Design and Development of a Computational Tool for a Dialyzer by Using Computational Fluid Dynamic (CFD) Model

In order to reduce the hemodialysis cost and duration, an investigation of the effect of dialyzer design and process variables on the solute clearance rate is required. It is not easy to translate the in vivo transfer process with in vitro experiments, as it involves a high cost to produce various designs and membranes for the dialyzer. The primary objective of this study was the design and development of a computational tool for a dialyzer by using a computational fluid dynamic (CFD) model. Due to their complexity, only researchers with expertise in computational analysis can use dialyzer models. Therefore, COMSOL Inc. (Stockholm, Sweden) has made an application on membrane dialysis to study the impact of different design and process parameters on dialyzed liquid concentration. Still, membrane mathematical modeling is not considered in this application. This void hinders an investigation of the impact of membrane characteristics on the solute clearance rate. This study has developed a stand-alone computational tool in COMSOL Multiphysics 5.4 to fill this void. A review of the literature conducted shows that there are no suitable stand-alone computational tools for kidney dialysis. Very little work has been undertaken to validate the stand-alone computational tool. Medical staff in the hospitals require a computational tool that can be installed quickly and provide results with limited knowledge of dialysis. This work aims to construct a user-friendly computational tool to solve this problem. The development of a user-friendly stand-alone computational tool for the dialyzer is described thoroughly. This application simulates a mathematical model with the Finite Element Method using the COMSOL Multiphysics solver. The software tool is converted to a stand-alone version with the COMSOL compiler. The stand-alone computational tool provides the clearance rate of six different toxins and module packing density. Compared with the previous application, the stand-alone computational tool of membrane dialysis enables the user to investigate the impact of membrane characteristics and process parameters on the clearance rate of different solutes. The results are also inconsistent with the literature data, and the differences ranges are 0.09–6.35% and 0.22–2.63% for urea clearance rate and glucose clearance rate, respectively. Statistical analysis of the results is presented as mean with 95% confidence intervals (CIs) and p values 0.9472 and 0.833 of the urea and glucose clearance rates, respectively.

Understand the difference between clinical measured ultrafiltrationand real ultrafiltration in peritoneal dialysis

Background It has been noticed for years that ultrafiltration (UF) is important for survival in peritoneal dialysis. On the other hand, precise and convenient UF measurement suitable for patient daily practice is not as straight forward as it is to measure UF in the lab. Both overfill and flush before fill used to be source of measurement error for clinical practice. However, controversy finding around UF in peritoneal dialysis still exists in some situation. The current study was to understand the difference between clinical measured UF and real UF. The effect of evaporation and specific gravity in clinical UF measurement were tested in the study. Methods Four different brands of dialysate were purchased from the market. The freshest dialysate available in the market were intentionally picked. The bags were all 2 L, 2.5% dextrose and traditional lactate buffered PD solution. They were stored in four different conditions with controlled temperature and humidity. The bags were weighted at baseline, 6 months and 12 months of storage. Specific gravity was measured in mixed 24 h drainage dialysate from 261 CAPD patients when they come for their routine solute clearance test. Results There was significant difference in dialysate bag weight at baseline between brands. The weight declined significantly after 12 month’s storage. The weight loss was greater in higher temperature and lower humidity. The dialysate in non-PVC package lose less weight than PVC package. The specific gravity of dialysate drainage was significantly higher than pure water and it was related to dialysate protein concentration. Conclusion Storage condition and duration, as well as the type of dialysate package have significant impact in dialysate bag weight before use. Evaporation is likely to be the reason behind. The fact that specific gravity of dialysate drainage is higher than 1 g/ml overestimates UF in manual exchanges, which contributes to systemic measurement error of ultrafiltration in CAPD. Trial registration ClinicalTrials.gov ID: NCT03864120 (March 8, 2019) (Understand the Difference Between Clinical Measured Ultrafiltration and Real Ultrafiltration).

Mapping Solute Clearance From the Mouse Hippocampus Using a 3D Imaging Cryomicrotome

The hippocampus is susceptible to protein aggregation in neurodegenerative diseases such as Alzheimer’s disease. This protein accumulation is partially attributed to an impaired clearance; however, the removal pathways for fluids and waste products are not fully understood. The aim of this study was therefore to map the clearance pathways from the mouse brain. A mixture of two fluorescently labeled tracers with different molecular weights was infused into the hippocampus. A small subset of mice (n = 3) was sacrificed directly after an infusion period of 10 min to determine dispersion of the tracer due to the infusion, while another group was sacrificed after spreading of the tracers for an additional 80 min (n = 7). Upon sacrifice, mice were frozen and sectioned as a whole by the use of a custom-built automated imaging cryomicrotome. Detailed 3D reconstructions were created to map the tracer spreading. We observed that tracers distributed over the hippocampus and entered adjacent brain structures, such as the cortex and cerebroventricular system. An important clearance pathway was found along the ventral part of the hippocampus and its bordering interpeduncular cistern. From there, tracers left the brain via the subarachnoid spaces in the directions of both the nose and the spinal cord. Although both tracers followed the same route, the small tracer distributed further, implying a major role for diffusion in addition to convection. Taken together, these results reveal an important clearance pathway of solutes from the hippocampus.

Glymphatic pathways in the gyrencephalic brain

Identification of the perivascular compartment as the point of exchange between cerebrospinal fluid (CSF) and interstitial fluid mediating solute clearance in the brain, named the glymphatic system, has emerged as an important clearance pathway for neurotoxic peptides such as amyloid-beta. However, the foundational science of the glymphatic system is based on rodent studies. Here we investigated whether the glymphatic system exists in a large mammal with a highly gyrified brain. CSF penetration into the brain via perivascular pathways, a hallmark of glymphatic function, was seen throughout the gyrencephalic cortex and subcortical structures, validating the conservation of the glymphatic system in a large mammal. Macroscopic CSF tracer distribution followed the sulci and fissures showing that these folds enhance CSF dispersion. Three-dimensional renditions from light sheet microscopy showed a PVS influx density 4-fold larger in the pig brain than in mice. This demonstrates the existence of an advanced solute transport system in the gyrencephalic brain that could be utilised therapeutically for enhancing waste clearance.

Scope and heterogeneity of outcomes reported in randomized trials in patients receiving peritoneal dialysis

Background Randomized trials can provide evidence to inform decision-making but this may be limited if the outcomes of importance to patients and clinicians are omitted or reported inconsistently. We aimed to assess the scope and heterogeneity of outcomes reported in trials in peritoneal dialysis (PD). Methods We searched the Cochrane Kidney and Transplant Specialized Register for randomized trials in PD. We extracted all reported outcome domains and measurements and analyzed their frequency and characteristics. Results From 128 reports of 120 included trials, 80 different outcome domains were reported. Overall, 39 (49%) domains were surrogate, 23 (29%) patient-reported and 18 (22%) clinical. The five most commonly reported domains were PD-related infection [59 (49%) trials], dialysis solute clearance [51 (42%)], kidney function [45 (38%)], protein metabolism [44 (37%)] and inflammatory markers/oxidative stress [42 (35%)]. Quality of life was reported infrequently (4% of trials). Only 14 (12%) trials included a patient-reported outcome as a primary outcome. The median number of outcome measures (defined as a different measurement, aggregation and metric) was 22 (interquartile range 13–37) per trial. PD-related infection was the most frequently reported clinical outcome as well as the most frequently stated primary outcome. A total of 383 different measures for infection were used, with 66 used more than once. Conclusions Trials in PD include important clinical outcomes such as infection, but these are measured and reported inconsistently. Patient-reported outcomes are infrequently reported and nearly half of the domains were surrogate. Standardized outcomes for PD trials are required to improve efficiency and relevance.

Prediction of Kidney Drug Clearance: A Comparison of Tubular Secretory Clearance and Glomerular Filtration Rate

BackgroundAlthough proximal tubular secretion is the primary mechanism of kidney drug elimination, current kidney drug dosing strategies are on the basis of eGFR.MethodsIn a dedicated pharmacokinetic study to compare GFR with tubular secretory clearance for predicting kidney drug elimination, we evaluated stable outpatients with eGFRs ranging from 21 to 140 ml/min per 1.73 m2. After administering single doses of furosemide and famciclovir (metabolized to penciclovir), we calculated their kidney clearances on the basis of sequential plasma and timed urine measurements. Concomitantly, we quantified eight endogenous secretory solutes in plasma and urine using liquid chromatography-tandem mass spectrometry and measured GFR by iohexol clearance (iGFR). We computed a summary secretion score as the scaled average of the secretory solute clearances.ResultsMedian iGFR of the 54 participants was 73 ml/min per 1.73 m2. The kidney furosemide clearance correlated with iGFR (r=0.84) and the summary secretion score (r=0.86). The mean proportionate error (MPE) between iGFR-predicted and measured furosemide clearance was 30.0%. The lowest MPE was observed for the summary secretion score (24.1%); MPEs for individual secretory solutes ranged from 27.3% to 48.0%. These predictive errors were statistically indistinguishable. Penciclovir kidney clearance was correlated with iGFR (r=0.83) and with the summary secretion score (r=0.91), with similar predictive accuracy of iGFR and secretory clearances. Combining iGFR with the summary secretion score yielded only modest improvements in the prediction of the kidney clearance of furosemide and penciclovir.ConclusionsSecretory solute clearance measurements can predict kidney drug clearances. However, tight linkage between GFR and proximal tubular secretory clearance in stable outpatients provides some reassurance that GFR, even when estimated, is a useful surrogate for predicting secretory drug clearances in such patients.

Glymphatic function in the gyrencephalic brain

ABSTRACTIdentification of the perivascular compartment as the point of exchange between cerebrospinal fluid (CSF) and interstitial fluid mediating solute clearance in the brain, named the glymphatic system, has emerged as an important clearance pathway for neurotoxic peptides such as amyloid-beta. However, the foundational science of the glymphatic system is based on rodent studies. Here we investigated whether the glymphatic system exists in a large mammal with a highly gyrified brain. CSF penetration into the brain via perivascular pathways, a hallmark of glymphatic function, was seen throughout the gyrencephalic cortex and subcortical structures, validating the conservation of the glymphatic system in a large mammal. Macroscopic CSF tracer distribution followed the sulci and fissures showing that the gyri enhance CSF dispersion. Three-dimensional renditions from light sheet microscopy showed that CSF influx through perivascular spaces was 4-fold more extensive in the pig brain than in mice. This demonstrates the existence of an advanced solute transport system in the gyrencephalic brain that could be utilised therapeutically for enhancing waste clearance.

The impact of intradialytic cycling on the removal of protein-bound uraemic toxins: A randomised cross-over study

The evidence on impact of intradialytic exercise on the removal of urea, is conflictive. Impact of exercise on kinetics of serum levels of protein-bound uraemic toxins, known to exert toxicity and to have kinetics dissimilar of those of urea, has so far not been explored. Furthermore, if any effect, the most optimal intensity, time point and/or required duration of intradialytic exercise to maximise removal remain obscure. We therefore studied the impact of different intradialytic cycling schedules on the removal of protein-bound uraemic toxins during haemodialysis (HD). This randomised cross-over study included seven stable patients who were dialysed with an FX800 dialyser during three consecutive midweek HD sessions of 240 min: (A) without cycling; (B) cycling for 60 min between 60th and 120th minutes of dialysis; and (C) cycling for 60 min between 150th and 210th minutes, with the same cycling load as in session B. Blood and dialysate flows were respectively 300 and 500 mL/min. Blood was sampled from the blood inlet at different time points, and dialysate was partially collected (300 mL/h). Small water soluble solutes and protein-bound toxins were quantified and intradialytic reduction ratios (RR) and overall removal were calculated per solute. Total solute removal and reduction ratios were not different between the three test sessions, except for the reduction ratios RR60–120 and RR150–210 for potassium. In conclusion, we add evidence to the existing literature that, regardless of the timing within the dialysis session, intradialytic exercise has no impact on small solute clearance, and demonstrated also a lack of impact for protein-bound solutes.

P1155REMOVAL OF PHOSPHATE AND CREATININE DURING PD WITH DIFFERENT GLUCOSE CONCENTRATIONS

Background and Aims Adequate removal of creatinine and phosphate is one of the key objectives in peritoneal dialysis (PD). Whereas the mechanism of creatinine removal is well known, there are gaps in understanding regulation of phosphate removal. Clinical studies show that although the size of both molecules is similar, their removal might behave differently (Badve et al CJASN 2008). Several, but not all, studies have suggested that peritoneal phosphate clearance is larger when using CAPD than APD prescriptions, suggesting the dwell time or duration is an important determinant of phosphate clearance. The aim of the study was to investigate specifically the effect of dwell duration at the level of single PD exchange with different glucose concentrations on peritoneal phosphate clearance. Method A prolonged 8-hour PET was carried out in 32 clinically stable PD patients with each of three glucose-based solutions: 1.36% (G1), 2.27% (G2), and 3.86% (G3) with temporary drainage at 1 and 4 hours of peritoneal dwell. Dialysate and blood samples were taken to measure infused and drained volume and concentration of phosphate and creatinine in dialysate and blood. Clearances were calculated for a single exchange for each solution and for 4-hour (4H) and 8-hour (8H) dwell periods. For each patient, the 4-hour creatinine D/P ratio for G3 was calculated. The clearance ratio, ClR, defined as the ratio of solute clearance for particular solution to its clearance for the G1 solution, was calculated for both solutes and each solution and dwell durations. Results The obtained values of 4H creatinine D/P ratio for G3 solution were 0.67±0.11 (mean±SD). The values of solute clearances per single exchange expressed in mL/min, are presented in table below. Creatinine and phosphate clearances were found to be solution and dwell duration dependent with p<0.001. The clearances of both solutes were correlated for the same dwell duration or solution (not for creatinine G2 for 4H vs 8H) with p<0.05. Moreover, solute clearances were also correlated with creatinine D/P for 4H but not for 8H. The clearances of phosphate were also correlated with that for creatinine each solution at both dwell durations with p<0.001. Both calculated ClR were found to be dependent on the solution (p<0.001) but not dwell duration. Similar dependence on solution and correlations are valid in one analyze solute mass removal. Conclusion Phosphate and creatinine clearances were found to be well correlated during a long, 8-hour PET proving similarities in their transport. Interestingly, the dependence of both clearances and ClR on solution glucose concentration suggest that the removal of phosphate as well as creatinine depends on the ultrafiltration induced by glucose concentration in dialysis solution.

Flexibility in peritoneal dialysis prescription: Impact on technique survival

Background: Patient burnout is a major cause of technique failure on peritoneal dialysis (PD). Reducing the PD prescription on an individual basis, dependent upon residual kidney function (RKF), may have a role in prolonging time on PD by reducing dialysis burden. This retrospective study aimed to determine the safety and impact of flexible PD prescribing on technique and patient survival. Methods: All patients (186) from our centre starting PD from 1st January 2012 to 31st December 2016 were included. Data on dialysis prescription were collected for each patient from the time they had started PD, and dialysis adequacy measured regularly (3–6 monthly) using PD Adequest. Results: Median age at start of dialysis was 61 years. Only 49% started on PD 7 days a week and this dropped to 27% at 3 months following the first clearance test. Over 90% achieved creatinine clearance > 50 L/week/1.73 m2 up to 2 years of follow-up, with 87% achieving this standard at 3 years. Patient and technique survival at 1, 2 and 3 years were 91%, 81%, and 72%, and 89%, 87% and 78% respectively. Factors on univariate analysis affecting technique survival included increasing age (HR 0.98, p = 0.04, 95% CI (0.96–0.999)), two or more episodes of PD-associated peritonitis (HR 4.52, p = 0.00, 95% CI (1.87–10.91)) and increasing PD intensity (HR 3.30, p = 0.02, 95% CI (1.22–8.93)). After multivariate adjustment which included baseline kidney function, low PD intensity continued to be associated with better technique survival (HR 0.17, p = 0.03, 95% CI (0.03–0.85)). Conclusion: Tailoring the PD prescription to RKF enables days off dialysis while still maintaining recommended levels of small solute clearance. This approach reduces dialysis burden and is associated with higher technique survival.