Abstract
Abstract Background and Aims Inhibitors of the renin-angiotensin system (RAS), sodium-glucose transporter (SGLT)-2, and the mineralocorticoid receptor (MR) have all demonstrated renoprotective effects in large clinical trials of diabetes-related CKD. Furthermore, dual RAS/SGLT2 blockade showed additive renoprotective effects also in non-diabetic CKD. We hypothesized that triple RAS/SGLT2/MR blockade would be even superior to dual RAS/SGLT2 blockade in non-diabetic CKD. Method We performed a “no touch” preclinical randomized controlled trial in Col4a3-deficient mice with spontaneous and progressive CKD (registry ID: PCTE0000266). Treatments were administered as food admix from 6-14 weeks of age at the following estimated doses: 10 mg/kg ramipril, 30 mg/kg empagliflozin, 10 mg/kg finerenone. The prespecified primary endpoint was total lifespan up to uremic death. Ancillary studies addressed baseline histology, and mechanistic studies on a subset of mice after 2.5 weeks of treatment. Results At the time of randomization, Col4a3-/- mice had albuminuria, elevated serum creatinine, glomerulosclerosis, tubular atrophy, and interstitial fibrosis. Total lifespan was 63.7 ± 9.99 days (vehicle), 77.25 ± 5.34 days (ramipril), 80.3 ± 10.98 days (ramipril+empagliflozin), and 103.05 ± 20.28 days (triple therapy), respectively. Artificial intelligence-based histopathology and RNA sequencing analysis documented a potent anti-sclerotic, -inflammation and -fibrotic effect of the triple combination. Conclusion Adding finereone to dual RAS/SGLT2 blockade significantly prolongs uremia-free lifespan even when started at an advanced stage of Alport nephropathy. Triple RAS/SGLT2/MR blockade could be a potent treatment strategy to prolong uremia-free lifespan in patients with CKD related to Alport syndrome and possibly other progressive kidney disorders.
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