Proximal renal tubular acidosis (ORPHA:47159)
A rare renal tubular disease characterized by impaired ability of the proximal tubule to reabsorb bicarbonate from the glomerular filtrate leading to hyperchloremic metabolic acidosis.
Epidemiology
Prevalence is unknown but isolated hereditary pRTA is very rare. Drug-induced pRTA occurs relatively frequently.
Clinical description
Onset of hereditary pRTA occurs in childhood, manifesting initially with very alkaline urine due to bicarbonate wastage. Autosomal recessive pRTA (AR pRTA) is associated with severe growth retardation leading to short stature, intellectual disability 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). Hypokalemia may be present in some cases of pRTA and can occasionally cause symptoms of hypokalemic periodic paralysis. Rickets and osteomalacia are common due to vitamin D deficiency and phosphate wasting. In cases where pRTA is associated with primary Fanconi syndrome, glycosuria, aminoaciduria, phosphaturia, uric acid wastage and tubular proteinuria can occur.
Etiology
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 electrogenic sodium bicarbonate cotransporter 1 (kNBC1). 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 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..
Diagnostic methods
Unlike patients with distal RTA (dRTA), 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.
Differential diagnosis
The main differential diagnosis is dRTA. Other inherited proximal tubulopathies such as oculocerebrorenal syndrome, Dent disease and glycogen storage disease due to GLUT2 deficiency should be excluded.
Antenatal diagnosis
Prenatal diagnosis is possible in AR pRTA where the pathogenic variants have previously been identified in a family member but is not applicable in AD forms.
Genetic counseling
In families with AR pRTA genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy. In families with AD pRTA genetic counselling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
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 (or citrate) salts can be necessary in some cases. Drug induced pRTA is usually reversible by cessation of the drug.
Prognosis
With proper treatment the prognosis of acidosis is good, but associated extrarenal features impact on patient outcome.

                            Last update: 
                            March 2022


                            - Expert reviewer(s): 
                            Pr Gema ARICETA  - Dr Daniel BATLLE