Oral Ketone β -Hydroxybutyrate Supplement Retards the Loss of GFR in Alport Mice on Dual Renin-Angiotensin System/Sodium-Glucose Transporter 2 Blockade

KEY POINTS: There is an unmet medical need for testing novel CKD substances to create more effective combination therapies. In our CKD mouse model, ketone supplementation retards the loss of GFR beyond the current standard of care, but no effect on lifespan was observed. Ketone supplementation suppresses kidney inflammation and fibrosis. BACKGROUND: Several studies suggest that dietary β-hydroxybutyrate (BHB) supplementation delays the progression of CKD by suppressing inflammation and fibrosis. We hypothesized that the oral supplementation with the BHB precursor 1,3-butanediol in addition to inhibitors of the renin-angiotensin system (RAS) and sodium-glucose transporter 2 (SGLT2) would be superior to dual RAS/SGLT2 blockade alone in attenuating the loss of GFR in Col4a3-deficient mice with Alport nephropathy, a spontaneous model of progressive CKD. METHODS: We performed a negative-controlled study in Col4a3-deficient mice with Alport nephropathy. Treatment was initiated at a late stage of the disease at the age of 6 weeks. Mice were fed food admixes of 10 μg/g ramipril plus 30 μg/g empagliflozin with or without addition of 0.04 g/g 1,3-butanediol (concentration per gram of bodyweight). The mice were monitored daily and sacrificed on reaching renal failure. The GFR was measured at the start of the treatment and after 1 and 4 weeks. RESULTS: The addition of BHB significantly attenuated the loss of GFR beyond the effect of dual RAS/SGLT2 blockade. The mean GFR after 4 weeks of treatment was 0 ± 0 μl/min (vehicle), 57 ± 54 μl/min (renin-angiotensin system inhibitors + sodium-glucose transporter 2 inhibitors), and 139 ± 69 μl/min (renin-angiotensin system inhibitors + sodium-glucose transporter 2 inhibitors+1,3-butanediol). No additional effects on lifespan could be observed. Kidney RNA sequencing revealed significant protective effects on inflammation when adding the BHB precursor 1,3-butanediol to RAS/SGLT2 inhibition. In histopathology, antifibrotic effects were seen on BHB addition. CONCLUSIONS: The results in mice suggest that BHB supplementation improves the GFR in Alport syndrome by suppressing inflammation and fibrosis. However, the effects did not lead to a significant increase in lifespan. Furthermore, the observed effects stay behind the effects of finerenone as a combination partner, which was tested earlier in the same mouse model.