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ASN DIALYSIS ADVISORY GROUP ASN DIALYSIS CURRICULUM Hemodiafiltration Martin K. Kuhlmann, MD Vivantes Klinikum im Friedrichshain Berlin, Germany Dialysis in ESRD: Problems with
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ASN DIALYSIS ADVISORY GROUP ASN DIALYSIS CURRICULUM Hemodiafiltration Martin K. Kuhlmann, MD Vivantes Klinikum im Friedrichshain Berlin, Germany Dialysis in ESRD: Problems with conventional diffusive hemodialysis -Excessive cardiovascular mortality -Insufficient removal of middle molecules -Insufficient removal of phosphate -High risk of intradialytic hypotension -Suboptimal dialysate quality -Internal back-filtration with potential translocation of bacterial DNA -Chronic inflammation and protein-energy wasting Rationale for increasing the elimination of higher molecular weight substances -Direct vascular toxicity has been documented for a number of uremic middle molecular size molecules (EuTox-group) -Higher circulating levels of middle molecules (such as vitamin B12 or b2-microglobulin) in dialysis patients are associated with cardiovascular and infectionrelated mortality in nonrandomized studies. (Liabeuf S et al. Kidney Int 2012; 82: 1297) -In the HEMO study secondary analysis revealed a favorable effect of high-flux HD on the risk of death and/or hospitalization due to cardiac causes. (Eknoyan et al. New Eng J Med 2002; 347: 2010) Rationale 2: The effects of flux on clinical outcome MPO-Study: High-flux vs. Low-flux MPO-study: Overall no clinical benefit of high-flux HD was observed in this RCT. However, diabetic patients and patients with base line serum albumin levels 4 g/l benefitted significantly from high-flux HD Locatelli F et al: JASN 20:645, 2009 Removal of middle molecules is increased by convective strategies High-Flux Dialysis HDF Convective dialysis therapies Convective dialysis therapies clear water across the dialysis membrane using positive transmembrane pressure. Most middle molecules and phosphate are dragged with water into the dialysate waste. Convective modes of dialysis: High-flux HD Hemofiltration [HF] Hemodiafiltration [HDF]* Acetate-free biofiltration * Note: HDF is not currently approved by the FDA in the US Basics of online-hemodiafiltration -In HDF, diffusive and convective dialysis modalities are combined. Diffusion occurs along the transmembrane concentration gradient between plasma and dialysate, while convective transport is obtained by filtering, through a highflux dialyzer, amounts of plasma water considerably in excess of those required to manage interdialytic weight gain. -Fluid balance is maintained by simultaneously infusing online generated sterile substitution fluid directly into the patient s bloodstream. -Fluid can be substituted before (pre-dilution), within (middilution), or after the dialyzer (post-dilution). -Clearance of middle- and large molecular-weight substances is substantially greater during HDF than during high-flux HD. HDF: Middle molecule clearance is related to ultrafiltration (UF) rate clearance (ml/min) diffusion convection urea vitamin B 12 inulin clearance (ml/min) clearance (ml/min) % 10% % % UF rate UF rate (ml/min) (ml/min) Calculated values UF rate (ml/min) Adapted from Ledebo I, Blankestijn PJ; NDT Plus 2010; 3:8 On-line HDF allows significant higher UF rates than high-flux HD and classical HDF High-flux HD with ml/min ultrafiltration rate Classical HDF with 50 ml/min ultrafiltration rate On-line HDF with 90 ml/min ultrafiltration rate blood ultrapure blood ultrapure blood dialysis dialysis fluid fluid ultrapure dialysis fluid Filter ml/min 290 substitution fluid from bags 290 online generated, sterile substitution fluid Adapted from Ledebo I, Blankestijn; PJ NDT Plus 2010; 3:8 Basics of online-hdf: Dosing -Generally, Dialysis dose can be defined as the net product of solute clearance (K) and treatment time (t) -In HDF, solute clearance K is determined by total convective volume (CV, Liters) achieved during treatment - CV is governed by ultrafiltration rate (UFR, ml/min) and treatment time (t) - UFR = substitution rate + water removal required to achieve target weight - UFR is determined by blood flow rate (Qb, ml/min) and filtration fraction (FF, ml/min) - FF is the fraction of plasma water filtered during passage of blood through the dialyzer -Blood is thickening during filtration; to prevent filter clotting, FF should not exceed 30 % of Qb HDF dosing: clinical example Prescription: Target convective volume (CV): 24 L per treatment Treatment time (t): 240 min Blood flow rate (Qb): 400 ml/min Then: Ultrafiltration rate (UFR) = CV/t = 100 ml/min Filtration fraction = UFR/Qb = 100/400 = 25 % of Qb Online-HDF: Expectations based on small, non-randomized clinical studies Increased removal of middle molecules Higher removal of phosphate Better intradialytic hemodynamic stability Less inflammation due to sterile dialysate Lower infection rates Improved appetite Better quality of life Improved cardiovascular outcome Most relevant clinical studies and meta-analyses on mortality outcome Observational studies DOPPS (Canaud B et al. Kidney Int 2006; 69:2087 Randomized controlled studies Dutch Study (CONTRAST; Grooteman MPC et al. JASN 2012; 23: 1087) Turkish Study (Ok E et al. Nephrol Dial Transplant 2013; 28: 192) Spanish Study (ESHOL; Maduell F et al. JASN 2013; 24: 487) Meta-analyses Wang F et al. Am J Kidney Dis 2014; 63: 968 Susantitaphong et al. Nephrol Dial Transplant 2013; 28: 2859 DOPPS shows survival advantage for pts on highefficiency HDF (convective volume 15 L per Tx) CV 15 L/Tx Canaud B et al. KI 2006; 69:2087 RCTs: Dutch HDF study CONvective TRAnsport STudy (CONTRAST) Idea Investigator initiated, multicenter trial Design Prospective, randomised, controlled, event-driven Study sites 29 Dialysis centers (26 NL, 2 CA, 1 NOR) Duration 01/ /2010 Population 714 prevalent HD-Pts. 18 years on low-flux-hd Groups Online-HDF (358) vs. low-flux HD (356) Treatment post-dilution ol-hdf, target UFR 6 L/h = 24 L/Tx minimum-kt/v: 1.2; fixed treatment time ultra-pure dialysate for ol-hdf and HD 1 outcome All-cause mortality (target: 250 events in 3 years) 2 outcome Composite of fatal and non-fatal cv events Grooteman MPC et al. JASN 2012; 23:1087 CONTRAST study: Primary Outcome All-cause mortality Cardiovascular events Grooteman MPC et al. JASN 2012; 23:1087 CONTRAST subanalysis: Achieved convective volume 22 L associates with better outcome Grooteman MPC et al. JASN 2012; 23:1087 CONTRAST: Further results Online-HDF had no significant effects on indicators of cardiovascular mortality risk, such as left ventricular mass, ejection fraction and pulse wave velocity (Mostovaya IM et al. CJASN 2014; 9: 520) Compared to low-flux HD with ultrapure dialysis fluid, treatment with online-hdf did not result in a decrease in ESA resistance. (Van der Weert NC et al. PLoS ONE 2014; 9(4): e94434) Online-HDF with ultrapure dialysate seems to reduce inflammatory activity over time compared to low-flux HD, but does not affect the rate of change in albumin. (Den Hoedt CH et al. Kidney Int. 2014;) RCTs: Turkish online-hdf-study Study sites 10 Fresenius dialysis centers Duration 01/ /2010 Population 782 prevalent HD-Pts. 18 years on high-flux-hd Groups Online-HDF (391) vs. high-flux HD (391) Treatment post-dilution ol-hdf, target UFR 15 L/Tx minimum-kt/v: 1.2; treatment time 240 min ultra-pure dialysate for ol-hdf and HD 1 outcome All-cause mortality, first non-fatal cardiovascular event 2 outcome Cardiovascular mortality, hospitalization rate, intradialytic complications Ok E. et al. NDT 2013; 28: Turkish online-hdf-study: Results The composite of all-cause mortality and nonfatal cardiovascular event rate was not different in the ol- HDF and in the high-flux HD groups. In a post-hoc analysis, ol-hdf treatment with substitution volumes 17.4 L per treatment was associated with better cardiovascular and overall survival. Comment: The Turkish ol-hdf study, like the CONTRAST study, reports a dose-effect relation between achieved convective volume and mortality risk. Ok E. et al. NDT 2013; 28: RCTs: The Spanish HDF study Maduell F. et al. JASN 2013; 24: ESHOL study: Primary Outcome High-volume ol-hdf superior to high-flux HD Maduell F. et al. JASN 2013; 24: ESHOL: Summary of 1 and 2 outcomes 30% reduction of overall mortality 33% reduction of cardiovascular mortality 61% reduction of stroke mortality 55% reduction of infection associated mortality 28% reduction of intradialytic hypotension 22% reduction of hospitalisation Maduell F. et al. JASN 2013; 24: ESHOL: Dose-effect relation Maduell F. et al. JASN 2013; 24: ESHOL: Summary and interpretation -This is the first study to show that high-efficiency postdilution ol-hdf reduces all-cause mortality compared with conventional HD -Target CV was 18 L/Tx; mean achieved CV was higher than in the other two studies; however, acc. to protocol, patients not reaching the target CV for 2 consecutive months were withdrawn from the study and also from study analysis. (Comment: this causes a selection bias and is a major criticism of the study) -The study also demonstrates a significant dose-effect relation, similar to the Dutch and the Turkish HDFstudies Meta-analysis: Convective vs. diffusive dialysis modalities Convective therapy Hemofiltration (n=274) High-flux HD (n=3,204) Hemodiafiltration (n=1,288) Duration of follow-up 7-12 months (n=377) 12 months (n=4,389) Study Quality Fair (n=452) Good (n=4,314) Susantitaphong et al. NDT 2013; 28: 2859 Meta-analysis: HDF vs. HD All-cause and cardiovascular mortality Cardiovascular outcomes HDF All-cause mortality HDF HF HDF or HF Schiffl (2007) OK (2011) Grotteman (2012) Maduell (2013) Overall (I 2 =41.7%, p=0.16) Locatelli (1996) Wizemann (2001) Schiffl (2007) OK (2011) Grotteman (2012) Maduell (2013) Subtotal (I 2 =58.6%, p=0.03) Beerenhout (2005) Santoro (2008) Alvestrand (2011) Subtotal (I 2 =0.0%, p=0.54) Locatelli (2010) Subtotal (I 2 =.., p=.) Overall (I 2 =38.3%, p=0.10) Wang AY et al. AJKD 2014; 63: Meta-analysis: HDF vs. HD Symptomatic intradialytic hypotension Symptomatic Hypotension HDF Lin (2001) Schiffl (2007) Maduell (2013) HF Subtotal (I 2 =86.1%, p=0.001) Santoro (2008) Subtotal HDF or HF Locatelli (2010) Subtotal Overall (I 2 =76.7%, p=0.002) Wang AY et al. AJKD 2014; 63: Online-HDF: Safety of online generated sterile replacement fluid None of the three RCTs were specifically designed to examine safety issues None of the three RCTs provided any indication that HDF is an unsafe treatment modality CONTRAST data indicate that substitution fluid of adequate quality can be produced online over a prolonged period of time In ESHOL, mortality risk from infectious causes was significantly lower among ol-hdf pts. vs. HD pts. Inflammation markers did not differ between ol-hdf and HD in any of the three trials online-hdf: Conclusion -ol-hdf may increase removal of middle molecules and phosphate; however, no clincial trial has shown an effect of HDF on blood levels of commonly measured middle molecules -Both, CONTRAST and the Turkish HDF study did not show survival benefits for HDF vs. conventional HD. In post-hoc analysis survival benefits for pts treated with high volume ol-hdf (CV L/Tx) were observed in both trials -ESHOL demonstrates better outcomes for high-volume ol-hdf (CV 22 L/Tx) vs. high-flux HD including a dose-effect relation -Two meta-analyses were unable to show significant survival benefits for ol- HDF vs. conventional HD; Further studies will be required to test the hypothesis that high-volume HDF is superior to high-flux HD -An individual patient data meta-analysis of all ol-hdf RCTs is currently being conducted to examine the effects of body size-adjusted HDF-dosing on outcome. -ol-hdf is safe with no increased risk for infection and associates with increased hemodynamic stability; ol-hdf may be slightly more costly than HD (+ 3%) -Current recommendations for HDF-dosing include an achieved CV 22 L/Tx
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