Fosfomycin single- and multiple-dose pharmacokinetics in patients undergoing prolonged intermittent renal replacement therapy

Background Fosfomycin is used increasingly in the treatment of MDR bacteria. It is eliminated by renal excretion, but data regarding dosing recommendations for patients undergoing modern means of renal replacement therapies are scarce. Objectives Evaluation of the pharmacokinetics (PK) of fosfomycin in patients undergoing prolonged intermittent renal replacement therapy (PIRRT) to guide dosing recommendations. Methods Fosfomycin was given in 11 (7 female) patients with severe infections undergoing PIRRT. Plasma levels were measured at several timepoints on the first day of fosfomycin therapy, as well as 5–6 days into therapy, before and after the dialyser, to calculate its clearance. Fosfomycin was measured in the collected spent dialysate. Results The median (IQR) plasma dialyser clearance for fosfomycin was 183.4 (156.9–214.9) mL/min, eliminating a total amount of 8834 (4556–10 440) mg of fosfomycin, i.e. 73.9% (45.3%–93.5%) of the initial dose. During PIRRT, the fosfomycin half-life was 2.5 (2.2–3.4) h. Data from multiple-dose PK showed an increase in fosfomycin Cmax from 266.8 (166.3–438.1) to 926.1 (446.8–1168.0) mg/L and AUC0–14 from 2540.5 (1815.2–3644.3) to 6714 (4060.6–10612.6) mg·h/L. Dialysis intensity during the study was 1.5 L/h. T>MIC was 100% in all patients. Conclusions Patients undergoing PIRRT experience significant fosfomycin elimination, requiring a dose of 5 g/8 h to reach adequate plasma levels. However, drug accumulation may occur, depending on dialysis frequency and intensity.

Predicting anemia using NIR spectrum of spent dialysis fluid in hemodialysis patients

Anemia is commonly present in hemodialysis (HD) patients and significantly affects their survival and quality of life. NIR spectroscopy and machine learning were used as a method to detect anemia in hemodialysis patients. The aim of this investigation has been to evaluate the near-infrared spectroscopy (NIRS) as a method for non-invasive on-line detection of anemia parameters from HD effluent by assessing the correlation between the spectrum of spent dialysate in the wavelength range of 700–1700 nm and the levels of hemoglobin (Hb), red blood cells (RBC), hematocrit (Hct), iron (Fe), total iron binding capacity (TIBC), ferritin (FER), mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC) in patient blood. The obtained correlation coefficient (R) for RBC was 0.93, for Hb 0.92, for Fe 0.94, for TIBC 0.96, for FER 0.91, for Hct 0.94, for MCV 0.92, for MCHC 0.92 and for MCH 0.93. The observed high correlations between the NIR spectrum of the dialysate fluid and the levels of the studied variables support the use of NIRS as a promising method for on-line monitoring of anemia and iron saturation parameters in HD patients.

MO660INTERRELATIONSHIP BETWEEN PROTEIN BOUND UREMIC TOXIN INDOXYL SULFATE CONCENTRATION IN BLOOD AND SPENT DIALYSATE DURING HEMODIALYSIS TREATMENT

Background and Aims Indoxyl sulfate (IS) is a representative of the protein-bound uremic retention solutes [1]. Among CKD patients, high serum levels of IS are associated with high cardiovascular and all-cause mortality – IS is linked to cardiovascular outcomes, induces acceleration of atherosclerosis and abnormal bone metabolism [2,3]. Optical monitoring of the uremic marker molecules in the spent dialysate has been proposed [4] to estimate on-line concentration and removal of uremic toxins, allowing to assess total removed solute and removal rate of uremic toxins. Although several studies have been published covering the on-line optical monitoring of the spent dialysate, there is scarce knowledge about relation between spent dialysate and blood concentrations for protein-bound uremic solutes. The aim of this study was to evaluate the relationship between protein bound uremic toxin IS concentration in blood and spent dialysate during hemodialysis (HD) and hemodiafiltration (HDF) with different treatment settings, with the potential of evaluating uremic toxins’ levels in blood by assessing uremic toxins’ concentration in spent dialysate. Method 22 ESKD patients (16 male and 8 female, 55±17 years) on chronic HDF were enrolled into the study (fistula N=15, graft N=7). For each patient 4 midweek dialysis sessions (length 240min, HD: N=1, Qb=200ml/min, Qd=300ml/min, 1,5m2; HDF: N=3, median (interquartile range) Qb = 298 (296-356) ml/min, Qd= 795 (500-800) ml/min, Vsubst = 21.8 (15-24.5) L, 1,8m2 and 2,2m2) were included. During each dialysis session, blood samples were taken at 0 min (start) and 240 min from the arterial blood line, and dialysate samples were taken at 7 min and 240 min from the outlet of the dialysis machine. After sample processing, serum total, serum free and spent dialysate IS concentrations were determined by HPLC. Regression analysis was carried out. Results Median (interquartile range) IS concentrations in blood were 10.02 (6.68 - 14.68) µmol/L for free IS, 101.33 (56.99- 125.66) µmol/L for total IS, and 3.74 (2.35- 5.93) µmol/L in dialysate at the beginning of dialysis, and 6.07 (3.58- 9.00) µmol/L, 56.70 (28.91-80.67) µmol/L, 1.94 (1.15-2.98) µmol/L at the end of dialysis, respectively. There was a strong correlation between IS concentration in blood and dialysate at the beginning and at the end of dialysis even without data normalization by treatment settings (Fig. 1), with the strongest correlation between free IS concentration and IS in dialysate at 240 min (R2 = 0,976) and at the beginning of dialysis (R2 = 0,962). The reason for the higher correlation between free IS in blood and IS in dialysate is that only protein non-bound fraction of IS is available for removal by dialysis from blood into dialysate. Conclusion There is a strong correlation between IS concentrations in blood and dialysate with different treatment settings during whole dialysis. Assessment of protein bound uremic toxins’ concentration in the spent dialysate by optical sensor could thus also provide information about the concentration of uremic toxins in blood. [1] Vanholder et al 2018; [2] Yamamoto et al 2020; [3] Barreto et al 2009; [4] Lauri et al 2019;

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.

Performance Evaluation and Fouling Propensity of Forward Osmosis (FO) Membrane for Reuse of Spent Dialysate

The number of chronic renal disease patients has shown a significant increase in recent decades over the globe. Hemodialysis is the most commonly used treatment for renal replacement therapy (RRT) and dominates the global dialysis market. As one of the most water-consuming treatments in medical procedures, hemodialysis has room for improvement in reducing wastewater effluent. In this study, we investigated the technological feasibility of introducing the forward osmosis (FO) process for spent dialysate reuse. A 30 LMH of average water flux has been achieved using a commercial TFC membrane with high water permeability and salt removal. The water flux increased up to 23% with increasing flowrate from 100 mL/min to 500 mL/min. During 1 h spent dialysate treatment, the active layer facing feed solution (AL-FS) mode showed relatively higher flux stability with a 4–6 LMH of water flux reduction while the water flux decreased significantly at the active layer facing draw solution (AL-DS) mode with a 10–12 LMH reduction. In the pressure-assisted forward osmosis (PAFO) condition, high reverse salt flux was observed due to membrane deformation. During the membrane filtration process, scaling occurred due to the influence of polyvalent ions remaining on the membrane surface. Membrane fouling exacerbated the flux and was mainly caused by organic substances such as urea and creatinine. The results of this experiment provide an important basis for future research as a preliminary experiment for the introduction of the FO technique to hemodialysis.

Comparison of dialysis dose through real-time Kt/V by ultraviolet absorbance of spent dialysate, single-pool Daugirdas II, and Kt/BSA according to sex and age

ABSTRACT Background: Kt/V OnLine (Kt/VOL) avoids inaccuracies associated with the estimation of urea volume distribution (V). The study aimed to compare Kt/VOL, Kt/V Daugirdas II, and Kt/BSA according to sex and age. Methods: Urea volume distribution and body surface area were obtained by Watson and Haycock formulas in 47 patients. V/BSA was considered as a conversion factor from Kt/V to Kt/BSA. Dry weight was determined before the study. Kt/VOL was obtained on DIALOG machines. Results: Pearson correlation between Kt/VOL vs Kt/VII and Kt/VOL vs Kt/BSA was significant for males (r = 0.446, P = 0.012 and r = -0.476 P = 0.007) and individuals < 65 years (0.457, P = 0.019 and -0.549 P = 0.004), but not for females and individuals ≥ 65 years. V/BSA between individuals < 65 and individuals ≥ 65 years were 18.28 ± 0.15 and 18.18 ± 0.16 P = 0.000). No agreement between Kt/VII vs Kt/BSA. Men and individuals > 65 years received a larger dialysis dose than, respectively, females and individuals < 65 years, in the comparison between Kt/VOL versus Kt/VII. V/BSA ratios among men and women were respectively 18.29 ± 0.13 and 18.12 ± 0.15 P = 0.000. Conclusions: Kt/VOL allows recognition of real-time dose regardless of sex and age.

SARS-CoV-2 in spent dialysate from chronic peritoneal dialysis patients with COVID-19

Background To date it is unclear whether SARS-CoV-2 is present in spent dialysate from peritoneal dialysis (PD) patients with COVID-19. Our aim was to assess the presence or absence of SARS-CoV-2 in spent dialysate from chronic PD patients with confirmed diagnosis of COVID-19. Methods Spent PD dialysate samples from COVID-19 positive PD patients were collected between March and August 2020. The multiplexed real-time reverse transcriptase-polymerase chain reaction assay contained primer/probe sets specific to different SARS-CoV-2 genomic regions and to bacteriophage MS2 as internal process control for nucleic acid extraction. Demographic and clinical data were obtained from patients' electronic health records. Results A total of 26 spent PD dialysate samples were collected from 11 patients from 10 dialysis centers. Spent PD dialysate samples were collected on average 25±13 days (median 20, range 10 to 45) after onset of symptoms. The temporal distance of PD effluent collection relative to the closest positive nasal swab RT PCR was 15±11 days (median 14; range 1 to 41). All 26 PD effluent samples tested negative at three SARS-CoV-2 genomic regions. Conclusions Our findings indicate the absence of SARS-CoV-2 in spent PD dialysate collected 10 days or later after the onset of COVID-19 symptoms. We cannot rule out presence of SARS-CoV-2 in spent PD dialysate in the early stage of COVID-19.

The Synergy of Thermally Reduced Graphene Oxide in Amperometric Urea Biosensor: Application for Medical Technologies

Thermally reduced graphene oxide (TRGO) is a graphene-based nanomaterial that has been identified as promising for the development of amperometric biosensors. Urease, in combination with TRGO, allowed us to create a mediator-free amperometric biosensor with the intention of precise detection of urea in clinical trials. Beyond simplicity of the technology, the biosensor exhibited high sensitivity (2.3 ± 0.1 µA cm−2 mM−1), great operational and storage stabilities (up to seven months), and appropriate reproducibility (relative standard deviation (RSD) about 2%). The analytical recovery of the TRGO-based biosensor in urine of 101 ÷ 104% with RSD of 1.2 ÷ 1.7% and in blood of 92.7 ÷ 96.4%, RSD of 1.0 ÷ 2.5%, confirmed that the biosensor is acceptable and reliable. These properties allowed us to apply the biosensor in the monitoring of urea levels in samples of urine, blood, and spent dialysate collected during hemodialysis. Accuracy of the biosensor was validated by good correlation (R = 0.9898 and R = 0.9982) for dialysate and blood, utilizing approved methods. The advantages of the proposed biosensing technology could benefit the development of point-of-care and non-invasive medical instruments.

In vitro efficacy and safety of a system for sorbent-assisted peritoneal dialysis

A system for sorbent-assisted peritoneal dialysis (SAPD) was designed to continuously recirculate dialysate via a tidal mode using a single lumen peritoneal catheter with regeneration of spent dialysate by means of sorbent technology. We hypothesize that SAPD treatment will maintain a high plasma-to-dialysate concentration gradient and increase the mass transfer area coefficient of solutes. Thereby, the SAPD system may enhance clearance while reducing the number of exchanges. Application is envisaged at night as a bedside device (12 kg, nighttime system). A wearable system (2.0 kg, daytime system) may further enhance clearance during the day. Urea, creatinine, and phosphate removal were studied with the daytime and nighttime system ( n = 3 per system) by recirculating 2 liters of spent peritoneal dialysate via a tidal mode (mean flow rate: 50 and 100 mL/min, respectively) for 8 h in vitro. Time-averaged plasma clearance over 24 h was modeled assuming one 2 liter exchange/day, an increase in mass transfer area coefficient, and 0.9 liters ultrafiltration/day. Urea, creatinine, and phosphate removal was 33.2 ± 4.1, 5.3 ± 0.5, and 6.2 ± 1.8 mmol, respectively, with the daytime system and 204 ± 28, 10.3 ± 2.4, and 11.4 ± 2.1 mmol, respectively, with the nighttime system. Time-averaged plasma clearances of urea, creatinine and phosphate were 9.6 ± 1.1, 9.6 ± 1.7, and 7.0 ± 0.9 mL/min, respectively, with the nighttime system and 10.8 ± 1.1, 13.4 ± 1.8, and 9.7 ± 1.6 mL/min, respectively, with the daytime and nighttime system. SAPD treatment may improve removal of uremic toxins compared with conventional peritoneal dialysis, provided that peritoneal mass transport will increase.