Extracellular vesicles regulate purinergic signaling and epithelial sodium channel expression in renal collecting duct cells.

Purinergic signaling regulates several renal physiological and pathophysiological processes. Extracellular vesicles (EVs) are nanoparticles released by most cell types, which, in non-renal tissues, modulate purinergic signaling. The aim of this study was to investigate the effect of EVs from renal proximal tubule (HK2) and collecting duct cells (HCD) on intra- and intersegment modulation of extracellular ATP levels, the underlying molecular mechanisms, and the impact on the expression of the alpha subunit of the epithelial sodium channel (αENaC). HK2 cells were exposed to HK2 EVs, while HCD cells were exposed to HK2 and HCD EVs. Extracellular ATP levels and αENaC expression were measured by chemiluminescence and qRT-PCR, respectively. ATPases in EV populations were identified by mass spectrometry. The effect of aldosterone was assessed using EVs from aldosterone-treated cells and urinary EVs (uEVs) from primary aldosteronism (PA) patients. HK2 EVs downregulated ectonucleoside-triphosphate-diphosphohydrolase-1 (ENTPD1) expression, increased extracellular ATP and downregulated αENaC expression in HCD cells. ENTPD1 downregulation could be attributed to increased miR-205-3p and miR-505 levels. Conversely, HCD EVs decreased extracellular ATP levels and upregulated αENaC expression in HCD cells, probably due to enrichment of 14-3-3 isoforms with ATPase activity. Pretreatment of donor cells with aldosterone or exposure to uEVs from PA patients enhanced the effects on extracellular ATP and αENaC expression. We demonstrated inter- and intrasegment modulation of renal purinergic signaling by EVs. Our findings postulate EVs as carriers of information along the renal tubules, whereby processes affecting EV release and/or cargo may impact on purinergically regulated processes.

The effectiveness of restarted lithium treatment after discontinuation: reviewing the evidence for discontinuation-induced refractoriness.

OBJECTIVES: We sought to determine whether the risk of relapse in patients with bipolar disorder is higher after discontinuation and restart of lithium treatment as compared to continuous lithium treatment in these same patients. METHODS: We conducted literature searches in the Pubmed, Embase, Cochrane, and PsycINFO databases with cross-reference checks. Relevant data were extracted and pooled for meta-analysis. RESULTS: Five relevant studies were included for review, of which three studies qualified for the meta-analysis and included a total of 212 analyzed cases. Two studies found lithium to be less effective after discontinuation and reintroduction and three studies found no decreased effectiveness. The pooled odds ratio for the occurrence of one or more relapses after interruption of lithium treatment compared to continuous treatment was 1.40 (95% confidence interval: 0.85-2.31; p = 0.19). CONCLUSIONS: Although studies are scarce, review and meta-analysis of the available literature does not provide convincing evidence that lithium is less effective when treatment is discontinued and restarted, compared to uninterrupted treatment.

Advances in safe insulin infusions.

Hyperglycaemia is recognized as a marker of adverse clinical outcomes for hospitalized patients with and without diabetes, including mortality, morbidity, increased length of stay, infections and overall complications. In some cases, intravenous (IV) insulin infusions are the optimal intervention and, to date, these have been compounded in hospital pharmacy departments or, alternatively, at the point of care, when timeliness is a concern or the pharmacy is closed. However, in-house compounding of high-risk medications such as IV insulin poses risks both for patients and institutions. The critical nature of certain high-risk therapies has led to the development of ready-to-administer products to improve the safety, timeliness, efficacy and efficiency of critical infusions. Recently, IV insulin, a high-alert therapy, has been added to the ready-to-use armamentarium. This narrative review explores the expanding indications, risks and opportunities associated with insulin infusions and potential options for improved safety.