Hemodiafiltration and Hemofiltration By Dr Tamaddondar Hormozgan university of medical science

V of solution used is 5fold higher than replacement in hemofiltration Diffusion V of solution used is 5fold higher than replacement in hemofiltration Convection +/-Diffusion HDF 8 – 15 L HF 20-40L replacement solution

A. Review of diffusion versus convection-based clearances B. Hemodiafiltration versus hemofiltration C. Clearance due to diffusion (dialysis) versus filtration in HDF D. Predilution versus postdilution mode E. Technical issues F.Risk and benefits Intermittent HDF versus slow continuous HDF (C-HDF)

PORE SIZE

PORE SIZE

HIGH-PERFORMANCE EXTRACORPOREAL THERAPIES FOR END-STAGE RENAL DISEASE 1-High-efficiency hemodialysis 2-High-flux hemodialysis 3-Hemofiltration(intermittent) 4-Hemodiafiltration( intermittent) Online Hemodiafiltration

Hemodiafiltration permits β2-microglobulin removal and high Kt/V, and is probably the best way to treat chronic renal failure (CRF). Why bother with hemodiafiltration? Simply because clearance is a function of the total volume of “cleansingâ€‌ solution used, which includes both dialysis solution and replacement solution. With hemodialysis, although removal of solutes is less efficient, the volume of solution used is fivefold higher than the amount of replacement solution used with hemofiltration. As a result, with hemodiafiltration, adding the dialysis component markedly increases the amount of small molecule removal. The increased solute removal with hemodiafiltration versus hemofiltration occurs only because a larger total volume of a-cleansing-‌ solution is used. On a liter for liter basis, hemofiltration is the most efficient way to remove solutes from the blood.

Clearance due to diffusion (dialysis) versus filtration in HDF Ktotal = KDiffusive + F/2 (if UF<100ml/min) (Gupta and Jaffrin, 1984), where Ktotal = total clearance, KDiffusive = diffusive clearance, and F = ultrafiltration rate. This equation tells us that adding 50 mL per minute of postdilution replacement fluid to dialysis will increase overall clearance by 25 mL per minute. The equation remains valid for values of F (ultrafiltration rate) up to 100 mL per minute with various molecular size substances.

Predilution versus postdilution mode The administration may take place either before (predilution) or after (postdilution) the hemofilter. Infusing replacement solution in predilution mode in HDF reduces significantly the effect on clearance due to a dilution of the blood entering the dialyzer. This loss of clearance affects both small and large molecular weight substances. Accordingly, it is necessary to increase substantially the ultrafiltration/infusion rate when using predilution mode

Technical issues Water Fluid paths(HF/HDF) Online preparation of replacement solution and dialysis solution Vascular access Membrane

Water ultrapure water (virtually sterile and nonpyrogenic water) Current AAMI recommendations <200(CFU)/mL of bacteria <2.0 endotoxin units (EU)/mL of endotoxin ultrapure dialysis solution<0.1 CFU/mL and <0.03 EU/mL endotoxin The ultrafilters are replaced periodically to prevent supersaturation and release of endotoxins. Basic technical options required to produce ultrapure water consists of a pretreatment system (microfiltration, softeners, activated carbon, downstream microfiltration) and then followed by two reverse-osmosis modules in series. Ultrapurified water is then delivered to dialysis machines via a distribution loop (with or without microfiltration technique), ensuring a continuous recirculation of water.

Fluid paths(HF/HDF)

post-dilution hemofiltration

post-dilution hemodiafiltration

Online preparation of replacement solution and dialysis solution Bicarbonate-based dialysate solution is universally used as the starting point. The production of sterile and nonpyrogenic dialysis fluid (ultrapure dialysate) is achieved by “cold sterilization” of the freshly prepared dialysate using an ultrafilter. The treatment options available on the dialysis machine in dialysis mode, such as ultrafiltration and sodium profiling, ionic dialysance measurement, and blood volume monitoring, can also be used in the HDF configuration.

balancing chamber flow-metric equalizer Infusion module 0-250 mL/min Fig. 1. Gambro 3-filter hemodialysis system. Online HDF-related components and simplified flow scheme for Gambro AK 200 S Ultra. Components not required for online HDF are not shown. Redrawn from HCEN9291: AK 200 Ultra S Service Manual, with kind permission of Gambro Corporate R&D, Lund, Sweden. Incoming process water is fi ltered through an ultrafilter (type U8000S, surface area 2.1 m2, membrane material polyamide S). The water fi lter is operated in cross-fl ow mode, in which a small amount of fl uid is continuously drained off to prevent accumulation of possible contaminants on the inlet side of the fi lter. operated only during the cleaning and disinfection cycle of the machine U8000S polyamide S Gambro 3-filter hemodialysis system

Diasafe® plus, Polysulfone® Fig. 2. FME 2-filter hemodialysis system. Online HDF-related components and simplified flow scheme for FME Online plus systems. Redrawn from Fresenius Medical Care Online plus 7/07.03 (OP), Fresenius Medical Care, Bad Homburg, Germany FME 2-filter hemodialysis system

Vascular access Patients treated with HF/HDF require an access capable of delivering an extracorporeal blood flow of at least 350 mL per minute, and preferably higher.

Membrane Flux Measure of ultrafiltration capacity Low and high flux are based on the ultrafiltration coefficient (Kuf) Low flux: Kuf <10 mL/h/mm Hg High flux: Kuf >20 mL/h/mm Hg Permeability Measure of the clearance of the middle molecular weight molecule (eg, β2-microglobulin) General correlation between flux and permeability Low permeability: β 2-microglobulin clearance <10 mL/min High permeability: β 2-microglobulin clearance >20 mL/min Efficiency Measure of urea clearance Low and high efficiency are based on the urea KoA value Low efficiency: KoA <500 mL/min High efficiency: KoA >600 mL/min Ko—mass transfer coefficient; A—surface area.

Membrane The membrane should have a high hydraulic permeability (KUF ≥50 mL / hour / mm Hg), high solute permeability (K0A urea >600) and beta2-microglobulin clearance >60 mL/ min), and large surface of exchange (1.50-2.10 m2).

Typical prescriptions and substitution fluid infusion rates The conventional HDF/HF treatment schedule is based on three dialysis sessions per week of 4 hours (12 hours per week).

the substitution volume HF postdilution= Kt/v*55% body weight predilution= 2*Kt/v*55% body weight Kt/v=1 BW=60KG Pre=60cc/min Post=30cc/min As a simple rule to prescribe the substitution volume in HF, the target Kt/V per session has to be multiplied by the patient's water volume (55% of body weight) or urea distribution volume in postdilution HF mode and by double the water volume in predilution HF mode. Total ultrafiltrate volume represents the sum of infusate volume and weight loss. Kt/v=1 BW=60KG Pre=60cc/min Post=30cc/min

the substitution volume HDF QB=500ml/min QD=500-1000ml/min Typical replacement fluid infusion flow rates= 100 mL/min (24 L for a 4-hour session) in postdilution HDF and 200 mL/min(48 L for a 40-hour session) in predilution HDF mode simple rule of thumb Pre=1/3*QB Post=1/2*QB The blood pump speed should be able to achieve high flow rates up to 500 mL per minute. Dialysate fluid production conventionally set at 500 mL per minute may be increased up to 1,000 mL per minute in high flow–proportioning dialysis machines. Typical replacement fluid infusion flow rates are 100 mL per minute (24 L for a 4-hour session) in postdilution HDF and 200 mL per minute (48 L for a 40-hour session) in predilution HDF mode. for prescribing replacement fluid flow rate is to set this at one third of the inlet blood flow rate in postdilution HDF and at half of the inlet blood flow rate in predilution HDF. To prevent transmembrane pressure alarms, it is recommended to set the infusion rate according to the effective blood flow to reduce the filtration fraction

Anticoagulation 1-increased sheer forces( activate blood platelets) 2-significant loss or clearance of heparin The large loss of the initial bolus (>50% for unfractionated heparin (12,000-15,000 daltons) and >80% for low molecular weight heparin (3,000-6,000 daltons HF and HDF result in higher blood procoagulatory activity when compared to standard hemodialysis due to

Sample protocol using LMWH Lovenox 0.5 mg/kg body weight or 50 IU/kg body weight ,Allow to systemically circulate 3-4 minutes before starting treatment No additional LMWH required unless treatment exceeds 4 hours If >4 hours inject 400 IU at mid point of treatment via venous injection port

unfractionated heparin Initial bolus 80-100 IU/kg body weight Inject bolus systemically via venous needle allowing 3-5 minutes for circulation of heparin systemically Continuous infusion of heparin via pump at 25-35 IU/kg per hr

Potential risks and hazards 1-Related to dialysate/water contaminants Acute reactions- fever, hypotension, tachycardia, breathlessness, cyanosis, and general malaise Leukopenia Chronic reactions- asymptomatic,chronic microinflammation 2- Protein loss(albumin,β2-microglobulin) 3- Deficiency syndromes/Soluble vitamins, trace elements, small peptides, and proteins (vit c 500mg/weekly)

Potential clinical benefits 1-Overall survival/hospitalization benefit 2- Other potential benefits

Overall survival/hospitalization benefit Canaud B, et al. Mortality risk for patients receiving hemodiafiltration versus hemodialysis: European results from the DOPPS. Kidney Int 2006a;69:2087-2093. ( 35% lower mortality than those treated with low-flux hemodialysis) Locatelli F, et al. Comparison of mortality in ESRD patients on convective and diffusive extracorporeal treatments. The Registro Lombardo Dialisi E Trapianto. Kidney Int 1999;55(1):286-293 (10% reductions in mortality compared to low-flux dialysis) Canaud B, et al. Overview of clinical studies in hemodiafiltration: what do we need now? Hemodial Int 2006c;10(Suppl 1):S5-S12.

Potential clinical benefits Intradialytic symptoms. Residual renal function. Lower levels of serum inflammatory markers. Anemia correction? Malnutrition? Dyslipidemia and oxidative stress β2 microglobulin amyloidosis small protein-bound compounds Removal rates of a number of other substances that may function as uremic toxins has been documented using an HDF/HF strategy, including complement factor D (a proinflammatory mediator), leptin (16 kDa; effective removal of leptin may favor the improvement of patient nutritional status), various cytokines, erythropoiesis inhibitors such as 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), and circulating advanced glycosylation end products (AGEs) and AGE precursors, among others. H. Clearance of phosphate Phosphate removal is enhanced somewhat, but not markedly Acknowledging the predictive value of خ²2-microglobulin concentrations on morbidity and mortality in hemodialysis (HD) patients as recently shown (in the HEMO study), it appears crucial to target low circulating levels of this uremic toxin when considering dialysis adequacy (Cheung et al., 2006, Canaud et al., 2006a). , such as hippuric acid and indoxyl sulfate, superior removal by hemodiafiltration has been demonstrated compared to conventional HD

convection (hemofiltration) Diffusion(dialysis) convection (hemofiltration) all solutes below the membrane pore size are removed at approximately the same rate(increased capacity to clear middle- and large-size uremic toxins) Water driven (solvent drag) low volume of replacement solution depends on solute size (limited capacity to clear middle- and large-size uremic toxins) random molecular motion the volume of solution used is fivefold higher than the amount of replacement solution used with hemofiltration On a liter for liter basis, hemofiltration is the most efficient way to remove solutes from the blood.

Convective Clearances as a Function of Ultrafiltration in L/Week ,as a Function of Sieving Coefficient Table 2 shows calculated convective solute clearances for various artificial kidney treatment techniques using the simple approximation that clearance equals the product of ultrafiltrate rate and sieving coefficient

HDF HF Hemodiafiltration combines the characteristics of conventional HD with hemofiltration, which permits increased clearance for middle and small molecules. only 8 – 15 L of replacement solution is used, which is infused into the venous return of the extracorporeal circuit. the ultrafiltrate flow through highly permeable membranes is augmented by increasingTMP and hydraulic permeability with absence of dialysate flow The total volume of exchange for classic hemofiltration ranges from 20 – 40 L per treatment On a liter for liter basis, hemofiltration is the most efficient way to remove solutes from the blood.

Intermittent HDF versus slow continuous HDF (C-HDF) Those who have read through Chapter 13 will notice that this Gupta-Jaffrin clearance equation is different from what was described for C-HDF (continuous hemodiafiltration), where the additive effect of replacement solution to clearance is almost 1:1 in postdilution mode. The difference is this: In C-HDF, unless quite high dialysate flow rates are used, the solute concentration of blood in the dialyzer is reduced only slightly (since the ratio of QB:QD is quite high). Because of this, increasing ultrafiltration across the membrane markedly increases solute removal. In intermittent HDF, the relatively high-efficiency dialysis taking place (with a much higher ratio of dialysate to blood flow) lowers the solute concentration of the blood in the dialyzer substantially. Adding a filtration component is less efficient because the ultrafiltrate now contains a lower concentration of solute