Renal Tubular Acidosis

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Basics

Description

  • Renal tubular acidosis (RTA) is a group of disorders characterized by an inability of the kidney to resorb bicarbonate (HCO3)/secrete hydrogen ions, resulting in normal anion gap metabolic acidosis. Renal function must be normal or near normal.
  • Several types have been identified:
    • Type I (distal) RTA: inability of the distal tubule to acidify the urine due to impaired hydrogen ion secretion, increased back leak of secreted hydrogen ions, or impaired sodium reabsorption; urine pH >5.5.
    • Type II (proximal) RTA: defect of the proximal tubule in HCO3 reabsorption. Proximal tubular HCO3 reabsorption is absent; plasma HCO3 concentration stabilizes at 12 to 18 mEq/L due to compensatory distal HCO3 reabsorption; urine pH <5.5
    • Type III RTA: extremely rare autosomal recessive syndrome with associated osteopetrosis, cerebral calcification, intellectual disability.
    • Type IV RTA (hypoaldosteronism): due to aldosterone resistance/deficiency that results in hyperkalemia. Urine pH usually is <5.5.

Epidemiology

Incidence
Predominant sex: male > female (with regard to type II RTA with isolated defect in HCO3 reabsorption)

Etiology and Pathophysiology

  • Type I RTA—caused by conditions and medications that impair adequate urine acidification at the distal tubule:
    • Autoimmune diseases: Sjögren syndrome, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), thyroiditis (1)
    • Medications: amphotericin B, lithium, ifosfamide, foscarnet, triamterene, trimethoprim, pentamidine
    • Obstructive uropathy (hyperkalemic)
    • Other familial disorders: Ehlers-Danlos syndrome, glycogenosis type III, Fabry disease, Wilson disease
    • Hematologic diseases: sickle cell disease (hyperkalemic), hereditary elliptocytosis
    • Toxins: toluene, glue
    • Hypercalciuria, diseases causing nephrocalcinosis
    • Vitamin D intoxication
    • Medullary cystic disease
    • Hypergammaglobulinemic syndrome
    • Chronic pyelonephritis
    • Chronic active hepatitis, primary biliary cirrhosis
    • Malnutrition
    • Incomplete distal RTA—a form in which patients are unable to appropriately acidify their urine, however are able to excrete sufficient acid to maintain normal serum HCO3 and pH (2). Cause and pathophysiology is poorly understood.
    • Voltage-dependent RTA—a form of distal RTA in which the impairment in urine acidification is due to poor delivery of Na+ to the distal tube, leading to disruption of favorable transepithelial voltage gradient, and retention of K+ and H+. This form will lead to hyperkalemia, as opposed to hypokalemia in classic distal RTA (3).
      • Amiloride causes voltage-dependent RTA rather than classic distal RTA (3).
  • Type II RTA—caused by conditions and medications that impair adequate HCO3 reabsorption in the proximal convoluted tubule (4):
    • Genetic inheritance (see below)
    • Primary Fanconi syndrome
    • Systemic diseases causing Fanconi syndrome: multiple myeloma and other dysproteinemic states, amyloidosis, paroxysmal nocturnal hemoglobinuria, tubulointerstitial nephritis
    • Medications
      • Carbonic anhydrase inhibitors: acetazolamide, methazolamide and dichlorphenamide
      • Chemotherapy agents: ifosfamide, oxaliplatin, cisplatin
      • Antiretroviral medications: tenofovir, didanosine
      • Anticonvulsant medications: topiramate, valproic acid
      • Antibiotics: sulfanilamide, outdated tetracycline, aminoglycosides
      • Other miscellaneous medications: deferasirox, apremilast, heavy metals
    • Familial (cystinosis, tyrosinemia, hereditary fructose intolerance, galactosemia, glycogen storage disease type I, Wilson disease, Lowe syndrome, inherited carbonic anhydrase deficiency)
    • Defects in calcium metabolism (hyperparathyroidism)
  • Type IV RTA (5)
    • Medications: NSAIDs, ACE inhibitors, ARBs, heparin/low-molecular-weight (LMW) heparin (hyperkalemia in 5–10% of patients), ketoconazole, tacrolimus, cyclosporine, spironolactone, eplerenone
    • Diabetic nephropathy
    • Tubulointerstitial nephropathies
    • Primary adrenal insufficiency
    • Markedly decreased distal Na+ delivery
    • Pseudohypoaldosteronism (PHA) (end-organ resistance to aldosterone)
      • PHA type 1
      • PHA type 2 (Gordon syndrome)

Genetics
  • Type I RTA: hereditary forms due to mutations affecting intercalated cells in collecting tubules. Loss of function mutations of a chloride-bicarbonate exchanger (AE1) found in the kidney and red blood cell are inherited in autosomal dominant and recessive manners and may be associated with hemolytic anemia, spherocytosis, or ovalocytosis. Loss of function mutations of a vacuolar-type H+ ATPase (V-ATPase) found in the kidney and inner ear are autosomal recessive, and are associated with enlarged vestibular aqueducts, dizziness, and sensorineural deafness (2). More recently, whole exome genomic sequencing has implicated mutations in a protein transcription factor FOXI1, which regulates both AE1 and V-ATPase, as another cause of distal RTA with early-onset sensorineural deafness.
  • Type II RTA: Autosomal dominant form is extremely rare. Autosomal recessive form is associated with mutation in a basolateral electrogenic sodium-bicarbonate cotransporter (NBCe1) and can be seen with severe growth retardation, ophthalmologic abnormalities, and intellectual disability. Fanconi syndrome, which is associated with several genetic diseases (e.g., cystinosis, Wilson disease, tyrosinemia, hereditary fructose intolerance, Lowe syndrome, galactosemia, glycogen storage disease, metachromatic leukodystrophy), can also be inherited by sporadic missense mutation in a sodium phosphate cotransporter. More recent studies identified other causes of inherited Fanconi syndrome, including mutation of EHHADH, a gene involved in peroxisomal fatty acid oxidation, and HNF4A, a gene that encodes a nuclear transcription factor (4).
  • Type IV RTA: Some cases are familial, such as PHA type I (autosomal dominant).

General Prevention

Careful use/avoidance of causative agents

Commonly Associated Conditions

  • Type I RTA in children: hypercalciuria leading to rickets, nephrocalcinosis
  • Type I RTA in adults: autoimmune diseases (Sjögren syndrome, RA, SLE), obstructive uropathy, hypercalciuria
  • Type II RTA: Fanconi syndrome (generalized proximal tubular dysfunction resulting in glycosuria, aminoaciduria, hyperuricosuria, phosphaturia, bicarbonaturia)
  • Type II RTA in adults: multiple myeloma, carbonic anhydrase inhibitors, aminoglycosides
  • Type IV RTA: diabetic nephropathy, solid-organ transplant (due to calcineurin inhibitors)

-- To view the remaining sections of this topic, please or --

Basics

Description

  • Renal tubular acidosis (RTA) is a group of disorders characterized by an inability of the kidney to resorb bicarbonate (HCO3)/secrete hydrogen ions, resulting in normal anion gap metabolic acidosis. Renal function must be normal or near normal.
  • Several types have been identified:
    • Type I (distal) RTA: inability of the distal tubule to acidify the urine due to impaired hydrogen ion secretion, increased back leak of secreted hydrogen ions, or impaired sodium reabsorption; urine pH >5.5.
    • Type II (proximal) RTA: defect of the proximal tubule in HCO3 reabsorption. Proximal tubular HCO3 reabsorption is absent; plasma HCO3 concentration stabilizes at 12 to 18 mEq/L due to compensatory distal HCO3 reabsorption; urine pH <5.5
    • Type III RTA: extremely rare autosomal recessive syndrome with associated osteopetrosis, cerebral calcification, intellectual disability.
    • Type IV RTA (hypoaldosteronism): due to aldosterone resistance/deficiency that results in hyperkalemia. Urine pH usually is <5.5.

Epidemiology

Incidence
Predominant sex: male > female (with regard to type II RTA with isolated defect in HCO3 reabsorption)

Etiology and Pathophysiology

  • Type I RTA—caused by conditions and medications that impair adequate urine acidification at the distal tubule:
    • Autoimmune diseases: Sjögren syndrome, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), thyroiditis (1)
    • Medications: amphotericin B, lithium, ifosfamide, foscarnet, triamterene, trimethoprim, pentamidine
    • Obstructive uropathy (hyperkalemic)
    • Other familial disorders: Ehlers-Danlos syndrome, glycogenosis type III, Fabry disease, Wilson disease
    • Hematologic diseases: sickle cell disease (hyperkalemic), hereditary elliptocytosis
    • Toxins: toluene, glue
    • Hypercalciuria, diseases causing nephrocalcinosis
    • Vitamin D intoxication
    • Medullary cystic disease
    • Hypergammaglobulinemic syndrome
    • Chronic pyelonephritis
    • Chronic active hepatitis, primary biliary cirrhosis
    • Malnutrition
    • Incomplete distal RTA—a form in which patients are unable to appropriately acidify their urine, however are able to excrete sufficient acid to maintain normal serum HCO3 and pH (2). Cause and pathophysiology is poorly understood.
    • Voltage-dependent RTA—a form of distal RTA in which the impairment in urine acidification is due to poor delivery of Na+ to the distal tube, leading to disruption of favorable transepithelial voltage gradient, and retention of K+ and H+. This form will lead to hyperkalemia, as opposed to hypokalemia in classic distal RTA (3).
      • Amiloride causes voltage-dependent RTA rather than classic distal RTA (3).
  • Type II RTA—caused by conditions and medications that impair adequate HCO3 reabsorption in the proximal convoluted tubule (4):
    • Genetic inheritance (see below)
    • Primary Fanconi syndrome
    • Systemic diseases causing Fanconi syndrome: multiple myeloma and other dysproteinemic states, amyloidosis, paroxysmal nocturnal hemoglobinuria, tubulointerstitial nephritis
    • Medications
      • Carbonic anhydrase inhibitors: acetazolamide, methazolamide and dichlorphenamide
      • Chemotherapy agents: ifosfamide, oxaliplatin, cisplatin
      • Antiretroviral medications: tenofovir, didanosine
      • Anticonvulsant medications: topiramate, valproic acid
      • Antibiotics: sulfanilamide, outdated tetracycline, aminoglycosides
      • Other miscellaneous medications: deferasirox, apremilast, heavy metals
    • Familial (cystinosis, tyrosinemia, hereditary fructose intolerance, galactosemia, glycogen storage disease type I, Wilson disease, Lowe syndrome, inherited carbonic anhydrase deficiency)
    • Defects in calcium metabolism (hyperparathyroidism)
  • Type IV RTA (5)
    • Medications: NSAIDs, ACE inhibitors, ARBs, heparin/low-molecular-weight (LMW) heparin (hyperkalemia in 5–10% of patients), ketoconazole, tacrolimus, cyclosporine, spironolactone, eplerenone
    • Diabetic nephropathy
    • Tubulointerstitial nephropathies
    • Primary adrenal insufficiency
    • Markedly decreased distal Na+ delivery
    • Pseudohypoaldosteronism (PHA) (end-organ resistance to aldosterone)
      • PHA type 1
      • PHA type 2 (Gordon syndrome)

Genetics
  • Type I RTA: hereditary forms due to mutations affecting intercalated cells in collecting tubules. Loss of function mutations of a chloride-bicarbonate exchanger (AE1) found in the kidney and red blood cell are inherited in autosomal dominant and recessive manners and may be associated with hemolytic anemia, spherocytosis, or ovalocytosis. Loss of function mutations of a vacuolar-type H+ ATPase (V-ATPase) found in the kidney and inner ear are autosomal recessive, and are associated with enlarged vestibular aqueducts, dizziness, and sensorineural deafness (2). More recently, whole exome genomic sequencing has implicated mutations in a protein transcription factor FOXI1, which regulates both AE1 and V-ATPase, as another cause of distal RTA with early-onset sensorineural deafness.
  • Type II RTA: Autosomal dominant form is extremely rare. Autosomal recessive form is associated with mutation in a basolateral electrogenic sodium-bicarbonate cotransporter (NBCe1) and can be seen with severe growth retardation, ophthalmologic abnormalities, and intellectual disability. Fanconi syndrome, which is associated with several genetic diseases (e.g., cystinosis, Wilson disease, tyrosinemia, hereditary fructose intolerance, Lowe syndrome, galactosemia, glycogen storage disease, metachromatic leukodystrophy), can also be inherited by sporadic missense mutation in a sodium phosphate cotransporter. More recent studies identified other causes of inherited Fanconi syndrome, including mutation of EHHADH, a gene involved in peroxisomal fatty acid oxidation, and HNF4A, a gene that encodes a nuclear transcription factor (4).
  • Type IV RTA: Some cases are familial, such as PHA type I (autosomal dominant).

General Prevention

Careful use/avoidance of causative agents

Commonly Associated Conditions

  • Type I RTA in children: hypercalciuria leading to rickets, nephrocalcinosis
  • Type I RTA in adults: autoimmune diseases (Sjögren syndrome, RA, SLE), obstructive uropathy, hypercalciuria
  • Type II RTA: Fanconi syndrome (generalized proximal tubular dysfunction resulting in glycosuria, aminoaciduria, hyperuricosuria, phosphaturia, bicarbonaturia)
  • Type II RTA in adults: multiple myeloma, carbonic anhydrase inhibitors, aminoglycosides
  • Type IV RTA: diabetic nephropathy, solid-organ transplant (due to calcineurin inhibitors)

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