Characterization of Spent Coffee Grounds’ Polyphenol Fraction and Its Potential as a Low-Cost Tool for Bioactivity-Guided Nephroprotective Modulation of Gut–Kidney Axis and NF-κB/Nrf2/TGF-β Signaling in Hypertension-Associated Kidney Injury

Background: Hypertension-associated kidney injury is driven by oxidative stress, inflammation, fibrosis, and gut-derived uremic toxins via the gut-kidney axis. Spent coffee grounds (SCG) represent a sustainable source of bioactive polyphenols with potential nephroprotective effects. This study aimed to characterize a bioactivity-guided SCG polyphenol fraction and evaluate its therapeutic potential. Methods: Bioactivity-guided fractionation was performed to enrich active polyphenols, followed by in silico target prediction and in vivo validation using L-NAME-induced hypertensive rats treated for 8 weeks. Renal function, oxidative stress, inflammatory and fibrotic markers, gut-derived metabolites, and endothelial function were assessed. Results: The enriched fraction was dominated by chlorogenic acid derivatives and showed predicted interactions with NF-κB, Keap1/Nrf2, TGF-β receptor, ACE, and AT1 receptor. In hypertensive rats, treatment significantly lowered blood pressure, improved renal function, reduced oxidative stress, inflammation, fibrosis, and gut-derived uremic toxins, while restoring Nrf2 activity, short-chain fatty acid production, and endothelial function. Across multiple biological endpoints, the polyphenol-enriched fraction consistently demonstrated greater efficacy than the crude extract. Conclusions: SCG polyphenol fraction shows strong nephroprotective potential via gut-kidney axis modulation and NF-κB/Nrf2/TGF-β regulation, supporting its development as a low-cost therapeutic candidate.