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, and intellectual disability
  • Type IV RTA (hypoaldosteronism): due to aldosterone resistance/deficiency that results in hyperkalemia; urine pH is usually <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
  • Medications: amphotericin B, lithium, ifosfamide, foscarnet, triamterene, trimethoprim, pentamidine; obstructive uropathy (hyperkalemic); genetic inheritance (see below); other familial disorders: Ehlers-Danlos syndrome, glycogenosis type III, Fabry disease, Wilson disease; hematologic diseases: sickle cell disease (hyperkalemic), hereditary elliptocytosis; toxins: toluene, glue
  • 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 (1). 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 (2).
    • Amiloride causes voltage-dependent RTA rather than classic distal RTA (2).
• Type II RTA—caused by conditions and medications that impair adequate HCO₃ reabsorption in the proximal convoluted tubule:
  • 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
  • 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)

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 cells is inherited in autosomal dominant and recessive manners and may be associated with hemolytic anemia, spherocytosis, or ovalocytosis.
• 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.
• 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)