Kidney Week

Abstract: SA-PO0505

Desmopressin Improves Urinary Concentrating Defect Caused by LRBA Deficiency

Session Information

• Fluid, Electrolyte, and Acid-Base Disorders: Basic Research
  November 08, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Fluid, Electrolytes, and Acid-Base Disorders

• 1101 Fluid, Electrolyte, and Acid-Base Disorders: Basic

Authors

• Nagaoka, Kanako, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan

Kanako Nagaoka, MD

• Ando, Fumiaki, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan

Fumiaki Ando, MD, PhD

• Hara, Yu, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan

Yu Hara, MD, PhD

• Fujiki, Tamami, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan

Tamami Fujiki, MD

• Kikuchi, Hiroaki, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan

Hiroaki Kikuchi, MD, PhD

• Mandai, Shintaro, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan

Shintaro Mandai, MD, PhD, FASN

• Mori, Yutaro, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan

Yutaro Mori, MD, PhD, FASN

• Susa, Koichiro, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan

Koichiro Susa, MD, PhD

• Mori, Takayasu, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan

Takayasu Mori, MD, PhD

• Sohara, Eisei, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan

Eisei Sohara, MD, PhD

• Uchida, Shinichi, Tokyo Kagaku Daigaku Daigakin Ishigaku Sogo Kenkyuka, Bunkyo, Tokyo, Japan

Shinichi Uchida, MD, PhD

Background

Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) is indispensable for membrane trafficking of a checkpoint immune molecule, CTLA-4, in regulatory T cells. Biallelic pathogenic variants in LRBA abolish LRBA protein expression, resulting in immune dysregulation and chronic diarrhea; however, the renal phenotype of LRBA deficiency remains unknown. We discovered the LRBA-protein kinase A (PKA) complex at renal recycling endosomes which promotes membrane trafficking of aquaporin-2 (AQP2) water channels. In this study, we further investigate physiological roles of LRBA in the kidneys to determine renal phenotypes of patients with LRBA deficiency.

Methods

Membrane fraction of kidneys from Lrba^-/- mice was analyzed by a quantitative proteomic analysis. We generated LRBA-deficient mice carrying pathogenic missense mutation of Lrba (p.R1442Q, which corresponds to the human LRBA p.R1445Q). The observational registry study was designed to assess urinary concentrating ability of patients with LRBA deficiency.

Results

Proteomic analysis detected 12 membrane proteins whose protein expression levels were decreased in Lrba^-/- mice. AQP4 was the primary candidate protein under direct regulation by LRBA because it comprises LRBA-binding motif, Y²⁷⁷MEV, in its C-tail. LRBA bound to AQP4-WT, but not to AQP4-Y277F. An alanine substitution of the PKA phosphorylation residue, AQP4-S276, also dissociated the LRBA-AQP4 interaction. Overexpression of LRBA increased cell surface expression of AQP4 in vitro. Contrastingly, Lrba knockout impaired AQP2 and AQP4 activities, causing decline in maximum urine osmolality (WT: 4045±657.01 mOsm/kg, Lrba^-/-: 1408±207.28 mOsm/kg). Of note, urinary concentrating defect in LRBA-deficient mice was alleviated by desmopressin treatment (Lrba^{R1442Q/R1442Q}: 2748±151.78 mOsm/kg). Although the registry study showed 97% of LRBA deficiency patients had chronic diarrhea, their urine specific gravity was relatively low (median, 1.008, n=17).

Conclusion

LRBA deficiency patients are at high risk of dehydration due to chronic diarrhea and recurrent infections. Low urine concentrating ability leads to deterioration in negative body fluid balance. Desmopressin is a promising treatment for dehydration resulting from LRBA deficiency.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025x5kexn9c