Paired Hemodiafiltration (HDF with on-line ... - APCN 2010

<strong>Paired</strong> <strong>Hemodiafiltration</strong>(PHF)&Hemofiltrate reinfusion(HFR)(hemodiafiltraton <strong>with</strong> endogenous reinfusion)Yonsei University Wonju College of MedicineDivision of Nephrology, Wonju, KoreaSeung Ok Choi, M.D., PhD.

Removal of waste products by dialysisFluid and solutes removalDiffusion and convection/ultrafiltration

DiffusionTransfer by diffusion is the passive transfer of solutesacross the membrane, <strong>with</strong>out the passage of solvent(water).1BloodMembrane2Dialysate1 - Red blood cell2 - BacteriaSodiumPotassiumBicarbonateUreaCreatinineBeta 2-mChlorideUric acid

Convection (Ultrafiltration)by a hydrostatic pressure gradient (convection) :causes a simultaneous passage of water and solutes fromplasma to dialysate or the reverse in the case of backfiltration.BloodMembraneDialysate

Improve Quality of Hemodialysis TechnologyESRD <strong>with</strong> HD: remained high mortalityVascular damageCV diseaseAnemia Amyloidosis Malnutrition

Steps of the Technological Evolution in HDConvective andEvolutionDiffusive-Convective TechniquesBicarbonate HDUF ControlTMP Control1979

<strong>Hemodiafiltration</strong>(<strong>HDF</strong>)Diffusion + ConvectionHemodialysis + Hemofiltration<strong>with</strong> high flux membraneRemoval of small and large solutesSuperior efficiency in total solutes removal

Evolution step of <strong>HDF</strong>By advances in the construction of dialysismembrane (high flux membrane)Development of accurate ultrafiltrationcontrol systemProduction of large amounts of ultrapuredialysate and replacement fluid(on-line)

<strong>HDF</strong> problem Interference between convection and diffusion –simultaneous process of both convection anddiffusion Quantity and quality of the reinfusion fluid –handling and costLoss of important physiological component in theultrafiltrate – essential and branched-chain aminoacids, vitamins, hormones, growth factor

Resolve of <strong>HDF</strong> problemInterference between convection & diffusion☞ Resolve : paired filtration dialysisQuantity & quality of the reinfusion fluid☞ Resolve : online production of reinfusion fluidsLoss of important physiological component in theultrafiltrate☞ Resolve : <strong>HDF</strong> <strong>with</strong> endogenous reinfusion(hemofiltrate reinfusion:HFR)

<strong>Hemodiafiltration</strong><strong>HDF</strong>Diff + ConvReinfusione (QR)

<strong>Hemodiafiltration</strong> ON-LINEQR<strong>HDF</strong>Diff + ConvQR

On-line <strong>Hemodiafiltration</strong>Advantages Higher Kt/V urea Higher elimination of larger uremic toxins Beta 2 -microglobulin Improved cardiovascular stability Improved treatment tolerance Reduced EPO requirements Improved immune response Improved biocompatibility Ultrapure dialysis fluid Sterile substitution fluid Biocompatible membrane Improved survival ?

<strong>Paired</strong> Filtration Dialysis (PFD)Classic To minimize the interference between convection and diffusionReinfusate bagHFHDUFLife Support Syst 1(suppl 1):271, 1983Trans Am Soc Artif Intern Organs 33:546, 1987

<strong>Paired</strong> <strong>Hemodiafiltration</strong> (PHF) by Ghezzi- Dual stage filter <strong>with</strong> high-flux membranes in both chamber- Physical separation of convection and diffusionBF<strong>HDF</strong>PUltrapure DialysateBidirectional pump for reinfusionor fiber integrity test

Ultrafiltrate:• Contents more then 18,000 protein, about 5,000 of them arepeptides, at 95% wt < 15 kDa• 55% : plasmatic protein fragments (fibrinogen A 13%,albumin 10%, β2-MG 8.5%, cystatin C 7%, fibrinogen B 6%)• 7% : hormons, grow factors and cytokines• 33% : complement factors, enzymes, enzymes inhibiter andtransport proteines• 5% : other peptids• Contents aminoacids• Contents Na + , K + , Ca ++ , phosphates,HCO 3- , glucoseRichter R et al. :J Chromatogr B Biomed Sci Appl 1999, 726: 25-35

Resolve of <strong>HDF</strong> problemInterference between convection & diffusion☞ Resolve : paired filtration dialysisQuantity & quality of the reinfusion fluid☞ Resolve : online production of reinfusion fluidsLoss of important physiological component in the ultrafiltrate☞ Resolve : endogenous reinfusion(hemofiltrate reinfusion:HFR)일석삼조( 一 石 三 鳥 )Three birds <strong>with</strong> one stone∥Hemodiafiltraton <strong>with</strong> endogenous reinfusion(HFR)

<strong>Hemodiafiltration</strong> <strong>with</strong> Endogenous Reinfusion (HFR): a new approach to high performance hemodiafiltrationHFHDAdsorbentDialysateRegeneratedreinfusion fluidNo problems in sterility and pyrogenicityConservation of physiologically important substances

Therapeutic Goal of HFRSeparate and retain “toxins”from a complex mixture in the ultrafiltrateTime = 0later“toxins”Physiological“good” molecules• Removal of toxins and inflammatory mediators• Maintain important physiological molecules(proteins, amino acids, hormones etc...)

Clinical benefits of HFR Indication of HFR☞ ESRD patients <strong>with</strong> increased risk ofcomplications related to inflammation,malnutrition, atherosclerosis : DM, high CRP,elderly, higher risk of CV problemsGood removal of uremic toxinGood reduction of inflammatory moleculesSparing amino acid

Long-term Data of HFR using Uncoated Carbon CartridgeDe Francisco AL: Nephrol Dial Transplant 12:528, 199733 chronic uremic patients were dialysed for 1 year using two haemodialysers in series inorder to separate convection from diffusionA cartridge containing 130 g of uncoated charcoal was used as adsorbent.

Characteristics of AdsorbentResin + CharcoalAdsorbs;Adsorbs;ß 2 -microglobulinCreatinine, uric acidHomocysteine, CytokinesUremic toxins <strong>with</strong> a lowmolecular weightAdsorbs amino acids only inpartDoes not adsorb;Urea, Na, K, phosphates,HCO 3-

“Regenerated UF” Used as Endogenous Reinfusion FluidSterilein adherence to the present legislation for medical devicesUltrapureno cytokine-inducing activityA balanced solution of Ca and bicarbonateSaving of NEAA, EAA and hydrosoluble vitamines 11 % in low flux memb. vs. up to 33 % in high permeability memb.Elimination of IN-OUT balancing systems

HFR: Unique RRT that Utilize Convection, Diffusion and AdsorptionConvective fieldBetter removal ofBetter removal of Highhigh MW toxinsMW ToxinsNo net fluid removalDiffusive fieldBetter removal ofhydrosoluble low MWtoxinsQufQdiQdoAdsorbent fieldReinfusion flow(QR)Removal of “bad toxins” byadsorptionReinfusion of importantphysiological molecules

Removal of beta 2 -microglobulin28 uremic patientsBalasco PG et al. : Int J Artif Organs 29: 1042-52, 2006 3 periods of observation: a) HD for three months; b) HFR for three months; c) HFR for a further 3months32.91±6.1mg/L26.4±8.1mg/L• No differences <strong>with</strong> regard to: dialytic efficiency, nutritional status, calcemia, phosphatemia

Inflammatory Markers (HD vs. <strong>HDF</strong> vs. HFR) :CRP• 25 uremic patientsPanichi V et al.:Nephrol Dial Transplant 21: 756–762, 2006• After a 1 month run-in period of standard HD, patients were randomized (A-B or B-A) to betreated by HFR or by online <strong>HDF</strong>.• Each study period of 4 months was separated by 1 month of HD and the entire length of thestudy was 10 months.1 2 3 4 5 6 7 8 9 10 mo.

Inflammatory Markers (HD vs. <strong>HDF</strong> vs. HFR) : IL-6Panichi V et al.:Nephrol Dial Transplant 21: 756–762, 20061 2 3 4 5 6 7 8 9 10 mo.

Effective Removal of Leptin via HFR TreatmentKim et al. Clin Nephrol 72(6), 442-448, 2009Patients11 stable ESRD patients on HD for at least 3 yearsStudy design4 weeks’ run-in-period of low flux hemodialysis12 weeks’ LHD12 weeks’ HFR (SG 30 Plus)4 wk 12 wk 12 wkLHDLHDHFR

Changes in serum leptin & adiponectin levels during HFR TxLeptin (log [ng/mL])17.1P=0.01412.3Adiponectin (log [µg/mL])1.66P=0.0011.1212 week 24 week12 week 24 week

Changes in serum ß 2 -microglobulinl levels measured before andafter HFR sessions every four weeksß2-microglobulin(mg/L)50403020P=0.007P=0.007P=0.027P=0.02737.3 28.3P=0.00116wk16wk20wk20wk24wk24wk

Effect of a hemodiafiltration session <strong>with</strong> on-line regeneration of theultrafiltrate on oxidative stress. Comparative study <strong>with</strong> conventionalhemodialysis <strong>with</strong> polysulfone.Gonnalez-Diez B: Blood Purif. 2008;26(6):505-10.Effect of haemodiafiltration <strong>with</strong> online regeneration of ultrafiltrate onoxidative stress in dialysis patients.Calò LA:Nephrol Dial Transplant. 2007 May;22(5):1413-9.CONCLUSIONS: These results show that HFR induces less oxidativestress than HD-PS.

Effect of on-line hemodiafiltration <strong>with</strong> endogenous reinfusion (HFR) onthe calcium-phosphorus metabolism: medium-term effects.Bolasco PG:Int J Artif Organs. 2006 Nov;29(11):1042-52.CONCLUSION: We are of the opinion that HFR - essentially thanks to theuse of ultrapure endogenous infusate - induces a deceleration in boneturnover due to 2PHT. In addition, phosphate subtraction in HFR is bettercompared to HD, thanks to the improvement of the anti-inflammatoryconditions by removing the cytokines harmful to bone metabolism andexcluding a priori the negative effects related to hyperphosphatemia.

The hemodiafiltration <strong>with</strong> endogenous reinfusion reducesthe erythroid progenitor inhibition by uremic serumAucella F et al. G Ital Nefrol. 2004 Nov-Dec;21 Suppl 30:S128-32CONCLUSIONS: This effect could be due to the removal ofuremic toxins or to a lower dialysis-induced cytokinerelease, both mechanisms involved in erythropoiesisinhibition in ESRD.

HFR vs <strong>HDF</strong>-ON line: plasmatic amino acids loss evaluationRagazzoni E. et al.G Ital Nefrol. 2004 Nov-Dec;21 Suppl 30:S85-90RESULTS: There was no difference detected in pre-dialytic plasmaticlevels of analyzed amino acids between the two groups.- Post-dialysis amino acid level averages were (<strong>HDF</strong> vs HFR):total AA :1852 +/- 302.6 vs 2395 +/- 492.8 micromol/L (p = 0.018)essential AA:428.8 ± 118.2 vs 510.3 ± 129.3 micromol/L (p = 0.022)- non-essential AA:1176±213 vs 1546 ± 339.2 micromol/L (p = 0.01)- BCAA:242.7 ± 83.42 vs HFR 286.7 ± 89.9 micromol/L (p = 0.03)CONCLUSIONS: Since low plasmatic BCAA levels are related to anorexiaand malnourishment, the loss of these amino acids can be important inthe dialytic technique choice. HFR can offer an outstanding advantage,combining a high convection treatment <strong>with</strong> medium molecule removal,<strong>with</strong>out compromising physiologic molecule loss.

Selective adsorption of homocysteine using an HFR-ON LINEtechniqueSplendiani G et al. Artif Organs. 2004 Jun;28(6):592-5.We have measured the Hcy, folate, and vitamin B12 predialysis andpostdialysis, and in the ultrafiltrate precartridge and postcartridge at 10, 120,and 240 min.Results :- The mean Hcy levels were 57.6 and 35.3 micromol/L (P = 0.005)predialysis and postdialysis, respectively- folate and vitamin B12 were unchanged.- Precartridge and postcartridge Hcy levels were 11.6 vs. 2.5 micromol/L(P = 0.005), 9.3 vs. 3.9 micromol/L (P = 0.005), and 7.7 vs. 4.6micro mol/L (P = 0.012) at the three time points consideredConclusion : HFR-ON LINE is able to reduce Hcy levels not only through alikely reduction of uremic toxins, but also through an actual removal of Hcyby adsorbance onto the charcoal-resin cartridge.

The effect of hemodiafiltration <strong>with</strong> endogenous reinfusion(HFR)on quality of life in dialysis patientsSeung Ok Choi 2 and Sung Kyu Ha 1Department of Nephrology, Gangnam Severance Hospital, Yonsei UniversityCollege of Medicine 1 and Yonsei University Wonju College of Medicine 2BackgroundHFR is a novel technique of hemodiafiltration therapy. Iteffectively removes middle molecules and minimizes thedepletion of plasma amino acids by regeneration of theultrafiltrate.Despite more than 20 year of HFR use, there is no studyabout the effect of HFR on quality of life (QOL) inhemodialysis patients.

MethodsTen patients, mean age of 58.5 ± 11.6 yrs (4 males)Dialysis machine ; Formula 2000(Bellco, Italy)Treated <strong>with</strong> low-flux dialysis for more than 3 months were recruited.- dialyzer : polyflux(Gambro, 1.4 m 2 )- Qb = 250mL/min, Qd = 500 mL/minThey underwent new hemodialysis modality, HFR (SPIRAFLO SG30,Plus:DIAPES+DIAPES, Bellco, 0.7 + 1.4 m 2 ) for 12 weeks.- Qb = 250mL/min, Qd = 500 mL/min- reinfusion volume : 50 ml/minCartridge containing styrene resin : Selecta, ItalyBiochemical parameters including β 2 -microglobulin and selfadministeredQOL questionnaire were performed at the beginning of thestudy and every month during HFR use.The questionnaire is composed of 26 variables, such as general healthperception, life enjoyment, physical and emotional stress, and selfsatisfactionto health status.

<strong>Hemodiafiltration</strong> on-line <strong>with</strong> endogenous reinfusion (HFR)

ResultsParametersLow flux HD(-12 wk)Age (year) 58.33 ± 12.38Sex (male/female) 4/6Dialysis period (months) 104.66 ± 35.61HFR(+12wk)p valueHeight (cm) 159.66 ± 7.22Weight (kg) 57.50 ± 10.41Systolic BP (mmHg) 133.66 ± 17.72 142.00 ± 19.46 NSDiastolic BP (mmHg) 70.88 ± 11.36 75.55 ± 10.95 NSHemoglobin (g/dL) 9.64 ± 0.99 10.03 ± 0.49 NSHematocrit (%) 28.47 ± 3.97 30.65 ± 1.35 NSUric acid (mg/dL) 6.60 ± 1.29 7.24 ± 0.90 NS

ResultsParametersLow flux HD(-12 wk)HFR(+12wk)p valueAlbumin (g/dL) 4.00 ± 0.20 3.84 ± 0.58 NSC reactive protein (mg/dL) 0.58 ± 0.86 2.04 ± 3.95 NSBeta 2 microglobulin (mg/L) 41.95 ± 11.13 28.47 ± 6.45 0.000Potassium (mmol/L) 5.78 ± 0.97 5.83 ± 0.83 NSPTH (pg/mL) 164.86 ± 149.41 178.94 ± 120.50 NSUric acid (mg/dL) 6.60 ± 1.29 7.24 ± 0.90 NSKt/V 1.41 ± 0.21 1.37 ± 0.17 NSURR (%) 63.36 ± 24.55 68.71 ± 5.86 NSWHO-QOL 55.12 ± 14.79 55.75 ± 16.06 NS

Beta2-MG41.95 ± 11.1328.47 ± 6.45

Kt/V

URR

WHO-QOL

ConclusionAlthough HFR treatment is useful in the removal ofserum β2-microglobulin, relatively short term usefor 3 months could not change QOL inhemodialysis patients.High contentment of patients during treatment <strong>with</strong>HFRFurther long-term study <strong>with</strong> larger sample isneeded

Natural kidney ≒ ≒ ≒ HFRGlomeruliTubule

ConclusionHFR A unique and effective therapy <strong>with</strong> the advantages ofConvection to better remove higher molecular weight toxinsReinfusion of vitamins, hormones and other physiologic compoundsAnd no need for exogenous replacement solutionPlasmaWaterreinfusionReducedOxidativeStressAdequacy beyondKt/VNoBackfiltrationSparing ofNutritionalComponentsHFR has superiority over <strong>HDF</strong>

Still Questions;Data of clinical relevance on(?) :- Anemia- Malnutrition- Cardiovascular diseases- Mortality- Cost effectiveness- QOL일석사조( 一 石 四 鳥 )Four birds <strong>with</strong> one stone