturia that may be present.
  • Fortunately, the alkali requirements of these patients are minimal compared with the requirements needed to treat patients with pRTA. A daily dose of 1-2 mEq/kg of NaHCO₃ is usually sufficient in most cases and can be provided in the form of sodium citrate solution (ie, Shohl Solution), which is well tolerated because it causes less abdominal distention and aerophagia than bicarbonate.
  • Providing bicarbonate via citrate salts that are metabolized to bicarbonate in the liver provides the additional advantage of exogenous citrate from the portion escaping hepatic metabolism.
  • Potassium supplements are indicated in the presence of hypokalemia. Hypokalemia can be severe, and patients can be symptomatic. Spironolactone can be used to maintain normokalemia.
  • Corrective alkali therapy results in normal growth in children with dRTA if therapy is started early.
  • Hypercalciuria, nephrolithiasis, and nephrocalcinosis are also prevented when alkali therapy is started in the early stages of dRTA.
• With hyperkalemic dRTA, entities amenable to intervention, such as obstructive uropathy, must be identified.
• • In general, distal sodium delivery is increased if patients increase ingestion of dietary salt, taking into account that many of these patients have concomitant cardiorenal compromise.
  • Fluid overload can be overcome with the addition of furosemide to a high-salt diet. This combination encourages distal delivery of sodium by rendering the collecting tubule impermeable to chloride, and it increases the exchange of sodium for hydrogen and potassium.
  • Mineralocorticoid therapy (ie, fludrocortisone in daily doses of 0.1-0.2 mg) is sometimes useful for aldosterone deficiency, but take care to combine mineralocorticoid therapy with diuretics in order to prevent heart failure.
  • Foods with a high potassium content and drugs that may aggravate hyperkalemia (eg, ACE inhibitors, potassium-sparing diuretics, beta-blockers) must be avoided.
  • Cation-exchange resins (eg, sodium polystyrene sulfonate [Kayexalate], alkalinizing salts) can be helpful in controlling hyperkalemia.
  • In many instances, careful evaluation of iatrogenic offenders (eg, beta-blockers, ACE inhibitors) can explain persistently high potassium levels in the absence of moderate-to-severe renal failure.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

The goals of pharmacotherapy are to correct the acidosis, to reduce morbidity, and to prevent complications.

Drug Category: Alkalinizing agents

Used as gastric, systemic, and urinary alkalinizers and have been used in treatment of acidosis resulting from metabolic and respiratory causes, including diarrhea, kidney disturbances, shock, and diabetic coma.

Drug Category: Electrolytes

Used to correct disturbances in fluid and electrolyte homoeostasis or acid-base balance and to reestablish osmotic equilibrium of specific ions.

Drug Category: Diuretics

Used to overcome fluid overload. Increase distal delivery of sodium by rendering collecting tubule impermeable to chloride and increase exchange of sodium for hydrogen and potassium.

Drug Category: Mineralocorticoids

May be useful for aldosterone deficiency. Combine with sodium loading and diuretics to prevent heart failure.

Drug Category: Vitamin D supplements

Fat-soluble vitamin that promotes absorption of calcium and phosphorus in the small intestine. Also promotes renal tubule phosphate resorption.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention:

• Avoiding drugs that can aggravate hyperchloremic acidoses
• • Drugs that increase GI bicarbonate loss include calcium chloride, magnesium sulfate, and cholestyramine.
  • Drugs or toxins that can induce pRTA include streptozotocin, lead, mercury, arginine, valproic acid, gentamicin, ifosfamide, and outdated tetracycline.
  • Drugs or toxins that can cause dRTA include amphotericin B, toluene, nonsteroidal anti-inflammatory drugs, lithium, and cyclamate.

Complications:

• Underlying GI, renal, or autoimmune conditions
• Hereditary disorders
• Effects of agents used in treatment (eg, cardiac complications)

Patient Education:

• Inform patients about the dietary issues related to the hyperchloremic acidoses.
• For excellent patient education resources, visit eMedicine's Endocrine System
  Center, Kidneys and Urinary System Center, and Growth Hormone Deficiency Center. Also, see eMedicine's patient education article Low Potassium.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Failure to confirm the cause of the acidosis
• Failure to diagnose a primary condition
• Failure to inform patients about dietary issues related to their acidosis
• Failure to recognize and to inform the patient about possible adverse effects of agents used for treatment

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Batlle D, Kurtzman NA. Distal renal tubular acidosis: pathogenesis and classification. Am J Kidney Dis. May 1982;1(6):328-44. [Medline].
• Burton DR. Metabolic acidosis. In: Clinical Physiology of Acid-Base and Electrolyte Disorders. 4th ed. New York, NY: McGraw-Hill; 1994:. 540-604.
• DuBose TD Jr. Hyperkalemic hyperchloremic metabolic acidosis: pathophysiologic insights. Kidney Int. Feb 1997;51(2):591-602. [Medline].
• Garella S, Salem MM. Clinical acid-base disorders. In: Oxford Textbook of Clinical Nephrology. 2nd ed. Oxford, UK: Oxford University Press; 1998:. 313-26.
• Lash JP, Arruda JA. Laboratory evaluation of renal tubular acidosis. Clin Lab Med. Mar 1993;13(1):117-29. [Medline].
• Rothstein M, Obialo C, Hruska KA. Renal tubular acidosis. Endocrinol Metab Clin North Am. Dec 1990;19(4):869-87. [Medline].
• Walmsley RN, White GH. Normal "anion gap" (hyperchloremic) acidosis. Clin Chem. Feb 1985;31(2):309-13. [Medline].

Article Last Updated: Jul 25, 2006