Primary Distal Renal Tubular Acidosis

Diagnosis and Testing

How do I get tested for primary distal renal tubular acidosis?

Testing for primary distal renal tubular acidosis (primary dRTA) often requires an examination by a doctor combined with a series of blood and urine tests. First, if a patient has symptoms of primary dRTA disease on exam, blood and urine tests will be done. Initial blood tests will look at the levels of electrolytes (such as potassium, sodium, and chloride), carbon dioxide (an acid), bicarbonate (a base), and pH. Initial urine tests will measure urinary electrolytes and pH levels. If testing finds a urine pH above 5.5, a normal blood anion gap, low serum potassium, and low blood pH levels it is suggestive of primary dRTA as possible diagnosis. Other early tests that may also help with diagnosis include the NH4Cl acidifying test and the furosemide test on blood. When doing these initial tests, it is important to collect the blood and urine samples before giving IV fluids (hydration therapy) as the extra fluid support it can interfere with test results and given false negatives.

If there are signs and symptoms of primary dRTA, the lab tests suggest primary dRTA, and other non-genetic causes of are ruled out, the doctor will often do a genetic blood test (called sequencing) looking at the "spelling" of the ATP6V1B1, ATP6V0A4, and/or SLC4A1 genes. The sequencing test looks for spelling changes in the code of the genes that cause them not to work correctly.

If a person has signs and symptoms of distal renal tubular acidosis (dRTA) and/or hearing loss, but has had a negative gene sequencing test, a genetic deletion/duplication test may be done next to look for missing or duplicated sections of the gene that would cause primary dRTA. Because of the methodology of a gene sequencing test, this missing or duplicated gene pieces can be overlooked during a standard sequencing genetic test.

A final testing option is a panel test for many genes at the same time. The panel test is run on blood, but tests for many genes that, when they have changes, are known to lead to distal renal tubular acidosis, kidney disease, or hearing loss.

For more information about genetic testing options, including panel testing, go to the Genetic Testing Registry.

A pediatric nephrologist (a pediatrician specializing in the kidney) can help with understanding more specifics about the disorder. A genetic counselor can help with ordering further diagnostic testing and determine which labs in the U.S. conduct testing for primary dRTA would be best if testing is appropriate. (Take a look at "Find a Genetic Counselor" in your area https://www.nsgc.org/findageneticcounselor).

References
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Is there newborn testing for Primary Distal Renal Tubular Acidosis?

Is there more than one test for primary distal renal tubular acidosis?

Who else in my family should I test for primary dRTA?

Is there newborn testing for Primary Distal Renal Tubular Acidosis?

Newborn screening is performed for several genetic conditions in the United States, and the conditions screened for are determined on a state by state basis. The Secretary of Health and Human Services makes recommendations for what diseases should be put on the newborn screen, but individual states have the final say in what is added. In 2018, there are no states doing automatic testing of newborns or newborn screenings for primary distal renal tubular acidosis (primary dRTA). However, if a doctor is suspicious that a newborn may be showing signs of primary dRTA the baby can be tested.

References
Is there more than one test for primary distal renal tubular acidosis?

Testing for primary distal renal tubular acidosis (primary dRTA) often takes a series of tests. First, if a baby, child, or adult has symptoms of primary dRTA disease, testing usually starts with a blood test looking at the potassium levels and pH. If the potassium levels and pH are low, there are signs of primary dRTA and other non-genetic causes are ruled out, the doctor will do a blood test (called sequencing) looking at the code of the ATP6V1B1 and ATP6V0A4 genes. The sequencing test looks for changes in the code of the genes that cause them not to work correctly. People with primary dRTA have two changes in this gene, one on the copy they inherited from their mother and one on the copy they inherited from their father.

Lastly, if a person has some symptoms of distal renal tubular acidosis (dRTA) and the doctor wants to test for many causes of dRTA (including primary dRTA) at the same time, the doctor can order a sequencing panel test. The panel test is also a blood test, but tests for many genes that, when they have changes, are known to lead to distal rental tubular acidosis.

For more information about genetic testing options, including panel testing, go to the Genetic Testing Registry.

References
Who else in my family should I test for primary dRTA?

While primary distal renal tubular acidosis (primary dRTA) is relatively rare, it can run in families as the gene changes are passed from parents to children. The main way that primary dRTA disease is passed down is called autosomal recessive inheritance; however it can also run in an autosomal dominant form.

In the autosomal recessive forms of primary dRTA, in order to develop symptoms of primary dRTA, a person must have inherited two non-working copies of the ATP6V1B1 or ATP6V0A4 genes, which are the 2 of the genes associated with primary dRTA. If a person has one working copy and one non-working copy, they are a carrier for primary dRTA and do not have any symptoms themselves. We assume that both parents of an affected person are carriers, so each of their children has a 1 in 4 or 25% chance of having primary dRTA as well. Testing the brothers and sisters of someone who has primary dRTA is important because it can find out who is a carrier and who is also affected by primary dRTA (but may not have visible symptoms yet). The aunts and uncles of people with primary dRTA may also be carriers. If other people in the family want to know their chances to have a baby with primary dRTA, they can be tested for the same gene changes as the person diagnosed with primary dRTA.

Distal renal tubular acidosis (primary dRTA) caused by loss-of-function variants in SLC4A1 are usually inherited in an autosomal dominant patter and occur when a baby inherits one nonworking copy of the SLC4A1 gene from one parent. Missing a single working copy of the SLC4A1 gene decreases the body's ability to control the pH of the blood, resulting in the medical issues of primary dRTA. In autosomal dominant inheritance, one parent of a person with primary dRTA disease probably has a non-working copy of the SLC4A1 gene and accordingly symptoms of primary dRTA themselves. When an individual with an autosomal dominant form of primary dRTA has children, there is a 1 in 2 or 50% chance of passing on the non-working copy to their child and having a child with primary dRTA. Even if a couple already has one child with primary dRTA, it is important to know that they can have another affected child because the chances are 1 in 2 for each pregnancy.

However, in Thailand, Malaysia, the Philippines and Papua New Guinea there is a common form of primary dRTA with anemia caused when a baby inherits two nonworking copies of the SLC4A1 gene, one from each parent. In this autosomal recessive situation, when both parents are carriers of one nonworking copy of the SLC4A1 gene, there is a 1 in 4 or 25% chance of both of them passing on the non-working copy and having a child with primary dRTA.

A genetic counselor can help with understanding the pattern that primary dRTA runs in a specific family, who may be at increased risk to have primary dRTA, and discuss genetic testing options as appropriate. To find a genetic counselor in your area, you can use the National Society of Genetic Counselor's "Find a Genetic Counselor" https://www.nsgc.org/findageneticcounselor).

References
  • Genetics Home Reference, renal tubular acidosis with deafness, published 10/23/2018 https://ghr.nlm.nih.gov/condition/renal-tubular-acidosis-with-deafness#sourcesforpage
  • Orphanet, autosomal recessive distal renal tubular acidosis, https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=402041
  • Khositseth S, Bruce LJ, Walsh SB, Bawazir WM, Ogle GD, Unwin RJ, et al. Tropical distal renal tubular acidosis: clinical and epidemiological studies in 78 patients. QJM. 2012;105(9):861-877.

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