Middle Molecule Uremic Toxins Research Articles

#1277 Comparing advanced glycation end products removal in super high-flux hemodialysis versus high-volume hemodiafiltration: a randomized, crossover study

Abstract Background and Aims Expanded hemodialysis using super high-flux membrane, is a promising therapy for effectively clearing middle molecule uremic toxins. However, its impact on advanced glycation end products (AGEs), which is related to an increase in cardiovascular mortality [1], remains inconclusive. Previous studies demonstrated that AGEs increased over time in patients treated with high-flux hemodialysis (HD) [2, 3] while remaining stabilized in online hemodiafiltration (ol-HDF) [3]. This study aims to compare the longitudinal tissue AGEs measured by skin autofluorescence (SAF) between super high-flux hemodialysis (SHF-HD) and high-volume post-dilution ol-HDF. Method In this open-label prospective cross-over 24-week trial, twenty-two prevalent HD patients were randomly assigned to undergone two sequences of 24-week treatment periods: SHF-HD followed by high-volume postdilution ol-HDF or vice versa, with a 4-week wash-out period with high-flux HD between. SAF was measured at baseline and 24 weeks. Midweek pre-HD measurements of beta-2 microglobulin (B2M), serum albumin, normalized protein catabolic rate (NPCR) and Kt/V were obtained every 8 weeks. The amount of dialysate albumin was collected by continuous sampling of spent dialysate method and determined by immunoturbidimetric assay Results Seventeen out of twenty-two patients completed the study. At baseline, SAF levels (3.88 ± 0.14 vs 3.99 ± 0.14 AU, p = 0.463) and pre-HD B2M (22.66 ± 1.41 vs 21.09 ± 1.41 mg/L, p = 0.228) were similar between the SHF-HD and ol-HDF groups. After 24 weeks, SAF levels showed no significant change in SHF-HD (from 3.88 ± 0.14 to 3.91 ± 0.14 AU, p = 0.846) and ol-HDF (from 3.99 ± 0.14 to 3.95 ± 0.14 AU, p = 0.796), with a mean difference of change 0.06 (95% CI −0.34, 0.47, p = 0.75). Similarly, mid-week pre-HD serum B2M at 24 weeks exhibited no significant change in the SHF-HD group (22.66 ± 1.41 to 22.18 ± 1.47 mg/L, p = 0.722) and the ol-HDF group (21.09 ± 1.41 to 21.83 ± 1.45 mg/L, p = 0.577), with a mean difference of change −1.22 (95% CI −4.94, 2.49, p = 0.519). The spKt/V urea did not exhibit any notable differences. Furthermore, pre-HD levels of all small uremic toxins after the 24-week periods did not differ between both groups. Nutritional status measured by serum albumin and NPCR were comparable despite higher dialysate albumin loss in postdilution ol-HDF group (0.82 ± 0.04 vs 1.92 ± 0.12 g, p < 0.001 in SHF-HD and ol-HDF, respectively) Conclusion After 24 weeks of treatment, SHF-HD demonstrated levels of AGEs, pre-HD serum B2M, and serum albumin comparable to high-volume ol-HDF. If high-volume postdilution ol-HDF is not feasible, SHF-HD may serve as a valuable alternative treatment for stabilizing AGEs in chronic hemodialysis patients.

Inhibiting advanced glycation end products (AGEs) of high-performance hemodialysis membranes self-assembled by gallic acid and Ti3C2Tx MXene

Current patients with chronic kidney disease (CKD) suffer from either accumulation of advanced glycation end products (AGEs) or inefficient clearance of the middle molecule uremic toxins, threatening their long-term survival rate. In particular, conventional hemodialysis membranes cannot prevent AGEs formation because of continuous oxidative stress from reactive oxygen species (ROS). Herein, a persistent ROS scavenging and efficient uremic toxin clearance of hemodialysis membrane is proposed by the in situ deposition of a gallic acid-Ti3C2Tx MXene (GA-MXene)n multilayers through a self-assembly method, where n denotes the number of deposition layers. These hemodialysis membranes have a highly interconnecting composite laminate with tunable pore size. In the dialysis experiment, the (GA-MXene)2 membrane with the vertical nano-slits shows the highest middle molecule uremic toxin clearance of 80.0% compared with state-of-the-art hemodialysis membranes, which has been approximately equal to the clearance of small molecule urea. Furthermore, GA conferring efficient ROS scavenging rate over dialysis treatment time allows anti-oxidative activities to inhibit AGEs’ formation. (GA-MXene)n multilayers enhanced the serum total antioxidant capacity and suppressed lipid peroxidation from oxidative damage. Ultimately, the (GA-MXene)n hemodialysis membranes provide excellent anticoagulant properties and cytocompatibility through the heparin-mimicking sulfonated Ti3C2Tx MXene and biological activity of GA. This work facilitates the blood purification application of MXenes and opens up an avenue for developing functional multilayers for high-performance hemodialysis membranes and beyond.

Comparison of the medium cutoff dialyzer and postdilution hemodiafiltration on the removal of small and middle molecule uremic toxins.

The medium cutoff (MCO) dialyzer increases the removal of several middle molecules more effectively than high-flux hemodialysis (HD). However, comparative data addressing the efficacy and safety of MCO dialyzers vs. postdilution hemodiafiltration (HDF) in Korean patients are lacking. Nine patients with chronic HD were included in this pre-post study. Patients underwent HD with an MCO dialyzer for 4 weeks, followed by a 2-week washout period using a high-flux dialyzer to minimize carryover effects, and then turned over to postdilution HDF for 4 weeks. Reduction ratios and differences in the uremic toxins before and after dialysis were calculated from the MCO dialysis, postdilution HDF, and high-flux HD. In the in vitro study, EA.hy926 cells were incubated with dialyzed serum. Compared to postdilution HDF, the MCO dialyzer achieved significantly higher reduction ratios for larger middle molecules (myoglobin, kappa free light chain [κFLC], and lambda FLC [λFLC]). Similarly, the differences in myoglobin, κFLC, and λFLC concentrations before and after the last dialysis session were significantly greater in MCO dialysis than in postdilution HDF. The expression of Bax and nuclear factor κB was decreased in the serum after dialysis with the MCO dialyzer than with HDF. Compared with high-volume postdilution HDF, MCO dialysis did not provide greater removal of molecules below 12,000 Da, whereas it was superior in the removal of larger uremic middle molecule toxins in patients with kidney failure. Moreover, these results may be expected to have an anti-apoptotic effect on the human endothelium.

#3367 NON-INVASIVE OPTICAL ESTIMATION OF INTRADIALYTIC CONCENTRATIONS OF UREMIC TOXINS IN BLOOD OF HEMODIALYSIS PATIENTS

Abstract Background and Aims Hemodialysis (HD) adequacy is generally estimated by the dialysis adequacy marker Kt/V urea that poorly describes removal of uremic toxins with different removal kinetics, such as protein bound or middle molecule uremic toxins, which have direct effect on morbidity and mortality of end stage kidney disease (ESKD) patients. We have recently shown the feasibility of estimating an alternative dialysis adequacy marker that can be applied to dialysis sessions with varying settings and different uremic toxins, intradialytic time average concentration (TAC) of uremic toxins, such as urea, uric acid (UA), indoxyl sulfate (IS) and beta-2-microglobulin in blood of ESKD patients, from spent dialysate concentrations determined by laboratory methods [1]. The aim of this retrospective observational study was to estimate intradialytic TAC of uremic toxins UA and IS non-invasively from spent dialysate concentrations determined by optical methods. Method Twenty-two ESKD patients on chronic HD were enrolled into the study. For each patient 4 midweek dialysis sessions with different treatment settings were included (1 HD: Qb = 200 mL/min, Qd = 300 mL/min, dialyzer 1,5m2; 3 HDF: median (interquartile range) Qb = 298 (296-356) mL/min, Qd = 795 (500–800) mL/min, Vsubst = 21.8 (15–24.5) L, dialyzers 1,8 m2 and 2,2 m2). During each dialysis session, blood samples were taken at 0 min (start) and 240 min after the start from the arterial blood line and dialysate samples were taken at 7 min and 240 min after the start from the outlet of the dialysis machine. Concentrations of UA and IS in serum and spent dialysate samples were determined with HPLC. In addition, UV absorbance and fluorescence of the spent dialysate samples were measured with spectrophotometer UV-3600 and spectrofluorometer RF-6000 (both from Shimadzu Corp., Japan), after which concentrations of UA and IS in spent dialysate samples were determined based on the optical properties of samples. Stability of HD treatment settings were monitored online and dialysis sessions with unstable blood and dialysate flow rates were excluded. TAC of UA and IS were calculated from serum concentrations and evaluated from laboratory and optically estimated logarithmic mean concentrations (Mln D) of spent dialysate. Results Mean intradialytic serum TAC values of UA and IS were 198.4±44.0 μmol/L and 69.5 ± 37.8 μmol/L and strongly correlated to those estimated from optically determined Mln D 198.0±38.9 μmol/L (R2 = 0.75) and 69.5 ± 37.8 μmol/L (R2 = 0.81), respectively. Mln D of UA and IS in spent dialysate based on laboratory methods were 102.2 ± 22.8 μmol/L and 5.9 ± 3.5 μmol/L and strongly correlated with the optically determined concentrations of 102.7 ± 23.1 μmol/L (R2 = 0.97) and 6.1 ± 3.4 μmol/L (R2 = 0.97), respectively. Conclusion Intradialytic serum TAC of UA and IS can be estimated non-invasively with optical methods from their concentration in spent dialysate independent of treatment modality. Optical online monitoring of spent dialysate in real-time could therefore provide additional information about treatment adequacy regarding the removal of uremic toxins’ other than urea. In future, TAC estimation models should be optimized for each uremic toxin to establish higher accuracy, considering real-time treatment settings, recirculation etc.

#3255 BETA2 MICROGLOBULIN IS AN INDEPENDENT PARAMETER RELATED WITH DYSFUNCTION OF NATURAL KILLER CELL ACTIVITY IN HEMODIALYSIS PATIENTS

Abstract Background and Aims End-stage renal disease patients are characterized by immune dysfunction. Natural killer (NK) cells area lymphocytes of innate immune system that play a key role in an immune response towards viral infections and tumors. We aimed to analyze clinical factors related to the NK cell activity in chronic hemodialysis (HD) patients. Method Clinically stable 196 patients who were treated by HD for more than 3 months were enrolled from 4 outpatient HD clinics. NK cell activity was assessed using NK Vue assay (NKMAX, Sungnam, Korea) that uses serum of ex-vivo stimulated whole blood to detect interferon (IFN)-γ secreted from NK cells as an indicator of NK cell activity. All patients were stratified as abnormal (<250 pg/ml) and normal (≥250 pg/ml) groups according to NK cell activity. Results Mean age of the HD patients was 62.7 years [range 31 to 95 years] and mean HD duration was 49.2 months [range 3 to 221 months]. In total, 68 (35%) of HD patients showed abnormal NK cell activity. The abnormal NK cell activity group showed significantly increased age and shorter HD duration compared to the normal NK cell activity group (66.7 ± 11.9 vs. 60.6 ± 13.4 years, p = 0.001; 33.8 ± 33.0 vs. 57.5 ± 48.5 months, p<0.001, respectively). The serum albumin and parathyroid hormone levels were significantly lower in the abnormal NK cell activity group (3.7 ± 0.4 vs. 3.9 ± 0.3 g/dL, p = 0.005 and 176 ± 153 vs. 240 ± 260 pg/mL, respectively). In contrast, hemoglobin, blood urea nitrogen, urea reduction ratio, and C-reactive protein levels were comparable between the two groups. In multivariate regression analysis, old age, short dialysis duration, low serum albumin and high beta2 microglobulin levels were independent risk factors of abnormal NK cell activity in HD patients (adjusted odd ratio [AOR], 1.033; 95% confidence interval [CI], 1.005-1.062, p = 0.02; AOR, 0.981; 95% CI, 0.971-0.992; p<0.001, AOR, 0.395; 95% CI, 0.157-0.995; p = 0.049, and AOR, 1.042; 95% CI, 1.011-1.075; p = 0.008, respectively). Conclusion Our results suggest that young age and good nutrition as well as lower burden of middle molecule uremic toxin is associated with greater NK cell activity in HD patients.

In vitro hemocompatibility and hemodialysis performance of hydrophilic ionic liquid grafted polyethersulfone hollow fiber membranes

Polymer-based hemodialyzers have been widely used to treat patients suffered from end stage renal disease clinically. Polyethersulfone (PES) is seen as one of the most important hemodialysis membrane materials. Numerous strategies have been done to increase the hemocompatibility of PES, but molecular chain modification of PES has been seldomly reported. In this work, a hydrophilic ionic liquid (IL) grafted PES (PES-g-IL) was used to prepare the hollow fiber membranes (HFMs). The structure and properties, including hemocompatibility, hemodialysis performance as well as the cytotoxicity of PES-g-IL HFMs were investigated systematically. It was found that PES-g-IL HFMs had higher porosity, lower protein adsorption, less platelet adhesion and longer clotting time than PES HFMs, indicating the enhanced hemocompatibility. Besides, both the toxins removal and BSA rejection of PES-g-IL HFMs were significantly higher than those of PES HFMs. Particularly, the middle molecule uremic toxin (lysozyme) clearance of PES-g-IL HFMs was twice higher than that of PES HFMs. At the same time, the BSA rejection of PES-g-IL HFMs achieved as high as 98%. Moreover, PES-g-IL showed negligible cytotoxicity. It is considered that the grafting of IL changed the microstructure and improved the hydrophilicity of PES-g-IL membranes, leading to the enhanced hemocompatibility, hemodialysis performance and cytocompatibility.

MO642: Comparison of Medium Cut-Off Dialyzer and Post-Dilution Hemodiafiltration on the Removal of Small and Middle Molecule Uremic Toxins

Abstract BACKGROUND AND AIMS The medium cut-off (MCO) dialyzer increases the removal of several middle molecules more effectively than high-flux hemodialysis (HD). However, there are no comparable data on the efficacy and safety of MCO dialyzers versus post-dilution hemodiafiltration (HDF) in Korean patients. METHOD A total of 9 patients with chronic HD were included in this crossover study. Patients received HD with an MCO dialyzer for 4 weeks, followed by a 2-week washout period, using a high-flux dialyzer to minimize carry-over effects and then crossed over to post-dilution HDF for 4 weeks. Reduction ratios and differences in the values before and after were calculated from the MCO dialysis, post-dilution HDF and high-flux HD. In the in vitro study, EA.hy926 cells were treated with dialyzed serum. RESULTS Compared with post-dilution HDF, the MCO dialyzer achieved significantly higher reduction ratios for larger middle molecules [myoglobin, kappa free light chain (κFLC) and lambda FLC (λFLC)]. Similarly, the differences between before and after the last dialysis session of myoglobin, κFLC, and λFLC were significantly greater in MCO dialysis than in post-dilution HDF. The expression of Bax and nuclear factor-κb was decreased in the serum after dialysis with the MCO dialyzer than with HDF. CONCLUSION Compared with high-volume post-dilution HDF, MCO dialysis showed no differences in the removal of molecules below 12 000 Da, whereas it was superior in the removal of larger uremic middle molecule toxins in patients with kidney failure. Moreover, these results might be expected to have an anti-apoptotic effect on the human endothelium.

MO889: High Flux Dialyzer 2.6 M2 is Promising for Free Light Chains Removal in High Flux Hemodialysis and Hemodiafiltration

Abstract BACKGROUND AND AIMS Immunoglobulin light chains are classified as middle molecule uremic toxins and its removal through effective dialyzer is needed with less albumin loss. This study assessed the free light chains removal using dialyzer surface area (SA) 2.6m2 in high flux dialysis (HD) versus hemodiafiltration (HDF) and its relation to cumulative albumin loss. METHOD A cross-over study included 25 patients who underwent hemodialysis using dialyzer surface area 2.6 m2 in high flux HD followed by online post-dilution hemodiafiltration with washout period 2 weeks using high flux dialyzers (max 2.0 m2 SA). All patients were subjected to single session measurement of dialysate albumin every hour and pre-post dialysis Free light chains (FLC) kappa and Lambda by ELISA. RESULTS Dialyzer (SA) 2.6m2 showed significant reduction in post-dialysis kappa and lambda in comparison to pre-dialysis level in high flux hemodialysis and hemodiafiltration (P < 0.001). HDF showed higher kappa and lambda FLC reduction ratio (45.16 ± 6.53 ng/mL), (28.68 ± 4.36 ng/mL), respectively compared with high flux HD (29.52 ± 6.38 ng/mL), (19.48 ± 1.96 ng/mL), respectively (P < 0.001). HDF/HD fold change of kappa and lamda were (1.56 ± 0.23) and (1.48 ± 0.26), respectively. Patients on HDF dialysis had significant total albumin loss in dialysate [median (IQR) 2.47 (1.16) gm/dL] compared with high flux dialysis [median (IQR) 0.65 (0.64) gm/dL] with (P < 0.001). Maximum albumin loss in patients on HDF was in the first hour [median (IQR) 1.22 (0.59)] gm/dL with lower albumin loss in the next hours reaching median {0.17 (0.15) gm/dL} in the fourth hour. Trans-membrane pressure was positively correlated with total albumin loss in high flux hemodialysis and hemodiafiltration (r 0.443, p 0.027, r 0.745, P = 0.001), respectively. CONCLUSION High flux dialyzer 2.6 m2 (SA) is effective for free light chains removal especially with online post-dilution hemodiafiltration with acceptable albumin loss.

Comparative Effectiveness between Expanded Hemodialysis (Hemodialysis Using a Medium Cut-Off Dialyzer) and Mixed-Dilution Online Hemodiafiltration Using a High-Flux Dialyzer in Removing Middle-Molecule Uremic Toxins

Introduction: Expanded hemodialysis (HD using a medium cut-off dialyzer [HD + MCO]) provides comparable or better removal of various uremic toxins, particularly large middle-molecule uremic toxins, than post-dilution online hemodiafiltration (olHDF). Uremic toxin-removing effectiveness between HD + MCO and mixed-dilution olHDF, one of the currently most efficient olHDF modalities, has not been assessed. Method: This randomized controlled trial was conducted in 14 prevalent thrice-a-week HD patients with blood flow rate above 400 mL/min. The patients were randomized into two sequences of 2-week treatment periods of HD + MCO and later mixed-dilution olHDF or vice versa. The reduction ratio (RR) values of small-molecule as well as middle-molecule uremic toxins and protein-bound uremic toxins were measured at baseline and at the end of the treatment. Results: When compared with mixed-dilution olHDF, HD + MCO provided slightly lower β₂M RR, but the value was still higher than 75%; showed similar κFLC RR, IS RR, and URR; and yielded significantly higher RR values of α₁M (p < 0.001) and λFLC (p < 0.001). Despite higher albumin loss in HD + MCO, the serum albumin levels at the end of the study were comparable between both groups. Conclusion: Expanded HD (HD + MCO) provided similar effectiveness in removing various uremic toxins and could exhibit greater removal of large middle-molecule uremic toxins, such as α₁M and λFLC. Expanded HD can be used as an effective alternative option for mixed-dilution olHDF.

Comparative efficacy between hemodialysis using super high-flux dialyzer with hemoperfusion and high-volume postdilution online hemodiafiltration in removing protein bound and middle molecule uremic toxins: A cross-over randomized controlled trial.

Hemodialysis (HD) using super high-flux dialyzer (HD+SHF) comparably removed uremic toxins to high-volume postdilution online hemodiafiltration (olHDF). Integration of hemoperfusion (HP) to HD+SHF (HD+SHF+HP) might provide superior uremic toxin removing capability to high-volume postdilution olHDF. The present study was conducted in thrice-a-week HD patients to compare the efficacy in removing indoxyl sulfate (IS), beta-2 microglobulin (β2 M), and urea between high-volume postdilution ol-HDF and HD+SHF+HP, comprising HD+SHF as the main treatment plus HD+SHF+HP 1/week in the first 4weeks and 1/2weeks in the second 4weeks. Ten prevalent HD patients with blood flow rate (BFR) above 400ml/min were randomized into two sequences of 8-week treatment periods of HD+SHF+HP and later high-volume postdilution olHDF or vice versa. When compared with high-volume postdilution olHDF (convective volume of 26.02±1.8 L/session), HD+SHF+HP provided comparable values of percentage reduction ratio of IS (52.0±11.7 vs. 56.3±7.5%, p=0.14) and β2 M (83.7±4.9 vs. 84.0±4.3%, p=0.37) and slightly lower urea reduction ratio. Despite greater dialysate albumin loss (p=0.008), there was no significant change in serum albumin level in HD+SHF+HP group. HD+SHF+HP could not provide superior efficacy in removing uremic toxins to high-volume postdilution olHDF. The use of low BFR of 200ml/min during the first 2h of HD+SHF+HP session, according to the instruction of manufacturer, might impair the efficacy of the HD+SHF part in removing uremic toxins.

Comparative Effectiveness Between Novel Medium Cut-Off Membrane Hemodialysis and Mixed-Dilution Online Hemodiafiltration on Middle Molecule Uremic Toxins Reduction: A Prospective Cross-Over Study

Comparative Effectiveness Between Novel Medium Cut-Off Membrane Hemodialysis and Mixed-Dilution Online Hemodiafiltration on Middle Molecule Uremic Toxins Reduction: A Prospective Cross-Over Study

MO208ASSOCIATION OF SERUM BETA-2 MICROGLOBULIN LEVEL WITH DIFFERENT CARDIAC AND METABOLIC RISK FACTORS IN CKD PATIENTS

Abstract Background and Aims Serum β M is a middle molecule uremic toxin that accumulates in serum and deposits at various tissues in chronic kidney disease (CKD), especially more in dialysis patients. The βâ M is generally considered as a predictor of cardiovascular morbidity and mortality and this is more investigated in dialysis group. However its relationship with several cardiac and metabolic risk factors in all stages of CKD is still under evaluation. This study was undertaken to evaluate the association of plasma βâ M level in different stages of chronic kidney disease patients with different cardiac, renal and metabolic risk factors that can predict future cardiovascular events Method This cross-sectional study was conducted by selecting consecutive 132 CKD subjects of stages 1-5D including both patients not requiring dialysis and those on maintenance hemodialysis. Their demographic, clinical and laboratory data were recorded in a data sheet. Fasting blood samples in dialysis non requiring subjects and predialysis samples in hemodialysis group (G5D) were taken for testin in laboratory for CBC, serum βâ M, hCRP, iPTH, lipid profile, creatinine, uric acid and serum albumin as cardiac, renal and metabolic risk markers. Urine sample was taken from predialysis patients for chemical test and ACR. The CKD staging were done by MDRD criteria. Additional 25 no CKD subject was taken as healthy referents. Results Primarily Beta-2 microglobulin was higher in CKD patients than in healthy group (13.53 ± 14.74 vs. 1.81 ± 0.47, mg/l; p&amp;lt;.001). The levels were gradually rising with the advancing stages of CKD (G1&amp;2-3.46 ± 2.39, G3-3.66 ± 1.08, G4-6.51 ± 2.20, G5-11.43 ± 2.98 and G5D-41.79 ± 8.58, mg/l). A Beta-2 microglobulin cut-off of &amp;gt;7.7 vs. &amp;lt; 7.7 mg/l showed significantly increased Systolic BP (136 ±22 vs. 123 ± 22, mmHg), diastolic BP (80 ± 12 vs. 75 ± 8.96, mmHg),( p&amp;lt;0.01); CRP (6.83 ± 6.03 vs. 4.39 ± 5.35, mg/l)( p&amp;lt;0.007); serum phosphate (4.84 ± 1.79 vs. 3.85 ±.92,mg/dl)( p&amp;lt;0.001); uric acid (5.89 ± 1.41 vs. 5.01 ± 1.57,mg/dl)( p&amp;lt;0.01); TG (189± 103 vs. 155 ± 88, mg/dl),( p&amp;lt;0.04); and PTH (239.83 ± 186.50 vs. 90.52 ± 81.77, pg/ml), ( p&amp;lt;0.001) indicating higher cardio metabolic risks in higher group. Similarly renal parameters were also more altered in high Beta-2 microalbumin group for serum creatinine (6.89 ± 3.54 vs. 1.58 ± .81, mg/dl) (p&amp;lt;0.001) and ACR (824 ± 917 vs. 320 ± 753, mg/g),( p&amp;lt;0.001). B-2 microglobulin also positively correlated with systolic blood pressure (r=.295, p&amp;lt;.001), serum creatinine (r=.879, p&amp;lt;.001), serum phosphate (r=.175, p =.047), serum iPTH (r=.403, p&amp;lt;.001) , hCRP ( r=.193, p =.050) , Triglycerides (r=.196, p =.023) and urine ACR in CKD patients. Conclusion Beta-2 microglobulin level was significantly higher in CKD with an increasing pattern towards advancing stages. The higher levels positively correlated with cardio renal and metabolic risk factors. Hence measuring Beta-2 microglobulin regularly can help to take preventive measures early to manage patients at risk.

Optical Method and Biochemical Source for the Assessment of the Middle-Molecule Uremic Toxin β2-Microglobulin in Spent Dialysate.

Optical monitoring of spent dialysate has been used to estimate the removal of water-soluble low molecular weight as well as protein-bound uremic toxins from the blood of end stage kidney disease (ESKD) patients. The aim of this work was to develop an optical method to estimate the removal of β2-microglobulin (β2M), a marker of middle molecule (MM) uremic toxins, during hemodialysis (HD) treatment. Ultraviolet (UV) and fluorescence spectra of dialysate samples were recorded from 88 dialysis sessions of 22 ESKD patients, receiving four different settings of dialysis treatments. Stepwise regression was used to obtain the best model for the assessment of β2M concentration in the spent dialysate. The correlation coefficient 0.958 and an accuracy of 0.000 ± 0.304 mg/L was achieved between laboratory and optically estimated β2M concentrations in spent dialysate for the entire cohort. Optically and laboratory estimated reduction ratio (RR) and total removed solute (TRS) of β2M were not statistically different (p > 0.35). Dialytic elimination of MM uremic toxin β2M can be followed optically during dialysis treatment of ESKD patients. The main contributors to the optical signal of the MM fraction in the spent dialysate were provisionally identified as tryptophan (Trp) in small peptides and proteins, and advanced glycation end-products.

A critical review of recent advances in hemodialysis membranes hemocompatibility and guidelines for future development

Hemodialysis is a life-sustaining procedure for patients with end-stage renal disease (ESRD). The efficiency of hemodialysis is limited by the dialysis membrane biocompatibility and the poor clearance of middle-molecule uremic toxins. As a result, hemodialysis is associated with acute chronic side-effects that threaten patients' lives. During hemodialysis, interfacial interactions of blood-polymeric membranes result in several consequences. These interactions lead to the body's various system activations, including the coagulation of blood components, leukocytes (i.e., immune system activation) and complement activations, thrombogenesis, cytokine production, and appearance of radicals with free oxygen. Despite advances in research, the most vital issue in dialysis therapies is the biocompatibility and hemoincompatibility of the membranes. The process of enhancing membrane hemocompatibility is currently posing a global challenge. Reactions to incompatibility can cause severe injuries to the patients and result in morbidity and mortality. This critical review offers a focused analysis of the latest efforts to enhance the hemodialysis membrane's hemocompatibility as well as emphasize current research gaps. Recent innovations (since 2014) in hemodialysis membranes are analyzed in correlation to categories of modified polymer structure chemistry tuning, and surface modifications and their influences on membrane hemocompatibility. Particular attention is paid to: (1) chemical immobilization of functional groups (surface grafting); (2) layer-by-layer chemical attachment of species (LBL); (3) covalent attachment of super hydrophilic-hydrogel; (4) mixed matrix membranes (MMM); and (5) base polymer membrane modification (blending method). This critical review provides an overview of the effects the modification methods can have on biocompatibility and how they can pave the way for optimum enhancement of hemodialysis membrane biocompatibility.

Iron oxide nanoparticles improved biocompatibility and removal of middle molecule uremic toxin of polysulfone hollow fiber membranes

ABSTRACTMiddle molecule uremic toxins constitute to a quarter of uremic toxins present in human blood. In a condition where these uremic toxins accumulate in bloodstream due to renal failure, blood purification process using a high performance membrane is required. Here, we develop biocompatible mixed matrix membranes (MMMs) made up of polysulfone (PSf) and iron oxide nanoparticles (Fe2O3 NPs) with the focus to remove middle molecule uremic toxin effectively. The MMMs were evaluated in terms of their biocompatibility and separation performance. At higher Fe2O3 NPs loading, the MMM displayed a huge reduction of protein adsorption and platelet adhesion while maintaining normal blood coagulation time and acceptable complement activation. The optimized MMM exhibited high permeability (110.47 L m−2 h−1 bar−1), protein retention (99.9%) and demonstrated excellent clearance of urea (82%) and lysozyme (46.7%). The PSf/Fe2O3 MMM is proven to have promising attributes for hemodialysis application. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2019, 136, 48234.

Nanofibrous composite hemodiafiltration membrane: A facile approach towards tuning the barrier layer for enhanced performance

In order to develop advanced hemodiafiltration membrane with favorable biocompatibility and efficient dialysis performance, novel thin film nanofibrous composite (TFNC) ultrafiltration (UF) membranes consisting of sulfonated poly(vinyl alcohol) (s-PVA) blended PVA hydrogel barrier layer and electrospun polyacrlonitrile (PAN) nanofibrous supporting layer were designed and fabricated by combining electrospinning and conventional surface coating techniques. The mesh sizes of hydrogel network of s-PVA/PVA barrier layer could be tuned by varying the blending content of s-PVA. The optimized s-PVA/PVA TFNC UF membrane (S-P-TFNC-1-3) possessed high pure water flux up to 380 L m−2 h−1 bar−1 with high bovine serum albumin (BSA) rejection (>90%). Besides, the introduction of s-PVA into the hydrogel barrier layer endowed the TFNC membranes with enhanced hydrophilicity, antifouling property and biocompatibility (decreased protein adsorption, prolonged clotting time, suppressed platelet adhesion, lower hemolysis ratio and more benefits for cell proliferation) due to the presence of sulfonic groups. The dialysis simulation experiment results of S-P-TFNC-1-3 showed that 84.2% of urea and 60.9% of lysozyme were cleaned and over 95% of BSA was retained after 4 h dialysis process. Especially, the removal of middle-molecule uremic toxin was more efficient than conventional hemodialysis membranes reported so far, and high retention of big proteins was achieved simultaneously. This work exposes a window of opportunity for modified PVA TFNC membranes in blood purification applications.

Parathyroid hormone contributes to the down-regulation of cytochrome P450 3A through the cAMP/PI3K/PKC/PKA/NF-κB signaling pathway in secondary hyperparathyroidism

Chronic kidney disease (CKD), which affects, not only renal clearance, but also non-renal clearance, is accompanied by a decline in renal function. Although it has been suggested that humoral factors, such as uremic toxins that accumulate in the body under CKD conditions, could be involved in the changes associated with non-renal drug clearance, the overall process is not completely understood. In this study, we report on the role of parathyroid hormone (PTH), a middle molecule uremic toxin, on the expression of drug metabolizing or transporting proteins using rats with secondary hyperparathyroidism (SHPT) as models. In SHPT rats, hepatic and intestinal CYP3A expression was suppressed, but the changes were recovered by the administration of the calcimimetic cinacalcet, a PTH suppressor. Under the same experimental conditions, a pharmacokinetic study using orally administered midazolam, a substrate for CYP3A, showed that the AUC was increased by 5 times in SHPT rats, but that was partially recovered by a cinacalcet treatment. This was directly tested in rat primary hepatocytes and intestinal Caco-2 cells where the expression of the CYP3A protein was down-regulated by PTH (1–34). In Caco-2 cells, PTH (1–34) down-regulated the expression of CYP3A mRNA, but an inactive PTH derivative (13–34) had no effect. 8-Bromo-cyclic adenosine monophosphate, a membrane-permeable cAMP analog, reduced mRNA expression of CYP3A whereas the inhibitors of PI3K, NF-κB, PKC and PKA reversed the PTH-induced CYP3A down-regulation. These results suggest that PTH down-regulates CYP3A through multiple signaling pathways, including the PI3K/PKC/PKA/NF-κB pathway after the elevation of intracellular cAMP, and the effect of PTH can be prevented by cinacalcet treatment.

Middle-Molecule Uremic Toxins and Outcomes in Chronic Kidney Disease.

In patients with chronic kidney disease (CKD), uremic toxins constitute a specific nontraditional risk factor. Research in this field started in the early 1990s, and a growing body of preclinical and epidemiological evidence suggests that elevated levels of uremic toxins are associated with poor outcomes in a CKD setting. The present review focuses on a specific class of uremic toxins (the "middle molecules"), which includes well-known candidates like beta-2 microglobulin and fibroblast growth factor 23. Here, we summarize the epidemiological evidence linking the middle-molecule uremic toxin (and especially the larger ones) with hard clinical end points. Our findings highlight the urgent need for clinical trials of interventions designed to decrease levels of these middle molecules in CKD patients.

High performance thin-film nanofibrous composite hemodialysis membranes with efficient middle-molecule uremic toxin removal

Membrane structure design is critical for the development of high-performance hemodialysis membranes. Here, a thin-film nanofibrous composite (TFNC) membrane, consisting of a two-tier composite structure, i.e., an ultrathin hydrophilic separation layer of chemically cross-linked polyvinyl alcohol (PVA), and an electrospun polyacrylonitrile (PAN) nanofibrous supporting layer, was demonstrated as the hemodialysis membrane for the first time. The optimized PVA/PAN TFNC membrane exhibited high permeability (~ 290.5L/m2h at 0.1MPa) and excellent selectivity which should be attributed to its unique structure with ultrathin separation layer and highly porous supporting layer. In addition, the TFNC membrane also possessed excellent overall mechanical properties, good hydrophilicity and comparable hemocompatibility properties (protein adsorption, platelet adhesion, complement activation, hemolysis ratio). The hemodialysis simulation experiments on optimized TFNC membrane showed that 82.6% of urea and 45.8% of lysozyme were cleaned and 98.8% of bovine serum albumin (BSA) was retained. The TFNC membranes exhibited excellent hemodialysis performances, especially for the middle-molecule uremic toxin removal, which was more efficient than conventional hemodialysis membranes reported so far, suggesting PVA/PAN TFNC membranes as promising alternatives for hemodialysis applications.

Optimal convection volume for improving patient outcomes in an international incident dialysis cohort treated with online hemodiafiltration

Online hemodiafiltration (OL-HDF), the most efficient renal replacement therapy, enables enhanced removal of small and large uremic toxins by combining diffusive and convective solute transport. Randomized controlled trials on prevalent chronic kidney disease (CKD) patients showed improved patient survival with high-volume OL-HDF, underlining the effect of convection volume (CV). This retrospective international study was conducted in a large cohort of incident CKD patients to determine the CV threshold and range associated with survival advantage. Data were extracted from a cohort of adult CKD patients treated by post-dilution OL-HDF over a 101-month period. In total, 2293 patients with a minimum of 2 years of follow-up were analyzed using advanced statistical tools, including cubic spline analyses for determination of the CV range over which a survival increase was observed. The relative survival rate of OL-HDF patients, adjusted for age, gender, comorbidities, vascular access, albumin, C-reactive protein, and dialysis dose, was found to increase at about 55 l/week of CV and to stay increased up to about 75 l/week. Similar analysis of pre-dialysis β2-microglobin (marker of middle-molecule uremic toxins) concentrations found a nearly linear decrease in marker concentration as CV increased from 40 to 75 l/week. Analysis of log C-reactive protein levels showed a decrease over the same CV range. Thus, a convection dose target based on convection volume should be considered and needs to be confirmed by prospective trials as a new determinant of dialysis adequacy.