Primary Distal Renal Tubular Acidosis

In many people from Tunisia and North Africa there is a common change or variant in the ATP6V1B1 gene called p.I386Afs*56. When this gene change is passed down from both parents, it causes primary distal renal tubular acidosis in their child. This gene change happened over 2400 years ago and was passed down through the generations in North Africa. One theory is that the gene change started in someone from the Berber (or Amazigh) ethnic group that lived throughout North Africa. As the group had children, the gene change became more common in the groups. The gene change then traveled with immigrants, sailors, traders, and explorers around the Mediterranean Sea during the Phoenician period into North Africa and Southern Europe.

The diagnosis of primary distal renal tubular acidosis (primary dRTA) should be made by a combination of evaluation, lab studies, and genetic testing. If two disease causing gene mutations or variants are found in the ATP6V1B1 or ATP6V0A4 gene this confirms the diagnosis. In some cases, an individual with primary dRTA will have all the signs and symptoms of the condition, but two gene mutations in the ATP6V1B1 or ATP6V0A4 genes are not found. In this case, the primary dRTA is still possible, but further genetic testing may be needed to confirm the diagnosis. It can be helpful to have a second opinion from a doctor familiar with the condition if there is a question about the confirmation of the diagnosis.

Although it is not directly related to the diagnosis of primary dRTA, internet searches may reveal that there was a controversy about doctors in Mexico who misdiagnosed patients with renal tubular acidosis and started them on treatment. In 2016, a results from retesting 170 children diagnosed with renal tubular acidosis in Mexico found that only 3 actually had renal tubular acidosis. The researchers found that the other children had a variety of underlying medical conditions, but not renal tubular acidosis. Although this was a difficult time for children and parents and serves as cautionary warning to always double check diagnoses, the misdiagnosis was for other causes of renal tubular acidosis and not the genetic condition primary dRTA.

Although progressive hearing loss is a common symptom of primary distal renal tubular acidosis (primary dRTA) and it is strongly recommended that every child with primary dRTA be closely monitored by an audiologist, not every person living with primary dRTA will have progressive hearing loss or become deaf. One clue to identifying children with primary dRTA who will develop hearing loss, is a change in the inner ear called an enlarged vestibular aqueduct which can be imaged by an audiologist. Another clue is that children with primary dRTA caused by gene changes in ATP6V1B1 most often have early onset hearing loss. In fact, 92% have sensorineural (inner ear) hearing loss. On the other hand, 56.7% of individuals with primary dRTA caused by gene changes in ATP6V0A4 have early or late onset sensorineural (inner ear) hearing loss. As an exception, there is a much lower chance for hearing loss in individuals who have primary dRTA caused by having two nonworking copies of the common founder splice site gene change (p.I386Afs*56) in the ATP6V1B1 gene found most frequently in individuals of North African descent.

If a child is not identified and treated early, primary distal renal tubular acidosis (primary dTRA) is a life-limiting diagnosis. With early diagnosis, alkali treatment (sodium bicarbonate or sodium citrate) and potassium supplements as needed (often potassium citrate), there usually is no decrease in life expectancy for individuals with primary distal renal tubular acidosis. Having said this, some children with primary dTRA may experience complications prior to diagnosis and about a 17-30% of treated patients may still progress to have chronic kidney disease which can affect life expectancy.

Although primary distal renal tubular acidosis (primary dRTA) can in occur in adults as primary genetic condition, there are other forms of distal renal tubular acidosis that are not caused by a genetic changes. These types of distal renal tubular acidosis occur as a complication of other health issues that cause abnormal calcium deposits to build up in the kidney and impair distal tubule function such as:

• sickle cell anemia
• hyperparathyroidism
• hyperthyroidism
• chronic active hepatitis
• primary biliary cirrhosis
• analgesic nephropathy
• rejection of a transplanted kidney
• renal medullary cystic disease
• obstructive uropathy
• chronic urinary tract infections

It is not a very common issue, but sometimes individuals living with primary distal renal tubular acidosis can have periods in which they are unable to move due to extreme muscle weakness. These episodes, called hypokalemic paralysis, are caused by having low levels of potassium in their blood (hypokalemia).

There is a form of primary distal renal tubular acidosis that is inherited in an autosomal dominant pattern (primary AD dRTA). Primary AD dRTA is most often diagnosed in teens and young adults and is usually due to mutations in the SLC4A1 gene. In Primary AD dRTA, only one disease-causing gene change or variation needs to be inherited to cause signs and symptoms of the condition. Typically, individuals with this form of primary AD dRTA do not have hearing loss or become deaf; however, evaluation by an audiologist is recommended to monitoring hearing before ruling out this symptoms of primary dRTA.

Many of the problems associated with primary dRTA can be decreased by prompt diagnosis and treatment. However, even though alkali therapy and potassium supplementation treatments help to correct the acidic blood levels, improve health, and reduce the start and/or progression of renal tract calcification, rickets, and muscle weakness, it cannot prevent the onset or progression of hearing loss. One theory behind the inability to treat the hearing loss is that the cochlea is anatomically separated from the blood stream and treat can't reach it. Having said this, hearing aids and cochlear implants have been found to be successful in the management of hearing loss in children with primary dRTA.

Hearing loss in primary distal renal tubular acidosis (primary dRTA) usually develops from birth to late childhood, although it may appear in early adulthood as well. The hearing loss can start during, before, or much later than the systemic acidosis. The degree and severity of hearing loss can be very different from person to person and does not correspond to the acid levels in the blood. Accordingly, all individuals living with primary dRTA should be closely monitored by an audiologist with routine hearing tests.

Hearing loss is a common symptom seen in people living with primary distal renal tubular acidosis. This hearing loss is typically managed by an audiologist and should be monitored closely. Severe or profound hearing loss may be treated with cochlear implants; however, in children where hearing loss was mild to moderate hearing aids were found to be equally as effective on tests of spoken language as cochlear implants.

The primary treatment for primary distal renal tubular acidosis (primary dRTA) is alkali therapy with sodium bicarbonate or sodium citrate. The dose and number of doses taken per day is determined by the treating doctor based on the age, size, and lab levels of the patient with primary dRTA. In some cases, the medication is given four to six times a day during waking hours. In other cases, the medication may need to be given during the night as well. The main goal is to manage the blood pH to keep it as close to between 7.35 to 7.45 as possible over the course of the day.

The primary treatment for primary distal renal tubular acidosis (primary dRTA) is alkali therapy with sodium bicarbonate or sodium citrate. The dose and number of doses taken per day is determined by the treating doctor based on the age, size, and lab levels of the patient with primary dRTA. In infants the medication is a liquid usually measured out and given via a plastic medication syringe into the mouth. This medication is often bitter in taste, but infants become used to the flavor. Giving medications to an infant or child can be difficult, but websites such as Seattle Childrens' Hospital suggests some techniques to have more success such as:

• Make sure the child is sitting upright.
• Slowly drip or pour the medicine onto the back of the tongue or the pouch inside the cheek.
• Do not squirt the medicine into the back of the throat.
• Give medicine 20 minutes after a small meal or snack to prevent vomiting.

One of the most worrying health issues in babies with primary distal renal tubular acidosis (primary dRTA) is the risk of dehydration due to feeding problems, vomiting, or lethargy. Severe dehydration is a serious issue that requires emergency care in infants as if it is untreated it can lead to health problems such as loss of consciousness, seizures, brain damage, or death. Key signs for dehydration in infants include:

• very sleepy
• child doesn't respond to your voice or touch
• child appears limp and too weak to cry
• decreased urine (infants, fewer than six wet diapers per day)
• sunken eyes
• sunken soft spot of the head in an infant or toddler
• no or fewer tears when crying
• pale or splotchy skin
• rapid heartbeat (more than 110 beats per minute in infants)

If there are concerns that an infant or child may be dehydrated, it is important to call the pediatrician immediately and/or go to the emergency room for treatment with fluids.