Renal Tubular Acidosis Syndromes

, Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock

South Med J. 2000;93(11) 

In This Article

Proximal Renal Tubular Acidosis

Since the proximal tubule is the major site of bicarbonate reabsorption, a defect at this site results in the delivery of large amounts of bicarbonate from the proximal tubule. Because the distal tubule has a limited capacity for bicarbonate reabsorption, urinary bicarbonate wastage occurs. The definitive method of diagnosing proximal RTA is to measure the fractional excretion of bicarbonate. Fractional excretion of bicarbonate is usually more than 15% in patients with proximal RTA when the plasma bicarbonate concentration is at least 20 mEq/L. Defect(s) responsible for proximal RTA remain unclear. As Figure 1 shows, impaired proximal tubule acidification may result from a defect in any of the following:

  • Apical Na+/H+ antiporter (labeled 1)

  • Basolateral Na+ /HCO 3 symporter (labeled 2)

  • Carbonic anhydrases (labeled 3 and 4)

  • Apical H+-ATPase

  • Impaired ability to maintain a low intracellular sodium concentration

Figure 1.

Potential cellular mechanisms of proximal (type 2) renal tubular acidosis. Possible causes of impaired proximal acidification include defects in luminal Na+-H+ antiporter (1); basolateral Na+-HCO 3 symporter (2); intracellular (3) or luminal (4) carbonic anhydrases; sodium permeability (5); Na+,K+-ATPase (6); intracellular generation of adenosine triphosphate (ATP) (7); or membrane recycling, metabolism, or trafficking (8). (Reprinted with permission from Cogan and Morris.[1])

Defects in areas numbered 1 through 4 will result in selective impairment of proximal acidification. The final defect will affect all Na+-coupled transport processes and thus produce Fanconi's syndrome. This abnormality might occur by several mechanisms:

  • Increased cell sodium permeability (labeled 5)

  • Decreased Na+,K+-ATPase activity (labeled 6)

  • Decreased ATP generation (labeled 7)

  • Impaired membrane recycling (labeled 8)

  • Impaired vacuolar transport or trafficking (labeled 8)

  • Loss of epithelial mass.

An abnormal form or deficient level of red blood cell carbonic anhydrase (isoform II) has been reported in several families with proximal RTA.[2] This abnormality has been posited as the cause of the syndrome. This is a reasonable supposition, but there are at least five isoforms of carbonic anhydrase. A defect in only one isoform might not compromise proximal acidification completely.

Etiology of Proximal Renal Tubular Acidosis

Proximal RTA can be divided in two categories, isolated bicarbonate wasting and generalized proximal tubule dysfunction (Fanconi's syndrome). Each type can be further divided according to whether it is accompanied by systemic or genetic disease ( Table 1 ).

Patients with proximal RTA generally have a plasma bicarbonate concentration more than 15 mEq/L; severe metabolic acidosis rarely develops. In fact, all the filtered bicarbonate will be completely reclaimed at the reduced plasma bicarbonate level, and these patients will have normal distal nephron acidification. Thus, in patients with proximal RTA, urine is acidified normally during acidemia. When plasma bicarbonate is raised by exogenous addition of alkali, the reduced proximal capacity to reabsorb bicarbonate leads to bicarbonaturia. After cessation of alkali administration, urinary bicarbonate wastage continues until the filtered load reaches the level at which the combined reabsorptive capacity of the proximal tubule and the distal tubule is no longer exceeded; urine bicarbonate concentration then becomes low and urine pH is appropriately acidic.

Isolated defects in proximal tubule bicarbonate reabsorption are rarely identified. Most patients with proximal RTA have multiple defects in proximal tubular function, including defective reabsorption of glucose, calcium, phosphate, citrate, uric acid, lysozymes, light-chain immunoglobulins, and amino acids.

Low serum potassium due to distal potassium wasting is a consistent finding in proximal RTA. Kaliuresis is promoted by increased distal delivery of sodium bicarbonate and by hyperaldosteronism resulting from volume contraction. Plasma renin levels are typically elevated. The rate of kaliuresis is, therefore, proportional to the bicarbonate delivery to the distal nephron and also to the plasma bicarbonate concentration. Administration of alkali to correct acidosis in these patients leads to an exaggeration of the kaliuresis and potassium deficiency.

Patients with proximal RTA may have high urinary calcium excretion; however, nephrocalcinosis and renal calculi are rare. This may be due to the relatively normal rate of citrate excretion in these patients as compared with that of most acidotic patients. Children with proximal RTA are likely to have growth retardation, rickets, osteomalacia, and abnormal vitamin D metabolism. In adults, osteopenia may develop but generally without pseudofractures.

Treatment of Proximal Renal Tubular Acidosis

Children and infants with proximal RTA require alkali therapy because of the high incidence of growth retardation due to acidemia. Generally, 5 to 15 mEq/kg daily of alkali therapy is sufficient to compensate for the urinary bicarbonate losses and the endogenous acid production. Alkali may be given as sodium bicarbonate or its metabolic equivalent (citrate). Potassium supplements are necessary due to the exacerbation of kaliuresis from high distal bicarbonate delivery after alkali therapy. Thiazide diuretics, which cause mild volume contraction and hence enhance proximal reabsorption of bicarbonate, can diminish alkali requirements. However, thiazides enhance kaliuresis and also worsen hypokalemia, which may require the addition of a potassium-sparing diuretic.

Despite the absence of significant metabolic abnormalities and bone disease, adult patients with proximal RTA may require alkali therapy when plasma bicarbonate is consistently less than 18 mEq/L. In such cases, therapy is given to prevent the development of severe acidosis after intercurrent illness.

Vitamin D and phosphate are appropriate treatments for patients with rickets and hypophosphatemia and may improve the acidification defect. Patients with fructose intolerance should avoid fructose.

The clinical course of proximal RTA in adults depends largely on the primary disease. Proximal RTA associated with intestinal malabsorption, vitamin D deficiency, secondary hyperparathyroidism, and hypophosphatemia can be cured by vitamin D and calcium therapy. Treatment with alkali, potassium, phosphate, and vitamin D can ameliorate bone disease.

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