The delayed diagnosis of acute kidney injury (AKI) episodes and the lack of specificity of current single AKI biomarkers hamper its management. Urinary peptidome analysis may help to identify early ...molecular changes in AKI and grasp its complexity to identify potential targetable molecular pathways.
In derivation and validation cohorts totalizing 1170 major cardiac bypass surgery patients and in an external cohort of 1569 intensive care unit (ICU) patients, a peptide-based score predictive of AKI (7-day KDIGO classification) was developed, validated, and compared to the reference biomarker urinary NGAL and NephroCheck and clinical scores.
A set of 204 urinary peptides derived from 48 proteins related to hemolysis, inflammation, immune cells trafficking, innate immunity, and cell growth and survival was identified and validated for the early discrimination (< 4 h) of patients according to their risk to develop AKI (OR 6.13 3.96-9.59, p < 0.001) outperforming reference biomarkers (urinary NGAL and IGFBP7.TIMP2 product) and clinical scores. In an external cohort of 1569 ICU patients, performances of the signature were similar (OR 5.92 4.73-7.45, p < 0.001), and it was also associated with the in-hospital mortality (OR 2.62 2.05-3.38, p < 0.001).
An overarching AKI physiopathology-driven urinary peptide signature shows significant promise for identifying, at an early stage, patients who will progress to AKI and thus to develop tailored treatments for this frequent and life-threatening condition. Performance of the urine peptide signature is as high as or higher than that of single biomarkers but adds mechanistic information that may help to discriminate sub-phenotypes of AKI offering new therapeutic avenues.
ABSTRACT
Background
Down-regulation of the enzymes involved in tryptophan-derived nicotinamide (NAM) adenine dinucleotide (NAD+) production was identified after acute kidney injury (AKI), leading to ...the hypothesis that supplementation with NAM may increase the kidney NAD+ content, rescuing tryptophan pathways and subsequently improving kidney outcomes.
Methods
Urinary measurement of tryptophan and kynurenin using liquid chromatography–mass spectrometry metabolomics was used in a cohort of 167 cardiac bypass surgery patients along with tests for correlation to the development of postoperative AKI. A mouse model of ischaemic AKI using ischaemia–reperfusion injury (bilateral clamping of renal arteries for 25 min) was also used.
Results
We identified a significant decrease in urinary tryptophan and kynurenin in patients developing AKI, irrespective of the Kidney Disease: Improving Global Outcomes (KDIGO) stage. Although a significant difference was observed, tryptophan and kynurenin moderately discriminated for the development of all AKI KDIGO stages {area under the curve AUC 0.82 95% confidence interval (CI) 0.75–0.88 and 0.75 0.68–0.83, respectively} and severe KDIGO Stages 2–3 AKI AUC 0.71 (95% CI 0.6–0.81) and 0.66 (0.55–0.77), respectively. Sparked by this confirmation in humans, we aimed to confirm the potential preventive effect of NAM supplementation in wild-type male and female C57BL/6 mice subjected to ischaemic AKI. NAM supplementation had no effect on renal function (blood urea nitrogen at Day 1, sinistrin–fluorescein isothiocyanate glomerular filtration rate), architecture (periodic acid–Schiff staining) and injury or inflammation (kidney injury molecule 1 and IL18 messenger RNA expression). In addition, NAM supplementation did not increase post-AKI NAD+ kidney content.
Conclusion
Notwithstanding the potential role of NAM supplementation in the setting of basal NAD+ deficiency, our findings in mice and the reanalysis of published data do not confirm that NAM supplementation can actually improve renal outcomes after ischaemic AKI in unselected animals and probably patients.
The aim of these studies was to provide reference data on intersubject variability and reproducibility of diffusion tensor imaging. Healthy volunteers underwent imaging on two occasions using the ...same 3T Siemens Verio magnetic resonance scanner. At each session two identical diffusion tensor sequences were obtained along with standard structural imaging. Fractional anisotropy, apparent diffusion coefficient, axial and radial diffusivity maps were created and regions of interest applied in normalised space. The baseline data from all 26 volunteers were used to calculate the intersubject variability, while within session and between session reproducibility were calculated from all the available data. The reproducibility of measurements were used to calculate the overall and within session 95% prediction interval for zero change. The within and between session reproducibility data were lower than the values for intersubject variability, and were different across the brain. The regional mean (range) coefficient of variation figures for within session reproducibility were 2.1 (0.9-5.5%), 1.2 (0.4-3.9%), 1.2 (0.4-3.8%) and 1.8 (0.4-4.3%) for fractional anisotropy, apparent diffusion coefficient, axial and radial diffusivity, and were lower than between session reproducibility measurements (2.4 (1.1-5.9%), 1.9 (0.7-5.7%), 1.7 (0.7-4.7%) and 2.4 (0.9-5.8%); p<0.001). The calculated overall and within session 95% prediction intervals for zero change were similar. This study provides additional reference data concerning intersubject variability and reproducibility of diffusion tensor imaging conducted within the same imaging session and different imaging sessions. These data can be utilised in interventional studies to quantify change within a single imaging session, or to assess the significance of change in longitudinal studies of brain injury and disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The aim of these studies was to provide reference data on intersubject variability and reproducibility of metabolite ratios for Choline/Creatine (Cho/Cr), N-acetyl aspartate/Choline (NAA/Cho) and ...N-acetyl aspartate/Creatine (NAA/Cr), and individual signal-intensity normalised metabolite concentrations of NAA, Cho and Cr. Healthy volunteers underwent imaging on two occasions using the same 3T Siemens Verio magnetic resonance scanner. At each session two identical Metabolic Imaging and Data Acquisition Software (MIDAS) sequences were obtained along with standard structural imaging. Metabolite maps were created and regions of interest applied in normalised space. The baseline data from all 32 volunteers were used to calculate the intersubject variability, while within session and between session reproducibility were calculated from all the available data. The reproducibility of measurements were used to calculate the overall and within session 95% prediction interval for zero change. The within and between session reproducibility data were lower than the values for intersubject variability, and were variable across the different brain regions. The within and between session reproducibility measurements were similar for Cho/Cr, NAA/Choline, Cho and Cr (11.8%, 11.4%, 14.3 and 10.6% vs. 11.9%, 11.4%, 13.5% and 10.5% respectively), but for NAA/Creatine and NAA between session reproducibility was lower (9.3% and 9.1% vs. 10.1% and 9.9%; p <0.05). This study provides additional reference data that can be utilised in interventional studies to quantify change within a single imaging session, or to assess the significance of change in longitudinal studies of brain injury and disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
IMPORTANCE: Combined oxygen 15–labeled positron emission tomography (15O PET) and brain tissue oximetry have demonstrated increased oxygen diffusion gradients in hypoxic regions after traumatic brain ...injury (TBI). These data are consistent with microvascular ischemia and are supported by pathologic studies showing widespread microvascular collapse, perivascular edema, and microthrombosis associated with selective neuronal loss. Fluorine 18–labeled fluoromisonidazole (18FFMISO), a PET tracer that undergoes irreversible selective bioreduction within hypoxic cells, could confirm these findings. OBJECTIVE: To combine 18FFMISO and 15O PET to demonstrate the relative burden, distribution, and physiologic signatures of conventional macrovascular and microvascular ischemia in early TBI. DESIGN, SETTING, AND PARTICIPANTS: This case-control study included 10 patients who underwent 18FFMISO and 15O PET within 1 to 8 days of severe or moderate TBI. Two cohorts of 10 healthy volunteers underwent 18FFMISO or 15O PET. The study was performed at the Wolfson Brain Imaging Centre of Addenbrooke’s Hospital. Cerebral blood flow, cerebral blood volume, cerebral oxygen metabolism (CMRO2), oxygen extraction fraction, and brain tissue oximetry were measured in patients during 18FFMISO and 15O PET imaging. Similar data were obtained from control cohorts. Data were collected from November 23, 2007, to May 22, 2012, and analyzed from December 3, 2012, to January 6, 2016. MAIN OUTCOMES AND MEASURES: Estimated ischemic brain volume (IBV) and hypoxic brain volume (HBV) and a comparison of their spatial distribution and physiologic signatures. RESULTS: The 10 patients with TBI (9 men and 1 woman) had a median age of 59 (range, 30-68) years; the 2 control cohorts (8 men and 2 women each) had median ages of 53 (range, 41-76) and 45 (range, 29-59) years. Compared with controls, patients with TBI had a higher median IBV (56 range, 9-281 vs 1 range, 0-11 mL; P < .001) and a higher median HBV (29 range, 0-106 vs 9 range, 1-24 mL; P = .02). Although both pathophysiologic tissue classes were present within injured and normal appearing brains, their spatial distributions were poorly matched. When compared with tissue within the IBV compartment, the HBV compartment showed similar median cerebral blood flow (17 range, 11-40 vs 14 range, 6-22 mL/100 mL/min), cerebral blood volume (2.4 range, 1.6- 4.2 vs 3.9 range, 3.4-4.8 mL/100 mL), and CMRO2 (44 range, 27-67 vs 71 range, 34-88 μmol/100 mL/min) but a lower oxygen extraction fraction (38% range, 29%-50% vs 89% range, 75%-100%; P < .001), and more frequently showed CMRO2 values consistent with irreversible injury. Comparison with brain tissue oximetry monitoring suggested that the threshold for increased 18FFMISO trapping is probably 15 mm Hg or lower. CONCLUSIONS AND RELEVANCE: Tissue hypoxia after TBI is not confined to regions with structural abnormality and can occur in the absence of conventional macrovascular ischemia. This physiologic signature is consistent with microvascular ischemia and is a target for novel neuroprotective strategies.
The emergence of carbapenemases in gram-negative aerobes is worrying. The aim of this prospective study was to estimate the incidence of acquisition of carbapenem-resistance during treatment in ICU ...and to identify the risk factors. This was a prospective, observational, cohort study. This study was conducted at intensive care unit, academic medical center, Toulouse Rangueil University Hospital. Patients were included if they received antibiotic treatment with carbapenem for more than 48 h. Biological samples were taken in accordance with current practice in the unit. The main endpoint was the occurrence of bacterial resistance to carbapenems occurring between the onset of treatment and the patient’s exit from the ICU. Uni- and multi-variate analyses were carried out. Of the 364 patients admitted to the unit between May and November 2014, 78 were included in our study and 16 (20.51%) developed resistance. The two main risk factors were a length of stay in ICU of more than 29 days (HR = 3.61,
p
= 0.01) and the presence of
Pseudomonas aeruginosa
in the samples taken before the start of treatment (HR = 5.31,
p
= 0.002). No resistance due to carbapenemase production was observed in this study. The prescription of carbapenems in the ICU setting must adhere to the expert guidelines. In light of our results, special attention must be paid to patients whose stay in intensive care is prolonged, and those in whom
Pseudomonas aeruginosa
is isolated from bacteriological samples taken before the beginning of antibiotic therapy.
Importance The chronic neuronal burden of traumatic brain injury (TBI) is not fully characterized by routine imaging, limiting understanding of the role of neuronal substrates in adverse outcomes. ...Objective To determine whether tissues that appear healthy on routine imaging can be investigated for selective neuronal loss using 11 Cflumazenil (FMZ) positron emission tomography (PET) and to examine whether this neuronal loss is associated with long-term outcomes. Design, Setting, and Participants In this cross-sectional study, data were collected prospectively from 2 centers (University of Cambridge in the UK and Weill Cornell Medicine in the US) between September 1, 2004, and May 31, 2021. Patients with TBI (>6 months postinjury) were compared with healthy control participants (all aged >18 years). Individuals with neurological disease, benzodiazepine use, or contraindication to magnetic resonance imaging were excluded. Data were retrospectively collated with nonconsecutive recruitment, owing to convenience and scanner or PET ligand availability. Data were analyzed between February 1 and September 30, 2023. Exposure Flumazenil voxelwise binding potential relative to nondisplaceable binding potential (BP ND ). Main Outcomes and Measures Selective neuronal loss identified with FMZ PET was compared between groups on voxelwise and regional scales, and its association with functional, cognitive, and psychological outcomes was examined using Glasgow Outcome Scale (GOS) scores, measures of sustained executive attention (animal and sustained fluency), and 36-Item Short Form Health Survey (SF-36) scores. Diffusion tensor imaging was used to assess structural connectivity of regions of cortical damage, and its association with thalamic selective neuronal loss. Results In this study, 24 patients with chronic TBI (mean SD age, 39.2 12.3 years; 18 men 75.0%) and 33 healthy control participants (mean SD age, 47.6 20.5 years; 23 men 69.7%) underwent FMZ PET. Patients with TBI had a median time of 29 (range, 7-95) months from injury to scan. They displayed selective neuronal loss in thalamic nuclei, over and above gross volume loss in the left thalamus, and bilateral central, mediodorsal, ventral-lateral dorsal, anterior, and ventral anterior thalamic nuclei, across a wide range of injury severities. Neuronal loss was associated with worse functional outcome using GOS scores (left thalamus, left ventral anterior, and bilateral central, mediodorsal, and anterior nuclei), worse cognitive outcome on measures of sustained executive attention (left thalamus, bilateral central, and right mediodorsal nuclei), and worse emotional outcome using SF-36 scores (right central thalamic nucleus). Chronic thalamic neuronal loss partially mirrored the location of primary cortical contusions, which may indicate secondary injury mechanisms of transneuronal degeneration. Conclusions and Relevance The findings of this study suggest that selective thalamic vulnerability may have chronic neuronal consequences with relevance to long-term outcome, suggesting the evolving and potentially lifelong thalamic neuronal consequences of TBI. FMZ PET is a more sensitive marker of the burden of neuronal injury than routine imaging; therefore, it could inform outcome prognostication and may lead to the development of individualized precision medicine approaches.
Ischemia and metabolic dysfunction remain important causes of neuronal loss after head injury, and we have shown that normobaric hyperoxia may rescue such metabolic compromise. This study examines ...the impact of hyperoxia within injured brain using diffusion tensor imaging (DTI). Fourteen patients underwent DTI at baseline and after 1 hour of 80% oxygen. Using the apparent diffusion coefficient (ADC) we assessed the impact of hyperoxia within contusions and a 1cm border zone of normal appearing pericontusion, and within a rim of perilesional reduced ADC consistent with cytotoxic edema and metabolic compromise. Seven healthy volunteers underwent imaging at 21%, 60%, and 100% oxygen. In volunteers there was no ADC change with hyperoxia, and contusion and pericontusion ADC values were higher than volunteers (P<0.01). There was no ADC change after hyperoxia within contusion, but an increase within pericontusion (P<0.05). We identified a rim of perilesional cytotoxic edema in 13 patients, and hyperoxia resulted in an ADC increase towards normal (P=0.02). We demonstrate that hyperoxia may result in benefit within the perilesional rim of cytotoxic edema. Future studies should address whether a longer period of hyperoxia has a favorable impact on the evolution of tissue injury.
We have previously shown that normobaric hyperoxia may benefit peri-lesional brain and white matter following traumatic brain injury (TBI). This study examined the impact of brief exposure to ...hyperoxia using diffusion tensor imaging (DTI) to identify axonal injury distant from contusions. Fourteen patients with acute moderate/severe TBI underwent baseline DTI and following one hour of 80% oxygen. Thirty-two controls underwent DTI, with 6 undergoing imaging following graded exposure to oxygen. Visible lesions were excluded and data compared with controls. We used the 99% prediction interval (PI) for zero change from historical control reproducibility measurements to demonstrate significant change following hyperoxia. Following hyperoxia DTI was unchanged in controls. In patients following hyperoxia, mean diffusivity (MD) was unchanged despite baseline values lower than controls (p < 0.05), and fractional anisotropy (FA) was lower within the left uncinate fasciculus, right caudate and occipital regions (p < 0.05). 16% of white and 14% of mixed cortical and grey matter patient regions showed FA decreases greater than the 99% PI for zero change. The mechanistic basis for some findings are unclear, but suggest that a short period of normobaric hyperoxia is not beneficial in this context. Confirmation following a longer period of hyperoxia is required.
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