Introduction

Bartter syndrome, first described in 1960 by Dr Frederic Bartter, is a rare disorder, affecting approximately one in 100,000 people in the general population.¹ It is a genetic condition that has profound effects on kidney function and overall health, disrupting the kidney’s ability to reabsorb salt and other electrolytes, such as calcium and magnesium. The associated symptoms that individuals with Bartter syndrome experience range from mild to potentially life-threatening,¹ with symptoms also becoming apparent before birth.² Although there is no cure and individuals face challenges living with Bartter syndrome, with the right treatment, it is generally managed well.¹ Let’s explore its characteristics and current treatments in order to understand the most effective ways to manage Bartter syndrome.

How does Bartter syndrome affect the kidneys?

The kidneys play a crucial role in removing waste from the body, filtering the blood, and controlling the body's exchange of water and electrolytes.³ Electrolytes are salts and other minerals that conduct electrical impulses in the body, they are necessary for the proper function of nerves, muscles and biochemical reactions in the body. The kidneys regulate the electrolyte concentration by filtering the blood and then reabsorbing electrolytes through the renal tubule of the kidneys back into the blood: this ensures that not too many electrolytes and salt are lost in urine. The renal tubule is split into four segments, the loop of Henle, the proximal convoluted tube, the distal convoluted tube, and the collecting duct. When one or more of these segments become dysfunctional, the regulation of electrolytes becomes disrupted, resulting in various symptoms. In most cases, Bartter syndrome is the result of the loop of Henle and in some cases, the distal convoluted tubule functioning incorrectly.¹

Bartter syndrome occurs due to a genetic mutation in the DNA that affects certain proteins which allow the movement of electrolytes in the kidney: these proteins are called ion channels. Particularly, sodium, magnesium, chloride and potassium channels are affected in the kidney, disrupting the way these substances are transported in and out of the kidneys.

This leads to an abnormal amount of water and salt to be expelled in the urine. There are five types of Bartter syndrome, depending on which mutation they exhibit. For example, Bartter syndrome type 3, also called classic Bartter syndrome, is caused by a mutation in the CLCNKB gene, which when mutated causes chloride ion channels to function abnormally. Each type of Bartter syndrome has different characteristics but ultimately all share the problem of disrupted electrolyte regulation.⁴

Symptoms and Health Implications

The symptoms of Bartter Syndrome can vary depending on the type of the condition and its severity. Also depending on the type of the condition, symptoms can first appear at different ages. Bartter syndrome-associated symptoms that occur before birth may lead to an increase in amniotic fluid and ultimately premature delivery.⁵

After birth, common Bartter syndrome symptoms include:

• Frequent need to urinate
• Repeated vomiting
• Muscle weakness and spasms
• Muscle cramps
• Excessive and persistent thirst
• Poor growth
• Fatigue
• Low blood pressure
• A craving for salt
• Mild hearing loss (generally only found in those with type 4 Bartter syndrome)⁵

Some affected infants may fail to grow and maintain a healthy weight, they may also present some facial characteristics, such as large eyes, a prominent forehead, and a triangular-shaped face. More severe symptoms of Bartter syndrome are deposits of calcium in the kidneys (kidney stones) and irregular heartbeats, which may lead to cardiac arrest.¹

Diagnosis of Bartter Syndrome

The excess of amniotic fluid, or polyhydramnios, in pregnant women raises clinicians’ suspicion of Bartter syndrome. Two possible options to confirm the diagnosis of the disorder are prenatal genetic testing and biochemical analysis of amniotic fluid, with genetic testing considered the most reliable method.⁶

On the other hand, diagnosis of Bartter syndrome after birth involves further analyses, clinicians start by examining family history of pregnancies with polyhydramnios complications and the medical history of polyuria (frequent and increased urination), repeated vomiting, episodes of dehydration, and unexplained fever. As failure to thrive is a common symptom of Bartter syndrome, growth charts are a great indicator of the condition. A renal ultrasound may be performed, which examines the kidneys for potential kidney stones. Similarly to diagnosing prenatally, genetic tests that detect mutations in Bartter syndrome-associated genes and biochemical tests that examine elevated levels of certain electrolytes in the body may be implemented.⁶

The age of diagnosis of Bartter syndrome may vary depending on the type and when symptoms begin to arise. Polyhydramnios can be detected as early as 20 to 30 weeks of pregnancy, however is detected later in individuals with type 1 and 2 Bartter syndrome compared with those with type 4 and 5. Type 5 Bartter syndrome typically presents before birth, whereas type 3 usually manifests later in life with most diagnoses occurring after 1 year.⁶

Treatment and Management

Although there is no current cure for Bartter syndrome, extensive research has been done on managing the condition. Several treatment strategies are available for individuals that aim to regulate their electrolyte levels, manage symptoms and prevent the risk of life-threatening complications. Although the kidneys are affected in patients with Bartter syndrome, the likelihood of kidney failure is unlikely, and so is the need for treatments like dialysis and kidney transplants.⁵

Medical Management

Due to the kidney’s inability to maintain a healthy electrolyte balance in individuals with Bartter syndrome, supplements are often prescribed to correct these imbalances. These include sodium, potassium chloride, and magnesium supplements. In other cases, medications like nonsteroidal anti-inflammatory drugs (NSAIDs) are prescribed, these drugs reduce the production of prostaglandins, which when produced excessively lead to increased urination. Prostaglandins are produced in abundance in patients with Bartter syndrome, therefore NSAIDs help alleviate some of the symptoms caused by dysfunctional kidneys.⁷ In more severe cases, intravenous (IV) therapy may be required to top up salt levels when they become critically low. For type 4 Bartter syndrome, hearing aids or cochlear implants may be given to individuals with hearing impairment.⁵

Dietary Recommendations

Nutritional counselling is always provided, they offer advice on dietary requirements which replenish the lost salt in individuals with Bartter syndrome. It is recommended that they increase their salt intake, as well as increase their consumption of foods that are high in potassium.¹

Long-term Monitoring and Psychological Support

Due to the nature of Bartter syndrome being a lifelong condition, people with the condition are given regular check-ups and blood tests to ensure that they stay on the correct treatment. The amount of supplements and medication is likely to change or reduce over time as management as an adult becomes easier. Genetic counselling is recommended for affected individuals and their families. Furthermore, psychosocial support is also offered which can help with coping with the emotional and social aspects of living with the condition.⁸

Research and Future Directions

Extensive research is ongoing on Bartter syndrome, scientists are researching novel treatment and diagnosis methods, these may eventually lead to a potential cure. A promising area of research is gene therapy, which is defined as the use of genetic material to treat a disease. Since Bartter syndrome is a genetic disorder and the genes affected have already been established, gene therapy can be implemented to edit or replace these genes with healthy ones.⁹ A study by García-Castaño et al. in 2023 successfully performed Next-Generation Sequencing on patients to detect their genetic mutations in order to reach a diagnosis. This method facilitates the provision of more accurate and personal treatment for individuals, as different mutations result in different symptoms thus requiring different therapies.¹⁰

Another area of research is cell therapy, which involves the transfer of viable, healthy cells into a patient in an attempt to replace or repair damaged cells. This can be used to potentially treat damaged or dysfunctional kidney tissue in patients with Bartter syndrome.⁹ Research has been conducted on stem and progenitor cells, which are types of cells that can self-renew and differentiate into specific cells, such as kidney cells. They show promise in restoring kidney function in adults with Bartter syndrome, thus enabling the regulation of their salt and electrolyte concentration.¹¹

Summary

Bartter syndrome is a rare genetic disorder, caused by mutations of various genes in the DNA, particularly affecting kidney function. The kidneys of these individuals cannot adequately reabsorb electrolytes and salt, leading to an array of symptoms such as frequent urination, poor growth, and more severe complications like kidney stones and cardiac issues. Although there is no cure for Bartter syndrome, there are many effective ways in which it can be managed through dietary adjustments, supplements, medications, and regular monitoring. This allows individuals to maintain a good quality of life and in most cases, symptoms reduce as they reach adulthood. Promising research areas in gene therapy and cell therapy offer hope for personalised treatment and a potential cure, brightening the future for those living with Bartter syndrome.