Estimated glomerular filtration rate is a poor predictor of the concentration of middle molecular weight uremic solutes in chronic kidney disease

Background: Uremic solute concentration increases as Glomerular Filtration Rate (GFR) declines. Weak associations were demonstrated between estimated GFR (eGFR) and the concentrations of several small water-soluble and protein-bound uremic solutes (MW500Da). Materials and Methods: In 95 CKD-patients (CKD-stage 2-5 not on dialysis), associations between different eGFR-formulae (creatinine, CystatinC-based or both) and the natural logarithm of the concentration of several LMWP's were analyzed: i.e. parathyroid hormone (PTH), Cystatin C (CystC), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), leptin, retinol binding protein (RbP), immunoglobin light chains kappa and lambda (Ig-kappa and Ig-lambda), beta-2-microglobulin (beta M-2), myoglobin and fibroblast growth factor-23 (FGF-23)). Results: The regression coefficients (R-2) between eGFR, based on the CKD-EPI-Crea-CystC-formula as reference, and the examined LMWP's could be divided into three groups. Most of the LMWP's associated weakly (R-2 0.7). Almost identical R-2-values were found per LMWP for all eGFR-formulae, with exception of CystC and beta M-2 which showed weaker associations with creatinine-based than with CystC-based eGFR. Conclusion: The association between eGFR and the concentration of several LMWP's is inconsistent, with in general low R-2-values. Thus, the use of eGFR to evaluate kidney function does not reflect the concentration of several LMWP's with proven toxic impact in CKD

Chronic kidney disease and neurological disorders: are uraemic toxins the missing piece of the puzzle?

Chronic kidney disease (CKD) perturbs the crosstalk with others organs, with the interaction between the kidneys and the heart having been studied most intensively. However, a growing body of data indicates that there is an association between kidney dysfunction and disorders of the central nervous system. In epidemiological studies, CKD is associated with a high prevalence of neurological complications, such as cerebrovascular disorders, movement disorders, cognitive impairment and depression. Along with traditional cardiovascular risk factors (such as diabetes, inflammation, hypertension and dyslipidaemia), non-traditional risk factors related to kidney damage (such as uraemic toxins) may predispose patients with CKD to neurological disorders. There is increasing evidence to show that uraemic toxins, for example indoxyl sulphate, have a neurotoxic effect. A better understanding of factors responsible for the elevated prevalence of neurological disorders among patients with CKD might facilitate the development of novel treatments. Here, we review (i) the potential clinical impact of CKD on cerebrovascular and neurological complications, (ii) the mechanisms underlying the uraemic toxins' putative action (based on pre-clinical and clinical research) and (iii) the potential impact of these findings on patient care

Circulating TRAIL Shows a Significant Post-Partum Decline Associated to Stressful Conditions

Background: Since circulating levels of TNF-related apoptosis inducing ligand (TRAIL) may be important in the physiopathology of pregnancy, we tested the hypothesis that TRAIL levels change at delivery in response to stressful conditions. Methods/Principal Findings: We conducted a longitudinal study in a cohort of 73 women examined at week 12, week 16, delivery and in the corresponding cord blood (CB). Serum TRAIL was assessed in relationship with maternal characteristics and to biochemical parameters. TRAIL did not vary between 12 (67.6627.6 pg/ml, means6SD) and 16 (64.0616.2 pg/ml) weeks ’ gestation, while displaying a significant decline after partum (49.3626.4 pg/ml). Using a cut-off decline.20 pg/ml between week 12 and delivery, the subset of women with the higher decline of circulating TRAIL (41.7%) showed the following characteristics: i) nullipara, ii) higher age, iii) operational vaginal delivery or urgent CS, iv) did not receive analgesia during labor, v) induced labor. CB TRAIL was significantly higher (131.6652 pg/ml) with respect to the corresponding maternal TRAIL, and the variables significantly associated with the first quartile of CB TRAIL (,90 pg/ml) were higher prepregnancy BMI, induction of labor and fetal distress. With respect to the biochemical parameters, maternal TRAIL at delivery showed an inverse correlation with C-reactive protein (CRP), total cortisol, glycemia and insulin at bivariate analysis, but only with CRP at multivariate analysis

Advances in tenascin-C biology

Tenascin-C is an extracellular matrix glycoprotein that is specifically and transiently expressed upon tissue injury. Upon tissue damage, tenascin-C plays a multitude of different roles that mediate both inflammatory and fibrotic processes to enable effective tissue repair. In the last decade, emerging evidence has demonstrated a vital role for tenascin-C in cardiac and arterial injury, tumor angiogenesis and metastasis, as well as in modulating stem cell behavior. Here we highlight the molecular mechanisms by which tenascin-C mediates these effects and discuss the implications of mis-regulated tenascin-C expression in driving disease pathology

Ulceration of the oral mucosa following direct contact with ferrous sulfate in elderly patients: a case report and a review of the French National Pharmacovigilance Database

Sophie Liabeuf,1–3 Valérie Gras,1 Julien Moragny,1 Marie-Laure Laroche,4 Michel Andrejak1,3On behalf of the French National Network of Pharmacovigilance Centers1Regional Pharmacovigilance Center, Division of Clinical Pharmacology, Amiens University Medical Center and Jules Verne University of Picardy, Amiens, France; 2Clinical Research Centre, Clinical Pharmacology Division, Amiens University Medical Center and the Jules Verne University of Picardy, Amiens, France; 3INSERM U1088, Amiens, France; 4Regional Pharmacovigilance Center, Department of Pharmacology, Toxicology and Pharmacovigilance, Limoges University Medical Center, Limoges, FranceObjective: To report a series of cases of ulceration of the oral mucosa linked to direct contact with ferrous sulfate in elderly patients.Case summary: The first case report concerns the occurrence of widespread oral ulceration in an 87-year-old woman with Alzheimer’s disease. The ulceration extended from the side of the tongue to the floor of the mouth. No clear explanation was found and various local treatments were ineffective. Once it was realized that the ferrous sulfate tablets (given as an iron supplement) were crushed prior to administration (due to the patient’s deglutition disorder), withdrawal of this treatment led to rapid resolution of the ulceration. Nine other cases of oral ulcerations associated with ferrous sulfate were identified in the French National Pharmacovigilance Database. All but one of the patients were over 80 years of age and the youngest patient (a 54-year-old) had dysphagia associated with facial paralysis.Discussion: Only two other reports of oral ulceration due to ferrous sulfate have been published to date. Mucosal toxicity of ferrous sulfate (which is probably related to oxidative stress) has previously been reported for the hypopharynx, the esophageal lumen, and (after inhalation of a tablet) the tracheobronchial tree.Conclusion: The mucosal toxicity of ferrous sulfate must be taken into account when deglutition disorders are present (as in elderly patients) and appropriate pharmaceutical formulations (such as syrups) should be administered to at-risk patients. The use of iron salts other than ferrous sulfate could be considered.Keywords: ferrous sulfate, drug ulceration, oral ulceration, elderl

Associations between Th1-mediated diseases and omalizumab: A post-marketing study of the World Health Organization pharmacovigilance database (VigiBase (R))

International audienc

Fetal adverse drug reactions with biologic Disease Modifying Anti-Rheumatic Drugs used during pregnancy: Insights from a World Health Organization pharmacovigilance database study (VigiBase (R))

International audienc

Cypress allergen immunotherapy and pru p 7 sensitization

International audienceBackground: Up to 60% of food allergies in school children, adolescent and adults are related to an inhalant allergy. Sensitization to Pru p 7, the first identified allergenic gibberellin-regulated protein (GRP), is likely associated to primary sensitization to cypress pollen. Pru p 7 is a major allergen in peach-allergic Mediterranean patients, while other GRPs have been characterized in orange, Japanese apricot, cherry, and pomegranate. It is currently unknown whether cypress allergen immunotherapy (CUP AIT) is a risk factor for subsequent Pru p 7 sensitization and clinical expression as fruit allergy. The objective of this study was to analyze Pru p 7 sensitization as a function of CUP AIT in cypress allergic patients with or without fruit allergy.Method: Monocentric retrospective (January 2014 – December 2019) study of 391 outpatients ≥ 15 years attending one of the allergy departments in the University Hospitals of Marseille, France.Results: Pru p 7 sensitization was found in 27/39 (69%) cypress allergic patients with a history of CUP AIT and in 93/228 (41%) cypress allergic patients who had never received CUP AIT, P < 0.001. Fruit allergy was found in 30/39 (77%) of cypress-allergic patients who had received cypress allergen immunotherapy and in 126/228 (55%) of those who did not, P = 0.006. Among cypress allergic patients with confirmed allergy to fruit, Pru p 7 sensitization was found in 26/30 (87%) having received CUP AIT and in 72/126 (57%) who had never received CUP AIT, P = 0.003. CUP AIT was also associated with higher levels of IgE to Pru p 7 (median 2.02 vs 0.05, P < 0.001), especially in fruit allergic as compared to fruit tolerant patients (median 4.8 v. 0.18, P < 0.01). The difference was not imputable to patients’ age, cypress pollinosis duration, or time elapsed since the initiation of CUP AIT.Conclusion: Among patients with cypress pollinosis, CUP AIT was associated with higher occurrence of fruit allergy, higher prevalence and higher levels of Pru p 7 sensitization. However, the causal link cannot be inferred given the limitations of the retrospective design, including the absence of consistent data on Pru p 7 sensitization prior to CUP AIT initiation. We report a positive association between CUP AIT and the occurrence of fruit allergy and Pru p 7 sensitization. These results raise the question of CUP AIT ability to foster Pru p 7 sensitization and its clinical expression as fruit allergy

Symmetric dimethylarginine as a proinflammatory agent in chronic kidney disease

Background & objectives Chronic kidney disease (CKD) is characterized by chronic inflammation, considered a nontraditional risk factor for cardiovascular disease, the major cause of death in CKD. Symmetric dimethylarginine (SDMA) was recently demonstrated to induce reactive oxygen species in monocytes. The present study further investigates the inflammatory character of SDMA compared with its structural counterpart asymmetric dimethylarginine (ADMA). Design, setting, participants, & measurements In vitro, the effect of SDMA on intracellular monocytic expression of IL-6 and TNF-alpha was studied followed by an evaluation of nuclear factor (NF)-kappa B activation. Additionally, an association of SDMA with inflammatory parameters in consecutive stages of CKD was evaluated in vivo. Results Monocytes incubated with SDMA showed increased IL-6 and TNF-a expression and a rise in active NF-kappa B. N-acetylcysteine abrogated both these effects. No significant effects were observed with ADMA. In vivo, 142 patients (67 +/- 12 years) at different stages of CKD showed an inverse association between serum SDMA and ADMA and renal function. Correlations between SDMA and IL-6, TNF-alpha, and albumin were more significant than for ADMA, while multiple regression analysis only retained TNF-alpha at a high significance for SDMA (P < 0.0001). In receiver operating characteristic analysis for inflammation, defined as an IL-6 level above 2.97 pg/ml (median), the discriminative power of SDMA (area under the curve [AUC]: 0.69 +/- 0.05) directly followed that of C-reactive protein (AUC: 0.82 +/- 0.04) and albumin (AUC: 0.72 +/- 0.05; for all, P < 0.0001) and preceded that of ADMA (P = 0.002). Conclusions The present study shows that SDMA is involved in the inflammatory process of CKD, activating NF-kappa B and resulting in enhanced expression of IL-6 and TNF-alpha, which is corroborated by the clinical data pointing to an in vivo association of SDMA with inflammatory markers in CKD at different stages