Scientists in Tokyo have uncovered a hidden vulnerability in LRBA deficiency—one that runs far deeper than the immune disorder doctors have known for over a decade. When Fumiaki Ando and his team at the Institute of Science Tokyo analyzed data from 43 patients with the rare genetic condition, they discovered something unexpected: the same protein malfunction that triggers immune chaos also quietly sabotages the kidneys' ability to manage water and salt, leaving some patients drenched in sweat from excessive urination and electrolyte imbalances.
LRBA deficiency has been recognized since 2012 as a serious condition marked by chronic diarrhea, recurrent infections, autoimmunity and organ enlargement. The lipopolysaccharide-responsive and beige-like anchor protein—LRBA for short—works like a cellular postal service, directing other proteins to their correct destinations inside cells. In immune cells, it escorts a crucial checkpoint protein called CTLA-4 back to the cell surface after use, allowing the immune system to maintain its protective brakes. When the LRBA gene mutates, CTLA-4 gets degraded instead of recycled, and the immune system spins out of control.
But LRBA doesn't just work in immune cells—it's also present in the kidney's delicate epithelial tissues, where it performs an entirely different, equally vital job. The research team, led by Ando along with graduate student Kanako Nagaoka and Professor Shinichi Uchida, found that LRBA regulates two water-channel proteins: aquaporin-2 and aquaporin-4. In the kidney's collecting duct, LRBA helps aquaporin-2 reach the cell surface during dehydration, allowing the body to reabsorb water from urine. It also stabilizes aquaporin-4 by binding directly to it, keeping it anchored on the cell membrane so water can move back into the bloodstream. In addition, LRBA activates a sodium transporter called NCC, which helps the kidneys conserve salt.
When LRBA is deficient, this finely tuned system falls apart. The kidneys lose their ability to concentrate urine, producing large amounts of dilute urine instead. Among the 43 patients in an international registry, about 20 percent showed impaired urine concentration. Eight patients developed polyuria—excessive urination—though three were excluded due to Type 1 diabetes. In laboratory mice lacking LRBA, researchers observed the same pattern: the animals produced massive quantities of dilute urine and developed dangerously low blood pressure when placed on a low-salt diet.
The implications are sobering but actionable. Patients with LRBA deficiency now need closer monitoring of their fluid and electrolyte balance, along with personalized treatment strategies designed to prevent dangerous 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," Ando said. The findings, published in the Proceedings of the National Academy of Sciences in May 2026, suggest that treating LRBA deficiency will require doctors to see beyond the immune system and pay closer attention to what's happening in the kidneys.