NORD gratefully acknowledges Daniel Batlle, MD, Earle, del Greco Levin Professor of Nephrology/ Hypertension, Professor of Medicine, Northwestern University Feinberg School of Medicine, Division of Nephrology/ Hypertension, for assistance in the preparation of this report.
Primary distal renal tubular acidosis (dRTA) is a rare genetic disorder that affects the ability of the kidneys to remove acid from the blood. This leads to metabolic acidosis. Metabolic acidosis is a condition in which the circulating chemical acids and bases are out of balance. The blood of affected individuals contains too much acid and the urine contains too little acid. Chronic metabolic acidosis can lead to a variety of symptoms. The specific signs, symptoms, and severity of this disorder can vary from one person to another. There are different forms of primary distal renal tubular acidosis. They are caused by a variation (mutation) in one of at least three different genes; the SLC4A1 gene, the ATP6V0A4 gene, and the ATP6V1B1 gene. A variation in the SLC4A1 gene is usually inherited in an autosomal dominant pattern, and less often in an autosomal recessive pattern. Variations in the ATP6V0A4 and ATP6V1B1 genes are usually inherited in an autosomal recessive pattern. A mixture of sodium and potassium salts in the form of sodium citrate or potassium citrate liquid solutions is usually recommended. Liquid preparations, however, have poor palatability and acceptance among patients. In this case, sodium bicarbonate tablets are used instead or in addition to the drinking solution. Often, potassium supplements may be necessary if not included in the alkali therapy.
Renal tubular acidosis is a general term for when the kidneys cannot properly remove acid from the body. The kidneys contain nephrons, which are hair-sized structures that are the basic filtering units of the kidneys. Each nephron consists of a glomerulus and a renal tubule. The renal tubule reabsorbs electrolytes such as sodium, chloride and potassium back into the blood so that not too much electrolyte is lost through the urine. The kidneys, through the tubules, reclaim bicarbonate, an electrolyte that helps to maintain the acid-base balance in the body, and then excrete acid through the urine. Acid is produced as a byproduct from a normal diet.
There are several types of renal tubular acidosis. According to their pathophysiological basis, 4 types of RTA were initially categorized. Distal type I RTA or classic RTA usually referred to as distal renal tubular acidosis (dRTA) is characterized by a buildup of acids in the blood as a consequence of the distal tubules in the kidneys not being able to rid the body of the daily acid load. This results in an inability to lower urine pH regardless of the degree of acidemia (acid level in the blood). pH is the measure of acidity of liquids. The higher the score more alkaline and less acidic a liquid is. Distal refers to being “distant” from the point of origin. In the nephron, it means the defect occurs away from the point where fluid enters the tubule. Distal renal tubular acidosis occurs because the kidneys fail to secrete acids into the urine.
Primary distal renal tubular acidosis is a highly variable disorder; this means that the disorder affects people differently. Some individuals may only have slightly elevated acid levels and no accompanying symptoms (asymptomatic). Some individuals living with primary dRTA may experience kidney stones and others may not. Generally, people with an autosomal dominant pattern of inheritance have milder symptoms and a later age of onset of symptoms than people with an autosomal recessive pattern of inheritance. However, this is not always true and sometimes more severe complications such as growth failure or rickets (bowing of the bones) can affect individuals with dominantly-inherited primary distal renal tubular acidosis.
Primary dRTA can cause severe complications in infants, especially if unrecognized and untreated. Affected infants can experience vomiting, dehydration, and poor growth that can result in being short for their age and gender (short stature). Additional symptoms can include excessive thirst (polydipsia), urinating frequently (polyuria), constipation, muscle weakness, and fatigue. Sometimes, affected individuals may have diminished reflexes. Many of these symptoms are related to metabolic acidosis, a serious and often life-threatening condition. Parents should seek prompt medical attention if a baby shows signs of metabolic acidosis. Some children develop rickets, which is a condition characterized by improper hardening (calcification) of the bones leading to softening and distortion/bowing of the bones and bone pain. If unrecognized and untreated, primary distal renal tubular acidosis usually causes too much calcium to build up in the kidneys (nephrocalcinosis), and the formation of kidney stones (nephrolithiasis). If untreated, nephrocalcinosis can progress to cause damage to the kidneys resulting in chronic kidney disease (CKD) and reduced kidney function.
In severe instances, if untreated, extreme muscle weakness (muscle paralysis), abnormal heartbeats (cardiac arrhythmia), and episodes of having difficulty breathing or stopping breathing (respiratory arrest) can develop. These symptoms are related to low levels of potassium in the blood (hypokalemia). Potassium is an important electrolyte for the health of nerve and muscles. The kidneys excrete excess potassium through the urine. However, in primary distal renal tubular acidosis the kidneys sometimes excrete too much potassium. Hypokalemia may also contribute to excessive urination (polyuria).
A subset of individuals with the autosomal recessive forms develop sensorineural hearing loss. Sensorineural hearing loss occurs when the nerves within the ear cannot properly send sensory input (sound) to the brain, and is not caused by problems with the ear itself. The degree and progression of sensorineural hearing loss can vary from one child to another, but often affects both ears (bilateral) and is usually severe.
Affected individuals with an autosomal dominant dRTA usually experience a milder form of the disorder with onset of symptoms in adolescence or adulthood. Affected adults may develop reduced bone mass (osteopenia) and abnormal softening of the bones (osteomalacia) and bone pain. Weakened bones may be prone to fracture. Some individuals may develop an abnormal increase in red blood cell mass (erythrocytosis). They may develop kidney stones or kidney issues as adolescents or adults if the disorder is unrecognized and untreated.
Occasionally, individuals with an inherited variation in the SLC4A1 gene have experienced the premature breakdown of red blood cells, which leads to low levels of circulating red blood cells (hemolytic anemia). The main function of red blood cells is to deliver oxygen throughout the body. People with hemolytic anemia can experience shortness of breath (dyspnea), lightheadedness, fatigue, weakness, pale skin color, and headaches.
Primary distal renal tubular acidosis is caused by a variation (mutation) in one of at least three different genes, the SLC4A1 gene, the ATP6V0A4 gene, and the ATP6V1B1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In some affected individuals, no variation in these three genes can be identified suggesting that other, as-yet-unidentified genes can play a role in primary dRTA.
The SLC4A1 gene contains instructions for producing (encoding) a protein called anion exchanger 1 or AE1. This protein helps negatively-charged atoms cross cell membranes; specifically, it helps exchange chlorine ions for bicarbonate ions. Bicarbonate is an electrolyte that helps maintain the acid-base balance in the body and is filtered by the kidneys; but, most of the bicarbonate is still retained in the blood and the urine contains very small amounts. The AE1 protein is found in the membranes of kidney cells and red blood cells. The kidneys reclaim filtered bicarbonate and then release acid into the urine to be excreted from the body. Researchers have speculated that a variation in the SLC4A1 gene prevents enough functional AE1 protein from reaching the cell membranes of kidney and red blood cells. Ultimately, this prevents the kidneys from releasing acid into the urine. Acid then builds up in the blood and tissues of the body (metabolic acidosis). The reason why some people develop metabolic acidosis and others do not is not fully understood. In red blood cells, AEI protein cannot reach the red cell membrane resulting in red blood cells that break down prematurely. Some altered AE1 protein can still reach the membranes of red blood cells because it is helped by another protein called glycophorin A. This is most likely why many people with a disease-causing variation in the SLC4A1 gene do not develop hemolytic anemia.
The ATP6V0A4 and the ATP6V1B1 genes encode specific proteins that are part of a protein complex called vacuolar H+-ATPase (V-ATPase). This protein complex acts as a proton pump that helps to move positively-charged atoms (protons) across cell membranes, and helps to regulate acid levels of cells and their surrounding areas. These proteins are commonly found in cells of the inner ear and within the nephron, which is the basic filtering unit of the kidneys. These proteins have a role in regulating the amount of acid removed from the blood to the urine, and in maintaining the proper acid balance within the ear.
Variations in the SLCA41 gene are usually inherited in an autosomal dominant pattern, and, less often, in an autosomal recessive pattern. Variations in the ATP6V0A4 and the ATP6V1B1 genes are inherited in an autosomal recessive pattern.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Disease-causing variations in the SLC4A1 gene can be inherited from a parent or it can occur as a new (sporadic or de novo) mutation, which means that the gene variation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. Affected individuals can then pass on the altered gene in an autosomal dominant pattern.
Disorders inherited in a recessive pattern occur when an individual inherits two variants in a gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Primary distal renal tubular acidosis affects females and males in equal numbers. The exact number of people who have this disorder is unknown. Rare disorders like primary distal renal tubular acidosis often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population.
A diagnosis of primary distal renal tubular acidosis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. The disorder may be suspected in individuals with unexplained metabolic acidosis and an elevated plasma chloride (so called normal anion gap metabolic acidosis).
Clinical Testing and Workup
Doctors may order blood and urine tests to show that the blood is more acidic than it should be and that the urine is less acidic than it should be. The pH levels in the urine of affected individuals is variable, but usually does not fall below 5.5. pH is the measure of acidity of these liquids. The higher the score, the more alkaline and less acidic a liquid is. This indicates that the kidneys are not filtering acid out from the blood. Consequently, blood tests will show excessive levels of acid, and may also be low in bicarbonate and potassium.
These tests may be followed by an estimation of the amount of ammonia excreted through the urine. Most laboratories usually do not perform a direct measurement of ammonia excretion. Urine ammonium is often roughly estimated indirectly by calculating the urine anion gap which is always positive (range 0-80 mEq/L) when the patient has distal renal tubular acidosis but negative (0 to -80 mEq/L) with other types of acidosis such as that caused by diarrhea.
A 24-urine test may be conducted to check for the levels of calcium, citrate, potassium, and oxalate. Individuals with primary distal renal tubular acidosis may have high levels of calcium (hypercalcinemia), significantly low levels of citrate (hypocitraturia), and potassium wasting, which is the excessive excretion of potassium in the urine. Citrate is an acid and low levels of this acid increases the risk of nephrocalcinosis and kidney stone formation. Oxalate is a natural chemical in the body that comes from various sources of food. Too much oxalate in the urine (hyperoxaluria) can have many causes including several genetic disorders affecting the kidneys.
Primary distal renal tubular acidosis needs to be distinguished from proximal distal renal tubular acidosis. This can be accomplished by examining the pattern of urinary bicarbonate excretion in the urine in conjunction with the urine pH. Patients with proximal renal tubular acidosis normally have a high urine pH but are able to lower it when the plasma bicarbonate is very low.
Plain x-rays (radiographs) or specialized imaging techniques such as computerized tomography (CT) scanning or ultrasonography can help to further confirm a diagnosis, or help determine the extent of disease. These tests can show the accumulation or deposition of calcium in the kidneys and help to rule out other conditions. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. During ultrasonography, reflected sound waves are used to create an image of structures within the body including the kidneys.
Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect disease-causing variants in the specific genes known to cause primary distal renal tubular acidosis, but is available only as a diagnostic service at specialized laboratories.
The treatment of primary distal renal tubular acidosis may require the coordinated efforts of a team of specialists. A kidney doctor (nephrologist) who specialize in diagnosing and treating kidney disorders may be a critical member of the care team. A pediatric nephrologist specializes in kidney disorders in children. Physicians who specialize in diagnosing and treating skeletal disorders (orthopedists), an audiologist to monitor hearing and other healthcare professionals may need to systematically and comprehensively help guide treatment.
Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family can be essential as well. The organizations listed in the Resources section of this report provide support and information for individuals with kidney disease.
Individuals with primary distal renal tubular acidosis are treated with alkali therapy. Alkali are chemical compounds that neutralize acids. Alkali therapy usually leads to normal growth in children, and can improve other symptoms including lowering the tendency to develop calcium build up in the kidneys and calcium stones and reverse bone disease. Alkali therapy usually consists of drinking a solution of sodium bicarbonate (baking soda) or sodium citrate every day to counteract the acids produced from eating each day. The dose and specific type of alkali therapy depends upon the bicarbonate and potassium concentrations in the blood serum. Children generally require larger doses; these doses are adjusted as a child ages. Most individuals do not experience symptoms (asymptomatic) when properly treated, except for irreversible kidney or skeletal damage that has occurred before treatment was begun.
If low potassium levels persist (hypokalemia), then affected individuals may require treatment with alkylating potassium salt like potassium citrate. Potassium citrate (versus sodium citrate) may also be recommended when calcium stones are present because sodium can increase calcium stone formation. Citrate salts like potassium citrate correct low levels of citrate (hypocitraturia) and prevent calcium stone formation.
The focus of treatment in individuals with severe hypokalemia that causes paralysis or breathing problems (respiratory compromise) should be to correct the low potassium levels with an intravenous potassium chloride.
Children with autosomal recessive primary distal renal tubular acidosis should receive routine hearing assessments through childhood to detect hearing loss. Hearing loss does not usually respond to alkali therapy. Other treatments can include supplementation with vitamin D or oral calcium supplements to help reduce skeletal abnormalities such as rickets or osteomalacia.
Individuals with low levels of potassium in the blood (hypokalemia) may require potassium supplementation. Treatment with amiloride could help to conserve potassium levels and reduce the need for potassium supplementation in some affected individuals but it could worsen the metabolic acidosis and therefore its use is not generally recommended. Amiloride is a diuretic or “water pill.”
ADV7103, a twice-a-day alkali therapy, is being studied in the US, Canada and Europe for the treatment of primary dRTA.
Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government website.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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Batlle D, Haque SK. Genetic causes and mechanisms of distal renal tubular acidosis. Nephrol Dial Transplant. 2012;27:3691-3704. https://academic.oup.com/ndt/article/27/10/3691/1830963
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Mattoo TK. Etiology and clinical manifestations of renal tubular acidosis in infants and children. UpToDate, Inc. 2018 Nov 30. Available at: https://www.uptodate.com/contents/etiology-and-diagnosis-of-distal-type-1-and-proximal-type-2-renal-tubular-acidosis Accessed December 11, 2018.
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