#263 Diet-induced kidney protection—a translational research approach

Abstract Background and Aims Acute kidney injury (AKI) is a common complication among hospitalized patients and is associated with significant mortality and morbidity. Although being a frequent and substantial threat, therapeutic and preventive strategies for AKI are still lacking. Importantly, a reduction of cellular stress resistance contributes to the development of AKI in rodents. Protective dietary strategies activate evolutionarily conserved metabolic pathways leading to an increase in cellular stress resistance and may prevent from AKI. However, the successful transfer to the clinic is still lagging behind since the optimal diet for humans and the underlying molecular mechanisms remain unknown. Method Five established dietary preconditioning protocols—caloric restriction (CR), a fasting-mimicking diet (FMD), a ketogenic diet (KD) and the dietary restriction of either branched-chained amino acids (BCAA) or sulfur-containing amino acids (SAA) - were systematically examined in a. rodent model of renal ischemia-reperfusion injury (IRI) to quantify diet-induced kidney protection. Based on this effort, the most beneficial dietary interventions were determined and are now examined in a prospective, randomized pilot trial (NCT05709600, DILKID trial) during living kidney donation in humans to elucidate feasibility and safety in humans. In addition, this trial allows to obtain human tissue and biofluids in the context of the beneficial dietary interventions. An integrative multi-layered omics approach including single nucleus RNA sequencing (snRNAseq) is used to delineate the underlying mechanisms of diet-induced kidney protection in rodents and man. Results FMD, a low-SAA diet and CR efficiently protect from IRI-induced kidney failure as quantified by survival rates, kidney function and tissue damage in mice. Of note, these beneficial dietary interventions show overlapping changes in cysteine catabolism as a potential underlying mechanism of diet-induced kidney protection. Preconditioning with KD leads to moderate benefits after IRI, whereas BCAA fails to protect from ischemic kidney damage. With regard to humans, more than 50% of participants have been enrolled in the DILKID-Trial to date without any indication towards relevant safety issues. This points towards an overall good feasibility and tolerability of the diets at hand. Conclusion Dietary preconditioning with FMD, CR, KD and low-SAA diets effectively protect against renal IRI in rodents. As these diets are feasible in humans, our findings provide an important outlook towards novel protective strategies in the clinic. Based on the identification of an underlying mechanism mediating diet-induced organ protection, our molecular analyses will provide additional information on potential future pharmacological approaches to protect from organ injury in the kidney and beyond.