While constant basal levels of macroautophagy/autophagy are a prerequisite to preserve long-lived podocytes at the filtration barrier, MTOR regulates at the same time podocyte size and compensatory hypertrophy. Since MTOR is known to generally suppress autophagy, the apparently independent regulation of these two key pathways of glomerular maintenance remained puzzling. We now report that long-term genetic manipulation of MTOR activity does in fact not influence high basal levels of autophagy in podocytes either in vitro or in vivo. Instead we present data showing that autophagy in podocytes is mainly controlled by AMP-activated protein kinase (AMPK) and ULK1 (unc-51 like kinase 1). Pharmacological inhibition of MTOR further shows that the uncoupling of MTOR activity and autophagy is time dependent. Together, our data reveal a novel and unexpected cell-specific mechanism, which permits concurrent MTOR activity as well as high basal autophagy rates in podocytes. Thus, these data indicate manipulation of the AMPK-ULK1 axis rather than inhibition of MTOR as a promising therapeutic intervention to enhance autophagy and preserve podocyte homeostasis in glomerular diseases.
Introduction Cytokine adsorption using the CytoSorb® adsorber has been proposed in various clinical settings including sepsis, ARDS, hyperinflammatory syndromes, cardiac surgery or recovery after cardiac arrest. The aim of this analysis is to provide evidence for the efficacy of the CytoSorb® adsorber with regard to mortality in various settings. Methods We searched PubMed, Cochrane Library database and the database provided by Cytosorbents™ (01.1.2010–29.5.2022). We considered randomized controlled trials and observational studies with control groups. The longest reported mortality was defined as the primary endpoint. We computed risk ratios and 95%-confidence intervals and used DerSimonian and Lairds random effects model. We analysed all studies combined and divided them into the subgroups: sepsis, cardiopulmonary bypass surgery (CPB), other severe illness, SARS-CoV-2 infection and recovery from cardiac arrest. The meta-analysis was registered in advance (PROSPERO: CRD42022290334). Results Of an initial 1295 publications, 34 studies were found eligible, including 1297 patients treated with CytoSorb® and 1314 controls. Cytosorb® intervention did not lower mortality (RR [95%-CI]: all studies 1.07 [0.88; 1.31], sepsis 0.98 [0.74; 1.31], CPB surgery 0.91 [0.64; 1.29], severe illness 0.95 [0.59; 1.55], SARS-CoV-2 1.58 [0.50; 4.94]). In patients with cardiac arrest, we found a significant survival advantage of the untreated controls (1.22 [1.02; 1.46]). We did not find significant differences in ICU length of stay, lactate levels, or IL-6 levels after treatment. Of the eligible 34 studies only 12 were randomized controlled trials. All observational studies showed moderate to serious risk of bias. Interpretation To date, there is no evidence for a positive effect of the CytoSorb® adsorber on mortality across a variety of diagnoses that justifies its widespread use in intensive care medicine.
BackgroundResistant hypertension is associated with a high risk of cardiovascular disease, chronic kidney disease and mortality. Yet, its management is challenging. This study aims to establish the comparative effectiveness of pharmacologic and interventional treatments by conducting a network meta-analysis.MethodsMEDLINE, Cochrane Register of Controlled Trials and Web of Science Core Collection were systematically searched in March 2022. Randomized controlled trials comparing treatment options for management of resistant hypertension were included. Outcomes were blood pressure changes, measured in the office and in 24h ambulatory blood pressure measurement. We applied a frequentist random effects model to perform a network meta-analysis combining placebo medication and sham procedure as the reference comparator.ResultsFrom 4771 records, 24 studies met the inclusion criteria with 3458 included patients in total. 12 active treatment alternatives were analyzed. Among all comparators, spironolactone had the highest-ranking probability and was considered the most effective treatment to reduce office systolic blood pressure (-13.30 mmHg [-17.89; -8.72];P< 0.0001) and 24h systolic blood pressure (-8.46 mmHg [-12.54; -4.38]; P < 0.0001) in patients with resistant hypertension.
Cytokine adsorption using the CytoSorb® device has been proposed in various clinical settings including sepsis, ARDS, hyperinflammatory syndromes, cardiac surgery or recovery after cardiac arrest. The aim of this analysis is to provide evidence for the efficacy of the CytoSorb® device with regard to mortality in various settings. Methods: We searched PubMed, Cochrane Library database and the database provided by Cytosorbents™ (01.1.2010–29.5.2022). We considered randomized controlled trials and intervention studies with control groups. The longest reported mortality was defined as primary endpoint. For analyzing the data, we computed risk ratios and 95%-confidence intervals and used DerSimonian and Lairds random effects model. We analyzed all studies combined and divided into the subgroups sepsis, cardiac surgery, other severe illness, SARS-CoV-2 infection and recovery from cardiac arrest. The meta-analysis was registered in advance (PROSPERO: CRD42022290334). Results: Of an initial 1295 publications, 34 studies were found eligible, including 1297 patients treated with CytoSorb® and 1314 controls. Cytosorb® did not lower mortality in all studies together (1.07 [0.88; 1.31] RR [95%-CI]), in sepsis (0.98 [0.74; 1.31]), CPB surgery (0.91 [0.64; 1.29]), severe illness (0.95 [0.59; 1.55]) or SARS-CoV-2 (1.58 [0.50; 4.94]). In patients with cardiac arrest, we found a significant survival advantage of the untreated controls (RR 1.22 [1.02; 1.46]). We did not find significant differences in ICU length of stay, lactate levels, or IL-6 levels after treatment. Interpretation: To date there is no evidence for a positive effect of the CytoSorb® adsorber on mortality across a variety of indications that justifies its widespread use in intensive care medicine.
Objective: Resistant hypertension is associated with a high risk of cardiovascular disease, chronic kidney disease and mortality. Yet, its management is still challenging. This study aims to establish the comparative effectiveness of pharmacologic and interventional treatments by conducting a network meta-analysis. Design and method: We systematically searched MEDLINE, Cochrane Register of Controlled Trials (CENTRAL) and Web of Science Core Collection in March 2022. Randomized controlled trials comparing treatment options as add-on therapy for management of resistant hypertension were included. Outcomes were blood pressure changes, measured in the office and in 24h ABPM. We applied a frequentist random effects model to perform a network meta-analysis combining placebo medication and sham procedure as the reference comparator. Results: From 4771 records, 24 studies met our inclusion criteria with 3458 included patients in total. 12 active treatment alternatives were analyzed. Among all comparators, spironolactone had the highest-ranking probability and was considered as the most effective treatment to reduce office systolic blood pressure (-13.30 mmHg [-17.89; -8.72]; P < 0.0001) and 24h systolic blood pressure (-8.46 mmHg [-12.54; -4.38]; P < 0.0001) in patients with resistant hypertension. Conclusions: Among all pharmacologic and interventional treatments, spironolactone has been found to be most effective in reducing office and 24h systolic blood pressure as an add-on therapy for resistant hypertension. Our study provides an evidence-based and valid reference in clinical decision-making.
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