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Thursday, 13. February 2003 12:20 PM GMT
Factors influencing rate of solute removal by dialysis
In order to be removed by dialysis any solute must pass from its site of generation to the fistula and across the dialysis membrane before it is removed. There are a numbers of factors which can influence the rate of removal, some can be modified and some can not.
Factors influencing rate of solute removal by dialysis:
(Vanholder and Ringoir, 1992)
Solute related factors:
Resistance of cell membrane
Patient related factors:
Distribution volume and body weight
Intake and generation rate
Residual renal function
Absorption from the intestine
Dialysis related factors:
Mean blood flow
Blood flow pattern
Dialyzer surface area
Dialyzer membrane resistance
Dialyzer pore size
On the dialyzer membrane
On other constituents of the dialyzer circuit
Intra-dialytic changes in efficacy
Free fatty acid concentration.
Solute related factors:
The relevant solute concentration with regard to dialyzer transport is the free concentration in plasma water. Protein binding reduces efficiency of removal (Farrell et al., 1972). Intra-dialysis protein binding changes with blood pH and with protein and solute concentration depends on ultrafiltration, dialysate buffer and competition at the binding sites with other legends (Uraemic toxins, metabolites and drugs). At (100 % binding dialytic elimination is reduced to zero (Niwat et al., 1988 and 1990).
Patient related factors:
Solute accumulation is proportional to generation, after metabolization of exogenous precursors. Removal by residual renal function becomes more critical with a low and or inadequate intradialytic removal (Milutinovic et al., 1974). Access quality may play a role as an important factor. A rise in hematocrit may decrease mass transfer (Nolph et al., 1974) due to blood viscosity (Henderson, 1976). Erythropoietin may thus have a negative influence on dialysis adequacy by its effect on hematocrit (Van Geelen et al., 1991). Objective assessment such as by kinetic analysis becomes important as clinical signs of uremia, such as fatigue, are masked (Canaud et al., 1990).
During haemodialysis, some of the blood entering the dialyzer inlet has flowed from the dialyzer outlet without passing through the peripheral capillaries. This flow of dialysed blood from dialyzer outlet to inlet is termed recirculation and is quantified as the flow rate of recirculated blood entering the dialyzer, expressed as a fraction of the extracorporeal blood flow rate. There are two types of recirculation, cardio-pulmonary and access (Sherman and levy, 1991).
Access recirculation occurs when a proportion of the blood returning to the patient in the venous line is immediately drawn into the arterial needle and dialysed again without leaving the fistula. Access recirculation occurs only when the arterial needle is placed downstream of the venous needle or when the extracorporeal blood flow rate exceeds the blood flow rate in the fistula. In the case of the incorrectly placed needles, the recirculated fraction will be the ratio of the extracorporeal blood flow rate to the fistula flow rate access (Sherman and levy, 1991).
Cardio-pulmonary recirculation is inevitable when haemodialysis is performed using a fistula as access .In cardio-pulmonary recirculation, blood recirculates from venous needle, fistula, venous circulation, right heart, lungs, left heart, aorta, and fistula and into the arterial needle. The recirculated fraction will be the ratio of the extracorporeal blood flow rate to the cardiac output. Cardio-pulmonary recirculation also causes a post-dialysis rebound which takes about one minute as the recirculated blood clears the pulmonary circulation (Schnedtiz et. al., 1992).
The effect of recirculation on dialysis efficiency
The rate at which solute mass is removed from the patient by the dialyzer (in mmol/min) is the dialyzer clearance rate (in L/min) multiplied by the concentration of solute at the dialyzer inlet (in mmol/l). Recirculation effectively reduces the solute concentration in the blood entering the dialyzer by diluting it with cleared blood. Dialyzer clearance is calculated from the ratio of concentrations entering and leaving the dialyzer and are unaffected by their absolute values. Therefore, recirculation does not affect the dialyzer clearance rate. However, by reducing the concentration in the dialyzer inlet, recirculation reduces the mass of solute removed (Tattersal et.al., 1998).
Measurement of recirculation:
a) The three-sample method
Until recently, this method was considered to be the "gold standard" for measuring fistula recirculation. This is calculated from the urea concentration in samples taken simultaneously from the dialyzer inlet and outlet and from a peripheral vein. This method assumes that the peripheral sample is representative of arterial blood. Any difference between urea concentrations at the dialyzer inlet and the peripheral vein is assumed to be due to recirculation from the dialyzer outlet directly into the arterial needle, i.e. access recirculation (Gibson et.al., 1990).
Recirculations measured by the three-sample method detects a combination of cardio-pulmonary and access recirculation and also the disequilibrium between body vascular compartments. Most studies have shown recirculation fractions around 12% using the three-sample method (Tattersal et. al., 1993).
b) The slow-flow method
This is a modification of the three-sample method. The peripheral sample is replaced by a sample from the dialyzer inlet taken after the blood pump has been slowed to 50 ml/min for 30 seconds. Under these conditions, the sample should reflect the arterial urea concentration and the method should detect only fistula recirculation. However, the timing of the slow-flow sample is critical. If the sample is taken too soon, there will have been insufficient time for dialysed blood to clear the fistula and for arterial blood to have been drawn up to the sample port. In this case the slow-flow sample will be identical to the dialyzer inlet sample and the recirculation fraction will have been wrongly assumed to be zero. If, on the other hand, the slow-flow sample is taken too late, the solute concentrations in the fistula will have started to rebound upwards as dialysed blood clears the central circulation and solute re-equilibrates within the patient. In practice, this method returns recirculation rates in the region of 5-15% due to this rebound artefact even when there is no fistula recirculation (Sharman and Levy, 1991).
c) Saline-dilution methods
A bolus of saline is injected into the venous line during dialysis and is detected in the arterial line a short time later. By comparing the volume of the bolus detected in the arterial line with its original volume as it enters the fistula, the recirculated fraction may be calculated. If there is access recirculation, the bolus will be detected in the arterial line within seconds of its entering the fistula. Cardio-pulmonary recirculation will result in the bolus being detected approximately one minute after its entering the fistula, after passage around the pulmonary circulation. Hence, this method can distinguish between fistula and cardio-pulmonary recirculation and calculate their fractions separately (Aldridge et. al., 1985).
d) The blood temperature module (BTM)
This method uses the same principle as the saline-dilution method, but a thermal bolus replaces the saline. A bolus of cold blood at about 35oC is produced by reducing the temperature of the dialysate for about two minutes. This cool blood bolus is detected and quantified by a temperature sensor on the venous line. Recirculation of the bolus into the arterial line is detected by another sensor. However, the method is much less invasive than others since no injections or samples are required. The method is also the simplest in practice as the module is part of the dialysis machine and under automatic control (Kramer and Polaschegg, 1993).
e) The occlusion method
The fistula is occluded between the arterial and venous needles by finger pressure. In the presence of access recirculation, the pressure in the arterial line falls rapidly and the machine alarms. Cardio-pulmonary recirculation is not detected but the method is simple. If the needles are very close together or the fistula is a deep prosthetic graft, occlusion by finger pressure may be difficult (Tattersal et.al.,1998).
Recirculation enhancing conditions:
Recirculation enhancing conditions are: (1) high dialyzer blood flow, (2) vascular access inflows lower than dialyzer blood flow, (3) stenosis at the access outflow, (4) common or close in- and outlet vascular pathways, (5) increased length of blood lines, (6) increased compliance of dialyzer outflow, (7) incorrect position of the needle in the AV-fistula, (8) small stroke volumes (in single needle dialysis), (9) small needle and tubing diameter (Vanholder an Ringoir, 1992).
Interpreting the recirculated fraction:
Since access recirculation is critically dependent on the extracorporeal blood flow rate, recirculation should always be measured at the highest extracorporeal blood flow rate likely to be used during dialysis. Methods, which detect a combination of cardio-pulmonary and access recirculation (BTM, slow-flow method) will generally return a value of up to 15% due to cardio-pulmonary recirculation. If the recirculation fraction is much greater than 15% then access recirculation is likely (Tattersal et.al., 1998).
Inter-compartment solute transfer:
The major component of the post-dialysis rebound is due to solute transfer between compartments .The body can be considered to be made up of multiple aqueous compartments, which contain solute. These compartments include the cells, gut, and regions of the body with relatively low blood flow, the main blood circulation and the fistula. The dialyzer clears only the fistula directly. Solute in all other compartments will transfer into the fistula at finite and variable rates (Pendrini et. al., 1988).
The mechanism of solute transfer between compartments may be diffusion, for example across cell membranes, or it may be flow, for example from poorly perfused areas into the main circulation. The solute concentration in the fistula depends, not only on the dialyzer clearance but also on the rate at which solute is transferred into the fistula from other compartments. The slower the intercompartment transfer relative to the dialyzer clearance the lower the solute concentration in the fistula. Differential inter-compartment solute transfer rates have the same effect on dialysis efficiency, as does recirculation. Solute concentration in the fistula and the dialyzer inlet is reduced, thus reducing the rate of solute removal without affecting dialyzer clearance. After dialysis the solute concentration in the arterial system rebounds upwards as the patient re-equilibrates. Rebound takes about 30 minutes to complete (Pendrini et. al., 1988).
Predicting the rebound:
A method using the standard predialysis and immediate postdialysis urea concentrations pre, post and an additional third concentration [Ci ] sample at time [ ti ], about 30 min after the end of dialysis, has been found to predict the post-rebound concentration . This method uses the following equation, which is derived from the formulas describing the following two-pool urea kinetics (Syme et.al., 1994):
A related approach, using only predialysis and immediate postdialysis samples and the patient clearance time may be a more practical but sufficiently precise alternative:
Dialysis related factors:
The most important resource of dialysis efficiency is the delivery of solute by blood flow. The relation between blood flow and clearance reaches a plateau once clearance becomes surface dependent (Gotch, 1986). This occurs sooner with higher molecular weight. Effective blood flows are often lower than pursued due to operator error, non occlusive pumps, malposition of the vascular access needle, access failure, tubing diameter changes, temperature and shear effects (Schimdt et al., 1991).
Mass transfer is dialysate flow and concentration gradient dependent. The curve flattens for higher flows. Dialysate recirculation will reduce the concentration gradient and hence removal dialyzer surface and volume influence solute elimination, especially at higher blood flows. Volume may change due to events not directly related to the dialyzer structure per se, such as clotting and protein clogging. Clotting and clogging at the hydrophobic surfaces and pores may also decrease filtration and sieving coefficients (Aoeckel et al., 1986).
Membrane resistance, electrostatic charge, thickness, pore size and/or protein accumulation on the membrane, differences in hydrophilic distribution (mosaicism) may alter transport patterns. Fluid layers in the direct proximity of the membrane create extra resistance. Lower blood and dialystae flows will decrease fluid mixing which increases film resistance for the small molecules (Rabb and Popovich, 1971). The sieving effect of membranes follows an S-shaped curve around the cut-off, depending on pore size of the membrane. Dialyzer geometry influences adequacy, overall resistance to transfer is higher and more variable in parallel plate than in capillary dialyzers (Hone et al., 1977) due to membrane stretching, increasing blood-film thickness and resistance, especially at high transmembrane pressure. A significant alteration of concentration of several solutes by adsorption has been demonstrated (Goldman et al., 1990) which may offset by reuse (Vanholder and Ringoir, 1990 and Petersen et al., 1991).
Solute elimination increases with dialysis time, as long as solute remains available in the vascular compartment. A high cellular transmembrane resistance inhibits removal except when frequently short dialyses are performed. The interdialytic time interval thus influences solute concentration "unphysiology" of intermittent dialysis (Kjellstrand et al., 1978). Buffer composition of dialysate and substitution fluid may influence acid-base balance, clinical tolerance and amount of dialysis (Feriani et al., 1990).
Backfiltration / backdiffusion is the process where dialysate enters the blood stream through interference of osmotic and concentration gradients, which depends on path length and pressure drop along the dialyzer. Dialysate contents, such as endotoxin, pesticides or insecticides, may enter the blood stream this way (Lonnemann et al., 1988) except when they are adsorbed at the dialysate side of the membrane. Ultrafiltration depends on transmembrane pressure (Blood side minus dialysate and colloid osmotic pressure), membrane permeability and blood dilution (Nolph et al., 1978) and is over a wide range correlated to blood flow (Ronco et al., 1990). It increases influence of the larger solutes (Vanholder et al., 1989) but diminishes diffusive clearance and indirectly diminishes adequacy by its association to hypotensive dialysis interruption (Daugirdas, 1991). It is a cause of increase of blood solute concentration when transmembrane transfer is zero, as is the case for beta2-microglobulin with small pore dialyzers. Correction far this ultrafiltration effect may disclose that there is no net change in body pool (Bergstrom and Wehle, 1987).
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