Valproic Acid Protects Against Acute Kidney Injury in Hemorrhage and Trauma.

INTRODUCTION: Trauma is the leading cause of death among young people. These patients have a high incidence of kidney injury, which independently increases the risk of mortality. As valproic acid (VPA) treatment has been shown to improve survival in animal models of lethal trauma, we hypothesized that it would also attenuate the degree of acute kidney injury. METHODS: We analyzed data from two separate experiments where swine were subjected to lethal insults.  Model 1: hemorrhage (50% blood volume hemorrhage followed by 72-h damage control resuscitation). Model 2: polytrauma (traumatic brain injury, 40% blood volume hemorrhage, femur fracture, rectus crush and grade V liver laceration). Animals were resuscitated with normal saline (NS) +/- VPA 150 mg/kg after a 1-h shock phase in both models (n = 5-6/group). Serum samples were analyzed for creatinine (Cr) using colorimetry on a Liasys 330 chemistry analyzer. Proteomic analysis was performed on kidney tissue sampled at the time of necropsy. RESULTS: VPA treatment significantly (P < 0.05) improved survival in both models. (Model 1: 80% vs 20%; Model 2: 83% vs. 17%). Model 1 (Hemorrhage alone): Cr increased from a baseline of 1.2 to 3.0 in NS control animals (P < 0.0001) 8 h after hemorrhage, whereas it rose only to 2.1 in VPA treated animals (P = 0.004). Model 2 (Polytrauma): Cr levels increased from baseline of 1.3 to 2.5 mg/dL (P = 0.01) in NS control animals 4 h after injury but rose to only 1.8 in VPA treated animals (P = 0.02). Proteomic analysis of kidney tissue identified metabolic pathways were most affected by VPA treatment. CONCLUSIONS: A single dose of VPA (150 mg/kg) offers significant protection against acute kidney injury in swine models of polytrauma and hemorrhagic shock.

Anti-inflammatory and antioxidant activity of essential amino acid α-ketoacid analogues against renal ischemia-reperfusion damage in Wistar rats. / Actividad antiinflamatoria y antioxidante de los α-cetoanálogos de aminoácidos esenciales en un modelo de daño por isquemia-reperfusión en ratas Wistar

INTRODUCTION: Essential amino acid α-keto acid analogs are used in the treatment of chronic kidney disease to delay the symptoms of uremia. However, it is unknown whether essential amino acid α-keto acid analogs affect the oxidative stress and the inflammation in acute renal injury such as those produced by ischemia-reperfusion. OBJECTIVE: To evaluate the effect of essential amino acid α-keto acid analogs on renal ischemia-reperfusion injury in Wistar rats. MATERIALS AND METHODS: Rats were divided into 11 groups (n=6/group): Two groups received physiological saline with or without ischemia-reperfusion injury (45 min/24 h), six groups received essential amino acid α-keto acid analogs (400, 800, or 1,200 mg/kg/24 h/7d) with or without ischemia-reperfusion injury (essential amino acid α-keto acid analogs + ischemia-reperfusion), and two groups received allopurinol (50 mg/kg/24 h/7d) with or without ischemia-reperfusion injury. Biochemical markers included creatinine and blood urea nitrogen (BUN), proinflammatory cytokines (IL-1ß, IL-6, and TNF-α), renal damage markers (cystatin C, KIM-1, and NGAL), and markers of oxidative stress such as malondialdehyde (MDA) and total antioxidant activity. RESULTS: The essential amino acid α-keto acid analog- and allopurinol-treated groups had lower levels of creatinine, BUN, renal damage markers, proinflammatory cytokines, and MDA than their corresponding ischemia-reperfusion groups. These changes were related to the essential amino acid α-keto acid analogs dosage. Total antioxidant activity was lower in essential amino acid α-keto acid analog- and allopurinol-treated groups than in the corresponding ischemia-reperfusion groups. CONCLUSIONS: This is a new report on the nephroprotective effects of essential amino acid α-keto acid analogs against ischemia-reperfusion injury. Essential amino acid α-keto acid analogs decreased the levels of biochemical markers, kidney injury markers, proinflammatory cytokines, and MDA while minimizing total antioxidant consumption.

Introducción. Los α-cetoanálogos de aminoácidos esenciales se utilizan en el tratamiento de la enfermedad renal crónica para retrasar los síntomas de la uremia. Sin embargo, se desconoce si los α-cetoanálogos de aminoácidos esenciales afectan el estrés oxidativo y la inflamación en la lesión renal aguda tal como en la producida por la isquemia-reperfusión. Objetivo. Evaluar el efecto de las α-cetoanálogos de aminoácidos esenciales sobre la lesión renal por isquemia-reperfusión en ratas Wistar. Materiales y métodos. Se emplearon 11 grupos de ratas (n=6): dos grupos recibieron solución salina fisiológica con lesión isquemia-reperfusión o sin ella (45 min/24 h), seis grupos recibieron α-cetoanálogos de aminoácidos esenciales (400, 800 o 1.200 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella (α-cetoanálogos de aminoácidos esenciales + isquemia-reperfusión), y dos grupos recibieron (50 mg/kg/24 h/7d) con lesión isquemia-reperfusión o sin ella. Los marcadores bioquímicos incluyeron creatinina y nitrógeno ureico en sangre (BUN), citocinas proinflamatorias (IL-1ß, IL-6 y TNF-α), marcadores de daño renal (cistatina C, KIM-1 y NGAL) y marcadores del estrés oxidativo como el malondialdehído (MDA) y la actividad antioxidante total. Resultados. Los grupos tratados con α-cetoanálogos de aminoácidos esenciales y alopurinol tuvieron niveles inferiores de creatinina, BUN, marcadores de daño renal, citocinas proinflamatorias, actividad antioxidante total y MDA que los grupos isquemia-reperfusión correspondientes. Estos cambios se asociaron con la dosis. La actividad antioxidante total fue menor en los grupos tratados con α-cetoanálogos de aminoácidos esenciales que en los grupos isquemia-reperfusión correspondientes. Conclusiones. Este es un nuevo informe de los efectos nefroprotectores de las α-cetoanálogos de aminoácidos esenciales contra la lesión isquemia-reperfusión. Los α-cetoanálogos de aminoácidos esenciales disminuyeron los niveles de los marcadores bioquímicos, de los de lesión renal, de las citocinas proinflamatorias y el MDA, a la vez que minimizaron el consumo total de antioxidantes.

Combined serum biomarkers in the noninvasive diagnosis of complicated parapneumonic effusions and empyema.

BACKGROUND: We previously demonstrated that the pleural levels of proteins (neutrophil gelatinase-associated lipocalin/NGAL, calprotectin, bactericidal permeability-increasing/BPI, azurocidin 1/AZU-1) were valuable markers for identifying complicated PPE (CPPE). Herein, this study was performed to evaluate whether these proteins are useful as serological markers for identifying CPPE and empyema. METHODS: A total of 137 participates were enrolled in this study. The levels of NGAL, calprotectin, BPI and AZU-1 were measured in serum and pleural fluid by enzyme-linked immunosorbent assay. We also characterized the diagnostic values of these markers between different groups. RESULTS: The serum levels of NGAL, calprotectin, and BPI in PPE patients were significantly higher than those in transudates, noninfectious exudates, and healthy controls. The area under the curve (AUC) values of NGAL, calprotectin, and BPI for distinguishing PPE from transudates or noninfectious exudates were around 0.861 to 0.953. In PPE group, serum NGAL and calprotectin levels were significantly elevated in patients with CPPE and empyema than in those with UPPE, whereas the serum BPI levels were similar between these two groups. In CPPE and empyema patients, the serum NGAL showed a positive correlation with the pleural fluid NGAL (r = 0.417, p <  0.01). When combined with serum CRP, the sensitivity and specificity of serum calprotectin for identifying CPPE and empyema were the highest at 73.52% and 80.55%, respectively. CONCLUSIONS: We concluded that serum calprotectin and NGAL were adjuvant serological markers for CPPE and empyema diagnosis. Patients present with pneumonia and pleural effusion signs in the chest x-ray and the combination of serum calprotectin and CRP constitutes a more highly sensitive and specific assay for identifying CPPE and empyema.

Nephro-toxic effects of intraperitoneally injected EGCG in diabetic mice: involvement of oxidative stress, inflammation and apoptosis.

Epigallocatechin gallate (EGCG) has been studied for its beneficial effects. However, some case reports have associated EGCG supplementation with hepato-toxicity. In the present study, we investigated the possible nephro-toxic effects of EGCG in diabetic mice. Streptozotocin (150 mg/kg, i.p.) was injected in mice for diabetes induction. EGCG (100 mg/kg/day, i.p.) was then given for 4 days. The administration of EGCG to diabetic mice caused 60% mortality with no death recorded in other groups. Blood samples were collected for estimation of serum cystatin C, neutrophil gelatinase-associated lipocalin and blood urea nitrogen. Animals were then sacrificed and kidneys were rapidly excised for estimation of oxidative stress markers (NADPH oxidase, reduced glutathione, total antioxidant capacity, nuclear factor erythroid 2-related factor 2, heat shock protein 90, hemeoxygenase-1), as well as inflammatory markers (nuclear factor kappa-B and tumor necrosis factor-α). Administration of EGCG to diabetic mice showed significant elevation in serum cystatin C and neutrophil gelatinase-associated lipocalin, marked increase in oxidative stress and inflammatory states in addition to marked over expression of active caspase-3. Histopathological examination confirmed EGCG induced renal damage in diabetic mice. In conclusion, despite of its well known favorable effects, EGCG could paradoxically exhibit nephro-toxic effect in the presence of diabetes.

Protective Effects of L-Carnitine Against Delayed Graft Function in Kidney Transplant Recipients: A Pilot, Randomized, Double-Blinded, Placebo-Controlled Clinical Trial.

OBJECTIVE: Delayed graft function (DGF) is an early complication after deceased donor kidney transplantation with significant adverse effects on graft outcomes. Ischemia-reperfusion injury during transplantation is a major cause of DGF. Tissue concentrations of carnitine, an antioxidant and regulator of cellular energy supply, decrease in the kidney following ischemia-reperfusion insult. Based on promising animal data, this study evaluated the possible protective effect of L-carnitine against DGF. DESIGN: This study is a pilot, randomized, double-blind, placebo-controlled clinical trial that was conducted on kidney transplantation patients in kidney transplant ward of Imam Khomeini hospital complex affiliated to Tehran University of Medical Sciences, Tehran, Iran. SUBJECTS: Patients older than 14 years old undergoing their first kidney transplantation from a deceased donor were evaluated for eligibility to take part in this study. Fifty-six patients were randomly assigned to L-carnitine or placebo groups. INTERVENTION: During this trial, 3 g of oral L-carnitine or placebo was administered in 3 divided doses each day for 4 consecutive days starting the day before kidney transplantation (i.e., days -1, 0, 1, and 2). MAIN OUTCOME MEASURE: The need for dialysis within the first week after transplantation, serum creatinine and urine output were assessed daily. After hospital discharge, patients were followed for 3 months regarding organ function. RESULTS: DGF incidence did not differ between the L-carnitine and placebo groups (18.51% vs. 23.8%, respectively; P = .68). Total allograft failure within 3 months after kidney transplantation happened in 6 patients in the placebo and 1 patient in the L-carnitine group (P = .05). CONCLUSION: This study showed no protective effects of oral L-carnitine supplementation against DGF occurrence recipients; however, 3-month graft loss was lower in the L-carnitine supplemented group.

Fecal neutrophil gelatinase-associated lipocalin as a biomarker for inflammatory bowel disease.

BACKGROUND AND AIM: Accurate, noninvasive biomarkers are needed to diagnose and monitor inflammatory bowel disease (IBD). Neutrophil gelatinase-associated lipocalin (NGAL), also known as lipocalin 2, is expressed in inflamed colonic epithelium and neutrophilic granulocytes. This study explores its properties as a biomarker in feces and plasma and, for the first time, compares fecal NGAL systematically with the existing fecal biomarker calprotectin. METHODS: Neutrophil gelatinase-associated lipocalin was measured in feces from 73 patients with IBD, 21 patients with infectious enterocolitis, 21 patients with irritable bowel syndrome, and 23 healthy subjects using ELISA. The results were correlated to calprotectin, clinical score, endoscopic score, and high-sensitive C-reactive protein. Plasma from 119 patients with IBD and 28 healthy controls was analyzed for NGAL. RESULTS: Fecal NGAL levels (median and interquartile range) were significantly elevated in active ulcerative colitis (UC) 6.05 (3.6-15.1) mg/kg and Crohn's disease (CD) 4.9 (1.5-7.7) mg/kg, compared with patients with inactive UC 1.3 (0.4-2.6) mg/kg, inactive CD 1.5 (0.5-1.7) mg/kg, irritable bowel syndrome 0.4 (0.2-0.6) mg/kg, and healthy controls (HC) 0.3 (0.1-0.4) mg/kg. Patients with infectious enterocolitis had significantly higher fecal-NGAL levels, 2.7 (1.4-5.6) mg/kg than HC. Sensitivity and specificity was 94.7% and 95.7%, respectively, for distinguishing between active IBD and HC. Stability of NGAL in stool was excellent for 7 days in room temperature. Plasma NGAL was significantly elevated in UC and CD compared with HC. CONCLUSIONS: Fecal NGAL is a promising biomarker for IBD. As existing biomarkers are expressed mainly in granulocytes, NGAL's epithelial localization may give supplementary diagnostic information.