Finerenone Added to RAS/SGLT2 Blockade for CKD in Alport Syndrome. Results of a Randomized Controlled Trial with Col4a3-/- Mice

J Am Soc Nephrol. 2023 Sep 1;34(9):1513-1520. doi: 10.1681/ASN.0000000000000186. Epub 2023 Jul 10.


Significance statement: We hypothesized that triple therapy with inhibitors of the renin-angiotensin system (RAS), sodium-glucose transporter (SGLT)-2, and the mineralocorticoid receptor (MR) would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression in Col4a3 -deficient mice, a model of Alport syndrome. Late-onset ramipril monotherapy or dual ramipril/empagliflozin therapy attenuated CKD and prolonged overall survival by 2 weeks. Adding the nonsteroidal MR antagonist finerenone extended survival by 4 weeks. Pathomics and RNA sequencing revealed significant protective effects on the tubulointerstitium when adding finerenone to RAS/SGLT2 inhibition. Thus, triple RAS/SGLT2/MR blockade has synergistic effects and might attenuate CKD progression in patients with Alport syndrome and possibly other progressive chronic kidney disorders.

Background: Dual inhibition of the renin-angiotensin system (RAS) plus sodium-glucose transporter (SGLT)-2 or the mineralocorticoid receptor (MR) demonstrated additive renoprotective effects in large clinical trials. We hypothesized that triple therapy with RAS/SGLT2/MR inhibitors would be superior to dual RAS/SGLT2 blockade in attenuating CKD progression.

Methods: We performed a preclinical randomized controlled trial (PCTE0000266) in Col4a3 -deficient mice with established Alport nephropathy. Treatment was initiated late (age 6 weeks) in mice with elevated serum creatinine and albuminuria and with glomerulosclerosis, interstitial fibrosis, and tubular atrophy. We block-randomized 40 male and 40 female mice to either nil (vehicle) or late-onset food admixes of ramipril monotherapy (10 mg/kg), ramipril plus empagliflozin (30 mg/kg), or ramipril plus empagliflozin plus finerenone (10 mg/kg). Primary end point was mean survival.

Results: Mean survival was 63.7±10.0 days (vehicle), 77.3±5.3 days (ramipril), 80.3±11.0 days (dual), and 103.1±20.3 days (triple). Sex did not affect outcome. Histopathology, pathomics, and RNA sequencing revealed that finerenone mainly suppressed the residual interstitial inflammation and fibrosis despite dual RAS/SGLT2 inhibition.

Conclusion: Experiments in mice suggest that triple RAS/SGLT2/MR blockade may substantially improve renal outcomes in Alport syndrome and possibly other progressive CKDs because of synergistic effects on the glomerular and tubulointerstitial compartments.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antihypertensive Agents / therapeutic use
  • Diabetes Mellitus, Type 2* / drug therapy
  • Female
  • Fibrosis
  • Glucose Transport Proteins, Facilitative / pharmacology
  • Glucose Transport Proteins, Facilitative / therapeutic use
  • Male
  • Mice
  • Nephritis, Hereditary* / drug therapy
  • Nephritis, Hereditary* / genetics
  • Nephritis, Hereditary* / pathology
  • Ramipril / therapeutic use
  • Receptors, Mineralocorticoid
  • Renal Insufficiency, Chronic* / drug therapy
  • Renin-Angiotensin System
  • Sodium
  • Sodium-Glucose Transporter 2 / pharmacology
  • Sodium-Glucose Transporter 2 / therapeutic use


  • Antihypertensive Agents
  • empagliflozin
  • finerenone
  • Glucose Transport Proteins, Facilitative
  • Ramipril
  • Receptors, Mineralocorticoid
  • Sodium
  • Sodium-Glucose Transporter 2