Subclinical Injury Research Articles

Subclinical Cardiac Injury And Clinical Congestion

<h3>Introduction</h3> Clinical congestion is associated with worse outcomes in patients with heart failure (HF). The pathophysiological mediators of this association remain uncertain. <h3>Hypothesis</h3> Detailed phenotyping of patients with HF, including clinical examination and measurement of invasive hemodynamics and cardiac biomarkers, will provide insights into the pathophysiology of clinical congestion. <h3>Methods</h3> In a prospective cohort of patients with HF and reduced LVEF, a clinical examination followed the same day by right heart catheterization and blood sampling for biomarker measurement was performed. A clinical congestion score was created based on JVP (cm H20 <10 = 0, 10-14 =1, >14 =2 points), bendopnea (0-1), S3 (0-1) and peripheral edema (0-2). Congestion tier was defined as Absent, Mild (1 point) or Moderate-Severe (≥ 2 points). Biomarker elevation was defined as high-sensitivity troponin T ≥52 ng/L or NT-proBNP ≥1000 pg/mL. Elevated right atrial pressure (RAP) was ≥10 mmHg and pulmonary capillary wedge pressure (PCWP) ≥22 mmHg. Univariate and multivariable analyses tested the association of biomarkers, RAP, and PCWP with clinical congestion. <h3>Results</h3> Of 154 subjects, 65 (42%) had no congestion, 35 mild (23%) and 54 (35%) moderate-severe. Increasing congestion tier was associated with NT-proBNP, troponin, RAP and PCWP (P<0.001 for each). Increasing congestion tier was associated with the combined presence of elevated troponin, NT-proBNP and PCWP (Figure). Only 22% of those with absent congestion had more than one of these findings, whereas 76% of those with moderate-severe congestion had at least 2 of them (p<0.001). In multivariable regression, elevated troponin was associated with the presence of clinical congestion (OR 2.8, 1.1-7.3, p=0.03) independently of RAP, PCWP, and NT-proBNP levels. <h3>Conclusions</h3> Increased ventricular filling pressures, elevated natriuretic peptide levels, and subclinical myocardial injury frequently coexist in patients with clinical congestion. Elevated troponin was associated with clinical congestion independently of ventricular filling pressures and natriuretic peptide levels, suggesting that subclinical cardiac injury contributes to the pathophysiology of clinical congestion.

De Novo Membranous Nephropathy Associated With Antibody-Mediated Rejection in Kidney Transplant Recipients

Membranous nephropathy (MN) is a rare autoimmune disease that can develop a persistent nephrotic syndrome and end-stage kidney disease, with a recurrence rate of 30% to 40% after kidney transplant. Retrospective case series of membranous nephropathy observed in a cohort of kidney transplant recipients with donor-specific anti-human leukocyte antigen antibodies and biopsy-proven antibody-mediated rejection (AMR). We report 4 cases of membranous nephropathy associated with AMR. MN was diagnosed 10 to 92 months posttransplant, associated with de novo donor-specific antibodies, specific to class I in 2 cases, and class II in another 2. All cases presented typical morphology of membranous nephropathy, with subepithelial deposits with spikes at electron microscopy. Immunostaining for immunoglobulin G4 was negative in all cases, and podocyte-expressed M-type phospholipase A2 receptor was detected in glomerular basement membrane of 3 cases. Biopsy specimens from patients with longer follow-up showed more intense microvascular inflammation and chronic injury markers, possibly because of subclinical immunologic injury. AMR therapy included immunoglobulin 2g/kg in 3 patients, isolated or associated with plasmapheresis. One patient was not treated because of an active disseminated infection. Two patients remain with functioning grafts and under antiproteinuric therapy. Two grafts were lost, 1 because of chronic failure and the other because of death secondary to infection. Despite treatment, donor-specific antibodies remain detectable in a 6-month follow-up. De novo MN is a rare manifestation associated with AMR in kidney transplant recipients. The occurrence of podocyte-expressed M-type phospholipase A2 receptor in de novo MN suggests antibody-mediated activation, despite the use of maintenance immunosuppression.

Abstract 047: Effects Of The Dash Diet On Change In High-Sensitivity Cardiac Troponin I Over Time: Results From The Dash-Sodium Trial

Background: The DASH (Dietary Approaches to Stop Hypertension) diet has been shown to reduce high-sensitivity cardiac troponin I (hs-cTnI), a biomarker of subclinical cardiac injury. However, the time course of the DASH diet’s effects on this biomarker has not been determined. Hypothesis: The DASH diet lowers hs-cTnI within 4 weeks and the effects gradually increase over time. Methods: We analyzed data from the DASH-Sodium trial, a randomized controlled feeding study of healthy adults with systolic blood pressure 120 to 159 mm Hg and diastolic blood pressure 80 to 95 mm Hg. Participants were randomly assigned to the DASH diet or a typical American diet (control). Within each arm of the study, participants were assigned three sodium levels, in random order, changed every 4 weeks. Hs-cTnI was measured from serum collected at baseline and at 4, 8, and 12 weeks of feeding. Energy intake was adjusted to maintain body weight throughout the trial. Results: Of the 411 participants included in the final analysis, their mean age was 48 years, 56% were women, and 56% were Black. The mean baseline systolic/diastolic blood pressure was 135/86 mm Hg. Compared with baseline, the control diet did not have a significant effect on hs-cTnI at any of the measured time points. In contrast, the DASH diet reduced hs-cTnI by 0.18 ng/l (95% CI: -0.32, -0.04) at 4 weeks, 0.14 ng/l (95% CI: -0.29, 0.00) at 8 weeks, and 0.33 ng/l (95% CI: -0.48, -0.18) at 12 weeks ( Figure ; P -trend = 0.025). The %-difference in mean change from baseline of hs-cTnI for DASH vs. control was -13.30% (95% CI: -25.34, 0.69), -10.47% (95% CI: -23.08, 4.21), and -17.78% (95% CI: -29.51, -4.09) at 4, 8, and 12 weeks, respectively. Conclusions: The DASH diet reduced hs-cTnI within 4 weeks of feeding with greater diet effects occurring at 12 weeks of feeding. These results suggest that the DASH diet has both early and cumulative effects on subclinical cardiac injury.

Abstract MP62: Sex-specific Associations Of Vascular Risk Factors And Brain Mri Measures In The Framingham Offspring

Aim: To examine if the associations between vascular risk factors (VRF) and brain MRI measures of brain aging and cerebral small vessel disease are different in men and women. Background: Men and women differ in their propensity to develop stroke and this is reflected in sex-specific versions of the widely used Framingham Stroke Risk Prediction (FSRP) index, that provides an estimate of 10-year risk of incident clinical stroke. However, sex-specific associations between the individual risk factor components of FSRP and subclinical vascular brain injury have not been previously explored in our data. Methods/Design: We related levels of blood pressure, diabetes, current smoking and prevalent non-stroke cardiovascular disease (CVD) to brain MRI measures of total cerebral brain, hippocampal and white matter hyperintensity volumes (TCBV, HPV, WMHV) and covert brain infarcts (CBI) in 1,579 stroke- and dementia-free Framingham Offspring who attended their 8th quadrennial examination (53% F; age 66±9 years). We examined age-adjusted, sex-stratified linear or logistic regression analyses for all VRF that suggested a sex-interaction at a p&lt;0.1. Results: Higher blood pressure (assessed as systolic blood pressure (SBP) or as JNC7 defined Stage 1 HTN (≥140/90 mm Hg or use of antihypertensive medication), had a greater adverse impact on WMHV in women compared to men (SBP: β±SE: 0.009±0.002, p&lt;0.001 versus 0.004±0.002, p&lt;0.031; HTN: β 0.176±0.066, p=0.008 versus non-significant association, in women and men respectively), although prevalent CVD, reflecting lifetime vascular risk factor exposure and injury, had a larger adverse effect on WMHV in men (β -0.221±0.087, p=0.012, versus a non-significant association in women). In addition, both Stage 1 HTN and diabetes had larger adverse effects on TCBV in men (β -0.309±0.141, p&lt;0.029 and -0.853±0.177, p&lt;0.001 respectively, versus non-significant associations in women). Conclusions: In our cohort of young-old participants, wherein most women were post-menopausal, current levels of VRF at the time of examination, were associated with a greater burden of vascular brain injury in women than in men of the same age, whereas current VRF levels appeared to have a greater global impact on brain volumes in men. Our data suggest that the greater risk of dementia noted in older women compared to men may be substantially attributable to modifiable vascular risk factors; more aggressively controlling these in women may reduce sex disparities.

Functional Reserve of the Kidney.

An exploration of the normal limits of physiologic responses and how these responses are lost when the kidney is injured rarely occurs in clinical practice. However, the differences between "resting" and "stressed" responses identify an adaptive reactiveness that is diminished before baseline function is impaired. This functional reserve is important in the evaluation of prognosis and progression of kidney disease. Here, we discuss stress tests that examine protein-induced hyperfiltration, proximal tubular secretion, urea-selective concentration defects, and acid retention. We discuss diseases in which these tests have been used to diagnose subclinical injury. The study and follow-up of abnormal functional reserve may add considerable understanding to the natural history of CKD.

Adoption of a novel biomarker-guided quality improvement treatment bundle for patients with subclinical acute kidney injury after cardiac surgery: a Royal Brompton Hospital-King’s Health Partners Innovation Project

Acute kidney injury (AKI) is a common major complication of cardiac surgery, affecting up to 40% of patients, with associated mortality of up to 50%.1 2 G1 cell cycle arrest biomarkers tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP7) have been shown to be predictive of AKI after cardiac surgery.3 Urinary biomarker-guided identification of high-risk patients, alongside implementation of a Kidney Disease: Improving Global Outcomes (KDIGO)-based care bundle, can reduce the incidence of post-cardiac surgery AKI.

Attention-based 3D CNN with residual connections for efficient ECG-based COVID-19 detection

BackgroundThe world has been suffering from the COVID-19 pandemic since 2019. More than 5 million people have died. Pneumonia is caused by the COVID-19 virus, which can be diagnosed using chest X-ray and computed tomography (CT) scans. COVID-19 also causes clinical and subclinical cardiovascular injury that may be detected on electrocardiography (ECG), which is easily accessible. MethodFor ECG-based COVID-19 detection, we developed a novel attention-based 3D convolutional neural network (CNN) model with residual connections (RC). In this paper, the deep learning (DL) approach was developed using 12-lead ECG printouts obtained from 250 normal subjects, 250 patients with COVID-19 and 250 with abnormal heartbeat. For binary classification, the COVID-19 and normal classes were considered; and for multiclass classification, all classes. The ECGs were preprocessed into standard ECG lead segments that were channeled into 12-dimensional volumes as input to the network model. Our developed model comprised of 19 layers with three 3D convolutional, three batch normalization, three rectified linear unit, two dropouts, two additional (for residual connections), one attention, and one fully connected layer. The RC were used to improve gradient flow through the developed network, and attention layer, to connect the second residual connection to the fully connected layer through the batch normalization layer. ResultsA publicly available dataset was used in this work. We obtained average accuracies of 99.0% and 92.0% for binary and multiclass classifications, respectively, using ten-fold cross-validation. Our proposed model is ready to be tested with a huge ECG database.

Role of Urinary Kidney Stress Biomarkers for Early Recognition of Subclinical Acute Kidney Injury in Critically Ill COVID-19 Patients.

A high proportion of critically ill patients with COVID-19 develop acute kidney injury (AKI) and die. The early recognition of subclinical AKI could contribute to AKI prevention. Therefore, this study was aimed at exploring the role of the urinary biomarkers NGAL and [TIMP-2] × [IGFBP7] for the early detection of AKI in this population. This prospective, longitudinal cohort study included critically ill COVID-19 patients without AKI at study entry. Urine samples were collected on admission to critical care areas for determination of NGAL and [TIMP-2] × [IGFBP7] concentrations. The demographic information, comorbidities, clinical, and laboratory data were recorded. The study outcomes were the development of AKI and mortality during hospitalization. Of the 51 individuals that were studied, 25 developed AKI during hospitalization (49%). Of those, 12 had persistent AKI (23.5%). The risk factors for AKI were male gender (HR = 7.57, 95% CI: 1.28–44.8; p = 0.026) and [TIMP-2] × [IGFBP7] ≥ 0.2 (ng/mL)2/1000 (HR = 7.23, 95% CI: 0.99–52.4; p = 0.050). Mortality during hospitalization was significantly higher in the group with AKI than in the group without AKI (p = 0.004). Persistent AKI was a risk factor for mortality (HR = 7.42, 95% CI: 1.04–53.04; p = 0.046). AKI was frequent in critically ill COVID-19 patients. The combination of [TIMP-2] × [IGFBP7] together with clinical information, were useful for the identification of subclinical AKI in critically ill COVID-19 patients. The role of additional biomarkers and their possible combinations for detection of AKI in ritically ill COVID-19 patients remains to be explored in large clinical trials.

Deformation analysis in post-hospitalised patients with moderate SARS-CoV-2 infection

Abstract Funding Acknowledgements Type of funding sources: None. Background SARS-CoV-2 infection is associated with multiple cardiac manifestations (1,2). Global longitudinal strain (GLS) by speckle tracking echocardiography (STE) is a novel transthoracic echocardiography (TTE) measure of myocardial deformation, which could early recognize subclinical cardiac injury in COVID-19 patients (3,4). Purpose We aimed to explore GLS profiles in post-hospitalized COVID-19 patients to identify features of eventual subclinical cardiac injury and to investigate the possible correlation with the severity of infection. Methods We enrolled 33 patients (mean age 59.2 ± 13, 64% men) with positive SARS-CoV-2 RT-PCR, hospitalized for moderate COVID-19 disease, with no admission to intensive care unit. Patients were submitted to TTE 1-2 months after discharge. Images were anonymised and analysed offline by two accredited cardiologists. Clinical parameters and laboratory findings from hospitalization were also collected. Acute myocardial infarction and pulmonary embolism were exclusion criteria. Results Mean duration of hospitalization was 12.9 ± 8.0 days. Study population had normal systolic function with a mean LV ejection fraction 58.6% (±3.6) while the majority of patients had relative low values of LV global longitudinal strain, mean 15.2% (±2.3). Arterial hypertension was present in 51.5% of patients and a history of previous myocardial infarction was referred in 6.1% of the population. Only 24.2% of patients had elevated troponin levels during the previous in-hospital period (mean maximal value of hs-troponin was 18.1 ±16.6 pg/mL) whereas 81.8% had abnormal D-Dimers values (mean 2424 μg /L, range ±2825) and 93.1% had high hs-CRP values (138.2 ±92.0 mg/L) . Duration of hospitalization had strong significant correlation with D-Dimers (rho: 0.708, p: &amp;lt;0.001) and hs CRP (rho:0383, p:0.028) and marginal association with troponin ( rho: 0.335, p:0.056). Moreover, global longitudinal strain showed significant association with duration of hospitalization (rho:-0.545, p: 0.007). Traditional systolic indices as LVEF and the various diastolic parameters showed no significant association with severity of disease reflected by the duration of hospitalization and the other clinical and laboratory biomarkers. Conclusion Cardiac manifestations of SARS-CoV-2 infections could be present in mild to moderate disease and seems to associate with the severity of infection. The novel echocardiographic parameters such as GLS could add valuable information and identify possible subclinical cardiac injury often unrecognized by traditional TTE examination.

Subclinical LV and RV Dysfunction in Patients Recovered From COVID-19

Cardiac injury is reported acutely in hospitalised COVID-19 patients, however sustained impairment in recovered patients is unclear. We evaluated cardiac involvement in patients who had recovered from acute COVID-19 infection but had ongoing symptoms, using echocardiography (TTE). Forty-two patients with recovered COVID-19 were followed up at a median time from infection of 112 [109] days and were compared to age and gender-matched healthy controls. Traditional TTE parameters left ventricular (LV), 2D global longitudinal strain (GLS), and right ventricular (RV) free wall strain were measured. Among COVID patients, 10 (23.8%) were hypertensive, 6 (14.3%) diabetic, 2 (4.8%) had atrial fibrillation and 1 (2.4%) a history of IHD. LV wall thickness was significantly higher in the COVID-19 group (Table). LV volumes and LVEF were similar to controls; however, LV GLS was significantly worse in the COVID-19 cohort (p=0.002, Table). Similarly, RV volumes and traditional function parameters (FAC, TAPSE, S’ velocity) were similar, but RV free wall strain (RVFWS, p=0.009) and RV global strain (p=0.015) were reduced. On univariant analysis, COVID-19 infection, sex, admission to ICU, LV volume and mass and RV area were associated with LV GLS. On multivariant analysis, COVID-19 infection was the only independent determinant of LV GLS (β=0.269, p=0.008). Prior COVID-19 infection was the only independent determinant of reduced LV GLS, suggesting persisting subclinical cardiac injury even in recovered patients with ongoing symptoms.Tabled 1ParametersControlsCOVID-19p valuePW ED (mm)8.12±1.648.76±1.560.029IVS ED (mm)8.17±1.829.17±1.890.002LVEDVI (ml/m2)47.10±10.8946.70±17.280.867LVESVI (ml/m2)19.25±5.1418.91±9.210.782LVEF (%)59.40±5.2760.19±5.430.427LV GLS (%)-19.86±1.90-18.33±2.430.002TAPSE (mm)22.41±3.7721.48±4.650.300RVS' (cm/s)11.51±1.6011.93±2.090.359RV FAC (%)40.81±6.7039.79±7.980.352RVFWS (%)-27.32±4.56-24.05±5.890.009 Open table in a new tab

Acute Kidney Injury in Cardiac Surgery with Cardiopulmonary Bypass

Changes in classification criteria and active introduction of biomarkers of acute kidney injury (KDIGO, 2012) are changing approaches to diagnosis and treatment of postoperative renal dysfunction including cardiac surgery patients operated with cardiopulmonary bypass (CPB). The objective: to compare the detection rate of AKI after surgery with CPB with the use of biomarkers and kidney disease improving global outcomes criteria, as well as to evaluate the cause and localization of structural changes of the nephron.Subjects and Methods. A monocenter observational study among elective cardiac surgery patients (n = 97) was conducted. Inclusion criteria: age over 18 years, duration of surgery (coronary bypass surgery, prosthetic heart valves) from 90 to 180 minutes, no signs of end stage kidney disease. AKI was diagnosed based on changes in serum creatinine and biomarkers (NGAL, IgG, albumin in urine). The studied parameters were recorded 15 minutes after the start and end of anesthesia, as well as 24 and 48 hours after surgery. Retrospectively, the group was divided into three subgroups: 1) patients without AKI after surgery; 2) patients in whom signs of AKI were detected after 24 hours but regressed by the 48th hour; 3) patients in whom AKI persisted during all 48 hours of follow-up.Results. 24 hours after surgery, AKI based on KDIGO criteria was recorded in 56.3% of patients. Using biomarkers, signs of tubular damage (NGAL) at the end of anesthesia were detected in 95.9% of patients; after 24 hours, they were registered in 73.2% of cases. In a subgroup where AKI persisted for more than 24 hours, glomeruli were damaged in addition to tubules which was manifested not only by selective but also by non-selective proteinuria. The duration of CPB, hemodilution (Hb &lt; 90 g/l), the release of free hemoglobin in the blood (&gt; 1.5 mg/l) at low (&lt; 1 g/l) values of haptoglobin were significantly associated with AKI development.Conclusion. The KDIGO criteria do not allow detecting a subclinical form of renal dysfunction which may occur in about 40% of patients after surgery with CPB. AKI can be caused by damage to both the tubular part of the nephron and glomeruli in cases of prolonged CPB with the development of hemolysis, the release of free hemoglobin in the blood, and persisting anemia at the end of the surgery. The NGAL assessment makes it possible to detect subclinical kidney injury in the absence of elevated serum creatinine levels.

Clinical outcomes from the Assessing Donor-derived cell-free DNA Monitoring Insights of kidney Allografts with Longitudinal surveillance (ADMIRAL) study

The use of routine monitoring of donor-derived cell-free DNA (dd-cfDNA) after kidney transplant may allow clinicians to identify subclinical allograft injury and intervene prior to development of clinically evident graft injury. To evaluate this, data from 1092 kidney transplant recipients monitored for dd-cfDNA over a three-year period was analyzed to assess the association of dd-cfDNA with histologic evidence of allograft rejection. Elevation of dd-cfDNA (0.5% or more) was significantly correlated with clinical and subclinical allograft rejection. dd-cfDNA values of 0.5% or more were associated with a nearly three-fold increase in risk development of de novo donor-specific antibodies (hazard ratio 2.71) and were determined to be elevated a median of 91 days (interquartile range of 30-125 days) ahead of donor specific antibody identification. Persistently elevated dd-cfDNA (more than one result above the 0.5% threshold) predicted over a 25% decline in the estimated glomerular filtration rate over three years (hazard ratio 1.97). Therefore, routine monitoring of dd-cfDNA allowed early identification of clinically important graft injury. Biomarker monitoring complemented histology and traditional laboratory surveillance strategies as a prognostic marker and risk-stratification tool post-transplant. Thus, persistently low dd-cfDNA levels may accurately identify allograft quiescence or absence of injury, paving the way for personalization of immunosuppression trials.

Emerging biomarkers in kidney transplantation and challenge of clinical implementation.

Despite improvement in short-term outcomes after kidney transplantation, long-term outcomes remain suboptimal. Conventional biomarkers are limited in their ability to reliably identify early immunologic and nonimmunologic injury. Novel biomarkers are needed for noninvasive diagnosis of subclinical injury, prediction of response to treatment, and personalization of the care of kidney transplant recipients. Recent biotechnological advances have led to the discovery of promising molecular biomarker candidates. However, translating potential biomarkers from bench to clinic is challenging, and many potential biomarkers are abandoned prior to clinical implementation. Despite these challenges, several promising urine, blood, and tissue novel molecular biomarkers have emerged and are approaching incorporation into clinical practice. This article highlights the challenges in adopting biomarker-driven posttransplant management and reviews several promising emerging novel biomarkers that are approaching clinical implementation.

Abstract 10334: The Association of Trimethylamine N-oxide (TMAO) with Findings of Vascular Brain Injury on Magnetic Resonance Imaging in the Cardiovascular Health Study (CHS)

Introduction: Findings on MRI of vascular brain injury, such as brain infarcts and white matter hyperintensities, are chronic manifestation of atherosclerosis. A gut-microbiome-generated metabolite, trimethylamine N-oxide (TMAO), is an independent predictor of clinical cardiovascular events. However, no study has examined associations between TMAO and subclinical vascular brain injury in the general population. Hypothesis: TMAO levels are positively associated with evidence of progressive subclinical vascular brain injury on serial MRI scans with incident brain infarcts and white matter worsening. Methods: The Cardiovascular Health Study (CHS) is a community-based prospective cohort study in adults aged &gt;65 years. Plasma TMAO was measured using mass spectrometry from samples collected in 1992-1993 and 1996-1997. Brain MRI was performed at 1991-1994 and again at 1997-1999. White matter was graded on a 10-point scale, higher being worse, and white matter worsening (WMW) was defined by an increase of least one point comparing initial and follow up scans. In these analyses, participants with prior TIA or stroke were excluded. Those with serum TMAO and both MRI scans were included: n=1196 for incident brain infarct and n=1553 for white matter worsening. Logistic regression was used for the association of baseline TMAO levels and incident brain infarcts, and Poisson regression, for the change in TMAO levels and WMW. Models were adjusted for age, sex, race, alcohol use, intake of meat and vegetable, and vascular risk factors. Results: Between the two MRI scans, 191(15.9%) participants had subclinical incident brain infarcts, and 423 (27.2%) participants had WMW. Comparing the highest vs. lowest quartile, the first TMAO were not significantly associated with incident brain infarcts: odds ratio 0.78 (95% CI: 0.49 to 1.25). Again comparing the highest vs. lowest quartile, changes in TMAO were not associated with WMW: 1.08 (0.77 to 1.51). Conclusions: Baseline and changes in plasma TMAO levels were not associated with findings of subclinical vascular brain injury on MRI in older US adults. The associations of TMAO with the adverse clinical events seen in prior clinical samples of patients were not seen at the subclinical level in our population-based study.

Abstract 10763: Atrial Fibrillation and Supraventricular Ectopy in Relation to Brain Morphology and Subclinical Vascular Brain Injury: The Multi-Ethnic Study of Atherosclerosis

Introduction: Atrial fibrillation (AF) increases stroke risk and is associated with accelerated cognitive decline. Information is mixed about the relationship of AF and other supraventricular (SV) arrhythmias with brain changes on magnetic resonance imaging (MRI). Hypothesis: Prevalent AF and SV ectopy are associated with reduced gray matter (GM) volume and subclinical vascular brain injury. Methods: In the Multi-Ethnic Study of Atherosclerosis (MESA), participants completed Zio Patch monitoring and brain MRI. Prevalent AF was estimated from ambulatory monitoring, hospital surveillance, Medicare claims, and MESA electrocardiogram (ECG). For secondary analyses, AF was categorized into continuous - AF during 100% of monitoring - and intermittent - prevalent AF with &lt;100% AF during monitoring. Brain MRI measures included GM volume, white matter (WM) lesion volume, WM fractional anisotropy, and presence of cerebral microbleeds (CMBs). Linear and Poisson regression analyses were adjusted for cardiovascular risk factors and socioeconomic status. Results: In MESA, 967 participants without a history of stroke or transient ischemic attack (TIA) completed &gt;24 hours of ECG monitoring (median, 14.0 days) and completed brain MRI a median 17 months later. Mean (standard deviation) age was 72 (8) years; 53% were women. A total of 116 participants had prevalent AF, of whom 20 had continuous AF. Compared with no AF, prevalent AF was associated with lower WM FA (-0.22 standard deviations, 95% CI: -0.39, -0.04) and higher prevalence of CMBs (prevalence ratio: 1.46, 95% CI: 1.18, 1.80). In secondary analyses, compared with no AF, continuous but not intermittent AF was associated with lower GM volume (-18.6 mL, 95% CI: -31.4, -5.8). Rates of premature atrial contractions and runs of SV tachycardia were not significantly associated with brain MRI measures. Conclusions: In a multi-ethnic sample free of a history of stroke or TIA, prevalent AF was associated with lower WM FA, a measure of WM injury, and presence of CMBs. These results highlight the importance of AF prevention for brain health. Further analysis of subclinical infarcts is needed in this sample, and study in other settings is needed to confirm whether greater AF burden is associated with reduced GM volume.

ATRvD1 Attenuates Renal Tubulointerstitial Injury Induced by Albumin Overload in Sepsis-Surviving Mice.

Novel strategies for the prevention and treatment of sepsis-associated acute kidney injury and its long-term outcomes have been required and remain a challenge in critical care medicine. Therapeutic strategies using lipid mediators, such as aspirin-triggered resolvin D1 (ATRvD1), can contribute to the resolution of acute and chronic inflammation. In this study, we examined the potential effect of ATRvD1 on long-term kidney dysfunction after severe sepsis. Fifteen days after cecal ligation and puncture (CLP), sepsis-surviving BALB/c mice were subjected to a tubulointerstitial injury through intraperitoneal injections of bovine serum albumin (BSA) for 7 days, called the subclinical acute kidney injury (subAKI) animal model. ATRvD1 treatment was performed right before BSA injections. On day 22 after CLP, the urinary protein/creatinine ratio (UPC), histologic parameters, fibrosis, cellular infiltration, apoptosis, inflammatory markers levels, and mRNA expression were determined. ATRvD1 treatment mitigated tubulointerstitial injury by reducing proteinuria excretion, the UPC ratio, the glomerular cell number, and extracellular matrix deposition. Pro-fibrotic markers, such as transforming growth factor β (TGFβ), type 3 collagen, and metalloproteinase (MMP)-3 and -9 were reduced after ATRvD1 administration. Post-septic mice treated with ATRvD1 were protected from the recruitment of IBA1+ cells. The interleukin-1β (IL-1β) levels were increased in the subAKI animal model, being attenuated by ATRvD1. Tumor necrosis factor-α (TNF-α), IL-10, and IL-4 mRNA expression were increased in the kidney of BSA-challenged post-septic mice, and it was also reduced after ATRvD1. These results suggest that ATRvD1 protects the kidney against a second insult such as BSA-induced tubulointerstitial injury and fibrosis by suppressing inflammatory and pro-fibrotic mediators in renal dysfunction after sepsis.

Particulate and drug-induced toxicity assessed in novel quadruple cell human primary hepatic disease models of steatosis and pre-fibrotic NASH

In an effort to replace, reduce and refine animal experimentation, there is an unmet need to advance current in vitro models that offer features with physiological relevance and enhanced predictivity of in vivo toxicological output. Hepatic toxicology is key following chemical, drug and nanomaterials (NMs) exposure, as the liver is vital in metabolic detoxification of chemicals as well as being a major site of xenobiotic accumulation (i.e., low solubility particulates). With the ever-increasing production of NMs, there is a necessity to evaluate the probability of consequential adverse effects, not only in health but also in clinically asymptomatic liver, as part of risk stratification strategies. In this study, two unique disease initiation and maintenance protocols were developed and utilised to mimic steatosis and pre-fibrotic NASH in scaffold-free 3D liver microtissues (MT) composed of primary human hepatocytes, hepatic stellate cells, Kupffer cells and sinusoidal endothelial cells. The characterized diseased MT were utilized for the toxicological assessment of a panel of xenobiotics. Highlights from the study included: 1. Clear experimental evidence for the pre-existing liver disease is important in the augmentation of xenobiotic-induced hepatotoxicity and 2. NMs are able to activate stellate cells. The data demonstrated that pre-existing disease is vital in the intensification of xenobiotic-induced liver damage. Therefore, it is imperative that all stages of the wide spectrum of liver disease are incorporated in risk assessment strategies. This is of significant consequence, as a substantial number of the general population suffer from sub-clinical liver injury without any apparent or diagnosed manifestations.

Estimated glomerular filtration rate may be an independent predictor for clinical outcomes regardless of acute kidney injury complication in the emergency department.

Study objectiveAcute kidney injury (AKI), chronic kidney disease (CKD), and decreased estimated glomerular filtration rate (eGFR) are all associated with poor clinical outcomes among emergency department (ED) patients. This study aimed to evaluate the effect of different types of renal dysfunction and the degree of eGFR reduction on the clinical outcomes in a real-world ED setting.MethodsAdult patients with an eGFR lower than 60 mL/min/1.73m2 in our ED, from October 1, 2016, to December 31, 2016, were enrolled in this retrospective observational study. Besides AKI and CKD, patients with unknown baseline renal function before an ED visit were categorized in the undetermined renal dysfunction (URD) category.ResultsAmong 1495 patients who had eGFR evaluation at ED, this study finally enrolled 441 patients; 22 patients (5.0%) had AKI only, 32 (7.3%) had AKI on CKD, 196 (44.4%) had CKD only, 27 (6.1%) had subclinical kidney injury (those who met neither criteria for AKI nor CKD), and 164 (37.2%) had URD. There was a significant association between eGFR and critical illness defined as the composite outcome of death or intensive care unit (ICU) need, hospitalization, ICU need, death, and renal replacement therapy need (odds ratio [95% confidence interval]: 1.72 [1.45–2.05], 1.36 [1.16–1.59], 1.66 [1.39–2.00], 1.73 [1.32–2.28], and 2.71 [1.73–4.24] for every 10 mL/min/1.73m2 of reduction, respectively). Multivariate logistic regression analysis showed eGFR was an independent predictor of critical illness composite outcome (death or ICU need), hospitalization, and ICU need even after adjustment with AKI or URD.ConclusionsEstimated GFR may be a sufficient predictor of clinical outcomes of ED patients regardless of AKI complication. Considerable ED patients were determined as URD, which might have a significant impact on the ED statistics regarding renal dysfunction.

РОЛЬ НОВЫХ БИОМАРКЕРОВ В ВЫЯВЛЕНИИ ОСТРОГО ПОВРЕЖДЕНИЯ ПОЧЕК У БОЛЬНЫХ В КРИТИЧЕСКОМ СОСТОЯНИИ

Acute kidney injury is a polyetiologic syndrome that is a sudden decrease in kidney function over several days or weeks, causing the accumulation of nitrogenous compounds in the blood, with or without a decrease in urine output. Acute kidney injury is common in hospitalized patients and is associated with increased morbidity, mortality, and financial costs. Currently, acute kidney injury is diagnosed after the onset of symptoms; Available diagnostic tests (presence of creatinine in the blood, microscopy of urine, urine volume) have shortcomings in identifying subclinical acute kidney injury. The lack of therapeutic strategies leads to the fact that the treatment of acute kidney injury is carried out with the help of supportive therapies. Early acute kidney injury detection is essential to minimize damage. Experimental and clinical studies have identified a new biomarker that contribute to the earlier diagnosis of acute kidney injury. With their help, it can be determined that patients are at risk of acute kidney damage. In this review, the authors describe some of the most promising new AKI biomarkers (neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule (KIM-1), interleukin-18 (IL18), tissue inhibitor of metalloproteinase-2 (TIMP-2), protein -7, which binds insulin-like growth factor (IGFBP7)).

Urinary neutrophil gelatinase-associated lipocalin—an early biomarker for renal injury in patients with beta-thalassemia major

INTRODUCTION : The iron overload and the development of secondary hemosiderosis in patients with β-thalassemia major (β-TM) lead to organ damages, including kidney disorders from early childhood. Contemporary urinary markers such as neutrophil gelatinase-association lipocalin (NGAL), β2-microglobulin (β2-MG), and N-acetyl-β-D-glucosaminidase (NAG) could be a useful tool for clinicians in diagnosis of early tubular lesions. AIM : The aim of this article is to make an assessment of contemporary urine biomarkers β2-microglobulin, neutrophil gelatinase-associated lipocalin, and N-acetyl-beta-D-glucosaminidase in the diagnosis of early renal injury in patients with β-TM. MATERIALS AND METHODS : The current study was conducted by examining 44 patients with β-thalassemia major and 30 controls. All participants were tested for NGAL, β2-MG, and NAG in the first sample morning urine using ELISA method. RESULTS : The results show statistically significant differences between the two examined groups in urinary NGAL. CONCLUSION : Urinary NGAL indicates subclinical kidney injury when the tubular reabsorption of molecules is impaired.