Human Proenkephalin A 119-159 (PenKid) in extracorporeal therapies: Ex-Vivo Sieving Coefficient, Diffusive Clearance and Hemoadsorption Kinetics.

Enkephalins are involved in the regulation of renal function. Proenkephalin A, also known as PenKid, has been demonstrated to be a reliable biomarker for kidney function and its plasma concentration correlates with measured glomerular filtration rate. PenKid is used for prediction and diagnosis of AKI, and need of renal replacement therapy (RRT). PenKid has also been used to predict the successful weaning from RRT in patients with AKI. Whether the concentration of PenKid is affected or not by RRT, is a controversial point and there are no studies describing the kinetics of the molecule. The low molecular weight (4.5 kDa) would imply free removal by the glomerulus and the dialysis membranes. During RRT, this reduction could not be detected due to the complex kinetics involving either low dialytic clearance or increased production in response to impaired kidney function. The aim of this study is to determine the sieving coefficient and the diffusive clearance of PenKid in conditions of in vitro continuous veno-venous hemofiltration (CVVH) and continuous veno-venous hemodialysis (CVVHD), respectively and also Penkid removal ratio in conditions of in vitro hemoadsorption (HA) using a synthetic microporous resin. In each experiment, the blood batch was adjusted at 1000 mL, maintained at 37° and stirred; blood was spiked with a lyophilized PenKid peptide. Samples were collected from blood, ultrafiltrate, and effluent at different times. Sieving, clearance and removal ratio were calculated. Significant removal of PenKid was observed in CVVH (sieving 1.04±0.27), CVVHD (clearance 23.08±0.89) and HA (removal ratio 76.1±1% after 120 minutes). PenKid is effectively removed by extracorporeal therapies. In presence of anuria, PenKid generation kinetics can be calculated based on extracorporeal removal and volume variation. In steady state conditions, declining values may be the result of an initial renal function recovery and may suggest discontinuation and successful liberation from RRT.

Use of eHealth and remote patient monitoring: a tool to support home dialysis patients, with an emphasis on peritoneal dialysis.

Implementing eHealth requires technological advancement, universal broadband and internet access, and devices to conduct telemedicine and remote patient monitoring in end-stage kidney disease patients receiving home dialysis. Although eHealth was beginning to make inroads in this patient population, the COVID-19 pandemic spurred telemedicine usage when many regulations were waived during the Public Health Emergency to limit the spread of infection by endorsing social distancing. At the same time, two-way communication automatic peritoneal dialysis cyclers were introduced to advance remote patient monitoring. Despite the numerous advantages and potential benefits afforded by both procedures, challenges and untapped resources remain to be addressed. Continuing research to assess the use of eHealth and technological innovation can make eHealth a powerful tool in home dialysis. We review the past, present and future of eHealth and remote patient monitoring in supporting home dialysis.

Exploring the Role of Cell-Free Nucleic Acids and Peritoneal Dialysis: A Narrative Review.

INTRODUCTION: Cell-free nucleic acids (cf-NAs) represent a promising biomarker of various pathological and physiological conditions. Since its discovery in 1948, cf-NAs gained prognostic value in oncology, immunology, and other relevant fields. In peritoneal dialysis (PD), blood purification is performed by exposing the peritoneal membrane. Relevant sections: Complications of PD such as acute peritonitis and peritoneal membrane aging are often critical in PD patient management. In this review, we focused on bacterial DNA, cell-free DNA, mitochondrial DNA (mtDNA), microRNA (miRNA), and their potential uses as biomarkers for monitoring PD and its complications. For instance, the isolation of bacterial DNA in early acute peritonitis allows bacterial identification and subsequent therapy implementation. Cell-free DNA in peritoneal dialysis effluent (PDE) represents a marker of stress of the peritoneal membrane in both acute and chronic PD complications. Moreover, miRNA are promising hallmarks of peritoneal membrane remodeling and aging, even before its manifestation. In this scenario, with multiple cytokines involved, mtDNA could be considered equally meaningful to determine tissue inflammation. CONCLUSIONS: This review explores the relevance of cf-NAs in PD, demonstrating its promising role for both diagnosis and treatment. Further studies are necessary to implement the use of cf-NAs in PD clinical practice.

CCL14 testing to guide clinical practice in patients with AKI: Results from an international expert panel.

PURPOSE: Urinary C-C motif chemokine ligand 14 (CCL14) is a strong predictor of persistent stage 3 acute kidney injury (AKI). Multiple clinical actions are recommended for AKI but how these are applied in individual patients and how the CCL14 test results may impact their application is unknown. METHODS: We assembled an international panel of 12 experts and conducted a modified Delphi process to evaluate patients at risk for persistent stage 3 AKI (lasting 72 hours or longer). Using a Likert scale, we rated 11 clinical actions based on international guidelines applied to each case before and after CCL14 testing and analyzed the association between the strength and direction of recommendations and CCL14 results. RESULTS: The strength and direction of clinical recommendations were strongly influenced by CCL14 results (P < 0.001 for the interaction). Nine (82%) recommendations for clinical actions were significantly impacted by CCL14 results (P < 0.001 comparing low to highest CCL14 risk category). CONCLUSIONS: Most recommendations for care of patients with stage 2-3 by an international panel of experts were strongly modified by CCL14 test results. This work should set the stage for clinical practice protocols and studies to determine the effects of recommended actions informed by CCL14.

Tissue Inhibitor Metalloproteinase-2·IGF-Binding Protein 7 for the Prediction of Acute Kidney Injury following Cardiac Surgery.

INTRODUCTION: Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common complication associated with increased morbidity and mortality. Tissue inhibitor metalloproteinase-2·insulin-like growth factor-binding protein 7 (TIMP-2·IGFBP7) determines tubular stress markers, which may occur prior to tubular damage. Previous studies on the use of TIMP-2·IGFBP7 for the prediction of CSA-AKI showed divergent results. Therefore, this study aimed to explore the predictive value of TIMP-2·IGFBP7 measurements for the early detection of acute kidney injury (AKI) and short-term adverse outcomes after cardiac surgery. METHODS: In the prospective cohort study, blood and urine samples were collected 6-12 h after cardiac surgery. Blood samples to monitor serum creatinine levels were additionally extracted from days 1 to 7. AKI was defined based on the KDIGO consensus guidelines. AKI within 7 days following surgery was the primary outcome. The initiation of renal replacement therapy, in intensive care unit mortality, and the combination of both were secondary outcomes. RESULTS: A total of 557 patients were enrolled; 134 (24.06%) of them developed AKI and 33 (5.9%) had moderate or severe AKI. AKI developed more frequently in elderly patients with diabetes or with higher baseline serum creatinine levels. Patients with AKI had higher EuroSCORE II, Cleveland Clinic Score, and simplified renal index (SRI) than those without AKI. Urinary TIMP-2·IGFBP7 was significantly higher in patients with AKI. The area under the curve was 0.66 in predicting all AKI and 0.70 in predicting stages 2 and 3 AKI. The resulting sensitivity and specificity were 44.0% and 83.9%, respectively, for a calculated threshold TIMP-2·IGFBP7 value of 0.265 (ng/mL)2/1,000. The TIMP-2·IGFBP7 values, SRI score, and age were significantly associated with AKI within 7 days postoperatively. A total of 33 patients reached the composite endpoint; the percentage of patients who reached the composite endpoint in the TIMP-2·IGFBP7 of >0.265 (ng/ml)2/1,000 group was significantly higher than that of ≤0.265 (ng/mL)2/1,000 group. CONCLUSIONS: Postoperative implementation of TIMP-2·IGFBP7 improved the prediction of CSA-AKI and may aid in identifying patients at risk of short-term adverse outcomes. We identified an ideal calculated cutoff value of 0.265 (ng/mL)2/1,000 for the prediction of CSA-AKI among all AKI patients.

Oxidative stress, defective proteostasis and immunometabolic complications in critically ill patients.

Oxidative stress (OS) develops in critically ill patients as a metabolic consequence of the immunoinflammatory and degenerative processes of the tissues. These induce increased and/or dysregulated fluxes of reactive species enhancing their pro-oxidant activity and toxicity. At the same time, OS sustains its own inflammatory and immunometabolic pathogenesis, leading to a pervasive and vitious cycle of events that contribute to defective immunity, organ dysfunction and poor prognosis. Protein damage is a key player of these OS effects; it generates increased levels of protein oxidation products and misfolded proteins in both the cellular and extracellular environment, and contributes to forms DAMPs and other proteinaceous material to be removed by endocytosis and proteostasis processes of different cell types, as endothelial cells, tissue resident monocytes-macrophages and peripheral immune cells. An excess of OS and protein damage in critical illness can overwhelm such cellular processes ultimately interfering with systemic proteostasis, and consequently with innate immunity and cell death pathways of the tissues thus sustaining organ dysfunction mechanisms. Extracorporeal therapies based on biocompatible/bioactive membranes and new adsorption techniques may hold some potential in reducing the impact of OS on the defective proteostasis of patients with critical illness. These can help neutralizing reactive and toxic species, also removing solutes in a wide spectrum of molecular weights thus improving proteostasis and its immunometabolic corelates. Pharmacological therapy is also moving steps forward which could help to enhance the efficacy of extracorporeal treatments. This narrative review article explores the aspects behind the origin and pathogenic role of OS in intensive care and critically ill patients, with a focus on protein damage as a cause of impaired systemic proteostasis and immune dysfunction in critical illness.

Hemoadsorption: Consensus report of the 30th Acute Disease Quality Initiative workgroup.

Adsorption-based extracorporeal therapies have been subject to technical developments and clinical application for close to five decades. More recently, new technological developments in membrane and sorbent manipulation have made it possible to deliver more biocompatible extracorporeal adsorption therapies to patients with a variety of conditions. There are several key rationales based on physicochemical principles and clinical considerations that justify the application and investigation of such therapies as evidenced by multiple ex-vivo, experimental, and clinical observations. Accordingly, unspecific adsorptive extracorporeal therapies have now been applied to the treatment of a wide array of conditions from poisoning to drug overdoses, to inflammatory states and sepsis, and acute or chronic liver and kidney failure. In response to the rapidly expanding knowledge base and increased clinical evidence, we convened an Acute Disease Quality Initiative (ADQI) consensus conference dedicated to such treatment. The data show that hemoadsorption has clinically acceptable short-term biocompatibility and safety, technical feasibility, and experimental demonstration of specified target molecule removal. Pilot studies demonstrate potentially beneficial effects on physiology and larger studies of endotoxin-based hemoadsorption have identified possible target phenotypes for larger randomized controlled trials (RCTs). Moreover, in a variety of endogenous and exogenous intoxications, removal of target molecules has been confirmed in vivo. However, some studies have raised concerns about harm or failed to deliver benefits. Thus, despite many achievements, modern hemoadsorption remains a novel and experimental intervention with limited data, and a large research agenda.

Immunomodulation Driven by Theranova Filter during a Single HD Session.

Background: Patients with end-stage kidney disease (ESKD) have altered immunity. Patients on hemodialysis (HD) present a coexistence of immunodeficiency and activation of the immune system. We evaluated the immunophenotypic profile induced by the medium cut-off of Theranova filter during a single HD session in the same individual. Methods: This pilot observational study explored 11 patients (75 ± 8 years and 73% male). Blood samples were collected prior to (predialytic, PRE) and after 4 h (postdialytic, POST) standard HD session with a medium cut-off, polyarylethersulfone and polyvinylpyrrolidone blend, BPA-free membrane. We performed an immunophenotyping characterization by using flow cytometry. We evaluated eryptosis RBCs and HLA-DR expression on monocytes and Treg cells. Results: The percentages of eryptosis in lymphocytes (CD3+), lymphocyte T helper (CD3+ and CD4+) cells, and monocytes (CD45+ and CD14+) were similar pre- and post-HD. On the contrary, HLA-DR expression and Treg cell numbers significantly decreased after HD. Conclusions: Many studies have focused on the comparison between healthy volunteers and HD patients, but very few have focused on the changes that occur after an HD session in the same individual. With this pilot observational study, we have revealed an immunomodulation driven by HD treatment with Theranova filter. Our preliminary results can be considered to be a hypothesis, generating and stimulating further studies with better designs and larger populations.

Peritoneal Inflammation in PD-Related Peritonitis Induces Systemic Eryptosis: In Vitro and In Vivo Assessments.

Erythrocytes (RBCs) have a highly specialized and organized membrane structure and undergo programmed cell death, known as eryptosis. Our preliminary data show a significant increase in the eryptosis during peritoneal dialysis (PD)-associated peritonitis. The objectives of the present study were assessment of the incrementation of eryptosis in PD patients with peritonitis, evaluation of the relationship between systemic eryptosis in peritonitis and specific peritonitis biomarkers in PD effluent (PDE), and confirmation of the induction of eryptosis by peritonitis in a vitro setting. We enrolled 22 PD patients with peritonitis and 17 healthy subjects (control group, CTR). For the in vivo study, eryptosis was measured in freshly isolated RBCs. For the in vitro study, healthy RBCs were exposed to the plasma of 22 PD patients with peritonitis and the plasma of the CTR group for 2, 4, and 24 h. Eryptosis was evaluated by flow cytometric analyses in vivo and in vitro. PDE samples were collected for biomarkers analysis.The percentage of eryptotic RBCs was significantly higher in PD patients with peritonitis than in CTR (PD patients with peritonitis: 7.7; IQR 4.3-14.2, versus CTR: 0.8; IQR 0.7-1.3; p < 0.001). We confirmed these in vivo results by in vitro experiments: healthy RBCs incubated with plasma from PD patients with peritonitis demonstrated a significant increase in eryptosis compared to healthy RBCs exposed to plasma from the control group at all times. Furthermore, significant positive correlations were observed between eryptosis level and all analyzed peritoneal biomarkers of peritonitis. We investigated a potential connection between systemic eryptosis and peritoneal biomarkers of peritonitis. Up-regulation of inflammatory markers could explain the increased rate of systemic eryptosis during PD-related peritonitis.

Acute kidney injury in patients with cirrhosis: Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) joint multidisciplinary consensus meeting.

Patients with cirrhosis are prone to developing acute kidney injury (AKI), a complication associated with a markedly increased in-hospital morbidity and mortality, along with a risk of progression to chronic kidney disease. Whereas patients with cirrhosis are at increased risk of developing any phenotype of AKI, hepatorenal syndrome (HRS), a specific form of AKI (HRS-AKI) in patients with advanced cirrhosis and ascites, carries an especially high mortality risk. Early recognition of HRS-AKI is crucial since administration of splanchnic vasoconstrictors may reverse the AKI and serve as a bridge to liver transplantation, the only curative option. In 2023, a joint meeting of the International Club of Ascites (ICA) and the Acute Disease Quality Initiative (ADQI) was convened to develop new diagnostic criteria for HRS-AKI, to provide graded recommendations for the work-up, management and post-discharge follow-up of patients with cirrhosis and AKI, and to highlight priorities for further research.

Extracorporeal removal of per- and polyfluoroalkyl substances (PFAS) by hemoadsorption: in vitro kinetic model.

INTRODUCTION: Per- and polyfluoroalkyl substances (PFAS) are known water pollutants leading to potential public health consequences. High blood levels of PFAS have been associated with several pathological conditions including testicular and kidney cancer. Classic extracorporeal therapies have demonstrated limited efficiency and new approaches should be explored. In this study we studied the possible role of hemoadsorption to achieve a fast, safe and effective removal of PFAS from blood in patients with high blood levels. METHODS: We developed an in vitro model of hemoadsorption to test the potential of PFAS removal by extracorporeal treatment. We recirculated a highly polluted batch of water (4 liters) through a sorbent cartridge (Jafron medical, Zuhai, China) for 120 minutes at a flow of 150 mL/min. We collected samples at different time points and analyzed 39 different PFAS compounds. RESULTS: For the PFAS compounds with concentrations significantly above normal, we observed a removal ratio close to 90% already within the first 60 minutes of circulation leading to almost complete elimination of all pollutants at 120 minutes. CONCLUSIONS: The in vitro model of hemoadsorption suggests the possible application in vivo of this technique to reduce/normalize the concentrations of PFAS in patients exposed to water or environmental pollution.

Ultrafiltration Tolerance: A Phenotype That We Need to Recognize.

BACKGROUND: The evaluation and management of fluid balance are key challenges in critical care patients who require renal replacement therapies because cumulative fluid balance is an independent factor that increases morbidity and mortality in different clinical scenarios. SUMMARY: One of the strategies when fluid overload is refractory to diuretics is extracorporeal fluid removal (i.e., net ultrafiltration [UFNET] during kidney replacement therapy). However, problems with UFNET without individualized assessment are cardiovascular events and intradialytic hypotension, events that contribute to decreasing organ perfusion and sympathetic stress. Therefore, we must consider and try to predict the best timing for the start of ultrafiltration and find the point where the patient is most tolerant to ultrafiltration, making a simile to the concept of fluid tolerance. KEY MESSAGES: UFNET is a continuous and dynamic process, going through moments of tolerance and intolerance to ultrafiltration; as nephrologists, we must take the necessary measures to move through this period.

Adsorption Mass Transfer Zone of Vancomycin in Cartridges With Styrene-Divinylbenzene Sorbent.

Cartridges for hemoadsorption containing styrene-divinylbenzene sorbent are used for multiple conditions, such as intoxication. The mass transfer zone comprises the extension along the longitudinal span of the cartridge where adsorption occurs. The aim of this experiment is to evaluate the mass transfer zone for vancomycin in the HA380 cartridge. The experiment was carried out twice. A saline solution with vancomycin passed through a HA380-modified cartridge at 100 ml/min in a single-pass fashion. The cartridge had four openings along its longitudinal dimension, at 3, 6, 9, and 12 cm. In both experiments, the collection of aliquots occurred at minute 4, in the four openings and pre- and post-cartridge, and an additional sample from the effluent bag at the end of each experiment. In the second experiment, an additional sampling of the same six sites occurred at minute 14. The sigmoidal shape of the curve for the mass transfer zone of vancomycin was similar to the theoretical one. In experiment one, at minute 4, vancomycin clearance was 98.75 ml/min. In experiment two, vancomycin clearance at minutes 4 and 14 was 93.76 and 93.20 ml/min, respectively. This implies an adequate and optimal design of the HA380 cartridge.

Effect of Mechanical Vibration on Kinetics of Solute Adsorption.

INTRODUCTION: Hemadsorption with new sorbent cartridges is an emerging extracorporeal blood purification technique. Flow distribution inside the sorbent is one of the main issues concerning the device's performance and optimal sorbent utilization. In this experiment, we aimed to investigate the efficacy of vibration during adsorption by measuring the removal of vancomycin. METHODS: In this experimental study, 1,000 mL of saline with 10 g of vancomycin was circulated in a closed circuit (set flow of 250 mL/min) simulating a hemadsorption blood run using HA380 minimodule cartridge containing 75 g of wet resin. This vibration model was implemented with a damping head device installed in front of the adsorption cartridge during the experiment. The kinetics of the vancomycin were assessed by removal ratio over 120 min. RESULTS: We found no difference between the two models. Adsorption with and without vibration did not differ significantly for partial reduction ratios, overall amount of adsorbed molecule, or adsorption kinetics. CONCLUSION: The current design and structure of the minimodule cartridge demonstrated no difference in small-middle solute removal. Further improvement with the addition of mechanical vibration to the device was not observed.

Development of a new miniaturized system for ultrafiltration.

Acute decompensated heart failure and fluid overload are the most common causes of hospitalization in heart failure patients, and often, they contribute to disease progression. Initial treatment encompasses intravenous diuretics although there might be a percentual of patients refractory to this pharmacological approach. New technologies have been developed to perform extracorporeal ultrafiltration in fluid overloaded patients. Current equipment allows to perform ultrafiltration in most hospital and acute care settings. Extracorporeal ultrafiltration is then prescribed and conducted by specialized teams, and fluid removal is planned to restore a status of hydration close to normal. Recent clinical trials and European and North American practice guidelines suggest that ultrafiltration is indicated for patients with refractory congestion not responding to medical therapy. Close interaction between nephrologists and cardiologists may be the key to a collaborative therapeutic effort in heart failure patients. Further studies are today suggesting that wearable technologies might become available soon to treat patients in ambulatory and de-hospitalized settings. These new technologies may help to cope with the increasing demand for the care of chronic heart failure patients. Herein, we provide a state-of-the-art review on extracorporeal ultrafiltration and describe the steps in the development of a new miniaturized system for ultrafiltration, called AD1 (Artificial Diuresis).