What renal transporter is affected in Bartter (Barter) syndrome?

From the Guidelines

Bartter syndrome primarily affects the Na-K-2Cl cotransporter (NKCC2) in the thick ascending limb of the loop of Henle in the kidney, as well as other renal transporters such as ROMK, ClC-Ka, ClC-Kb, and NCC, depending on the subtype of the disease. The pathophysiology of Bartter syndrome involves defects in these transporters, which are responsible for reabsorbing sodium, potassium, and chloride ions from the tubular fluid back into the bloodstream 1. When these transporters are dysfunctional due to genetic mutations, it leads to increased sodium, potassium, and chloride excretion in the urine, resulting in the characteristic features of Bartter syndrome: hypokalemia, metabolic alkalosis, and normal to low blood pressure despite elevated renin and aldosterone levels.

Key Transporters Affected

• Na-K-2Cl cotransporter (NKCC2) in the thick ascending limb, which is mutated in BS type 1
• Potassium channel ROMK (KCNJ1), which is mutated in BS type 2
• Chloride channel ClC-Kb, which is mutated in BS type 3
• Accessory subunit barttin, which is mutated in BS types 4a and 4b, affecting both ClC-Ka and ClC-Kb chloride channels
• NaCl cotransporter NCC in the distal convoluted tubule, which is affected in some forms of the disease The syndrome mimics the effects of loop diuretics like furosemide, which specifically block NKCC2, and thiazide diuretics, which block NCC 1. Understanding this pathophysiology helps explain why patients with Bartter syndrome experience salt wasting, electrolyte abnormalities, and why treatments focus on electrolyte replacement and prostaglandin inhibitors.

From the Research

Renal Transporter Affected in Bartter Syndrome

• The renal transporter affected in Bartter syndrome is the Na-K-2Cl cotransporter (NKCC2) 2, 3, 4.
• This transporter is responsible for sodium, potassium, and chloride reabsorption in the thick ascending limb of Henle's loop.
• Mutations in the NKCC2 gene can lead to nonfunctional transporters, resulting in impaired salt reabsorption and the characteristic symptoms of Bartter syndrome 2.
• Other transporters, such as the ROMK channel, can also be affected in certain types of Bartter syndrome 5, 4.
• The specific transporter affected can vary depending on the subtype of Bartter syndrome, with different subtypes involving different transporters or channels 4.

Subtypes of Bartter Syndrome

• Bartter syndrome can be classified into different subtypes based on the underlying cause and affected transporter 4.
• Type I Bartter syndrome is caused by mutations in the NKCC2 gene 2.
• Type II Bartter syndrome is caused by mutations in the ROMK channel gene 5.
• Other subtypes involve different transporters or channels, such as the sodium-chloride cotransporter NCCT or the chloride channel ClC-Kb 4.

Clinical Implications

• Understanding the specific transporter affected in Bartter syndrome can help guide diagnosis and treatment 6, 4.
• Treatment for Bartter syndrome typically involves managing symptoms and preventing complications, rather than correcting the underlying transporter defect 6.
• Further research into the mutated transporters and channels may lead to the development of targeted therapies for Bartter syndrome 6.