The Role of Dialyzers in Cardiac Protection. Prof. Dr. Eng. Jörg Vienken BioSciences, Fresenius Medical Care, Bad Homburg, Germany

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1 The Role of Dialyzers in Cardiac Protection Prof. Dr. Eng. Jörg Vienken BioSciences, Fresenius Medical Care, Bad Homburg, Germany

2 With a Sense for Details! 1999 Peter Vienken, 11 years Prof. Pim Kolff, 88 years

3 The Role of Dialyzers in Cardiac Protection Facts of today, figures of tommorrow Physiological approaches and properties of dialysers Examples Clinical consequences, new targets Conclusion

4 Future Therapy Modifications? Example USA Prevalence per age group Consequences: variations of dialysis technology? 8978 Re: C Hsu, J Am Soc Nephrol, 21: (2010)

5 The Role of Dialyzers in Cardiac Protection Facts of today, figures of tommorrow Physiological approaches and properties of dialysers Examples Clinical consequences, new targets Conclusion

6 Chronic Kidney Diseases & Cardiovascular Problems * *Cardiovascular event: hospitalisation due to chronic kidney diseasse, cardiopathy, myocardial infarction, etc Re: Go et al., N Engl J Med, 351: (2004)

7 Methods of Dialysis Intensification..some with dialyser impact Time - night - day Location - in centre - home Frequency - 3 x per week - every 2. day - daily Dialysis Time - 2 hrs - 4 hrs - 8 hrs Re: J Perl & CT Chan Am J Kidney Dis, 6: (2009)

8 Elderly patients with high profit from longer dialysis treatment times % years survival in Europe, USA and Tassin > > 64 Age at onset of Dialysis USA, mean dialysis time 3 x3-4 hrs Europe, mean dialysis time 3 x4-5 hrs Tassin, mean dialysis time 3 x8 hrs Re: Charra et al., 1992

$Improvement of therapeutic performance by a more frequent or more efficient dialysis LV Ejection fraction$

9 Improvement of therapeutic performance by a more frequent or more efficient dialysis LV Ejection fraction Systolic blood pressure Index of left Ventricular mass Re: Susantitaphong P et al., Am J Kidney Dis, 2012

10 Medicines are nothing in themselves if not properly used. Herophilus, 300 B.C. 3690

11 Efficient Dialysis by Solvent drag convective clearance Convective clearance = QF x SC Membrane type: lowflux highflux f(δp) f(tmp) SC = sieving coefficient; Q F = filtrate flux; TMP = transmembrane pressure

12 Filtration Profiles Low-flux vs high-flux Dialysers Filtrate flux (Q F ) & membrane permeability In vitro, human blood, Hct.32 %, TP 6 %, Q B = 300 ml/min High flux Ultrafiltration [ml/h] Potential avantage in K convective Low flux TMP [mmhg] F4HPS F5HPS F6HPS F7HPS F8HPS F60 F70 HF80 HDF100S 7922

13 Sieving by size exclusion with polysulfone membranes Sieving Coefficient 1 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 Dialysis PSu F6 Low flux Zone of permeability PSu F60S High Flux Fx60 Zone of impermeability PSu FX CorDiax ß 2 -m Albumin IgG Fibrinogen IgM Molecular weight

210 µm Larger internal diameter needed to avoid clotting

14 Optimization of Membrane Capillaries for their Use in Hemodiafiltration Fx-Class (Helixone) CordiaX HDF 185 µm 210 µm Larger internal diameter needed to avoid clotting due to hemoconcentration in post dilution HDF Re: FMC 2012

15 FX CorDiax Elimination of Uremic Toxins Sieving Coefficient e.g., Phosphate clearance Phosphate Clearance ml/min FX CordiaX 60 Competitor 1 Competitor 2 of similar surface area Comparison of sieving coefficient FX 60 and FX CordiaX 60 Comparison of aqueous in vitro clearance QB: 300 ml/min; QD: 500 ml/min, (EXcor Lab GmbH, Obernburg, Germany 2011) 15 International Marketing & Medicine

16 Clinical Sequaelae following Efficient Treatment Modes HD vs online HDF with FX-dialysers 25 Without hypotension Number of Treatments With hypotension 0 HD online HDF Re: Donauer et al; Nephrol Dial Transplant, 8: (2003)

Hydraulics dialyser Dialysis Dialysate Blood

17 Concept of modern dialysis machines Synergies between dialyser and monitor Sensors Control Hydraulics dialyser Dialysis Dialysate Blood Patient machine Sensors Sensors Sensors OCM BTM, BVM BPM

18 BVM: Automatic Adaptation of Relative Bloodvolume Through controlled Ultrafiltration RBV [%] UFR [l/h] RBV [%] UFR [l/h] time [min] time [min] Treatment with RBV Control UFV = 3.8L The same patient, 2 days later UFV = 3.6L RBV: relative Bloodvolume 9352

19 The dialysis membrane is not a one-way street!

20 Water Quality in OnLine HDF: Better safe than sorry Reverse Osmosis Endotoxin Adsorber Diasafe I Endotoxin adsorber Diasafe II Substitution Fluid Dialysis- Fluid Endotoxin Adsorber III PSu-Filter

21 Polysulfone Capillary Membranes: - adsorptive capacity for endotoxins Dialysate Blood Artificial Organs, 32(9): (2008) 8100

22 The Role of Dialyzers in Cardiac Protection Facts of today, figures of tommorrow Physiological approaches and properties of dialysers Examples Clinical consequences: new targets? Conclusion

23 Inflammation, the main risk factor of CVD

24 Microinflammation with Impact on Endothelial Damage in a Co-Culture Model HUVEC Results of Study 1. Release of cytokines after stimulation of monocytes with bacterial DNA (1,8µg/ml) in vitro 2. CD14 + CD16 ++ monocytes most efficient 3. ROS activity and apoptosis in overlayer endothelial cells Re: A Merino et al., Contrib Nephrol, (2008)

25 Toxins with Elevated Concentrations in Uremia Metabolic substances Homocysteine p-cresol sulfate Indoxyl sulfate Asymmetric-dimethyl-arginine (ADMA) Inflammatory mediators Complement factor D C-reactive protein (CRP) Cytokines Free radicals & products of oxidative cycle Free radicals Reactive oxygen species (ROS) Ox-LDL Carbonyls Advanced glycation end-products (AGEs)

26 Pathomechanism of CRP at the Endothelium B C Re: Verma et al., Circulation 2002

27 The active Role of CRP in AKI Agonist not only indicator! 9931 Abstract ASN 2012

Immunhistologic Staining for C-reactive Protein (CRP) in myocardial tissue Magnificiation: x 300 60-year old man

28 Immunhistologic Staining for C-reactive Protein (CRP) in myocardial tissue Magnificiation: x year old man without renal disease Magnificiation: x year old uremic man Re: E Ritz et al., Contrib Nephrol,149:1-9 (2005)

29 General Features of CRP Background CRP, an acute phase protein Is released from hepatocytes after IL-6 stimulation. Activates the classical complement cascade. Stimulates mononuclear cells to phagocytosis. Promotes endothelial dysfunction through downregulation of enos (NO ). Promotes the proinflammatory milieu through ET1- and IL-6- release from endothelial cells. CRP is not only an indicator for inflammation, but acts as an agonist

30 Mechanisms leading to Cell Damage Cell membrane Cytoplasm/ Cell interior spla2 CRP spla2 C4 b C3b C2b FcγRIIa C1q CR1 Phagocyte Phosphatidylcholine Phosphatidylserine/-ethanolamine Sphingomyelin spla2 secretoric phospolipase A 2

31 Erythrocytes and Phosphatidyl-Serine (PS) Filtered uremic plasma factor(s) induce PS* exposure at red cell surface RBC PS exposure x-fold increase Uremic Ultrafiltrate ** # ** # ** # HD F70S HD FX80 HDF F70S ol-hdf FX80 Analysis of toxic factors from ultrafiltrate following different treatment modes Time of dialysis min *PS: Phosphatidyl-Serine, n = 8 M Bonomini et al., Nephrol Dial Transplant, 19: (2004)

32 The Role of Dialyzers in Cardiac Protection Facts of today, figures of tommorrow Physiological approaches and properties of dialysers Examples Clinical consequences Conclusion

33 Summary and Conclusion Cardiovascular problems with high incidence in ESRD Increased tendency to be expected due to a higher rate of elderly dialysis patients. Highly efficient treatments including sophisticated dialysers with chances to counteract online HDF, Sensor-controlled UF, ultrapure water In depth understanding of CRP mechanisms with chances for new therapies

Dialysers Increasing Cost and Treatment Efficiency

Haemodialysis Dialysers Increasing Cost and Treatment Efficiency Fluid Substitution Calculator Content Haemodialysis yesterday 3 Haemodialysis today 4 Dialyser selection criteria 5 Relation of blood flow