Abstract: FR-PO1035
Finerenone Added to Renin-Angiotensin System (RAS)/SGLT2 Blockade for Non-Diabetic CKD: Results of a Preclinical Randomized Controlled Trial
Session Information
- CKD Mechanisms: From Mendel to Mars
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Zhu, Zhihui, Medizinische Klinik und Poliklinik IV, LMU Klinikum, Munich, Germany
- Kusunoki, Yoshihiro, Medizinische Klinik und Poliklinik IV, LMU Klinikum, Munich, Germany
- Li, Chenyu, Medizinische Klinik und Poliklinik IV, LMU Klinikum, Munich, Germany
- Klaus, Martin, Medizinische Klinik und Poliklinik IV, LMU Klinikum, Munich, Germany
- Boor, Peter, RWTH University Hospital Aachen, Aachen, Germany
- Romagnani, Paola, Department of Biomedical Experimental and Clinical Sciences "Mario Serio", University of Florence, Florence, Italy
- Anders, Hans J., Medizinische Klinik und Poliklinik IV, LMU Klinikum, Munich, Germany
Background
Dual inhibition of RAS plus SGLT2 or plus MR demonstrated additive renoprotective effects in large clinical trials. We hypothesized that triple therapy with a combination of RAS/SGLT2/MR inhibitors would be superior to dual RAS/SGLT2 blockade in prolonging kidney lifespan.
Methods
We performed a preclinical randomized controlled trial (PCTE0000266) in Col4a3-/- Alport mice. Treatment was initiated late (6 weeks of age) in mice with elevated serum creatinine and albuminuria and in presence of glomerulosclerosis, interstitial fibrosis and tubular atrophy. We randomized male and female mice to either nil (vehicle) or late onset food admixes of either monotherapy, ramipril (10 mg/kg) plus empagliflozin (30 mg/kg) or ramipril plus empagliflozin plus finerenone (10 mg/kg). Other control mice received empagliflozin or finerenone monotherapy.
Results
Mean lifespan was 63.7 ± 10.0 days (vehicle), 77.3 ± 5.3 days (ramipril), 70.4 ± 9.2 days (empagliflozin), 71.1 ± 7.1 days (finerenone), 80.3 ± 11.0 days (dual), and 103.1 ± 20.3 days (triple), respectively. Sex did not affect outcome. Histopathology, pathomics, and RNA sequencing revealed significant add-on anti-inflammatory and anti-fibrotic effects on the tubulointerstitial compartment when adding finerenone to dual RAS/SGLT2 inhibition.
Conclusion
This pRCT suggests that triple RAS/SGLT2/MR blockade may significantly prolong uremia-free lifespan significantly in patients with Alport syndrome and possibly other progressive chronic kidney disorders for its synergistic protective effects on the glomerular and tubulointerstitial compartment, respectively.
Overall survival and other markers of excretory kidney function; Albuminuria and other markers of kidney barrier function.
Funding
- Government Support – Non-U.S.