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Proximal renal tubular acidosis

Orpha number ORPHA47159
Synonym(s) Renal tubular acidosis type 2
pRTA
Prevalence Unknown
Inheritance
  • Autosomal recessive
  • Autosomal dominant
  • Sporadic
Age of onset Variable
ICD-10
  • N25.8
OMIM
UMLS -
MeSH -
MedDRA
  • 10037080
SNOMED CT
  • 24790002

Summary

Proximal renal tubular acidosis (pRTA) is a tubular kidney disease characterized by impaired ability of the proximal tubule to reabsorb bicarbonate from the glomerular filtrate leading to hyperchloremic metabolic acidosis.

Prevalence is unknown but isolated hereditary pRTA is very rare. Drug-induced pRTA occurs relatively frequently.

The onset of hereditary pRTA varies from infancy to adulthood, manifesting initially with very alkaline urine due to bicarbonate wastage. Autosomal recessive pRTA (AR pRTA; see this term) is associated with severe growth retardation leading to short stature, intellectual deficits and ocular abnormalities such as band keratopathy, cataracts, and glaucoma. Growth retardation and reduced bone density, due to metabolic acidosis, are seen in autosomal dominant pRTA (AD pRTA; see this term). Hypokalemia may be present in some cases of pRTA and can occasionally cause symptoms of periodic paralysis (see this term). Rickets and osteomalacia are common due to vitamin D deficiency and phosphate wasting. In cases where pRTA is associated with primary Fanconi syndrome (see this term), glycosuria, aminoaciduria, phosphaturia, uric acid wastage and tubular proteinuria can occur.

Isolated pRTA can be acquired or is inherited either recessively (in most cases) or dominantly. AR pRTA is due to a mutation in the SLC4A4 gene (4q13.3) that encodes the sodium bicarbonate cotransporter, member 4 (NBCe1). AD pRTA is due to mutations in a gene that has not yet been identified. As the proximal tubule reabsorbs around 80% of the filtered load of bicarbonate, a defect in it leads to the loss of bicarbonate. Certain drugs can be responsible for the development of acquired pRTA. Carbonic anhydrase inhibitors cause isolated pRTA while others (including oxaplatin, ifosfamide, adefovir, tenofovir, cidofovir, valproic acid, aminoglycosides, topiramate and didanosine) can all cause pRTA associated with Fanconi's syndrome. In glomerular diseases, pRTA has been rarely reported and attributed to associated tubular damage and, in some cases, has been associated with multiple myeloma (see this term).

Unlike patients with distal RTA (dRTA; see this term), patients with pRTA retain the ability to lower urine pH < 5.5 when the plasma HCO3 is low enough and below the renal threshold for tubular HCO3 reabsorption. Diagnosis involves the demonstration of urinary HCO3-wastage (increased fractional HCO3- excretion). An HCO3 titration test confirms a diagnosis of pRTA by demonstrating an exaggerated increase in urinary HCO3- excretion and urine pH as plasma HCO3- rises above the renal threshold. Molecular genetic analysis can identify a mutation in the SLC4A4 gene.

The main differential diagnosis is dRTA. Other inherited proximal tubulopathies such as oculocerebrorenal syndrome, Dent disease and glycogen storage disease due to GLUT2 deficiency (see these terms) should be excluded.

Antenatal diagnosis is not performed.

In sporadic cases, genetic counseling is not possible but it can be given to those where pRTA is inherited either in an autosomal dominant or recessive manner.

Treatment depends on the etiology of the disease. Inherited pRTA requires life-long bicarbonate replacement therapy. Large amounts of bicarbonate (10-15 mEq/kg/day) are needed to normalize serum bicarbonate in children. Thiazide diuretics (e.g. hydrochlorothiazide 25-50 mg daily) are also sometimes prescribed in order to enhance bicarbonate reabsorption and thereby reduce the amount of bicarbonate needed. Plasma potassium should be monitored and a mixture of sodium and potassium bicarbonate salts can be necessary in some cases. Drug induced pRTA is usually reversible by cessation of the drug.

With proper treatment the prognosis is good.

Expert reviewer(s)

  • Dr Daniel BATLLE
  • Dr Syed HAQUE

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