Citrate anion improves chronic dialysis efficacy, reduces systemic inflammation and prevents Chemerin-mediated microvascular injury

Systemic inflammation and uremic toxins (UT) determine the increased cardiovascular mortality observed in chronic hemodialysis (HD) patients. Among UT, the adipokine Chemerin induces vascular dysfunction by targeting both endothelial and vascular smooth muscular cells (EC and VSMC). As Citrate anion modulates oxidative metabolism, systemic inflammation and vascular function, we evaluated whether citrate-buffered dialysis improves HD efficiency, inflammatory parameters and chemerin-mediated microvascular injury. 45 patients were treated in sequence with acetate, citrate and, again, acetate-buffered dialysis solution (3 months per interval). At study admission and after each treatment switch, we evaluated dialysis efficacy and circulating levels of chemerin and different inflammatory biomarkers. In vitro, we stimulated EC and VSMC with patients' plasma and we investigated the role of chemerin as UT. Citrate dialysis increased HD efficacy and reduced plasma levels of CRP, fibrinogen, IL6 and chemerin. In vitro, patients' plasma induced EC and VSMC dysfunction. These effects were reduced by citrate-buffered solutions and paralleled by the decrease of chemerin levels. Consistently, chemerin receptor knockdown reduced EC and VSMC dysfunction. In conclusion, Switching from acetate to citrate improved dialysis efficacy and inflammatory parameters; in vitro, chemerin-induced EC and VSMC injury were decreased by using citrate as dialysis buffer

Management of Acute Kidney Injury and Extracorporeal Blood Purification Therapies During the COVID-19 Pandemic: The Italian SIN-SIAARTI Joint Survey (and Recommendations for Clinical Practice)

Background and aim: The novel coronavirus disease 2019 remains challenging. A large number of hospitalized patients are at a high risk of developing AKI. For this reason, we conducted a nationwide survey to assess the incidence and management of AKI in critically ill patients affected by the SARS-CoV-2 infection. Methods: This is a multicenter, observational, nationwide online survey, involving the Italian Society of Nephrology and the critical care units in Italy, developed in partnership between the scientific societies such as SIN and SIAARTI. Invitations to participate were distributed through emails and social networks. Data were collected for a period of 1 week during the COVID-19 pandemic. Results: A total of 141 responses were collected in the SIN-SIAARTI survey: 54.6% from intensivists and 44.6% from nephrologists. About 19,000 cases of COVID-19 infection have been recorded in hospitalized patients; among these cases, 7.3% had a confirmed acute kidney injury (AKI), of which 82.2% were managed in ICUs. Only 43% of clinicians routinely used the international KDIGO criteria. Renal replacement therapy (RRT) was performed in 628 patients with continuous techniques used most frequently, and oliguria was the most common indication (74.05%). Early initiation was preferred, and RRT was contraindicated in the case of therapeutic withdrawal or in the presence of severe comorbidities or hemodynamic instability. Regional anticoagulation with citrate was the most common choice. About 41.04% of the interviewed physicians never used extracorporeal blood purification therapies (EBPTs) for inflammatory cytokine or endotoxin removal. Moreover, 4.33% of interviewed clinicians used these techniques only in the presence of AKI, whereas 24.63% adopted them even in the absence of AKI. Nephrologists made more use of EBPT, especially in the presence of AKI. HVHF was never used in 58.54% of respondents, but HCO membranes and adsorbents were used in more than 50% of cases. Conclusion: This joint SIN-SIAARTI survey at the Italian Society of Nephrology and the critical care units in Italy showed that, during the COVID-19 pandemic, there was an underestimation of AKI based on the "non-use" of common diagnostic criteria, especially by intensivists. Similarly, the use of specific types of RRT and, in particular, blood purification therapies for immune modulation and organ support strongly differed between centers, suggesting the need for the development of standardized clinical guidelines

Extracorporeal Treatments in Patients with Acute Kidney Injury and Sepsis

Acute kidney injury (AKI) is one of the most common sepsis complications, and AKI development increases the risk of sepsis episodes by affecting host immune competence. The concomitance of these 2 clinical syndromes is associated with an extremely poor prognosis with mortality rates ranging from 50 to 70%. These unacceptable outcomes reflect the poor knowledge of the underlying pathogenic mechanisms and the lack of appropriate diagnostic and therapeutic methodologies as well as of appropriate experimental models. However, in recent years new insights have revolutionized the scientific and clinical approach to sepsis-induced AKI (S-AKI) leading to encouraging results. The aim of this paper is to review the extracorporeal treatment of S-AKI with a focus on the most promising experimental techniques and the underlying molecular mechanisms

Role of the CD40-CD40 Ligand Pathway in Cardiovascular Events, Neurological Alterations, and Other Clinical Complications of Chronic Hemodialysis Patients: Protective Role of Adsorptive Membranes

Despite the recent advances in dialysis technology, mortality rate of chronic uremic patients still remains excessively high: of note, in comparison to age- and sex-matched healthy controls, this frail population shows a higher incidence of infections, cancer, cognitive decline, and, in particular, major adverse cardiovascular events (MACE) that represent nowadays the first cause of mortality. Several traditional and nontraditional factors contribute to this increased risk for MACE and accelerated cellular senescence: among these, inflammation has been shown to play a key role. The costimulatory pathway CD40-CD40 Ligand (CD40L) is harmfully activated during inflammation and uremia-associated clinical complications: in particular, the soluble form of CD40L (sCD40L) can bind to the CD40 receptor triggering a cascade of detrimental pathways in immune and nonimmune cells. In this narrative review, we summarize the current concepts of the biological role of the CD40-CD40L pathway in uremia-associated organ dysfunction, focusing on the above-described main causes of mortality. Moreover, we discuss the interaction of the CD40-CD40L pathway with extracellular vesicles, microparticles recently identified as new uremic toxins. The biological effects of sCD40L in MACE, cognitive decline, infections, and cancer will be also briefly commented. Last, based on recent studies and ongoing clinical trials, we herein describe the modulatory activity of adsorptive dialysis membranes in polymethylmethacrylate on CD40-CD40L detrimental activation

Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury

Extracellular vesicles form a complex intercellular communication network, shuttling a variety of proteins, lipids, and nucleic acids, including regulatory RNAs, such as microRNAs. Transfer of these molecules to target cells allows for the modulation of sets of genes and mediates multiple paracrine and endocrine actions. EVs exert broad pro-inflammatory, pro-oxidant, and pro-apoptotic effects in sepsis, mediating microvascular dysfunction and multiple organ damage. This deleterious role is well documented in sepsis-associated acute kidney injury and acute respiratory distress syndrome. On the other hand, protective effects of stem cell-derived extracellular vesicles have been reported in experimental models of sepsis. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, regenerative, and immunomodulatory properties of parental cells and have shown therapeutic effects in experimental models of sepsis with kidney and lung involvement. Extracellular vesicles are also likely to play a role in deranged kidney-lung crosstalk, a hallmark of sepsis, and may be key to a better understanding of shared mechanisms underlying multiple organ dysfunction. In this review, we analyze the state-of-the-art knowledge on the dual role of EVs in sepsis-associated kidney/lung injury and repair. PubMed library was searched from inception to July 2022, using a combination of medical subject headings (MeSH) and keywords related to EVs, sepsis, acute kidney injury (AKI), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Key findings are summarized into two sections on detrimental and beneficial mechanisms of actions of EVs in kidney and lung injury, respectively. The role of EVs in kidney-lung crosstalk is then outlined. Efforts to expand knowledge on EVs may pave the way to employ them as prognostic biomarkers or therapeutic targets to prevent or reduce organ damage in sepsis

Extracorporeal blood purification therapies for sepsis-associated acute kidney injury in critically ill patients: expert opinion from the SIAARTI-SIN joint commission

: Sepsis-Associated Acute Kidney Injury is a life-threatening condition leading to high morbidity and mortality in critically ill patients admitted to the intensive care unit. Over the past decades, several extracorporeal blood purification therapies have been developed for both sepsis and sepsis-associated acute kidney injury management. Despite the widespread use of extracorporeal blood purification therapies in clinical practice, it is still unclear when to start this kind of treatment and how to define its efficacy. Indeed, several questions on sepsis-associated acute kidney injury and extracorporeal blood purification therapy still remain unresolved, including the indications and timing of renal replacement therapy in patients with septic vs. non-septic acute kidney injury, the optimal dialysis dose for renal replacement therapy modalities in sepsis-associated acute kidney injury patients, and the rationale for using extracorporeal blood purification therapies in septic patients without acute kidney injury. Moreover, the development of novel extracorporeal blood purification therapies, including those based on the use of adsorption devices, raised the attention of the scientific community both on the clearance of specific mediators released by microorganisms and by injured cells and potentially involved in the pathogenic mechanisms of organ dysfunction including sepsis-associated acute kidney injury, and on antibiotic removal. Based on these considerations, the joint commission of the Italian Society of Anesthesiology and Critical Care (SIAARTI) and the Italian Society of Nephrology (SIN) herein addressed some of these issues, proposed some recommendations for clinical practice and developed a common framework for future clinical research in this field

Regional citrate anticoagulation (RCA) in critically ill patients undergoing renal replacement therapy (RRT): expert opinion from the SIAARTI-SIN joint commission

: Renal replacement therapies (RRT) are essential to support critically ill patients with severe acute kidney injury (AKI), providing control of solutes, fluid balance and acid-base status. To maintain the patency of the extracorporeal circuit, minimizing downtime periods and blood losses due to filter clotting, an effective anticoagulation strategy is required.Regional citrate anticoagulation (RCA) has been introduced in clinical practice for continuous RRT (CRRT) in the early 1990s and has had a progressively wider acceptance in parallel to the development of simplified systems and safe protocols. Main guidelines on AKI support the use of RCA as the first line anticoagulation strategy during CRRT in patients without contraindications to citrate and regardless of the patient's bleeding risk.Experts from the SIAARTI-SIN joint commission have prepared this position statement which discusses the use of RCA in different RRT modalities also in combination with other extracorporeal organ support systems. Furthermore, advise is provided on potential limitations to the use of RCA in high-risk patients with particular attention to the need for a rigorous monitoring in complex clinical settings. Finally, the main findings about the prospective of optimization of RRT solutions aimed at preventing electrolyte derangements during RCA are discussed in detail