Unraveling the molecular pathogenesis of isolated proximal renal tubular acidosis

Proximal renal tubular acidosis (pRTA) results from an impairment of bicarbonate (HCO3-) reabsorption in the renal proximal tubules and is characterized by a decreased renal HCO3- threshold. Proximal RTA most commonly occurs in association with multiple defects of proximal tubular transport (renal Fanconi syndrome). Although much more rare, pRTA may occur without other functional defects in proximal tubules (isolated pRTA). The presenting clinical symptom of isolated pRTA is usually growth retardation in infancy or early childhood. Three categories of isolated pRTA have been identified: (1) autosomal dominant pRTA; (2) autosomal recessive pRTA with ocular abnormalities; and (3) sporadic isolated pRTA. Autosomal dominant and autosomal recessive pRTA are usually permanent; life-long alkali therapy is needed. In contrast, sporadic isolated pRTA is transient; alkali therapy can be discontinued after several years without reappearance of symptoms. Recent genetic studies have begun to elucidate the molecular pathogenesis of inherited isolated pRTA. Studies in knockout mice have identified a candidate gene for autosomal dominant pRTA, SLC9A3, a gene encoding one of the five plasma membrane Na+/H+ exchangers (NHE3). Patients with autosomal recessive pRTA and ocular abnormalities have recently been found to have mutations in the kidney type Na+/HCO3- cotransporter gene (SLC4A4). Identification of these gene mutations provides new insights into the molecular pathogenesis of pRTA.