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Kidney Week

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

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.