Inborn errors of Metabolism

distal Renal Tubular Acidosis (dRTA)


distal Renal Tubular Acidosis (dRTA)
Distal renal tubular acidosis (dRTA) is a disease that occurs when the kidneys do not properly remove acids from the blood into the urine. As a result, too much acids remain in the blood which generates an unbalanced pH in the blood. The inability to remove acids from the body often results in failure to thrive. It may also, as a result of the body’s attempt to buffer the acid blood with molecules from the bone, lead to softening and weakening of the bones, called rickets in children and osteomalacia in adults.

dRTA is one of 4 distinct forms of renal tubular acidosis (RTA)

  • Distal RTA (dRTA) – also called Type I
  • Proximal RTA (pRTA) – also called Type II
  • Mixed RTA – also called Type III
  • Hyperkalaemic RTA – also called Type IV

Different forms of RTA have different pathophysiology, biochemical signs, clinical signs, specific diagnosis, and distinct treatments.

All forms of distal RTA (dRTA) are chronic and may have significant effects on growth and development. Although with treatment there is no decrease in life expectancy and renal failure is uncommon, progressive chronic kidney disease may sometimes occur if there are recurrent kidney stones and if nephrocalcinosis is severe.

The main differential diagnosis of dRTA is proximal RTA along with other causes of chronic metabolic acidosis (i.e. diarrhoea).

dRTA can be acquired or inherited.


How common is dRTA?
As no reliable epidemiological studies have been published, the number of patients with the disease is unknown. Disease onset can occur at any age, depending on cause. Hereditary dRTA subtypes include autosomal dominant (AD) and autosomal recessive (AR) dRTA. AR forms are mostly diagnosed in infants and young children, while AD dRTA is mostly diagnosed in adolescents and young adults.

Symptoms of dRTA
Patients with dRTA can be asymptomatic or can present with:

  • Polyuria
  • Polydipsia
  • Weakness and fatigue (symptoms associated with hypokalaemia)
  • Failure to thrive
  • Rickets, stunting of growth (seen in children)
  • Osteomalacia or osteopenia (seen in adults)
  • Hypercalciuria
  • Nephrolithiasis and nephrocalcinosis usually occur
  • Low plasma potassium levels in those with the classic form of dRTA can cause cardiac arrhythmias, paralysis and even death
  • In the recessive forms of dRTA, progressive and irreversible deafness may occur

How dRTA can be diagnosed
The disease is characterised by hyperchloremic metabolic acidosis. The inability to lower urine pH below 5.5 and a positive urine anion gap during spontaneous metabolic acidosis is indicative of dRTA. Provocative tests for further diagnosis include the NH4Cl acidifying test and the furosemide test. Patients with dRTA also show renal potassium wasting, with the exception of the hyperkalaemic type of dRTA. Detection of a causal genetic mutation through genetic testing can confirm the diagnosis.

inborn errors

How dRTA is inherited
Autosomal dominant dRTA is usually due to mutations in the SLC4A1 gene (17q21.31). Mutations in the ATP6V1B1 gene (2p13) or ATP6V0A4 gene (7q34) are responsible for autosomal recessive dRTA with deafness. Autosomal recessive dRTA without deafness or with late onset deafness has been mainly described in patients with mutations in the ATP6V0A4 gene, but overlap does exist in that some patients with this mutation develop deafness and others do not.

Acquired forms of dRTA
Acquired forms of dRTA can be caused by diseases such as Sjögren syndrome, sickle cell anaemia, systemic lupus erythematosus, chronic obstructive uropathy, or autoimmune chronic liver diseases. They can also occur after renal transplantation and as adverse reactions to certain drugs.

How dRTA can be treated
Alkali therapy is the standard treatment used to achieve normal serum bicarbonate levels. Patients are usually given sodium bicarbonate or potassium citrate. Children may require very high doses (4–8 mEq/kg/day), whereas adults often need much lower doses (1–2 mEq/kg/day). Potassium replacement is also necessary in hypokalaemic patients, and potassium citrate is usually recommended. The dose depends on the severity of the hypokalaemia. Hyperkalaemic types require low dietary potassium intake and other therapies.

Control of homeostasis over 24 hours is key in order to prevent long-term complications. Oral alkali therapy is the first-line therapy, but the salts that are currently available have a short duration of action and require repeated intake night and day. Moreover, they have a poor tolerance profile and poor palatability. Compliance is thus often low, resulting in poor control of homeostasis. There is no registered treatment for this disease.