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Renal tubular acidosis

  • Ammonium excretion low in renal tubular acidosis
  • Ammonium in urine = (urine osmolal gap)/2
  • Urine osmolal gap= Measured osmolality-calculated osmolality
  • Calculated osmolality= 2(Na + K) + urea + glucose

Distal RTA



Distal RTA ("classical", "gradient", type I)

Characterized by an inability to generate a normal minimum urinary pH even in the presence of severe systemic acidosis


Primary: hereditary (autosomal dominant)/sporadic

- associated with auto-immune disease, especially Sjogren’s. Also other conditions associated with dysglobulinaemia or hypergammaglobulinaemia, primary biliary cirrhosis
- drugs: ampthotericin, analgesic nephropathy
- nephrocalcinosis (eg due to hyperparathyroidismh, chronic vitamin D poisoning)

- direct damage to renal medulla: pyelonephritis, papillary necrosis, chronic obstructive uropathy, medullary sponge kidney, sickle cell

- fibrosing alveolitis (rare)


  • due to a failure of distal nephron and collecting duct to generate the 800-900:1 H+ gradient found in normals. Results in failure to reabsorb filtered bicarbonate that was not reabsorbed in proximal tubule. Also results in failure of titration of phosphate buffer and decreased excretion of NH4+ (decreased by alkaline urine). Failure of excretion of NH4+ encourages urea synthesis (as an alternative route of excretion of nitrogen) and hence H+ synthesis
  • precise nature of defect is not known. Could be a failure of active hydrogen ion secretion in the distal nephron or it could be abnormal permeability to H+ allowing leak-back after secretion into tubule. Latter mechanisms occurs in RTA-1 associated with amphotericin: this inserts itself into the luminal cell membrane and provides a channel for back leakage of H+ into the cell or of bicarbonate out of the cell into the lumen
  • except in rare patients with mixed syndromes proximal tubular function is normal in terms of H+ excretion and bicarb reabsorption
  • hypokalaemia that is frequently present is due to lack of H+ flux out of the tubular cell into the lumen which encourages K+ exchange instead and to secondary hyperaldosteronism due to impaired Na reabsorption due to decreased Na/H exchange. Correction of acidosis allows more H+ secretion and hence ameliorates Na and K loss
  • renal stones generally due to hypercalciuria and hypercitraturia

Clinical features

  • presents in infancy, childhood or adult life
  • usually presents with acute acidosis and hyperventilation, often accompanied by muscular weakness due to hypokalaemia
  • in most patients attacks of acute acidosis represent a worsening of mild chronic hyperchloraemic metabolic acidosis which may have been fully compensated until presentation
  • 70% have either nephrocalcinosis (very rarely a feature of other types) or calcium containing renal calculi
  • rickets and growth stunting are frequent features in childhood cases. ± osteomalacia in adults


  • in acute state diagnosis is usually simple: urinary pH>5.5 (and usually 6) in the presence of a normal anion-gap metabolic acidosis, hyperchloraemia, and normal or near normal urea and creatinine
  • severe hypokalaemia
  • hypercalciuria
  • ± evidence of renal calcification
  • failure to acidify urine maximally in presence of severe acidosis (bicarb <12) helps to distinguish condition from RTA 2 and 4
  • diagnosis during the chronic non-acute state requires a short acid load test. This should not be performed if bicarbonate <19 mmol/l


  • correct hypokalaemia before acidosis
  • isotonic sodium bicarbonate IV. Aim to restore abnormality over a few hours
  • oral sodium bicarbonate is required in chronic condition

RTA-2 (bicarbonate wasting)

  • Superficially clinically similar to RTA-1
  • Rare as an isolated defect and in the great majority of patients is associated with multiple abnormalities of proximal tubular function with reabsorption defects for glucose, amino acids and phosphate (Fanconi syndrome)


  • Nearly always some factor which damages proximal tubular function can be identified. Causes of an isolated defect include a familial autosomal dominant form, treatment with acetazolamide and carbonic anhydrase II deficiency
  • Causes of Fanconi syndrome include:
    Genetic causes: cystinosis, Wilson’s disease, hereditary fructose intolerance
    Acquired: - vitamin D deficiency
    - lead poisoning
    - multiple myeloma
    - outdated tetracycline therapy
    - hyperPTH
    - nephrotic syndrome


  • depression of capacity of proximal tubule to secrete H+ and thus reabsorb bicarbonate. Usually bicarbonate does not appear in urine until plasma bicarb >25-28 mmol/l. In RTA-2 this threshold is lowered so that distal nephron is flooded with bicarbonate. This exceeds the capacity of the distal nephron to secrete sufficient H+ to reabsorb the bicarb, which therefore spills over into the urine
  • loss of bicarb results in a fall of plasma bicarb. and thus a fall in filtered bicarbonate. Eventually this reaches a level at which the proximal nephron can cope and then the distal nephron is fully capable of producing a normally minimal urinary pH of 4.5-5.3
  • acidosis is predominantly due to the bicarbonate leak but is in part due to failure of titration of phosphate and failure of appropriate NH4+ excretion due to inappropriately high urine pH (at least while plasma bicarbonate remains above renal threshold)
  • high distal load of sodium bicarbonate responsible for Na wastage. This leads to secondary hyperaldosteronism and hypokalaemia due to K wastage
  • polyuria due to distal sodium bicarbonate load and effects of K deficiency on renal concentrating mechanism

Clinical features

  • provided patient is sufficiently acidotic urine pH falls to normal minimum
  • nephrocalcinosis and renal calcul are virtually never present
  • ± marked polyuria and polydipsia, especially in those patients in whom the acidosis has been fully controlled by bicarbonate therapy
  • proximal myopathy, osteomalacia or rickets are common associations. Probably because of frequent aetiological involvement of disorders of vitamin D supply or metabolism
  • presents with chronic ( or acute exacerbation) of normal anion gap acidosis with a marked tendency to K deficiency


  • large amounts of bicarbonate may be required
  • correction of acidosis does not help and may worsen K deficiency and polyuria by increasing sodium bicarbonate load to distal nephron. Give K supplements as potassium bicarbonate
  • if amount of oral bicarbonate is intolerable hydrochlorothiazide may help by decreasing the filtered load of bicarbonate. However it may increase the need for potassium supplements

RTA-4 (hyperkalaemic)

Often associated with slight/moderate glomerular impairment but hyperkalaemia is quite out of proportion to this


  • basic abnormality in most cases is hypoaldosteronism or failure of aldosterone action
  • this diminishes the capacity of the H+ secreting mechanism in the distal nephron but not its power to sustain a pH gradient if bicarbonate delivery from the proximal tubule is small
  • hyperkalaemia (due to aldosterone deficiency) suppresses renal production of NH4+ with resultant increased production of urea and H+. This is largely responsible for the acidosis
  • amiloride may lead to RTA-4 by blocking reabsorption of Na in the cortical collecting ducts. This reduces the negative luminal potential required for K and H secretion


Primary adrenal disease (eg Addison’s) and some in-born errors of steroid synthesis

Renin deficiency:
- chronic renal disease, especially diabetic and chronic tubulointerstitial disease (including pyelonephritis)
- NSAIDs (renin production is to some extent dependent on PGs)
- ACE inhibitors
- b blockers
- potassium sparing diuretics and aldosterone antagonists

Clinical features

Presents with metabolic acidosis with normal or near-normal anion gap and hyperkalaemia. If the plasma bicarbonate fall sufficiently the distal tubule is able to mount a normal blood/urine pH gradient


Mineralocorticoid (typically 0.05-0.15 mg/day of fludrocortisone) for those with significant acidosis or potentially dangerous hyperkalaemia

Further reading

Cohen RD. The renal tubular acidoses. Oxford Textbook of Medicine, 3rd ed, 1996

© Charles Gomersall December 1999

©Charles Gomersall, April, 2014 unless otherwise stated. The author, editor and The Chinese University of Hong Kong take no responsibility for any adverse event resulting from the use of this webpage.
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