Renal Tubular Acidosis

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DESCRIPTION

  • Renal tubular acidosis (RTA) is a group of disorders characterized by an inability of the kidney to excrete fixed acids or resorb filtered bicarbonate (HCO3), resulting in chronic normal anion gap hyperchloremic 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 (H+) excretion, increased back leak of secreted H+, or impaired sodium (NA+) reabsorption; urine pH >5.5
    • Type II (proximal) RTA: inability to reabsorb HCO3 in proximal tubule with compensatory distal HCO3 reabsorption accompanied by hypokalemia; urine pH <5.5
    • Type III (mixed) RTA: extremely rare autosomal recessive syndrome with associated osteopetrosis, cerebral calcification, intellectual disability.
    • Type IV (hyperkalemic) RTA: heterogenous group of disorders accompanied by hyperkalemia. Urine pH is usually <5.5 (1).

EPIDEMIOLOGY

The most prevalent subtype worldwide and in the United States is type IV, primarily caused by diabetic nephropathy and urinary tract obstruction. RTA incidence exceeds 20% postrenal transplant, particularly with rejection or immunosuppressive drugs. Type III mainly affecting children of Arabic, North African, and Middle Eastern descent.

Incidence

Incidence of distal RTA (DRTA) is 1 in 10,000 people; proximal RTA (PRTA) is less common

ETIOLOGY AND PATHOPHYSIOLOGY

  • Type I—caused by conditions and medications that impair adequate urine acidification at the distal tubule (inability to generate bicarb); often associated with hypokalemia
    • Autoimmune diseases, obstructive uropathy, genetic inheritance and familial disorders, hematologic diseases; medications: NSAIDs, lithium, amphotericin b, aminoglycosides, topiramate, valproic acid, etc.; toxins: toluene, glue, etc.
    • 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.
    • 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).
  • Type II—caused by conditions and medications that impair adequate HCO3 reabsorption in the proximal convoluted tubule causing bicarbonate leak. Often associated with hypokalemia:
    • Primary Fanconi syndrome or systemic diseases causing Fanconi syndrome (multiple myeloma and other dysproteinemic states, amyloidosis, paroxysmal nocturnal hemoglobinuria, tubulointerstitial nephritis).
    • Medications (carbonic anhydrase inhibitors, chemotherapy agents, antiretrovirals, anticonvulsant medications; other: deferasirox, apremilast, heavy metals, aminoglycosides)
    • Familial (cystinosis, tyrosinemia, hereditary fructose intolerance, galactosemia, glycogen storage disease type I, Wilson disease, Lowe syndrome, inherited carbonic anhydrase deficiency)
    • Defects in calcium metabolism (secondary hyperparathyroidism, vitamin D deficiency)
  • Type IV—caused by aldosterone resistance or deficiency that results in hyperkalemia, which lead to impaired ammonia genesis in proximal tubule and decreased acidification of urine:
    • Medications: NSAIDs, ACE inhibitors, ARBs, heparin products, potassium-sparing diuretics, beta blockers, TMP/SMX, calcineurin inhibitors, renin inhibitors
    • Diabetic nephropathy; tubulointerstitial nephropathies; primary adrenal insufficiency; pseudohypoaldosteronism (PHA) (end-organ resistance to aldosterone) (3)

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) 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 III RTA: Mutations of chromosome 8q22 resulting in carbonic anhydrase II (CA II) deficiency.
  • 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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