LRBA deficiency has long been viewed primarily as an immune disorder, but researchers at Science Tokyo have found that the condition may also impair urinary concentrating ability. Using patient registry data from 43 individuals, mouse models, and protein analysis, the study found that LRBA deficiency can cause excessive urination and electrolyte abnormalities, highlighting the need for closer fluid and sodium monitoring in affected patients.
In the body, the lipopolysaccharide-responsive and beige-like anchor protein (LRBA) plays a crucial role in directing proteins to their correct locations within cells. In immune cells, LRBA helps control the movement of an immune checkpoint protein called cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), which prevents the immune system from becoming overactive.
Normally, LRBA helps recycle CTLA-4 back to the cell surface after use, allowing it to continue suppressing abnormal immune responses. Mutations in the LRBA gene cause a rare inherited condition called LRBA deficiency. Without this function, CTLA-4 is instead broken down inside the cell rather than being recycled, making it harder for the body to control immune activity, leading to immune dysregulation. First described in 2012, LRBA deficiency has been primarily associated with chronic diarrhea, recurrent infections, autoimmunity, organ enlargement, and poor growth.
Now, a research team led by Assistant Professor Fumiaki Ando, graduate student Kanako Nagaoka, and Professor Shinichi Uchida from the Department of Nephrology, Graduate School of Medical and Dental Sciences, Institute of Science Tokyo (Science Tokyo), Japan, in collaboration with Endowed Project Professor Hirokazu Kanegane from the Department of Child Health and Development, Science Tokyo, has found that LRBA deficiency may also impair kidney function by disrupting the body’s ability to regulate water and sodium balance. Their findings, which were made available online on April 28, 2026, and published in Volume 123, Issue 18 of the journal Proceedings of the National Academy of Sciences on May 5, 2026, reveal that patients with LRBA deficiency can develop polyuria, or excessive urination, along with electrolyte abnormalities, increasing the risk of dehydration.
“The study is the first to show that LRBA deficiency causes polyuria with electrolyte abnormalities in addition to immune dysfunction, highlighting the need for careful monitoring of dehydration risk and personalized treatment strategies,” says Ando.
LRBA has also been found in epithelial tissues, including the kidney, which plays an essential role in maintaining the body’s fluid balance. The researchers found that LRBA plays an important role in regulating two water-transporting channels, aquaporin-2 (AQP2) and aquaporin-4 (AQP4), and sodium balance.
In the collecting duct of the nephron, LRBA helps AQP2 reach the cell surface during dehydration, allowing water to be reabsorbed from urine. LRBA also stabilizes AQP4 by binding directly to it and helping maintain its position on the basolateral membrane, where it helps move water into the bloodstream. In distal convoluted tubule cells, LRBA promotes the trafficking of a protein called sterile 20/SPS1-related proline/alanine-rich kinase (SPAK), which in turn activates the Na–Cl cotransporter (NCC) salt transporter and supports sodium reabsorption.
When LRBA is deficient, these carefully coordinated systems become disrupted. As a result, the kidneys become less able to concentrate urine, and water and sodium balance become impaired. The researchers observed these effects in patient registry data and mouse models. Among 43 patients in an international registry, about 20% showed impaired urine concentration, and 8 had polyuria, although 3 of these cases were excluded because of type 1 diabetes. In mice lacking LRBA, the animals produced large amounts of dilute urine and developed low blood pressure when fed a low-salt diet.
The researchers also explored whether these kidney-related effects could be improved. In mice carrying the LRBA mutation R1442Q, treatment with desmopressin, an antidiuretic drug, improved urine concentration within 1 hour. The findings suggest that desmopressin may help manage excessive urination in some patients with specific LRBA mutations.
LRBA deficiency has long been viewed primarily as an immune disorder. The findings of this study provide new insights into its effects beyond the immune system, revealing that the kidneys are also significantly affected, which may increase the risk of dehydration and electrolyte imbalances. These problems may further worsen fluid and sodium loss already caused by common symptoms of LRBA deficiency, such as chronic diarrhea and reduced food intake during illness. “These molecular and physiological findings emphasize the need for fluid and sodium management in patients with LRBA deficiency, particularly during sick days,” says Ando.
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About Institute of Science Tokyo (Science Tokyo)
Institute of Science Tokyo (Science Tokyo) was established on October 1, 2024, following the merger between Tokyo Medical and Dental University (TMDU) and Tokyo Institute of Technology (Tokyo Tech), with the mission of “Advancing science and human wellbeing to create value for and with society.”
Proceedings of the National Academy of Sciences
Experimental study
People
LRBA organizes distinct vesicular trafficking systems in distal nephron segments for water and sodium conservation
5-May-2026
The authors declare no competing interest.