Renal tubular acidosis

Hereditary RTA typically manifests in infancy with poor weight gain, growth deficiency, polyuria, polydipsia, episodes of dehydration, and refractory rickets. Later presentations occur, particularly in autosomal dominant SLC4A1-related distal RTA. Electrolyte features include hypokalemia and hyperchloremic non-anion-gap metabolic acidosis with inappropriately elevated urine pH. Renal complications include , medullary cysts, and chronic kidney disease, which can lead to renal insufficiency, especially if left untreated. Sensorineural hearing loss occurs with pathogenic variants in ATP6V0A4, ATP6V1B1, or FOXI1, with either childhood or adult onset and variable severity. Proximal RTA is characterised by a high fractional excretion of bicarbonate (>10–15%) when blood bicarbonate levels are normalised, and is typically a component of generalised proximal tubular dysfunction (renal Fanconi syndrome). Isolated hereditary proximal RTA is extremely rare, and mixed proximal-distal RTA is associated with CA2-related carbonic anhydrase II deficiency.

The estimated prevalence of distal RTA is 0.46 to 1.60 per 10,000. Approximately 22% of the confirmed diagnosed cohort were identified as having primary (inherited) RTA.

More than 10 genes are associated with hereditary RTA. The genetic forms can be grouped into distal RTA (Type 1), proximal RTA (Type 2), and mixed RTA (Type 3). In distal RTA, ATP6V1B1 and ATP6V0A4 (V-type H⁺-ATPase subunits) are most frequently reported, with SLC4A1 and FOXI1 also implicated. Proximal RTA typically occurs within renal Fanconi syndrome. Mixed RTA is exemplified by carbonic anhydrase II deficiency (CA2; with osteopetrosis and cerebral calcifications).

The genetic conditions associated with RTA follow heterogeneous inheritance patterns. Most hereditary distal RTA caused by loss-of-function variants in ATP6V0A4, ATP6V1B1, SLC4A1, FOXI1, or WDR72 is inherited in an autosomal recessive manner, whereas dominant-negative SLC4A1 variants and specific heterozygous ATP6V1B1 p.Arg394 variants follow autosomal dominant inheritance. Mixed and proximal hereditary forms are predominantly autosomal recessive.

• Where RTA is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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• Bianic F, Guelfucci F, Robin L, Martre C, Game D, Bockenhauer D. Epidemiology of distal renal tubular acidosis: a study using linked UK primary care and hospital data. Nephron. 2021;145(5):486-95. doi:10.1159/000516876. PMID:.
• Giglio S, Montini G, Trepiccione F, Gambaro G, Emma F. Distal renal tubular acidosis: a systematic approach from diagnosis to treatment. J Nephrol. 2021;34(6):2073-83. doi:10.1007/s40620-021-01032-y. PMID:; PMCID:PMC8610947.
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