Abstract
Currently accepted measures of dialysis dose for hemodialysis often are referred to as measures of dialysis adequacy. Dialysis can perform many functions to partially correct kidney failure, such as improve balance of fluid volume, correct metabolic acidosis and electrolyte abnormalities, and clear toxins or solutes that are retained in the setting of kidney failure. This chapter is limited to discussion of the removal of solutes that are retained in the setting of advanced kidney failure, known as uremic retention solutes, and how best to measure their removal with widely available techniques.
Keywords
adequacy, dialysis dose, equilibrated Kt/V, hemodialysis, Kt/V, middle molecule, single pool, standard Kt/V, urea reduction ratio, uremia, uremic retention solutes
Outline
Uremic Retention Solutes, 379
Mechanisms of Molecular Movement During Dialysis, 380
Using Urea to Quantify Dialysis Dose, 381
Collection of Blood Samples Before and After Hemodialysis, 381
Urea Reduction Ratio, 382
Single-Pool Kt/V, 382
Equilibrated Kt/V, 383
Standard Kt/V, 384
Urea Kinetic Modeling, 385
Normalized Protein Catabolic Ratio, 385
Limitations of Urea-Based Measures of Dialysis Adequacy, 386
Key Studies of Optimal Dialysis Dose, 387
Since the early days of dialysis, providers and patients have wrestled with the question of the proper amount needed to treat end-stage kidney failure. Currently accepted measures of dialysis dose for hemodialysis often are referred to as measures of dialysis adequacy . Dialysis can perform many functions to partially correct kidney failure such as improve balance of fluid volume, correct metabolic acidosis and electrolyte abnormalities, and clear toxins or solutes that are retained in the setting of kidney failure. This chapter is limited to discussion of the removal of solutes that are retained in the setting of advanced kidney failure, known as uremic retention solutes , and how best to measure their removal with widely available techniques. The practicing clinician and patients with kidney failure often understand that although dialysis treatments may be described as being adequate, in reality, they fall far short of adequate replacement of native kidney function.
Uremic Retention Solutes
When renal function declines, the excretory capacity of the kidney fails and the body accumulates substances that normally would be excreted in the urine. Numerous compounds of varying sizes and origins are retained with decline in kidney function. Some of the solutes that are retained in the course of kidney failure are known to be toxic. Historically, the first solute recognized to be retained in individuals with kidney failure was urea, hence the use of the term uremia to describe the clinical condition that patients with advanced kidney failure display. Urea, measureable as blood urea nitrogen (BUN), is generated predominantly by the liver as a product of the urea cycle. The generation of urea is a method by which ammonia can be detoxified. Ammonia generation is a result of protein metabolism and its accumulation can lead to encephalopathy if not properly handled by the liver. Although urea itself is not particularly toxic, except at high concentrations, it is believed that the majority of uremic retention solutes are generated during the course of normal protein metabolism or formed by modifications of amino acids in the gastrointestinal tract by microbial flora. Therefore, because urea also is formed as a result of protein metabolism and is easily measureable, it represents an acceptable surrogate marker for the uremic condition. However, it should be recognized that many of the solutes retained in kidney failure have size, shape, charge, and protein-binding characteristics that are very different from that of urea. Therefore it stands to reason that many uremic retention solutes would not behave in the same manner as urea.
Classically, uremic retention solutes have been categorized based on molecular weight ( Table 24.1 ). Size comparison has utility in evaluating expected clearance during dialysis. As is discussed in detail here, the removal of a solute from the body during dialysis depends on many modifiable factors such as membrane characteristics, dialysis technique, and those that are patient specific. Clearance also is affected by the unique characteristics of the solute itself and its resident environment such as molecular weight, solubility, shape, charge, protein binding, Gibbs–Donnan equilibrium, and volume of distribution. Many uremic retention solutes, particularly middle, large, and protein-bound molecules, do not behave in the same manner as urea during dialysis. Reliance on urea-based measures of dialysis dose therefore can lead to the misconception that dialysis is adequate for the removal of all toxins retained during the course of kidney failure when in reality the actual clearance may be quite different for larger or protein-bound solutes than what is measured for urea.
| Solute Type | Size (Da) | Examples | Most Effective Means of Removal |
|---|---|---|---|
| Small molecules | <500 | Urea, creatinine, sodium, potassium, uric acid, oxalate, asymmetrical dimethylarginine | Diffusive clearance (dialysis) Increase the speed of dialysis: faster blood flow (Qb) and/or dialysate flow (Qd) |
| Middle molecules Large molecules | 500–60,000 | 3-deoxyglucose, β 2 -microglobulin, advanced glycation end products, oxidation products, cytokines, Interleukins, cystatin C, atrial natriuretic peptide, tumor necrosis factor, κ and λ light chains, parathyroid hormone, FGF23, dinucleoside polyphosphates | Increase dialysis time Increase dialyzer surface area, pore size, pore density (high-flux dialyser) Convective clearance (hemofiltration) |
| Protein bound | Variable | Fructoselysine, hippuric acid, homocysteine, indoxyl sulfate, retinol-binding protein, p -cresol | Increase dialysis time Increase dialysate flow Sorbent technology Albumin dialysis |
| Gut derived | Variable | Phenylacetyl- l -glutamine, 5-hydroxyindole, indoxyl glucuronide, p -cresol, indoxyl sulfate, urea | Nutritional modifications Maintenance of gastrointestinal motility Potential in the future: oral sorbents, absorbents Antibiotics or probiotics |
Mechanisms of Molecular Movement During Dialysis
During contemporary extracorporeal techniques to replace the function of the kidneys, solutes are removed via three mechanisms: diffusion, convection, and absorption.
Diffusion ( Fig. 24.1 ) describes movement of solutes across a semipermeable membrane from an area of higher solute concentration to one of lower solute concentration. Diffusion of solute across the dialyzer and into the dialysate is the predominant method of solute clearance that occurs during standard hemodialysis. Diffusion is bidirectional and limited by the concentration of solute in a solution and membrane characteristics.
Convection ( Fig. 24.2 ) describes the movement of solute suspended in solvent down a pressure gradient from an area of higher pressure to one of lower pressure. This method of solute removal is also termed solute drag . During convection, a given amount of solute that is dissolved in a given volume of solvent is cleared after a pressure gradient forces the solvent through the pores of a semipermeable membrane. If the solute is smaller than the pore size of the membrane, it will be dragged along with the solvent into the effluent. Convective clearance is at play during routine ultra- or hemofiltration, the latter example usually representing a larger volume of clearance necessitating replacement fluid administration compared with the relatively minimal convective clearance seen with routine ultrafiltration for volume management.
Absorption refers to the binding of solutes in the blood to parts of the extracorporeal circuit. Given the large surface area and porous nature of most dialysis filters, there is some entrapment of solute that occurs within the membrane. This method of solute removal is comparatively small with contemporary dialysis devices. Historically, sorbent-based systems used for water-efficient dialysis and regeneration of dialysate were quite effective in removal of solute via absorption to sorbent and resin columns and there is some interest in reviving this technology currently.
Properties of the membrane can have an effect on the removal of solute during dialysis. During both diffusion and convection, movement of molecules depends on membrane pore size with molecules that are larger than the pore not passing the membrane. One way to describe the porosity of the membrane to an individual solute is by using the sieving coefficient. The sieving coefficient describes the membrane passage of a certain solute and is determined by dividing the solute concentration in the filter effluent by the solute concentration in the blood. Solute with a sieving coefficient of 1 easily passes the dialysis membrane, whereas a sieving coefficient of 0 indicates no movement across the membrane. Differing dialyzers can vary in their efficiency of removal of uremic retention solutes. When discussing dialyzers, the term efficiency refers to a dialyzer’s ability to facilitate removal of uremic retention solutes. High-efficiency dialyzers have membrane properties that allow them to be more effective at removal of solute compared with low-efficiency dialyzers. The expected clearance of a dialyzer can be determined by in vitro studies and is usually provided on the manufacturer’s dialyzer specification sheets in the form of calculated clearances of various solutes (urea, creatinine, phosphorus, vitamin B 12 ) at various blood flow rates (Qb 200, 300, 400, 500 mL/min) and a preset dialysate flow rate (usually 500 to 800 mL/min). Another method for comparison of the performance of different dialyzers is provided by the dialyzer mass transfer-area coefficient (KoA) urea. This is a theoretical clearance of urea provided at infinite blood and dialysate flows. In other words, the KoA urea provides an idea of the maximum ability of the dialyzer to clear small molecule urea when not limited by blood and dialysate flow rates. In this way, it is a reflection of clearance provided by membrane properties alone such as surface area and pore size. A higher value for KoA indicates a more efficient membrane. Manufacturers of hemodialyzers usually will provide KoA urea values as well. These clearance values can be useful for selecting a particular dialyzer from among other dialyzers by allowing the comparison of the expected clearances provided by different dialyzers with urea (MW 60 Da) representing small molecule clearance and vitamin B 12 (MW 1355 Da) representing middle molecule clearance. However, they are not reliable for calculating expected clearances for individual patients and are not widely used clinically. Methods to directly measure urea removal in the individual patient without comparing expected clearances have gained clinical acceptance and are described in detail here.
Using Urea to Quantify Dialysis Dose
Over the years, various mathematical constructs have been developed to help describe the drop of urea between the pre- and postdialysis periods as a form of a dialysis index to measure the adequacy of the delivered treatments. This section highlights the more commonly used urea-based measures of dialysis adequacy.
Collection of Blood Samples Before and After Hemodialysis
Accurate measurement of pre- and postdialysis BUN levels is important to ensure proper interpretation of dialysis adequacy. The predialysis urea sample should be drawn before the patient is placed on dialysis and without any influence of dilution from heparin or saline. This is easily accomplished immediately after placement of the dialysis needles if the patient has an arteriovenous access. If the patient has a central venous catheter, care should be taken to discard the lumen dwell content. The postdialysis sample should be drawn at the end of the dialysis procedure. In the postdialysis period, equilibration of urea occurs between various body compartments. The first and shortest period of equilibration is known as access recirculation . Access recirculation occurs over a matter of seconds when previously dialyzed blood, which has returned to the venous portion of the dialysis access, is taken up by the arterial needle and sent back through the extracorporeal circuit, decreasing the efficiency of the dialysis procedure. This phenomenon takes place in the dialysis access itself and is more predominant in the setting of a dysfunctional dialysis access and high blood flow through the dialysis circuit. Keeping the possibility of access recirculation in mind, methods have been developed to help ameliorate falsely low BUN levels due to access recirculation. One such method is the “slow-blood-flow” method. At the completion of dialysis, dialysate flow and ultrafiltration are turned off (or if unable to turn off ultrafiltration completely, the ultrafiltration rate can be reduced to 50 mL/h), and the blood pump is slowed to 100 mL/min for 15 to 30 seconds. The sample is subsequently obtained. Alternatively, the “stop-dialysate-flow” method can be used. With this method dialysate flow and ultrafiltration are turned off, 3 minutes are allowed to pass without any changes in the blood flow rate, and blood is subsequently sampled. The idea behind this method is that by stopping the dialysate for the 3-minute period, the dialysate compartment will equilibrate with the blood compartment yielding identical dialyzer blood inlet and outlet concentration. Both methods have been found to be equally effective in eliminating access recirculation. The stop-dialysate-flow method may yield slightly lower indices of dialysis adequacy if a significant amount of tissue equilibration of urea occurs in the 3-minute period when dialysate flow is stopped.
Urea Reduction Ratio
The amount of urea removed during a dialysis session can be described as a fractional reduction of urea:
URR = [ BUN ] pre − [ BUN ] post / [ BUN ] pre
Retrospective analyses have been able to demonstrate an inverse relationship between URR and the risk for death. However, this inverse relationship does not always hold up in patients with high URRs as there seems to be a paradoxical relationship between high URR (>75%) and higher risk for death. This has been demonstrated in a reverse J-shape curve between mortality and URR. The paradoxical relationship may be explained by nutritional factors and patient body size. Mortality in dialysis patients is strongly correlated with body weight, with larger patients demonstrating better survival. Patients with lower body weight more frequently have higher URR. There also seems to be differences in the relationship between URR and mortality among different demographic groups. These observations draw into question the utility of the URR as a measure of outcome in a population. However, similar to other indices of adequacy, the URR can be useful in trending the adequacy of treatments over time in an individual patient.
Single-Pool Kt/V
The single-pool Kt/V (spKtV) is a mathematical construct that has been proposed as a method by which clinicians can understand the adequacy of dialysis treatments. Although widely used clinically and ever present in clinical practice guidelines, it should be noted that higher Kt/V is not associated with better patient outcomes in clinical trials. To understand the concept of the spKt/V, one must understand the concept of clearance. Clearance is defined as the volume from which a substance has been completely removed and usually is expressed per unit time (e.g., mL/min). Clearance does not describe the amount of a substance, or mass removed; rather it describes a volume that has been cleared of a particular substance. Urea resides in the body water and is freely distributed among the body water both in the intracellular and extracellular space. It often is referred to as an ineffective osmole due to its relative ease of diffusion across cellular membranes and relatively rapid equilibration between the intracellular and extracellular space compared with other solutes such as sodium. During a typical hemodialysis treatment session, around 120 to 190 L of urea-free dialysate is brought into the dialyzer in contact with the blood, resulting in a net diffusion of urea from the plasma into the dialysate. This volume of dialysate is not routinely collected and is not available for measurement of volume or concentration. Therefore, unlike clearance calculations that may be performed to describe residual renal function, where volume of urine output is known and can be collected for measurement of concentration of urea, or clearance calculations that can be performed in peritoneal dialysis, where volume of peritoneal dialysate effluent is known and can be collected, in hemodialysis we rely on blood side measurements of solute and describe the drop in solute from pre- to postdialysis.
Urea concentration in the blood does not decline in a linear fashion during a dialysis treatment. To express the fractional reduction of urea with a dialysis treatment, a kinetic equation can be proposed that describes the exponential curve of urea disappearance during dialysis.
C = C 0 e − Kt / V
Kt / V = − ln ( C / C 0 )
The concept of spKt/V urea relies on the assumption that urea is evenly distributed in a single pool of body water that has equal access to the dialyzer. Although urea is an “ineffective osmole” and moves relatively rapidly among the various compartments in the body, due to the extremely efficient and nonphysiological nature of a modern dialysis treatment session where urea is removed from the plasma space at a rate that exceeds equilibration from outside the plasma space, this assumption does not hold true. In contrast to the assumption of the single-pool model, urea is actually distributed in varying concentration throughout the body during dialysis, evidenced by the rebound phenomenon of equilibration at the end of dialysis when urea moves from tissue areas of lower perfusion back into the vascular space. This is sometimes referred to as two-compartment distribution or the double-pool model where one compartment is considered the vascular space and the other is everything outside of the vascular space. The original logarithmic equations of spKt/V are further flawed in that they do not take into account any fluid removed during the dialysis procedure, which would have an effect on the volume of distribution and alter the concentration of the urea, which in turn affects the clearance. A small amount of urea also is removed via convection or solute drag during ultrafiltration. Furthermore, the simplified single-pool model does not account for urea generation, which would occur during the dialysis session. More advanced formulas have attempted to account for fluid removed with dialysis and estimate urea generation during dialysis. An example follows of a commonly used formula for spKt/V, often referred to as a second-generation equation or the Daugirdas II equation (not to be confused with the double-pool model, discussed under equilibrated Kt/V [eKt/V]):
spKt / V = − ln ( R − 0.008 ∗ t ) + ( 4 − 3.5 ∗ R ) ∗ UF / W
One disadvantage of using simplified single-pool equations for calculation of dialysis dose is that unlike formal urea kinetic modeling, it does not generate useful information about protein catabolic rate (PCR). Information regarding discrepancy between delivered and prescribed dose may not be appreciated in the way they would with urea kinetic modeling. The equation also is prone to error if used outside standard thrice-weekly 4-hour dialysis in regimens of short, long, or frequent dialysis. To accurately measure the spKt/V using the equation, the decrease in BUN during the dialysis treatment must be significant otherwise error is introduced due to mathematical variance. This inherent property makes the spKt/V models presented here inappropriate for frequent hemodialysis regimens such as daily or nocturnal dialysis. Furthermore, these equations would not be appropriate to calculate continuous clearances such as delivered with peritoneal dialysis where the urea concentration remains at a relative steady state. Fortunately, in such steady-state situations, simple and more direct clearance calculations can be undertaken because the volume of effluent dialysate is known and can be easily sampled. In addition, the calculation or estimation of V by Watson’s method or otherwise is likely to be fraught with error and particularly inaccurate at extremes of body size or in women. Finally, there is no adjustment for urea equilibration, or the rebound elevation of urea that occurs after dialysis if the postdialysis BUN level is drawn at the conclusion of the treatment session compared with waiting a period of 30 to 60 minutes for urea to equilibrate.
Equilibrated Kt/V
As already mentioned, one limitation of the spKt/V concept during contemporary dialysis is that urea removal from the plasma space occurs at a rate that exceeds the rate of equilibration from outside the plasma space. To address this problem, dialysis samples could be drawn 1 hour after dialysis to allow adequate time for urea to equilibrate equally between all body compartments. This approach is not practical for the typical dialysis provider nor is it acceptable to the dialysis patient who already has a large amount of time obligated to complete dialysis treatments. The eKt/V, occasionally referred to as the double-pool Kt/V , was developed to estimate and adjust the spKt/V for post-urea rebound in lieu of the more time-consuming alternative.
Postdialysis urea rebound is largely believed to have three phases: access recirculation, cardiopulmonary recirculation, and urea redistribution from less accessible body compartments. The phenomenon of disparate urea content in various body compartments is particularly evident with the use of an arteriovenous dialysis access. The first phase, access recirculation, usually resolves in a period of 10 to 15 seconds after the blood pump is stopped or slowed to 50 to 100 mL/min. Cardiopulmonary recirculation refers to the distribution of dialyzed blood to the heart and quickly back to the dialysis access through the cardiopulmonary circuit, bypassing slower areas of circulation that would allow for more even distribution of urea. The effect of cardiopulmonary recirculation lasts only for about a minute after dialysis. The third component, the slow movement of urea from areas of lower perfusion and cellular spaces and can take up to 30 to 60 minutes after the completion of dialysis.
Urea rebound is variable between patients. Dialysis-related factors such as blood flow, dialysate flow, volume of ultrafiltration, and patient-related factors such as age, heart function, muscle mass, and blood pressure can affect the amount of urea rebound. For example, muscle is thought to contain about 60% of the total body water, yet blood flow to the muscle during dialysis is relatively low contributing to a rebound in urea level after dialysis. In contrast, organs receive a large amount of cardiac output but relatively less body water. This situation is somewhat mitigated by the fact that urea concentration in organ compartments that receive higher amounts of systemic blood flow is likely to be higher than in muscle, which is less perfused during dialysis. Due to these gradients established during dialysis, in the postdialysis period when organ blood combines with muscle blood, one would expect a urea rebound. Furthermore, the rate of dialysis can affect the amount of urea rebound. The following equations were developed through studies of urea equilibration and linear regression analysis with time of dialysis and the value of the spKt/V used as inputs for an equation that converts the spKt/V to an adjusted, eKt/V.
eKt / V = spKtV − 0.6 ( spKtV / T ) + 0.03 ( arteriovenous access )
eKt / V = spKtv − 0.47 ( spKtv / T ) + 0.02 ( venous catheter access )
The key advantage of the eKt/V is the avoidance of the error with single-pool methods that overestimate dialysis dose due to urea rebound. This advantage is particularly evidenced when the treatment time is short and the dialysis technique efficient (short, fast dialysis). It should be recognized that the equation provides an approximation based on population data and the coefficients involved are not always accurate for every patient. For example, if blood flow to the muscle is lower in a particular patient then the coefficient of 0.6 is likely to be lower. Limitations of the single-pool model described here are still applicable to the eKt/V and should be kept in mind during interpretation of the results.
Standard Kt/V
The methods just described have utility in describing the kinetics of urea removal during an intermittent dialysis session and are predominantly designed for thrice-weekly intermittent dialysis. More frequent methods of dialysis require a different approach where the dose of dialysis is expressed independently of the frequency of dialysis as a continuous clearance. This concept relies on the steady-state assumption where if one was to maintain a steady plasma concentration then clearance of a solute is equal to the amount that is generated divided by the solute concentration. Thus clearance is inversely proportional to solute concentration and directly affected by the solute generation rate. Furthermore, under a steady-state assumption, urea generation and time-averaged urea concentration can be used to calculate a continuous clearance.
K = G /C urea
Standard K = G / C m
stdKt / V = G / C m ∗ 10080 / V
stdKt / V = 10,080 1 − e − eKt / V t 1 − e − eKt / V eKt / V + 10,080 Ft − 1
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