On-line Hemodiafiltration Fresenius Dializis Centrum, Sopron State of the Art: On-line Hemodiafiltration Dr. Vaslaki Lajos orvos-igazgató Fresenius Dializis Centrum, Sopron

State of the Art On-line Hemodiafiltration Vaslaki Lajos Fresenius MC Sopron

A hemodiafiltrácio az uremiás plazma epurációjának jelenleg leghatásosabb formája „ Amit sohasem vontak kétségbe, az nincs bebizonyítva „ Diderot

Solute transport in different dialysis modalities  Haemodialysis  Diffusive transport of solutes Relevant: - cut-off of membrane - weight of solutes  Haemofiltration  Convective transport of solutes Relevant: - cut-off of membrane - flow across membrane  Haemodiafiltration  Diffusive transport of small solutes  Convective transport of large solutes Diffusion Membrane Convection Membrane Pressure

A konvencionalis/diffuzión alapuló dializis limitjei/szövődményei β-2 Mikroglubulin okozta amyloidozis Accelerált arteriosclerozis Bal kamra hypertrophia Inflammációs folyamatok Malnutrició/ gyorsult öregedés

Miért hatékonyabb az OLHDF mint a hagyományos HD?! Az ol-HDF a nativ vese élettani működését próbálja utánozni ( intuitiv megközelítés) hemokompatibilis in vitro rendszerben A glomerulus bazalis membránjához, annak müködésében, tehát áteresztőképességében hasonló, biokompatibilis membrán használata A különböző molekula-súlyú uremiás toxinok konvektiv és diffuziv módon történő – jelenleg leghatékonyabb eltávolítása

Konvencionális dializistől az On-line Hemodiafiltrációig Hemokompatibilis technikai rendszerek Technikai feltételek Nagyteljesítményű részben hydrophil „high-flux” dializis membránok megjelenése,klinikai eredmények Zárt rendszerű, pontos ultrafiltrációs controllal működő dializis gépek – HDF-re alkalmas szoftverrel. Ultratiszta/steril szubsztituciós oldat on-line előállítása korlátlan mennységben

Szintetikus membránok biokompatibilis hemodiafilterekben Szintetikus membránok biokompatibilis hemodiafilterekben.Kliniai eredmények Okuno et al : beta – 2 MG szint a mortalitás önálló prediktora Cheung et al : szignifikáns összefüggés a beta -2 MG plazma szint és az infekcio okozta mortalitás között HEMO study : beta-2 MG – közép molsulyú toxinok markere High-flux filterek jelentősége MPO ( Membrane Permeability OutcomeStudy ). A high-flux dializis klinikailag előnyös a rossz prognozisú betegek kezelésében( diabetes..)

HD -, HF és On-line HDF kezelési eljárások müködési vázlata From: A Grassmann et al., Composition and Management of Hemodialysis Fluids; Pabst Publishers, 2000

Predilution On-Line HDF Filtrate (UF + HDF) blood (in) blood pump Substituate (pre) HDF pump blood (out) Improved membrane permeability - filtration from diluted blood! But … dilution also reduces efficiency lower diffusion gradient reduced clearance for small molecules Substitution solution enters extracorporeal circuit before dialyser

Postdilution On-Line HDF Best removal of small and middle size uremic toxins – filtration from undiluted blood! But … ultrafiltration limited by haemoconcentration high blood viscosity secondary protein layer membrane polarization and high blood flow rates are needed blood (out) Substituate (post) HDF pump Filtrate (UF + HDF) blood pump blood (in) Substitution solution enters extracorporeal circuit after dialyser

Improved water and solute permeability of the dialyser! Due to… individual dilution management and improved blood rheology high filtration rates → optimised convective flux → increased solute removal safe against albumin loss (occuring at high TMPs) Best of both worlds! feedback control Filtrate (UF + HDF) blood (in) blood pump Substituate (pre) HDF pump 1 blood (out) Substituate (post) HDF pump 2 Substitution solution enters extracorporeal circuit simultaneously before and after the dialyser -regulated by feedback control system

Software: ON-LINE menu: H(D)F screen Total infusion volume is diverted between pre- and post-dilution at optimised ratio Initial phase: slow increase of post-dilution → minimises albumin loss Feedback control: TMP is kept constant in pre-set safe corridor → maintenance of hydraulic characteristics of the dialyser → maximal convection Automatic adaptation and control of infusion ratio and volume maintains the haemodynamic stability in the dialyser

* ° * QB = 400 ml/min QUF post-HDF : 8.7 L/hour low-flux HD post-HDF 20 40 60 80 100 120 * * ° mixed HDF p< 0.05 * vs HD, ° vs post-HDF 2-m KDQ ml/min QB = 400 ml/min QUF post-HDF : 8.7 L/hour mixed HDF : 15 L/hour 14

Az On – line HDF alkalmazásának kritikai szempontjai. SAFETY ISSUE Lehetséges-e szubsztituciós oldat „hideg-sterilizálással” történő on-line előállítása ? A dializáló oldatból történő un. back transfer-filtráció ( visszaáramlás) a high – flux filterekben / dia-filterekben elkerülhetetlen.Tehát, a steril szubsztituciós oldat itt is feltétlenül szükséges. Az FMC hálózatban már hét éve,csak High-Flux dializist (On-line HDF-et)alkalmazunk

Safety issue Certified dialysis machines Ultrapure dialysis water (CFU < 1 ; ET < 0.25 I.U) Steril substitution fluid (CFU:steril ; ET<0.03 I.U) Microbiological monitoring (monthly) Regular (monthly) desinfection of the system Biocompatible high-flux polysulphon/polyamid dialyzer with high adsorbtive capacity These measures _based on EBPG _ can prevent cytokine-inducing substances passing through dialysis membrane in daily,clinical routine

Recommendations for the quality A szubsztituciós oldat mínőségi mutatói az OLHDF és HF kezelési eljárásokban. Az Eropean Best Practice Guideline ajánlásai Raw water Water treatment system Highly purified water  100 CFU/ml  0.25 IU/ml Endotoxin filter/redundant Endotoxin filter Bicarbonate dialysis fluid  100 CFU/ml  0.5 IU/ml Ultrapure dialysis fluid < 1 CFU/ml  0.03 IU/ml Substitution fluid sterile pyrogenfree Recommendations for the quality of fluids used in the preparation of on-line Substitution Fluid for HF and HDF ( EBPG ) Pure bicarbonate concentrate

Safety :Endotoxins and Cytokine(CIS) Activity in Substitution Fluids NDT Endotoxins (LAL reactivity, IU/ml) Cytokine inducing activity (pg IL-1Ra/106 WBC) Double stage ultrafiltration of dialyzis fluid was associated with a high retention of pyrogenes by a single filtration step; no difference was found between the filtrates and ,commercial HFsolutions and depyrogenated saline control. The same results were obtained when assessing the overall cytokine-inducing activity by cellular IL-1Ra release Vaslaki L et al. Nephrol Dial Transplant (Suppl. 1): 74-78, 2000

A High-efficiency ol-HDF klinikai előnyei ( Reduceed overall morbidity) Reduced hypotenziv epizodes Altieri P., Sorba G. J.Nephrol 2004 Better blood pressure control Stegmayer BG.Artif.Organs 2003 Reduction of left ventricular hypertension Maduell F. 2005 Longer and better preservation of residual kidney function McKane Kidney Int.2003 Improved Hemocompatibilty& Reduced inflammation Canaud B Nephrol Dial Trasp 2001 Improved anemia control Vaslaki L., Major L. Blood Purif.2006.24 Pozitiv impact on nutritional state Basil C.,Nephrol Dial Transplant 2003 Nephrol Dial Transp 2007 Improvement of lipid profil and reduce oxidativ stress Calo L. Artif Organs 2007 Growth retardation correction by ol-HDF+growth hormon+ EPO Fischbach M. Pediatr Nephrol 2006 Improved MORTALITY…………………

Less Inflammation with On-line HDF Endotoxins IL-6 (pg/ml) Dialysis membrane Monocytes CD14+ & CD16+ UNPURE DYALYSATE IL - 1 Hepatocytes : acut phase reactans : CRP IL – 6 TNFalfa Soluble endothelial adheziv factors :sVCAM and sICAM ( Independent predictor of mortality in pre-dial patients (Stenwinkel ) Recent evidence suggest that IL-6 is the key pro-atherogenic mediator.generated upon induction of pro-imflammatrory Il-1 and stimulates the production of soluble endothelial adhesiv factors such as sICAM and sVCAM.So the upregulated IL-6 expression plays a substantial role in the generation of atherosclerotic plaque.Predialysis plasma level of IL-6 were significantly higher in ESRD patients both HD and OLHDF patients than in normal control .In the OLHDF patient’s group the IL-6 significantly reduced compared to HD patients group. Low-flux HD On-line HDF Arteriosclerotic plaque Vaslaki L., Major.. 2006 Blood Purification

The need for high exchange rates DOPPS : sets the goal (from medical point of view) -> we need to avoid hemoconcentration and high TMPs To guarantee the achievement of high exchange volumes, the technical solution is a simultaneous infusion pre and post with a TMP feedback control DOPPS Study B.Canaud 35% lower mortality risk for patients treated with HDF with a volume exchange of >15 L/ treatment vs. patients on low-flux HD.

Mortality risk for patients: epidemiological evaluation Study EuClid Database FMC Total Pts (No.) = 2564 Epidemiological evaluation Total Pts (No.) = 2567 Kidney Int 2006 Jirka at al

Results: Odds Ratio Estimation ** 35,4 % RR Odds ratio as a risk estimation shows in fact clearly that by correcting the overall mortality by the confounding factors like age,gender, comorbidities and time on RRT in statistical analysis there is still a significant reduction ( - 35%) of risk to die. P=0.05 ) ** Comorbids: Diabetes, Neoplasms, Heart Failure, Peripheral arterial disease, etc. Kidney Int. Jirka at al .

Total HD and On-line HDF treatment number 2008 – 2000 in FME Network

The share of On-line HDF treatments in total HD treatments 2008 - 2000

Conclusion … allows the premium therapy to become standard!

„ Erős képzelet szüli az okokat ” Montaigne Köszönöm a figyelmet!

A leghosszabb út is az első lépéssel kezdődik… A leghosszabb út is az első lépéssel kezdődik…..a konvektiv oldat transzport alkalmazása Brull L 1928 Realisation d’ultrafiltration Bluemle LW 1987 Early days of Hemodiafiltration Leber H. et all. 1978 Hemodiafiltration: a new alternative to hemofiltration and conventional hemodialysis Henderson LW 1978 Present status of Hemodiafiltration 1982 Historical review and principles of HDF 2003 The beginning of clinical hemodiafiltration : a personal account

The modality’s is benefical effects on patient outcomes are not related to dialysis dose for small molecules (Kt/Vurea) but may be related to factors particular to HDF which combines enhanced removal of larger molecular weight substances with an improved biocompatible system Bernard Canaud

A szubsztituciós oldat On-line előállításának vázlata Endotoxin filter Endotoxin filter Highly purified water Steril Substitution fluid Ultrapure dialysis fluid Dialysis fluid Bicarbonate concentrate Predilution Retentate Hemodiafilter Dialysis fluid Ultrafiltrate Dialysate Blood Post-dilution