Removal Of Uremic Toxins Research Articles

Development of Hollow Fiber Membranes Suitable for Outside-In Filtration of Human Blood Plasma

Hemodialysis (HD) is a critical treatment for patients with end-stage kidney disease (ESKD). The effectiveness of conventional dialyzers used there could be compromised during extended use due to limited blood compatibility of synthetic polymeric membranes and sub-optimal dialyzer design. In fact, blood flow in the hollow fiber (HF) membrane could trigger inflammatory responses and thrombus formation, leading to reduced filtration efficiency and limiting therapy duration, a consequence of flowing the patients’ blood through the lumen of each fiber while the dialysate passes along the inter-fiber space (IOF, inside-out filtration). This study investigates the development of HF membranes for “outside-in filtration” (OIF) in HD. In OIF, blood flows through the inter-fiber space while dialysate flows within the fiber lumens, reducing the risk of fiber clogging and potentially extending treatment duration. For the OIF mode, the membrane should have a blood-compatible outer selective layer in contact with the patient’s blood. We develop HFs for OIF via liquid-induced phase separation using PES/PVP (polyethersulphone/polyvinylpyrrolidone) blends. The fibers’ surface morphology (SEM, scanning electron microscopy), chemistry (ATR-FTIR—attenuated total reflection-Fourier transform infrared spectroscopy, XPS—X-ray photoelectron spectroscopy), transport properties, and uremic toxin removal from human plasma are evaluated and compared to commercial HFs. These membranes feature a smooth, hydrophilic outer layer, porous lumen, ultrafiltration coefficient of 13–34 mL m2 h−1 mmHg−1, adequate mechanical properties, low albumin leakage, and toxin removal performance on par with commercial membranes in IOF and OIF. They offer potential for more efficient long-term HD by reducing clogging and systemic anticoagulation needs and enhancing treatment time and toxin clearance.

Hemodiafiltration with endogenous reinfusion for uremic toxin removal in patients undergoing maintenance hemodialysis: a pilot study

Objective To delineate the efficacy and safety profile of hemodiafiltration with endogenous reinfusion (HFR) for uremic toxin removal in patients undergoing maintenance hemodialysis (MHD). Methods Patients who have been on MHD for a period of at least 3 months were enrolled. Each subject underwent one HFR and one hemodiafiltration (HDF) treatment. Blood samples were collected before and after a single HFR or HDF treatment to test uremic toxin levels and to calculate clearance rate. The primary efficacy endpoint was to compare uremic toxin levels of indoxyl sulfate (IS), λ-free light chains (λFLC), and β2-microglobulin (β2-MG) before and after HFR treatment. Secondary efficacy endpoints was to compare the levels of urea, interleukin-6 (IL-6), P-cresol, chitinase-3-like protein 1 (YKL-40), leptin (LEP), hippuric acid (HPA), trimethylamine N-oxide (TMAO), asymmetric dimethylarginine (ADMA), tumor necrosis factor-α (TNF-α), fibroblast growth factor 23 (FGF23) before and after HFR treatment. The study also undertook a comparative analysis of uremic toxin clearance between a single HFR and HDF treatment. Meanwhile, the lever of serum albumin and branched-chain amino acids before and after a single HFR or HDF treatment were compared. In terms of safety, the study was meticulous in recording vital signs and the incidence of adverse events throughout its duration. Results The study enrolled 20 patients. After a single HFR treatment, levels of IS, λFLC, β2-MG, IL-6, P-cresol, YKL-40, LEP, HPA, TMAO, ADMA, TNF-α, and FGF23 significantly decreased (p < 0.001 for all). The clearance rates of λFLC, β2-MG, IL-6, LEP, and TNF-α were significantly higher in HFR compared to HDF (p values: 0.036, 0.042, 0.041, 0.019, and 0.036, respectively). Compared with pre-HFR and post-HFR treatment, levels of serum albumin, valine, and isoleucine showed no significant difference (p > 0.05), while post-HDF, levels of serum albumin significantly decreased (p = 0.000). Conclusion HFR treatment effectively eliminates uremic toxins from the bloodstream of patients undergoing MHD, especially protein-bound toxins and large middle-molecule toxins. Additionally, it retains essential physiological compounds like albumin and branched-chain amino acids, underscoring its commendable safety profile.

How dialysis frequency and duration impact uremic toxin and fluid removal: a pediatric perspective.

Three-weekly 4-h hemodialysis/hemodiafiltration (HD/HDF) per week has become the "standard HD/HDF" regimen in children across the globe, although increasingly criticized, since crucial determinants such as residual kidney function and patient preferences are not considered. As a consequence, several children fail to achieve adequate dialysis while on a "standard HD/HDF." In these circumstances, an extended dialysis prescription such as short daily (2-3h/session, 5-7days a week) or nocturnal HD/HDF (6-9h/session, 3-5days a week), either at home or in a dialysis center, may be considered. The purpose of this educational review is to summarize the impact of dialysis duration and frequency on uremic toxin and fluid removal. Moreover, we aim to summarize the existing literature on HD/HDF strategies with extended dialysis duration and/or increased frequency (> 12h dialysis time per week) in pediatrics. Dialysis duration and frequency plays a crucial role in uremic toxin removal, in particular for uremic toxins with retarded transport in patients, such as phosphate, β2-microglobulin (β2m), and protein-bound uremic toxins. Also, increasing dialysis duration and/or frequency decreases the gap between plasma refilling and ultrafiltration volume), thereby decreasing the need for a high ultrafiltration rate. Observational studies in children demonstrate a beneficial effect of extended dialysis regimens (i.e., more frequent or longer duration) on blood pressure control, left ventricular hypertrophy, growth, and quality of life. PTH levels tend to decrease in the majority of studies, while hypocalcemia or suppressed PTH levels were also reported. Dietary restrictions were decreased or stopped, along with tapering of phosphate binders and potassium chelators. Extended HD/HDF regimens are beneficial in a particular group of children. Pediatric-specific international guidelines are needed to support pediatric nephrologists in determining for which children extended HD regimens are beneficial, along with increasing efforts to decrease the financial, organizational, and psychosocial barriers that are present in extended HD/HDF.

Zirconia encrusted ceramic composite membrane for uremic toxins removal: Fabrication and assessment of biocompatibility

In this study, tubular zirconia composite membranes (ZM1-ZM3) were developed using low-cost tubular substrate which was prepared utilizing naturally available clay materials by an extrusion approach. The zirconia nanoparticles were encrusted on a low-cost tubular substrate using spray pyrolysis technique. The membranes were investigated for their biocompatibility in addition to pore size, chemical stability, water permeability, porosity, contact angle, thermogravimetric (TGA), and X-ray diffraction (XRD). Water permeability, pore size and porosity of optimized membrane (ZM3) were 3.05 × 10–4 ± 0.03 L.m-2.h-1.Pa-1, 119 ± 0.57 nm and 36 ± 0.12 %, respectively. Platelets adhesion and protein adsorption were measured to be 4630 ± 46 platelets.mm-2, and 1.05 ± 0.02 μg.cm-2 respectively, while the activated partial thromboplastin time (APTT) and prothrombin time (PT) were 80 ± 0.51 s and 27 ± 0.26 s, respectively. Complement activation C3 and C4 concentrations were assessed to be 76.2 ± 0.88 mg.dL-1 and 21.57 ± 0.80 mg.dL-1, respectively and hemolysis ratio was 0.31 ± 0.01 %. Moreover, the membrane had a considerable antifouling nature with a flux recovery ratio of 89.22 ± 0.58 %. Protein retention was found to be 81.14 ± 0.58 %, in addition to outstanding sieving coefficients of uremic toxins like urea (0.95 ± 0.005), creatinine (0.93 ± 0.004), and phosphate (0.90 ± 0.004). These findings suggest that the produced tubular zirconia composite membrane has the potency for hemofiltration.

Future of Uremic Toxin Management.

During the progression of chronic kidney disease (CKD), the retention of uremic toxins plays a key role in the development of uremic syndrome. Knowledge about the nature and biological impact of uremic toxins has grown exponentially over the past decades. However, the science on reducing the concentration and effects of uremic toxins has not advanced in parallel. Additionally, the focus has remained for too long on dialysis strategies, which only benefit the small fraction of people with CKD who suffer from advanced kidney disease, whereas uremic toxicity effects are only partially prevented. This article reviews recent research on alternative methods to counteract uremic toxicity, emphasizing options that are also beneficial in the earlier stages of CKD, with a focus on both established methods and approaches which are still under investigation or at the experimental stage. We will consequently discuss the preservation of kidney function, the prevention of cardiovascular damage, gastro-intestinal interventions, including diet and biotics, and pharmacologic interventions. In the final part, we also review alternative options for extracorporeal uremic toxin removal. The future will reveal which of these options are valid for further development and evidence-based assessment, hopefully leading to a more sustainable treatment model for CKD than the current one.

Adsorption Study of Uremic Toxins (Urea, Creatinine, and Uric Acid) Using Modified Clinoptilolite

The development of materials for uremic toxin removal is under continuous research. In this work, a natural zeolite (clinoptilolite) was modified using tartaric acid through two different methods: conventional reflux heating and ultrasound energy. The resulting materials were used as an adsorbent material for the removal of uremic toxins such as urea, creatinine, and uric acid. In the uremic toxin removal study, it was observed that the material modified using ultrasound for 100 min had the highest removal values (74.49%, 40.31%, and 51.50% for urea, creatinine, and uric acid, respectively), while unmodified zeolite removed 30.57%, 18.07%, and 22.84% of the same toxins. The best results for conventional heating modification were 67.08%, 31.97%, and 32.39%, respectively. Therefore, acid group incorporation considerably improved the adsorption properties of the clinoptilolite. Regarding adsorption kinetics, it was found that the pseudo-second-order model better described the behavior of all the modified materials. Equilibrium adsorption data were adjusted to the Langmuir and Freundlich models. The Freundlich model (multilayer adsorption) described urea adsorption, while the Langmuir model (monolayer adsorption) described creatinine and uric acid.

Simultaneous removal of endotoxins, inflammatory mediators and uremic toxins in ICU patients with septic shock: a retrospective cohort study

Sepsis, one of the leading causes of death, is still lacking specific treatment. OXIRIS (BAXTER, Deerfield, IL, USA) is the first device allowing combined removal of endotoxins, inflammatory mediators and uremic toxins, alongside fluid balance control. Available data is very limited. This retrospective propensity score-matched cohort study of adult patients with septic shock aimed to evaluate septic shock duration and mortality in patients treated with either standard of care renal replacement therapy (RRT) or RRT with combined hemoadsorption, who were admitted to the interdisciplinary surgical intensive care unit at Heidelberg University Hospital during the years 2018 through 2021. Main outcomes were duration of shock, thirty-day mortality and plasma interleukin-6 levels before and after initiation of hemoadsorption. Included were 117 patients (female, 33%; male 67%); median age: 67 (16) years. After matching: 42 patients (female, 33%; male, 67%); mean age: 59.1 ± 13.8 years. There was no statistically significant difference in septic shock duration (p = 0.94; hazard ratio (HR) 0.97 (95% CI, 0.48–1.97)). Thirty-day survival analysis showed a non-statistically significant survival difference. (p = 0.063; HR 0.43 (95% CI, 0.17–1.09)). A post-hoc 90-day survival analysis revealed statistically significant longer survival and lower death hazard ratio in patients treated with RRT + HA (p = 0.037; HR = 0.42 (95% CI, 0.18–0.99). In conclusion, RRT with combined hemoadsorption of endotoxins, inflammatory mediators and uremic toxins is a modality worth further investigation.

Online Hemodiafiltration: A New Perspective for Patients With End-Stage Renal Disease.

Introduction Online hemodiafiltration (OL-HDF) is the most effective renal replacement therapy (RRT), which allows the enhanced removal of small and large uremic toxins by combining diffusion and convective transport of solutes. Although the goal of OL-HDF is to provide greater clearance of solutes with a preference for intermediate molecules responsible for many of the complications of chronic kidney disease (CKD), the studies reported to date and their meta-analyses are conflicting in nature and do not show a significant advantage of convective therapies on patient prognosis. Materials and methods At the Clinic of Nephrology and Dialysis, University Hospital "St. Marina", Varna, Bulgaria, 41 patients were monitored in a retrospective study for a two-year period, randomized into two groups, conducting OL-HDF after dilution and hemodialysis (HD) with the aim of studying the effect of convective therapies on the clinical outcome, the achieved quality of life, and the prognosis of the patient. Results The study found a significantly higher quality of life in patients undergoing OL-HDF with significantly higher values ​​of indicators of dialysis adequacy and nutritional status, better control of the anemic syndrome with the reduction of erythropoietin doses, significantly lower frequency of episodes of intradialytic hypotension with improved recovery, and 3.6-fold lower risk of death compared with conventional dialysis. Discussion Three major randomized controlled trials have compared survival outcomes in patients receiving HD or post-dilution OL-HDF, reporting conflicting results. Meta-analyses of the published studies have also been unable to provide a clear and definitive answer regarding the potential benefits of choosing one treatment over the other. Overall mortality, anemia, phosphate control, and small molecule clearance appear to be insufficiently influenced by the treatment method. On the other hand, cardiovascular mortality, hemodynamic stability, and clearance of middle and protein-bound molecules seem to be better in patients treated with OL-HDF. Conclusions Despite the conflicting data reported so far, OL-HDF is associated with better clinical outcome and prognosis for end-stage renal disease (ESRD) patient and undoubtedly warrants extensive future study with a view to improved quality of life in the growing dialysis population.

Potential of electrospun fibrous membranes involving tri-n-octylphosphine oxide for selective clearance of uremic toxin p-cresol over urea and creatinine

In this study, various electrospun and electrosprayed fibrous membranes from polyethersulfone (PES) and polyvinylpyrrolidone (PVP) were fabricated, to which a common solvating extractant tri-n-octylphosphine oxide (TOPO) was incorporated. Such TOPO-involved PES membranes were attempted to selectively clear p-cresol, one of trace amounts of small uremic toxins, from simulated serum via hydrogen bonding. Morphological and physicochemical properties of the as-synthesized fibrous membranes were first studied. Batch tests displayed that the equilibrium of p-cresol adsorption on all fibrous membranes were attained within 2 h. Analysis of adsorption isotherms of p-cresol by the Langmuir equation revealed that the adsorption was improved in the presence of TOPO; moreover, the distribution state of TOPO powders along the fibers played an important role in membrane performance. Among the six as-prepared TOPO-incorporated membranes, the highest adsorption capacity of p-cresol in simulated serum at 37oC and pH 7.4 reached to be 21.7 mmol per gram of TOPO. The operational stability of as-prepared fibrous membranes was evaluated by checking their adsorption ability, membrane weight, water contact angle, structural changes by SEM imaging, and PVP dissolution using UV–Vis spectroscopy, both before and after exposure to PBS solution. Crossflow permeation-adsorption of a multicomponent mixture (0.46 mmol/L of p-cresol, 1.33 mmol/L of creatinine, and 38.3 mmol/L of urea) for 4 h indicated that the prepared membranes yielded a high selectivity toward p-cresol against creatinine and urea of 21.2–43.0 and 10.8–18.5, respectively. Hemolysis tests and viability measurements of both human umbilical vein endothelial cells and THP 1 monocytic leukemia cells demonstrated that the proposed configurations of the TOPO-incorporated fibrous membranes were hemo- and bio-compatible. Our results on the composition and systematic design of these fibrous membranes suggested that they can serve as an advanced hemoperfusion unit, maintaining high p-cresol removal and bio-compatibility. These well-designed membrane-based devices could be connected in series with the conventional hemodialysis devices to further improve the overall removal of small uremic toxins.

#332 Dermatological manifestations in pediatric CKD patients

Abstract Background and Aims Chronic kidney disease (CKD), regardless of its cause, may be accompanied by various skin lesions. The most common symptom in children suffering from CKD is pruritus however other signs that may be seen are xerosis, skin hyperpigmentation, ecchymoses, acquired perforating dermatoses, nail lesions, calcinosis cutis, as well as eczematous lesions at the site of an arteriovenous fistula and skin infections. Data on different skin lesions in children with CKD is very limited; only few reports have been published discussing xerosis in pediatric patients and most studies were conducted on a small number of patients who needed renal replacement therapy . This study aimed primarily to screen the different dermatological manifestations in pediatric patients with CKD, in addition to studying the relationship of dermatological manifestations with the CKD stage, types of dialysis, various clinical and metabolic parameters. Method This was a cross sectional study, that was conducted at Pediatric Dialysis and Nephrology unit, Children's Hospital, Faculty of Medicine, Ain Shams University Hospital, Cairo, Egypt, during the period from February 2023 to August 2023, where 70 patients were enrolled in our study being divided into two groups: group 1 including CKD patients stages (2-4) and group 2 including CKD patients with stage 5 on regular hemodialysis. Detailed dermatological &amp; nail examination were conducted. Xerosis severity was assessed using a four-point xerosis assessment scale (0, normal skin, without any xerosis; 1, mild xerosis; 2, moderately dry skin with minimal flaking; 3, severe xerosis, heavy scaling visible), whereas pruritus was assessed using a visual analogue scale (VAS) on a scale of 1 (no itch) to 10 (worst possible itch). Laboratory data were withdrawn at the time of examination to correlate with different dermatological manifestation. Results In our study, xerosis was the most frequent dermatological manifestation (78.6%) following it pruritus (62.9%) then pallor (35.7%), hyperpigmentation (20%), hypertrichosis (10 %), nail and hair abnormalities (8.5%) &amp; post inflammatory hyperpigmentation (4.3%). The prevalence of xerosis was not affected by clinico-demographic data, CKD duration &amp; stage, type and duration of dialysis, the only significant relation was between efficacy of dialysis (Kt/V) and incidence of xerosis, where the higher dialysis efficacy rates were associated with low incidence rates of xerosis, in which effective hemodialysis contributes to better removal of uremic toxins, &amp; hence decrease the xerosis. Leukocytosis was noticed in xerotic &amp; pruritic patients, where xerosis &amp; impaired skin barrier in children with CKD pose a risk for different cutaneous infections &amp; inflammation, and hence pruritis. Conclusion Xerosis and pruritis are not uncommon dermatological manifestations among pediatric patients with chronic kidney disease, meanwhile the age of the patients and the underlying CKD etiology had no direct effect on skin changes. The most determinant factory affecting the xerosis was the hemodialysis efficacy, where higher efficacy was associated with less xerosis, meanwhile leukocytosis was associated with higher xerosis and pruritis. Further studies are needed to detect various skin manifestations in CKD patients with different CKD stages and correlate it with the used dialysis modalities.

#1573 Effects of haemodialysis coupled with hemadsorption on uremic toxins removal, oxidative stress and cellular death.

Abstract Background and Aims The retention of middle-molecules and Protein Bound Uraemic Toxins (PBUT) in dialysis patients are directly linked to specific clinical complications such as anaemia, inflammation and cardiovascular disease leading to increased mortality. These toxins, not adequately cleared by current dialysis techniques, could be removed by adsorption as demonstrated in numerous studies on dialysis patients. Furthermore, in dialysis patients there's an increased inflammation and oxidative stress only partially attenuated by biocompatibility of newly developed membraned. This pathologic inflammatory response lead to tissue damage and cellular death. A particular form of programmed cellular death involving red blood cells is called Eryptosis and is detectable as changes in the morphology and in the shape of human erythrocytes. The aim of this study was to assess the safety of dialysis coupled with hemadsorption (HA+HD) in terms of biocompatibility and efficacy in terms of removal of middle-molecules and PBUTs. Method This was a preliminary analysis of a multicentre observational study that evaluated 4 dialysis session focusing on 7 chronic dialysis patients of our dialysis centre. Patients were treated with HA+HD with HA130 cartridge (Jafron) only in the early-week dialysis session and then returned to their usual prescription. Blood samples were taken before and after dialysis session in order to measure Eryptosis as a marker of biocompatibility and few uremic toxins to assess the efficacy of the treatment by using Removal Ratio. Eryptototic RBCs were identified by FS (cell volume dimension) and FITC_AnnexinV-binding (Beckman Coulter, Brea, CA, USA) using Navios Flow Cytometer (Beckman Coulter, Brea, CA, USA). A minimum 100.000 events were collected on each sample. Statistical analysis was performed using the SPSS Software package. A p-value of &amp;lt;0.05 was considered statistically significant. Results This study was carried out on 7 patients (4 women) with a mean age of 65.7 ± 11.5 years and a median dialysis vintage of 33 months (IQR 28-51). All patients had AVF with Qb of 330 ml/min. Dialysis length was 210 minutes. We didn't find any differences between Eryptosis values measured before and after dialysis (Table 1), and between different timepoints. We found significant reduction of PTH (pre: 391.5 ng/L, IQR 206.5-602.8 vs post: 162.0 ng/L, IQR 95.0-363.3; p=0.005) and β2-microglobulin (pre: 23.10 mg/L, IQR 22.1-24.1 vs post: 6.72 mg/L, IQR 6.2-8.3; p&amp;gt;0.005) throughout the dialysis session coupled with hemadsorption (Fig. 1). Conclusion In this preliminary analysis, we found that the association of Dialysis with Hemadsorption allows a great removal of middle molecular-weight uremic toxins without compromise biocompatibility and thus represent a better treatment option in patients with high retention of these toxins.

#1351 Assessment of safety and efficacy of expanded hemodialysis in comparison to HDF

Abstract Background and Aims In end-stage kidney disease, solutes with a wide spectrum of molecular weight, called uremic toxins, are retained due to impaired kidney cleansing capacity. Particularly, the retention of toxins in the middle molecular weight range 15–45 kDa might negatively affects multiple organ systems and metabolic pathways. The removal of such large uraemic toxins is still a challenge. HDF has produced some results although large convective volume, optimal vascular access to increase the blood flow rate and strict water quality management are required. Medium Cut-Off, high Retention Onset membrane have been recently developed introducing the concept therapy called “expanded haemodialysis” (HDx). Furthermore, vitamin E-coated membrane has potential beneficial effects on inflammation and oxidative stress. Method A prospective longitudinal single-center study was conducted for 3 months among 18 chronic haemodialysis patients. Patients were randomly assigned into either HDF with high flux membrane or HDx with Theranova or ViE-X membrane. The primary goal was to assess albumin loss among the three types of dialyzers. Secondary goals included assessment of depurative efficacy for uraemic toxins and clinical outcomes. Throughout the treatment, a proportional part of the dialysis fluid was collected to quantify albumin loss. Blood samples were taken before and after dialysis session in order to calculate the Removal Ratio and at two different intradialytic timepoints from arterial and venous line of the circuit in order to calculate instantaneous clearance. Results Mean albumin loss was significantly higher in patients undergoing HDx with Theranova membrane (ANOVA, p&amp;lt;0.001) without any difference in serum albumin concentration among the three groups. Instantaneous clearance of small and middle molecules was significantly higher in patients undergoing HDF, but we didn't find differences in removal ratio. Reduction of Erythropoietin resistance index was observed in patients treated with ViE-X membrane but it was related to their lower dialysis vintage. Conclusion HDx with Theranova membrane was associated with higher albumin loss without any effect on pre-dialysis serum albumin. Moreover, patients treated Theranova membrane, in the presence lower Qb, lower convective dose and lower instantaneous clearance reached same dialysis efficacy compared to HDF.

#828 Non-invasive determination of uric acid in blood during hemodialysis with an optical spent dialysate sensor

Abstract Background and Aims Kt/V urea is conventionally used hemodialysis (HD) adequacy marker, whereas many other uremic toxins with differing removal kinetics affect the mortality of end stage kidney disease (ESKD) patients. Among them, uric acid (UA) has been shown to cause cardiovascular mortality of ESKD patients. Recently, determination of UA concentration in blood with optical sensors during HD has been attempted by Lin et al in 2021 and Żyłka et al in 2023, but the accuracy has been relatively low. Moreover, Żyłka et al measured light absorption of spent dialysate at 573 nm to determine UA concentration, whereas previous research has shown that dialysate and UA have negligible light absorption in that region. The aim of this observational study was to predict concentration of UA with higher accuracy in ESKD patients’ blood during HD with various treatment settings by monitoring spent dialysate noninvasively with an optical sensor. Method Twenty-two ESKD patients on chronic HD were included into the study. Each patient received four 4 h long midweek HD sessions: one standard HD and three haemodiafiltration (HDF) sessions with different settings. Median (interquartile range) settings of the 1 HD session were: effective blood flow (Qb) = 199 (198-199) mL/min, dialysate flow (Qd) = 297 (297-298) mL/min, ultrafiltration rate (UF) = 13 (8-16) mL/min, dialyzer area 1.5 m2 and for the 3 HDF sessions: Qb = 298 (296-356) mL/min, Qd = 788 (489-792) mL/min, substitution fluid flow (Qsubs) = 96 (66-106) mL/min, UF = 11 (8-15) mL/min, dialyzer areas 1.8 m2 and 2.2 m2. Blood samples were collected before the start and at the end of each HD session from the arterial blood line and spent dialysate samples were collected 7, 60, 120, 180 and 240 min after the start from the outlet of the HD machine. Concentration of UA in spent dialysate and serum samples were determined with HPLC. An optical sensor (Optofluid Technologies OÜ, Tallinn, Estonia) was connected to the spent dialysate outlet of the HD machine and ultraviolet (UV) light absorption of spent dialysate was measured online in real time for each HD session. A linear interactions regression model was created using light absorbance at four different UV wavelengths to predict UA concentrations in collected spent dialysate samples. A curve of UA concentration for the whole HD session was determined based on the model and UV absorbance data measured with the optical sensor. Thereafter, UA concentration in spent dialysate at the start and at the end of each session (UAsensor hereinafter) was found from the concentration curve. The data of 88 HD sessions were equally divided into calibration and validation sets. Linear regression model was created using data of calibration set to predict concentration of UA (UApredicted) in blood as follows: UApredicted = a • UAsensor • $\frac{{{\rm{Qd}} + {\rm{\ Qsubs}} + {\rm{UF\ }}}}{{{\rm{Qb}}}}$, where “a” is the slope, UAsensor is the UA concentration in spent dialysate found from the concentration curve of the optical sensor, Qb is effective blood flow and Qd+Qsubs+UF is the total flow of spent dialysate. Subsequently, the accuracy of the model was evaluated on the calibration and validation data using Bland Altman analysis. Results UA concentrations in spent dialysate determined with HPLC and estimated with the optical sensor were strongly correlated (R2 = 0.992) and with comparable accuracy (BIAS±SE) (0.1 ± 3.84) µmol/L. Coefficient of determination 0.951 with the accuracy of 0.00 ± 31.43 µmol/L was achieved for calibration group, and coefficient of determination 0.962 with the accuracy of −7.64 ± 32.06 µmol/L was achieved for validation group between the UA concentration in blood determined with HPLC and corresponding values predicted by the optical sensor, respectively (Fig. 1). Conclusion Concentration of UA in dialysate and blood can be estimated noninvasively and accurately with the optical sensor in real time. This can be used to estimate removal efficiency and levels of UA during HD. In future, removal of other uremic toxins could be additionally monitored leading to a more personalized HD treatment.

#2567 Protein-bound uremic toxins are better removed with short-daily Home Haemodialysis using low dialysate flow rate: randomized clinical trial results

Abstract Background and Aims Short daily home hemodialysis (HDD) with low dialysate flow rate has been shown in recent years as an attractive alternative for portable dialysis home use. Although the effectiveness of the technique for volume control and elimination of small solutes and middle molecules has been demonstrated, data are scarce for the elimination of protein-bound uremic toxins. The aim of this study was to compare the reduction ratios (RRs) of p-cresol sulfate (pCS) and indoxyl sulfate (IS) in the Physidia HHD system with high-volume online-hemodiafiltration (OL-HDF) treatment. Methods In an open, randomized, cross-over, single-center, controlled study, 40 adult chronic HD patients were treated with a 2.5 h-length HD session with low dialysate flow rate with the Physidia HDD system, and a 4 h-length OL-HDF session in post-dilution mode during two successive weeks. During the sessions, pre-HD and post-HD plasma samples were collected and single and weekly RRs of pC and IS were intraindividually compared for the two dialysis types with linear mixed models. Results Whereas single-session RRs of p-CS and IS were similar in both groups, weekly RRs of both protein-bound uremic toxins were significantly higher with the short-daily HDD Physida system than those obtained with OL-HDF (Table 1). Conclusion The short-daily home hemodialysis using low dialysate flow rate with the Physidia system appears to be a potential technologic step ahead in terms of improved protein-bound uremic toxins removal for dialysis patients, and might contribute to a more adequate dialysis therapy than in-center high-volume online-hemodiafiltration (OL-HDF) treatment.

Hydrophilic Modification of Dialysis Membranes Sustains Middle Molecule Removal and Filtration Characteristics.

While efficient removal of uremic toxins and accumulated water is pivotal for the well-being of dialysis patients, protein adsorption to the dialyzer membrane reduces the performance of a dialyzer. Hydrophilic membrane modification with polyvinylpyrrolidone (PVP) has been shown to reduce protein adsorption and to stabilize membrane permeability. In this study we compared middle molecule clearance and filtration performance of nine polysulfone-, polyethersulfone-, and cellulose-based dialyzers over time. Protein adsorption was simulated in recirculation experiments, while β2-microglobulin clearance as well as transmembrane pressure (TMP) and filtrate flow were determined over time. The results of this study showed that β2-microglobulin clearance (-7.2 mL/min/m2) and filtrate flow (-54.4 mL/min) decreased strongly during the first 30 min and slowly afterwards (-0.7 mL/min/m2 and -6.8 mL/min, respectively, for the next 30 min); the TMP increase (+37.2 mmHg and +8.6 mmHg, respectively) showed comparable kinetics. Across all tested dialyzers, the dialyzer with a hydrophilic modified membrane (FX CorAL) had the highest β2-microglobulin clearance after protein fouling and the most stable filtration characteristics. In conclusion, hydrophilic membrane modification with PVP stabilizes the removal capacity of middle molecules and filtration performance over time. Such dialyzers may have benefits during hemodiafiltration treatments which aim to achieve high exchange volumes.

Assessment of the Influence of Postdilution Online Hemodiafiltration on the Rate of Removal of Middle Molecular Weight Uremic Toxins

Abstract Hemodiafiltration is a method of treatment used to replace kidney function, which effectively removes uremic toxins of middle molecular weight from the blood of patients with the end-stage of chronic kidney disease. The aim of this study was to examine the effect of postdilution online hemodiafiltration on the degree of β2- microglobulin removal. Thirty patients treated with postdilution online hemodiafiltration were examined. The main parameter for assessing the removal efficiency of uremic toxins of middle molecular weight was the concentration of β2-microglobulin in the serum before and after a single session of postdilution online hemodiafiltration. The following tests were used for statistical analysis: Shapiro-Wilk test, Student’s T test for bound samples and Wilcoxon test. The average total convective volume is 21.38 ± 2.97 liters per session. The reduction index of β2-microglobulin during a single session of postdilution online hemodiafiltration is 70.86 ± 6.87%. The average loss of albumin during a single postdilution online hemodiafiltration is 2.50 ± 0.92 g/4h, and the albumin reduction index is 6.20 ± 2.12%. Postdilution online hemodiafiltration effectively removes β2-microglobulin from the blood of patients with end-stage chronic kidney disease. The reduction index of β2-microglobulin is ˜ 71.00% and the loss of albumin is less than 4.0 g/4h. This dialysis modality prevents the development of dialysis-related amyloidosis and atherosclerotic cardiovascular diseases in the population of patients treated with regular hemodiafiltration.

Hemoadsorption Combined with Hemodialysis and the “Inflammation Mitigation Hypothesis”

ABSTRACT Clinical outcomes are still unsatisfactory in patients undergoing chronic maintenance dialysis. Signs and symptoms of uremic intoxication are often present even in presence of an adequate dialysis delivery. These along with cardiovascular and skeletal complications, have been correlated to the accumulation of inflammatory chemical mediators, beta-2 microglobulin (β2M), parathyroid hormone (PTH) and other middle to large molecular weight toxins that are insufficiently cleared by current dialysis techniques. Such condition determines a vicious loop where a subclinical status of inflammation causes a disruption of the immunological response affecting outcomes by accelerated atherosclerosis, anemia, and frequent infections. The overall picture can be described as a systemic inflammatory syndrome with simultaneous activation of the innate and the adaptive immunity. In such condition, new options and techniques are required to achieve a more effective blood purification and to correct the altered immuno-homeostasis. New efficient and biocompatible sorbents are today available (HA 130 Cartridge, Jafron Medical, Zhuhai, China) and they can be advantageously coupled in series with the hemodialyzer to perform hemoadsorption combined with hemodialysis (HA-HD). This technique has been already studied in at least two randomized trials demonstrating an effective improvement of clinical and biochemical outcomes. We have calculated the kinetics of β2M in a single session, in a series of three consecutive sessions of a week and in a period of three months using different frequencies of application (first month: Three sessions per week; second month: Two sessions per week; third month: One session per week). In the single session the reduction ratio was superior to other techniques such as hemodialysis (HD), high-flux hemodialysis (HFD) or hemodiafiltration (HDF). In the thrice weekly regime, the time average concentration (TAC) of β2M resulted inferior to HD and HDF. In the long period, a lower concentration of β2M was maintained even with a once-a-week regime. Considering the parallel reduction of inflammatory parameters, we could hypothesize that the enhanced removal of uremic toxins and chemical mediators led to a mitigation of the systemic inflammation with a progressive reduction in the generation of β2M. This “inflammation mitigation hypothesis (IMH)” supports the prescription of HA-HD once a week, possibly after a month of thrice weekly regime.

Most recently developed polyester polymer alloy dialyzer: A new medium cut-off membrane?

New versions of the polyester polymer alloy (PEPA) membrane have appeared over the years, with increases in both the pore size and the amount of polyvinylpyrrolidone (PVP) to optimize hydrophilicity performance. This study aimed to assess the efficacy of the most recently developed PEPA dialyzer, the FDY series, in hemodialysis (HD) modality in terms of uremic toxin removal and albumin loss and to compare it with that of several high-flux dialyzers currently used in HD and post-dilution hemodiafiltration (HDF) treatments. A prospective study was carried out in 21 patients. All patients underwent six dialysis sessions with the same routine dialysis parameters; only the dialyzer and/or the dialysis modality varied: FX80 in HD, FDY 180 in HD, Clearum HS17 in HDF, Elisio 19H in HDF, Vitapes 180 in HDF, and FX80 in post-dilution HDF. The reduction ratios (RR) of urea, creatinine, ß2 -microglobulin, myoglobin, κFLC, prolactin, α1 -microglobulin, α1 -acid glycoprotein, λFLC, and albumin were compared intraindividually. Dialysate albumin loss was also measured. Both membranes FDY and FX80 are high-flux dialyzers and are applied here in high-flux HD. The average RR of β2 -microglobulin was slightly lower in the two HD treatments than in the HDF treatments. Comparison of dialysis treatments revealed that the PEPA FDY dialyzer in the HD modality was more effective than the FX80 dialyzer in high-flux HD and was as effective as post-dilution HDF, especially in terms of myoglobin, κFLC, prolactin, α1 -microglobulin, and λFLC RRs. The FDY treatments obtained similar albumin RR in blood and slightly higher dialysate albumin loss, although the values were clinically acceptable. The most recently developed PEPA dialyzers in the HD modality were as effective as all treatments in the HDF modality and were clearly superior to high-flux helixone HD treatment. These results confirm that this dialyzer should be categorized within the medium cut-off (MCO) membrane classification.

Pruritus and protein-bound uremic toxins in patients undergoing hemodialysis: a cross-sectional study.

Patients undergoing hemodialysis frequently experience pruritus; its severity is associated with poor quality of life and mortality. Recent progress in hemodialysis treatment has improved the removal of small- and middle-molecular-weight molecules; however, the removal of protein-bound uremic toxins (PBUTs) remains difficult. It is possible that pruritus is associated with serum PBUTs in patients undergoing hemodialysis. We conducted a multicenter cross-sectional study in patients undergoing hemodialysis (n=135). The severity of pruritus was assessed using the 5D-itch scale and medication use. Serum PBUTs, including indoxyl sulfate, p-cresyl sulfate, indole acetic acid, phenyl sulfate, and hippuric acid, were measured using mass spectrometry; the PBUT score was calculated from these toxins using principal component analysis. Univariate and multiple regression analyses were performed to examine independent predictors of pruritus. Pruritus was reported by 62.2%, 21.5%, and 13.3%, 1.5% and 0.7% as 5 (not at all), 6-10, 11-15, 16-20, and 21-25 points, respectively. The PBUT score was higher in patients undergoing dialysis having pruritus than those without pruritus (0.201 [-0.021 to 0.424] vs -0.120 [-0.326 to 0.087]; P=0.046). The PBUT score was shown to have an association with the presence of pruritus (coefficient 0.498[Formula: see text]0.225, odds ratio: 1.65 [1.06-2.56]; P=0.027). Uremic pruritus was frequently found and associated with the PBUT score in patients undergoing hemodialysis. Further studies are required to clarify the impact of PBUTs on uremic pruritus and to explore therapeutic strategies in patients undergoing hemodialysis.

Comparison of uremic toxin removal between expanded hemodialysis and high volume online hemodiafiltrations in different modes.

Various high-efficiency hemodialysis techniques exist, including different online high- volume hemodiafiltration (HDF) modes and expanded hemodialysis (HDx) utilizing dialyzers with medium cut-off (MCO) membranes. This study aimed to evaluate the efficacy of uremic toxin removal among four modalities: (I) HDx, (II) pre-dilution HDF (PRE-HDF), (III) mixed-dilution HDF (MIX-HDF), and (IV) post-dilution HDF (POST-HDF), each applied for 1week in a randomized order. This research was a single-center, prospective, open-label, exploratory crossover study. The reduction ratio (RR) for small molecular toxins (urea and phosphate), a middle molecular toxin (beta-2-microglobulin, β2M), a large-middle molecular toxin (Chitinase-3-like protein 1, YKL-40), and a protein- bound uremic toxin (indoxyl sulfate, IS) was evaluated during a single mid-week dialysis session. Twelve patients were included, with an average age of 52.5 ± 15.47years and an average dialysis duration of 42.05 ± 31.04months. The dialysis parameters, including; post-dialysis weight, session duration, dialysate composition, blood and dialysate flow; rates, dialysate temperature, and anticoagulation dosage, were maintained consistently across all modalities. No significant differences in RR for urea, phosphate, β2M, YKL-40, and IS were observed between the treatments. Although the highest IS clearance, though not statistically significant, was observed with POST-HDF and HDx, the differences were not substantial enough to favor any particular modality as the most effective.