Preoperative Short‐Term Restriction of Sulfur‐Containing Amino Acid Intake for Prevention of Acute Kidney Injury After Cardiac Surgery: A Randomized, Controlled, Double‐Blind, Translational Trial

Abstract

Background Acute kidney injury (AKI) is a major risk factor for chronic kidney disease and increased mortality. Until now, no compelling preventive or therapeutic strategies have been identified. Dietary interventions have been proven highly effective in organ protection from ischemia reperfusion injury in mice and restricting dietary intake of sulfur‐containing amino acids (SAA) seems to be instrumental in this regard. The UNICORN trial aimed to evaluate the protective impact of restricting SAA intake before cardiac surgery on incidence of AKI. Methods and Results In this single‐center, randomized, controlled, double‐blind trial, 115 patients were assigned to a SAA‐reduced formula diet (LowS group) or a regular formula diet (control group) in a 1:1 ratio for 7 days before scheduled cardiac surgery. The primary end point was incidence of AKI within 72 hours after surgery, secondary end points included increase of serum creatinine at 24, 48, and 72 hours as well as safety parameters. Quantitative variables were analyzed with nonparametric methods, while categorical variables were evaluated by means of Chi‐square or Fisher test. SAA intake in the group with SAA reduced formula diet was successfully reduced by 77% (group with SAA reduced formula diet, 7.37[6.40–7.80] mg/kg per day versus control group, 32.33 [28.92–33.60] mg/kg per day, P <0.001) leading to significantly lower serum levels of methionine. No beneficial effects of SAA restriction on the rate of AKI after surgery could be observed (group with SAA reduced formula diet, 23% versus control group, 16%; P =0.38). Likewise, no differences were recorded with respect to secondary end points (AKI during hospitalization, creatinine at 24, 48, 72 hours after surgery) as well as in subgroup analysis focusing on age, sex, body mass index and diabetes. Conclusions SAA restriction was feasible in the clinical setting but was not associated with protective properties in AKI upon cardiac surgery. Registration URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT03715868.

Evaluation of the contribution of gut microbiome dysbiosis to cardiac surgery-associated acute kidney injury by comparative metagenome analysis

“…In fact, L-methionine, an essential amino acid, is closely related to the metabolism of sulfur-containing compounds in organisms, and L-homoserine is an intermediate in the biosynthesis of L-methionine. Restriction of sulfur-containing amino acid intake seems to be instrumental in kidney protection and relief of ischemia/reperfusion injury ( Pan et al, 2020 ; Osterholt et al, 2022 ). More specifically, Escherichia coli , Oscillibacter sp.…”

Fueling the success of transplantation through nutrition: recent insights into nutritional interventions, their interplay with gut microbiota and cellular mechanisms

“…Notably, all beneficial dietary strategies activate evolutionary conserved metabolic pathways responsible for cellular and organismal resilience as an important prerequisite for potential translation to human medicine [27]. As fasting mimicking, ketogenic and diets restricted in sulfur-containing amino acids are already broadly used in clinical trials, their administration as a preconditioning strategy in living organ donation could add substantially to our therapeutic armamentarium [28][29][30][31][32]. However, to our knowledge, randomized controlled trials dealing with tailored dietary interventions in the context of living organ transplantation remain scarce [13][14][15].…”

Gut Microbiota Interventions to Retain Residual Kidney Function

“…Based on the premise of the possible effects of dietary restriction of sulfur-containing amino acids in the protection of ischemia/reperfusion injury, a randomised clinical trial aimed to evaluate the protective impact of restricting sulfur-containing amino acids intake before cardiac surgery on the incidence of acute kidney injury (AKI). However, no beneficial effects of sulfur-containing amino acids restriction on the rate of AKI after surgery was observed [ 113 ]. The protein source, the content of other components in the diet, processing-related factors, protein oxidation and glycation, digestibility and the bioavailability of dietary proteins can influence protein fermentation and the effects on gut microbiota [ 110 ].…”