Kidney Week

Abstract: SA-PO0481

Inhibition of the Chloride-Bicarbonate Exchanger Pendrin as a New Diuretic Strategy in CKD

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

• Rudolphi, Crissy, Erasmus MC, Rotterdam, ZH, Netherlands

Crissy Rudolphi, MS, MSc

• Goos, Yoëlle, Erasmus MC, Rotterdam, ZH, Netherlands

Yoëlle Goos

• Bhaggoe, Usha M., Erasmus MC, Rotterdam, ZH, Netherlands

Usha M. Bhaggoe

• Van Veghel, Richard, Erasmus MC, Rotterdam, ZH, Netherlands

Richard Van Veghel

• Garrelds, Ingrid M., Erasmus MC, Rotterdam, ZH, Netherlands

Ingrid M. Garrelds

• Danser, Alexander H., Erasmus MC, Rotterdam, ZH, Netherlands

Alexander H. Danser, PhD

• Karmakar, Joy, University of California San Francisco, San Francisco, California, United States

Joy Karmakar, MSc, PhD

• Cil, Onur, University of California San Francisco, San Francisco, California, United States

Onur Cil, MD, PhD

• Imenez Silva, Pedro Henrique, Erasmus MC, Rotterdam, ZH, Netherlands

Pedro Henrique Imenez Silva, PhD

• Hoorn, Ewout J., Erasmus MC, Rotterdam, ZH, Netherlands

Ewout J. Hoorn, MD, PhD

Group or Team Name

• Rotterdam Kidney Lab.

Background

The chloride-bicarbonate exchanger pendrin is a potential diuretic target in the context of chronic kidney disease (CKD), as it has been implicated both in acid-base balance and salt-sensitive hypertension. This study aimed to evaluate pendrin inhibition as a diuretic strategy in the 5/6^th nephrectomy model of CKD.

Methods

5/6^th nephrectomy was performed in 7-week-old Sprague Dawley rats. Telemetry devices were implanted for continuous blood pressure monitoring. Four weeks after surgery, all rats were placed on a high-salt diet to induce salt-sensitive hypertension. After 8 days, animals were randomly assigned into 4 treatment groups (n=7-9/group) receiving daily subcutaneous injections for 3 days: vehicle, pendrin inhibitor (10 mg/kg PDSinh-C01), loop diuretic (6 mg/kg furosemide), or combination therapy. Diuretic response was assessed via 24-hour urine volume, plasma measurements and blood pressure.

Results

5/6^th nephrectomy recapitulated the hallmarks of CKD, including decreased eGFR, salt-sensitive hypertension, proteinuria and mild hyperkalemic metabolic acidosis. Compared to treatment with vehicle or furosemide, the pendrin inhibitor resulted in significantly higher plasma bicarbonate levels either alone or in combination with furosemide (21 ± 1 vs. 23 ± 3 vs. 24 ± 2 vs. 24 ± 1 mmol/L, P < 0.05 vehicle vs. pendrin inhibitor and combination therapy). Compared to vehicle, the pendrin inhibitor and furosemide alone increased diuresis, while the combination therapy further enhanced this (58 ± 13 vs. 67 ± 13 vs. 70 ± 15 vs. 80 ± 14 ml/day, P < 0.05 vehicle vs. combination therapy). The pendrin inhibitor and furosemide alone decreased telemetric blood pressure during the 3-day treatment period only minimally compared to vehicle (both -1 mmHg), while the combination therapy produced a greater and significant effect (-6 mmHg).

Conclusion

Pharmacological inhibition of the chloride-bicarbonate exchanger pendrin combined with loop diuretics, but not either therapy alone, improved metabolic acidosis and salt-sensitive hypertension in experimental CKD.

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025kq2cj1rm