eMedicine Specialties > Nephrology > Acid-Base, Fluid, and Electrolyte Disorders

Hyperchloremic Acidosis

Author: Mahendra Agraharkar, MD, MBBS, FACP, FASN, Clinical Associate Professor of Medicine, Baylor College of Medicine, President & CEO, Space City Associates of Nephrology
Coauthor(s): Mark T Fahlen, MD, Inc; Kanwarpreet Baweja, MD, Fellow in Nephrology, Division of Renal Diseases and Hypertension, University of Texas Health Science Center
Contributor Information and Disclosures

Updated: Jul 30, 2009

Introduction

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.

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^1,2 :

• 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.

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]),³ 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,³ 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).

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.⁴ 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

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 hypercalciuria
    • 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.

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