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 (Delta creatinine). Further analyses included incidence of AKI and safety evaluation. Delta creatinine 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: Delta creatinine -0.03(-0.20,0.08) mg/dL vs. control n = 24: Delta creatinine 0.10(-0.08,0.24)mg/dL; p = 0.041) and in patients with <= 2 risk factors for AKI (DR: n = 27; Delta creatinine -0.01(-0.18,0.07)mg/dL vs. control n = 31: Delta creatinine 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

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

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

Baseline characteristics of 14 weeks old male BL6 mice treated with GlcNAc or kept on ad libitum standard chow.

<p>A) and B) Baseline creatinine and urea values (control n = 5, GlcNAc i.p. n = 5, GlcNAc gavage n = 6) C) Plasma GlcNAc levels 2 hours after gavage of 250 μl of a 10% GlcNAc solution (n = 6) and in control animals with ad libitum access to water and standard chow (n = 5). D) Weight curves of control mice (n = 10) and mice kept on a 4 weeks ad libitum diet of chow enriched with 0.5% GlcNAc (n = 9).</p

TUNEL stainings of mouse kidneys.

<p>A) Control kidney without IR damage. B) and C) Mouse kidneys 24 hours after IR. B) Control mouse on standard ad libitum chow and drinking water. C) Mouse treated with twice oral gavage of 250 μl of 10% GlcNAc solution.</p

Histology before and after IR.

<p>A) Damage score after inspection of 5 HPF at the corticomedullary border (control baseline n = 5, control 24 hours n = 6, GlcNAc baseline n = 11, GlcNAc 24 hours n = 14). Sections were evaluated in a blinded manner by an experienced nephropathologist. B)–D) Representative PAS stainings from kidneys before and after IR. (X 200) B) Uninephrectomy section from undamaged kidney. C) and D) Kidney sections 24 hours after the end of ischemia. Asterix marks vanishing or missing nuclei. Black arrows mark tubular casts consisting of tubular cells. Yellow arrows show necrotic areas and denuded tubuli with regions just consisting of naked basement membrane. C) Kidney from animal treated with twice oral gavage of 10% GlcNAc solution before IR. (D) Kidney from control animal with twice oral gavage of PBS before IR.</p

Kidney failure 24 hours after ischemia-reperfusion injury in preconditioned and control animals.

<p>Creatinine and urea values after unilateral nephrectomy followed by 40 minutes of ischemia and 24 hours of reperfusion (IR) of the contralateral kidney. Different dosing regimens for GlcNAc were used. A) and D) Mice were kept on a four-week ad libitum diet enriched with 0.5% GlcNAc (n = 17) or received standard chow ad libitum (n = 15). B) and E) Mice received a 250 μl PBS twice, 24 and 2 hours before IR by gavage (n = 5). In the verum group PBS contained 10% GlcNAc (n = 10). C) and F) Verum mice were injected 20 mg GlcNAc in PBS either one hour before surgery i.p (n = 3) or immediately at the end of ischemia at the beginning of reperfusion (n = 4) directly into the abdominal cavity. Baselines represent control animals from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0161315#pone.0161315.g001" target="_blank">Fig 1A and 1B</a> without ischemia-reperfusion injury A) and D) for untreated animals (n = 5), B) and E) for mice after gavage of 10% GlcNAc solution (n = 6) and C) and F) for mice after i.p. injection of 10 mg GlcNAc (n = 5). After four weeks of caloric restriction (n = 4) with standard chow mice are protected against ischemia-reperfusion damage compared to controls having ad libitum access to standard chow (n = 5) (G+H).</p

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