Renal Tubular Acidosis

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  • Renal tubular acidosis (RTA) is composed of 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 (glomerular filtration rate [GFR]) 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 (interfering with the generation of negative luminal charge required for hydrogen/potassium secretion); 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 unless plasma HCO3 brought above reabsorptive threshold
    • Type III RTA: extremely rare autosomal recessive syndrome due to carbonic anhydrase II deficiency; causes mixed type I and type II RTA, osteopetrosis, cerebral calcification, intellectual disability
    • Type IV RTA (hypoaldosteronism): due to aldosterone resistance/deficiency that results in hyperkalemia. Urine pH usually is <5.5.


  • Predominant age: all ages
  • Predominant sex: male > female (with regard to type II RTA with isolated defect in HCO3 reabsorption)

Etiology and Pathophysiology

  • Type I RTA
    • Autoimmune diseases: Sjögren syndrome, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), thyroiditis (1)
    • Medications: amphotericin B, lithium, ifosfamide, foscarnet, amiloride, triamterene, trimethoprim (2), pentamidine
    • Obstructive uropathy (hyperkalemic)
    • Genetic: autosomal dominant, autosomal recessive associated with sensorineural deafness
    • Sporadic
    • 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 renal transplant rejection
    • Leprosy
    • Chronic active hepatitis, primary biliary cirrhosis
    • Malnutrition
  • Type II RTA
    • Multiple myeloma, other dysproteinemic states
    • Amyloidosis
    • Medications: acetazolamide, ifosfamide, tenofovir, sulfanilamide, outdated tetracycline, topiramate (3), aminoglycosides
    • Familial (cystinosis, tyrosinemia, hereditary fructose intolerance, galactosemia, glycogen storage disease type I, Wilson disease, Lowe syndrome, inherited carbonic anhydrase deficiency)
    • Sporadic
    • Heavy metal poisoning (e.g., cadmium, lead, mercury, copper)
    • Interstitial renal disease
    • Paroxysmal nocturnal hemoglobinuria
    • Defects in calcium metabolism (hyperparathyroidism)
  • Type IV RTA (4)
    • Medications: NSAIDs, ACE inhibitors, ARBs, heparin/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)

  • Type I RTA: hereditary forms due to mutations affecting intercalated cells in collecting tubules (5). May occur in association with other genetic diseases (e.g., Ehlers-Danlos syndrome, hereditary elliptocytosis, or sickle cell nephropathy). The autosomal recessive form is associated with sensorineural deafness.
  • Type II RTA: Autosomal dominant form is rare. Autosomal recessive form is associated with ophthalmologic abnormalities and intellectual disability; occurs in 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)
  • 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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