Description

Acute kidney injury (AKI) is one of the most common disorders in hospitalized patients and the incidence of AKI is rapidly rising, especially among high-risk patients. In a meta-analysis including 49 million patients, AKI occurred in every fifth adult and in every third children suffering from an acute illness, defined as critical care with admission to the intensive care unit (ICU), cardiac surgery, trauma, heart failure or underlying disease within the field of haematology/oncology. AKI is associated with substantial mortality, even in non-ICU patients mortality ranges high between 10-20% and AKI severity is related to increased mortality. In addition, non-recovery of kidney function rates between 13-29% and progression to chronic kidney disease (CKD) requiring dialysis after AKI is common. Despite the considerable burden associated with AKI, effective therapeutic approaches, including prevention strategies, are currently lacking.

Since impaired cellular stress resistance contributes to AKI, preconditioning protocols that augment stress resistance such as caloric restriction (CR) are attractive strategies in the search for organprotection. CR protects from kidney damage in rodent models of AKI, induced by either ischemia-reperfusion injury or by injection of nephrotoxic cisplatin. However, the translation of this potential to the clinical setting has been hampered by both the limited understanding of the underlying mechanisms paired with the risk of malnourishment and significant comorbidity in the target patient population in terms of frailty, multi-morbidity or preoperative settings.

Based on more recent results regarding novel dietary regimens, three well-established targeted diets (a fasting mimicking diet, a ketogenic diet and the dietary restriction of sulfur-containing amino acids and the dietary restriction of branched chained amino acids), which already proved their safety and feasibility in both phase-II and I clinical trials, are promising novel targeted dietary strategies beyond CR.

Intermittent fasting with fasting mimicking diets enables the activation of cellular signal transduction similar to CR with high nourishment. Fasting mimicking diet efficiently protects from acute kidney injury in rodents. Human FMD (Prolon®) is a plant-derived diet to achieve fasting-like effects on serum levels of insulin growth factor-1 (IGF-1), insulin growth factor protein-1 (IGFP-1), glucose and ketone bodies, while providing both macro- und micronutrients. Intermitted fasting with fasting mimicking diets have extensively been studied in rodents. Additionally, phase-II and phase-I studies proofed safety, feasibility and favorable outcome in healthy volunteers and patients with autoimmune disorders or diabetes.

Ketogenic diets are high in fat and very low in carbohydrates and result in ketogenesis with the synthesis of ketone bodies, exceeding β-oxidation of fatty acids and anti-inflammation. Furthermore, ketogenic diets extend the lifespan in rodents with preserved physiological functions. Ketone bodies, such as β-hydroxybutyrate, suppress oxidative stress resulting in nephroprotection. Due to their additional neuroprotective effects, ketogenic diets have been in medical use in pharmacoresistant epilepsy proofing their feasibility and safety in humans. Moreover, ketogenic diets in women with ovarian and endometrial cancer revealed favorable effects on physical activity, perceived energy and food cravings. Considering that CR actually does induce ketogenesis due to feeding cycles, ketogenic diets are a key strategy that needs to be examined as a replacement for caloric restriction.

The amino acid methionine is the start codon in protein translation and is essential in the synthesis of the amino acid cysteine, which is also a precursor for glutathione and s adenosylmethionine, both needed in detoxification and methylation. Dietary restriction of these two sulfur-containing amino acids has been shown to be required for the beneficial effects of caloric restriction in a rodent model of liver damage. In addition, restriction in sulfur containing amino acids efficiently protects from acute kidney injury in rodents. Cysteine/methionine restriction activates the transsulfuration pathway resulting in the generation of hydrogen sulfide (H2S) and is associated with anti-inflammation, increased stress resistance, reduction of reactive oxygen species and alteration in lipid-metabolism. Sulfur containing amino acids are abundant in animal-derived protein, but also exist in certain vegetables, fruits and grains. A dietary restriction of sulfur containing amino acids can be achieved by a vegan-based diet without fish, meat, dairy products and certain plant-based foods as well as using specific formula diets Objective of the proof-of-principle, pilot-DILKID-trial is to decipher the underlying mediating mechanisms of different, well-established, dietary regimens as well as to prove their feasibility, tolerability and safety in nephrology patients. Additionally, the organprotective effects of those preoperative dietary interventions in terms of the transplant function in the kidney recipient will be analyzed. Inter-group differences on transcriptome, lipidome, metabolome, epigenome and (phospho-) proteome in the collected tissue (kidney, vessel and fat tissue), as well as in blood cells, plasma and serum will be compared between the different study arms.

In addition, the DILKID-trial aims to prove nephroprotective effects observed in rodent studies in humans and to correlate them with clinical surrogate parameters for kidney function. Another goal of our study consists in the identification of distinct metabolic pathways that are mediated by the dietary preconditioning strategies mentioned above and resulting in novel therapeutic approach protecting from AKI in nephrology patients