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Journals | Policy | Permission World Journal of Nephrology & Urology Search  HOME ABOUT LOG IN REGISTER SEARCH ARCHIVES SUBMIT FEES EDITORS ONLINE-FIRST ARTICLE TOOLS Abstract HTML PDF World Journal of Nephrology and Urology, ISSN 1927-1239 print, 1927-1247 online, Open Access Print this article Article copyright, the authors; Journal compilation copyright, World J Nephrol Urol and Elmer Press Inc How to cite item Journal website http://www.wjnu.org Finding References Review policy Email this article (Login required) Case Report QUICK LINKS Volume 6, Number 1-2, June 2017, pages 14-17 Instructions to Authors Submit Manuscript Editorial Board Publication Ethics Do Sterilization Processes Really Make Difference in Dialysis-Induced Human & Animal Rights Genotoxicity? Informed Consent Conflict of Interest a, c a a a, b a, b a a Emna El Golli-Bennour , Chiraz Zaied , Chayma Bouaziz , Yosra Guedri , Abdellatif Achour , Salwa Abid , Hassen Bacha Copyright and Permission a Journal Contact Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Monastir, Tunisia b Publishing Charge Nephrology Department, CHU, Sousse, Tunisia c Corresponding Author: Emna El Golli-Bennour, Laboratory for Research on Biologically Compatible Compounds, Faculty of Dentistry, Monastir, Tunisia Manuscript accepted for publication December 14, 2016 Short title: Sterilization in Dialysis-Induced Genotoxicity doi: https://doi.org/10.14740/wjnu296e Abstract Introduction Case Report Discussion References Abstract ▴Top The major problem associated with hemodialysis (HD) therapy is the choice of dialyzer membrane matters as well as the mode of sterilization required before utilization. In this context, we aimed to determine the effect of two sterilization processes (steam and gamma rays) on genotoxicity of polysulfone dialysis membranes. A 38- year-old man with end-stage renal disease and one age-matched healthy subject were enrolled in our study. We analyzed lipid peroxidation measured by serum malondialdehyde (MDA) formation and DNA fragmentation assessed by agarose gel electrophoresis and diphenylamine quantification. Our results clearly showed that there is a rising generation of MDA and DNA fragmentation in patient sera during HD session when compared COVID-19 RESEARCH to healthy subject data. This increase in MDA and DNA fragmentation amounts followed respectively the The COVID-19 outbreak sterilization process. As classified from the more biocompatible one, the steam sterilized polysulfone dialyzer is presents the unprecedented the top ranked, followed by the gamma rays sterilized one. We concluded that using steam instead of gamma challenge for world public and medical practitioners and rays for sterilization may improve the biocompatibility of polysulfone dialyzer membranes. health care providers, the post COVID-19 condition (or long Keywords: Dialyzer membranes; Sterilization process; Oxidative stress; Genotoxicity COVID) includes long term symptoms which may persist for months or years after Introduction ▴Top SARS-CoV-2 infection. We will consider submissions related to all aspects of COVID-19 and Hemodialysis (HD) is the routine treatment for chronic renal failure [1, 2]. The major problem associated with Long COVID, and process the this therapy is the bioincompatibility of dialyzer membranes [3]. Several polymeric membranes have been used manuscripts in priority. as materials for HD and these require sterilization processes before utilization. The methods currently used for sterilization of dialyzers include treatment with ethylene oxide and gamma irradiation. Meanwhile, alternative Collection of COVID-19 Articles sterilization modes such as steam sterilization have been suggested [4, 5]. In this study, we tried to check if the sterilization process really makes any difference in dialysis-induced genotoxicity. Case Report ▴Top Subjects This study involved one HD patient (man, aged 38 years) with end-stage renal disease, who had undergone chronic HD treatment for 4 h, three times a week for 6 years. The patient has given his informed consent. For this study, before sample collecting, the patient underwent dialysis with every membrane type for at least 3 months. Results were then compared with those from one age-matched healthy subject from the general population. Samples Blood venous samples (5 mL) were drawn from HD patient at the beginning (T0), the middle; after 2 h (T2) and the end; after 4 h (T4) of HD session and were placed in heparinized tubes. Serum was obtained by centrifugation at 1,500 × g for 10 min at 4 °C. Dialyzer membranes Dialyzer membranes include: 1) F6-HPS: polysulfone dialyzer, surface area 1.3 m2 sterilized by steam (M1) and from Fresenius Medical Care AG, Bad Homburg, Germany. 2) APS 650: polysulfone dialyzer, surface area 1.3 m2 sterilized by gamma rays (M2) and from Asahi Kasei Medical, Tokyo, Japan. All dialyzers are high-flux dialyzers. Methods Lipid peroxidation measurement Lipid peroxidation was carried out by the measurement of malondialdehyde (MDA) according to the method of Ohkawa et al (1979) [6]. Serum (100 µL) was combined with 0.2 mL of 8.1% SDS, 1.5 mL of 20% acetic acid adjusted to 3.5 of pH and 1.5 mL of 0.8% thiobarbituric acid. The mixture was brought to a final volume of 4 mL with distilled water and heated at 95 °C for 2 h. After being cooled at room temperature, 5 mL of n-butanol and pyridine mixture (15:1, v/v) was added to each sample and the whole was shaken vigorously. After centrifugation at 15,000 rpm for 10 min, the supernatant fraction was isolated and the absorbance was measured at 532 nm. The concentration of MDA was determined according to a standard curve. DNA extraction and quantification DNA was extracted from peripheral blood leucocytes using blood DNA purification kit (Promega) and was quantified by UV spectrophotometry at 260 nm. DNA fragmentation by agarose gel electrophoresis Loading buffer (0.25% bromophenol blue and 40% saccharose) was added to 5 µg of DNA for each sample. Samples were then analyzed by electrophoresis on a 1% agarose gel (1 h at 80 V/30 mA) with a Tris-Borate- EDTA running buffer (44 mM Tris-HCl, 44 mM boric acid, 50 mM EDTA, pH 8.0), stained with ethidium bromide and photographed with a SynGene GeneStore system. DNA quantification by diphenylamine DNA fragmentation was measured according to the method described by Sandau et al (1997) [7]. Diphenylamine solution (320 µL) (in 10 mL glacial acetic acid: 150 mg diphenylamine, 150 mL H2SO4 and 50 mL acetaldehyde 16 mg/mL) was added to each sample tube containing 5 µg of DNA, followed by incubation overnight at room temperature. The optical density was determined at 600 nm. DNA fragmentation was calculated as follows: % fragmented DNA = (OD supernatant/OD supernatant + OD pellet) × 100. Discussion ▴Top In the uremic state, many factors could be involved in DNA damage, in particular an enhanced generation of oxidative stress [8, 9]. The increased DNA damage in cells of patients with chronic renal insufficiency and long- term HD therapy may be causally linked to the high cancer incidence, in particular, cancer of the kidney, prostate, liver, and uterus, compared with the general population [10, 11]. In the present study, we have demonstrated that the sterilization processes of dialyzer membranes can interfere with the oxidative and genotoxic status of HD patient. As compared to healthy subject, there was a rising generation of MDA in patient blood during HD session. Nevertheless, this MDA production differs with the sterilization process. Indeed, at the end of HD session (T4), the serum MDA amounts were about 5 and 15 folds respectively for steam sterilized M1 and gamma rays sterilized M2 as compared to the MDA amount in control (Fig. 1). Consequently, utilization of radiation as sterilization process induced more ROS than the steam procedure. Even so, the steam method for sterilization is still the most biocompatible one. In fact, we have previously shown that steam-sterilized membranes improve endothelial cell viability and limit lipid peroxidation enhancement when compared to ethylene oxide or gamma rays-sterilized ones [12]. Figure 1. Lipid peroxidation levels in patient and healthy subject sera measured by production of malondialdehyde (MDA), at the beginning (T0), the middle (after 2 h, T2) and the end (after 4 h, T4) of HD session and using different dialyzer sterilization processes: M1 (sterilized by steam) and M2 Click for large image (sterilized by gamma rays). MDA amounts (µg/mL) were determined according to a standard curve. Results were expressed as mean ± SD from three independent experiments. Slight DNA fragmentation was observed with dialyzer sterilized by steam (M1). The DNA fragmentation profile was more pronounced with dialyzer sterilized by gamma rays (M2). DNA fragments (DNA ladders) showing varying sizes between 750 and 2,000 base pairs were clearly visible after agarose gel electrophoresis, but no specific DNA fragments were detected when controls were analyzed (Fig. 2). Using a quantitative analysis of DNA fragmentation, a significant effect was observed after peripheral blood leucocytes exposure to different sterilized dialyzer membranes. This DNA fragmented level reached at the end of HD session 19±0.624% and 28±0.975%, respectively for steam sterilized M1 and gamma rays-sterilized M2 (Fig. 3). However, these genotoxic effects should be consequences of oxidative injury. Our finding is in concordance with other data that report a significant DNA fragmentation level in HD patient lymphocytes [13, 14]. Figure 2. DNA fragmentation induced by exposure to different dialyzer membranes sterilization mode: M1 (sterilized by steam) and M2 (sterilized by Click for large image gamma rays), in patient leucocytes at the end (after 4 h, T4) of HD session and revealed by agarose gel electrophoresis. Figure 3. Percentage of DNA fragmentation caused by exposure to different dialyzer membranes sterilization mode: M1 (sterilized by steam) and M2 (sterilized by gamma rays), in patient leucocytes at the beginning (T0), the middle (after 2 h, T2) and the end (after 4 h, T4) of HD session and Click for large image determined using the diphenylamine assay. Results were expressed as mean ± SD from three independent experiments. Finally, steam sterilization of dialyzers offers considerable safety advantages to the patient and is preferred to other sterilization modes, such as gamma irradiation. Acknowledgments This research was supported by Le Ministere Tunisien de l’Enseignement Superieur, de la Recherche Scientifique et de la Technologie, through the Laboratoire de Recherche sur les Substances Biologiquement Compatible. References ▴Top 1. Iseki K, Tozawa M, Takishita S. Determinants of prescribed dialysis dose and survival in a cohort of chronic hemodialysis patients. Clin Exp Nephrol. 2003;7(3):231-237. doi pubmed 2. Chan R, Brooks R, Erlich J, Chow J, Suranyi M. The effects of kidney-disease-related loss on long-term dialysis patients' depression and quality of life: positive affect as a mediator. Clin J Am Soc Nephrol. 2009;4(1):160-167. doi pubmed 3. Hoenich NA. Membranes for dialysis: can we do without them? Int J Artif Organs. 2007;30(11):964-970. pubmed 4. Muller TF, Seitz M, Eckle I, Lange H, Kolb G. Biocompatibility differences with respect to the dialyzer sterilization method. Nephron. 1998;78(2):139-142. doi pubmed 5. Aucella F, Tetta C, Tessore V, De Nitti C, Vigilante M, Gatta G, Grandone E, et al. Is steam sterilization really making any difference in dialysis-induced cytokine release? Int J Artif Organs. 2002;25(9):832- 837. pubmed 6. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979;95(2):351-358. doi 7. Sandau K, Pfeilschifter J, Brune B. Nitric oxide and superoxide induced p53 and Bax accumulation during mesangial cell apoptosis. Kidney Int. 1997;52(2):378-386. doi pubmed 8. Inagi R, Miyata T. Oxidative protein damage with carbohydrates and lipids in uremia: 'Carbonyl stress'. Blood Purif. 1999;17(2-3):95-98. doi pubmed 9. Himmelfarb J, Stenvinkel P, Ikizler TA, Hakim RM. The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia. Kidney Int. 2002;62(5):1524-1538. doi pubmed 10. Matas AJ, Simmons RL, Kjellstrand CM, Buselmeier TJ, Najarian JS. Increased incidence of malignancy during chronic renal failure. Lancet. 1975;1(7912):883-886. doi 11. Iseki K, Osawa A, Fukiyama K. Evidence for increased cancer deaths in chronic dialysis patients. Am J Kidney Dis. 1993;22(2):308-313. doi 12. Golli-Bennour EE, Kouidhi B, Dey M, Younes R, Bouaziz C, Zaied C, Bacha H, et al. Cytotoxic effects exerted by polyarylsulfone dialyser membranes depend on different sterilization processes. Int Urol Nephrol. 2011;43(2):483-490. doi pubmed 13. Horoz M, Bolukbas C, Bolukbas FF, Kocyigit A, Aslan M, Koylu AO, Gumus M, et al. Assessment of peripheral DNA damage by alkaline comet assay in maintenance hemodialysis subjects with hepatitis C infection. Mutat Res. 2006;596(1-2):137-142. doi pubmed 14. Bagatini PB, Palazzo RP, Rodrigues MT, Costa CH, Maluf SW. Induction and removal of DNA damage in blood leukocytes of patients with type 2 diabetes mellitus undergoing hemodialysis. Mutat Res. 2008;657(2):111-115. doi pubmed This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. World Journal of Nephrology and Urology is published by Elmer Press Inc. 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The information provided in this journal should not be used for diagnosis and treatment, those seeking medical advice should always consult with a licensed physician. This website uses cookies to ensure you get the best experience on our website. Learn more Got it!  Cardioprotective Haemodialysis FX CorDiax Designed to Dialyse. Built for Cardioprotection Cardioprotective Haemodialysis SP T  Protect your Patient Cardioprotective Haemodialysis Wide-ranging cardioprotection The reduction of risk factors for cardiovascular There have been tremendous improvements in the diseases (CVD) is core to the development of dialysis quality and efficacy of haemodialysis (HD) therapy systems and products at Fresenius Medical Care. in recent years. Despite this, cardiovascular diseases Outstanding cardioprotection must be reflected in (CVD) remain the leading cause of death for patients all levels of product development and application. with end-stage renal disease (ESRD). Cardioprotective Services Products Over 30 years of experience in dialysis State-of-the-art technologies enable advanced at your service. cardioprotective therapies. }CorDiax product line: }Project Planning and Consulting • 5008 CorDiax and 5008S CorDiax }Training and Education • FX CorDiax haemodiafilter }Technical Services • BCM-Body Composition Monitor }Water Quality Service (WQS) }Classix product line: }Medical Information Services • 4008S classix • FX classix dialysers }Therapy Data Management System (TDMS) }Online Purification Cascade (OPC) 2  Moreover, both overall and cardiovascular mortality are achieve the best therapeutic performance – meaning markedly greater in ESRD patients than in the general improved clinical outcomes and better quality of life, population. This is why we put Cardioprotective Haemo- enhanced control of therapy costs, and simpler, safer dialysis on the SPOT. A comprehensive approach that handling. includes services, products and therapies is needed to Haemodialysis Outcomes Therapies Achieving better outcomes with cardioprotective Cardioprotective therapies designed by therapies. the world market leader in haemodialysis. }Reduced mortality risk }High-Flux dialysis }Fewer cardiovascular complications }HighVolumeHDF ® }Optimised use of resources }Advanced Fluid Management 3  The new FX CorDiax Cardioprotection – at the heart of long-term haemodialysis The effects of chronic kidney disease (CKD) as well as Middle molecule removal means the selective the effects of dialysis itself can lead to cardiovascular filtration of a broad range of uraemic toxins with a diseases [e.g. atherosclerosis and left ventricular molecular weight higher than 500 Dalton (Da). At the hypertrophy (LVH)], the largest causes of death in same time, the membrane should prevent the loss of haemodialysis patients. Improved middle molecule 1 substances known to be associated with patient removal, through enhanced High-Flux membranes survival, such as serum albumin. This high sieving for haemodiafiltration, can substantially reduce potential must be accompanied by excellent these risks.2 biocompatibility. Innovative membranes such as Helixone® provide A number of large, multi-centre studies show that enhanced filtration, with high sieving of low molecular the use of High-Flux membranes improves patient weight (LMW) and middle molecular weight (MMW) survival and quality of life. 3 substances as well as volume exchange, while Urea Albumin β2-microglobulin PR O D U CT S 4 reducing the induction of inflammatory cascades SPOT on: CVD are the largest that are central to many aspects of CVD. } causes of death in State-of-the-art technologies such as Fresenius’ dialysis patients. Nano Controlled Spinning (NCS™) and INLINE steam } High-Flux membranes enhance middle sterilisation are the result of continual innovation at molecule removal and reduce risk factors. Fresenius Medical Care. } FX CorDiax for Advances in material and production technologies enhanced survival and have permitted improvements in the wall structure better outcomes. by opening up the support region of the membrane. The Helixone®plus membrane in the new FX CorDiax dialysers improves the clearance of middle molecules while the loss of essential blood components such as albumin is curtailed. The Helixone®plus membrane upgrades the FX-class® dialyser into the CorDiax product line, which provides products for superior cardioprotective therapies. 5  The new FX CorDiax Advances in fibre design allow better removal of uraemic toxins The fibre support region underneath the inner } surface has been “opened up”, optimising porosity and therefore also the convective filtration (“flushing”) of larger uraemic toxins such as β2-microglobulin (5 11,800 Da) or myoglobin (5 17,000 Da). } At the same time the size of the pores of the inner surface area was not increased to avoid flushing of albumin. FX CorDiax eliminates more middle molecules 100 90 than FX 80 Removal ratio [%] Maduell et al. determined middle molecule removal of 70 60 FX CorDiax 60 compared to FX 60 in HDF postdilution 50 treatments. Significantly higher removal rates were 40 observed with FX CorDiax for 30 20 }Urea (60 Da) 10 }β2-microglobulin (11.8 kDa) 0 0 10,000 20,000 30,000 40,000 50,000 60,000 70,000 }Myoglobin (17.2 kDa) Molecular weight [Da] }Prolactin (22.9 kDa) FX CorDiax 60 FX 60 }α1-microglobulin (33 kDa) Removal ratios of FX 60 and FX CorDiax 60 dialysers in post- dilution HDF 1 (QB = 400 mL/min, QD = 500 mL/min) The authors concluded that “… treating patients with online haemodiafiltration and FX CorDiax 60 instead of FX 60 dialysers results in significantly increased reduction ratios of middle sized molecules without clinically relevant changes in albumin loss. PR O D U CT S 1 Maduell et.al.; ERA-EDTA Congress 2013, May 20, Poster Number MP 390. 6 }The benefits of the advanced fibre design is SPOT on: High selective not limited to better middle molecule removal. } permeability for The reduced transmembrane resistance of middle molecules the FX CorDiax improves the removal of low Improved removal } of phosphate molecular weight substances, e.g. phosphate. 280 Phosphate clearance (mL/min) 260 240 220 200 180 FX CorDiax 60 Xevonta Hi 15 Polyflux® 140 H Comparison of aqueous in-vitro clearances of phosphate (QB = 300 mL/min, QD = 500 mL/min). Investigations carried out by EXcorLab GmbH, an Accredited Calibration and Testing Laboratory. }In a postdilution HDF treatment the use of FX CorDiax 100 dialysers resulted in a significantly higher clearance of β2-microglobulin than FX 100 and Polyflux® 210H dialysers. The albumin loss was low and similar for all dialysers.2 * p < 0.001 FX CorDiax 100 vs. FX 100 vs. Polyflux® 210 H 200 Albumin loss (g/4h) β2-m clearance (mL/min) 150.4* 136.6 150 115.5 FX CorDiax 100 1.74 ± 1.01 100 50 FX 100 2.10 ± 1.00 0 FX CorDiax 100 FX 100 Polyflux® 210H Polyflux® 210H 1. 31 ± 0.12 FX CorDiax offers significantly better β2-m clearance Comparison of albumin loss in a post-dilution HDF treatment than FX and Polyflux® 2 (QB = 350 mL/min, QD = 800 mL/min, QS = 80 mL/min) 2 2 Bock A. et al., J Am Soc Nephrol (2013); 24: SA-PO404. 7  The new FX CorDiax Clearing middle molecules improves survival rates The use of High-Flux membranes instead of Low-Flux membranes improved patient survival rates. }A meta-analysis of 33 randomised controlled trials and 3,820 patients showed a reduction in cardiovascular mortality of 17 %.1 }All-cause mortality in diabetics and patients with albumin ≤ 4 g/dl was significantly improved.2 250 Patients with serum albumin ≤ 4 g/dL p < 0.001 Survival probability of patients 235 1.0 200 Cardiovascular events 17 % 195 0.8 Reduction p = 0.032 150 0.6 100 0.4 High-Flux Membrane 50 0.2 Low -Flux Membrane 0 0 0 12 24 36 48 60 72 80 Low-Flux HD High-Flux HD N = 1,302 N = 1,310 Months Comparison of cardiovascular mortality when High-Flux Comparison of all-cause mortality when High-Flux instead of Low-Flux dialysers were used 1 instead of Low-Flux dialysers were used 2 (Graph adapted from original publication) (Graph adapted from original publication) PR O D U CT S 1 Palmer S.C. et al., Cochrane Database of Systematic Reviews (2012); Issue 9. 2 Locatelli F. et al., J Am Soc Nephrol (2009); 20: 645-654. 8 Cardioprotective Haemodialysis FX-class® Design Innovation at all Levels FX-class® Design Cardioprotective Haemodialysis SP T  Protect your Patient Superior by Design Several state-of-the-art technologies have Optimised dialysate flow been combined to create the distinctive, The 3-dimensional microwave structure of functional features of FX-class dialysers, ® the fibre ensures uniform radial dialysate which are refined and optimised for flow around each fibre within the bundle by performance, safety and handling: preventing fluid channelling, thereby further enhancing clearance values and improving Design of dialyser housing and fibre }  the overall performance of the dialyser. bundle for more uniform dialysate flow. Better haemodynamics Refined blood inlet port for improved }  The lateral blood-inlet port ensures more haemodynamics. homogenous blood flow in the dialyser header, preventing stagnation zones. The Advances in material and production design essentially eliminates the risk of technologies have permitted improvements kinking, contributing to improved safety. in the wall structure of the Helixone®plus membrane of the FX CorDiax. Enhanced convection The more open structure of the More porous Helixone plus membrane }  ® Helixone®plus membrane support region wall for higher clearance of middle serves to reduce diffusion resistance molecules. and increases convective filtration. This facilitates clearance of a broad range of uraemic toxins, especially the middle molecules. PR O D U CT S 10 Kind to the environment SPOT on: Optimised performance Advanced design goes beyond direct } due to radial dialysate functionality, it also has to be easy on flow. the environment. FX-class® dialysers weigh Enhanced clearance } of middle molecules less than half as much as previous dialysers, enabled by a more porous support region and at the same time use ecologically of the membrane. friendly plastics. This means a lower car- bon-footprint as a result of fewer materials, less packaging, less fuel for transport and cleaner waste management. Due to less priming volume and easy preparation, costs are reduced as well. Homogenous blood Advanced flow path Helixone®plus membrane 3-dimensional wave structure of the fibre Radial dialysate flow 11 Cardioprotective Haemodialysis INLINE Steam Sterilised Dialysers The Pure Difference INLINE Steam Sterilised Dialysers Cardioprotective Haemodialysis SP T  Protect your Patient Clean and safe Purity ensured – with steam FX-class® dialysers are sterilised using No chemical residuals with INLINE the unique INLINE steam sterilisation steam sterilisation process specifically developed by No need for gamma sterilisation – high en- Fresenius Medical Care. ergy ionising radiation can degrade and alter the material chemistry, producing potential During the INLINE steam sterilisation cytotoxic and carcinogenic residuals inside process, both the blood and the dialysate the dialyser.1 compartments are rinsed continuously with steam > 121°C. Since no additional Low rinsing volumes chemicals are needed for cleaning or Minimal preparation time – since dialysers sterilisation, the finished dialysers have are clean on arrival, rinsing times prior to use extremely low levels of residuals. are substantially reduced. Less rinsing – lower costs Lower rinsing volumes mean reduced preparation times and costs. PR O D U CT S 1 Shintani H. et al., Journal of Analytical Toxicology (1989); 13: 354-357. 2 Müller T. F. et al., Nephron (1998); 78: 139-142. 14  SPOT on: Reduced risk of blood }  contact with toxic residuals.1 Activation of the }  complement system is reduced.2 Integrity test: Air pressure is applied to the fibre bundle from one side while the other side contains sterile water. If any leakages were present in the membrane, air would pass the membrane and create bubbles. INLINE steam sterilisation process and integrity test 15 Cardioprotective Haemodialysis Superior Endotoxin Retention Purity by Design Superior Endotoxin Retention Cardioprotective Haemodialysis SP T  Protect your Patient What are endotoxins? Greater protection through active prevention Endotoxins are large molecules from the Once in the patient’s blood, endotoxins can outer membrane wall of gram-negative induce complement and leucocyte activation, bacteria. Chemically, endotoxins are lipopoly- leading to inflammatory responses. saccharides (LPS), having lipid and poly- Sometimes, these may result in acute reactions saccharide components. such as fever, headaches, convulsions or low blood pressure. In the longer term, they may Microbial contamination of water or fluid also contribute to chronic conditions such as conduits can therefore lead to the presence amyloidosis, an increased need for EPO, of endotoxins in dialysis fluid. immune disorders or accelerated atheroscler- osis. Atherosclerosis and cardiovascular While intact endotoxins are relatively large mol- diseases are the most frequent causes of ecules, their smaller endotoxin fragments death for dialysis patients. may pass across dialysis membranes into the patient’s blood via backdiffusion or backfiltration. Endotoxins Dialysate Dialysis Membrane Complement Activation Blood Membrane-Leucocyte Interaction + C5a C5b Blood Leucocyte Activation Reactive Cytokine Oxygen Release Species (IL-1, IL-6, TNF-_) Complement + Endotoxin Mediated Leucocyte Activation Inflammatory responses simulated by blood-membrane interactions and bacterial dialysate contaminants PR O D U CT S 18 Membranes, such as Helixone®, which have SPOT on: Absence of endotoxins a high endotoxin retention capacity, protect the } minimises inflammation. patient from inflammation, particularly when Reduced cardiovascular } ultrapure dialysate is not available.1 risk factors. 4.5 4.0 0.56 3.5 Endotoxin Adsorption (EU/cm2 membrane) 3.0 2.5 2.0 0.48 1.5 0.17 1.0 0.5 0.03 0 Polyflux® Nephral® FX 60 – Diacap® 140H – ST 400 – Helixone® HI PS 18 – Polyether- Polyacrylo- α-Poly- sulfone nitrile sulfone Endotoxin adsorption per cm2 membrane surface area after 120 min in-vitro dialysis with contaminated dialysate (endotoxin from bacterial culture filtrates; initial concentra- tion 50 EU/mL).1 (Graph adapted from original publication) How to prevent endotoxins entering dialysis fluids } Improved overall hygiene management. } Mandatory use of ultrapure dialysis fluid by using dialysis fluid filters such as DIASAFE®plus to remove residual endotoxins from dialysis fluid. } Use of dialysis membranes with high endotoxin retention capacities, particularly when ultrapure dialysate is not available (e.g. Helixone® or Helixone®plus). 1 Weber V. et al., Blood Purif (2003); 21: 365. 19 Cardioprotective Haemodialysis Enhanced Middle Molecule Removal Open up to Porosity Enhanced Middle Molecule Removal Cardioprotective Haemodialysis SP T  Protect your Patient Key to optimal middle molecule removal Solutes encounter resistance while traversing the membrane wall. Resistance to solute transport is affected, in part, by pore size Inner surface at the inner surface and the porosity of the membrane wall. Furthermore, wall structure and thickness Support region as well as inner fibre dimensions and 3-dimensional microwave structure play important roles in transmembrane flux. Close-up of the inner surface and the support region of the Helixone®plus membrane The new membrane structure of Helixone®plus allows the easy passage of middle molecules across the more porous support region of the membrane. }The structure of the support region is crucial to overall performance. }Membrane porosity, together with the pore size, regulates the transport of middle molecules. PR O D U CT S 22 Refined membrane architecture SP T New production technology combined with SPOT on: Optimised membrane INLINE steam sterilisation allows crucial } porosity for enhancements of membrane porosity, enhanced removal of middle molecules. reducing flow resistance and improving transport across the membrane. }Significantly improved removal of middle molecules while preventing the loss of useful substances, such as serum albumin. 23 Cardioprotective Haemodialysis High-Flux Dialysis Improved Survival – Better Outcomes High-Flux Dialysis Cardioprotective Haemodialysis SP T  Protect your Patient Extended survival Use of High-Flux membranes enhances the lities such as HighVolumeHDF® may contribute removal of uraemic toxins, particularly middle towards reduced risk of death. molecules such as β2-microglobulin. The results of the MPO study indicate the bene- A growing body of evidence has emerged in recent ficial effect of High-Flux membranes in terms of years demonstrating that use of High-Flux dialysis reduced mortality for patients with serum albumin membranes as well as advanced treatment moda- levels ≤ 4.0 g/dL or diabetes.1 High-Flux Membrane Diabetic patients (p = 0.039) Low-Flux Membrane 1.00 0.90 Survival probability of patients 0.80 0.70 0.60 0.50 0.40 0.30 0.20 0 12 24 36 48 60 72 84 Months Kaplan-Meier survival curves for the subpopulation of patients with diabetes (log-rank test p = 0.039) 1 (Graph adapted from original publication) PR O D U CT S 26 Reduced complications Enhanced middle molecule removal contributes SPOT on : High-Flux dialysis towards reducing the complications of haemo- } can reduce secondary dialysis as well as improving long-term patient diseases. outcomes by affecting:2 Prolonging patients’ } lives.1 Control of anaemia } } Inflammation – lower CRP levels.3 and amyloidosis. } Anaemia – haemoglobin levels improve at lower EPO doses.4 } Amyloidosis – efficient removal of β2-micro- globulin and other middle molecules can redu- ce the relative risk of developing amyloidosis by up to 50 %.5, 6 } Immune dysfunction – aberrant suppression of IFN-amay be corrected.7 The clinical benefits of High-Flux HDF are described in more detail in the chapter “Clinical Benefits of the Removal of Middle Molecules”. 27  Protect your Patient Evolution of fibre design Reducing the inner fibre diameter from 200 µm to partments. Together with structural refinements 185 µm acts to increase internal filtration, thereby to the support region of the fibre, this enables increasing the pressure gradient along the length improvements in both diffusive and convective of the fibre. This results in a greater pressure transport, which is of particular importance when difference between the blood and dialysate com- performing High-Flux haemodialysis. Blood Inlet Pressure Dialysate Inlet Pressure 6p 6p Dialysate Outlet Blood Outlet Pressure Pressure Ultrafiltration Internal Filtration Length Dialyser PR O D U 1 Locatelli F. et al., Journal of American Society of Nephrology CT (2009); 20: 645-654. S 2 Tattersall J. et al., Nephrol Dial (2007); 22(Suppl.2); ii5-ii21. 3 Pedrini L. A. et al., Nephrol Dial Transplant (2011); doi: 10.1093/ndt/gfq761. 4 Merello Godino J. I. et al., Int J Artif Organs (2002); 25(11): 1049-1060. 28 } Modification of the inner diameter increases the SPOT on: Specific fibre design pressure gradient between blood and dialysate } leads to increased removal compartments. of middle molecules. } The result is improved clearance of middle molecules such as vitamin B12, inulin, β2-microglobulin and myoglobin.8 } The increased pressure gradient combined with structural refinements to the membrane (support region) enhances diffusive as well as convective filtration, especially when performing High-Flux haemodialysis with FX CorDiax. 70 210 β2-microglobulin 60 200 β2-m clearance (mL/min) Urea Clearance (mL/min) 50 190 Urea 40 180 30 170 20 160 10 150 QB= 250 mL/min, QD= 500 mL/min 0 140 175 200 250 Inner diameter of membrane [µm] Reduced inner diameter improves middle molecule elimination8 (Graph adapted from original publication) 5 Koda Y. et al., Kidney Int (1997); 52: 1096-1101. 6 Locatelli F. et al., Kidney Int (1999); 55: 286-293. 7 Lonnemann G. et al., Blood Purif (2003); 21(3): 225-231. 8 Dellanna F. et al., (1996); NDT 11 (Suppl 2): 83-86. 29 Protect your Patient Guidelines recommend High-Flux dialysers Clinical practice guidelines in Europe recommend the use of High-Flux haemodialysers: European Renal Best Practice Advisory Board; Guideline 2.1: “Synthetic High-Flux membranes should be used to delay long-term complications of haemodialysis therapy … even in low-risk patients...” 1 The Renal Association (UK): “Suggest that high-flux dialysers should be used instead of low-flux dialysers to provide haemodialysis. Evidence of improved patient survival with the use of high-flux membranes is restricted to incident patients, who have lower serum albumin concentrations (< 4 g/L) or have diabetes mellitus, and prevalent patients who have been on haemodialysis > 3.7 years” 2 1 Tattersall J., Nephrol Dial Transplant (2010); 25: 1230–1232. 2 Mactier R. et al., Renal Association 2009, Renal Association Clinical Practice Guidelines. Haemodialysis membranes (Guidelines 4.1 to 4.5). http://www.renal.org/clinical/ GuidelinesSection/Haemodialysis.aspx. Accessed 2 Dec. 2012. Cardioprotective Haemodialysis HighVolumeHDF ® Advance the Experience HighVolumeHDF ® Cardioprotective Haemodialysis SP T  Protect your Patient Better filtration In recent years, there has been increased interest in HighVolumeHDF ® improves patient outcomes and more efficient haemodialysis treatment modalities. exerts beneficial effects on the main cardiovascular The main emphasis today is on the efficient removal risk factors: of a wide range of uraemic toxins, particularly larger middle molecules such as β2-microglobulin, a }Intradialytic haemodynamic stability 1 surrogate of middle molecules. However, excessive }Anaemia 2 loss of useful substances such as albumin needs }Inflammation 3 to be curtailed. }Serum β2-m and phosphate levels 4, 5, 6 The high removal of larger solutes during HighVolumeHDF ® is currently considered as the HighVolumeHDF® is achieved through a combina- most efficient renal replacement therapy. tion of two principles: diffusion and convection at high substitution volumes. Solute removal by con- vection occurs along a pressure gradient facilitated by the ultrafiltration of fluid across a highly perme- able membrane. PR O D U CT S 32 Improved survival The Catalonian high-volume HDF study,7 on behalf SPOT on: High convective of the Estudio de Supervivencia de Hemodiafil- }  transport enhances tración On-Line (ESHOL) study group, is a mul- the removal of uraemic toxins, especially in the ti-centre, prospective randomised controlled trial, middle molecular range. which showed a wide range of benefits for patients being treated with high-efficiency post-dilution HDF (HighVolumeHDF ®). Achieving a mean delivered total substitution volume of 21 L/session should therefore be the target for every HDF treatment. The primary outcome all-cause mortality was significantly reduced for the patients being treated with HighVolumeHDF ®. Follow-up (months) 1.0 Survival probability of patients 0.8 0.6 p = 0.010 0.4 Online haemodiafiltration* 0.2 High-Flux HD** 0 0 6 12 18 24 30 36 Results from the Catalonian high-volume HDF study 7 *median delivered convective volume ranged from 23 to 24L / session **92% on High-Flux HD Improved survival Reduced treatment costs 30% (p = 0.01) 22% risk risk reduction in all-cause mortality reduction in all-cause hospitalisation (p = 0.001) 55% risk reduction in mortality from infection (p = 0.03) Better patient well-being 61% risk 28% risk reduction in mortality from stroke reduction in incidence of (p = 0.03) hypotensive episodes (p < 0.001) 1 Locatelli F. et al., J Am Soc Nephrol (2010); 21: 1798–1807. 2 Bonforte G. et al., Blood Purif (2002); 20: 357–363. 3 Pedrini L. et al., Nephrol Dial Transplant, advanced access published Jan 18, 2011. 4 Canaud B., Contrib Nephrol (2007); 158: 216–224. 5 Penne L. et al., Clin J Am Soc Nephrol (2010); 5: 80–86. 6 Davenport A., Nephrol Dial Transplant (2010); 25: 897–901. 7 Maduell F. et al., J Am Soc Nephrol (2013); 24: 487–497. 33  Protect your Patient FX CorDiax haemodiafilter – Superior by design HighVolumeHDF ® therapy requires specially p < 0.001 designed filters. Stepping up to this challenge, we 650 developed the FX CorDiax haemodiafilter for 600 HighVolumeHDF with the most efficient removal of ® 550 middle molecules while minimising albumin loss. 500 PDP mmHg 450 }Increased fibre lumen for better flow 400 conditions 350 An increase of its inner diameter results in a 300 200 substantially reduced pressure drop within 15' 1h 2h 3h 4h 15' 1h 2h 3h 4h FX 80 FX 800 a hollow fibre according to the Hagen Poiseuille law. Differences in the capillary diameter of a Reduced dialyser inlet pressure of FX 800 (210 µm) vs. FX 80 dialyser can therefore affect its performance and (185 µm) 1 the quality of the treatment provided to a (Graph adapted from original publication) patient. The inner diameter of FX-class® haemo- diafilters is 210 µm compared to 185 µm of FX-class® HD filters. The larger inner diameter facilitates improved flow conditions which allowed for a significantly higher convective volume in a HDF treatment.1 210 µm The 210 µm fibre lumen of FX CorDiax haemodiafilters optimises blood flow conditions within the dialyser for maximal HighVolumeHDF ® performance. PR O D U CT S 1 Vega Vega O. et.al.; ERA-EDTA Congress 2012, Poster 457—FP. 34 Cardioprotective Haemodialysis Clinical Benefits of the Removal of Middle Molecules When Performance is Priority Clinical Benefits of the Removal of Middle Molecules Cardioprotective Haemodialysis SP T  Protect your Patient Improved survival with High-Flux membranes On top of traditional cardiovascular risk factors, in- creased middle molecule levels such as β2-micro- globulin (β2-m) pose an additional risk for the devel- opment of cardiovascular diseases (CVD) in end stage renal disease (ESRD) patients. The European Uremic Toxin Work Group (EUTox) confimed the power of β2-m to predict overall and cardiovascular mortality and cardiovascular events in patients at different stages of CKD.1 Thus, enhanced middle molecule removal contrib- utes towards improving long-term patient outcomes and reducing dialysis related complications. 1.0 Cardiovascular event-free survival 0.8 0.6 Log-rank P-value 0.0077 0.4 0.2 Above median β2-m Below median β2-m 0 0 200 400 600 800 1000 1200 1400 Months Kaplan-Meier estimates of the probability of cardiovascular event-free survival of predialysis patients, as a function of median plasma β2-m level 1 (Graph adapted from original publication) PR O D U CT S 36 Cardioprotective Haemodialysis } Dyslipidaemia – the use of High-Flux Helixone® SPOT on: Improved patient membranes improves plasma lipid profiles,2 } survival.1 reducing levels of LDL (low-density lipoprotein) Reduced risk factors of }  and VLDL (very low-density lipoprotein) and atherosclerosis.3 increasing those of protective HDL (high-density lipoprotein). The levels of triglycerides and oxidised LDL, an indicator of oxidative stress and a specific risk factor for atherosclerosis, are also significantly reduced using Helixone® membranes.3 300 60 p = 0.02 p = 0.008 250 50 Triglycerides (mg/dL) 200 40 Ox-LDL (U/L) 150 30 100 20 50 10 0 0 F7 HPS FX 100 F7 HPS FX 100 Improving plasma lipid profiles: reduction of ox-LDL and triglycerides with FX 100 dialysers 3 (Graph adapted from original publication) 37  Protect your Patient Cardioprotective Haemodialysis }Amyloidosis – a debilitating complication of }Inflammation – specialised production processes longterm haemodialysis, amyloidosis involves the such as INLINE steam sterilisation as well as the build-up of β2-microglobulin. FX-class High-Flux ® high endotoxin retention properties of FX-class® dialysers efficiently remove β2-microglobulin dialysers contribute to reducing the levels of endo- and other middle molecules, reducing the risk of toxin exposure during haemodialysis. This results in carpal tunnel syndrome.4, 5 the reduced induction of inflammatory responses.2 Haemoglobin constant at 10.5 g/dL 7,000 HDF EPO dosage (U/week) 6,000 5,000 4,000 0 0 3 6 9 Months With High-Flux membranes, it was possible to progressively reduce the EPO dose while maintaining Hb control 6 (Graph adapted from original publication) PR O D U CT S 38 }Anaemia management – it was shown that SPOT on: Improved anaemia High-Flux membranes improved control of anaemia }  control.6, 7 in EPO hypo-responsive patients while allowing a Reduced inflammation.2 } progressive reduction in the exogenous EPO dose Reduced risk of CVD }  due to minimising the by 25 to 45 %.7 Hence, High-Flux membranes offer risk factors. the potential to reduce EPO costs. Low-Flux Fresenius High-Flux Fresenius High-Flux Fresenius Polysulfone® Polysulfone® Polysulfone® 14.0 250 p < 0.001 Weekly EPO dose [IU/kg/week] 12.0 200 Haemoglobin (g/dL) 10.0 p < 0.001 8.0 150 6.0 100 4.0 50 2.0 0.0 0 before after 6 before after 6 before after 6 months months months Recovery of haemoglobin (Hb) levels was significantly better after 6 months for patients treated with High-Flux vs Low-Flux membranes. Further, in this patient group the mean EPO dose was significantly lower.7 (Graph adapted from original publication) The FX CorDiax allows the enhanced removal of middle molecules which, together with other factors, contributes towards improved survival. 1 Liabeuf S. et al., Kidney International (2012) 82, 1297. 2 Merello Godino J. I. et al., Int J Artif Organs (2002); 25(11): 1049-1060. 3 Wanner C. et al., JASN (2002); 13 (SU-P0645): 600A. 4 Ahrenholz P. G. et al., Clinical Nephrology (2004); 62: 21-28. 5 Koda Y. et al., Kidney Int (1997); 52: 1096-1101. 6 Bonforte G. et al., Blood Purif (2002); 20: 357-363. 7 Ayli D. et al., J Nephrol (2004); 17: 701-706. 39  Performance Data Sieving coefficients of FX CorDiax High-Flux Dialysers Molecular weight and Haemodia filters (Dalton) Albumin 66,500 < 0.001 Myoglobin 17,053 0.5 β2-microglobulin 11,731 0.9 Inulin 5,200 1 Membrane material Helixone®plus Sterilisation method INLINE steam Housing material Polypropylene Potting compound Polyurethane Units per box 24 FX CorDiax High-Flux Dialysers FX CorDiax 40 FX CorDiax 50 FX CorDiax 60 FX CorDiax 80 FX CorDiax 100 FX CorDiax 120 Clearance (QB = 300 mL/min) Cytochrome c 12,230 48 * 76 96 111 125 136 Inulin 5,200 56 * 88 116 127 144 149 Vitamin B12 1,355 96 * 144 175 190 207 213 Phosphate 132 142 * 215 237 248 258 262 Creatinine 113 155 * 229 252 261 272 274 Urea 60 175 * 255 271 280 283 284 Clearance (QB = 400 mL/min) Cytochrome c 12,230 – – 100 117 133 145 Inulin 5,200 – – 122 135 154 160 Vitamin B12 1,355 – – 191 209 229 237 Phosphate 132 – – 270 285 299 305 Creatinine 113 – – 290 303 321 325 Urea 60 – – 319 336 341 343 * Clearance (Q B = 200 mL/min) Ultrafiltration coeff. (mL/h x mmHg) 21 33 47 64 74 87 In vitro performance: Q D = 500 mL /min, Q F = 0 mL /min, T = 37 °C (EN 1283). Sieving coefficients: human plasma, Q Bmax, Q F = 0.2 x Q Bmax (EN1283). Ultrafiltration coefficients: human blood (Hct 32 %, protein content 6 %). Effective surface (m²) 0.6 1.0 1.4 1.8 2.2 2.5 K 0 A Urea 547 886 1,164 1,429 1,545 1,584 Priming volume (mL) 32 53 74 95 116 132 Article number F00001588 F00001589 F00001590 F00001591 F00001592 F00002384 FX CorDiax Haemodiafilters FX CorDiax 600 FX CorDiax 800 FX CorDiax 1000 Clearance (QB = 300 mL/min, QF = 75 mL/min) Cytochrome c 12,230 131 141 151 Inulin 5,200 144 156 166 Vitamin B12 1,355 204 217 225 Phosphate 132 257 267 271 Creatinine 113 271 277 280 Urea 60 285 291 292 Clearance (QB = 400 mL/min, QF = 100 mL/min) Cytochrome c 12,230 149 160 172 Inulin 5,200 166 178 190 Vitamin B12 1,355 235 251 262 Phosphate 132 307 321 328 Creatinine 113 327 339 343 Urea 60 354 365 367 Ultrafiltration coeff. (mL / h x mmHg) 46 62 76 In vitro performance: Q D = 500 mL /min, T = 37 °C (EN 1283). Sieving coefficients: human plasma, Q B max, Q F = 0.2 x Q B max (EN1283). Ultrafiltration coefficients: human blood (Hct 32 %, protein content 6 %). Effective surface (m²) 1.6 2.0 2.3 K 0 A Urea 1,148 1,365 1,421 Priming volume (mL) 95 115 136 Article number F00001593 F00001594 F00001595 40 41  certified, PEFC/04-31-0000 © Copyright 2012 Fresenius Medical Care Deutschland GmbH F00006435 MT-EN (1.0 BG-pppp 08.14) Head office: Fresenius Medical Care Deutschland GmbH · 61346 Bad Homburg v. d. H. · Germany Phone: +49 (0) 6172-609-0 · Fax: +49 (0) 6172-609-2191 www.fmc-ag.com  Theranova DIALYZER CHANGE CHANGE ONE THING EVERYTHING INTRODUCING THERANOVA FOR EXPANDED HEMODIALYSIS [HDx] Specifications and Comparison Guide The Theranova Dialyzer is indicated for patients with chronic kidney failure who are prescribed intermittent hemodialysis. It provides an expanded solute removal profile with increased removal of various middle and large molecules (up to 45 kDa) that may play a pathologic role in the uremic clinical syndrome. The Theranova Dialyzer is not intended for hemofiltration or hemodiafiltration therapy. The total extracorporeal blood volume for the Theranova Dialyzer and the set should represent less than 10% of the patient’s blood volume. For single use only. Rx Only. For safe and proper use of this device refer to the Instructions for Use. HDx ENABLED BY THERANOVA: ONE STEP CLOSER TO THE NATURAL KIDNEY Theranova, the next evolution in hemodialysis brings us a step closer to the natural kidney by expanding clearance of conventional/large middle molecules (500 – 45,000 Da)* compared to traditional high-flux membranes. 1-5 50% High-Flux T Conventional/large middle CVD is associated with Traditional high-flux molecular (500-45,000 Da) inflammation, atherosclerosis membranes have limited uremic toxins have been linked to and calcification. capability to remove conventional the development of inflammation, ~ 50% of patients with kidney and large middle molecular uremic cardiovascular disease (CVD) and failure (KF) die from CVD 10-12 toxins (up to 45,000 Da) 13 other dialysis related comorbidities 4,6,9 CHANGE ONE THING. HDx therapy showed a significant The unique design of the Theranova reduction in hospital days and membrane delivers superior in-center medication usage, in HDx therapy may improve removal of conventional/ a retrospective analysis (n=81) . 15 patient reported kidney disease large middle molecules (up to A Randomized Control Trial (n=171) Quality of Life (QoL) outcomes 45,000 Da), compared to high-flux 2-5 showed a significant reduction of including symptom burden, membranes, while selectively 45% in all-cause hospitalizations . 19 restless leg syndrome (RLS) retaining essential proteins and Improvement in certain inflammatory criteria, uremic pruritus, and maintaining stable albumin levels 2,7,8 markers were observed in select dialysis recovery time. 1,2,5,14,17 patients (n=41) . 16 CHANGE EVERYTHING. SIMPLY CHANGE THE DIALYZER MEMBRANE AND EXPAND CLEARANCE FOR HD PATIENTS.5 *Conventional middle molecules, 500 Da – <25,000 Da, such as κ-Free Light Chains, large middle molecules 25,000 Da – 45,000 Da such as λ-Free Light Chains1. THERANOVA 400 PRODUCT CODE 955691 CLEARANCE/REDUCTION RATIOS Theranova 400 Dialyzer Clearance (± 10 %, Cytochrome C ± 20 %, Myoglobin ± 30 %) UF=0 mL/min QD = 300 mL/min QD = 500 mL/min QD = 800 mL/min QB (mL/min) 200 300 400 500 600 200 300 400 500 600 200 300 400 500 600 Urea (60 Da) 191 246 272 285 291 198 282 344 388 418 199 293 376 445 502 Phosphate (95 Da) 179 225 250 266 276 192 261 311 348 376 196 279 345 400 446 Creatinine (113 Da) 184 232 258 273 282 194 269 323 362 391 198 285 357 416 465 Vitamin B12 (1.4 kDa) 148 178 199 214 226 164 207 239 264 285 174 227 267 301 329 Inulin (5.2 kDa) 119 140 156 169 180 133 161 183 200 216 144 178 204 225 245 Cytochrome C (12 kDa) 109 128 142 153 164 122 146 165 180 194 133 161 183 202 219 Myoglobin (17 kDa) 93 108 119 129 138 104 123 137 150 161 114 135 152 166 180 Mean Reduction Mean Overall Albumin Removal Ratio (%)2 Clearance (mL/min)2 (g/treatment)2 300/500 400/600 300/500 400/600 QB/QD (mL/min) 300/500 400/600 β2-microglobulin [β2m] (12 kDa) 71.5 78.5 67.9 84.7 Median (range) 2.9 (1.5-3.9) 3.2 (1.9-3.9) Myoglobin (17 kDa) 63.1 67.9 52.0 58.7 Kappa free light chains [κ-FLC] (23 kDa) 66.3 72.9 26.2 35.0 Complement Factor D [CFD] (24 kDa) 56.9 63.0 26.5 26.3 α1-microglobulin [α1m] (33 kDa) 21.7 24.8 3.8 3.3 Chitinase-3-like protein 1 [YKL-40] (40 kDa) 60.5 63.6 Only Reduction Ratio available Lambda free light chains [λ-FLC] (45 kDa) 42.5 48.1 8.5 10.0 Theranova 400 Randomized Controlled Trial (RCT)18 Theranova High-Flux HD Mean ± STD Reduction Ratio (%) Theranova 400 ELISIO-17H p value (N=86) (N=85) Lambda free light chains [λ-FLC] (45 kDa) 33.3±11.0* (p<0.001) 17.2±12.9 Hospitalization Events 18 31 -- Complement Factor D [CFD] (24 kDa) 45.0±10.4* (p<0.001) 23.6±12.1 Total Patient-Years 32.4 30.5 -- Kappa free light chains [κ-FLC] (23 kDa) 63.8±11.8* (p<0.001) 50.0±13.2 Hospitalization Rate (per PY) 0.56 1.02 0.0495 β2-microglobulin [β2m] (12 kDa) 18 73.6±10.4* (p<0.001) 65.4±9.4 Hospital Length of Stay (days) 4.11 4.63 0.4060 Open Label, Randomized Controlled Trial evaluating safety and efficacy; 21 US clinics; A post-hoc analysis of this RCT showed a significant N=171; 86-Theranova 400; 85-Elisio-17H; 24 week study reduction of 45% (p<0.049) in all-cause hospitalizations.19 *Statistical signficance (< 0.001). Pre-dialysis serum albumin levels (g/dL)18 Group Baseline Week 4 Chg vs Baseline Week 4 Week 8 Change vs Baseline Wk 8 Week 24 Control 4.0±0.3 4.0±0.2 0.0±0.2 4.0±0.3 0.0±0.2 4.1±0.4 Theranova 4.0±0.3 4.0±0.3 -0.1±0.2 3.9±0.3 -0.1±0.3 4.0±0.3 • Although small, a statistically-significant reduction in serum albumin noted at Weeks 4 and 8. • The observed changes at 4 and 8 weeks were well below 5% and the mean levels were still below normal laboratory ranges. • Changes from baseline were not statistically significant between the two study groups at Week 12 and thereafter. • The primary safety endpoint of this study was the pre-dialysis serum level of albumin after 24 weeks of treatment. • The analysis of the endpoint confirmed that Theranova 400 is non-inferior to Elisio-17H in maintaining pre-dialysis serum albumin after 24 weeks of treatment based on a 5% non-inferiority margin (-0.1765 g/dL). THERANOVA 400 PRODUCT CODE 955691 CHARACTERISTICS/COMPARISON GUIDE* Characteristics Theranova 400 Membrane Characteristics Surface area (m ) 2 1.7 Maximum TMP (mmHg) 600 UF Coefficient in Vitro (mL/h.mmHg) 48 Storage conditions <30 °C / 86 °F Residual blood volume (mL) <1 Blood flow rate QB (mL/min) 200 – 600 Priming volume (mL) ≥300 Dialysate flow rate QD (mL/min) 300 – 800 Comparison Guide Baxter Fresenius Asahi KASEI Nipro BBraun Theranova REVACLEAR Optiflux (mL/min) 400 400 F200NR REXEED-18A REXEED-21A ELISIO-19H ELISIO-21H Diacap Pro 19H Urea (60 Da) 344 338 330 330 340 343 346 332 Creatinine (113 Da) 311 315 289 309 317 309 319 305 Phosphate (95 Da) 323 297 290 289 299 296 304 278 Vitamin B12 (1.4 kDa) 239 213 189 197 212 215 219 202 UF Coefficient 48 54 62 71 74 76 82 97 Surface Area (m²) 1.7 1.8 2.0 1.8 2.1 1.9 2.1 1.9 Membrane PAES/PVP PAES/PVP Polysulfone Polysulfone Polysulfone Polynephron Polynephron Polysulfone Electron Sterilization Method Steam Steam Gamma-Ray Gamma-Ray Dry Gamma Dry Gamma Gamma Beam NOTE: Clearances in Vitro; QB=400 mL/min; QD=500 mL/min. Comparison criteria is based on stated clearance values (Vitamin B12, Phosphate, Creatinine, Urea - in order, QB=400 mL/min). This table may not be all-inclusive. *Recommended cross-reference based on data from manufacturers’ published specification sheets. FOR MORE INFORMATION, CONTACT YOUR BAXTER REPRESENTATIVE, OR VISIT: HTTPS://HEMODIALYSIS.BAXTER.COM/HDx REFERENCES 1. Theranova IFU, 2020. 2. Kirsch AH, et al. Performance of hemodialysis with novel medium cut-off dialyzers. Nephrol Dial Transpl 2017; 32(1):165-72. 3. Boschetti-de-Fierro A, Voigt M, Storr M. et al. MCO Membranes: Enhanced Selectivity in High-Flux Class. Sci Rep 5, 18448 (2015). https://doi.org/10.1038/srep18448. 4. Zweigart C, Boschetti-de- Fierro A, Hulko M, et al. Medium cut-off membranes - closer to the natural kidney removal function. Int J Artif Organs. 2017;40(7):328 -334. doi:10.5301/ijao.500060. 5. Lim JH, Park Y, Yook JM, et al Randomized controlled trial of medium cut-off versus high-flux dialyzers on quality of life outcomes in maintenance hemodialysis patients. Nature/Sci Rep. 2020; 10:7780. 6. Hutchison CA, et al. The Rationale for Expanded Hemodialysis Therapy (HDx). Contrib Nephrol 2017; 191:142-52. 7. Krishnasamy R, Hawley CM, Jardine MJ, Roberts MA, Cho Y, Wong M, Heath A, Nelson CL, Sen S, Mount PF, Pascoe EM, Vergara LA, Paul-Brent PA, Toussaint ND, Johnson DW, Hutchison CA. A tRial Evaluating Mid Cut-Off Value Membrane Clearance of Albumin and Light Chains in HemoDialysis Patients (REMOVAL-HD): A Safety Device Study. Blood Purif. 2020; 1-11. 8. Bunch A, Sanchez R, Nilsson LG, Bernardo AA, Vesga JI, Ardila F, Guerrero IM, Sanabria RM, Rivera AS. Medium Cut-Off Dialyzers in a Large Population of Hemodialysis Patients in Colombia: COREXH Registry. Ther Apher Dial. 2020; 1-11. doi: 10.1111/1744-9987.13506. 9. Wolley M, Jardin M, Hutchison CA, Exploring the Clinical Relevance of Providing Increased Removal of Large Middle Molecules. Clin J Am Soc Nephrol 2018;13:805-814. 10. Foley RN et al. Clinical epidemiology of cardiovascular disease in chronic renal disease Am J Kidney Dis. 1998;32 (Suppl 3):112-9. 11. Cobo G et al. C-reactive Protein: Repeated Measurements Will Improve Dialysis Patient Care. Sem Dialysis 2016;29:7-14. 12. Yeun JY, et al. C-Reactive Protein Predicts All-Cause and Cardiovascular Mortality. Am J Kidney Dis 2000;35:469-476. 13. Ronco C & La Manna G. Expanded Hemodialysis: A New Therapy for New Class of Membranes. Contrib Nephrol, 2017:190:124-133. 14. Alarcon JC et al. Impact of medium cut-off dialyzers on patient-reported outcomes (PROs): COREXH Registry. Blood Purif. 2020. doi: 10.1159/000508803. 15. Ariza JG et al. Measuring the association of switching patients from hemodialysis to expanded hemodialysis, with hospitalizations, medication use, costs and patient utility. Virtual International ISPOR 2020. Poster PUK15. 16. Cantaluppi V et al. Removal of large-middle molecules, inhibition of neutrophil activation and modulation of inflammation-related endothelial dysfunction during expanded hemodialysis (HDx). Nephrol Dial Transplant 2019. Abstract FO048. 17. Kharbanda K et al. A randomised study investigating the effect of medium cut-off haemodialysis on markers of vascular health compared with on-line haemodiafiltration (MoDal study). Manchester University NHS Foundation Trust. Poster clinicaltrials.gov (NCT03510520). 18. Weiner DE et al. Efficacy and safety of expanded hemodialysis with the Theranova 400 dialyzer: A randomized controlled trial. CJASN 2020. doi:10.2215/CJN.01210120. 19. Tran H et al. Reduction in All-Cause Hospitalization Events Seen in a Randomized Controlled Trial Comparing Expanded Hemodialysis vs. High-Flux Dialysis. ADC Conference 2021 Poster #1070 Baxter and Theranova are trademarks of Baxter International Inc. or its subsidiaries All other trademarks are the property of their respective owners. US-RC46-200002 v5.0 03/21  INSPIRED BY LIFE B. Braun Dialyzers Diacap® Pro Dialyzer - THE TRUSTED PERFORMER Easy Handling Low priming volume Efficient air elimination during preparation Easy-to-open packaging and easy to remove and tighten protection caps help staff to efficiently prepare and perform treatment Removable second label for documentation Efficient Performance High permeability of a-Polysulfone Pro membrane enables HD targets to be efficiently achieved during treatment High fiber package density for consistent dialysate flow distribution and less trapped air High micro-undulation for homogeneous streaming behavior and less membrane clustering Wall thickness designed for better diffusive behavior Technical and In-vitro Performance Data Pro 13H Pro 16H Pro 19H Blood flow (QB) mL/min 200 300 400 200 300 400 200 300 400 Urea 194 263 303 196 270 322 197 280 332 Creatinine 185 236 269 189 248 284 194 260 305 Clearance Dialysate flow = 500mL/min Phosphate 178 220 249 184 230 261 186 242 278 Ultrafiltration flow (QF)=0mL/ Vitamin B12 133 151 167 143 166 183 150 180 202 min Inulin 86 92 101 96 106 116 102 117 128 Cytochrome C 65 73 75 72 81 86 80 90 95 Inulin 1.0 SC, (Sieving Coefficient) QB = 300mL/min ß₂-Microglobulin 0.7 QF = 60mL/min Albumin < 0.001 Ultrafiltration coefficient mL/h/mmHg QB = 300mL/min 70 85 97 KoA Urea (QB = 300mL/min) 1010 1145 1415 Volume of blood compartment (mL) 82 100 120 Membrane material a Polysulfone Pro Surface Area (m2) 1.3 1.6 1.9 Sterilization Oxygen-free Gamma Recommended blood flow rate (mL/min) 200-500 200-500 200-500 Max. dialysate flow (mL/min) 800 800 800 Pressure drop blood (QB = 300mL/min) mmHg 101 82 72 Article No. 720DH13 720DH16 720DH19 Measuring conditions and physical data according to ISO 8637. Ultrafiltration coefficient according to ISO 8637: bovine blood, Hct. 32%, protein 60 g/l, T=37 °C, For more information: bbraunusa.com/diacappro xevonta® Dialyzer - THE SCIENCE-BASED EXPERT xevonta is the state-of-the-art dialyzer that pushes the limits for the most challenging dialysis tasks. The unique amembris membrane is designed to accomplish dialysis therapy targets for non-adhering patients. Sufficient elimination of uremic toxins (such as urea and phosphate) The high permeability enables a high removal of middle molecules Despite high permeability and toxin removal, albumin loss is minimal2 Maximized numbers of pores with precisely defined pore size for a distinctive sieving profile X-design provides the consistent homogeneous distribution of dialysis fluid in the dialyzer Technical and In-vitro Performance Data Hi 18 Hi 20 Hi 23 Dialysate flow (Qd) mL/min 500 500 500 800 500 500 500 800 500 500 500 800 Blood flow (Qb) mL/min 200 300 400 500 200 300 400 500 200 300 400 500 Urea 198 281 341 414 199 287 349 427 199 290 354 439 Clearance Creatinine 194 263 304 372 196 271 316 390 197 276 324 403 Ultrafiltration flow (QF)=0mL/min Phosphate 194 263 297 196 271 309 198 277 320 Vitamin B12 155 184 210 239 161 195 220 259 166 204 227 272 SC, (Sieving Coefficient) ß₂-Microglobulin > 0.8 QB = 300 mL/min QF = 60mL/min Albumin < 0.001 Ultrafiltration coefficient mL/h/mmHg QB = 300mL/min 99 111 124 KoA Urea (QB = 300mL/min, QD = 500mL/min) 1450 1714 1900 Volume of blood compartment (mL) 110 125 141 Membrane material amembris polysulfone Surface area (M2) 1.8 2.0 2.3 Sterilization Oxygen-free gamma Wall thickness/inner diameter (µm) 35/195 Units per box 20 Article No. 7204403 7204404 7204405 Technical and In-vitro Performance Data is contained in product instructions for use. For more information: bbraunusa.com/xevonta Diacap® Pro and xevonta® Dialyzers What is the Difference? Diacap Pro Dialyzer xevonta Dialyzer a Polysulfone Pro Type/Name Amembris Polysulfone Inner 200 µm Diameter 195 µm Wall 37 µm 35 µm Thickness ~ 31,000 Da Cut Off ~ 35,000 Da Permeability 70-97 99-124 Kuf mmHg Surface 1.3/1.6/1.9 1.8/2.0/2.3 Area High Flux Flux High Flux Maximum 300mL Priming 300-450mL Designed to achieve HD Designed for patients targets with a smaller Strength with difficulty in surface area achieving HD targets Data On File A better dialysis experience doesn’t just come from a box. It’s built from better products, better partnerships, and better support. For more information contact B. Braun Medical Inc. at 1-800-848-2066 www.bbraunusa.com/DiacapPro B. Braun Medical Inc. | Bethlehem. PA | www.bbraunusa.com/xevonta Rx Only ©2019 B. Braun Medical Inc., Bethlehem, PA. All rights reserved. AVT005 12/19  Riigihangete vaidlustuskomisjon Tartu mnt 85 10115 Tallinn Meie:23.01.2024 nr 2-10/7-1 [email protected] VOLIKIRI 1. Käesolevaga volitab AS Lääne-Tallinna Keskhaigla (edaspidi LTKH) õigus- ja hankeosakonna juristi Kaisa Suvi (isikukood 48705290369) esindama LTKH-t riigihangete vaidlustuskomisjonis vaidlustusmenetluses riigihankele „Dialüüsi tarvikute ostmine“, viitenumber 272185. Esindajal on õigus teha LTKH nimel kõiki menetlustoiminguid. 2. Volikiri on antud edasivolitamise õiguseta ning on tähtajatu. (allkirjastatud digitaalselt) Arkadi Popov juhatuse esimees [email protected] AS Lääne-Tallinna Keskhaigla, Paldiski mnt 68, 10617 Tallinn, Eesti Vabariik Telefon: 650 7393, Faks 650 7265, e-post [email protected] Registrikood: 10822269, Arvelduskonto: EE081010220022881019 SEB Pank  Riigihangete vaidlustuskomisjon Teie: [email protected] Meie: 23.01.2024 nr 2-6/14-3 Vastus OÜ MP AlpinTech vaidlustusele riigihankes „Dialüüsi tarvikute ostmine“, viitenumber 272185 Hankija: AS Lääne-Tallinna Keskhaigla registrikood: 10822269 aadress: Paldiski mnt 68, 10617 Tallinn Hankija esindaja: jurist Kaisa Suvi telefon: 6507 399 e-post: [email protected] Vaidlustaja: OÜ MP AlpinTech registrikood: 16209624 Vaidlustaja esindaja: advokaat Ringo Heidmets Adokaadibüroo GLIMSTEDT Estonia OÜ registrikood: 14233883 e-post: [email protected] telefon: 5663 2589 1. SENINE MENETLUS OÜ MP AlpinTech (vaidlustaja) esitas 17.01.2024 vaidlustuse (vaidlustus) riigihankes „Dialüüsi tarvikute ostmine“ viitenumbriga 272185 (riigihange). Vaidlustaja taotles Riigihangete vaidlustuskomisjoni (VAKO) kohustama AS-i Lääne-Tallinna Keskhaigla (hankija) viima riigihanke alusdokumendid osades 1, 6 ja 35 vaidlustaja soovidega kooskõlla. VAKO edastas vaidlustuse hankijale 18.01.2024 ning palus hankijal esitada kirjalik seletus vaidlustuse kohta ja asja lahendamiseks vajalikud dokumendid hiljemalt 23.01.2024. Käesolevaga esitab hankija enda vastuse vaidlustuse osas. AS Lääne-Tallinna Keskhaigla, Paldiski mnt 68, 10617 Tallinn, Eesti Vabariik Telefon: 650 7393, Faks 650 7265, e-post [email protected] Registrikood: 10822269, Arvelduskonto: EE081010220022881019 SEB Pank 2. HANKIJA KAHTLUS VAIDLUSTAJA REAALSES VÕIMALUSES RIIGIHANKES OSALEDA Riigihangete seaduse (RHS) § 192 lg 3 p 6 kohaselt jätab vaidlustuskomisjon vaidlustuse läbi vaatamata ja tagastab selle oma otsusega vaidlustajale, kui vaidlustaja ei tõenda riigihanke alusdokumentide vaidlustamisel vaidlustuskomisjonile vastuvõetaval viisil, et tal on reaalne võimalus riigihankes osaleda. Riigihangete seaduse kommenteeritud väljaande kohaselt võib riigihankes osalemise võime hindamisel arvestada ettevõtja senist tegevusvaldkonda, praktilisi kogemusi, asjatundjate ja oskustööliste töölerakendamise võimalusi, käivet jne1. Riigihangete registrist nähtub, et vaidlustaja on varasemalt pakkujana osalenud kahes riigihankes: 1. „Holste-Polli kunstlume tootmiseks vajaliku taristu ehitustööd“, viitenumber 269495; 2. „Pannjärve kunstlume tootmise süsteemi III etapi ehitus“, viitenumber 264505. Kumbki eelpool nimetatud riigihangetest ei ole vähimalgi määral seotud dialüüsi tarvikute müümisega. Avalikult kättesaadavate andmete kohaselt ei ole vaidlustaja ettevõttes töötajaid. Viimase aasta jooksul pole vaidlustajal tekkinud maksustatavat käivet. Vaidlustaja 2022. majandusaasta aruande kohaselt on vaidlustaja müügitulu 41651 eurot 100 %-liselt tekkinud EMTAK-i koodi „Ärinõustamine jm juhtimisalane nõustamine“ alusel. Majandustegevuse registri kohaselt on vaidlustaja 18.07.2023 esitanud kaks majandustegevusteadet, vastavalt ehitamise ja elektritööde kohta. Vaidlustaja poolt vaidlustatud riigihankega soovib hankija tervishoiuteenuse osutajana osta dialüüsi tarvikuid 36 kuu jooksul kasutamaks neid lõppstaadiumi neerupuudulikkusega patsiendite ravis. Sealjuures on riigihanke vaidlustatud osade eeldatav maksumus vastavalt: 1. osa 1 - 1 078 700,00 EUR; 2. osa 6 - 508 000,00 EUR; 3. osa 34 - 23 700,00 EUR; s.o. kokku 1 610 400 EUR, mis ületab vaidlustaja 2022. a müügitulu rohkem kui 38-kordselt. Lähtudes eelpool toodust on hankijal tekkinud kahtlus, et vaidlustajal ei pruugi vaidlustuse rahuldamise korral olla reaalset võimalust riigihankes osaleda ning pakkumust esitada. Ka vaidlustust lugedes jääb hankijale selgusetuks millise tootja milliseid tooteid plaanib vaidlustaja hankija riigihankele pakkuda. Seetõttu on hankija seisukohal, et vaidlustaja vaidlustus tuleb jätta läbi vaatamata ning tagastada vaidlustajale RHS § 192 lg 3 p 6 alusel. 1 I.Pilving, M. Parind. § 192 kommentaar 22, lk 1091 M. Parind, M.A. Simovart (koost). Riigihangete seadus. Kommenteeritud väljaanne. Juura 2019. AS Lääne-Tallinna Keskhaigla, Paldiski mnt 68, 10617 Tallinn, Eesti Vabariik Telefon: 650 7393, Faks 650 7265, e-post [email protected] Registrikood: 10822269, Arvelduskonto: EE081010220022881019 SEB Pank Alternatiivselt esitab hankija oma seisukoha vaidlustusele, kui vaidlustust ei peaks läbi vaatamata jätma. 3. RIIGIHANKE OSA 1 Esiteks heidab vaidlustaja hankijale ette, et hankija poolt riigihanke osale 1 esitatud tingimus „[...] auruga steriliseeritud [...]“ on seadusega vastuolus. Vaidlustaja hinnangul takistab tingimus riigihankes osalemast pakkujatel (sh vaidlustajal), kes soovivad pakkuda kiirgusega steriliseeritud dialüsaatoreid. Vaidlustaja leiab, et ei saa eksisteerida ühtegi eluliselt usutavat ja objektiivset põhjendust sellele, miks peavad dialüsaatorid olema steriliseeritud just auruga. Hankija vaidlustaja seisukohaga ei nõustu. Vaidlustaja on õigesti märkinud, et kiirgusega steriliseeritud dialüsaatorid on maksumuselt ja funktsionaalsuselt konkurentsivõimelised auruga steriliseeritud dialüsaatoritega. Kindlasti on kiirgusega dialüsaatori steriliseerimine ka lihtsam ja odavam, kui auruga steriliseerimine. Dialüsaatori membraani funktsionaalseid omadusi (kliirens, läbilaskvuskoefitsient, UF koefitsient) steriliseerimise meetod ei mõjuta. Samas on oluline rõhutada, et hemodialüüsi protseduuri vajavad enamasti kroonilised haiged, kes käivad protseduuril 3-4 korda nädalas ja sageli mitukümmend aastat. Patsiendi tervise seisukohast on seega dialüsaatori biosobivus mitte vähem oluline, kui dialüsaatori funktsionaalsed omadused. Meditsiinikirjanduses on küllaldaselt artikleid, mis näitavad, et suures doosis kiirgus tekitab dialüsaatorite materjalides (polüuretaan jt) muutusi ning tekkivad genotoksilised ühendid ning vabad radikaalid, mille suurenenud kontsentratsiooni on määratud patsiendi vereseerumis. Hankija lisab vaidlustusele ühe näitena väljaandes World Journal of Nephrology & Urology avaldatud asjakohase teadusartikli „Do Sterilization Process Really Make Difference in Dialysis-Induced Genotoxicity“ (Lisa 1). Hankija soovib oma patsientidele pakkuda parimat võimalikku dialüüsravi ja auruga dialüsaatorite steriliseerimine ei ole unikaalne vaid mõnele üksikule tootjale. Antud meetodit kasutavad näiteks kaks maailma juhtivat dialüüsitarvikute tootjat Fresenius (Lisa 2, lk 14) ja Baxter (Lisa 3, lk 4). Hankija lisab täpsustuse korras, et riigihanke osale 2 „Sünteetiline hepariniseeritud High-Flux dialüsaator“ on hankija esitanud, erinevalt riigihanke osast 1, tingimuse „gammakiirtega steriliseeritud“, kuna hepariniseeritud (kaetud) membraani ei saa auruga steriliseerida. Hepariniseeritud membraaniga dialüsaatorit kasutab hankija vaid erandolukorras tõsise hüübimisprobleemiga patsiendil, kellele tavapäraselt hemodialüüsi protseduuri ajal kasutatavat antikoagulanti (peamiselt madalamolekulaarset hepariini) manustada ei saa. Hankija kasutab riigihanke osas 2 nimetatud dialüsaatorit vaid erandolukorras, sest oma olemuselt ei ole hepariiniga kaetud membraaniga dialüsaator nii füsioloogiline ja ohutu kui ilma hepariinita membraaniga dialüsaatorid. Teiseks heidab vaidlustaja hankijale ette, et hankija poolt riigihanke osale 1 esitatud tingimus „[...] Tsütokroom C kliirens vähemalt 120 ml/min (verevoolukiirus 300 ml/min, dialüsaadi voolukiirus 500 ml/min, Qf=75 ml/min vastavalt EN 1283 või ISO8637)“ ei ole objektiivselt põhjendatav ega vajalik. AS Lääne-Tallinna Keskhaigla, Paldiski mnt 68, 10617 Tallinn, Eesti Vabariik Telefon: 650 7393, Faks 650 7265, e-post [email protected] Registrikood: 10822269, Arvelduskonto: EE081010220022881019 SEB Pank Samuti on vaidlustaja seisukohal, et tsütokroom C kliirens ei ole dialüsaatori parameetrina üleüldse laialt levinud. Hankija vaidlustaja seisukohaga ei nõustu. Tsütokroom C kliirens iseloomustab suuremate neerutoksiinide eemaldamise suutlikkust ning vaidlustaja väide, et antud parameeter on omane vaid ühe kindla tootja dialüsaatoritele, ei pea paika. Hankija toob näitena kolme juhtiva dialüsaatorite tootja brošüürid - Fresenius (Lisa 2, lk 40), Baxter (Lisa 3, lk 3) ja B.Braun (Lisa 4, lk 2). Eeltoodust lähtuvalt on hankija seisukohal, et vaidlustaja vaidlustus riigihanke osas 1 tuleb jätta rahuldamata. 4. RIIGIHANKE OSAD 6 JA 35 Vaidlustaja hinnangul on põhjendamatu ja asjakohatu hankija poolt riigihanke osale 6 esitatud tingimus „[...] täitmise mahuga mitte rohkem, kui 125ml.“ Hankija on seisukohal, et mida väiksem on dialüüsi protseduuril ekstrakorporaalse ringe maht, seda väiksem on tõenäosus hüpotensiooni tekkeks ning 125 ml maht on kindlasti eelistatum kui 135 ml. Hankija möönab samas, et dialüüsi saab läbi viia ka 135 ml täitmise mahuga vereliinidega ning on teinud seetõttu menetlusökonoomiast lähtuvalt riigihanke alusdokumentides vastava muudatuse. Vaidlustaja hinnangul on ebaseaduslik hankija poolt riigihanke osale 36 esitatud tingimus, mille kohaselt on lubatud pakkuda üksnes Clear Surf Wipes lappe, mis on niisutatud 1% Clear Surf lahusega. Hankija eelistuseks on kasutada hankija kasutuses olevate dialüüsiaparaatide tootja poolt soovitatud desinfitseerimislappe, mis on vajaliku efektiivsusega bakteritele, viirustele ja seentele ning oleks ohutud aparatuuri pinnamaterjalidele. Hankija möönab samas, et samasuguse efektiivsusega võivad olla mõne teise tootja pakutavad desinfitseerimislapid ning on teinud seetõttu riigihanke alusdokumentides vastava muudatuse. 5. MENETLUSKULUD Hankija on seisukohal, et vaidlustaja menetluskulud tuleb jätta vaidlustaja kanda. Vaidlustaja oleks võinud enne vaidlustuse esitamist pöörduda hankija poole läbi riigihangete registri ettepanekuga riigihanke alusdokumentide muutmiseks. Vaidlustaja seda pole aga teinud. Riigihange on riigihangete registris ja Euroopa Liidu Teatajas avaldatud 21.11.2023, s.o. 2 kuud tagasi. Hankija hinnangul on 2 kuud enam kui piisav aeg hankijale ettepaneku esitamiseks ning vastuse ära ootamiseks. Selle asemel on vaidlustaja alustanud koheselt vaidlustusmenetlust. Kui vaidlustaja oleks pöördunud hankija poole omapoolse ettepanekuga, poleks riigihanke osade 6 ja 35 osas menetlustuskulusid üldse tekkinud. Riigihanke osa 1 osas on hankija seisukohal, et vaidlustus tuleb jätta rahuldamata ning menetluskulud jätta vaidlustaja kanda. Eeltoodud asjaolusid arvesse võttes palub hankija: 1. jätta vaidlustaja vaidlustus läbi vaatamata RHS § 192 lg 3 p 6 alusel; 2. jätta vaidlustuse esitamisega seotud kulud vaidlustaja kanda; 3. lahendada asi kirjalikus menetluses. AS Lääne-Tallinna Keskhaigla, Paldiski mnt 68, 10617 Tallinn, Eesti Vabariik Telefon: 650 7393, Faks 650 7265, e-post [email protected] Registrikood: 10822269, Arvelduskonto: EE081010220022881019 SEB Pank või alternatiivselt: 1. jätta vaidlustaja vaidlustus rahuldamata riigihanke osa 1 osas; 2. jätta vaidlustaja vaidlustus riigihanke osade 6 ja 35 osas läbi vaatamata RHS § 192 lg 3 p 5 alusel ning lõpetada vaidlustusmenetlus RHS § 197 lg 1 p 8 alusel; 3. jätta vaidlustuse esitamisega seotud kulud vaidlustaja kanda; 4. lahendada asi kirjalikus menetluses. Lugupidamisega (allkirjastatud digitaalselt) Kaisa Suvi Volitatud esindaja Lisatud: Lisa 1 Teadusartikkel väljaandes World Journal of Nephrology & Urology „Do Sterilization Process Really Make Difference in Dialysis-Induced Genotoxicity“ Lisa 2 Fresenius brošüür Lisa 3 Baxter brošüür Lisa 4 B.Braun brošüür Lisa 5 Volikiri AS Lääne-Tallinna Keskhaigla, Paldiski mnt 68, 10617 Tallinn, Eesti Vabariik Telefon: 650 7393, Faks 650 7265, e-post [email protected] Registrikood: 10822269, Arvelduskonto: EE081010220022881019 SEB Pank