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Assessment of adequacy of dialysis
The prescription of dialysis requires knowledge of the normal function of the kidney, of patient metabolism and physiology and of dialysis technology. Central to this process is the need to define and quantify both the dialysis procedure and the needs of the patient. Uncertainties about the reliability of the dialysis, the response of the patient to the procedure and pathophysiological changes within the patient require that objective measurements of dialysis adequacy are made regularly. These measurements are designed to quantify the effect of dialysis on the patient. This allows continuous adaptation of the treatment to changing patient needs and the rapid detection of treatment failure in each patient. The exercise also allows each dialysis unit to audit its performance, guiding systematic improvement in therapy. Since the functions of dialysis are diverse, measurement of dialysis adequacy is multi-dimensional. Monitoring includes clinical assessment and objective measurement, including weight, blood pressure, laboratory investigations and some measure of the amount of solute cleared during the dialysis process (Tattersal et.al., 1998).
Detection of under dialysis by clinical parameters depends on awareness and frequency of control; the risk that under dialysis is overlooked is substantial. Inadequate therapy can remain unrecognized when therapeutic decisions are exclusively based on clinical parameters. Nevertheless, the inverse is as true, and follow up of dialysis adequacy should never be restricted to static or dynamic biochemical parameters (Solute concentration, clearance, kinetic modeling) when estimating adequacy, clinical signs of under dialysis should never be ignored (Raja et.al., 1978).
Kjellstrand et al.(1978) have suggested that there is an increase of morbidity and mortality when dialysis is started late. The current trend to restrict protein in pre-end stage renal disease may reduce subjective complaints and postpone the start of dialysis, but will not necessarily improve overall outcome, especially as protein restriction per se may increase morbidity on dialysis (Degoulet et al., 1988).
Clinical signs that may reflect underdialysis:
(Vanholder and Ringoir, 1992)
Static biochemical tests:
Single "Static" evaluations are influenced by other factors than dialysis adequacy as well. The concentration of retention products is proportional to 1/clearance rate. If the retention product is toxic (e.g. K) then you need to be sure that the concentration of the product remains below the toxic range. When protein intake is deficient, pre-dialysis urea will remain low inspite of inadequate dialysis, this may incorrectly instigate a decrease in the dialysis quantity concentration as unstable indices (Shapiro et.al., 1983). In a study by Degoulet et.al.,(1982), low urea corresponded to a high mortality risk. In parallel, Oksa et.al.,(1987), demonstrated that survival was higher for a low urea/creatinine. Lowrie and Lew (1990), demonstrated that low serum albumin and low serum creatinine were associated with a high death risk. All these findings refute the general belief that bad outcome is only found at high pre-dialysis serum solute concentrations.
Serum levels of albumin, creatinine and body mass index were found to have significant survival predictive value, other variables such as total cholesterol, serum uric acid, total protein had no significant predictive value. Potassium, phosphate and calcium, may contribute to survival, high serum creatinine was associated with low risk of death, but was also associated with high dialysis dosage. While increased dialysis may lead to greater patient body mass and generation of creatinine, it is also possible that physicians consider serum creatinine value and provide dialysis at greater doses to better nourished patients. If albumin and creatinine values rather than diabetes mellitus were applied as predictors of mortality risk. It might be found that the extremely high mortality associated with diabetes mellitus is related as much to undernutrition as it is to diabetes mellitus per se (Iseki et.al., 1993).
One of the functions of the human kidney is to regenerate bicarbonate. Haemodialysis achieves this by including a supra-physiological concentration of bicarbonate in the dialysis fluid. During dialysis, bicarbonate diffuses into the blood across the dialyzer membrane. One of the aims of dialysis is to normalise the serum bicarbonate concentration. Optimal survival has been shown to relate to normal pre-dialysis serum bicarbonate concentration (Lowrie and Lew, 1990). This is achievable if the dialysis is correctly prescribed and planned. Bicarbonate has a similar molecular weight as urea so the relative mass of bicarbonate transferred into the blood will be proportional to the Kt/V (will be discussed in the dynamic biochemical tests) and the bicarbonate concentration gradient across the membrane. To some extent, a natural homeostasis occurs in that those patients who are acidotic will have lower bicarbonate and a higher concentration gradient. A dialysate bicarbonate concentration of 40 mM will keep the patients bicarbonate concentration at 22-26 mM in virtually all cases if the Kt/V is 1. If the Kt/V is increased, a proportional reduction in concentration gradient is required so that for a Kt/V of 1.5, the dialysate bicarbonate concentration should be reduced to 35 mM. Individual variations in the dialysate bicarbonate concentration may be required to cope with differing metabolic rates, diets and oral base intake (e.g. calcium carbonate). Most dialysis machines allow individualised control of the dialysis fluid bicarbonate concentration from the front control panel. Assessment of dialysis adequacy is not complete without measurement of the pre-dialysis plasma bicarbonate concentration. In the adequately dialysed patient, the bicarbonate concentration should be in the normal range (Tattersal et.al., 1995).
Static biochemical parameters used in the assessment of dialysis adequacy: (Vanholder and Ringoir, 1992)
Dynamic biochemical tests:
Kt/V is the mainstay of dialysis adequacy (Gotch, 1990). Originally the term was function of dialyzer clearance (K), dialysis time (t) and urea distribution volume (V). An approximate value from K can be read of a graph on the dialyzer data sheet or calculated from the dialyzer performance characteristics, blood and dialysate flow rates. (V) is equal to the body water volume and can be calculated approximately from patient measurements. Kt/V is precisely the exponential term describing the decline in BUN during dialysis for the case in which we assume no interdialytic weight gain. Kt/V may be interpreted as the fractional urea clearance (Levine and Bernard, 1990). This approach has the following advantages;
* The dose of dialysis predicted to be delivered by any dialysis prescription can be calculated from (K), (t) and (V). This is termed the prescribed Kt/V.
* The dialysis time needed to achieve a target dialysis dose can be calculated for a given patient size (from which V can be calculated) and a given combination of dialyzer type, blood and dialysate flow rate (from which K can be calculated).
* The dose of dialysis actually delivered to the patient can be calculated directly from measurements of blood urea made pre- and post-dialysis. This is termed the delivered Kt/V.
* The comparison of the prescribed Kt/V and delivered Kt/V quantifies any inefficiency in the process or any errors in K or V (which cannot easily be measured precisely). This information can be used for diagnosis and trouble-shooting and to fine-tune the dialysis prescription to ensure that adequacy targets are met.
The equation can be re-arranged to return Kt/V from only measurements of pre-and post-dialysis urea thus;
This is the delivered Kt/V. it is calculated directly from blood concentration measurements and no hard-to-measure values such as V or K are needed. This simple equation assumes that V remains constant and that no urea is generated during dialysis. To take account of these factors, the equation is expanded to take the form;
Where Vpre and Vpost are the urea distribution volumes pre- and post- dialysis and UG is the mass of urea generated during the dialysis. In effect Kt/V is the natural logarithm of the mass of urea in the patient at the start of dialysis divided by (the mass of urea in the patient at the end of dialysis minus any urea generated during the dialysis). The effect of the urea generation is small but important. If it is ignored, long dialyses will be significantly underestimated. In an extreme example, continuous dialysis will always result in a Kt/V=0 if urea generation (which is opposing the fall in urea concentration due to dialysis) is ignored. The effect of ultrafiltration is also small but important. The contribution of ultrafiltration dose depends on V but since its contribution is small, errors in V are relatively unimportant.
It is now known that other factors within the patient which limit the rate of transfer of solutes from peripheral parts of the body into the fistula are important. These factors include the rate of diffusion and blood flow between body compartments. These factors reduce the effective K and, therefore Kt/V and result in the post-dialysis rebound. To take account of these factors, Kt/V should, ideally, be calculated using a post-dialysis sample taken 30-60 minutes after dialysis when the urea concentrations have re-equilibrated. It is not usually practical to measure this post rebound concentration directly but it can be calculated with acceptable accuracy from the pre-and post- dialysis concentrations and the time between these samples. The effects of ultrafiltration and urea generation can be included by using the correct equation:
If rebound is ignored, Kt/V will be overestimated by up to 30%, especially in short dialyses. For this reason, recently, the term Kt/V has been expanded to include the rebound effects. The combination of the urea generation and rebound corrections ensure that treatments with the same Kt/V and the same frequency per week will remove the same mass of urea (relative to the pre-dialysis mass) regardless of the actual values of K, t and V.
Blood compartment clearance:
Clearance can be defined as the volume of blood that is purified per unit of time, which depends both on diffusion and convection. Higher clearance equals principally better adequacy (Vanholder and Ringoir, 1992).
Clearance is calculated based on blood flow (QB) determinations and concentration in blood samples collected from the inlet and outlet bloodlines. Several influencing factors should be considered. The error in blood flow determinations might be substantial. QB Can most readily be estimated by injecting an air bubble into a disposable additional track of known cross sectional area and length the measured transit time over a known length yields a reliable blood flow calculation (Flanigan et al., 1991).
A mass ratio between red blood and plasma of 0.85 has been reported for urea which acknowledges that respective plasma and erythrocyte water contents are 93% and 79% (Flanigan et al., 1991). The use of photoelectric cells may reduce observer error (Peoples et al., 1973).
An alternative is the Electro-magnetic flow probe, but this approach necessitates frequent calibration and sterilization. Ultrafiltration adds extra solute flux to diffusion, so that elimination is increased by a quantity that does not match ultrafiltration rate (QF) (Gupta and Jaffrin, 1984), its negative impact on diffusive clearance was first recognized in coil dialyzers (Husted et al., 1976) and appeared later to be present for all types of dialyzers and should always be considered for the calculation of QB based clearances. The additional clearance delivered by ultrafiltration equals ultrafiltration, multiplied by 100% minus percentage removal. The greater the diffusive removal, the less is the impact of ultrafiltration removal and vice versa. Recirculation occurs when dialyzed blood is recycled through the dialyzer inlet. It is considered to be a typical drawback of single needle (SN) dialysis. But is as well present in two needle dialysis, especially high efficiency dialysis (Collins et al., 1988 and Sherman et al., 1991) whereby blood flow and recirculation are related. Enhancing conditions are:
* High dialyzer blood flows.
* Vascular access in flows lower than dialyzer blood flow.
* Stenosis at the access outflow.
* Common or close inlet and outlet vascular pathways.
* Increased length of bloodlines.
* Increased compliance of dialyzer outflow.
* Incorrect position of the needle in arterio-venous fistula.
* Small stroke volumes (in single needle dialysis).
* Small needle and tubing diameter.
The non-homogenesity of blood may hinder removal by imposing a slower transport from blood cells to blood water than from blood water to dialysate. This necessitates erythrocyte equilibration with plasma (Skalsky et a1.,1978) and/or cell lysis (Bass et al., 1973), before determination of concentration to calculate blood clearance, or determination of plasma clearances after immediate processing before re-equilibration (Basile et al., 1986).In summary, blood cells side clearance are subjected to important flows, which necessitates correct blood flow and concentration measurements and correction for recirculation and ultrafiltration, protein binding and red blood cells / plasma disequilibrium (Skalsky et al., 1978). Most errors will result in an overestimation of clearance and create a false feeling of security. Even if determined cautiously, it is suggested to match blood side clearances to simultaneous dialysate clearances (Sargent and Gotch, 1989).
Clearance based on distribution volume based on first order kinetic principles, this calculation multiplies the ratio of single pool distribution volume (V) over dialysis time with the negative logarithm of the ratio concentration pre/post dialysis (Sargent et al., 1975 and Casino et al., 1990). The source of error with this approach is minimal and depends on only two factors, concentration and distribution volume. This approach used for the determination of urea clearance. Volume of urea may be estimated from its distribution over body water, which, however, occupies a variable fraction of body weight (Moore et al., 1952).
In addition, urea distribution volume doesn't always concur with body water. The current trend of considering Vurea (volume distribution of urea) as 58% of total body weight is thus a source of error. The use of morphometeric data may result in more reliable calculations although those data are currently based on non-uraemic subjects. Exact estimations of Vurea can only be obtained by injection of radioactive urea, or by the use of multiple pool model .In conclusion, clearance values based on pre and post dialysis concentrations and distribution volume, will give acceptable results, as far as the approximation of V is reliable. Whatever the method, the clearance approach estimates solute elimination in function of the dialyzer and the dialysis technique, but doesn't take into account patient (body size), solute (generation) and/or kinetic characteristics (protein binding, cell membrane transport) (Vanholder and Ringoir, l990).
The principal is the same as for genuine "urinary" renal clearance: collection of all dialysate and calculation of total solute waste. Calculations of mean pre and post dialysis values may result in an underestimation of clearance, as a linear decay of blood solute concentration is presumed. Further error sources are low dialysate concentrations and incorrect determinations of dialysate volume. Specific devices that collect small timed aliquots of dialysate may be less cumbersome than large graduated tanks (Garred et. al., 1989). Dialysate clearance, by its concept, is not subject to the vagaries of QB determination, ultrafiltration or recirculation (Gibson and Gotch, 1976).
The dialysate collection method has the advantage of avoiding the need for a rebound or urea generation correction, even a post-dialysis urea sample is not needed, however, unlike the blood concentration method, the dialysate method relies heavily on an accurate value for (V) (Argiles et.al., 1997).
In the dialysate collection method, the total mass of solute removed by dialysis including ultrafiltration is calculated from the total dialysate output volume (dv) multiplied by the average solute concentration in the dialysate (dc). In this way, the dialysis is quantified in exactly the same way as in the renal function.
Urea kinetic model:
The use of mathematical models to describe the physical processes involved in dialysis therapy is well known (Abrecht and Prodany, 1971).
During recent years urea kinetic modeling has been widely used in dialysis therapy as an analytic tool to improve clinical understanding of the uraemic syndrome and to prescribe and deliver reproducible and quantified doses of dialysis (Sargent,1983).
Several models have been developed in the past with two major goals: first, the understanding and quantitative analysis of the physiological processes of patients on hemodialysis (Abrecht and Prodany, 1971) second, the estimation of patient parameters in order to deliver adequate doses of dialysis by controlling the removal of toxic solutes (Sargent and Gotch, 1975) thus reducing possible complications since the rigorous description of uraemic state would require the knowledge of the kinetics of all toxic substances . Urea is usually assumed to be a marker solute for all toxins with low molecular weight (Gotch and Keen, 1991).
Single pool models:
Single pool models relate to small water-soluble compounds, with equal distribution. Distribution volume (V) and generation rate (G) are interactive and are calculated by titration from intra- and interdialytic shifts (Gotch, 1976). The single pool model assumes:
* Instantaneous mixing without shifts within the pool.
* Constant generations.
* Constant rate of interdialytic weight gain.
These assumptions are correct only by approximation. Pitfalls of the single pool urea kinetics was incomplete delivery if dialysis prescription (Sargent, 1990) induces, when not recognized, flaws in kinetic calculation. Errors in registration of dialysis time due to connection, disconnection, turning down of blood flow and interruptions, manufacturer clearances that overestimate true clearance, dialysis devices that overestimate true blood flow, and lack of correction for recirculation all will result in a misconception of dialysis dose, and hence of G and V (Aebischer et al., 1985),
Multiple pool models:
Many solutes and potential uraemic toxins distribute over several pools, substances with slow transport from intracellular to extracellular, protein binding, and/or a middle to high molecular weight such as peptides (Peeters et al., 1974) or guanidine (Giovannetti and Barsotti, 1974). The site of generation may affect concentration both in the cell and in the plasma, especially when the cell membrane restricts transport, When metabolite is generated in one small well perfused specialized organ (for example the liver for urea, generation can be considered to be extracellular. Use of more than two pools may add little accuracy (Popovitch et al., 1975).
Multiple pool models can predict changes in body compartments normally inaccessible to the clinician. Since toxicity will mainly affect intracellular systems, It may be clinically more relevant to focus on predicted intracellular or intratissular concentrations, rather than on plasma concentrations, according to the concept of biologically active distribution volume. Two pool models should thus not be discarded as overly complex, as they may disclose important new information. Even the intradialytic behavior of urea is better described by a multiple than by a one compartment model (Keshaviah et. al., 1985) whereby transcapillary exchange between intravascular and slow equilibrating interstitial fluid spaces may be the rate limiting step (Bowsher et. al., 1985).
Mathews and Downey, (1984) demonstrated that both pools are nearly equal in volume and much larger than the intravascular volume of a normal adult they postulated that the urea of the blood rapidly mixes with intracellular water of well-perfused organs, whereas it mixes more slowly with poorly perfused organs, and interstitial water. If an exact scientific approach of the intradialytic behavior of urea is to be pursued, a two-pool model may thus be more appropriate. A single pool model is more attractive for routine clinical conditions, because of its easy applicability. A phenomenon related to the two compartment behavior of urea is the postdialysis rebound that is especially observed with short high efficiency dialysis (Pedrini et al., 1988).
The urea rebound may not be caused exclusively by transtissular disequilibrium, but may be affected by an increase in protein catabolism (Farell, 1986) induced by loss of amino acids and glucose and/or a catabolic effect induced by blood contact with the dialysis membrane (Gutierrez et al., 1990). Lim and Flanigan,(1989) showed patients on a constant protein diet with decrease in protein catabolic rate when interdialytic intervals were increased from two to three days, which suggests a catabolic effect of dialysis. The occurrence of urea rebound, even with radiolabeled exogenous urea, however, suggests a multi-compartment behavior
The Solute removal index:
In order to correct for the intermittency and rebound effects in haemodialysis, a new method of quantifying small solute removal has been proposed. The solute removal index (SRI) is the ratio of mass of urea removed by dialysis to the mass present at the start of dialysis (Keshaviah and Star, 1994).
A dialysis strategy aimed at achieving the greatest SRI is required. In continuous treatments and in normal renal function, SRI is almost the same as Kt/V (it is reduced slightly by 2-pool effects). However, in intermittent treatments (such as hemodialysis), SRI may be much less than Kt/V, depending on the frequency and duration of dialysis (the degree of intermittency) and the total weekly Kt/V delivered. For a given weekly Kt/V, daily or very long thrice-weekly dialyses have greater SRI than the shorter treatments (Tattersal et.al., 1998).
The solute removal method (urea or other solutes) becomes the preferred and accurate method to quintitate dialysis as it abolishes all the errors of urea kinetic modeling, so it should be regarded as the gold standard of dialysis quantification, but its draw-back was the difficulty in collecting the whole spent dialysate (Shohate and Boner, 1997).
Using urea appearance as a measure of protein catabolism:
Assessing the nutritional status of patients with chronic renal failure can be extremely difficult (Schoenfeld et. al., 1983). Since urea is the predominant nitrogenous product of protein catabolism, a number of investigators have examined the question whether the easily measured urea appearance rate could be used as an index of protein catabolism, and hence dietary protein intake? (Maroni et. al., 1985). PCR (protein catabolic rate) diverges from protein intake estimated by delivery anamnesis (Panzetta et. al., 1990). The assumed cause is that outpatient food intake records are of limited value (Schoenfled et. al., 1983). Patients may overestimate a low food intake and vice versa, Imbalance may, however, also be due to the unsuspected presence of catabolism or anabolism. Controls in metabolic wards of the reliability of PCR as an index of protein intake are rant (Cogan et.al., 1981). Asymmetry in protein intake, dialysis efficiency and/or dialysis schedule may render kinetic results unreliable. Gross changes (infection, pericarditis, fluid overload) may require larger increases in dialysis quantity than those proposed by the National Cooperative Dialysis Study (NCDS) in mostly well equilibrated patients (Depner and Chear, 1989).
For a fixed relationship to exist between the urea appearance rate (G) and (PCR) there are two basic requirements. First, all urea degraded within the gut must be quantitatively reconverted back to urea; this guarantees that all of the urea appearance reflects protein catabolism. Second, non-urea nitrogen appearance defined as the sum of the accumulation of non-urea forms of nitrogen (e.g., creatinine, urate, etc) and of the total-body excretion of non-urea nitrogenous wastes (e.g. fecal nitrogen, non-urea urinary nitrogen, etc) must be fairly constant irrespective of a patient's diet or level of renal function. The following equation, describing the fixed relationship between the urea appearance rate and the protein catabolic rate, was derived by (Borah et. al., 1978).
G = 0.154 PCR
G represents the urea appearance rate in grams of urea nitrogen per day; the symbol (G) is used because it is the net generation of urea (G), as defined by (Sargent, 1983) and PCR represents the rate of protein catabolism (from both dietary and endogenous protein sources) in grams of protein per day. Although this equation was derived for dialyzed patients, it has wide applicability. The slope of 0.154 implies that for each 10 gram of protein that is catabolized, 1.54 gram of urea nitrogen will be generated. This is approximately 96% of the nitrogen content of the protein (assuming that on average the complete degradation of 6.25 g of protein will yield 1.0 gram of nitrogen), and is consistent with the observation that urea represents the predominant nitrogenous waste product of protein catabolism. When G equals zero, there is still a positive PCR of 11.04 g/day. This positive PCR, deposit a urea appearance rate of zero, represents an obligatory catabolism of protein leading to non-urea nitrogen. When PCR equals zero, we calculate a value for G of 1.7 g/d, implying a net consumption of urea, but G always has a positive value.
The final equation PCR= 9.35 * G + 0.294 * V
(V represents the kinetically determined volume of distribution of urea)
Using PCR to assess nitrogen balance:
The definition of balance can be given in terms of either tissue nitrogen or tissue protein stores. The relevant equations are: - (Sargent et al., 1978)
(Tissue N stores) = Dietary N. intake - Non-protein N. Appearance
= Dietary N. intake (urea N. Appearance + Non-urea N. Appearance)
= Dietary N intake (G + Non-urea N. Appearance)
(Tissue protein stores) = DPI (dietary protein intake)- PCR
(N. Represent nitrogen)
In a stable hemodialysis patients, a (tissue protein stores) will be zero, and the kinetically derived value of PCR may be used as an estimate of DPI. Since dietary histories and records are notoriously inaccurate, this calculated value of PCR may in fact prove a more reliable estimate of DPI (Wineman et al., 1977). Therefore, by permitting a reliable estimate of DPI to be obtained, urea kinetic modeling represents a powerful tool for ensuring adequate nutrition among dialyzed chronic renal failure patients.
The threshold of adequacy:
While it is now generally accepted that Kt/V relates to outcome, the optimal value for Kt/V is still under debate. Most of this debate followed on from Gotch and Sargent, (1985) analysis of the NCDS study suggesting that a threshold Kt/V value divided adequate from inadequate treatment. This threshold Kt/V was described as being in the region between 0.8 and 1. While it was considered necessary to ensure that a patient receives the adequate Kt/V, there was considered to be little extra benefit to be gained by increasing Kt/V further.
The concept of the threshold of adequacy is theoretically plausible for hemodialysis. At a Kt/V of 1.1, 65 % of the total urea in the patient has already been removed. There are rapidly diminishing returns from increasing Kt/V, and an infinite increase in Kt/V is required to remove the remaining 35%. However, the concept of this "threshold" has been challenged. Re-analyses of the NCDS (Hakim et. al., 1992) have suggested that there may be progressive improvement in outcome as Kt/V increases above 1. A number of dialysis units around the world routinely deliver Kt/V up to 1.6 by thrice weekly hemodialysis (Charra et. al., 1992). These units appear to have significantly better outcome, even when the effect of co-morbidity has been corrected. Retrospective analyses of quality-adjusted survival (Hornberger, 1993), have suggested that there may be a continuous improvement in outcome as Kt/V increases beyond 1. Limitations of the NCDS study have been recognized (Lindsay and Spanner, 1989). These included relatively small numbers of patients, a short follow-up period and a fairly atypical study population as patients with significant co-morbidity were excluded. The study was not designed to detect differences in long-term morbidity and mortality between patients receiving Kt/V of 1 and higher values. Pending the conclusion of further studies current opinion is moving towards acceptance of "adequate" Kt/V values as being much higher than 1 in hemodialysis.
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