Biomarkers Of Organ Injury Research Articles

Mesoporous Silica Administration as a New Strategy in the Management of Warfarin Toxicity; In Vitro and In Vivo Study

Purpose: Warfarin is one of the most widely used anticoagulants that function by inhibiting vitamin K epoxide reductase. Warfarin overdose, whether intentional or unintentional, can cause life-threatening bleeding. Here, we present a novel warfarin adsorbent based on mesoporous silica that can act as an antidote to warfarin toxicity. Method: Amino-functionalized mesoporous silica (MS-NH2) was synthesized based on co-condensation method through a soft template technique followed by template removal. The prepared structure and functional group were studied by FT-IR, XRD. The morphology was checked by SEM and TEM. The capacity of MS-NH2 in the adsorption of warfarin was evaluated in vitro, at pH=7.4 and pH=1.2. In vivo evaluation was performed in control and warfarin-overdosed animal models. Overdosed animals were treated with MS-NH2 by oral gavage. Biomarkers of organ injury were assessed in animal serum. Results: The MS-NH2 were relatively uniform, spherical with defined diameters (400 nm) and homogeneous structure. synthesized particles had a large surface area (1015 m2 g-1) and mean pore diameter 2.4 nm which leaded considerable adsorption capacity for warfarin 1666 mg/g. In vivo studies revealed that oral administration of MS-NH2 in mice poisoned with warfarin caused a significant difference (p < 0.05) on International Normalized Ratio (INR) and prothrombin time (PT). Moreover, the warfarin with MS-NH2 group demonstrated a notable decrease in biomarkers associated with tissue damage, such as bilirubin, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), and aspartate aminotransferase (AST). Conclusion: The results confirm that MS-NH2 administration can be an effective treatment for warfarin toxicity and could potentially mitigate the adverse effects of warfarin poisoning.

Efficacy of propofol-supplemented cardioplegia on biomarkers of organ injury in patients having cardiac surgery using cardiopulmonary bypass: a statistical analysis plan for the ProMPT-2 randomised controlled trial

BackgroundThe ProMPT-2 trial (Propofol for Myocardial Protection Trial #2) aims to compare the safety and efficacy of low- and high-dose propofol supplementation of the cardioplegia solution during adult cardiac surgery versus sham supplementation. This update presents the statistical analysis plan, detailing how the trial data will be analysed and presented. Outlined analyses are in line with the Consolidated Standards of Reporting Trials and the statistical analysis plan has been written prior to database lock and the final analysis of trial data to avoid reporting bias (following recommendations from the International Conference on Harmonisation of Good Clinical Practice).Methods/designProMPT-2 is a multi-centre, blinded, parallel three-group randomised controlled trial aiming to recruit 240 participants from UK cardiac surgery centres to either sham cardioplegia supplementation, low dose (6 µg/ml) or high dose (12 µg/ml) propofol cardioplegia supplementation. The primary outcome is cardiac-specific troponin T levels (a biomarker of cardiac injury) measured during the first 48 h following surgery.The statistical analysis plan describes the planned analyses of the trial primary and secondary outcomes in detail, including approaches to deal with missing data, multiple testing, violation of model assumptions, withdrawals from the trial, non-adherence with the treatment and other protocol deviations. It also outlines the planned sensitivity analyses and exploratory analyses to be performed.DiscussionThis manuscript prospectively describes, prior to the completion of data collection and database lock, the analyses to be undertaken for the ProMPT-2 trial to reduce risk of reporting and data-driven analyses.Trial registrationISRCTN ISRCTN15255199. Registered on 26 March 2019.

Efficacy of propofol-supplemented cardioplegia on biomarkers of organ injury in patients having cardiac surgery using cardiopulmonary bypass: A protocol for a randomised controlled study (ProMPT2).

Cardiac surgery with cardiopulmonary bypass and cardioplegic arrest is known to be responsible for ischaemia and reperfusion organ injury. In a previous study, ProMPT, in patients undergoing coronary artery bypass or aortic valve surgery we demonstrated improved cardiac protection when supplementing the cardioplegia solution with propofol (6mcg/ml). The aim of the ProMPT2 study is to determine whether higher levels of propofol added to the cardioplegia could result in increased cardiac protection. The ProMPT2 study is a multi-centre, parallel, three-group, randomised controlled trial in adults undergoing non-emergency isolated coronary artery bypass graft surgery with cardiopulmonary bypass. A total of 240 patients will be randomised in a 1:1:1 ratio to receive either cardioplegia supplementation with high dose of propofol (12mcg/ml), low dose of propofol (6mcg/ml) or placebo (saline). The primary outcome is myocardial injury, assessed by serial measurements of myocardial troponin T up to 48hours after surgery. Secondary outcomes include biomarkers of renal function (creatinine) and metabolism (lactate). The trial received research ethics approval from South Central - Berkshire B Research Ethics Committee and Medicines and Healthcare products Regulatory Agency in September 2018. Any findings will be shared though peer-reviewed publications and presented at international and national meetings. Participants will be informed of results through patient organisations and newsletters. ISRCTN15255199. Registered in March 2019.

SODIUM SELENITE ABROGATES THE EFFECTS OF ARSENIC TOXICITY ON ORGAN INJURY BIOMARKERS IN THE BLOOD

Heavy metals are becoming ubiquitous in our environment due to its natural abundance and anthropogenic uses. Arsenic an example of heavy metal, can cause deleterious effects in numerous organs and biochemical pathways. Use of noninvasive testing procedures had been used in diagnosis, monitoring of pathological events during treatment. In order to investigate the effects of sodium selenite on biomarkers of organ injury in arsenic-exposed rats for a period of 5 weeks, twenty-four male albino rats divided into four groups (n = 6) were exposed to sodium arsenite (SA) and sodium selenite (SS). Group I (control) received only distilled water, groups II and III were exposed to 40 ppm SA in drinking water ad libtum, in addition group III received 0.25 mg/kg bwt SS orally and group IV received 0.25 mg/kg bwt SS orally only. Activities and levels of organ-injury markers were determined in the blood using spectrophotometric method. In the SA exposed group (group II), there were significant increases (p ˂ 0.05) in the activities of plasma xanthine oxidase, lactate dehydrogenase, aldolase, glutamate dehydrogenase, NAD glycohydrolase, aspartate and alanine aminotransferases, and levels of plasma nitric oxide and hydrogen sulphide (in plasma and erythrocyte) when compared to control. Sodium selenite administration abrogated the observed effects of SA exposure by decreasing the measured biomarkers to the normal level as observed in group III and IV. In conclusion, this results suggests the use of SS is safe and non-invasive approach for the prevention of SA-induced toxicity in humans.

Patterns of acute kidney and hepatic injury and association with adverse outcomes in infants undergoing therapeutic hypothermia for hypoxic ischemic encephalopathy.

To describe patterns of renal and hepatic injury in infants with hypoxic ischemic encephalopathy (HIE). Retrospective cohort of infants receiving therapeutic hypothermia for HIE was classified into groups based on organ injury: neither acute kidney injury (AKI) nor acute hepatic injury (AHI), isolated AKI, isolated AHI, or both AKI/AHI. Biomarkers and outcomes were described and analyzed. Among 188 infants, 55% had no AKI nor AHI, 7% had only AKI, 22% had only AHI and 16% had both AKI and AHI. Infants with both AKI/AHI had the highest mortality (47%) and worse outcomes, compared to other injury groups, although AKI/AHI was not significantly associated with mortality (hazard ratio 2.5; 95% CI 0.9-6.9), after accounting for severity of HIE. For surviving infants, biomarkers of organ injury, on average, normalized by discharge. Infants with HIE with both AKI/AHI have worse outcomes than infants with AKI or AHI alone.

Toxicity assessment of watermelon seed supplemented diet in rats

Health benefits have been attributed to the consumption of watermelon (Citrullus lanatus L.) seeds in sub-Saharan Africa and Asia but the potential toxicity especially on chronic use remains to be investigated. Here, diets containing watermelon seeds (WMSs) at 2.5% or 5% were eaten ad libitum daily for 21 d by male and female Wistar rats. Changes in body and organ (liver, kidney, brain, testis, and ovary) weights following diet supplementation were monitored. Biomarkers of organ injury, such as alanine aminotransferase (ALT), alkaline phosphatase (ALP), cholesterol (CHO), triglyceride (TRI), urea, and creatinine (CRE) were measured. WMS-formulated diet led to a decrease in body weight in male but not in female rats compared to the control group. Also, testes weight significantly increased, whereas a decrease in that of the ovaries was noted. Although the ingestion of WMS did not significantly alter the weights of the liver and brain, a trend toward reduction was noticed. No significant changes were observed for the serum levels of ALT, ALP, CHO, and TRI in all rats. However, the kidney may be targeted for toxicity as indicated by significant elevations in serum urea and CRE levels in male and female rats when compared to controls. Furthermore, the sperm morphology anomalies observed after WMS supplementation demonstrate the potentially detrimental effects of high consumption of the seeds on the male reproductive system. We conclude that WMSs at 2.5% or 5% dose in the diet may elicit negative effects in organs particularly on the kidney and testes in rats.

Abstract 141: Early Cytokine Profile in Selectively Vulnerable Brain Regions, Heart and Serum After Asphyxial Cardiac Arrest vs. Ventricular Fibrillation Cardiac Arrest in Rats

Background: Currently, post-resuscitative care for survivors of cardiac arrest (CA) is independent of the etiology of CA. We have previously reported that asphyxial CA (ACA) results in different injury pattern vs. ventricular fibrillation CA (VFCA). Exploration of the early inflammatory response could identify insult-specific targets for future therapies. We hypothesized that the early systemic and regional neuroinflammatory cytokine response could differ between ACA vs. VFCA. Methods: Adult male rats were subjected to a 10 min ACA, or 10 min VFCA (n=12/group). Naives (n=12) and shams (n=12) subjected to anesthesia and instrumentation but not CA served as controls. Serum, heart and regional brain cytokine signatures were assessed in selectively vulnerable brain regions: cerebellum, cortex, hippocampus and striatum at 3 h. NSE, S100b and troponin T were also assessed. Results: Asphyxiation produced an ~4 min period of severe hypoxemia followed by a no-flow duration of ~ 6±1 min. VF immediately induced no-flow. Brain cytokines in naïve rats were low or undetectable. Shams had a modest effect on selected cytokines. Both ACA and VFCA resulted in robust selected cytokine responses in serum, heart and brain (Fig. 1) with significant regional differences in brain that identified striatum as a selective neuroinflammatory target. No significant differences in cytokines between CA models were observed. NSE, S100b and troponin T were similarly increased after ACA and VFCA vs. naives and/or shams. Conclusions: Both models of CA resulted in marked systemic, heart and brain cytokine response. Biomarkers of organ injury were also comparable. Contrasting prior studies showing greater oxidative stress and brain injury in ACA, but greater hemodynamic impairment after VFCA, systemic and brain cytokine profiles revealed similar increases across insults, suggesting that the cytokine response may not mediate key secondary injury differences between these two CA phenotypes.

A randomised double-blind pilot trial comparing a mean arterial pressure target of 65 mm Hg versus 72 mm Hg after out-of-hospital cardiac arrest.

After resuscitation from out-of-hospital cardiac arrest, mean arterial pressure below 65 mm Hg is avoided with vasopressors. A higher blood-pressure target could potentially improve outcome. The aim of this pilot trial was to investigate the effect of a higher mean arterial pressure target on biomarkers of organ injury. This was a single-centre, double-blind trial of 50 consecutive, comatose out-of-hospital cardiac arrest patients randomly assigned in a 1:1 ratio to a mean arterial pressure target of 65 mm Hg (MAP65) or 72 mm Hg (MAP72). Modified blood pressure modules with a -10% offset were used, enabling a double-blind study design. End-points were biomarkers of organ injury including markers of endothelial integrity (soluble trombomodulin) brain damage (neuron-specific enolase) and renal function (estimated glomerular filtration rate). Mean arterial pressure was significantly higher in MAP72 with a mean difference of 5 mm Hg (pgroup=0.03). After 48 h, soluble trombomodulin (median (interquartile range)) was 8.2 (6.7-12.9) ng/ml and 8.3 (6.0-10.8) ng/ml (p=0.29), neuron-specific enolase was 20 (13-31 μg/l) and 18 (13-44 μg/l) p=0.79) and estimated glomerular filtration rate (mean (±standard deviation)) was 61±19 ml/min/1.73m2 and 48±22 ml/min/1.73 m2 (p=0.08) for the MAP72 and MAP65 groups, respectively. Renal replacement therapy was needed in eight patients (31%) in MAP65 and three patients (13%) in MAP72 (p=0.14). Double-blind allocation to different mean arterial pressure targets is feasible in comatose out-of-hospital cardiac arrest patients. A mean arterial pressure target of 72 mm Hg compared to 65 mm Hg did not result in improved biomarkers of organ injury. We observed a trend towards preserved renal function in the MAP72 group.

Optimal VAsopressor TitraTION in patients 65 years and older (OVATION-65): protocol and statistical analysis plan for a randomised clinical trial

IntroductionVasodilatory hypotension is common among intensive care unit (ICU) patients; vasopressors are considered standard of care. However, optimal mean arterial pressure (MAP) targets for vasopressor titration are unknown. The objective...

Abstract 199: TNF-Alpha Response After Experimental Cardiac Arrest in Rats is Not Attenuated by Thalidomide

Background: Resuscitation from cardiac arrest (CA) results in systemic cytokines response, and neuroinflammation. Thalidomide has been reported to selectively decrease tumor necrosis factor alpha (TNFa) and shown to be neuroprotective. Hypothesis: Thalidomide would decrease systemic and organ-specific cytokine response and biomarkers of injury after CA in rats. Methods: Adult male rats were subjected to 10 min ventricular fibrillation CA. Three groups were studied (n=4-6 per group): naives, CA treated with vehicle and CA treated with thalidomide (CA+T, 50 mg/kg i.p.). TNFa was assessed at 3 h in the cortex, hippocampus, striatum, cerebellum, plasma, heart and lung (Luminex). NSE and S100b were used to assess neuronal and glial injury, cardiac troponin I (cTnI) cardiac ichemia and IFABP to assess intestinal damage (ELISA). Results: CA resulted in a robust increase of TNFa in plasma (Figure 1) and tissues (Figure 2) with no differences between CA and CA+T groups in any region. NSE, S100b, cTnI and IFABP were increased after CA or CA+T vs. naives (all p<0.05) without differences between CA vs. CA+T. Conclusions: CA resulted in an early massive TNFa response systemically and in target organs, with increased biomarkers of organ injury. Thalidomide in a dose reported previously to improve outcome of in vivo models of brain ischemia did not decrease TNFa levels in plasma, brain or extracerebral organs, or biomarkers of injury in our model of experimental CA. Cytokine response to CA was identified as a therapeutic target for future interventions on systemic and end-organ levels. Other promising anti-TNFa strategies incl. anti-TNFa antibodies are currently being evaluated in CA models.

Alterations in tissue microRNA after heat stress in the conscious rat: potential biomarkers of organ-specific injury

BackgroundHeat illness remains a significant cause of morbidity in susceptible populations. Recent research elucidating the cellular mechanism of heat stress leading to heat illness may provide information to develop better therapeutic interventions, risk assessment strategies, and early biomarkers of organ damage. microRNA (miRNA) are promising candidates for therapeutic targets and biomarkers for a variety of clinical conditions since there is the potential for high specificity for individual tissues and unique cellular functions. The objective of this study was to identify differentially expressed microRNAs and their putative mRNA targets in the heart, liver, kidney, and lung in rats at three time points: during heat stress (i.e., when core temperature reached 41.8 °C), or following a 24 or 48 h recovery period.ResultsRats did not show histological evidence of tissue pathology until 48 h after heat stress, with 3 out of 6 rats showing cardiac inflammation and renal proteinosis at 48 h. The three rats with cardiac and renal pathology had 86, 7, 159, and 37 differentially expressed miRNA in the heart, liver, kidney, or lung, respectively compared to non-heat stressed control animals. During heat stress one differentially expressed miRNA was found in the liver and five in the lung, with no other modulated miRNA after 24 h or 48 h in animals with no evidence of organ injury. Pathway enrichment analysis revealed enrichment in functional pathways associated with heat stress, with the greatest effects observed in animals with histological evidence of cardiac and renal damage at 48 h. Inhibiting miR-21 in cultured cardiomyocytes increased the percent apoptotic cells five hours after heat stress from 70.9 ± 0.8 to 84.8 ± 2.2%.ConclusionsGlobal microRNA and transcriptomics analysis suggested that perturbed miRNA due to heat stress are involved in biological pathways related to organ injury, energy metabolism, the unfolded protein response, and cellular signaling. These miRNA may serve as biomarkers of organ injury and potential pharmacological targets for preventing heat illness or organ injury.

A scrutiny of circulating microRNA biomarkers for drug-induced tubular and glomerular injury in rats

Drug-induced acute kidney injury (AKI) is a frequent cause of adverse drug reaction. Serum creatinine (CRE) and blood urea nitrogen (BUN) are widely used as standard biomarkers for kidney injury; however, the sensitivity and specificity are considered to be low. In recent years, circulating microRNA (miRNAs) have been attracting considerable attention as novel biomarkers for organ injury, but there are currently no established miRNA biomarkers for drug-induced AKI. The present study aimed to identify plasma miRNAs that may enable early and specific detection of drug-induced tubular and glomerular injury through next-generation sequencing analysis. Six-week old male Sprague-Dawley (SD) rats were intravenously administered cisplatin (CSP, 6 mg/kg) and gentamicin (GEN, 120 mg/kg) to induce tubular injury. To create glomerular injury models, puromycin (PUR, 120 mg/kg) and doxorubicin (DOX, 7.5 mg/kg) were intravenously administered, and these models were always accompanied by tubular damage. Small RNA-sequencing was performed to analyze time-dependent changes in the plasma miRNA profiles. The cluster analyses showed that there were distinct plasma miRNA profiles according to the types of injury, and the changes reflected the progress of renal damages. In the differential analysis, miR-3473 was specifically up-regulated in the glomerular injury models. miR-143-3p and miR-122-5p were commonly down-regulated in all models, and the changes were earlier than the traditional biomarkers, such as plasma CRE and BUN. These data indicated that changes in the specific miRNAs in plasma may enable the early and sensitive detection of tubular and glomerular injuries. The present study suggests the potential utility of plasma miRNAs in the early and type-specific detection of drug-induced AKI.

Baseline, Time-Updated, and Cumulative HIV Care Metrics for Predicting Acute Myocardial Infarction and All-Cause Mortality.

After adjustment for cardiovascular risk factors and despite higher mortality, those with human immunodeficiency virus (HIV+) have a greater risk of acute myocardial infarction (AMI) than uninfected individuals. We included HIV+ individuals who started combination antiretroviral therapy (cART) in the Veterans Aging Cohort Study (VACS) from 1996 to 2012. We fit multivariable proportional hazards models for baseline, time-updated and cumulative measures of HIV-1 RNA, CD4 counts, and the VACS Index. We used the trapezoidal rule to build the following cumulative measures: viremia copy-years, CD4-years, and VACS Index score-years, captured 180 days after cART initiation until AMI, death, last clinic visit, or 30 September 2012. The primary outcomes were incident AMI (Medicaid, Medicare, and Veterans Affairs International Classification of Diseases-9 codes) and death. A total of 8168 HIV+ individuals (53 861 person-years) were analyzed with 196 incident AMIs and 1710 deaths. Controlling for known cardiovascular risk factors, 6 of the 9 metrics predicted AMI and all metrics predicted mortality. Time-updated VACS Index had the lowest Akaike information criterion among all models for both outcomes. A time-updated VACS Index score of 55+ was associated with a hazard ratio (HR) of 3.31 (95% confidence interval [CI], 2.11-5.20) for AMI and a HR of 31.77 (95% CI, 26.17-38.57) for mortality. Time-updated VACS Index provided better AMI and mortality prediction than CD4 count and HIV-1 RNA, suggesting that current health determines risk more accurately than prior history and that risk assessment can be improved by biomarkers of organ injury.

Identification of microRNA biomarker candidates in urine and plasma from rats with kidney or liver damage.

MicroRNAs (miRNA) are short single‐stranded RNA sequences that have a role in the post‐transcriptional regulation of genes. The identification of tissue specific or enriched miRNAs has great potential as novel safety biomarkers. One longstanding goal is to associate the increase of miRNA in biofluids (e.g., plasma and urine) with tissue‐specific damage. Next‐generation sequencing (miR‐seq) was used to analyze changes in miRNA profiles of tissue, plasma and urine samples of rats treated with either a nephrotoxicant (cisplatin) or one of two hepatotoxicants (acetaminophen [APAP] or carbon tetrachloride [CCL4]). Analyses with traditional serum chemistry and histopathology confirmed that toxicant‐induced organ damage was specific. In animals treated with cisplatin, levels of five miRNAs were significantly altered in the kidney, 14 in plasma and six in urine. In APAP‐treated animals, five miRNAs were altered in the liver, 74 in plasma and six in urine; for CCL4 the changes were five, 20 and 6, respectively. Cisplatin treatment caused an elevation of miR‐378a in the urine, confirming the findings of other similar studies. There were 17 in common miRNAs elevated in the plasma after treatment with either APAP or CCL4. Four of these (miR‐122, −802, −31a and −365) are known to be enriched in the livers of rats. Interestingly, the increase of serum miR‐802 in both hepatotoxicant treatments was comparable to that of the well‐known liver damage marker miR‐122. Taken together, comparative analysis of urine and plasma miRNAs demonstrated their utility as biomarkers of organ injury. Copyright © 2016 The Authors. Journal of Applied Toxicology published by John Wiley & Sons Ltd.

Identification and Expression Profiles of microRNA in Dolphin.

Recently, microRNAs (miRNAs) are focused on the role of biomarker because they are stable in serum and plasma, and some of them express in the specific organs and increase with the organ injury. Thus miRNAs may be very useful as biomarkers for monitoring the health and condition of dolphins and for detecting disorders in aquariums. Here, a small RNA library was made from dolphin lung, liver and spleen, and miRNA expression patterns were then determined for 15 different tissues. We identified 62 conserved miRNA homologs in the dolphin small RNA library and found high expression miRNAs in specific tissues: miR-125b and miR-221 were highly expressed in brain, miR-23b in heart, miR-199a and miR-223 in lung, and miR-122-5p in liver. Some of these tissue-enriched miRNAs may be useful as specific and sensitive diagnostic blood biomarkers for organ injury in dolphins.

Vascular surgery-related organ injury and protective strategies: update and future prospects

Whilst there has been a reduction in the prevalence of peripheral vascular disease worldwide, a significant proportion of the world's growing population is still affected by disease of the aorta, carotid, iliac and lower limb arteries. These if left untreated can result in severe morbidity and mortality. However vascular surgery, the main definitive treatment for such conditions, is associated with subsequent injury to vital organs including the kidneys, heart, brain, intestines and lungs, with a consequent increase in both morbidity and mortality. The current thinking is that the underlying mechanism of injury is direct organ ischaemia and ischaemia induced formation of free radicals, cytokine release and mitochondrial failure. Various methods to alleviate such injuries have been investigated including pre- and postconditioning strategies, pharmacological therapies including volatile anaesthetic and alpha2 adrenoceptor agonist drugs and more recently remote conditioning strategies. Although these interventions have demonstrated some reduction in the biomarkers for organ injury, attempts to translate these benefits into clinical practice have not been successful in terms of morbidity, mortality or length of hospital stay. For this reason, further research is needed in this area to facilitate the translation of the potential interventional benefits from bench to bedside.

Biomarkers of Organ Injury

Biomarkers of Organ Injury