La cystinose (physiopathologie, aspects thérapeutiques, perspectives)

MONTPELLIER-BU Médecine UPM (341722108) / SudocPARIS-BIUM (751062103) / SudocMONTPELLIER-BU Médecine (341722104) / SudocSudocFranceF

The constitutively active V2 receptor mutants conferring NSIAD are weakly sensitive to agonist and antagonist regulation.

Patients having the nephrogenic syndrome of inappropriate antidiuresis present either the R137C or R137L V2 mutated receptor. While the clinical features have been characterized, the molecular mechanisms of functioning of these two mutants remain elusive. In the present study, we compare the pharmacological properties of R137C and R137L mutants with the wild-type and the V2 D136A receptor, the latter being reported as a highly constitutively active receptor. We have performed binding studies, second messenger measurements and BRET experiments in order to evaluate the affinities of the ligands, their agonist and antagonist properties and the ability of the receptors to recruit beta-arrestins, respectively. The R137C and R137L receptors exhibit small constitutive activities regarding the G(s) protein activation. In addition, these two mutants induce a constitutive beta-arrestin recruitment. Of interest, they also exhibit weak sensitivities to agonist and to inverse agonist in term of G(s) protein coupling and beta-arrestin recruitment. The small constitutive activities of the mutants and the weak regulation of their functioning by agonist suggest a poor ability of the antidiuretic function to be adapted to the external stimuli, giving to the environmental factors an importance which can explain some of the phenotypic variability in patients having NSIAD

Coupling properties of the wild-type and mutants receptors.

<p><b>a</b>, Basal, agonist induced and antagonist-inhibited cAMP accumulation was measured on cos 7 cells expressing wild-type or mutants receptors. Values of cAMP accumulation were normalized to the number of receptors expressed at the surface of the cells determined by ligand binding [3H]AVP. <b>b</b>, AVP dose-response experiments performed on cells expressing wild-type, R137C or R137L V2 receptor. <b>c</b>, effect of an inverse agonist, SR121463, on AVP-induced stimulation.</p

β-arrestin 1 recruitment to V2R studied by BRET.

<p><b>a</b>, For BRET measurements, V2 receptors and β-arrestin 1 were fused to Rluc and YFP proteins, respectively, and co-expressed in COS-7 cells treated or not with AVP for 45 minutes. <b>b</b>, AVP-induced β-arrestin 1 recruitment to either V2 wild-type, R137C, R137L or D136A mutants. Data are means±S.E.M of three independent experiments. <b>c</b>, Expression levels of BRET partners determined by Rluc luminescence and YFP fluorescence <b>d</b>, Dose-response of AVP-induced BRET after AVP stimulation for 45 minutes. <b>e</b>, BRET time-course: BRET increase between V2 receptors and β-arrestin 1 after AVP stimulation (1 µM) at the indicated time. Data are means±S.E.M of three independent experiments.</p

Pharmacological properties of the R137C and R137L V2 receptors compared to the those of the wild-type and D136A receptor.

*<p>: the values cannot be determined since the curves do not reach a plateau.</p>**<p>: values from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008383#pone.0008383-Morin2" target="_blank">[19]</a>.</p

Pediatr Nephrol

BACKGROUND: Hemolytic uremic syndrome related to Shiga-toxin-secreting Escherichia coli infection (STEC-HUS) remains a common cause of acute kidney injury in young children. No specific treatment has been validated for this severe disease. Recently, experimental studies highlight the potential role of complement in STEC-HUS pathophysiology. Eculizumab (EC), a monoclonal antibody against terminal complement complex, has been used in severe STEC-HUS patients, mostly during the 2011 German outbreak, with conflicting results. METHODS: On behalf of the French Society of Pediatric Nephrology, we retrospectively studied 33 children from 15 centers treated with EC for severe STEC-HUS. Indication for EC was neurologic involvement in 20 patients, cardiac and neurologic involvement in 8, cardiac involvement in 2, and digestive involvement in 3. Based on medical status at last follow-up, patients were divided into two groups: favorable (n = 15) and unfavorable outcomes (n = 18). RESULTS: Among patients with favorable outcome, 11/14 patients (79%) displayed persistent blockade of complement activity before each EC reinjection. Conversely, in patients with unfavorable outcome, only 9/15 (53%) had persistent blockade (p = n.s.). Among 28 patients presenting neurological symptoms, 19 had favorable neurological outcome including 17 with prompt recovery following first EC injection. Only two adverse effects potentially related to EC treatment were reported. CONCLUSIONS: Taken together, these results may support EC use in severe STEC-HUS patients, especially those presenting severe neurological symptoms. The study, however, is limited by absence of a control group and use of multiple therapeutic interventions in treatment groups. Thus, prospective, controlled trials should be undertaken

Low incidence of SARS-CoV-2, risk factors of mortality and the course of illness in the French national cohort of dialysis patients

International audienceThe aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed