Excess Soluble fms-like Tyrosine Kinase 1 Correlates With Endothelial Dysfunction and Organ Failure in Critically Ill Coronavirus Disease 2019 Patients.

Excess soluble fms-like tyrosine kinase 1 (sFlt-1), a soluble inhibitor of vascular endothelial growth factor pathway, has been demonstrated to promote endothelial dysfunction. Here, we demonstrate that sFlt-1 plasma levels correlate with respiratory symptom severity, expression of endothelial dysfunction biomarker, and incidence of organ failure in coronavirus disease 2019 patients. Clinical Trials Registration: NCT04394195.

AgeR deletion decreases soluble fms-like tyrosine kinase 1 production and improves post-ischemic angiogenesis in uremic mice.

Peripheral arterial disease occurs more frequently and has a worse prognosis in patients with chronic kidney disease (CKD). The receptor for advanced glycation end products (RAGE) is involved in multiple aspects of uremia-associated vasculopathy. Previous data suggest that the RAGE pathway may promote soluble fms-like tyrosine kinase 1 (sFlt1) production, an anti-angiogenic molecule. Thus, we tested the hypothesis that the deletion of AgeR would decrease sFlt1 production and improve post-ischemic revascularization in uremic condition. We used a well-established CKD model (5/6 nephrectomy) in WT and AgeR-/- C57/Bl6 mice. Hindlimb ischemia was induced by femoral artery ligation. Revascularization was evaluated by complementary approaches: ischemic limb retraction, LASCA imagery, and capillary density. The production of sFlt1 was assessed at both RNA and protein levels. After hindlimb ischemia, uremic mice showed slower functional recovery (p < 0.01), decreased reperfusion (p < 0.01), lower capillary density (p = 0.02), and increased circulating sFlt1 levels (p = 0.03). AgeR deletion restored post-ischemic angiogenesis and was protective from sFlt1 increase in uremic mice. These findings show the main role of RAGE in post-ischemic angiogenesis impairment associated with CKD. RAGE may represent a key target for building new therapeutic approaches to improve the outcome of CKD patients with PAD.

Intra-abdominal hypertension in early post-kidney transplantation period is associated with impaired graft function.

BACKGROUND: Moderate hyperhydration is often achieved in the early post-kidney transplantation period. Whether this strategy could lead to the development of intra-abdominal hypertension (IAH) has never been assessed so far. We aimed to study the incidence of IAH after kidney transplantation and its association with graft function recovery. METHODS: We conducted a prospective monocentric study among patients undergoing kidney transplantation at the University Hospital of Reims between May 2017 and April 2019. Intravesical pressure (IVP) was monitored every 8 h from Day 0 to 3. RESULTS: A total of 107 patients were enrolled. Among 55 patients included in the analysis, 74.5% developed IAH. Body mass index >25 kg/m2 was associated with IAH development {odds ratio [OR] 10.4 [95% confidence interval (CI) 2.0-52.9]; P = 0.005}. A previous history of peritoneal dialysis was protective [OR 0.06 (95% CI 0.01-0.3); P = 0.001]. IAH Grades III and IV occurred in 30.9% of patients and correlated with higher Day 3 creatininaemia (419.6 ± 258.5 versus 232.5 ± 189.4 µmol/L; P = 0.02), higher delayed graft function incidence (41.2 versus 7.9%; P = 0.04), lower Kirchner index measured using scintigraphy (0.47 ± 0.09 versus 0.64 ± 0.09; P = 0.0005) and decreased Day 30 estimated glomerular filtration rate (35.8 ± 18.8 versus 52.5 ± 21.3, P = 0.05). IAH patients had higher fluid balance (P = 0.02). Evolution of IVP correlated with weight gain (P < 0.01) and central venous pressure (P < 0.001). CONCLUSIONS: IAH is frequent after kidney transplantation and IAH Grades III and IV are independently associated with impaired graft function. These results question current haemodynamic objectives and raise for the first time interest in intra-abdominal pressure monitoring in these patients. CLINICAL TRIAL NOTATION: ClinicalTrials.gov identifier: NCT03478176.

Outcome of autosomal dominant polycystic kidney disease patients on peritoneal dialysis: a national retrospective study based on two French registries (the French Language Peritoneal Dialysis Registry and the French Renal Epidemiology and Information Network).

Background: Pathological features of autosomal dominant polycystic kidney disease (ADPKD) include enlarged kidney volume, higher frequency of digestive diverticulitis and abdominal wall hernias. Therefore, many nephrologists have concerns about the use of peritoneal dialysis (PD) in ADPKD patients. We aimed to analyse survival and technique failure in ADPKD patients treated with PD. Methods: We conducted two retrospective studies on patients starting dialysis between 2000 and 2010. We used two French registries: the French Renal Epidemiology and Information Network (REIN) and the French language Peritoneal Dialysis Registry (RDPLF). Using the REIN registry, we compared the clinical features and outcomes of ADPKD patients on PD (n = 638) with those of ADPKD patients on haemodialysis (HD) (n = 4653); with the RDPLF registry, those same parameters were determined for ADPKD patients on PD (n = 797) and compared with those of non-ADPKD patients on PD (n = 12 059). Results: A total of 5291 ADPKD patients and 12 059 non-ADPKD patients were included. Analysis of the REIN registry found that ADPKD patients treated with PD represented 10.91% of the ADPKD population. During the study period, PD was used for 11.2% of the non-ADPKD population. Compared with ADPKD patients on HD, ADPKD patients on PD had higher serum albumin levels (38.8 ± 5.3 versus 36.8 ± 5.7 g/dL, P < 0.0001) and were less frequently diabetic (5.31 versus 7.71%, P < 0.03). The use of PD in ADPKD patients was positively associated with the occurrence of a kidney transplantation but not with death [hazard ratio 1.15 (95% confidence interval 0.84-1.58)]. Analysis of the RDPLF registry found that compared with non-ADPKD patients on PD, ADPKD patients on PD were younger and had fewer comorbidities and better survival. ADPKD status was not associated with an increased risk of technique failure or an increased risk of peritonitis. Conclusions: According to our results, PD is proposed to a selected population of ADPKD patients, PD does not have a negative impact on ADPKD patients' overall survival and PD technique failure is not influenced by ADPKD status. Therefore PD is a reasonable option for ADPKD patients.

A diabetic ketoacidosis in a context of hyperglycemia addiction.

We herein present a case of a 20-year-old woman who suffered from type I diabetes mellitus and died from a diabetic ketoacidosis in a context of addiction to hyperglycemia. Diabetic ketoacidosis is a lethal complication of insulin-dependent diabetes mellitus, which can result from insulin therapy stoppage. This can occur voluntarily with suicidal intent or involuntarily due to treatment inaccessibility, forgotten injections, or material deficiency. A new possibility is investigated in our case study: hyperglycemia addiction. The patient was treated by insulin glargine and insulin aspartate. She regularly stopped insulin glargine injections seeking the asthenia sensation produced by hyperglycemia, keeping the insulin aspartate injections to treat the disabling symptom related to hyperketonemia.

Multiomic profiling of new-onset kidney function decline: insights from the STANISLAS study cohort with a 20-year follow-up.

Background: Identifying the biomarkers associated with new-onset glomerular filtration rate (GFR) decrease in an initially healthy population could offer a better understanding of kidney function decline and help improving patient management. Methods: Here we described the proteomic and transcriptomic footprints associated with new-onset kidney function decline in an initially healthy and well-characterized population with a 20-year follow-up. This study was based on 1087 individuals from the familial longitudinal Suivi Temporaire Annuel Non-Invasif de la Santé des Lorrains Assurés Sociaux (STANISLAS) cohort who attended both visit 1 (from 1993 to 1995) and visit 4 (from 2011 to 2016). New-onset kidney function decline was approached both in quantitative (GFR slope for each individual) and qualitative (defined as a decrease in GFR of >15 ml/min/1.7 m2) ways. We analysed associations of 445 proteins measured both at visit 1 and visit 4 using Olink Proseek® panels and 119 765 genes expressions measured at visit 4 with GFR decline. Associations were assessed using multivariable models. The Bonferroni correction was applied. Results: We found several proteins (including PLC, placental growth factor (PGF), members of the tumour necrosis factor receptor superfamily), genes (including CCL18, SESN3), and a newly discovered miRNA-mRNA pair (MIR1205-DNAJC6) to be independently associated with new-onset kidney function decline. Complex network analysis highlighted both extracellular matrix and cardiovascular remodelling (since visit 1) as well as inflammation (at visit 4) as key features of early GFR decrease. Conclusions: These findings lay the foundation to further assess whether the proteins and genes herein identified may represent potential biomarkers or therapeutic targets to prevent renal function impairment.

Aetiology, clinical features, diagnostic studies, and outcomes of community-acquired pneumonia in kidney transplant recipients admitted to hospital: a multicentre retrospective French cohort study.

OBJECTIVES: To assess the aetiology, clinical features, diagnostic studies and outcomes of community-acquired pneumonia (CAP) in a French cohort of hospitalized kidney transplant recipients. METHODS: We performed a retrospective, multicentre study in kidney transplant recipients admitted to ten French centres for CAP from January 2016 to December 2018. CAP discharge diagnoses were clinically and radiologically validated. We assessed a descriptive analysis of all confirmed CAP including medical ward and intensive care unit admissions. RESULTS: One hundred sixty-five CAP episodes in 132 patients were included. Median time from transplantation to admission was 6.4 (interquartile range, 1.6-12.3) years, with corticosteroid exposure in 112/165 (67.9%) cases. Sputum culture was performed in 47/165 (28.5%) cases including 7/47 (14.9%) positive samples. Bronchoscopy was performed in 87/165 (52.7%) cases with pathogens identified in 39/87 (44.8%) cases. Microbiological studies led to identifying a respiratory pathogen in 64/165 (38.8%) CAP episodes including 11/64 (17.2%) polymicrobial cases. Among these 64 episodes, 75 microorganisms were identified; 46/75 (61.3%) were core respiratory pathogens and 29/75 (38.7%) were opportunistic or drug-resistant organisms including Pneumocystis jirovecii 9/75 (12%), Pseudomonas aeruginosa 5/75 (6.7%), multidrug-resistant Enterobacteriaceae 4/75 (5.3%), and Aspergillus 4/75 (5.3%). Patients required intensive care unit admission in 26/165 (15.8%) episodes, invasive ventilation in 20/165 (12.1%) cases, and 22/165 (13.3%) needed in-hospital dialysis. DISCUSSION: CAP episodes occurred in kidney transplant recipients with a long history of immunosuppressive drug exposure. Diagnostic studies identified a microorganism in more than one-third of CAP episodes, including drug-resistant and opportunistic pathogens.

Associations of childhood adiposity with adult intima-media thickness and inflammation: a 20-year longitudinal population-based cohort.

BACKGROUND: The associations between childhood adiposity and adult increased carotid intima-media thickness (cIMT) have been well established, which might be corroborated by the association between adiposity in children and inflammation in adults. However, longitudinal data regarding biological pathways associated with childhood adiposity are lacking. METHODS: The current study included participants from the STANISLAS cohort who had adiposity measurements at age 5-18 years [ N  = 519, mean (SD) age, 13.0 (2.9) years; 46.4% male], and who were measured with cIMT, vascular-related and metabolic-related proteins at a median follow-up of 19 ±â€Š2 years. BMI, waist-to-height ratio and waist circumference were converted to age-specific and sex-specific z -scores. RESULTS: A minority of children were overweight/obese (16.2% overweight-BMI z -score >1; 1.3% obesity- z -score >2). Higher BMI, waist-height ratio and waist circumference in children were significantly associated with greater adult cIMT in univariable analysis, although not after adjusting for C-reactive protein. These associations were more pronounced in those with consistently high adiposity status from childhood to middle adulthood. Participants with higher adiposity during childhood (BMI or waist-height ratio) had higher levels of insulin-like growth factor-binding protein-1, protein-2, matrix metalloproteinase-3, osteopontin, hemoglobin and C-reactive protein in adulthood. Network analysis showed that IL-6, insulin-like growth factor-1 and fibronectin were the key proteins associated with childhood adiposity. CONCLUSION: In a population-based cohort followed for 20 years, higher BMI or waist-to-height ratio in childhood was significantly associated with greater cIMT and enhanced levels of proteins reflective of inflammation, supporting the importance of inflammation as progressive atherosclerosis in childhood adiposity.

Difficulties interpreting concentrations in fatal cases: example of 2,5-dimethoxy-4-chloroamphetamine.

PURPOSE: Death related to the use of drugs is evident when drugs are detected in biological matrices within toxic levels, but sometimes it can be less obvious. Intoxications after 2,5-dimethoxy-4-chloroamphetamine (DOC) use are occurring but up to date, only one fatality has been reported. Here we present the case of a young woman admitted to hospital as she presented vomiting, convulsions and cardiorespiratory arrest. METHODS: Blood ethanol concentration was determined using gas chromatography with flame ionization detection and toxicological screenings (blood, gastric content and hair samples) were performed using liquid chromatography with diode array detection, gas chromatography or liquid chromatography with mass spectrometry detection. RESULTS: Her health state declined with cardiac troubles, organs failure and cerebral edema till death occurring 4 days later. The autopsy revealed the presence of hemorrhagic infiltration inside the left ventricle, pulmonary edema and hemorrhagic infiltration of the terminal ileum. The analysis of biological fluids confirmed the presence of DOC (< 10 ng/mL in cardiac blood sample), buprenorphine, cocaine and cannabis metabolites. The analysis of hair highlighted a history of drugs abuse. CONCLUSION: In the absence of evident identified cause, the hypothesis of a death due to acute drugs use within a history of chronic consumption of drugs has been put forward. The concentration of some substances such as new psychoactive substances can be low in biological matrices but the toxic effects can be additive and lead to death even within young people, hence the importance of the knowledge of consumption history.

Impact of early mean arterial pressure level on severe acute kidney injury occurrence after out-of-hospital cardiac arrest.

BACKGROUND: The optimal early mean arterial pressure (MAP) level in terms of renal function remains to be established in patients with out-of-hospital cardiac arrest (OHCA). We aimed to evaluate the association between early MAP level and severe acute kidney injury (AKI) occurrence in patients with OHCA. RESULTS: In 568 consecutive patients, the percentage time spent below a predefined MAP threshold and the corresponding area below threshold (ABT) were calculated from continuous MAP measurement. Both MAP-derived variables were calculated for different MAP thresholds (65, 75 and 85 mmHg) and time periods (the first 6 and 12 after ICU admission). 274 (48%) patients developed severe AKI defined as stage 3 of KDIGO. Both ABT and percentage time were independently associated with severe AKI, regardless of the MAP threshold and time period considered. Highest adjusted odds ratios for developing severe AKI were observed while considering the first 6 h period. Within the first 6 h, every 100 mmHg-h increase in ABT under MAP thresholds of 65, 75 and 85 mmHg increased severe AKI risk by 69% (OR = 1.69; 95% CI 1.26-2.26; p < 0.01), 13% (OR = 1.13; 95% CI 1.07-1.20; p < 0.01) and 4% (OR = 1.04; 95% CI 1.02-1.06; p < 0.01), respectively. Every 10% increase in percentage time spent under MAP thresholds of 65, 75 and 85 mmHg increased severe AKI risk by 19% (OR = 1.19; 95% CI 1.06-1.33; p < 0.01), 12% (OR = 1.12; 95% CI 1.04-1.19; p < 0.01) and 8% (OR = 1.08; 95% CI 1.02-1.14; p < 0.01), respectively. CONCLUSIONS: Both severity and duration of early arterial hypotension after ICU admission remained associated with severe AKI occurrence while considering a MAP threshold as high as 85 mmHg after OHCA.

Impaired renal reserve contributes to preeclampsia via the kynurenine and soluble fms-like tyrosine kinase 1 pathway.

To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms-like tyrosine kinase 1 (sFLT1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. Maternal hypertension in UNx mice was associated with low plasma volumes, an increased rate of fetal resorption, impaired spiral artery remodeling, and placental ischemia. To evaluate potential mechanisms, we studied plasma metabolite changes using mass spectrometry and noted that l-kynurenine, a metabolite of l-tryptophan, was upregulated approximately 3-fold during pregnancy when compared with prepregnant concentrations in the same animals, consistent with prior reports suggesting a protective role for l-kynurenine in placental health. However, UNx mice failed to show upregulation of l-kynurenine during pregnancy; furthermore, when UNx mice were fed l-kynurenine in drinking water throughout pregnancy, their preeclampsia-like state was rescued, including a reversal of placental ischemia and normalization of sFLT1 levels. In aggregate, we provide a mechanistic basis for how impaired renal reserve and the resulting failure to upregulate l-kynurenine during pregnancy can lead to impaired placentation, placental hypoperfusion, an antiangiogenic state, and subsequent preeclampsia.

[How to explain glomerular filtration rate decrease in intra-abdominal hypertension?] / Comment expliquer la baisse du débit de filtration glomérulaire en cas d'hypertension intra-abdominale ?

Intra-abdominal hypertension (IAH) is a frequent and serious condition affecting critical care patients. IAH diagnostic needs intravesical pressure (IVP) measurement which is recommended for monitoring patients presenting IAH risk factors. IVP monitoring is probably insufficient in daily practice. This could be explained by lack of knowledge about IAH physiopathology, which leads to absence of therapeutic target. Acute kidney injury (AKI) is the earliest and most described organ dysfunction associated with IAH. Moreover, AKI gravity seems to correlates with IAH severity. Physiopathological aspects explaining glomerular filtration rate (GFR) decrease with IAH are probably multifactorial and not completely understood. The role of renal venous congestion is essential to explain AKI in IAH. GFR decrease may reflect a "glomerular capillary shunt" due to a decrease of renal plasmatic flow. Monitoring IVP in daily practice in patients presenting risk factors of IAH would improve knowledge about this condition and the associated AKI.

Outcome of polycystic kidney disease patients on peritoneal dialysis: Systematic review of literature and meta-analysis.

BACKGROUND: Polycystic kidney disease (PKD) is the most frequent hereditary cause of chronic kidney disease. Peritoneal dialysis (PD) is often avoided for patients with PKD because of the suspected risk of mechanical and infectious complications. Only a few studies have analyzed the outcome of PKD patients on PD with sometimes conflicting results. The purpose of this meta-analysis was to investigate outcomes of patients with PKD treated by PD. METHODS: A systematic review and meta-analysis were performed examining all studies which included "Polycystic kidney disease" and "Peritoneal dialysis" in their titles, excluding commentaries, letters to the authors and abstracts. PubMed, Embase, Google scholar and Scopus were searched to December 31st 2017. The primary outcome was overall patient survival. Additional outcomes were PD technique survival, incidence of peritonitis and incidence of abdominal wall hernia. RESULTS: 9 studies published between 1998 and 2016 were included for analysis with a total of 7,197 patients including 882 PKD patients. Overall survival of PKD patients was found to be better compared to non-PKD patients (HR = 0.70 [95% CI, 0.54-0.92]). There were no statistical differences between PKD and non-PKD patients in terms of peritonitis (OR = 0.86 [95% CI, 0.66-1.12]) and technical survival (HR = 0.98 [95% CI, 0.83-1.16]). There was an increased risk of hernia in PKD patients (OR = 2.28 [95% CI, 1.26-4.12]). CONCLUSIONS: PKD is associated with a better global survival, an increased risk of abdominal hernia, but no differences in peritonitis rate or technical survival were found. PD is a safe dialysis modality for PKD patients. Properly designed controlled studies are needed to determine whether all PKD patients are eligible for PD or whether some specific criteria should be determined.