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.

Endotoxin removal therapy with Polymyxin B immobilized fiber column: a single center experience from EUPHAS2 registry.

Although the precise clinical indication for initiation of PMX-HA is widely debated in the literature, a proper patient selection and timing of treatment delivery might play a critical role in the clinical course of a specific subphenotype of septic shock (endotoxic shock). In light of this view, since 2019, we have introduced in our clinical practice a diagnostic-therapeutic flowchart to select patients that can benefit the most from the treatment proposed. In addition, we reported in this study our experience of PMX-HA in a cohort of critically ill patients admitted to our intensive care unit (ICU). We analyzed a single centre, retrospective, observational web-based database (extracted from the EUPHAS2 registry) of critically ill patients admitted to the ICU between January 2016 and May 2021 who were affected by endotoxic shock. Patients were divided according to the diagnostic-therapeutic flowchart in two groups: Pre-Flowchart (Pre-F) and Post-Flowchart (Post-F). From January 2016 to May 2021, 61 patients were treated with PMX-HA out of 531 patients diagnosed with septic shock and of these, fifty patients (82%) developed AKI during their ICU stay. The most common source of infection was secondary peritonitis (36%), followed by community-acquired pneumonia (29%). Fifty-five (90%) out of 61 patients received a second PMX-HA treatment, with a statistically significant difference between the two groups (78% of the Pre-F vs. 100% of the Post-F group, p = 0.005). In both groups, between T0 and T120, the Endotoxin Activity Assay (EAA) decreased, while the SOFA score, mean arterial pressure (MAP), and Vasoactive Inotropic Score (VIS) improved with no statistically significant difference. Furthermore, when performing a propensity score matching analysis to compare mortality between the two groups, statistically significant lower ICU and 90-day mortalities were observed in the Post-F group [p = 0.016]. Although in this experienced centre data registry, PMX-HA was associated with organ function recovery, hemodynamic improvement, and current EAA level reduction in critically ill patients with endotoxic shock. Following propensity score-matched analysis, ICU mortality and 90-day mortalities were lower in the diagnostic-therapeutic flowchart group when considering two temporal groups based on strict patient selection criteria and timing to achieve PMX. Further Randomised Control Trials focused on centre selection, adequate training and a flowchart of action when assessing extracorporeal blood purification use should be performed.

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.

Wearable artificial kidney and wearable ultrafiltration device vascular access-future directions.

BACKGROUND: Since 2005, three human clinical trials have been performed with the Wearable Artificial Kidney (WAK) and Wearable Ultrafiltration (WUF) device. The lack of an adequate vascular access (VA) has been pointed out as the main limitation to their implementation. Based on the current level of understanding, we will make the first conceptual proposal of an adequate VA suitable for the WAK and the WUF. METHODS: All the literature related to WAK and WUF was reviewed. Based on eight main publications the VA major characteristics were defined: a mean blood flow of 100 mL/min; the capability to allow prolonged and frequent dialysis treatments, without interfering in activities of daily living (ADL); safe and convenient connection/disconnection systems; reduced risk of biofilm formation and coagulation; high biocompatibility. A research was done in order to answer to each necessary technological prerequisites. RESULTS: The use of a device similar to a CVC with a 5Fr lumen, seems to be the most feasible option. Totally subcutaneous port devices, like the LifeSite(R) or Dialock (R) systems can be a solution to allow WAK or WUF to operate continuously while patients carry out their ADL. Recently, macromolecules that reduce the risk of thrombosis and infection and are integrated into a CVC have been developed and have the capability of overcoming these major limitations. CONCLUSION: With an adequate VA, portable HD devices can be acceptable options to address several unmet clinical needs of HD patients.

How can we advance in renal replacement therapy techniques?

End-Stage Renal Disease (ESRD) is one of the major causes of morbidity and mortality worldwide. Although the incidence of ESRD is relatively stable, the prevalence of maintenance dialysis is increasing, and it is expected to reach a staggering 5439 million patients worldwide by 2030. Despite the great technological evolution that has taken place in recent years, most patients are still treated with in-centre haemodialysis and their prognosis remains far from desirable. Since 1980, there has been an increasing interest in the development of a portable device for renal replacement therapy (RRT), which ultimately led to the creation of the Wearable Artificial Kidney (WAK) and the Wearable Ultrafiltration (WUF) system. Portable RRT devices may be acceptable alternatives that deal with several unmet clinical needs of ESRD patients. So far, 3 important human studies with WAK and WUF have been carried out and, although these devices require considerable technological improvement, their safety and efficacy in solute clearance and fluid removal is undeniable. In this article, we review the evolution of the WAK and the WUF and the main clinical trials performed, highlighting some of their technical features. Some of the main possible clinical advantages that could be achieved with these devices, as well as some economic aspects, are also pointed out. In the future, all renal replacement therapy techniques should evolve to perfectly match the clinical and personal needs of each patient, allowing for an improved health-related quality of life.

ACUsmart Continuous Renal Replacement Therapy Platform: Multicenter Pilot Study for Technical and Clinical Assessment (A.M.P. Study).

BACKGROUND: ACUsmart (Medica S.P.A., Italy) is a new-generation, continuous renal replacement therapy (CRRT) machine for critically ill patients with acute kidney injury. We designed a multicenter international pilot study to provide a description of outlines of the ACUsmart system, evaluation aspects of functionality, usability, and feasibility, discriminating reasons of possible treatment's withdrawals or discontinuations and highlighting strong and weak points of the machine. METHODS: Data of 23 CRRT (and 11 plasma exchange) treatments were collected from 4 intensive care units. Parameters such as treatment duration, downtime, delivered dose, and number and type of alarms were recorded. The general perception of the machine was quantified through the administration of a survey to each component of the evaluating staff. RESULTS: A total treatment time of 447 h was carried with ACUsmart. Eleven continuous veno-venous hemofiltration, 4 continuous veno-venous hemodialysis , and 8 continuous veno-venous hemodiafiltration were performed. The average percentage of net treatment duration with respect to total treatment duration was 92.37%. The mean prescribed dose and delivered dose were 26.33 and 24.10 mL/kg/h, respectively. In general, the machine was rated by users involved as practical and easy to use, although few components need to be slightly improved. CONCLUSION: ACUsmart is a new multifunctional machine that meets most of the features required in a fourth-generation CRRT equipment.

Remote Patient Management in Peritoneal Dialysis: Impact on Clinician's Practice and Behavior.

Peritoneal dialysis (PD) is a self-administered chronic renal replacement therapy. It is a home-based therapy, and thus subject to the risk of discrepancy between prescribed dose and effective dialysis delivery. Till now automated peritoneal dialysis (APD) cyclers have recorded the dialysis treatments on a card that patients bring to the hospital for consultation in the PD unit. This card contains the operative parameters of each APD session. Recently, Baxter Healthcare developed a cloud-based tool for remote patient and treatment management. The new platform named Sharesource® embedded into the cycler HOMECHOICE CLARIA® allows to overcome the problems related to poor compliance and feeling of uncertainty by the patient, reducing the number of hospital visits and the workload for physician and nurses of the PD Unit. This new system uploads all treatment information to a secure cloud-based software. The 2-way communication platform gives remote visibility to patient's treatment and allows for feedback and correction of inadequate treatment program. Remote patient management (RPM) allows to visualize the course of home PD day after day, evaluating adherence to prescription, possible alarms during treatment, drainage times, and ultrafiltration amount. The evaluation of all the data can be done by the physician at his desk in the Hospital in front of the computer. RPM allows a patient's dialytic management in real time and enables the nephrologist to remotely modify treatment operative parameters, leaving the patient at home saving kilometers, money and time. In this chapter, we describe a simple algorithm used in our unit to define alarm thresholds and to describe actions to be instituted to correct any possible problem occurring during APD.

Presepsin and Procalcitonin Levels as Markers of Adverse Postoperative Complications and Mortality in Cardiac Surgery Patients.

Backgound: This study was aimed at evaluating the presepsin and procalcitonin levels to predict adverse postoperative complications and mortality in cardiac surgery patients. METHODS: A total of 122 cardiac surgery patients were enrolled for the study. Presepsin and procalcitonin levels were measured 48 h after the procedure. The primary endpoints were adverse renal, respiratory, and cardiovascular outcomes and mortality. RESULTS: Presepsin and procalcitonin levels were significantly higher in patients with adverse renal and respiratory outcome (p < 0.001 and 0.0081). The presepsin levels were significantly higher in patients with adverse cardiovascular outcome (p = 0.023) and the procalcitonin values in patients with sepsis (p = 0.0013). Presepsin levels were significantly higher in patients who died during hospitalization (382 pg/mL, interquartile range [IQR] 243-717.5 vs. 1,848 pg/mL, IQR 998-5,451.5, p = 0.049). In addition, the predictive value for in-hospital, 30-days, and 6-months mortality was higher for presepsin, with a significant difference between the 2 biomarkers (p = 0.025, p = 0.035, p = 0.003; respectively). Presepsin and procalcitonin seem to have comparable predictive value for adverse renal, cardiovascular, and respiratory outcome in cardiac surgery patients. Although a positive trend was notable for presepsin and adverse renal outcome (area under the ROC [receiver operating characteristic] curves [AUC] of 0.760, 95% CI 0.673-0.833 versus procalcitonin: AUC 0.692; 95% CI 0.601-0.773): no statistically significant difference was evident between the AUC of the 2 biomarkers (p = 0.25). CONCLUSIONS: Presepsin and -procalcitonin seem to have comparable predictive value for -adverse renal, cardiovascular, and respiratory outcome in cardiac surgery patients. Also, presepsin possesses a better predictive value for in-hospital, 30-days, and 6-months mortality.

Expanded haemodialysis: from operational mechanism to clinical results.

Recent advances in chemical composition and new production techniques resulted in improved biocompatibility and permeability of dialysis membranes. Among these, the creation of a new class of membranes called medium cut-off (MCO) represents an important step towards improvement of clinical outcomes. Such membranes have been developed to improve the clearance of medium to high molecular weight (MW) solutes (i.e. uraemic toxins in the range of 5-50 kDa). MCO membranes have peculiar retention onset and cut-off characteristics. Due to a modified sieving profile, MCO membranes have also been described as high-retention onset. The significant internal filtration achieved in MCO haemodialysers provides a remarkable convective clearance of medium to high MW solutes. The marginal loss of albumin observed in MCO membranes compared with high cut-off membranes is considered acceptable, if not beneficial, producing a certain clearance of protein-bound solutes. The application of MCO membranes in a classic dialysis modality characterizes a new technique called expanded haemodialysis. This therapy does not need specific software or dedicated hardware, making its application possible in every setting where the quality of dialysis fluid meets current standards.

Modeling of Internal Filtration in Theranova Hemodialyzers.

High retention onset (HRO) is the designation for a new class of hemodialysis membranes. A unique characteristic of this class is the highly selective and controlled porosity resulting in sieving properties that provide a clinically desirable balance between middle/large molecular weight solute removal and albumin loss. Another defining feature of this membrane class is the relatively small fiber diameter, which produces high convective volumes in the form of internal filtration. The aim of the present study was to estimate, by semi-empirical methods, convective volumes for 2 new HRO dialyzers: Theranova 400 and Theranova 500 (Baxter International Inc., Deerfield, IL, USA). Axial blood and dialysate compartment pressure drop along with transmembrane pressure, measured in vitro with blood (Qb = 300 or 400 mL/min; Qd = 500 mL/min; net ultrafiltration rate = 0), served as input parameters for 3 different models: linear, geometric, and (non-linear) mathematical. Based on the most rigorous mathematical model, the estimated convective volumes were 1,661 mL/h (Qb = 300 mL/min) and 1,911 mL/h (Qb = 400 mL/min) for Theranova 400 and 1,864 mL/h (Qb = 300 mL/min) and 1,978 mL/h (Qb = 400 mL/min) for Theranova 500. These results suggest that the unique fiber characteristics of this new class of membranes provide substantial convective volumes without the need for exogenous substitution fluid. As such, HRO membranes are a major end-stage renal disease treatment advance in the quest to enhance the removal of larger-sized uremic toxins.

Evaluation of a new polysulfone hemofilter for continuous renal replacement therapy.

New strategies using continuous renal replacement therapy as a tool to achieve immunomodulation in septic acute kidney injury have been proposed. The hypothesis is based on the possibility to remove inflammatory mediators and oxidants in a wide spectrum of molecular weights, thanks to new, highly permeable synthetic membranes. A new polysulfone hemofilter with high permeability and a sharp high cut-off membrane (CUREFLO™; Asahi Kasei Kuraray Medical Co., Ltd., Tokyo, Japan) has been evaluated in this study to assess IL-6 and advanced oxidation protein product removal in critically ill patients undergoing continuous renal replacement therapy. Unit performance, sieving coefficients and clearances were evaluated in fourteen patients undergoing continuous veno-venous hemofiltration and continuous veno-venous hemodialysis.

Prevalence of CKD in northeastern Italy: results of the INCIPE study and comparison with NHANES.

BACKGROUND AND OBJECTIVES: Sufficiently powered studies to investigate the CKD prevalence are few and do not cover southern Europe. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: For the INCIPE study, 6200 Caucasian patients ≥40 years old were randomly selected in northeastern Italy in 2006. Laboratory determinations were centralized. The albumin to creatinine ratio in urine and estimated GFR from calibrated creatinine (SCr) were determined. A comparison with 2001 through 2006 NHANES surveys was performed. RESULTS: Prevalence of CKD was 13.2% in northeastern (NE) Italy (age and gender standardized to the U.S. 2007 Caucasian population). Prevalence of CKD in U.S. Caucasians is higher (20.3%), the major difference being in CKD 3. Risk factors for CKD are more prevalent in the United States than in Italy. With use of CKD 3a and 3b stages, CKD prevalence decreased in NE Italy (8.5%) and in the United States (12.8%). CONCLUSIONS: The prevalence of CKD is high in NE Italy, but lower than that in the United States. A large part of the difference in CKD prevalence in NE Italy versus that in the United States is due to the different prevalence of CKD 3. The higher prevalence of a number of renal risk factors in persons from the United States explains in part the different dimensions of the CKD problem in the two populations.

Long-term treatment with potassium citrate and renal stones in medullary sponge kidney.

BACKGROUND AND OBJECTIVES: Medullary sponge kidney (MSK) is a renal malformation typically associated with nephrocalcinosis and recurrent calcium stones. Incomplete distal renal tubular acidosis, hypocitraturia, and hypercalciuria are common. For stone prevention, patients with MSK generally receive the standard "stone clinic" recommendations and often receive potassium citrate (KC). However, the effect on stone recurrence of citrate treatment in these patients has never been studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The issue was retrospectively analyzed on an outpatient basis in 97 patients with a radiologic diagnosis of MSK: 65 had at least one stone risk factor (SRF; hypercalciuria, hypocitraturia, hyperuricosuria, hyperoxaluria) and received KC [29 +/- 8 (SD) mEq/d]; 10 patients with SRF and 22 without received only general stone clinic suggestions. Follow-up was 78 +/- 13, 72 +/- 15, and 83 +/- 14 months, respectively. The 24-hour urinary excretion of calcium, oxalate, uric acid, citrate, and morning urine pH were investigated at baseline and at the end of follow-up. RESULTS: Parallel to a significant rise in urinary citrate and decreased urinary calcium (all P < 0.001), KC led to a dramatic reduction in the stone event rate (from 0.58 to 0.10 stones/yr per patient). The existence of a group of patients with MSK, those without SRF, with a very low stone rate and no SRF was recognized. CONCLUSIONS: Treatment with KC is effective in preventing renal stones in the typical patient with MSK. It seems that two clinical phenotypes among patients showing typical MSK features during radiologic study exist.

Identification of GDNF gene sequence variations in patients with medullary sponge kidney disease.

BACKGROUND AND OBJECTIVES: Medullary sponge kidney (MSK) is a rare nephropathy characterized by cystic anomalies of precalyceal ducts, nephrocalcinosis, renal stones, and tubule dysfunctions. Its association with various malformations and cases of familial aggregation supports the conviction that genetic factors are involved, but no genetic studies have been conducted to date. It is hypothesized that MSK is due to a disruption at the "ureteric bud/metanephric blastema" interface caused by critical developmental genes functioning abnormally. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Fifty-five apparently sporadic MSK patients were analyzed by direct DNA sequencing of all exons and exon-intron boundaries of glial cell-derived neurotrophic factor (GDNF) gene and rearranged during transfection (RET) gene, which have a leading role in renal development. RESULTS: Two novel variants were found in heterozygosity in the MSK case population: GDNF{ENST00000344622}:c.-45G>C and c.-27+18G>A in a putative binding domain for paired-box 2 transcription factor. As a whole, eight patients showed these variations: four patients carried the c.[-45G>C; -27+18G>A] complex allele, and the others had the c.-27+18G>A alone. A case-control study revealed that these two alleles were significantly associated with MSK. Five of the eight cases were found to be familial, and the allele variants cosegregated with the disease in a seemingly dominant pattern of inheritance. Patients revealed no mutations in the RET gene. CONCLUSIONS: This is the first report identifying GDNF gene sequence variations in patients with MSK and suggesting a role for this gene in the pathogenesis of some cases of the disease.

Bone disease in medullary sponge kidney and effect of potassium citrate treatment.

BACKGROUND AND OBJECTIVES: In medullary sponge kidney (MSK)-a common malformative renal condition in patients with calcium nephrolithiasis-hypercalciuria, incomplete distal renal tubular acidosis, and hypocitraturia are common. Clinical conditions with concomitant hypercalciuria and/or incomplete distal renal tubular acidosis are almost invariably associated with bone disease, making osteopathy highly likely in MSK, too. Patients with MSK have never been investigated for osteopathy; neither has the potential effect of potassium citrate administration (CA) on their urinary metabolic risk factors and on bone mineralization. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: These issues were retrospectively analyzed in 75 patients with MSK and primary stone risk factor (PSRF; hypercalciuria, hypocitraturia, hyperuricosuria, and/or hyperoxaluria) on an outpatient basis; 65 received CA (2.9 +/- 0.8 g/d), whereas 10 received only general "stone clinic" suggestions. The 24-h urinary excretion of calcium, phosphate, oxalate, uric acid, and citrate; morning urine pH; serum biochemistry; and bone mineral density were investigated at baseline and at the end of follow-up (78 +/- 13 and 72 +/- 15 mo in groups A and B, respectively). RESULTS: CA led to a significant rise in urinary pH and citrate and decreased urinary calcium and phosphate (all P < 0.001). Patients with MSK and PSRF had reduced bone density. Bone density improved significantly in the group that was treated with oral CA. CONCLUSIONS: Bone disease is very frequent in patients with MSK and concomitant PSRF. Long-term CA improves bone density. The concurrent effects of treatment on PSRF suggest that the subtle acidosis plays a pivotal role in bone disease and hypercalciuria in patients with MSK.