In vivo / in vitro Correlation of Pharmacokinetics of Gentamicin, Vancomycin, Teicoplanin and Doripenem in a Bovine Blood Hemodialysis Model

Background: Elimination of a drug during renal replacement therapy is not only dependent on flow rates, molecular size and protein binding, but is often influenced by difficult to predict drug membrane interactions. In vitro models allow for extensive profiling of drug clearance using a wide array of hemofilters and flow rates. We present a bovine blood based in vitro pharmacokinetic model for intermittent renal replacement therapy.Methods: Four different drugs were analyzed: gentamicin, doripenem, vancomicin and teicoplanin. The investigated drug was added to a bovine blood reservoir connected to a hemodialysis circuit. In total seven hemofilter models were analyzed using commonly employed flow rates. Pre-filter, post-filter and dialysate samples were drawn, plasmaseparated and analyzed using turbidimetric assays or HPLC. Protein binding of doripenem and vancomycin was measured in bovine plasma and compared to previously published values for human plasma.Results: Clearance values were heavily impacted by choice of membrane material and surface as well as by dialysis parameters such as blood flow rate. Gentamicin clearance ranged from a minimum of 90.12 ml/min in a Baxter CAHP-170 diacetate hemofilter up to a maximum of 187.90 ml/min in a Fresenius medical company Fx80 polysulfone model (blood flow rate 400 ml/min, dialysate flow rate 800 ml/min). Clearance of Gentamicin vs Vancomicin over the F80s hemofilter model using the same flow rates was 137.62 mL vs 103.25 ml/min. Doripenem clearance with the Fx80 was 141.25 ml/min.Conclusion: Clearance values corresponded very well to previously published data from clinical pharmacokinetic trials. In conjunction with in silico pharmacometric models. This model will allow precise dosing recommendations without the need of large scale clinical trials.

Effect of increased blood flow rate on renal anemia and hepcidin concentration in hemodialysis patients

Background Increasing the blood flow rate (BFR) is a useful method for increasing Kt/V and the clearance for low molecular solutes. Hemodialysis patients are often anemic due to hypoerythropoiesis and their chronic inflammatory state. Hepcidin, a hormone that regulates iron homeostasis, is considered as an indicator of iron deficiency in patients with end-stage renal disease. This study aimed to investigate the effects of an increased BFR during hemodialysis on serum hepcidin levels and anemia. Methods Between April 2014 and March 2016, 22 chronic dialysis patients (11 men [50.0 %]; mean [± standard deviation] age, 72 ± 12 years) undergoing maintenance hemodialysis treatment, thrice weekly, were enrolled and followed prospectively for 24 months. In April 2014, the BFR was 200 mL/min; in April 2015 this was increased to 400 mL/min, which was within acceptable limits. The dialysate flow rate remained stable at; 500mlL/min. Blood samples were collected in March 2015 and 2016. The primary endpoint was the comparison of the amounts of erythropoiesis-stimulating agent (ESA) required. Results The increased BFR increased the Kt/V and contributed to significantly decreased urea nitrogen (UN) (p = 0.015) and creatinine (Cr) (p = 0.005) levels. The dialysis efficiency was improved by increasing the BFR. Ferritin (p = 0.038), hepcidin (p = 0.041) and high-sensitivity interleukin-6 (p = 0.038) levels were also significantly reduced. The ESA administered was significantly reduced (p = 0.004) and the Erythropoietin Resistant Index (ERI) significantly improved (p = 0.031). The reduction rates in UN (p < 0.001), Cr (p < 0.001), and beta-2 microglobulin (p = 0.017) levels were significantly greater post the BFR increase compared to those prior to the BFR increase. However, hepcidin was not affected by the BFR change. Conclusions Increasing BFR was associated with hemodialysis efficiency, and led to reduce inflammatory cytokine interleukin-6, but did not contribute to reduce C-reactive protein. This reduced hepcidin levels, ESA dosage and ERI. Hepcidin levels were significantly correlated with ferritin levels, and it remains to be seen whether reducing hepcidin leads to improve ESA and iron availability during anemia management.

MO477SERUM C-REACTIVE PROTEIN AND PROCALCITONIN LEVELS IN HEMODIALYSIS AND INTRADIALYTIC ALTERATIONS

Introduction C-reactive protein (CRP) and procalcitonin (PCT) are widely used as markers of inflammation and infection in general population and in chronic hemodialysis (HD) as well. However, in dialysis (D) patients, serum CRP and PCT levels may be elevated even in the absence of inflammatory or infectious disease and diagnostic process is a challenge in such cases. We studied HD patients' laboratory profile concerning CRP and PCT. Subjects and Methods We studied 25 stable HD patients, M/F=22/3, aged 68(44-89) years, dialyzed thrice weekly for 55(6-274) months with a dialysate flow rate of 700 ml/min, with a residual daily diuresis less than 200 ml, Kt/V values of 1,44±0,3 and no signs of infection. Patients were classified in two groups. Group A included 10 patients on pre-dilution online hemodiafiltration (HDF). Group B consisted of 15 patients on conventional HD with low-flux polysulfone membrane. Twenty healthy subjects formed a control group C. Serum CRP and PCT levels were measured in duplicate in A and B groups before and at the end of mid-week dialysis sessions and also in C group. Results Pre-D serum CRP values in the total of patients were higher than those in healthy controls (10,89±19,29 vs 2,54±1,28 mg/L-p=0,004). Compared with group C, pre-D CRP values were higher only in B group (15,98±24,54 mg/L-p=0,001) but not in A group (4,09±3,33 mg/L-p=NS). There was a significant difference in pre-D serum CRP values between A and B groups (p=0,028). At the end of D session serum CRP values showed a tendency to increase in both groups A (5,16±4,81 mg/L) and B (17,00±27,00 mg/L) but differences were not significant. Pre-D serum PCT values in the total of patients were higher than those in healthy controls (0,82±0,9 vs 0,29±0,55 ng/ml-p&lt;0,001). Compared with group C, pre-D PCT values were higher in both A group (0,52±0,15 ng/ml-p&lt;0,001) and B group (1,01±1,13 ng/ml-p=0,006). There was no significant difference in pre-D serum PCT values between A and B groups (p=0,261). At the end of D session serum PCT values decreased in A group (0,32±0,11 ng/ml-p&lt;0,001) and increased in B group (1,12±1,21 ng/ml-p=0,014). Conclusions In patients on both conventional low-flux HD and online HDF pre-D serum CRP and PCT levels were higher than those in healthy subjects. Dialysis modality and membrane flux did not affect post-D serum CRP values, but post-PCT values decreased in online HDF. PCT usefulness might be limited in dialysis with high-flux membranes. Cut-off values have to be established for both markers to eliminate confusion in diagnosis of inflammatory and infectious diseases in hemodialyzed patients.

MO1052GREEN DIALYSIS: FROM MITH TO FUTURE

Background and Aims Over 2 million persons of the 7.8 billion world population undergo hemodialysis (HD). The need is underestimated because dialysis is not available free of charge for more of half of the word population. HD is costly process and produces a large quantity of medical waste. Reducing the environmental burden should be addressed as part of implementation dialysis programs. While collaboration between physicians and several different professionals is needed to design and develop projects in this direction, these are lingering and the literature is still scant. We overviewed literature to frame what is in progress and find clues for development. Method We conducted a systematic review of the literature from 2000 searching in PubMed, Scopus, Web of Science, and Google Scholar using search keywords including dialysis, green, recycling, ecology. We retrieved 41 publications in medical and technological fields. The results were summarized in a narrative review. Results Facilities: the points on which attention is focused are the design of new buildings, whose project should encompass green solutions, including solar power and water conservation, to reduce long-term expenses and ensure an eco-friendly development. Water: water consumption remains high, and the essential targets to improve efficiency are the optimization of the reverse osmosis system, and of the dialysate flow rate, and the waste-water management. The current idea is to substitute standard reverse osmosis, which have a high percent of waste-water, with recirculating systems. Likewise, lowering of dialysate flow rate could spare water consumption with no significant difference in term of efficiency. Moreover, different solutions have been proposed to reuse reject water: local sanitation, laundry departments, sterilization units within health facilities using redirected water, landscaping and irrigation. Power: electricity needed per dialysis session is twice the average daily consumption of a family of four people. Use of renewable energies, as solar or wind power, has been proposed, and are occasionally applied to home HD. To date just one attempt has been made to recycling energy by using hydroturbine. Disposable materials: most of dialysis disposables is made of plastic, over half of which is labeled as “potentially hazardous”. Only a minimal part of the plastic used in dialysis disposables is recyclable, both because of its composition and its assembly which makes in fact impossible the segregation of the different components. Present research regards bioplastics, new assembling techniques, alternative technologies of incineration, microwave treatment, alkaline hydrolysis, biological treatment and the new steam sterilize-then-shred system. Dialysis machines: at the best of our knowledge there are no studies available about dialysis machine recycling. Personnel education: the role of dialysis staff is essential in recycling and reusing materials as well as in correctly dividing contaminated and non-contaminated waste. Conclusion The development of sustainable buildings, devices and procedures requires a multidisciplinary approach: medical, chemical, biological, engineering; in addition producers contribution and government regulation are needed. Talking about these issues, involving specialists, spreading the concepts of planet friendly treatments, gives the opportunity to share ideas, experiences and turn them into relevant innovations. A good starting point could be data collection to identify critical issues and outline pragmatic operational possibilities to reduce consumption, increase reuse and recycle, involve and instruct health care personnel, integrate dialysis facilities in the environment they are built in.

16 Sustained Low Efficiency Dialysis (SLED) in Burn Patients with Acute Kidney Injury

Introduction Acute Kidney Injury (AKI) is common among patients with major burns and may require treatment with renal replacement therapy (RRT). Although continuous renal replacement therapy (CRRT) modalities are widely used and offer many advantages over traditional intermittent hemodialysis (IHD), CRRT is expensive, labour-intensive, and may not be available in some burn centers. Sustained Low Efficiency Dialysis (SLED) is a moderately efficient alternative to IHD, but its use in burn patients with AKI has not been described. The purpose of this study was to review our experience with SLED. Methods Retrospective review of adult burn patients with AKI treated by SLED between 07/2013 and 03/2020 at an adult regional ABA-verified burn center. Data was obtained from the electronic medical record including daily dialysis forms completed by the nephrology service. Values are shown as mean +/- SD or median (IQR) as appropriate. Results We evaluated 367 distinct SLED sessions provided to 33 patients [age 55.8 +/- 14 yrs., %TBSA burn 33 +/-19, % TBSA full thickness burn 10.5 (0, 35.8), and 54.5% with inhalation injury]. The serum creatinine (sCr) prior to the start of SLED was 2.96 (2.3, 4.17) mg/dL. SLED was initiated 5 (3, 10.8) days (range 0–24 d) post burn, and 7 (3.3, 12.8) sessions (range 1–44) with a duration of 4 (4,6) hours each were given per patient. Heparinization was required in 22 sessions (6%), and 46 sessions (12.5%) were aborted, most commonly due to clotting of the lines or circuit, and rarely (4%) due to hypotension. The net ultrafiltrate removal was 1.2 (0.7–2) L, with a dialysate flow rate of 350 (350, 500) mL/min. Among 208 sessions where patients were not on vasopressors (VPs) Pre-SLED, one or more VPs were required in 19 sessions (9%) during or at the termination of SLED. Among 116 sessions where patients were receiving norepinephrine (NEpi) infusions pre-SLED, the NEpi dose dropped from 7.3 +/- 4.2 µgm/min to 6 +/- 4.5 µgm/min (p=0.03). Pre and Post SLED values for blood pressure, creatinine, and potassium are shown in the table. The mortality rate was 36.4%, hospital length of stay was 42 (20.5, 61.5) days, and among surviving patients, 2 (9.5%) required dialysis post discharge. Conclusions SLED was effective and well tolerated. Hemodynamic instability was infrequently encountered.

Novel use of premixed dialysate bags during water supply interruption in acute hospital setting

Dialysis patients are exposed to large amounts of water during conventional intermittent hemodialysis (IHD) hence strict regulations exist for the quality of water used to prepare dialysate. Occasionally water systems fail due to natural disasters or structural supply issues such as water main breaks or unplanned changes in municipal or facility water quality. It is critical to regularly monitor and immediately recognize such a failure and take steps to avoid exposing the patients to contaminants. In addition to the recognition of the problem, the ability to pivot and continue to provide safe treatment to dialysis dependent inpatients is essential both from ultrafiltration and clearance standpoint. At our hospital, an unforeseen water disruption occurred and we were able to continue to provide renal replacement therapy with pre-made bagged dialysate to mitigate the impact on our dialysis patients. This is a novel method in utilizing available machines and dialysate, which we normally stock for continuous renal replacement therapy, for short dialysis sessions. The methodology is similar to that which has been widely used for short daily home hemodialysis with low dialysate flow rate. As this situation occurred in the midst of the Sars CoV2 pandemic we had to be mindful of dialysate volumes as well as staffing time. Here we present our investigation into the cause of water system failure and how we quickly implemented the alternative dialysis method. Short dialysis with low flow dialysate will not deliver the same Kt/V per session as standard dialysis, however it was successful as implemented and tailored with adjustments for patients requiring higher clearance for specific indication such as severe hyperkalemia.

P1117EXPLORATORY COMPARISON OF DIALYSIS EFFICIENCY AT DIFFERENT DIALYSATE FLOW (QD) IN EXPANDED HEMODIALYSIS IN TWO CENTERS IN COLOMBIA

Background and Aims Dialysate flow rate (Qd) has minimal effect in removal of molecules in hemodialysis, allowing to use lower amounts of dialysate with no effect in clearance of molecules. According to recent literature, Expanded hemodialysis (HDx) improves the clearance of middle size molecules, diminishing the effect of Qd in adequacy. We found no data about clearance at different dialysate flow rates in HDx. Our aim is to evaluate the clearance of middle molecules (beta 2 microglobuline [Mβ2], interleukin-6 [IL-6], interleukin-10 [IL-10 light chains (CLL-κ -λ) with HDx at different Qd using membranes TheranovaMR in patients with body weight less than 70 Kg. Method We performed an observational retrospective analysis of clearance of Mβ2, IL-6, IL-10, CLL-κ; CLL-λ in HDx using TheranovaMR filters with Qd 400 mL/min and 500 mL/min. We performed variance analysis, T student test and Wilcoxon test. Data were extracted from an HDx multicentric trial performed in Bogotá, Colombia in 2018. Results 11 (47%) patients received Qd 400 mL/min and 12 (52.1%) patients with Qd 500ml/min. Demographic data are included in table 1. We found no differences in reduction rate of mid-molecules. (Table 2) We found that lower water consume in the Qd 400 mL/min group, with water savings of 24 Liters/patient (13824 L in 12 weeks of follow up). (Table 3) Conclusion Expanded hemodialysis seems to allow diminishing Qd rate without changes in mid-size molecules clearance.

P1116IS DIALYSIS ADEQUACY AMELIORATED AFTER INCREASING DIALYSATE FLOW RATE IN CHRONIC HEMODIALYSIS? - ONE YEAR FOLLOW-UP

Background and Aims Hemodialysis (HD) adequacy, as measured by single pool (sp) Kt/V and urea reduction rate (URR), has been reported to be ameliorated after increasing dialysate flow rate (DFR). However, this is a matter of controversy as no benefit has been observed with dialyzers incorporating features to enhance dialysate flow distribution. We investigated the effect of increasing DFR on dialysis adequacy and on various laboratory parameters. Method Twenty-three patients, M/F=20/3, aged 65(44-89) years, dialyzed thrice weekly for 50(6-274) months, using polysulfone low flux dialyzers, participated in an annual randomized cross-over study. Patients were dialyzed with DFR of 500 ml/min and 700 ml/min for 6 consecutive months respectively, according to their usual dialysis prescription and with ultrafiltration volumes according to clinical need. Blood was sampled before and at the end of midweek sessions at the beginning of the first, 7th and 13rd month for urea, creatinine, potassium, sodium, albumin, total Ca and phosphate (sP). URR, spKt/V, corrected for albumin Ca(sCa) and sCa x sP product (CaxP) values were calculated. Results Under both 500 and 700 ml/min DFRs used, the expected post-dialysis alterations were found: decreased values in serum urea (respectively 161,5±38,0 to 49,9±20.1-p&lt;0,001 and 140,3±30 to 56,0±20.4 mg/dl-p&lt;0,001), creatinine (respectively 10,2±2 to 3.9±1,2-p&lt;0,001 and 10,2±3,3 to 4,1±1,6 mg/dl-p&lt;0,001), potassium (respectively 5,2±0,7 to 3,7±0,3 mM-p&lt;0,001 and 5,3±0,6 to 3,9±0,3mM-p&lt;0,001) and phosphate (respectively 5,4±1,7 to 2,9±0,6-p&lt;0,001 and 5,7±1,6 to 2,6±0,6 mg/dl-p&lt;0,001); increased values in serum albumin (respectively 4,3±0,4 to 4,7±0,4 g/dl-p=0,001 and 4,2±0,3 to 4,7±0,4 g/dl-p&lt;0,001) and sCa (9,1±0,7 to 11,3±0,9 mg/dl-p&lt;0,001 and 8,7±0,6 to 9,9±0,7 mg/dl-p&lt;0,001). After increasing DFR from 500 to 700 ml/min we observed no reductions in pre-dialysis serum urea and creatinine levels or URR (68,6±8,1% to 69,9±7,9%-p=NS) and Kt/V (1,41±0,4 to 1,42±0,3-p=NS) values. However, under DFR of 700ml/min post-dialysis sCa, sP and sCa x sP product values were always lower compared with those under DFR of 500 ml/min (respectively 9,9±0.7 vs 10,8±0.8 mg/dl-p&lt;0,001, 2,6±0,6 vs 2,9±0,6 mg/dl-p=0,02 and 25,6±6,2 vs 30,9±6,7 mg2/dl2-p&lt;0,001). Conclusion DFR increase from 500 to 700 ml/min did not lead to favorable effects on dialysis adequacy but resulted in post-dialysis amelioration of serum calcium and phosphate levels and may be useful in cases of hypercalcemia, hyperphosphatemia and calcifications. DFR increase utility needs further investigation in patients with disorders of calcium-phosphate metabolism.

P1051ASINGLE SESSION AND WEEKLY BETA 2 MICROGLOBULIN REMOVAL DURING SHORT FREQUENT HEMODIALYSIS USING PHYSIDIA TECHNOLOGY

Background and Aims S3 Physidia monitor is a dedicated system for short frequent hemodialysis at home based on push pull dialysis mode. Clinical data is provided to show the Beta 2 microglobulin elimination, used as a model for middle molecule removal. The aim of the study is to compare Beta 2 microglobulin removal between hemodialysis systems with low dialysate flow rate and conventional hemodialysis or hemodiafiltration. Method Analyzed data is collected during multicentric clinical study performed to evaluate the safety and performances level with S3 Physidia system. This clinical investigation has been conducted in accordance with the Good Clinical Practices (Helsinki Declaration), every patient was informed by the investigator and has signed the consent form prior to the completion of the study. The project has been approved by the local Committee and authorities. Anonymized data of 10 patients (age: 55.3 +/- 12.3 years, weight: 72.8 +/- 17.2 kg) is collected during 126 dialysis sessions (blood flow rate: 293 +/- 24 ml/min, dialysate flow rate: 190 +/- 14 ml/min). The convection volume (Ultrafiltration and back filtration generated by the push pull technique) is between 1 to 8 l per session (dialyzer used: Smartflux HFP190). For each session, Beta 2 microglobulin (β2M) removal rate is calculated by using pre and post dialysis β2M blood concentrations. Post concentration is corrected by using Bergström formula to take into account the hemoconcentration and rebound. Both single session (2hours) and weekly (12 hours/week) β2m removal rates were calculated. Single session and weekly β2m removal levels are compared to published data with conventional hemodialysis or post dilution hemodiafiltration. Weekly dialysis performance is evaluated according to the standardized Kt / V (sdt) according to the Gotch calculation method. Results Using S3 daily hemodialysis, weekly dialysis diffusive performance for urea (standardized Kt / V is 2.56 +/- 0.39, higher than KDIGO recommendations for frequent dialysis (min 2.1). β2M removal rate per session is 52.9 +/- 6.6 % with pre dialytic concentration average value of 25 mg/l corresponding to 73 mg of β2M removed per session. Calculated weekly β2M removal is 438 mg. These results are compared to β2M removal obtained by standard treatment procedures (ref1) and by short frequent hemodialysis using diffusive low dialysate flow (Nx Stage system One, ref 2). During conventional hemodialysis (4h, 3 sessions per week), the β2M removal rate is between 60 to 80 % corresponding to a removal of 300 to 380 mg/week (ref 1) During high volume post dilution hemofiltration (4h, 3 sessions per week, convection &gt; 20 l per session), the average β2M removal rate is 80% corresponding to a removal of 380 mg/week (ref 1) With Nx Stage device, without convective component, single session β2M removal rate is between 40 and 50 % depending on blood flow rate (maximum obtained with blood flow rate 400 ml/min) (ref 2) Ref 1: J. Potier et al, Int J Artif Organs. 2016 Nov 11;39(9):460-470 Ref 2 : M. Leclerc et al, Blood Purif 2018;46:279–285 Conclusion β2M reduction rate obtained with the S3 Physidia system is greater than 50%, removing any dowry concerning the performance of a low dialysate flow rate system. The convective component, provided by the push pull technique, must be confirmed, but these initial results are encouraging (reduction rate &gt; 50% despite a relatively low blood flow rate). Due to the frequency, the quantity of β2M weekly removed is higher than that obtained with conventional treatment methods.

P1055REMARKABLE REMOVALS OF BETA-2-MICROGLOBULIN AND PHOSPHATE WITH SHORT-DAILY HOME HEMODIALYSIS USING LOW DIALYSATE FLOW RATE

Background and Aims Short-daily hemodialysis (HD) with low-dialysate volume is an appealing portable dialysis approach for home use. Although this type of HD has proved being effective for the volume control and the clearance of low molecular-weight uremic toxins, limited data are available on the impact on the removal rates of other uremic toxins like β2-microglobulin (β2M) or phosphate (P), whose clearance is limited by sequestration into compartments, poor diffusion, high time-dependency, or protein binding. We evaluated the impact of short-daily HD with slow dialysate flow rate on the removal of solutes of different molecular weights and distribution volumes. Method Single-session and weekly balances of β2M, P, urea, and creatinine were prospectively assessed with total dialysate collection and serum measurements before and after 341 dialysis sessions (mean dialysate volume: 30963 ± 862 mL; mean length of dialysis session: 153 ± 8 min) in 31 stable patients (female; 9, 29 %; mean age: 55.6 ± 13.6 y; dry weight: 74.9 ± 13.3 kg) undergoing short-daily home HD with NxStage cycler, between July 2014 and October 2019. The mean blood flow rate was 365 ± 17 mL/min, whereas the mean dialysate flow rate was 194 ± 12 mL/min. Results Single-session β2M, P, urea, and creatinine removals were 0.138 ± 0.050 g, 0.610 ± 0.161 g, 18.89 ± 6.07 g and 1.07 ± 0.31 g, respectively, whereas the reduction rates (%) were 38.0 ± 13.0, 46.8 ± 8.6, 48.2 ± 7.0 and 46.6 ± 6.6, for β2M, P, urea and creatinine, respectively. The estimated weekly β2M, P, urea and creatinine removals in HDD patients dialyzing 5-6 days per week were comparable with 4-h in-center thrice-weekly on-line hemodiafiltration according to previous studies (Table 1). Conclusion Treating patients with short-daily HD with low-dialysate volume at a 5-6 days per week prescription may achieve an efficient weekly β2M and P removal.