Clinical Applications of Adsorption: The New Era of Jafron Sorbents.

The Jafron series of sorbent cartridges provides a comprehensive array of coated, highly biocompatible sorbent beads made of styrene-divinylbenzene copolymers. Such beads carry a mean diameter of 0.8 mm with a range from 0.60 to 1.18 mm. The maximal pore size of these coated beads and the volume of the cartridge vary according to the type of cartridge ranging between 50 Da and 60 kDa. The sorbents, the size of the cartridge, the volume of sorbent, and the pore size (which reaches 60 kDa with the HA330 cartridge) aim to take advantage of the principles of molecular adsorption in a variety of diseases from uremic toxin retention to poisoning and drug overdose, from kidney disease to liver failure, from acute respiratory distress syndrome to sepsis, from toxic skin injury to COVID-19. The preliminary data from ex vivo studies, animal investigations, and human pilot work look promising and justify a program of systematic investigation of these products to advance our understanding of how they may be incorporated into our therapeutic arsenal.

Study protocol of a phase 2, randomised, placebo-controlled, double-blind, adaptive, parallel group clinical study to evaluate the efficacy and safety of recombinant alpha-1-microglobulin in subjects at high risk for acute kidney injury following open-chest cardiac surgery (AKITA trial).

INTRODUCTION: Acute kidney injury (AKI) is a common complication after cardiac surgery (CS) and is associated with adverse short-term and long-term outcomes. Alpha-1-microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme binding and mitochondrial-protective mechanisms. RMC-035 is a modified, more soluble, variant of A1M and has been proposed as a novel targeted therapeutic protein to prevent CS-associated AKI (CS-AKI). RMC-035 was considered safe and generally well tolerated when evaluated in four clinical phase 1 studies. METHODS AND ANALYSIS: This is a phase 2, randomised, double-blind, adaptive design, parallel group clinical study that evaluates RMC-035 compared with placebo in approximately 268 cardiac surgical patients at high risk for CS-AKI. RMC-035 is administered as an intravenous infusion. In total, five doses will be given. Dosing is based on presurgery estimated glomerular filtration rate (eGFR), and will be either 1.3 or 0.65 mg/kg.The primary study objective is to evaluate whether RMC-035 reduces the incidence of postoperative AKI, and key secondary objectives are to evaluate whether RMC-035 improves postoperative renal function compared with placebo. A blinded interim analysis with potential sample size reassessment is planned once 134 randomised subjects have completed dosing. An independent data monitoring committee will evaluate safety and efficacy data at prespecified intervals throughout the trial. The study is a global multicentre study at approximately 30 sites. ETHICS AND DISSEMINATION: The trial was approved by the joint ethics committee of the physician chamber Westfalen-Lippe and the University of Münster (code '2021-778 f-A') and subsequently approved by the responsible ethics committees/relevant institutional review boards for the participating sites. The study is conducted in accordance with Good Clinical Practice, the Declaration of Helsinki and other applicable regulations. Results of this study will be published in a peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: NCT05126303.

Rationale for sequential extracorporeal therapy (SET) in sepsis.

Sepsis and septic shock remain drivers for morbidity and mortality in critical illness. The clinical picture of patients presenting with these syndromes evolves rapidly and may be characterised by: (a) microbial host invasion, (b) establishment of an infection focus, (c) opsonisation of bacterial products (e.g. lipopolysaccharide), (d) recognition of pathogens resulting in an immune response, (e) cellular and humoral effects of circulating pathogen and pathogen products, (f) immunodysregulation and endocrine effects of cytokines, (g) endothelial and organ damage, and (h) organ crosstalk and multiple organ dysfunction. Each step may be a potential target for a specific therapeutic approach. At various stages, extracorporeal therapies may target circulating molecules for removal. In sequence, we could consider: (a) pathogen removal from the circulation with affinity binders and cartridges (specific), (b) circulating endotoxin removal by haemoperfusion with polymyxin B adsorbers (specific), (c) cytokine removal by haemoperfusion with sorbent cartridges or adsorbing membranes (non-specific), (d) extracorporeal organ support with different techniques for respiratory and cardiac support (CO2 removal or extracorporeal membrane oxygenation), and renal support (haemofiltration, haemodialysis, or ultrafiltration). The sequence of events and the use of different techniques at different points for specific targets will likely require trials with endpoints other than mortality. Instead, the primary objectives should be to achieve the desired action by using extracorporeal therapy at a specific point.

Data on immunogenicity and reactogenicity to COVID-19 vaccination among patients receiving maintenance dialysis.

Compared with the general population, patients receiving maintenance dialysis are at increased risk for morbidity and mortality associated with coronavirus disease 2019 (COVID-19). Currently, data on severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2)-specific immunity post-vaccination in patients on maintenance dialysis are scarce given that the effectiveness of the vaccines has not been explicitly tested in this population due to their common exclusion from SARS-CoV-2 vaccination trials. We herein present data of the specific cellular (interferon-γ and interleukin-2 ELISpot assays) and humoral immune responses (dot plot array and chemiluminescent microparticle immunoassay) at 4 weeks and 6 weeks following a single dose or a complete homologous dual dose SARS-CoV-2 vaccine regimen in 60 adult patients on maintenance dialysis (six with a history of COVID-19). The data was produced in a framework of a project focused on a) quantifying the immune response after full vaccination, b) evaluating the short-term durability of immune response, and c) examining the reactogenicity of SARS-CoV-2 vaccine regimens in patients on maintenance dialysis.

In hospital risk factors for acute kidney injury and its burden in patients with Sars-Cov-2 infection: a longitudinal multinational study.

Acute kidney injury (AKI) is associated with increased mortality in most critical settings. However, it is unclear whether its mild form (i.e. AKI stage 1) is associated with increased mortality also in non-critical settings. Here we conducted an international study in patients hospitalized with SARS-CoV-2 infection aiming 1. to estimate the incidence of AKI at each stage and its impact on mortality 2. to identify AKI risk factors at admission (susceptibility) and during hospitalization (exposures) and factors contributing to AKI-associated mortality. We included 939 patients from medical departments in Moscow (Russia) and Padua (Italy). In-hospital AKI onset was identified in 140 (14.9%) patients, mainly with stage 1 (65%). Mortality was remarkably higher in patients with AKI compared to those without AKI (55 [39.3%] vs. 34 [4.3%], respectively). Such association remained significant after adjustment for other clinical conditions at admission (relative risk [RR] 5.6; CI 3.5- 8.8) or restricting to AKI stage 1 (RR 3.2; CI 1.8-5.5) or to subjects with AKI onset preceding deterioration of clinical conditions. After hospital admission, worsening of hypoxic damage, inflammation, hyperglycemia, and coagulopathy were identified as hospital-acquired risk factors predicting AKI onset. Following AKI onset, the AKI-associated worsening of respiratory function was identified as the main contributor to AKI-induced increase in mortality risk. In conclusion, AKI is a common complication of Sars-CoV2 infection in non-intensive care settings where it markedly increases mortality risk also at stage 1. The identification of hospital-acquired risk factors and exposures might help prevention of AKI onset and of its complications.

Immunogenicity and reactogenicity of homologous mRNA-based and vector-based SARS-CoV-2 vaccine regimens in patients receiving maintenance dialysis.

Patients receiving maintenance dialysis (MD) are vulnerable to COVID-19-related morbidity and mortality. Currently, data on SARS-CoV-2-specific cellular and humoral immunity post-vaccination in this population are scarce. We conducted a prospective single-center study exploring the specific cellular (interferon-γ and interleukin-2 ELISpot assays) and humoral immune responses (dot plot array and chemiluminescent microparticle immunoassay [CMIA]) at 4 weeks and 6 weeks following a single dose or a complete homologous dual dose SARS-CoV-2 vaccine regimen in 60 MD patients (six with a history of COVID-19). Our results show that MD patients exhibit a high seroconversion rate (91.7%) but the anti-spike IgG antibodies (CMIA) tend to wane rapidly after full immunization. Only 51.7% of the patients developed T cell immune response. High anti-spike IgG antibodies may predict a better cellular immunity. While patients with prior COVID-19 showed the best response after one, SARS-CoV-2-naïve patients may benefit from a third vaccine injection.

Fluctuations in Interleukin-6 Levels during Hemodialysis Sessions with Medium Cutoff Membranes: An Analysis on COVID-19 Case Series.

INTRODUCTION: Interleukin-6 (IL-6) is one of the most important mediators of inflammation. It is also the culprit for a severe disease course in COVID-19. While COVID-19 has higher mortality in hemodialysis (HD) patients, medium cutoff (MCO) membranes were previously suggested as promising tools for better patient outcomes by purging inflammatory mediators. The aim of this study was to analyze changes in IL-6 levels of HD patients who were dialyzed via MCO membranes during their COVID-19 treatments. METHODS: This is an observational study on a group of HD patients who were admitted with COVID-19 diagnosis in a university hospital and intermittently dialyzed using MCO membranes during their hospital stay. IL-6 levels of the patients were measured before and after consecutive dialysis sessions by a commercial kit. Measurements were interpreted together with the clinical data. RESULTS: Nine patients with a total of 54 measurements were evaluated. IL-6 levels were significantly higher in patients who died (median and interquartile ranges [IQRs] of IL-6 levels for patients who died and survived were 112.0 pg/mL [48.3-399.4] and 5.3 pg/mL [2.2-27.4], respectively; p < 0.001). In the comparison of changes in IL-6 levels with dialysis sessions, patients who survived had lower post-dialysis levels (median: 4.5 pg/mL; IQR: 2.2-7.6). However, IL-6 levels had a tendency to increase with dialysis sessions in patients who could not survive COVID-19 (median: 237.0 pg/mL; IQR: 53.8-418.2). CONCLUSION: This study describes over time variations in IL-6 levels of COVID-19 patients undergoing HD with MCO membranes. The trend for the changes of IL-6 levels during dialysis sessions was not uniform for all patients. Surviving patients had decreasing levels of IL-6 with consecutive dialysis sessions, while nonsurvivors had an increasing trend.

The utility of remote patient management in peritoneal dialysis.

Remote patient management (RPM) programs are one of the most crucial innovations in the peritoneal dialysis (PD) field that have been developed in the last decade. RPM programs are associated with favourable clinical outcomes by increasing the adherence of the patients to PD prescription. The literature supports that RPM is associated with increased blood pressure control and technique survival, and decreased hospitalization rate, length of hospital stay and health costs. RPM programs also facilitate patient follow-up during the coronavirus disease 2019 pandemic, increase treatment adherence and lead to better clinical outcomes. However, published data remain scarce and mainly consist of observational or retrospective studies with relatively low numbers of patients. Therefore, randomized controlled trial results will be more informative to demonstrate the effect of RPM programs on clinical outcomes.

COVID-19 and the Kidney: Should Nephrologists Care about COVID-19 rather than Maintaining Their Focus on Renal Patients?

Clinical Background: The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) rapidly spread globally from late 2019, reaching pandemic proportions. Epidemiology: The related disease, COVID-19, exacerbates and progresses due to patients' abnormal inflammatory/immune responses, widespread endothelial damage, and complement-induced blood clotting with microangiopathy. COVID-19 manifests mainly as a respiratory illness. In cases of severe viral pneumonia, it may lead to acute respiratory distress syndrome, respiratory failure, and death. Challenges: Many extrapulmonary manifestations commonly occur, and a substantial proportion of patients with severe COVID-19 exhibit signs of kidney damage. Clinically, kidney involvement ranges from mild/moderate proteinuria and hematuria to acute kidney injury (AKI) requiring renal replacement therapy (RRT). The pathophysiologic mechanisms of kidney damage and AKI in patients with COVID-19 remain unclear but are known to be multifactorial. Current knowledge implies direct SARS-CoV-2-dependent effects on kidney cells (tubular epithelial cells and podocytes) and indirect mechanisms through the systemic effect of viral infection secondary to the critical pulmonary illness and its management. Prevention and Treatment: Standard-of-care strategies apply, as there is no specific evidence to suggest that COVID-19 AKI should be managed differently from other types in severely ill patients. If conservative management fails, RRT should be considered. The choice of RRT approaches and sequential extracorporeal therapies depends on local availability, resources, and expertise. The focus should now be on the long-term follow-up of COVID-19 patients, especially those who developed kidney injury and dysfunction. This represents an opportunity for integrated multidisciplinary research to clarify the natural history of COVID-19 renal sequelae and the best therapeutic interventions to mitigate them.

Renal Resistive Index as a Predictor of Acute Kidney Injury and Mortality in COVID-19 Critically Ill Patients.

BACKGROUND: Acute kidney injury (AKI) in patients with COVID-19 can be caused by multiple mechanisms. Renal resistive index (RRI) is a noninvasive instrument to evaluate kidney hemodynamics, and it is obtained by analysis of intrarenal arterial waves using Doppler ultrasound. This study aimed to determine the role of RRI in predicting AKI and adverse outcomes in critically ill patients with COVID-19. METHODS: This cross-sectional study included 65 patients with confirmed SARS-CoV-2 pneumonia admitted to the critical care unit from April 1, 2020, to June 20, 2020. Informed consent was obtained from all individual participants included in the study. Cardiac, pulmonary, and kidney ultrasonographic evaluations were performed in a protocolized way. RESULTS: In this cohort, 65 patients were included, mean age was 53.4 years, 79% were male, and 35% were diabetic. Thirty-four percent of patients developed AKI, 12% required RRT, and 35% died. Of the patients who developed AKI, 68% had RRI ≥ 0.7. Also, 75% of the patients who required RRT had RRI ≥ 0.7. In the adjusted Cox model, the RRI ≥ 0.7 was associated with higher mortality (HR 2.86, 95% CI: 1.19-6.82, p = 0.01). CONCLUSIONS: Critical care ultrasonography is a noninvasive, reproducible, and accurate bedside method that has proven its usefulness. An elevated RRI may have a role in predicting AKI, RRT initiation, and mortality in patients with severe SARS-CoV-2 pneumonia.

Peritoneal dialysis for acute kidney injury: Equations for dosing in pandemics, disasters, and beyond.

BACKGROUND: Peritoneal dialysis (PD) is a viable option for renal replacement therapy in acute kidney injury (AKI), especially in challenging times during disasters and pandemics when resources are limited. While PD techniques are well described, there is uncertainty about how to determine the amount of PD to be prescribed toward a target dose. The aim of this study is to derive practical equations to assist with the prescription of PD for AKI. METHODS: Using established physiological principles behind PD clearance and membrane transport, a primary determinant of dose delivery, equations were mathematically derived to estimate dialysate volume required to achieve a target dose of PD. RESULTS: The main derivative equation is VD = (1.2 × std-Kt/V × TBW)/(tdwell + 4), where VD is the total dialysate volume per day, std-Kt/V is the desired weekly dose, TBW is the total body water, and tdwell is the dwell time. VD can be expressed in terms of dwell volume, vdwell, by VD = (0.3 × std-Kt/V × TBW) - (6 × vdwell). Two further equations were derived which directly describe the mathematical relationship between tdwell and vdwell. A calculator is included as an Online Supplementary Material. CONCLUSIONS: The equations are intended as a practical tool to estimate solute clearances and guide prescription of continuous PD. The estimated dialysate volume required for any dose target can be calculated from cycle duration or dwell volume. However, the exact target dose of PD is uncertain and should be adjusted according to the clinical circumstances and response to treatment. The equations presented in this article facilitate the adjustment of PD prescription toward the targeted solute clearance.

Polymyxin B hemoperfusion in coronavirus disease 2019 patients with endotoxic shock: Case series from EUPHAS2 registry.

The coronavirus disease 2019 (COVID-19) has been shown to involve the gastrointestinal tract, which implies bacterial translocation and endotoxemia. The aim of this study was to evaluate the role of extracorporeal endotoxin removal by Polymyxin B hemoperfusion (PMX-HP), in the treatment of patients with COVID-19 and secondary bacterial infection. We conducted a subgroup analysis of a multicenter, multinational, prospective, and observational web-based database (EUPHAS2 registry). We included 12 patients with severe acute respiratory syndrome coronavirus 2 infection confirmed by real-time reverse transcriptase-polymerase chain reaction from nasal/oral swab, admitted to the intensive care unit between February and May 2020, who were affected by septic shock and received PMX-HP as per clinical indication of the attending physician. Septic shock was diagnosed in nine patients (75%), with a median time between symptoms onset and PMX-HP treatment of 16 (14-22) days. We identified Gram-negative bacteria in most of the microbiological cultures (N = 17, 65%), followed by Gram-positive bacteria in (N = 4, 15%), fungi (N = 3, 12%) and no growth (N = 2, 8%). Sequential Organ Failure Assessment (SOFA) score progressively improved over the next 120 hours following PMX-HP and it was associated with median endotoxin activity assay (EAA) decrease from 0.78 [0.70-0.92] at T0 to 0.60 [0.44-0.72] at T120 (P = .245). A direct correlation was observed between SOFA score and EAA. Lung Injury Score decreased and was associated with hemodynamic improvement over the same period. No statistically significant difference was observed for RIFLE score at each time point. Nine out of 12 patients (75%) required continuous renal replacement therapy because of acute kidney injury. In a series of consecutive COVID-19 patients with endotoxic shock, PMX-HP was associated with organ function recovery, hemodynamic improvement, and contemporary EAA level reduction. No PMX-HP-related complications were observed.

Medium Cut-Off Dialysis Membranes: Can They Have Impact on Outcome of COVID-19 Hemodialysis Patients?

INTRODUCTION: Severe acute respiratory syndrome coronavirus-2 may lead to high levels of expression of inflammatory cytokines. Medium cut-off (MCO) membranes may make greater clearances for large-middle molecules (including cytokines) than low-flux (LF) membranes. In this study, we aimed to evaluate the impact of MCO membranes on outcome of COVID-19 patients on hemodialysis (HD). METHODS: Sixty COVID-19 HD patients were included in this study. The patients were categorized into 2 groups regarding type of HD membranes. Clinical data were taken from medical records. RESULTS: Initial crp and ferritin levels, which are surragates of cytokine storm and severity of disease in COVID-19, were significantly higher in MCO membrane group compared to LF group (p = 0.037 and 0.000, respectively). Although there were more patients with severe disease in MCO group, there were no significant differences regarding need for intensive care unit and death. CONCLUSION: It may be an option to use MCO membranes in HD patients with COVID-19 in order to reduce cytokine levels and prevent cytokine storm.