Kidney Week

Abstract: TH-PO402

Selective V2 Vasopressin Receptor Blockade Increases Urinary Exosome Pendrin Expression in Patients with Autosomal Dominant Polycystic Kidney Disease

Session Information

• Genetic Diseases: Cystic - Therapeutic Investigations and Prognosis
  November 02, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

• 1201 Genetic Diseases of the Kidneys: Cystic

Authors

• Bargagli, Matteo, Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Matteo Bargagli,

• Albano, Giuseppe, Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Giuseppe Albano,

• Fuster, Daniel G., Department of Nephrology and Hypertension, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

Daniel G. Fuster,

• Ferraro, Pietro Manuel, U.O.S. Terapia Conservativa della Malattia Renale Cronica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy

Pietro Manuel Ferraro,

Background

Tolvaptan, a selective V2 vasopressin receptor (V2R) antagonist, has shown to improve kidney function and acid retention biomarkers in ADPKD-treated patients. However, the underlying mechanisms of this association remain unclear. Here we investigated the effect of Tolvaptan on renal acid-base handling in ADPKD by analyzing the abundance in urinary exosomes of Pendrin and the B1 subunit of V-ATPase, which regulate HCO₃⁻ and H⁺ transport in the collecting ducts.

Methods

In this prospective study, 24 ADPKD patients were enrolled from the Bern ADPKD registry. Patients were allocated with a 1:1 ratio in the Tolvaptan and no-Tolvaptan groups. All patients performed baseline and 2-year follow-up visits. Net acid excretion (NAE) and net gastrointestinal alkali absorption (NGIA), markers of acid and alkali intake, were calculated from 24h urines. Second morning spot urine samples with freshly added protease inhibitors and immediately frozen at −80 °C were used to isolate urinary exosome proteins with an already established differential centrifugation method. Primary polyclonal anti-rabbit antibodies for Pendrin and the B1 subunit of V-ATPase were used for immunoblotting. Changes in urinary exosome abundance were normalized by Alix (exosome housekeeping protein).

Results

19 patients (9 with and 10 without Tolvaptan) were included in the final analysis. 5 patients were excluded because Alix was not detectable. Compared to baseline, urinary exosome Pendrin abundance increased by 134.4% only in Tolvaptan-treated patients (p < 0.01) after two years. Pendrin abundance strongly and directly correlated with NGIA (rho 0.75, p < 0.01) at baseline, and inversely with NAE (rho −0.51, p = 0.03) during follow-up. Urinary HCO₃⁻ excretion was associated with Pendrin expression over time (rho 0.73, p < 0.01). Ultimately, changes in urinary exosomal Pendrin were inversely associated with plasma potassium (rho −0.71, p = 0.03) only in the Tolvaptan group.

Conclusion

Urinary exosome Pendrin expression is sensitive to subtle changes in the acid-base status of ADPKD patients. Tolvaptan increases the expression of Pendrin in urinary exosomes, supporting the hypothesis that selective V2R blockade exerts an effect on systemic acid-base status of ADPKD patients.