Galectin-3 and soluble CD146 identify cardiorenal injuries in severe burn patients: a biomarker-based approach.

INTRODUCTION: Acute kidney injury (AKI) and myocardial injury (MI) are severe conditions in patients with severe burn injury, and combination of both is even worst and is called the cardiorenal syndrome (CRS). Identifying a distinct cardiorenal phenotype could significantly enhance the management of these patients. Galectin-3 (Gal3) and soluble CD146 (sCD146) are biomarkers for renal and cardiac injuries. This study aims to assess the occurrence and reliability of these biomarkers in recognizing CRS in individuals who have been severely burn. METHODS: This study is a single-center prospective proof of concept study involving patients with severe burn injuries. Plasma samples for Gal3 and sCD146 measurements were collected daily during the initial 7 days following admission. CRS was defined after 24h of admission by the association of AKI stage 1 or more (KDIGO definition) and MI defined on high sensitive troponine (hsTnT) (variation > 20 % baseline value or absolute value > 40 ng/mL). RESULTS: Forty patients met the inclusion criteria and were included in this study. Thirty-eight patients had CRS. The pooled values of Gal3, or combination of Gal3 and sCD146 values following 7 days after admission were associated with CRS with an OR of 1.145 [CI 95% (1.081-1.211)], p < 0.001, and 1.147 [CI 95% (1.085-1.212)], p < 0.001, respectively. Gal3 values at admission (D0) had a predictive performance for CRS with an AUC of 0.78 [CI 95% (0.63-0.93)], and this performance improved when using the combination of Gal3 and sCD146 values at admission (D0), with an AUC of 0.81 [CI 95% (0.66-0.96)]. Gal3 levels during the first 7 days were associated with patients experiencing AKI and no MI, with an Odds Ratio (OR) of 1.129 [CI 95% (1.065-1.195)], p < 0.001 and MI without AKI with an OR of 1.095 [CI 95% (1.037-1.167)], p < 0.001. sCD146 alone was not associated with AKI without MI or MI without AKI and was poorly associated with CRS. CONCLUSION: In severely burned patients, cardiorenal syndrome is a frequent and severe condition. Gal3 values during the first 7 days following admission were associated with cardiorenal syndrome. The use of sCD146 with Gal3 improved prediction performance for CRS identification. The use of such biomarkers to identify cardiorenal syndrome is important and needs to be confirmed in other studies.

Evolution, control and success of combination therapy with Ampicilin-sulbactam/Ceftazidime-Avibactam during a Carbapenem-Resistant Acinetobacter baumannii outbreak in burn Intensive Care Unit.

We present our findings on interpatient transmission, epidemic control measures, and the outcomes of a series of ten critically ill burn patients who were either colonized or infected with carbapenem-resistant Acinetobacter baumannii (CRAB). None of the five infected patients achieved clinical cure, and all experienced relapses. Microbiological failure was observed in 40% of the infected patients. The isolated CRAB strains were found to carry blaOXA-23 and armA resistance genes. Despite the lack of clinical cure, all five infected patients survived and were discharged from the Burn Intensive Care Unit.

A Real-World Study of Nusinersen Effects in Adults with Spinal Muscular Atrophy Type 2 and 3.

BACKGROUND: Spinal muscular atrophy (SMA) is a progressive genetic disorder characterized by muscle weakness ultimately leading to pulmonary impairments that can be fatal. The recent approval of nusinersen, a disease-modifying therapy, substantially changed the prognosis for patients, particularly in children. However, real-world evidence about its long-term effectiveness in adults remains limited. This study aimed to document longitudinal data on motor function, pulmonary function and patient-reported outcome measures of Canadian adults with SMA type 2 and 3 treated with nusinersen. METHODS: Outcomes from 17 patients were collected at the Institut de réadaptation en déficience physique de Québec during routine clinical visits over 36 months post nusinersen treatment, using the Hammersmith Functional Motor Scale Expanded for SMA (HFMSE), Revised Upper Limb Module (RULM), 6-Minute Walk Test (6MWT), Children's Hospital of Philadelphia Adult Test of Neuromuscular Disorders (CHOP-ATEND), SMA functional rating scale (SMAFRS), pulmonary function testing and subjective changes reported by patients. RESULTS: After 36 months, 9 patients showed motor function improvement. Changes beyond the minimal clinically important difference were seen for four patients on the HFMSE, four patients on the RULM and five patients on the 6MWT. Pulmonary function remained stable for most subjects. Subjective positive changes were reported in 88% of patients and five patients showed improvement in the SMAFRS. CONCLUSION: This real-world study demonstrates the positive effects of nusinersen in adults with SMA types 2 and 3. Although stabilizing the patient's condition is considered therapeutic success, this study shows an improvement in motor function and subjective gains in several patients.

Early post-operative lactate increase following kidney transplant is associated with delayed graft function: A retrospective cohort study.

INTRODUCTION: Delayed graft function (DGF) is a frequent complication following kidney transplant. This study aimed to assess the association between early post-operative lactate variation and DGF. METHODS: This was a single center, retrospective cohort study between February 2021 and December 2022 in Saint-Louis Hospital (APHP, France). Venous lactate levels were measured immediately (H0) and 4 h (H4) after kidney transplant. The primary outcome was the occurrence of DGF (need for renal replacement therapy between transplantation and day 7). Secondary outcome was the occurrence of complications (i.e., death, vascular thrombosis, hemorrhagic shock, urological complications (hematoma, urinoma), local or systemic infection) between transplant and day 7. RESULTS: Two hundred 12 patients were included, and 38 (17.9%) developed DGF. Venous lactate variation between H0 and H4 was higher in patients who developed DGF (-30 (IQR -83, -6)% vs. -15 (IQR -62, -11)%, p = .037), but the variation of level was more often positive (corresponding to an increased lactate production over time between H0 and H4) in patients who developed DGF ((28(85%) vs. 94(62%), p = .011). In multivariate logistic regression, positive venous lactate level variation between H0 and H4 was strongly associated with a reduced risk of developing DGF (OR .30 [.09-.79], p = .024). We did not find any association between post-operative hyperlactatemia and occurrence of complications between transplant and day 7. DISCUSSION: DGF is a frequent complication following kidney transplantation. Its early prediction could help physicians optimize treatment and protect the kidney. Early venous lactate variation after kidney transplant could help to predict the occurrence of DGF.

The role of CD146 in renal disease: from experimental nephropathy to clinics.

Vascular endothelial dysfunction is a major risk factor in the development of renal diseases. Recent studies pointed out a major interest for the inter-endothelial junction protein CD146, as its expression is modulated during renal injury. Indeed, some complex mechanisms involving this adhesion molecule and its multiple ligands are observed in a large number of renal diseases in fundamental or clinical research. The purpose of this review is to summarize the most recent literature on the role of CD146 in renal pathophysiology, from experimental nephropathy to clinical trials.

Subclinical and clinical acute kidney injury share similar urinary peptide signatures and prognosis.

PURPOSE: Acute kidney injury (AKI) is a frequent and severe condition in intensive care units (ICUs). In 2020, the Acute Dialysis Quality Initiative (ADQI) group proposed a new stage of AKI, referred to as stage 1S, which represents subclinical disease (sAKI) defined as a positive biomarker but no increase in serum creatinine (sCr). This study aimed to determine and compare the urinary peptide signature of sAKI as defined by biomarkers. METHODS: This is an ancillary analysis of the prospective, observational, multinational FROG-ICU cohort study. AKI was defined according to the Kidney Disease Improving Global Outcome definition (AKIKDIGO). sAKI was defined based on the levels of the following biomarkers, which exceeded the median value: neutrophil gelatinase-associated lipocalin (pNGAL, uNGAL), cystatin C (pCysC, uCysC), proenkephalin A 119-159 (pPENKID) and liver fatty acid binding protein (uLFABP). Urinary peptidomics analysis was performed using capillary electrophoresis-mass spectrometry. Samples were collected at the time of study inclusion. RESULTS: One thousand eight hundred eighty-five patients had all biomarkers measured at inclusion, which included 1154 patients without AKI (non-AKIKDIGO subgroup). The non-AKIKDIGO subgroup consisted of individuals at a median age of 60 years [48, 71], among whom 321 (27.8%) died. The urinary peptide signatures of sAKI, regardless of the biomarkers used for its definition, were similar to the urinary peptide signatures of AKIKDIGO (inflammation, haemolysis, and endothelial dysfunction). These signatures were also associated with 1-year mortality. CONCLUSION: Biomarker-defined sAKI is a common and severe condition observed in patients within intensive care units with a urinary peptide signature that is similar to that of AKI, along with a comparable prognosis.

Radiomic analysis of abdominal organs during sepsis of digestive origin in a French intensive care unit.

BACKGROUND: Sepsis is a severe and common cause of admission to the intensive care unit (ICU). Radiomic analysis (RA) may predict organ failure and patient outcomes. The objective of this study was to assess a model of RA and to evaluate its performance in predicting in-ICU mortality and acute kidney injury (AKI) during abdominal sepsis. METHODS: This single-center, retrospective study included patients admitted to the ICU for abdominal sepsis. To predict in-ICU mortality or AKI, elastic net regularized logistic regression and the random forest algorithm were used in a five-fold cross-validation set repeated 10 times. RESULTS: Fifty-five patients were included. In-ICU mortality was 25.5%, and 76.4% of patients developed AKI. To predict in-ICU mortality, elastic net and random forest models, respectively, achieved areas under the curve (AUCs) of 0.48 (95% confidence interval [CI], 0.43-0.54) and 0.51 (95% CI, 0.46-0.57) and were not improved combined with Simplified Acute Physiology Score (SAPS) II. To predict AKI with RA, the AUC was 0.71 (95% CI, 0.66-0.77) for elastic net and 0.69 (95% CI, 0.64-0.74) for random forest, and these were improved combined with SAPS II, respectively; AUC of 0.94 (95% CI, 0.91-0.96) and 0.75 (95% CI, 0.70-0.80) for elastic net and random forest, respectively. CONCLUSIONS: This study suggests that RA has poor predictive performance for in-ICU mortality but good predictive performance for AKI in patients with abdominal sepsis. A secondary validation cohort is needed to confirm these results and the assessed model.

The Role of Connexin 43 in Renal Disease: Insights from In Vivo Models of Experimental Nephropathy.

Renal disease is a major public health challenge since its prevalence has continuously increased over the last decades. At the end stage, extrarenal replacement therapy and transplantation remain the only treatments currently available. To understand how the disease progresses, further knowledge of its pathophysiology is needed. For this purpose, experimental models, using mainly rodents, have been developed to unravel the mechanisms involved in the initiation and progression of renal disease, as well as to identify potential targets for therapy. The gap junction protein connexin 43 has recently been identified as a novel player in the development of kidney disease. Its expression has been found to be altered in many types of human renal pathologies, as well as in different animal models, contributing to the activation of inflammatory and fibrotic processes that lead to renal damage. Furthermore, Cx43 genetic, pharmacogenetic, or pharmacological inhibition preserved renal function and structure. This review summarizes the existing advances on the role of this protein in renal diseases, based mainly on different in vivo animal models of acute and chronic renal diseases.

Galectin-3 in Kidney Diseases: From an Old Protein to a New Therapeutic Target.

Galectin-3 (Gal-3) is a 30KDa lectin implicated in multiple pathophysiology pathways including renal damage and fibrosis. Gal-3 binds ß-galactoside through its carbohydrate-recognition domain. From intra-cellular to extra-cellular localization, Gal-3 has multiple roles including transduction signal pathway, cell-to-cell adhesion, cell to extracellular matrix adhesion, and immunological chemoattractant protein. Moreover, Gal-3 has also been linked to kidney disease in both preclinical models and clinical studies. Gal-3 inhibition appears to improve renal disease in several pathological conditions, thus justifying the development of multiple drug inhibitors. This review aims to summarize the latest literature regarding Gal-3 in renal pathophysiology, from its role as a biomarker to its potential as a therapeutic agent.

Blunt Traumatic Aortic Injury Management, a French TraumaBase Analytic Cohort.

OBJECTIVE: Blunt traumatic aortic injury (BTAI) in severe trauma patients is rare but potentially lethal. The aim of this work was to perform a current epidemiological analysis of the clinical and surgical management of these patients in a European country. METHODS: This was a multicentre, retrospective study using prospectively collected data from the French National Trauma Registry and the National Uniform Hospital Discharge Database from 10 trauma centres in France. The primary endpoint was the prevalence of BTAI. The secondary endpoints focused chronologically on injury characteristics, management, and patient outcomes. RESULTS: 209 patients were included with a mean age of 43 ± 19 years and 168 (80%) were men. The calculated prevalence of BTAI at hospital admission was 1% (162/15 094) (BTAI admissions/all trauma). The time to diagnosis increased with the severity of aortic injury and the clinical severity of the patients (grade 1: 94 [74, 143] minutes to grade 4: 154 [112, 202] minutes, p = .020). This delay seemed to be associated with the intensity of the required resuscitation. Sixty seven patients (32%) received no surgical treatment. Among those treated, 130 (92%) received endovascular treatment, 14 (10%) open surgery (two were combined), and 123 (85%) were treated within the first 24 hours. Overall mortality was 20% and the attributed cause of death was haemorrhagic shock (69%). Mortality was increased according to aortic injury severity, from 6% for grade 1 to 65% for grade 4 (p < .001). Twenty-six (18.3%) patients treated by endovascular aortic repair had complications. CONCLUSION: BTAI prevalence at hospital admission was low but occurred in severe high velocity trauma patients and in those with a high clinical suspicion of severe haemorrhage. The association of shock with high grade aortic injury and increasing time to diagnosis suggests a need to optimise early resuscitation to minimise the time to treatment. Endovascular treatment has been established as the reference treatment, accounting for more than 90% of interventional treatment options for BTAI.

Acute Kidney Injury Induces Remote Cardiac Damage and Dysfunction Through the Galectin-3 Pathway.

Acute kidney injury is associated with increased risk of heart failure and mortality. This study demonstrates that acute kidney injury induces remote cardiac dysfunction, damage, injury, and fibrosis via a galectin-3 (Gal-3) dependent pathway. Gal-3 originates from bone marrow-derived immune cells. Cardiac damage could be prevented by blocking this pathway.

Prediction of major adverse kidney events in critically ill burn patients.

OBJECTIVE: We aimed at assessing the predictive value of plasmatic Neutrophil Gelatinase Associated Lipocalin (pNGAL) at admission and severity scores to predict major adverse kidney events (MAKE, defined as death and/or need for renal replacement therapy (RRT) and/or non-renal recovery at day 90) in critically ill burn patients. MATERIAL AND METHODS: Single-center cohort study in a burn critical care unit in a tertiary center, including all consecutive severely burn patients (total burned body surface >20%) from January 2012 until January 2015 with a pNGAL dosage at admission. Reclassification of patients was assessed by Integrated Discrimination Improvement (IDI). MEASUREMENTS AND RESULTS: 87 patients were included. Mean age was 47.7 (IQ 25-75: 33.4-65.2) years; total burn body surface area was 40 (IQ 25-75: 30-55) % and ICU mortality 36%. 39 (44.8%) patients presented a MAKE, 32 (88.9%) patients died at day 90. pNGAL was higher in the MAKE group (423 [IQ 25-75: 327-518]pg/mL vs 184 [IQ 25-75: 147-220]pg/mL, p<0.001). In multivariate analysis, pNGAL and abbreviated burn severity index (ABSI) remained associated with MAKE (OR 1.005 [CI 95% 1.0005-1.009], p=0.03 and OR 1.682 [CI95%1.038-2.726], p=0.035 respectively). Adding pNGAL to abbreviated burn severity index, simplified organ failure assessment and the simplified acute physiology score 2 did outperform clinical scores for the prediction of MAKE and AKI and for most severe forms of AKI and allowed a statistically significant reclassification of patients compared to ABSI for MAKE, RRT, AKI at Day 7 and AKI during hospitalization with a number of patients needed to screen to detect one extra episode of MAKE was 44, 13 for severe AKI and 15 for AKI. CONCLUSIONS: pNGAL at admission is associated with the risk of MAKE in this population, and outperform severity scores when associated. Interventional studies are now needed to assess if impact of biomarkers-guided strategies would improve outcome.

Detection of Circulating Mucorales DNA in Critically Ill Burn Patients: Preliminary Report of a Screening Strategy for Early Diagnosis and Treatment.

BACKGROUND: Invasive wound mucormycosis (IWM) is associated with an extremely poor outcome among critically ill burn patients. We describe the detection of circulating Mucorales DNA (cmDNA) for the early diagnosis of IWM in those patients and report the potential value of detecting cmDNA for treatment guidance. METHODS: Severely ill burn patients admitted to our tertiary referral center between October 2013 and February 2016 were included. Retrospective plasma samples were tested for the presence of cmDNA by quantitative real-time polymerase chain reaction (qPCR). Patients were then prospectively screened twice a week, and liposomal amphotericin-B therapy initiated based on a positive qPCR. The primary endpoint was the time between cmDNA detection and standard diagnosis. Secondary endpoints were the time from cmDNA detection and treatment initiation and mortality. RESULTS: Seventy-seven patients (418 samples) were included. The average age was 46 (28-60) years, abbreviated burn severity index was 8 (7-10), and simplified acute physiology score was 33 (23-46). The total body surface area was 33% (22%-52%). cmDNA was detected 11 (4.5-15) days before standard diagnosis. The in-hospital mortality was 62% for patients with IWM and 24% for those without (P = .03). The mortality due to IWM was 80% during period A and 33% during period B (P = .46). CONCLUSIONS: This study suggests that the detection of cmDNA allows earlier diagnosis of IWM in severely ill burn patients and earlier initiation of treatment. Further studies are needed to confirm the impact of earlier treatment initiation on patient outcome.