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).

The Cytotoxic Effect of Septic Plasma on Healthy RBCs: Is Eryptosis a New Mechanism for Sepsis?

Sepsis is a life-threatening multiple-organ dysfunction induced by infection and is one of the leading causes of mortality and critical illness worldwide. The pathogenesis of sepsis involves the alteration of several biochemical pathways such as immune response, coagulation, dysfunction of endothelium and tissue damage through cellular death and/or apoptosis. Recently, in vitro and in vivo studies reported changes in the morphology and in the shape of human red blood cells (RBCs) causing erythrocyte death (eryptosis) during sepsis. Characteristics of eryptosis include cell shrinkage, membrane blebbing, and surface exposure to phosphatidylserine (PS), which attract macrophages. The aim of this study was to evaluate the in vitro induction of eryptosis on healthy RBCs exposed to septic plasma at different time points. Furthermore, we preliminary investigated the in vivo levels of eryptosis in septic patients and its relationship with Endotoxin Activity Assay (EAA), mortality and other biological markers of inflammation and oxidative stress. We enrolled 16 septic patients and 16 healthy subjects (no systemic inflammation in the last 3 months) as a control group. At diagnosis, we measured Interleukin-6 (IL-6) and Myeloperoxidase (MPO). For in vitro study, healthy RBCs were exposed to the plasma of septic patients and CTR for 15 min, 1, 2, 4 and 24 h. Morphological markers of death and eryptosis were evaluated by flow cytometric analyses. The cytotoxic effect of septic plasma on RBCs was studied in vitro at 15 min, 1, 2, 4 and 24 h. Healthy RBCs incubated with plasma from septic patients went through significant morphological changes and eryptosis compared to those exposed to plasma from the control group at all time points (all, p < 0.001). IL-6 and MPO levels were significantly higher in septic patients than in controls (both, p < 0.001). The percentage of AnnexinV-binding RBCs was significantly higher in septic patients with EAA level ≥0.60 (positive EAA: 32.4%, IQR 27.6-36.2) compared to septic patients with EAA level <0.60 (negative EAA: 14.7%, IQR 5.7-30.7) (p = 0.04). Significant correlations were observed between eryptosis and EAA levels (Spearman rho2 = 0.50, p < 0.05), IL-6 (Spearman rho2 = 0.61, p < 0.05) and MPO (Spearman rho2 = 0.70, p < 0.05). In conclusion, we observed a quick and great cytotoxic effect of septic plasma on healthy RBCs and a strong correlation with other biomarkers of severity of sepsis. Based on these results, we confirmed the pathological role of eryptosis in sepsis and we hypothesized its use as a biomarker of sepsis, potentially helping physicians to face important treatment decisions.

New Miniaturized System for Ultrafiltration: Rationale and Design of a Single-Center, Crossover, Randomized, Open-Label, Pilot Study Protocol.

INTRODUCTION: Fluid overload and congestion are common features in patients with heart failure and are associated with negative clinical outcomes. Therapies for these conditions are diuretic-centered but frequently fail to achieve patient-adequate hydration status, prompting the use of extracorporeal ultrafiltration. Artificial Diuresis 1 (AD1) is a miniaturized, portable, and wearable system designed to deliver isolated ultrafiltration with the finest degree of simplicity and practicality. METHODS/DESIGN: Single-center, crossover, randomized, open-label pilot study to investigate the safety and the efficacy (concerning ultrafiltration accuracy) of extracorporeal ultrafiltration with the device AD1 in comparison to isolated ultrafiltration with a traditional machine (PrisMaX). Patients with chronic kidney disease stage 5D (on hemodialysis) or intensive care patients presenting acute kidney injury stage 3D (requiring hemodialysis) will carry out a single session of isolated ultrafiltration with each of the machines. The safety primary outcomes will be the occurrence of adverse events. The efficacy primary outcome will be the accuracy of ultrafiltration rate (delivered/prescribed) on each of the devices. CONCLUSION: AD1 is a novel miniaturized device for extracorporeal ultrafiltration. This study will be the first-in-human use of AD1 in patients with fluid overload.

Oxidants and Cardiorenal Vascular Remodeling-Insights from Rare Genetic Tubulopathies: Bartter's and Gitelman's Syndromes.

Two human genetic tubulopathies, Bartter's (BS) and Gitelman's (GS) syndromes, have normo/hypotension and absent cardiac remodeling despite their apparent angiotensin system (RAS) activation. This seeming contradiction has led to an extensive investigation of BSGS patients, the result of which is that BSGS represents a mirror image of hypertension. BSGS's unique set of properties has then permitted their use as a human model to probe and characterize RAS system pathways and oxidative stress in cardiovascular and renal remodeling and pathophysiology. This review details the results using GSBS patients that provide a deeper understanding of Ang II signaling and its associated oxidants/oxidative stress in humans. By providing a more complete and complex picture of cardiovascular and renal remodeling pathways and processes, studies of GSBS can inform the identification and selection of new targets and therapies to treat these and other oxidant-related disorders.

Artificial Diuresis: Animal Studies on Efficacy and Safety of a New Miniaturized Device for Extracorporeal Ultrafiltration.

INTRODUCTION: We have recently developed a new miniaturized device for extracorporeal ultrafiltration (UF) to be used in patients with fluid overload: Artificial Diuresis-1 (AD1) (Medica S.p.A., Medolla, Italy). The device has a reduced priming volume, operates at very low pressures and flow regimes, and is designed to perform extracorporeal UF at bedside. After accurate experiments were carried out in vitro, we report in this paper the results of in vivo UF sessions carried out in selected animals according to veterinary best practice. MATERIALS AND METHODS: The AD1 kit is pre-filled with sterile isotonic solution and operates with a polysulfone mini-filter, MediSulfone (polysulfone at 50,000 Dalton). A collection bag with a volumetric scale is connected to the UF line, and the ultrafiltrate is obtained by gravity based on the height at which the ultrafiltrate collection bag is placed. Animals were prepared and anesthetized. The jugular vein was cannulated with a double-lumen catheter. Three 6-h sessions of UF were scheduled with a target fluid removal of 1,500 mL. Heparin was used as anticoagulant. RESULTS: In all treatments, the target value of UF was obtained in the absence of major clinical or technical problems with a maximum deviation from the scheduled UF rate lower than 10%. The device resulted to be safe, reliable, accurate, and easily usable thanks to a user-friendly interface and its very small dimensions. CONCLUSIONS: This study opens the way for clinical trials in different settings including departments with low intensity of care and even in ambulatory centers or patient's home.

The Science of Extracorporeal Ultrafiltration: Introducing a Novel Miniaturized Device.

INTRODUCTION: Fluid overload has been associated with untoward outcomes in a variety of clinical settings. Isolated extracorporeal ultrafiltration (UF) allows for mechanical extraction of excess fluid and optimization of volume status without the established risks associated with use of high-dose diuretics. Conventional machines for renal replacement therapy can be used to perform isolated UF. However, they typically need high blood flow rates with high circuit volumes and the therapy has to be performed by trained nurses. Herein, we describe a novel device, the Artificial Diuresis-1, or AD 1 (Medica S.p.A., Medolla, Italy), which is a portable technology designed to perform extracorporeal UF at bedside. MATERIALS AND METHODS: The AD 1 uses a polysulfone mini-filter to generate ultrafiltrate with the help of two forces: blood flow (Qb) and gravity (based on the height at which the ultrafiltrate collection bag is placed). In vitro experiments were performed using human blood to evaluate vascular access pressures and ultrafiltrate volumes using various central venous catheters (CVCs; 12 Fr bilume, 10 Fr with 2 separate lumens, pediatric catheter 7 Fr). A variety of combinations were tested with Qb of 20, 35, 50 mL/min and collection bag height at 20, 40, 60 cm, measuring the UF rate per minute while monitoring the pressures in the venous and arterial lines and filtration fraction. RESULTS: The device's performance was as expected. Regarding the pediatric CVC, it was possible to perform measurements only with a Qb of 20 mL/min due to increased venous pressure. UF rates when lines were directly connected to the blood container as well as for CVC Tesio ranged from 3.7 to 11 mL/min, for the CVC Niagara™ from 4.5 to 12.5 mL/min, and for the CVC 7 Fr from 8.5 to 10 mL/min. The pressures of the vascular accesses were kept within a range of -5/-40 mm Hg for the artery and +10/+70 mm Hg for the vein. The highest venous pressure values were found with the CVC 7 Fr (+80/+100 mm Hg). CONCLUSIONS: This novel device allows to treat patients with fluid overload in a variety of settings, from low-intensity department such as long-term care facilities to the intensive care unit. The device is small and portable, has a simple design, and is user friendly. Future studies will be needed to evaluate whether gentle UF and treatment of volume overload will translate into improvement in clinical outcomes such as a reduction in congestion-related hospital admissions.

Rationale and need for simpler and effective miniaturized bedside ultrafiltration devices.

Fluid overload in different acute or chronic clinical settings results in unfavorable outcomes. The use of restrictive strategies for fluid control or the use of diuretics is frequently ineffective and requires extracorporeal ultrafiltration for the removal of excess volume. These extracorporeal treatments are performed with bulky machinery and require highly specialized personnel. The creation of a miniaturized device for extracorporeal ultrafiltration (Artificial Diuresis) would fill the technological gap in this sector by responding to the needs of cost containment and rehabilitation of the patient. In this article we explain the rationale that led to the design of this device.

Extracorporeal Ultrafiltration for Acute Heart Failure.

Acute decompensated heart failure (ADHF) has the highest rate of hospital re-admission among all medical conditions and portends a significant financial burden on healthcare systems worldwide. Hospitalization for ADHF is primarily driven by congestion, with intravenous loop diuretics representing the cornerstone of therapy. However, it is well described that a significant subset of patients are discharged with residual fluid overload. While the cause of the incomplete decongestion is multifactorial, development of diuretic resistance is a well-characterized contributing factor with consequent poor outcomes. Moreover, the therapeutic response to diuretics is known to lack predictability. Extracorporeal ultrafiltration (a mechanical pump-driven therapy) has emerged as an option to overcome shortcomings of the diuretics. It allows clinicians to customize the volume and rate of fluid removal to the needs and clinical characteristics of the patients. The results of the currently available studies indicate that this therapy is associated with more efficient fluid and sodium removal comparted to medical therapy, hence leading to reduction in the rate of re-admissions and a potential salutary impact on the financial burden associated with the care of these patients. While isolated ultrafiltration can be performed by conventional machines used for renal replacement therapy, the advent of simplified, portable, and user-friendly devices that are specifically designed for extracorporeal ultrafiltration therapy has further enhanced the interest in this therapeutic modality and increased the potential for its more widespread use. Further development in this direction through device miniaturization may extend the horizons of indications and the applicability of this therapy even in the ambulatory settings.

Fluid Overload and Precision Net Ultrafiltration in Critically Ill Patients.

BACKGROUND: Fluid overload is present in two-thirds of critically ill patients with acute kidney injury and is associated with morbidity, mortality, and increased healthcare resource utilization. Kidney replacement therapy is frequently used for net fluid removal (i.e., net ultrafiltration) in patients with severe oliguric acute kidney injury. However, ultrafiltration has considerable risks associated with it and there is a need for newer technology to perform ultrafiltration safely and to improve outcomes. SUMMARY: Caring for a critically ill patient with oliguric acute kidney injury and fluid overload is one of the most challenging problems. Although diuretics are the first line treatment for management of fluid overload, diuretic resistance is common. Various clinical practice guidelines support fluid removal using ultrafiltration during kidney replacement therapy. Emerging evidence from observational studies in critically ill patients suggests that both slow and fast rates of net fluid removal during continuous kidney replacement therapy are associated with increased mortality compared with moderate UFNET rates. In addition, fast UFNET rates are associated with an increased risk of cardiac arrhythmias. Randomized trials are required to examine whether moderate UFNET rates are associated with a reduced risk of hemodynamic instability, organ injury and improved outcomes in critically ill patients. There is a need for newer technology for fluid removal in patients who do not meet traditional criteria for initiation of KRT. Emerging newer and miniaturized ultrafiltration devices may address an unmet clinical need.

Assisted peritoneal dialysis: strategies and outcomes.

Assisted peritoneal dialysis (asPD) is a modality intended for not self-sufficient patients, mainly elderly, who are not able to perform peritoneal dialysis (PD) alone and require some help to manage the treatment. In the last decades, many countries developed strategies of asPD to face with aging of dialysis population and give an answer to the increasing demand of health service for elderly. Model of asPD varies according to the type of assistants employed and intensity of assistance provided. Both health care and non-health care assistants have been used with good clinical results. A mixed model of help, using different professional figures for short time or for longer according to patients' need, has been proved successful and cost-effective. Outcomes of asPD are reported in different ways, and the comparative effect of asPD is unclear. Quality of life has rarely been evaluated; however, patients seem to be satisfied with the assistance provided, since it allows them to both retain independence and to be relieved from the burden of self-care. Assisted PD should not be intended as a PD-favoring strategy, but as a model that allows home dialysis also in patients who would not be eligible for PD because of social, cognitive or physical barriers.

Regional Hypertonic Citrate Anticoagulation in Membrane Therapeutic Plasma Exchange: A Case Series.

RATIONALE: Protocols for regional citrate anticoagulation with the hypertonic 4% trisodium citrate solution have been recently described as an anticoagulation strategy during membrane therapeutic plasma exchange (mTPE). The effect of citrate in the patient's systemic hemostasis is negligible, thus regional citrate anticoagulation application is advantageous in circumstances in which heparin-based protocols are deemed unsafe for patients with a high risk of bleeding. The downsides of using hypertonic citrate solutions are mainly hypocalcemia and hypernatremia that ultimately can cause adverse clinical events. PRESENTING CONCERNS OF THE PATIENT: (1) A 57-year-old Caucasian female with a history of active vaginal bleeding secondary to endometrial hyperplasia. She had a history of antiphospholipid syndrome, and systemic lupus erythematosus with marked refractory autoimmune thrombocytopenia. Her platelet count was persistently below 4,000/mm3 even after different immunosuppressive regimens and daily platelet transfusions. (1) A 70-year-old Caucasian female was hospitalized presenting acute kidney injury stage 3 due to rapidly progressive antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, however without the need for renal replacement therapy. At admission, serum creatinine (sCr) was 3.56 mg/dL (normal range: 0.53-1.00 mg/dL). Her baseline sCr was 0.8 mg/dL obtained 6 months earlier. Chest tomography revealed bilateral masses compatible with granulomatous lesions and no signs of alveolar bleeding. Since severe cases of ANCA vasculitis involving the lungs may evolve with alveolar hemorrhage, heparin was avoided. DIAGNOSES: (1) Systemic lupus erythematosus-associated autoimmune thrombocytopenia and (2) ANCA-associated vasculitis with kidney and lung involvement. INTERVENTIONS: Herein, we describe a case series of 12 consecutive mTPE treatments in 2 different patients using regional 4% trisodium citrate anticoagulation. OUTCOMES: All the sessions were uneventful, presented only minor electrolyte imbalances, and were effectively completed without early interruptions due to clotting of the plasmafilter. TEACHING POINTS: In our 2 cases, extracorporeal regional citrate anticoagulation was successful in optimizing plasmafilter patency without bleeding events in 2 high-risk patients using established protocols for the citrate and calcium infusions.

FONDEMENT: Les protocoles d'anticoagulation régionale avec une solution hypertonique à 4 % de citrate trisodique ont récemment été décrits comme stratégie d'anticoagulation pendant les séances d'échange plasmatique par filtration (mTPE ­ membrane therapeutic plasma exchange). L'effet du citrate étant négligeable sur l'hémostase systémique du patient, l'anticoagulation régionale au citrate s'avère avantageuse dans les cas où les protocoles avec l'héparine sont jugés dangereux pour les patients dont le risque d'hémorragie est élevé. Les inconvénients liés aux solutions hypertoniques de citrate sont principalement l'hypocalcémie et l'hypernatrémie, lesquelles peuvent éventuellement entraîner des effets indésirables sur le plan clinique. PRÉSENTATION DES CAS: a) Une femme de race blanche âgée de 57 ans qui présentait des saignements vaginaux actifs en raison d'une hyperplasie de l'endomètre. La patiente avait des antécédents de syndrome antiphospholipide et de lupus érythémateux disséminé avec thrombopénie autoimmune réfractaire marquée. Sa numération plaquettaire demeurait invariablement inférieure à 4 000/mm3 malgré différents traitements immunosuppresseurs et la transfusion quotidienne de plaquettes. b) Une femme de race blanche âgée de 70 ans hospitalisée pour une insuffisance rénale aiguë de stade 3 due à une vascularite à évolution rapide associée aux anticorps cytoplasmiques antineutrophiles (ANCA). La patiente ne nécessitait aucun traitement de remplacement rénal. Son taux de créatinine sérique (SCr) à l'admission était de 3,56 mg/dL (plage normale : 0,53 à 1,00 mg/dL) alors que son taux initial, mesuré 6 mois plus tôt, était de 0,8 mg/dL. Une tomographie thoracique a révélé des masses bilatérales compatibles avec les lésions granulomateuses et l'absence de saignement alvéolaire. L'héparine a été écartée puisque les cas graves de vascularite associée aux ANCA avec atteinte des poumons peuvent évoluer vers une hémorragie alvéolaire. DIAGNOSTICS: a) Thrombocytopénie autoimmune associée à un lupus érythémateux disséminé; b) vascularite associée aux ANCA avec atteinte des reins et des poumons. INTERVENTIONS: Nous décrivons une série de cas impliquant deux patientes ayant subi 12 séances de mTPE consécutives avec un anticoagulant régional à 4 % de citrate trisodique. RÉSULTATS: Toutes les séances se sont déroulées sans incident, seuls des déséquilibres électrolytiques mineurs ont été observés. Toutes les séances ont été réalisées efficacement, sans interruption précoce due au blocage du filtre à plasma. ENSEIGNEMENTS TIRÉS: Dans deux cas qui présentaient un risque élevé d'hémorragie, l'anticoagulation régionale extracorporelle avec citrate, réalisée conformément aux protocoles établis pour les perfusions de citrate et de calcium, a permis d'optimiser la perméabilité du filtre à plasma sans causer d'événement hémorragique.

ACE2 and SARS-CoV-2 Infection Risk: Insights From Patients With Two Rare Genetic Tubulopathies, Gitelman's and Bartter's Syndromes.

COVID-19 is spreading globally with the angiotensin converting enzyme (ACE)-2 serving as the entry point of SARS-CoV-2 virus. This raised concerns how ACE2 and the Renin-Angiotensin (Ang)-System (RAS) are to be dealt with given their roles in hypertension and their involvement in COVID-19's morbidity and mortality. Specifically, increased ACE2 expression in response to treatment with ACE inhibitors (ACEi) and Ang II receptor blockers (ARBs) might theoretically increase COVID-19 risk by increasing SARS-CoV-2 binding sites. However, ACE2 is part of the protective counter-regulatory ACE2-Ang1-7-MasR axis, which opposes the classical ACE-AngII-AT1R regulatory axis. We used Gitelman's and Bartter's syndromes (GS/BS) patients, rare genetic tubulopathies that have endogenously increased levels of ACE2, to explore these issues. Specifically, 128 genetically confirmed GS/BS patients, living in Lombardia, Emilia Romagna and Veneto, the Northern Italy hot spots for COVID-19, were surveyed via telephone survey regarding COVID-19. The survey found no COVID-19 infection and absence of COVID-19 symptoms in any patient. Comparison analysis with the prevalence of COVID-19 in those regions showed statistical significance (p < 0.01). The results of the study strongly suggest that increased ACE2 does not increase risk of COVID-19 and that ACEi and ARBs by blocking excessive AT1R-mediated Ang II activation might favor the increase of ACE2-derived Ang 1-7. GS/BS patients' increased ACE2 and Ang 1-7 levels and their characteristic chronic metabolic alkalosis suggest a mechanism similar to that of chloroquine/hydroxychloroquine effect on ACE2 glycosylation alteration with resulting SARS-COV-2 binding inhibition and blockage/inhibition of viral entry. Studies from our laboratory are ongoing to explore GS/BS ACE2 glycosylation and other potential beneficial effects of BS/GS. Importantly, the absence of frank COVID-19 or of COVID-19 symptoms in the BS/GS patients cohort, given no direct ascertainment of COVID-19 status, suggest that elevated ACE2 levels as found in GS/BS patients at a minimum render COVID-19 infection asymptomatic and thus that COVID-19 symptoms are driven by ACE2 levels.

A Continuous Renal Replacement Therapy Protocol for Patients with Acute Kidney Injury in Intensive Care Unit with COVID-19.

COVID-19 often leads to acute respiratory distress syndrome complicated by acute kidney injury (AKI). The indications for renal replacement therapy for these patients are those commonly accepted to treat AKI. We describe a continuous veno-venous haemodialysis (CVVHD) protocol for AKI, which aims to provide the best treatment according to the particular patient's and medical personnels' needs in biohazard settings with limited human and technological resources. We designed a CVVHD protocol with a high cut-off (HCO) filter in regional citrate anticoagulation (RCA). The HCO filter in diffusion determines the enhanced cytokines clearance with less filter clotting due to a lower filtration fraction. In our hospital, at the beginning of the pandemic outbreak, we treated seven COVID-19 patients with AKI stage 2 and 3 and recorded the circuit lifespan and the number of interventions on monitors. CVVHD in RCA appears to be safe, effective and easy to be performed in a biohazard scenario using lower blood flows and less bag changes with fluid savings, a biohazard reduction and sparing of resources. Although the data come from a very small cohort, our protocol seems related to a low mortality.