Etiology and Pathogenesis
Proximal Renal Tubular Acidosis (pRTA) results from impaired bicarbonate (HCO3-) reabsorption in the proximal renal tubules and can be classified as either primary or secondary.
Primary pRTA
This is a hereditary disorder of proximal tubular function, most commonly inherited in an autosomal recessive manner. It is associated with mutations in the SLC4A4 gene, which encodes the basolateral sodium-bicarbonate cotransporter (NNA+-HCO3-).
Secondary pRTA
This occurs in the context of various acquired tubulointerstitial diseases, with drug-induced causes being the most common. Medications such as acetazolamide, ifosfamide, valproic acid, and antiretroviral drugs are frequently implicated. Other causes include:
- Systemic hereditary diseases, such as Lowe syndrome, glycogen storage diseases, Wilson disease, and Dent disease.
- Acquired conditions, such as heavy metal poisoning, vitamin D deficiency, multiple myeloma, and amyloidosis.
Secondary pRTA is often accompanied by Fanconi syndrome. Isolated secondary pRTA is rare and is usually caused by carbonic anhydrase inhibitors.
Clinical Manifestations
pRTA primarily presents with hyperchloremic metabolic acidosis. Unlike distal RTA (dRTA), the acidification function of the distal tubules remains intact in pRTA, so urinary pH can remain normal. In cases of severe metabolic acidosis, urinary pH can drop below 5.5. Patients with secondary pRTA frequently exhibit features of Fanconi syndrome, such as renal glycosuria. Because pRTA does not involve hypercalciuria, kidney stones or nephrocalcinosis are rarely observed.
Diagnosis
The diagnosis of pRTA is based on the presence of normal anion gap (AG) hyperchloremic metabolic acidosis, which may be accompanied by hypokalemia and hyperkaluria. Elevated urinary bicarbonate (HCO3-) confirms the diagnosis. For incomplete pRTA, a bicarbonate reabsorption test is required. Following oral or intravenous administration of sodium bicarbonate, a fractional excretion of bicarbonate (HCO3-) greater than 15% confirms the diagnosis.
Treatment
Correction of Acidosis and Electrolyte Imbalance
Sodium bicarbonate therapy (either oral or intravenous) is used to correct acidosis. Low-dose thiazide diuretics may be added to enhance bicarbonate reabsorption in the proximal tubules. However, the combination of sodium bicarbonate and thiazide diuretics may exacerbate hypokalemia, so potassium levels should be closely monitored.
Treatment of Secondary Causes
For patients with secondary pRTA, treatment should focus on addressing the underlying cause.