Caloric restriction reduces the pro-inflammatory eicosanoid 20-hydroxyeicosatetraenoic acid to protect from acute kidney injury.

Acute kidney injury is a frequent complication in the clinical setting and associated with significant morbidity and mortality. Preconditioning with short-term caloric restriction is highly protective against kidney injury in rodent ischemia reperfusion injury models. However, the underlying mechanisms are unknown hampering clinical translation. Here, we examined the molecular basis of caloric restriction-mediated protection to elucidate the principles of kidney stress resistance. Analysis of an RNAseq dataset after caloric restriction identified Cyp4a12a, a cytochrome exclusively expressed in male mice, to be strongly downregulated after caloric restriction. Kidney ischemia reperfusion injury robustly induced acute kidney injury in male mice and this damage could be markedly attenuated by pretreatment with caloric restriction. In females, damage was significantly less pronounced and preconditioning with caloric restriction had only little effect. Tissue concentrations of the metabolic product of Cyp4a12a, 20-hydroxyeicosatetraenoic acid (20-HETE), were found to be significantly reduced by caloric restriction. Conversely, intraperitoneal supplementation of 20-HETE in preconditioned males partly abrogated the protective potential of caloric restriction. Interestingly, this effect was accompanied by a partial reversal of caloric restriction--induced changes in protein but not RNA expression pointing towards inflammation, endoplasmic reticulum stress and lipid metabolism. Thus, our findings provide an insight into the mechanisms underlying kidney protection by caloric restriction. Hence, understanding the mediators of preconditioning is an important prerequisite for moving towards translation to the clinical setting.

Modulation of Endocannabinoids by Caloric Restriction Is Conserved in Mice but Is Not Required for Protection from Acute Kidney Injury.

Acute kidney injury (AKI) is a frequent and critical complication in the clinical setting. In rodents, AKI can be effectively prevented through caloric restriction (CR), which has also been shown to increase lifespan in many species. In Caenorhabditis elegans (C. elegans), longevity studies revealed that a marked CR-induced reduction of endocannabinoids may be a key mechanism. Thus, we hypothesized that regulation of endocannabinoids, particularly arachidonoyl ethanolamide (AEA), might also play a role in CR-mediated protection from renal ischemia-reperfusion injury (IRI) in mammals including humans. In male C57Bl6J mice, CR significantly reduced renal IRI and led to a significant decrease of AEA. Supplementation of AEA to near-normal serum concentrations by repetitive intraperitoneal administration in CR mice, however, did not abrogate the protective effect of CR. We also analyzed serum samples taken before and after CR from patients of three different pilot trials of dietary interventions. In contrast to mice and C. elegans, we detected an increase of AEA. We conclude that endocannabinoid levels in mice are modulated by CR, but CR-mediated renal protection does not depend on this effect. Moreover, our results indicate that modulation of endocannabinoids by CR in humans may differ fundamentally from the effects in animal models.

Are gamers better laparoscopic surgeons? Impact of gaming skills on laparoscopic performance in "Generation Y" students.

BACKGROUND: Both laparoscopic surgery and computer games make similar demands on eye-hand coordination and visuospatial cognitive ability. A possible connection between both areas could be used for the recruitment and training of future surgery residents. AIM: The goal of this study was to investigate whether gaming skills are associated with better laparoscopic performance in medical students. METHODS: 135 medical students (55 males, 80 females) participated in an experimental study. Students completed three laparoscopic tasks (rope pass, paper cut, and peg transfer) and played two custom-designed video games (2D and 3D game) that had been previously validated in a group of casual and professional gamers. RESULTS: There was a small significant correlation between performance on the rope pass task and the 3D game, Kendall's τ(111) = -.151, P = .019. There was also a small significant correlation between the paper cut task and points in the 2D game, Kendall's τ(102) = -.180, P = .008. Overall laparoscopic performance was also significantly correlated with both the 3D game, Kendall's τ(112) = -.134, P = .036, and points in the 2D game, Kendall's τ(113) = -.163, P = .011. However, there was no significant correlation between the peg transfer task and both games (2D and 3D game), P = n.s.. CONCLUSION: This study provides further evidence that gaming skills may be an advantage when learning laparoscopic surgery.

Preconditioning strategies to prevent acute kidney injury.

Acute kidney injury is a common clinical disorder resulting in significantly increased morbidity and mortality. However, despite extensive research, strategies for prevention or treatment are still lacking in routine clinical practice. Already decades ago, several preconditioning strategies (e. g. ischemic/hypoxic preconditioning and calorie restriction) have been published and their extraordinary effectiveness - especially in rodents - has raised the hope for powerful clinical tools to prevent acute kidney injury. However, the underlying mechanisms are still not completely understood and translation to the clinics has not been successful yet. In this review, the most attractive strategies and the current mechanistic concepts are introduced and discussed. Furthermore, we present clinical trials evaluating the feasibility of preconditioning in the clinical setting.

Dietary restriction for prevention of contrast-induced acute kidney injury in patients undergoing percutaneous coronary angiography: a randomized controlled trial.

Short-term dietary restriction (DR) may prevent organ damage from ischemic or toxic insults in animals, but clear evidence in humans is missing. While especially intraarterial administration of contrast media represents a cause of hospital-acquired acute kidney injury (AKI), targeted preventive strategies are not available. This trial investigated the feasibility and effectiveness of pre-interventional DR for preventing AKI in patients undergoing percutaneous coronary intervention (PCI). Patients were randomized to receive a formula diet containing 60% of daily energy requirement (DR group) or ad-libitum food during the 4-day-interval before PCI. Primary endpoint was change of serum creatinine 48 h after PCI (Δcreatinine). Further analyses included incidence of AKI and safety evaluation. Δcreatinine post PCI in the DR group vs. the control group did not show any difference (DR: 0.03(-0.15,0.14)mg/dL vs. control: 0.09(-0.03,0.22)mg/dL;p = 0.797). Subgroup analyses revealed a significant beneficial impact of DR in patients that received ≤100 ml of contrast agent (DR n = 26: Δcreatinine -0.03(-0.20,0.08)mg/dL vs. control n = 24: Δcreatinine 0.10(-0.08,0.24)mg/dL; p = 0.041) and in patients with ≤2 risk factors for AKI (DR: n = 27; Δcreatinine -0.01(-0.18,0.07)mg/dL vs. control n = 31: Δcreatinine 0.09(-0.03,0.16)mg/dl; p = 0.030). Although the primary endpoint was not met, the results of this trial suggest a beneficial impact of DR in low-to-moderate risk patients.

The Integrated RNA Landscape of Renal Preconditioning against Ischemia-Reperfusion Injury.

BACKGROUND: Although AKI lacks effective therapeutic approaches, preventive strategies using preconditioning protocols, including caloric restriction and hypoxic preconditioning, have been shown to prevent injury in animal models. A better understanding of the molecular mechanisms that underlie the enhanced resistance to AKI conferred by such approaches is needed to facilitate clinical use. We hypothesized that these preconditioning strategies use similar pathways to augment cellular stress resistance. METHODS: To identify genes and pathways shared by caloric restriction and hypoxic preconditioning, we used RNA-sequencing transcriptome profiling to compare the transcriptional response with both modes of preconditioning in mice before and after renal ischemia-reperfusion injury. RESULTS: The gene expression signatures induced by both preconditioning strategies involve distinct common genes and pathways that overlap significantly with the transcriptional changes observed after ischemia-reperfusion injury. These changes primarily affect oxidation-reduction processes and have a major effect on mitochondrial processes. We found that 16 of the genes differentially regulated by both modes of preconditioning were strongly correlated with clinical outcome; most of these genes had not previously been directly linked to AKI. CONCLUSIONS: This comparative analysis of the gene expression signatures in preconditioning strategies shows overlapping patterns in caloric restriction and hypoxic preconditioning, pointing toward common molecular mechanisms. Our analysis identified a limited set of target genes not previously known to be associated with AKI; further study of their potential to provide the basis for novel preventive strategies is warranted. To allow for optimal interactive usability of the data by the kidney research community, we provide an online interface for user-defined interrogation of the gene expression datasets (http://shiny.cecad.uni-koeln.de:3838/IRaP/).

Serious Games in Surgical Medical Education: A Virtual Emergency Department as a Tool for Teaching Clinical Reasoning to Medical Students.

BACKGROUND: Serious games enable the simulation of daily working practices and constitute a potential tool for teaching both declarative and procedural knowledge. The availability of educational serious games offering a high-fidelity, three-dimensional environment in combination with profound medical background is limited, and most published studies have assessed student satisfaction rather than learning outcome as a function of game use. OBJECTIVE: This study aimed to test the effect of a serious game simulating an emergency department ("EMERGE") on students' declarative and procedural knowledge, as well as their satisfaction with the serious game. METHODS: This nonrandomized trial was performed at the Department of General, Visceral and Cancer Surgery at University Hospital Cologne, Germany. A total of 140 medical students in the clinical part of their training (5th to 12th semester) self-selected to participate in this experimental study. Declarative knowledge (measured with 20 multiple choice questions) and procedural knowledge (measured with written questions derived from an Objective Structured Clinical Examination station) were assessed before and after working with EMERGE. Students' impression of the effectiveness and applicability of EMERGE were measured on a 6-point Likert scale. RESULTS: A pretest-posttest comparison yielded a significant increase in declarative knowledge. The percentage of correct answers to multiple choice questions increased from before (mean 60.4, SD 16.6) to after (mean 76.0, SD 11.6) playing EMERGE (P<.001). The effect on declarative knowledge was larger in students in lower semesters than in students in higher semesters (P<.001). Additionally, students' overall impression of EMERGE was positive. CONCLUSIONS: Students self-selecting to use a serious game in addition to formal teaching gain declarative and procedural knowledge.

Oral Supplementation of Glucosamine Fails to Alleviate Acute Kidney Injury in Renal Ischemia-Reperfusion Damage.

Acute kidney injury is a leading contributor to morbidity and mortality in the ageing population. Proteotoxic stress response pathways have been suggested to contribute to the development of acute renal injury. Recent evidence suggests that increased synthesis of N-glycan precursors in the hexosamine pathway as well as feeding of animals with aminosugars produced in the hexosamine pathway may increase stress resistance through reducing proteotoxic stress and alleviate pathology in model organisms. As feeding of the hexosamine pathway metabolite glucosamine to aged mice increased their life expectancy we tested whether supplementation of this aminosugar may also protect mice from acute kidney injury after renal ischemia and reperfusion. Animals were fed for 4 weeks ad libitum with standard chow or standard chow supplemented with 0.5% N-acetylglucosamine. Preconditioning with caloric restriction for four weeks prior to surgery served as a positive control for protective dietary effects. Whereas caloric restriction demonstrated the known protective effect both on renal function as well as survival in the treated animals, glucosamine supplementation failed to promote any protection from ischemia-reperfusion injury. These data show that although hexosamine pathway metabolites have a proven role in enhancing protein quality control and survival in model organisms oral glucosamine supplementation at moderate doses that would be amenable to humans does not promote protection from ischemia-reperfusion injury of the kidney.