Nitric Oxide-Releasing Hemodialysis Catheter Lock Solutions.

In an attempt to address the significant morbidity, mortality, and economic cost associated with tunneled dialysis catheter (TDC) dysfunction, we report the development of nitric oxide-releasing dialysis catheter lock solutions. Catheter lock solutions with a range of NO payloads and release kinetics were prepared using low-molecular-weight N-diazeniumdiolate nitric oxide donors. Nitric oxide released through the catheter surface as a dissolved gas was maintained at therapeutically relevant levels for at least 72 h, supporting clinical translatability (interdialytic period). Slow, sustained NO release from the catheter surface prevented bacterial adhesion in vitro by 88.9 and 99.7% for Pseudomonas aeruginosa and Staphylococcus epidermidis, respectively, outperforming a burst NO-release profile. Furthermore, bacteria adhered to the catheter surface in vitro prior to lock solution use was reduced by 98.7 and 99.2% for P. aeruginosa and S. epidermidis, respectively, when using a slow releasing NO donor, demonstrating both preventative and treatment potential. The adhesion of proteins to the catheter surface, a process often preceding biofilm formation and thrombosis, was also lessened by 60-65% by sustained NO release. In vitro cytotoxicity of catheter extract solutions to mammalian cells was minimal, supporting the non-toxic nature of the NO-releasing lock solutions. The use of the NO-releasing lock solution in an in vivo TDC porcine model demonstrated decreased infection and thrombosis, enhanced catheter functionality, and improved outcome (i.e., likelihood of survival) as a result of catheter use.

Water quality and adverse health effects on the hemodialysis patients: An overview.

Hemodialysis is considered a treatment of choice for patients with renal failure worldwide, allowing the replacement of some kidney functions by diffusion and ultrafiltration processes. Over 4 million people require some form of renal replacement therapy, with hemodialysis being the most common. During the procedure, contaminants in the water and the resulting dialysate may pass into the patient's blood and lead to toxicity. Thus, the quality of the associated dialysis solutions is a critical issue. Accordingly, the discussion of the importance of a dialysis water delivery system controlled by current standards and recommendations, with efficient monitoring methods, disinfection systems, and chemical and microbiological analysis, is crucial for improving the health outcomes of these patients. The importance of treatment, monitoring, and regulation is emphasized by presenting several case studies concerning the contamination of hemodialysis water and the adverse effects on the respective patients.

The effects of glucose-free and glucose-containing dialysate during dialysis in MHD patients: a prospective cross-over study.

OBJECTIVE: To investigate the effects of glucose-free and glucose-containing dialysates during dialysis in maintenance hemodialysis (MHD) patients by the prospective cross-over study, and detect glucose control methods in MHD patients. METHODS: A total of 66 MHD 18-75 years old patients in our hospital from Nov. 2019 to Mar. 2020 were recruited. All patients underwent HD with 4 hours per time, three times per week. Glucose-free dialysate (glucose-free group) and then 5.55 mmol/L glucose-containing dialysate (glucose-5.55 group) were used alternately in dialysis. The demographics and parameters of pre- and post-dialysis were recorded. RESULTS: A total of 60 patients were analyzed, and 28 patients among them had type 2 diabetes. Serum glucose pre and post dialysis were 8.64 ± 4.18 mmol/L versus 5.74 ± 1.82 mmol/L (p < 0.01) in glucose-free dialysate, and 9.31 ± 4.89 mmol/L versus 7.80 ± 2.59 mmol/L (p < 0.01) in glucose-5.55 dialysate. The post-dialysis blood glucose of glucose-free group was lower than glucose-5.55 group (5.74 ± 1.82 vs 7.80 ± 2.59, p < 0.01). About 18 (30.00%) patients in glucose-free group and 1 patient (1.67%) in glucose-5.55 group whose blood glucose was lower than 4.44 mmol/L (p < 0.01). About 29 patients (48.33%) in glucose-free group and 17 patients (28.33%; p = 0.02) in glucose-5.55 group have hunger feeling. Serum sodium level in the glucose-free group was higher than that in Glucose-5.55 group (137.92 ± 1.64 vs 136.70 ± 1.64, p < 0.01). Post-dialysis blood glucose had no significant differences between patients not using diabetes-related medication (13 patients) and patients using diabetes-related medication (15 patients) in glucose-free group (7.13 ± 1.78 mmol/L vs 6.08 ± 2.84 mmol/L, p = 0.23) and glucose-5.55 group (9.22 ± 2.59 mmol/L vs 9.35 ± 2.88 mmol/L, p = 0.90). CONCLUSIONS: Glucose-free and glucose-5.55 dialysate both decrease the blood glucose post-dialysis. Dialysates containing 5.55 mmol/L glucose can reduce the incidence of hypoglycemia and lower serum sodium, but have no effect on blood pressure during dialysis. Stopping insulin and oral anti-diabetic drugs once before dialysis may not affect the control of blood glucose.

Metabolic alkalosis in hemodialysis patients.

BACKGROUND: Hemodialysis solutions typically contain a high alkali concentration designed to counter interdialytic acidosis, but this could result in persistent alkalosis in some patients. The prevalence and significance of persistent alkalosis were therefore examined at four outpatient centers over a 10-year period. METHODS: Alkalosis was defined as a pre-dialysis serum [HCO3 ] ≥ 26 meq/L in >6 months of a 12-month period and was persistent if present in a majority of months thereafter. Control patients had a serum [HCO3 ] of 19-23 meq/L > 6 of every 12 months. Standard, citrate-containing dialysate was used in all patients without adjustment of bicarbonate concentration. RESULTS: 444 of 1271 patients had alkalosis that persisted in 73. Compared to control patients, persistently alkalotic patients were older, but gender, race, starting weight, comorbidities, and mortality did not differ. Dialysis dose was 7% greater, protein catabolic rate was 11% lower, and interdialytic weight gain was 29% lower, all p < 0.001. Persistently alkalotic patients had double the incidence of cardiac arrhythmias (p = 0.07) and a 20% greater intradialytic blood pressure decrease (p < 0.001). CONCLUSIONS: Alkalosis is common in hemodialysis patients and can be persistent, likely due to decreased protein catabolic rate and increased dialysis dose, and may have detrimental cardiovascular effects.

Safety Management of Dialysis Fluid in Japan: Important Duties and Responsibilities of Clinical Engineers.

Dialysis therapy is the predominant choice for renal failure in Japan, and almost 30% of the patients with renal failure have been treated for 10 years or more. Dialysis became the standard procedure to treat renal failure nationwide in the 1980s. However, at that time, managing the increased number of patients on maintenance hemodialysis as well as operating and maintaining the newly developed advanced medical technologies at extensive numbers of clinical sites proved problematic. To help address this, the clinical engineer system was established in 1987 and certain aspects of the clinical engineers' role remain unique to Japan today. For the last 30 years, clinical engineers have worked as frontline medical personnel not only operating dialysis-related devices but also placing their hands directly on patients when providing care, routinely performing puncture, and administering drugs through the blood circuit under physicians' instructions. As part of their work, they crucially maintain the use of central dialysis fluid delivery systems (CDDSs) - also unique to Japan - which prepare and deliver a large quantity of dialysis fluid through a central circuit to individual dialysis consoles. CDDSs are widely used because they effectively alleviated the early confusion at clinical sites caused by the rapidly increasing hemodialysis population and the serious shortage in medical personnel. Moreover, clinical engineers alone have the technical ability to provide safe dialysis fluids adjusted to strict standards at clinical sites. In this review article, we focus on the crucial roles that clinical engineers have in maintaining the safety of dialysis-related medical devices and the preparation and delivery of dialysis fluid at many dialysis facilities across the country.

Bioanalysis of INCB000928 in hemodialysate: prevention of nonspecific binding and validation of surrogate matrices.

Aim: To develop and validate a bioanalytical method for the quantification of INCB000928 in hemodialysate. Materials & methods: Blank dialysate and phosphate-buffered saline were compared with hemodialysate for surrogate matrix selection. Direct addition of internal standard without analyte extraction and a high-performance LC-MS/MS were used for analysis. Results & conclusion: INCB000928 in hemodialysate exhibited strong nonspecific binding to polypropylene containers. In the presence of 10% isopropyl alcohol, the loss of INCB000928 was fully recovered, regardless of pre- or post-addition of the solvent. Blank dialysate and phosphate-buffered saline were determined to be appropriate surrogate matrices by using a three-way cross-comparison and were subsequently validated in the quantitative analysis of INCB000928 in hemodialysate.

Fibrodysplasia ossificans progressiva (FOP) is a very rare disease characterized by congenital malformation of the great toes and progressive heterotopic ossification. The genetic cause of FOP is mutation in the gene ALK2. INCB000928 is a novel and orally available drug that inhibits ALK2 protein activity and has been shown to prevent ossification in a laboratory mouse model of FOP. Patients with end-stage renal disease who undergo hemodialysis may require a different dose of INCB000928. This study showed that INCB000928 was heavily adsorbed by the container wall, resulting in underestimated drug levels in hemodialysate. We present a method to accurately measure INCB000928 levels in hemodialysate by using isopropyl alcohol as an antiadsorption agent and cost-effective surrogate matrix.

A convenient online desalination tube coupled with mass spectrometry for the direct detection of iodinated contrast media in untreated human spent hemodialysates.

BACKGROUND: Mass spectrometry (MS) analysis using direct infusion of biological fluids is often problematic due to high salts/buffers. Iodinated contrast media (ICM) are frequently used for diagnostic imaging purposes, sometimes inducing acute kidney injury (AKI) in patients with reduced kidney function. Therefore, detection of ICM in spent hemodialysates is important for AKI patients who require urgent continuous hemodiafiltration (CHDF) because it allows noninvasive assessment of the patient's treatment. In this study, we used a novel desalination tube before MS to inject the sample directly and detect ICM. METHODS: Firstly, spent hemodialysates of one patient were injected directly into the electrospray ionization (ESI) source equipped with a quadrupole time-of-flight mass spectrometer (Q-TOF MS) coupled to an online desalination tube for the detection of ICM and other metabolites. Thereafter, spent hemodialysates of two patients were injected directly into the ESI source equipped with a triple quadrupole mass spectrometer (TQ-MS) connected to that online desalination tube to confirm the detection of ICM. RESULTS: We detected iohexol (an ICM) from untreated spent hemodialysates of the patient-administered iohexol for computed tomography using Q-TOF MS. Using MRM profile analysis, we have confirmed the detection of ICM in the untreated spent hemodialysates of the patients administered for coronary angiography before starting CHDF. Using the desalination tube, we observed approximately 178 times higher signal intensity and 8 times improved signal-to-noise ratio for ioversol (an ICM) compared to data obtained without the desalination tube. This system was capable of tracking the changes of ioversol in spent hemodialysates of AKI patients by measuring spent hemodialysates. CONCLUSION: The online desalination tube coupled with MS showed the capability of detecting iohexol and ioversol in spent hemodialysates without additional sample preparation or chromatographic separation. This approach also demonstrated the capacity to monitor the ioversol changes in patients' spent hemodialysates.

Efficacy of Supra-HFR in Removing FGF23 and Cytokines: A Single Session Analysis.

BACKGROUND/AIM: Supra hemodiafiltration with reinfusion of the endogenous ultrafiltrate (Supra-HFR) is a dialysis technique used to improve uremic toxin removal in the range of the middle molecular weight molecules. Supra-HFR does not require the preparation and online infusion of high-purity dialysis water because it allows the production of an endogenous ultrafiltrate that undergoes detoxification through an adsorbing resin. PATIENTS AND METHODS: We investigated the ability of Supra-HFR to remove fibroblast growth factor 23 (FGF23), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-alpha), interleukin 8 (IL-8), and transforming growth factor alpha (TGF-alpha) after a single session dialysis in nine patients affected by end stage renal disease (ESRD). The same patients underwent a single session of online hemodiafiltration (OL-HDF) to evaluate possible differences in FGF23 and IL-6 levels. RESULTS: A significant reduction in FGF23 was observed with both Supra-HFR (p=0.001) and OL-HDF. As for TNF-alpha and TGF-alpha, which were measured using Supra-HFR only, their percentage values were significantly lower at the end of dialysis than at the start (p=0.0028 and p=0.03, respectively). This did not change with post-dialysis rebound. Supra-HFR was found to have no effect on IL-6 and IL-8. Interestingly, the removal rate for FGF23 and IL-6 was similar to that observed with OL-HDF. CONCLUSION: Supra-HFR was not superior to OL-HDF, with suboptimal convective volume in the removal of the molecules tested, especially FGF23, which is considered a large middle molecular weight uremic toxin.

Changes in blood glucose and lactate concentrations with hemodialysis.

INTRODUCTION: Blood glucose concentrations are recognized to vary during hemodialysis (HD), with hypoglycemia reported with glucose-free dialysates. As glucose can be converted to lactate, and conversely lactate to glucose, we wished to study factors associated with peri-dialytic changes in blood glucose. METHODS: We prospectively collected data including patient profile, dialysis prescription, hemodynamic parameters, medications, dialysis adequacy and monthly blood tests for three consecutive months. All patients used a 100 mg/dl glucose dialysate. Linear mixed model, general estimated equation and binary logistic regression were used for analysis. RESULTS: We studied 157 sessions in 55 patients, median age 67.1 (58.5-72.6) years, 67% male, 71% diabetic, 40% prescribed insulin, dialysis vintage 20.4 (10.7-57.7) months. Mean single pool Kt/Vurea and normalized protein nitrogen appearance rate (nPNA) were 1.70 ± 0.34 and 1.01 ± 0.30 g/kg/day respectively. Hypoglycemia (<70 mg/dl) occurred during 10 sessions (6.4%). 25% of non-diabetes experienced hypoglycemia. The % change in peri-dialytic blood glucose was associated with the % change in lactate (estimate of fixed effect = 0.23 p < 0.001) and pre-HD glucose (estimate of fixed effect = 0.09, p < 0.001). The fall in glucose was not associated with urea clearance, consumption of food, administration of insulin or antidiabetic medications, nPNA, body mass index, or pyridoxine concentrations. CONCLUSIONS: Peri-dialytic hypoglycemia cannot simply be explained by dialyzer clearance, as the corresponding fall in lactate would potentially suggest increased gluconeogenesis. Despite using a glucose containing dialysate, asymptomatic hypoglycemia occurred in 6.4% of sessions, suggesting a role for peri-dialytic blood glucose monitoring and avoiding fasting during dialysis.

Antimicrobial activity of hemodialysis catheter lock solutions in relation to other compounds with antiseptic properties.

Proper protection of vascular access after haemodialysis is one of the key measures for the prevention of catheter-related infections. Various substances with bactericidal and anticoagulant properties are used to fill catheters, but due to the unsatisfactory clinical effects and occurrence of adverse reactions, the search for new substances is still ongoing. In the present paper, we compared the in vitro antimicrobial activity of solutions used for tunnelled catheter locking (taurolidine, trisodium citrate) and solutions of substances that could potentially be used for this purpose (sodium bicarbonate, polyhexanide-betaine). The studies have been conducted on bacteria that most commonly cause catheter-related infections. The values of both minimum inhibitory concentration and minimum biofilm eradication concentration of the substances were determined. The ability of the tested substances to eradicate biofilm from the dialysis catheter surface was also evaluated. The results showed that polyhexanide-betaine inhibited the growth of all microbes comparably to taurolidine, even after ≥ 32-fold dilution. The activity of trisodium citrate and sodium bicarbonate was significantly lower. Polyhexanide exhibited the highest activity in the eradication of bacterial biofilm on polystyrene plates. The biofilm formed on a polyurethane dialysis catheter was resistant to complete eradication by the test substances. Polyhexanide-betaine and taurolidine showed the highest activity. Inhibition of bacterial growth regardless of species was observed not only at the highest concentration of these compounds but also after dilution 32-128x (taurolidine) and 32-1024x (polyhexanide-betaine). Therefore, it can be assumed that taurolidine application as a locking solution prevents catheter colonization and systemic infection development. Taurolidine displays high antimicrobial efficacy against Gram-positive cocci as well as Gram-negative bacilli. On the contrary, the lowest antibacterial effect displayed product contained sodium bicarbonate. The inhibitions of bacterial growth were not satisfactory to consider it as a substance for colonization prevention. Polyhexanidine-betaine possessed potent inhibitory and biofilm eradication properties comparing to all tested products. PHMB is applied as a wound irrigation solution worldwide. However, based on our results, we assume that the PHMB is a promising substance for catheter locking solutions thanks to its safety and high antimicrobial properties.

Methods for dose quantification in continuous renal replacement therapy: Toward a more precise approach.

Periodic dose assessment is quintessential for dynamic dose adjustment and quality control of continuous renal replacement therapy (CRRT) in critically ill patients with acute kidney injury (AKI). The flows-based methods to estimate dose are easy and reproducible methods to quantify (estimate) CRRT dose at the bedside. In particular, quantification of effluent flow and, mainly, the current dose (adjusted for dialysate, replacement, blood flows, and net ultrafiltration) is routinely used in clinical practice. Unfortunately, these methods are critically influenced by several external unpredictable factors; the estimated dose often overestimates the real biological delivered dose quantified through the measurement of urea clearance (the current effective delivered dose). Although the current effective delivered dose is undoubtedly more precise than the flows-based dose estimation in quantifying CRRT efficacy, some limitations are reported for the urea-based measurement of dose. This article aims to describe the standard of practice for dose quantification in critically ill patients with AKI undergoing CRRT in the intensive care unit. Pitfalls of current methods will be underlined, along with solutions potentially applicable to obtain more precise results in terms of (a) adequate marker solutes that should be used in accordance with the clinical scenario, (b) correct sampling procedures depending on the chosen indicator of transmembrane removal, (c) formulas for calculations, and (d) quality controls and benchmark indicators.

Optical Method and Biochemical Source for the Assessment of the Middle-Molecule Uremic Toxin ß2-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 ß2-microglobulin (ß2M), 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 ß2M 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 ß2M concentrations in spent dialysate for the entire cohort. Optically and laboratory estimated reduction ratio (RR) and total removed solute (TRS) of ß2M were not statistically different (p > 0.35). Dialytic elimination of MM uremic toxin ß2M 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.

Cardiac arrhythmia during early-week and mid-week dialysis in hemodialysis patients.

Data on cardiac arrhythmia and electrolyte changes during the dialysis cycle have been limited. Fifty-two hemodialysis (HD) patients underwent 48-h Holter monitoring during early-week and mid-week HD sessions. Pre-HD and post-HD blood samples were collected in both HD sessions. The 48-h Holter data were divided into five phases: (1) 4-h during the early-week HD (HD1), (2) 12-h post-HD1, (3) 16-h period between Phases 2 and 4 (used as the patient's baseline electrocardiography [ECG]), (4) 12-h pre-HD2 phase, and (5) 4-h during the mid-week HD (HD2). The patients' mean age was 68.54 ± 13.37 years. We found that the dialysate-to-serum[K] gradient and changes of S[K] were significantly higher in HD1 than in HD2, as well as changes of S[Mg]. There were no significant ECG changes during the 4-h HD1 and HD2 when compared with the baseline ECG. Phase 2 of Holter ECG was the most common phase that showed significant changes (increased QT interval dispersion (QTD), increased ventricular events, increased number of premature ventricular contractions, ST elevation and ST depression), which was contributed from the dialysate[K] 2 mmol/L subgroup, but not the dialysate[K] 3 mmol/L subgroup. In the subgroup of patients with a high ultrafiltration rate (UFR; mean UFR ≥10 mL/kg/h), there were significantly increased ventricular events and ST-segment changes in Phase 2. In conclusion, ECG changes were associated with the dialysis cycle, significantly in the 12-h after early-week HD sessions. These may be associated with low dialysate[K] or high dialysate-to-S[K] gradient, high ultrafiltration rate and duration of the interdialytic interval.

Euglycemic Ketosis During Continuous Kidney Replacement Therapy With Glucose-Free Solution: A Report of 8 Cases.

In this report, we describe 8 patients with critical illness and diabetes mellitus who developed euglycemic ketosis during continuous kidney replacement therapy (CKRT) with a glucose-free CKRT solution. Two patients had chronic kidney disease stage 5, while the rest had acute kidney injury. The patients had improvement in all metabolic parameters following CKRT commencement, except for a worsening high anion gap metabolic acidosis, in spite of improvement in serum lactate. This led to detection of elevated serum ß-hydroxybutyrate in the setting of normoglycemia. Following diagnosis of ketosis, the patients' caloric intake was increased from a median of 15 (IQR, 10-20) to 25 (IQR, 20-29) kcal/kg/d by adding a dextrose infusion. This allowed for a corresponding increase in the insulin administered, from a median of 0.2 (IQR, 0-0.2) to 3.0 (IQR, 2.3-3.9) U/h. These contributed to a complete resolution of ketosis. This report of 8 cases demonstrates that critically ill patients are at risk of developing euglycemic ketosis during CKRT, which can be mitigated by providing adequate caloric intake and using glucose-containing CKRT solutions with appropriate insulin therapy. We recommend vigilance in evaluating for euglycemic ketosis in patients who have a persistent metabolic acidosis despite improvements in solute control during CKRT.

Management of Acute Kidney Injury in Coronavirus Disease 2019.

Acute kidney injury is a common complication in hospitalized patients with coronavirus disease 2019. Similar to acute kidney injury associated with other conditions such as sepsis and cardiac surgery, morbidity and mortality are much higher in patients with coronavirus disease 2019 who develop acute kidney injury, especially in the intensive care unit. Management of coronavirus disease 2019-associated acute kidney injury with kidney replacement therapy should follow existing recommendations regarding modality, dose, and timing of initiation. However, patients with coronavirus disease 2019 are very hypercoagulable, and close vigilance to anticoagulation strategies is necessary to prevent circuit clotting. During situations of acute surge, where demand for kidney replacement therapy outweighs supplies, conservative measures have to be implemented to safely delay kidney replacement therapy. A collaborative effort and careful planning is needed to conserve dialysis supplies, to ensure that treatment can be safely delivered to every patient who will benefit for kidney replacement therapy.