a proposed glossary for dialysis kinetics

EDITORIAL OPINION

A Proposed Glossary for Dialysis Kinetics Joel D. Kopple, MD, Michael R. Jones, PhD, Prakash R. Keshaviah, PhD,

Jonas Bergstrijm, MD, Robert M. Lindsay, MD, John Moran, MD, Karl D. Nolph, MD, and Brendan P. Teehan, MD

0 Quantification of the dialysis dose and assessment of nutritional status and response to nutritional therapy have become standard parts of the management of the chronic dialysis patient. Atthough advances in these areas have led to a more rational basis for therapy, certain misconceptions and points of confusion appear to have occurred. Recognizing the importance of a standard nomenclature to the development of concepts and the communication of research findings, we have attempted to compile a list of terms that are commonly used in the field of dialysis. New terms have been proposed for current ones that do not seem adequate. In addition, we have discussed potential methodologies for obtaining more accurate data for dialysis kinetics and for precise monitoring of nutritional intake and status. lt is hoped that this glossary will stimulate discussion that will lead to refinements in terminology and concepts that will, in turn, improve research and practice in nephrology. It is anticipated that many of these definitions and recommendations will be modiii or superseded as the management of patients with renal failure continues to advance. 0 1995 by the National Kidney Foundation, Inc.

INDEX WORDS Protein catabolic rate; anthropometry; urea kinetics; urea nitrogen appearance; Protein equivalent of nitrogen appearance; dialysis dose; nutrition; hemodialysis; peritoneal dialysis; renal failure.

T HE DEVELOPMENT of a kinetic and quantitative approach to the prescription of

dialysis therapy and the assessment of adequacy of dialysis treatment by Gotch, Sargent, and other researchers was a major advance toward placing maintenance dialysis treatment on a rational basis.‘-16 These innovative steps have resulted in a more systematic and rational approach to the management of patients with end-stage renal disease. However, there appears to be some confusion regarding the terms used for dialysis quantification and, hence, there is potential for both conceptual errors and misinterpretation of data. This is also true with regard to the calculation and normalization of estimates of dietary protein intake (DPI) and the characterization of body mass.

Due to these concerns, we have re-examined the terms used for the estimation of nitrogen output, DPI, and quantification of dialysis dose. The goal was to develop a glossary of terms that would be less confusing, more precise, and widely accepted by clinicians and investigators in this field. There appears to be consensus with regard to the definitions of some terms. However, there is considerable variance in the meaning and interpretation of other terms, particularly those concerning nutritional status. In the latter in- stances, we will discuss the issues surrounding the controversial terms and make recommendations for their standardization. Many of the defi-

nitions of nutritional status are standard or commonly used in the nutrition community. It is hoped that all the definitions in this glossary eventually will be validated by experimental studies.

Considerable discussion was devoted to the term “protein catabolic rate” (PCR) for estimating DPI from urea appearance. In addition, particular attention was given to the different methods for standardizing protein intake and small molecule clearance to body mass or fluid volume. For example, the terms “body weight,” “ideal body weight,” and “dry weight” are used in different ways by investigators. Some of these terms have traditional and precise definitions in the nutrition literature. To use these terms in a different way for dialysis patients introduces the likelihood for confusion and error. For those

From Harbor-UCLA Medical Center, Torrance, CA, and UCLA Schools of Medicine and Public Health; Renal Divi- sion, Research Group, Baxter Healthcare, McGaw Park, IL: Karolinska Institute, Huddinge. Sweden; Victoria Hospital, London, Ontario, Canada; University of Missouri, Columbia, MO: and Lankenau Hospital, Philadelphia, PA.

Received August 8, 1995; accepted in revised form August 11, 1995.

Address reprint requests to Joel D. Kopple, MD, Division of Nephrology and Hypertension, Harbor-UCLA Medical Center, 1000 W Carson St, Torrance, CA 90509.

0 1995 by the National Kidney Foundation, Inc. 0272-6386/95/2606-0014$3.00/O

American Journal of Kidney Diseases, Vol26, No 6 (December), 1995: pp 963-981 963

964 KOPPLE ET AL

terms, such as relative or desirable body weight (DBW) and lean body mass, which have a well- defined meaning, the traditional definitions have been retained to be consistent with the other medical disciplines. We also have proposed some new definitions that are especially appropriate for the dialysis community. We therefore attempted to bring together, in one list, definitions of these and other quantities that are both accurate and practical. Although several excellent reviews and books have been written on kinetic modeling, to our knowledge, there is not a concise list of terms that can be referred to by investigators in the field.

It is hoped that these revised definitions and the attendant discussion concerning the rationale for the proposed changes will lead to improved clarity of thinking regarding dialysis-related treatment and research. We believe that the development of techniques for the quantification of dialysis therapy and the measurement of the uremic and nutritional status of renal failure patients is an iterative process. These methods and definitions should continue to undergo revision as new information is developed and more effective techniques for quantification are devised.

ANTHROPOMETRIC PARAMETERS

Anthropometric parameters are used to assess nutritional status and standardize the dose of dialysis therapy. There is general agreement as to the meaning and use of the terms discussed below.

Actual Body Weight

An individual’s actual (ie, current) body weight (aBW) is usually expressed in kilograms. No adjustment is made in the aBW for an abnormal proportion of total body water (TBW) or fat. For patients undergoing peritoneal dialysis, body weight should be measured with the abdomen drained of fluid. Patients should be weighed according to a standardized protocol that indicates the type and amount of clothing that individuals may wear during weighing.

Dry Body Weight or Edema-Free Body Weight

The body weight of an individual who has no edema fluid and no abnormally high or low fraction of body water is usually expressed in kilograms. In practice, dry body weight is almost always estimated using clinical criteria, although

direct measurement of TBW as a percentage of body weight may be more accurate. Examples of current usage are (1) a body weight that is not associated with edema or hypertension, and (2) the lowest body weight that is not associated with an increase in malaise or muscle cramps or, in an individual who is not receiving blood pressure- lowering medication, with hypotension. This assessment should be performed when the rate of fluid removal has not exceeded approximately 1.0 to 1.2 L/hr, because greater rates of fluid removal often cause these symptoms before the edema-free body weight is attained. Hemodialy- sis patients who have a marked increase in TBW are particularly likely to have symptoms before the desirable amount of fluid is removed. All operational definitions of dry body weight have limitations, and it is perhaps most important to define the method by which dry body weight is estimated. For hemodialysis patients, the weight obtained postdialysis rather than predialysis usually is closer to the dry body weight.

It is recognized that the aBW or edema-free body weight of a dialysis patient may be mark- edly abnormal. There is confusion in the literature as to the method for assigning a weight goal or a standard reference weight to a given patient. We propose a standard weight, referred to as “normal body weight” (nBW), based on data from the US National Health and Nutrition Eval- uation Survey (NHANES).“.‘*

Normal Body Weight

Defined as the median body weight of normal Americans with the same age range, height, sex, and skeletal frame size as the individual in question, the nBW is expressed in kilograms. The values for normal individuals are obtained from the NHANES data, which are periodically up- dated on the basis of new surveys.“~‘* The extent to which the NHANES data are normative for individuals living in other nations or societies is not known. However, similar types of data are available for the indigenous populations of a number of countries.

The reference median body weights obtained from the NHANES data are summarized in Table 1. It should be noted that height is not given in this table as a separate variable, but is combined with elbow breadth as an indicator of skeletal frame size” to give a frame index. Measurement

PROPOSED GLOSSARY OF DIALYSIS KINETICS

Table 1. Median (50th Percentile) BoUy Weight (kg)

965

Age Range(yr) Males Females

18.0-24.9 Frame index Median body weight (kg)











~38.4 38.4-41.6 >41.6 <35.2 35.2-38.6 >38.6 68.3 71.5 74.7 55.1 58.1 62.9

<38.6 38.6-41.8 >41.8 <35.7 35.7-38.7 >38.7 71.8 75.9 82.2 55.6 58.6 68.7

<38.6 38.6-42.1 >42.1 <35.7 35.7-39.0 >39.0 74.6 77.8 85.4 57.6 60.7 72.7

<39.1 39.1-42.4 >42.4 <36.2 36.2-39.8 >39.8 75.9 80.4 84.1 59.5 61.8 76.7

<39.3 39.3-42.5 >42.5 <36.7 36.7-40.2 >40.2 76.1 79.3 84.9 59.1 62.8 77.1

<39.6 39.6-43.0 >43.0 <37.2 37.2-40.7 >40.7 76.2 79.8 84.0 60.3 63.4 76.8

<39.9 39.9-43.3 >43.3 <37.2 37.2-41.6 >41.6 74.7 78.3 83.1 80.3 64.4 77.7

<40.2 40.2-43.6 >43.8 <37.8 37.8-41.9 >41.9 74.8 77.9 84.5 59.9 66.3 77.6

<40.2 40.2-43.6 73.4 76.3

<40.2 40.2-43.6 >43.6 <38.2 38.2-41.8 >41.8 70.3 74.5 78.9 60.2 84.9 74.5

<40.2 40.2-43.6 >43.8 <38.2 38.2-41.8 >41.8 70.1 72.6 76.7 60.2 62.9 74.5

>43.6 80.7

<38.2 60.9

38.2-41.8 >41.8 64.5 76.8

Obtained from the NHANES Data as reported by Frishancho (19). Frame Index has no units and is calculated as follows: [Elbow Breadth (mm)/Height (cm)] x 100.

of elbow breadth is described in Appendix 1. These NHANES weights are approximately 8% to 10% greater than the weights in the Metropoli- tan tables for individuals of the same age range, height, sex, and frame size.20s2’ For patients who have had an amputation or who have lost body parts of substantial weight, the NHANES or the Metropolitan Life reference standards may not be applicable.

Relative Body Weight The relative body weight (RBW) is a patient’s

body weight (aBW or dry body weight for dialysis patients) expressed as a percentage of nBW for a normal American of the same age range, height, sex, and skeletal frame size.

RBW = (aBW/nBW)* 100%

Desirable Body Weight

(1)

Also referred to less correctly as “ideal body weight,” the DBW is usually expressed in kilograms, and is the midpoint of the range of body weights that are associated with the greatest longevity for normal individuals of the same age range, height, sex and skeletal frame size as the individual in question. These body weights were published in the 1959 and 1983 actuarial tables by the Metropolitan Life Insurance Company.20,2’ It is recommended that the term “desirable body weight” not be used indiscriminately, but rather reserved for these reference weights derived from the Metropolitan life tables. It is further recom-

966 KOPPLE ET AL

mended that the term “ideal body weight” not be used at all.

A patient’s aBW or dry weight may be expressed as a percentage of DBW (%DBW):

%DBW = (aBW/DBW)* 100% (2)

In general, the nBW obtained from the NHANES data are preferable to the DBW from the Metropolitan Life data, primarily because of the quality of the information collected and the greater range of applicability to the whole popu- lation. An analysis of the strengths and weak- nesses of these databases, as reviewed by Robin- ett-Weiss et al,** is summarized in Appendix 2.

There is increasing use in the literature of the term “lean body mass.” We believe that this term, which often is used to denote nonobese body weight, edema-free body weight (ie, dry body weight), or muscle mass, has caused much confusion, and its use should be restricted to its precise, traditional definition.

Lean Body Mass

The total body mass or weight minus body fat is expressed in kilogram~.*~ Total body fat (kg) is estimated, usually from skinfold thickness measurements and equations relating these measurements to body fat.24 This definition of lean body mass is well-accepted and traditional, particularly in the nutrition and body composition literature. Therefore, we believe that the definition should not be changed. Lean body mass does not refer to muscle mass, body cell mass, dry body weight, nBW, or DBW. The use of lean body mass to indicate these latter meanings has caused much confusion. Since lean body mass, by definition, includes TBW, lean body mass will be large in edematous patients and small in dehy- drated or volume depleted individuals. For these reasons, we do not recommend that the protein equivalent of total nitrogen appearance (PNA; see below), DPI, or any dialysis kinetic measurements be normalized to lean body mass. Dry body weight, nBW, or DBW often will serve the purposes for which lean body mass has been currently used. Other parameters that might be used for standardization include total body nitrogen, total body potassium, fat-free solids, or creatinine appearance. These latter parameters are not, as yet, widely accepted methods for charac-

terizing or standardizing body mass or muscle mass for patients with renal failure.

Body Su$ace Area

Body surface area (BSA) is the total surface area of the body, usually expressed in square meters and derived from height and weight. Body surface area can be estimated from a nomogram or the following equation?

BSA = 0.007 184 * aBW’.425 . Ht”.725 (3)

where aBW is expressed in kilograms and height (Ht) is expressed in centimeters.

Total Body Water

Total body water historically is estimated by the volume of distribution of labeled water or by underwater weighing and is usually expressed in liters.*” The use of tritiated or deuterated water to measure TBW is most accurate but is too laborious and expensive for routine clinical use. Total body water also may be measured by bioelectri- cal impedance, although currently there are some limitations to this method.27-2y In hemodialysis patients, urea kinetic modeling can be used to estimate TBW. The limitations to using urea kinetic modeling to estimate TBW appear to be largely due to the time necessary for equilibration of the body urea pools with the plasma compartment and are discussed in the section below entitled Compartmental Disequilibrium. For peritoneal dialysis patients, estimates of TBW by urea kinetic modeling may be more difficult. In non- edematous hemodialysis or peritoneal dialysis patients, TBW may be estimated by the formula 0.58 * aBW (for men) or 0.55 * aBW (for women), or from the Watson or Hume-Weyers equations.3.4”0’“l Although these methods are useful and probably sufficiently accurate under most circumstances, neither of these latter techniques has been carefully validated in chronic dialysis patients, and these approaches may not give an accurate estimate of TBW, at least for edematous, obese, or very thin dialysis patients.

Should Nutrient Intake and Dialysis Dose Be Related to Different Parameters of Body Mass?

A rationale can be advanced for relating nutritional requirements and dialysis dosage to different parameters of body mass. Many dietary nutri-

PROPOSED GLOSSARY OF DIALYSIS KINETICS 967

ent needs appear to be determined by body metabolic activity, which, in turn, may be related to the body pools of specific nutrients, especially protein.” Dietary energy requirements are defined by energy expenditure (eg, resting energy consumption, physical activity, the specific dy- namic action of foods, and, in growing individuals, the energy requirement for growth”?). Dietary protein requirements are related to body protein mass. Thus, the prescription and assessment of adequacy of dietary energy and protein intake might be determined most physiologically according to the edema-free aBW, with modification for any special metabolic needs. Energy intake should be further adjusted for physical activity. For patients who are obese or very thin, prescribing nutrient intake according to their aBW or nBW might lead to an excessively high or low intake. For example, a massively obese dialysis patient might be prescribed too much protein if the DPI were normalized to aBW or edema-free body weight. On the other hand, prescribing a DPI based on such an individual’s nBW might provide too little protein. The adjusted body weight will help to rectify this di- lemma. For this reason, nutrient intake might be more appropriately normalized to an adjusted aBW. Such a method, which has been gaining in popularity but has not yet been validated by experimental data, is as follows’4:

Adjusted aBW = edema-free aBW

+ [(nBW - edema-free aBW) * 0.251 (4)

Since the current methods for prescribing or evaluating dialysis dosage usually are based on urea removal (eg, KtN,,, and urea reduction ratio [URR], see below) and since urea seems to be a rather good marker of uremic toxicity, it seems appropriate to relate the dialysis urea clearance to the volume of distribution of urea (V).

ASSESSMENT OF DIETARY PROTEIN INTAKE

Dietary protein intake usually is measured or calculated for a 24-hour cycle. The DPI can be expressed in absolute units, such as grams of protein per day, or may be factored by a number of terms, including the patient’s edema-free aBW, nBW, or adjusted aBW, as indicated above. We recommend that the method for weight adjustment of DPI always be clearly stated and that it be con-

sistent with the method of weight adjustment for the PNA (see below). There are direct and indirect methods for estimating the DPI, and these are discussed in the following sections.

Direct Methods for Estimating Dietary Protein Intake

Dietary Diaries and Interviews .

Such diaries usually are collected for 2- to 7- day periods. Accuracy is increased by an inter- view based on the results of the diaries. Dietary diaries and interviews conducted by carefully trained personnel can provide rather accurate information.‘53”6 The difference between the intake of nutrients reported in dietetic diaries and directly observed in one large study was reported to be 10% or less in half of the subjects.“’ For energy, the reported intake was within 20% of observed in 85% of subjects; the accuracy was almost as good for protein. Group means were much closer. Twenty-four hour recall methods and food frequency questionnaires also can be used to assess dietary intake. The information obtained is entered into computer databases that will indicate the daily intake of many nutrients in addition to protein.

Indirect Methods for Estimating Dietary Protein Intake

Dietary protein intake also can be estimated from urea nitrogen appearance (UNA) and total nitrogen appearance (TNA). These terms and their use are described below.

Urea Nitrogen Appearance

Urea nitrogen appearance is the net production or appearance of urea nitrogen in body fluids and all measurable outputs (eg, urine, dialysate, fistula drainage). The term “urea nitrogen appearance” is preferred over “urea production” or “urea generation” because some urea that is produced (or generated) is degraded in the intes- tinal tract; the ammonia thus released from urea is largely transported to the liver and converted back to urea.?’

UNA (g/d) = urinary urea N

+ dialysate urea N + Abody urea N (5)

ABody urea N = (SUNf - SUNi). aBWi * 0.58

+ (aBWf - aBWi)* SUNf (6)

968 KOPPLE ET AL

where i and f are the initial and final values for the period of measurement, respectively, SUN is serum urea nitrogen (g/L), aBW is actual body weight (kg), and 0.58 (or 0.60) is the fraction of body weight that is water.“” The proportion of body weight that is water may be increased in patients who are edematous or lean and decreased in individuals who are obese or very young. If actual V is known from urea kinetics, it may be used instead of 0.58 * aBW. Changes in body weight during the I- to 3-day period of measurement of UNA are assumed to be due entirely to changes in body water.

When serum urea (SU) is expressed in milli- moles per liter, the change in body urea nitrogen (g/d) can be calculated as follows:

ABody urea N

= O.O28[(SUr - SUi) * aBWi 0 0.58

+ (aBWr - aBWi) * SUV] (7)

Urea nitrogen appearance can be calculated for maintenance hemodialysis patients as follows. In hemodialysis patients, the UNA is traditionally calculated using the single pool urea kinetic model requiring three blood samples: predialysis SUN (C,), postdialysis SUN (C,), and predialysis SUN for the next dialysis (C,) and the dialyzer clearance, &. There are two unknown values: V (volume of urea distribution) and UNA. To determine these two unknown values, two equations are required. The first equation examines the change of body content of urea nitrogen during dialysis, and the second equation is related to the change of body content of urea nitrogen between two dialyses. In the more rigorous variable volume single-pool model, the influence of UNA on body content of urea nitrogen during dialysis as well as the influence of residual renal clearance, K,, on body content of urea nitrogen during dialysis and between dialyses are considered. The resulting equations are rather complex and are presented in Appendix 3. For conceptual simplicity, we will consider the case of an aneph- ric patient with a relatively negligible change of body volume during dialysis (fixed volume model) and ignore the small impact of UNA on body content during the dialysis (because of the short duration involved):

c2 = c, . e-WIW (8)

where td and tad are dialytic and interdial, +ic time intervals, respectively, and C,, CZ, and CX are measured. K is measured in vivo or calculated for the operating conditions of blood and dialysate flow, knowing the in vivo mass transfer area coefficient of the dialyzer. The two equations are iteratively solved for the unknown V and UNA. If K,, is not explicitly known or measured, the equation can be solved for KJV and UNA/V.

Methods for estimating UNA from only two blood samples (C, and C,) have been derived recently. These approaches are discussed below in the Estimation of Dose of Dialysis Therapy section.

Urea nitrogen appearance can be calculated for patients undergoing continuous ambulatory peritoneal dialysis (CAPD) as follows:

UNA = (V, *DUN + V;UUN)t

+ Abody urea N (10)

where Vd and V, are dialysate and urine volumes, respectively (L), DUN and UUN are dialysate and urine concentrations of urea nitrogen (g/L), respectively, and t is the time of collection (typi- cally 1 day).3,4” Since with CAPD the daily changes in body urea nitrogen are usually negligible, the UNA can be estimated closely as follows:

UNA (g/d) = (V,.DUN + V;UUN)/t (11)

Total Nitrogen Appearance

Total nitrogen appearance is the sum of all outputs of nitrogen from the body, including dialysate, urine, and feces, plus the change in body urea nitrogen, usually expressed in grams of nitrogen per day. The TNA includes the nitrogen losses from the body in the form of urea, protein, peptides, amino acids, and all other nitrogen-con- taining compounds. In a patient who is in nitrogen equilibrium, TNA plus any unmeasured nitrogen losses should roughly equal total nitrogen intake. The latter quantity, when multiplied by the factor 6.25, should approximate protein intake.

The TNA can be quantitated by measurement

PROPOSED GLOSSARY OF DIALYSIS KINETICS

of total nitrogen in urine, dialysate, and feces using rather laborious and expensive techniques.4’.42 The factor that has made the indirect methods for estimating protein intake more prac- ticable is the very strong correlation between TNA and UNA?‘a4” Thus, using relatively simple and inexpensive measurements of urea nitrogen, regression equations can be used to estimate TNA. It should be appreciated that although the correlation between TNA and UNA is strong, the 95% confidence limits for the regression equation are approximately 220% of the mean.’ The Y intercept for the regression of TNA on UNA is an average value for non-UNA. If a patient has unusually large protein losses into dialysate or a large urinary ammonium excretion, is in marked positive or negative protein balance, or is preg- nant, these regression equations may not accurately predict TNA for that individual.

Since not all nitrogen losses can be easily measured (eg, skin desquamation, sweat, nail and hair loss, respiration, flatus), the TNA predicted by these equations underestimates actual nitrogen appearance by an unknown amount, thought to be at least 5 mg nitrogen/kg aBW/d in normal adults.47 This quantity has not been quantified in dialysis patients and could be larger because of unusual losses, such as methylamines in the breath!8 Moreover, there is some evidence that these unmeasured nitrogen losses may not be constant, but rather may increase with large protein intake.49

In the dialysis literature, protein intake estimated from the UNA has been referred to as the “protein catabolic rate.” It was thus named in recognition of the fact that urea is the major nitrogenous waste product from the breakdown of exogenous and endogenous proteins.44 We believe that although it is a useful concept, the term “protein catabolic rate” is misleading because, first, intact proteins, peptides, and amino acids lost in dialysate and urine comprise a portion of the PCR, but they are not catabolized to urea or other nitrogenous products, and second, in clinical nutrition and metabolism, the term “protein catabolism” refers to the absolute rate of protein breakdown, commonly measured by isotopically labeled amino acids. The absolute rate of protein breakdown is much greater than the net degrada- tion of exogenous and endogenous proteins, which results in urea excretion. In healthy adults

weighing about 70 kg, protein synthesis and breakdown generally are measured to be approximately 250 to 300 g protein/d,50~5’ whereas both the typical protein intake and the net rate of protein breakdown estimated from the UNA are approximately 50 to 100 g/d in such individuals.

Therefore, the new term “protein equivalent of total nitrogen appearance” (PNA) is proposed. This expression is more in keeping with the original definition suggested by Borah et al.““ The PNA is calculated exactly the same way as PCR. The advantage of the term “protein equivalent of total nitrogen appearance” is that it describes more correctly the metabolic processes that it represents, whereas “protein catabolic rate” is a misnomer that may be more likely to cause confusion.

Protein Equivalent of Total Nitrogen Appearance

The PNA expresses TNA in terms of protein. The equivalent amount of protein lost, PNA is usually expressed in grams per day or grams per kilogram per day. The conversion of TNA to PNA (equation 12) is based on the fact that the nitrogen content of mixed proteins is relatively constant at 16%, and that, quantitatively, most of the nitrogenous compounds lost from the body are either metabolites of protein (eg, urea) or are proteins and peptides (eg, in peritoneal dialysate).

PNA (g protein/d) = 6.25 * TNA (g N/d) (12)

The PNA can be estimated from UNA in nondialyzed patients with chronic renal failure4’*45.46 and in maintenance dialysis patients as described below. The regression equations relating UNA to PNA differ slightly for hemodialysis and peritoneal dialysis patients. When originally published, these equations were expressed in the traditional terms of PCR and urea generation. They have been modified here to be consistent with the proposed nomenclature.

Hemodialysis patients.

PNA (g/d) = 6.49.UNA + 11.04 (13)

with UNA expressed in grams of nitrogen per day. Equation 13 was derived by Borah et al.““ The second term on the right-hand side is an average value for non-urea nitrogen losses expressed in terms of protein (g protein/d). Since

970 KOPPLE ET AL

the average V in their patients was 38 L, these investigators lateti* modified the equation by di- viding the constant term by 38 L resulting in equation 14.

PNA (g/d) = 6.49.UNA + 0.294-V (14)

where V is the volume of distribution of urea (L) and the coefficient for the second term is expressed as grams of protein per liter per day. Since the second term represents non-urea losses, which vary primarily with body size, this modification allows use of the equation for patients of various sizes.

Delayed equilibration of body urea pools after hemodialysis may lead to a disproportionately lower urea concentration in plasma compared with other body pools. Failure to adjust for the postdialysis plasma urea rebound may lead to an overestimation of the PNA of 10% or greater. This is especially likely to occur in patients who receive high-efficiency hemodialysis (see section below entitled Compartmental Disequilibrium).

Continuous ambulatory peritoneal dialysispa- tients.

PNA (g/d) = 6.49.UNA + 0.294. V

+ protein losses (15)

This is the modified equation of Borah et al (equation 14) further modified4’ by inclusion of a term for peritoneal protein losses, expressed in grams of protein per day.

PNA (g/d) = 10.76(0.69 * UNA + 1.46) (16)

Equation 16 is essentially the equation of Ran- derson et al?” which was derived from data collected in CAPD patients. In the original form of the equation, UNA was expressed as G,, (mg urea nitrogen/min). In equation 16, the recommended term UNA (g urea nitrogen/d) is used instead (G,, = UNA/1.44 = 0.69 * UNA).

PNA (g/d) = 6.25 (UNA + 1.81)

+ 0.031.aBw (17)

Equation 17 was derived by Teehan et al54 from data collected in CAPD patients. The second term ( 1.8 1 g nitrogen/d) -is an average value from the literature for protein and amino acid nitrogen losses in CAPD patients. The third term (0.031 g/kg/d) is an average value taken from the litera-

ture for non-urea losses. For a discussion of these various approaches for calculating the PNA in chronic peritoneal dialysis patients, see Kesha- viah and Nolph,40 who have reported that these equations, in general, give similar results. Berg- striim et al” have argued that the relationship between UNA and TNA may be different for hemodialysis and peritoneal dialysis patients. Since peritoneal losses of protein may vary sub- stantially from patient to patient, especially if peritoneal inflammation is present, it may be more accurate to use equation 15. This may be of more importance in research studies than in the clinical setting. Other investigators have published equations that can be used to calculate PNA in CAPD patients.56,57

Normalized Protein Equivalent of Total Nitrogen Appearance

For comparison of an individual patient’s PNA to published standards or data from other patient populations, PNA can be divided by aBW, nBW (as defined above), or a body weight derived from the urea distribution space (ie, V/0.58). The PNA may be useful for evaluating nitrogen output or intake (see below) using a normal reference value for body mass. The PNA divided by aBW may provide useful information when prescribing a dietary intake or when evaluating the appropriateness of a patient’s actual nutritional intake, but may present special difficulties when the patient is edematous, obese, or emaciated (ie, when the actual and standard weights of a patient are very different). Division of PNA by V/O.58 is commonly used and has the advantage that it relates protein metabolism to the body’s compartment of urea, the major nitrogenous metabo- lite of protein removed by dialysis. It has the disadvantage that the values obtained represent neither a standard body weight nor the patient’s aBW. In edematous, obese, or severely under- weight patients, the term V/O.58 may give misleading data. As always, clinical judgment must be used when the PNA is expressed as a function of body mass.

Limitations to the Estimation of Dietary Protein Intake by Indirect Methods

Because PNA, TNA, and UNA do not include nitrogen from unmeasured losses, PNA almost always underestimates the actual DPI. In nonure-


mic subjects the difference is approximately 2.5 to 7.5 g protein/d!7 For nondialyzed chronic renal failure, maintenance hemodialysis, or chronic peritoneal dialysis patients, less is known about the degree of underestimation of DPI by PNA, but it is probably of at least the same magnitude. Theoretically, because of the possibility of increased respiratory or dermal nitrogen losses in renal failure,48 it may be greater. The degree to which the PNA underestimates DPI is not entirely constant, and also may be greatly increased in individuals ingesting high nitrogen intakes49 or when protein or nitrogen balance is positive. In patients who are in negative protein or nitrogen balance, PNA may be greater than the DPI. Since transient periods of positive or negative nitrogen balance may be common, this may be a common source of error. To these sources of error must be added the variance intrinsic to UNA measurements. Clearly, PNA must be interpreted in light of the patient’s clinical condition. It is also appar- ent that more research is needed to define more precisely the relationships between UNA, TNA, PNA, and the DPI in chronic renal failure and maintenance dialysis patients.

Expression of Dietary Protein Intake

Since the PNA (formerly the PCR) often will be used to estimate the DPI, it is important to determine the relationship between DPI and PNA as precisely as possible. There are essentially no published data that directly examine this relationship. Until such information is forthcoming, it would seem reasonable to add 30 to 60 mg protein/kg aBW/d to the PNA to approximate the usual unmeasured nitrogen losses.”

The DPI can be expressed in absolute units, such as grams of protein per day, or may be factored by a number of terms, including the patient’s aBW, nBW, or V/0.58. We recommend that the methods for estimation of DPI (ie, direct or indirect) and for weight adjustment of DPI (ie, aBW, nBW, or V/0.58) always be clearly stated.

ESTIMATION OF DOSE OF DIALYSIS THERAPY

The dose of dialysis therapy is the product of clearance (K) and duration of therapy (t). The Kt product usually is normalized to reflect body size. For urea, it has become accepted practice to nor- malize Kt to the volume of urea distribution V,

resulting in the index of urea removal Kt/V, which has been shown to be a marker of dialysis morbidity and mortality.2~“~9 In peritoneal dialysis, in addition to the Kt/V urea index, an index based on weekly creatinine clearance normalized to BSA (expressed per 1.73 m2 of BSA), is often used to quantify the dose of dialysis therapy.

Clearance

Clearance (K) is the volume of a solution that is completely cleared or depleted of a solute during a given period of time. An alternate definition of clearance is the rate of mass transport per unit of concentration gradient.

For hemodialysis, the clearance of a solute from blood can be expressed as follows:

K = (Qin . G - Qout * GJG (18)

where Q and C represent blood flow rates and concentrations, respectively, the subscripts in and out represent the inflow and outflow sites for the measurement of blood flow and concentration, respectively, and QO,, = Qin - Q.r, where Quf is the rate of ultrafiltration.

It is common but incorrect for the concentrations C,,, and Ci” to be given as plasma concentrations and Qin to be given as the whole blood flow rate. For a correct calculation of clearance, concentration and flow rate should be measured for the same solution that is being cleared of the solute. If K is a whole blood clearance, then Q and C should refer to the whole blood flow rate and the whole blood concentration.58 The whole blood concentration is calculated as follows:

CB = C,[(l - H) + H*Ea] (19)

where C, is the solute concentration in whole blood, Cp is the concentration in plasma, H is the hematocrit, and ER is an equilibrium ratio between red blood cell and plasma concentrations. Values for ER in the literature, for normal red blood cells, range from 0.76 to 0.96 (mean, 0.86) for urea and 0.70 to 0.76 (mean, 0.73) for creatinine.59.m For an inert solute that does not bind to blood components, the E, would be ex- pected to be 0.77 based on a red blood cell water fraction of 72% and a plasma water fraction of 92%. The measurements of ER for urea by Cheung et a16’ give a value of 0.76 for normal subjects and 0.77 for uremic patients. The data

972 KOPPLE ET AL

of Descombes et al”’ for dialysis patients are consistent with values of 0.77 for urea and 0.73 for creatinine.

Use of equation 19 to convert plasma concentration to whole blood concentration assumes that there is concentration equilibrium between red blood cells and plasma. For urea, this assumption is probably valid for blood both entering and leaving the dialyzer. However, for creatinine, while the assumption may be reasonable for blood entering the dialyzer, it is certainly not the case for blood leaving the dialyzer. Creatinine is preferentially removed from plasma during the transit of blood through the dialyzer, and little creatinine is removed from within the red blood cell. If the outflow blood is allowed to sit in a container, some degree of equilibration will occur between the red blood cells and plasma. Ac- cording to Skalsky et al,63 the time for 95% equilibration of creatinine is on the order of 105 minutes. However, according to Descombes et al,” it may take as long as 6 to 12 hours for complete equilibration of creatinine between the red blood cells and plasma. Furthermore, Des- combes et al report that for creatinine, red blood cells and plasma are not in equilibrium even in the blood entering the dialyzer. A small but significant creatinine concentration increase of 4% was noted in inlet plasma allowed to equilibrate with inlet red blood cells at room temperature. This inlet disequilibrium was not seen in the data of Skalsky et aL6’ who used fairly low blood flow rates of approximately 150 rnL/min compared with 315 mL/min in the work of Descombes et a1.62 At the higher blood flow rates, the time interval between two successive transits of red blood cells through the dialyzer is decreased to as little as 12 to 15 minutes, an interval that may not be sufficient for red blood cell-plasma equilibration in vivo.

An alternate and preferred calculation for clearance is based on the measurement of solute concentrations in dialysate and incoming blood, as follows:

K = QD~ * G&Bin (20)

where QDo is the dialysate outflow flow rate, C, is the solute concentration in outflow, and Csi, is the solute concentration in inflow blood. The blood concentration can be calculated from the plasma concentration, hematocrit, and equilib-

rium concentration ratio as above. Since concentrations in dialysate are often much lower than in blood, they need to be measured carefully with duplicate or triplicate determinations.

In equation 20, the numerator represents aque- ous flows and concentrations, whereas the denominator is a whole blood concentration. Some investigators therefore prefer to use a blood water concentration in the denominator. Thus calculated, the clearance is a blood water clearance rather than a whole blood clearance.h4 In the inflow blood, plasma water and red blood cell water are in equilibrium so that the plasma water concentration can be used in the denominator instead.

C pW = CJ(1 - 0.0107’ C,,,,iJ (21)

where Cp is the concentration of the solute in plasma and Cpmtein is the total plasma protein concentration in grams per deciliter.“’ For Cprotein = 7 g/dL, Cpw = Cd0.925.

For peritoneal dialysis, the clearance of a solute is usually measured as an average value for an entire exchange, as follows:

K = (V,*C,)/(C,*t) (22)

where Vd is the volume of drained dialysate, Cd is the solute concentration in drained dialysate, C, is the serum/plasma solute concentration during the exchange, and t is the time for that exchange. Thus, the clearance usually reflects a serum/plasma clearance.

If it is desirable to calculate whole body clearance rather than blood clearance, C, should be replaced by CTBW, the concentration in TBW. Be- cause peritoneal dialysis is a slow transport process in which there is almost constant equilibrium between TBW and plasma water (PW), Cpw (plasma water concentration) can be used instead of CTsW (equation 21).

For peritoneal dialysis, clearance is usually measured as an average value for an entire exchange, but also may be measured as an average value based on the pooled volumes and concentrations of a number of exchanges. This is usually the case for CAPD, in which the total drained volume for a 24-hour duration is pooled and the urea nitrogen concentration of this pooled sample is used in the calculation. It should be noted from equation 22 that the clearance-time product Kt


is equal to V,, * (C&Z,), ie, the drained volume times the dialysate to SUN concentration ratio.

Residual Renal Function

Residual renal function is the renal function in an individual with advanced renal failure who is usually receiving dialysis treatments. Residual renal function generally refers to the glomerular filtration rate (GFR), expressed in milliliters per minute or liters per day. The GFR may be accurately estimated by inulin, iothalamate, or EDTA clearances or, for patients with renal failure, somewhat less accurately by the mean of the urinary clearances of urea and creatinine.66.67 For urea kinetic modeling, the renal urea clearance may be more relevant than measurements of GFR. However, when calculating the weekly creatinine clearance normalized to 1.73 m* as an index of the dialysis dose, the use of GFR or estimate of GFR rather than the residual creatinine clearance is recommended.

Kt/V

Kt/V is defined as the dose of dialysis treatment as determined by the solute clearance-time product normalized to the individual’s volume of urea distribution. Kt/V is a dimensionless param- eter that is dependent on K, the total clearance (dialytic plus residual renal clearance, mL/min), t, the duration of the dialysis (mm), and V, the volume of solute distribution (mL). Kt/V is most often expressed per dialysis treatment for hemodialysis and per day or per week for peritoneal dialysis, as discussed below. For clarity, the time basis for the Kt/V dose should be indicated (eg, Kt/V weekly). Kt/V was first introduced by Gotch and Sargent’ as a measurement of dialysis dose for the small solute urea, based on their reanalysis of the National Cooperative Dialysis Study data. However, Kt/V can be calculated for other solutes as well, if the volume of distribution and the intercompartmental equilibration rates for the solute are known.

Kt/V Hemodialysis

If Kt/V is calculated simply as the product of the measured total clearance (dialysis clearance I(d + residual renal clearance K,) and duration of dialysis (t) normalized to the volume of distribution (V), the result will overestimate the true delivered Kt/V because the delivered K is usually

less than (I<d + K,) for the reasons discussed below.

Access recirculation. If the blood flow rate set by the blood pump is higher than the access blood flow, some of the blood outflow from the dialyzer will be recirculated within the access, back into the inflow stream:* The blood flowing into the dialyzer will therefore be a mixture of “fresh” blood entering the access from the arterial segment and dialyzed blood recirculated from the “venous” needle. The actual blood clearance will therefore be less than the measured dialyzer clearance and an access recirculation correction will be necessary. Access recirculation and the reduction in clearance due to access recirculation is calculated using the following equations:

Access recirculation R (%)

= [(C, - C,)/(C, - C,)] x 100 (23)

where Cf is the solute concentration in “fresh” blood not contaminated by access recirculation and C, and C, are solute concentrations in the “arterial” and “venous” segments of the extracorporeal blood circuit. Access recirculation is normally calculated using urea and/or creatinine concentrations. In the past, Cr was measured by drawing a peripheral venous blood sample, usually from the nonaccess arm. However, it has been shown that because of a phenomenon known as cardiopulmonary recirculation,“9‘7’ which is described below, the peripheral blood sample is not representative of the fresh blood entering the access. The current procedure is to stop or slow down the blood pump so as to elimi- nate recirculation and to draw a sample from the arterial line of the extracorporeal circuit. With this stop-flow technique, the dead space in the arterial needle and connecting tubing between the access and the point of sampling must be flushed to obtain a representative sample.

%Reduction in Clearance

R =R+(l -R)/E

x 100 (24)

where R is expressed as a fraction of unity rather than as a percentage, and E, the dialyzer extrac- tion ratio, is equal to (1 - CJC,).

974 KOPPLE ET AL

Cardiopulmonary recirculation. In the case of access recirculation, blood from the “venous” needle is recirculated within the access back into the arterial needle and the “venous” blood di- lutes the solute concentration in the “fresh” blood entering the access. In the case of cardiopulmonary recirculation, dialyzed blood from the venous outflow of the blood access is recirculated back into the arterial inflow of the blood access through a circulation loop that includes the central veins, right heart, lungs, and left heart7’ When the venous outflow blood mixes with the rest of the cardiac output in the central vein, there is dilution of solute concentration because the dialyzed venous outflow has a much lower solute concentration than the blood entering the central veins from the peripheral capillary beds. As a consequence of this recirculation within a larger blood loop than the access loop, the old method of drawing a peripheral blood sample to determine recirculation exaggerates the actual access recirculation because this technique measures the combined effect of access and cardiopulmonary recirculation. Even in a good access with no access recirculation, the old technique would result in a recirculation value of 5% to lo%, representing the contribution of cardiopulmonary recirculation. It is because of this phenomenon that one notices a very steep drop in “arterial” blood urea nitrogen (BUN) in the first few minutes of dialysis, representing the “dialysis” of the cardiopulmonary loop only and not of TBW. As with access recirculation, cardiopulmonary recirculation further reduces effective blood clearance.

Compartmental disequilibrium. The single- pool kinetic model assumes that solute is distributed in a single, well-mixed homogenous body pool and that the dialyzer removes solute uni- formly from this total volume. In reality, the dialyzer removes solute preferentially from a peripheral compartment, the central compartment lagging behind at a higher concentration than in the peripheral compartment. At the start of the dialysis procedure, both compartments are in equilibrium; the dialytic process perturbs this equilibrium. At the end of dialysis, the disequilibrium induced between body compartments is manifested by a rebound of solute concentration in the peripheral compartment as solute diffuses down the concentration gradient established by compartmental disequilibrium.72 Although it has

been speculated that rebound may be a manifes- tation of an increased UNA resulting from dialysis-induced hypercatabolism, the magnitude of increase in UNA that must be postulated to account for the rapid rebound is too large to be plausible. While hypercatabolism may cause a small increase in UNA lasting for several hours following dialysis, the rapid rebound in the 30 to 45 minutes immediately following dialysis is, for the most part, a result of compartmental disequilibrium. This conclusion is strengthened by the correlation noted between the magnitude of the rebound and the efficiency of dialysis (K/V). The single-pool model assumes that blood solute concentrations represent concentrations in the entire body pool. As a consequence, the single pool estimation of clearance and, hence, Kt/V gives an overestimation of the true whole body clearance and whole body Kt/V. As long as V represents the entire body pool of solute, K must represent the clearance of this whole body pool and not merely blood clearance or dialyzer clearance. With the increasing use of high-efficiency and high-flux therapies, which require higher dialyzer clearances to compensate for the shorter time duration, the magnitude of this compartmental disequilibrium has become more significant; the overestimation of the actual dose of delivered dialysis may be 15% to 20% or greater.

Our understanding of compartmental disequilibrium introduced by dialysis is still very incom- plete. The mass transfer coefficient governing urea transfer between body compartments may be highly variable among patients and may even vary from day to day within a given patient. This variability may support a regional blood flow model of disequilibrium rather than an intracellu- lar to extracellular disequilibrium model. Erics- son et al7-1 and Kjellstrand et a174 suggest that deviation from single-pool behavior is greater in patients who are overhydrated and have labile blood pressures, pulse rates, and body tempera- tures. Shirai et a175 showed that urea, creatinine, and uric acid are removed more slowly from edema fluid than from plasma; concentrations of these solutes in plasma are 15% to 17% lower than in edema fluid at the end of dialysis. Silver et al,76 investigating the dialysis disequilibrium syndrome in a rat model, provided evidence that the increase in brain water observed during dialysis is related to the more rapid removal of urea


from plasma relative to its removal from the brain. The resulting osmotic gradient between plasma and the brain causes cerebral edema. Me- try et a177 used a novel microdialysis technique to measure interstitial concentrations of urea during dialysis, and noted a close correspondence between urea concentrations in plasma and interstitial fluid during the course of dialysis. However, postdialysis, the urea rebound in plasma was complete in 2 hours, whereas urea rebound in interstitial fluid was delayed by approximately 60 minutes and continued for approximately 4 hours postdialysis. Metry et al speculate that the more rapid urea rebound in plasma may represent urea influx from the enterohepatic recirculation of urea nitrogen. All these studies emphasize that if urea nitrogen concentrations measured immediately postdialysis are used to measure the efficiency of the dialysis process, an overestimation of dialysis efficiency results. A more realistic appraisal of dialysis efficiency must take postdialysis rebound into consideration.

As can be seen from the above considerations, the calculation of Kt/V based on individual measurements of K, t, and V is complicated and not suited to routine clinical monitoring. We will now consider several approaches to measuring delivered Kt/V without explicitly measuring K.

Three-Point and Two-Point Serum Urea Nitrogen Methods for Measuring Kt/V for Hemodialysis

Using the single-pool urea kinetic model reported by Sargent et al,’ predialysis, postdialysis, and the next predialysis values of SUN and the clearance K are inputs, and the iterative solution of equations 8 and 9 results in V and UNA as outputs. If K is overestimated because the appropriate corrections (eg, the blood water correction, recirculation correction) are not applied, then V also will be overestimated and the ratio K/V will only be slightly underestimated. If t is known accurately, then Kt/V can be calculated with reasonable accuracy despite the uncertainty in K and V as individual values. Even if K is not a measured input, a reasonable estimate of K can be used as an input and a corresponding V can be derived. The ratio K/V will be reasonably accurate even with this approach. This approach is known as the three-SUN or three-point urea kinetic model. It suffers from the invalid assump-

tion that the urea pool is a single, well-mixed pool. The Kt/V thus derived will therefore overestimate whole body Kt/V. However, in the three-SUN model, if the SUN measured after a postdialysis rebound period of 30 to 60 minutes is used instead of the immediate postdialysis SUN, a more valid whole body Kt/V will be obtained.

Since the three-point SUN method with its iterative solution was considered to be too complex for routine clinical use, a two-point SUN approach based on predialysis and postdialysis SUN levels has become popular. Several simple formulae have been proposed for calculating Kt/ V based on the post-SUN to pre-SUN ratio, R. A recent study78 comparing nine of these simplified formulae based on the same set of SUN measurements reports a resulting Kt/V range as wide as 1.0 to 1.5. One example of a simplified formula is as follows:

Kt/V = -In (R)

where In (R) is the natural logarithm of the post- SUN to pre-SUN ratio. This simple formula is valid if there is no ultrafiltration-induced volume change and if the UNA rate during dialysis is ignored. In the presence of ultrafiltration and with typical values for the UNA, this simple logarithmic formula will underestimate Kt/V by as much as 20% to 30%.

Another simple formula for Kt/V that corrects the logarithmic approach for ultrafiltration and for UNA during dialysis has been proposed by Daugirdas79:

Kt/V = -In (R - 0.03)

+ (4 - 3.5 *R).UF/W (26)

where R is the ratio of the postdialysis to predialysis plasma urea nitrogen concentrations, UF is the ultrafiltration volume (L) removed during dialysis, W is the postdialysis weight (kg), and the factor 0.03 is a constant that adjusts for UNA during dialysis. (Note that data concerning Kt/V should always indicate the method and equation used to calculate Kt/V.)

This formula results in Kt/V values that are very similar to those of the more rigorous three- point SUN method of Gotch and Sargent. As with the three-point SUN approach, if the postrebound SUN is used instead of the immediate postdial-

976 KOPPLE ET AL

ysis SUN in the Daugirdas formula, a more representative whole body Kt/V is derived.

As originally proposed, the two-point SUN method was useful only for estimating Kt/V but not the UNA or PCR. However, Depner” and Gotch’ proposed methods for calculating UNA and PCR (PNA in the proposed nomenclature) from the two-point BUN approach by assuming that the patient is in a steady state and calculating the average UNA over the duration of the weekly cycle that achieves the measured steady-state predialysis and postdialysis values of SUN. For example, in the Depner approach, if the Monday values of SUN predialysis and postdialysis are measured and the KtN is calculated, a value of UNA can be assumed that will allow calculation of the Wednesday and Friday predialysis and postdialysis SUN as well as the next Monday predialysis SUN. If too high a value for UNA is assumed, then the predialysis SUN on the next Monday will overestimate the predialysis SUN of the previous Monday. If too low a value of UNA is assumed, the next Monday predialysis SUN will be lower than the previous Monday’s predialysis SUN. By a trial-and-error or iterative approach, a value for UNA is arrived at that represents the steady-state UNA over a l-week cycle. It must be noted that this estimation of UNA is based on a 7-day treatment cycle, whereas the three-point SUN approach calculates a UNA that applies to the interdialytic interval between the end of the first dialysis and the start of the next dialysis. This interdialytic value of UNA may not represent the steady-state UNA calculated by the Depner approach. The Gotch approach to calculating a UNA from two-point SUN measurements is similar conceptually to the Depner approach in that it represents a steady-state UNA. However, the methodology used is different and is a graphical approach based on the Gotch domain map that relates predialysis SUN, normalized PCR (PNA divided by aBW), and Kt/V. If predialysis SUN and Kt/V are known, then the appropriate Kt/V line of the domain map is iden- tified and the normalized PNA corresponding to the intercept of the predialysis SUN value with theappropriate Kt/V line can be read off the domain map. Direct Dialysis Quanti$cation

In addition to the two-point SUN and three- point SUN kinetic approaches to calculating

Kt/V and PCR (PNA), these latter parameters may be determined from direct measurements of urea in the total effluent dialysate or in aliquots of the dialysate. Although some investigators consider the direct measurement of dialysate urea nitrogen to be the definitive standard for de- termining dialysis urea removal, there are also limitations to this technique. It has been laborious and time-consuming, and several measurements of the dialysate are required because a small error in the measurement becomes greatly magnified when it is multiplied by the dialysate volume. The direct measurement of effluent dialysate is probably more suitable for research procedures than for clinical use. Direct dialysis quantification requires the direct measurement of total effluent or of representative aliquots and measurements of predialysis and 30- to 60minute postdialysis SUN.8’ Urinary urea excretion during the interdialytic interval and the subsequent predialysis SUN also are determined. From these data, two equations can be solved, one for the urea mass balance during dialysis and the other representing urea mass balance in the interdialytic interval. These two equations are similar in concept to equations 8 and 9, but represent a mass balance rather than a kinetic approach. As with equations 8 and 9, these mass balance equations are solved for V and UNA. As originally proposed, the direct dialysis quantification methodology was flawed in that it did not take into account either volume changes during dialysis resulting from ultrafiltration or the postdialysis rebound.

Urea Reduction Ratio

Another simplified approach8* to quantifying the dose of hemodialysis is the URR.

t-RR(%) = (1 - postSUN/preSUN) * 100

(27)

The limitations to using the URR are that it does not take into account either the influence of volume changes due to ultrafiltration on the dose of dialysis or the postdialysis rebound. Therefore, one cannot strictly correlate URR and whole body Kt/V without accounting for the volume ultrafiltered and the urea rebound postdialysis. Nevertheless, a target URR between 60% and 70% corresponds to a single pool Kt/V between


1 .l and 1.4. Using a large database, URR has been shown to be a significant predictor of mortality in hemodialysis patients with serum albumin concentrations in the range of 3.0 to 3.9 g/dL.”

KtN Peritoneal Dialysis The delivered KtN for chronic peritoneal dial-

ysis indicates the patient’s solute clearance, normalized to the body’s volume of distribution for that solute, usually urea. Both clearance and the volume of distribution are expressed in liters; hence, the units of Kt/V for peritoneal dialysis are also dimensionless. The K includes contribu- tions from both the dialytic (K,) and renal (K,) clearances.

The dialytic contribution (K,t) is calculated as the product of the volume of dialysate outflow and the dialysate to plasma/serum water concentration ratio. The plasma/serum water solute concentration can be calculated using equation 21. The dialysate sample should be obtained from a pooled, mixed, complete 24-hour collection. In the case of CAPD, this is simply equal to the 24- hour drained dialysate vohime. FOT nightperito- neal dialysis, this includes both the complete dialysate volume drained overnight as well as any daytime dialysate outflow. Although the dialysis dwell times with night peritoneal dialysis may be less than 24 hours, if a daytime dwell is not used, the value for the clearance-time product K,t can still be expressed in liters per day since that is, in fact, the total peritoneal clearance for that 24-hour period. The procedure for dialysate collection for continuous cycling peritoneal dialysis is essentially the same as for night peritoneal dialysis. The residual renal contribution (K,t) is calculated from a 24-hour urine collection that should be obtained during the same day in which the dialysate is collected for the calculation of K,t.

The delivered Kt/V may be expressed as (K,t + K,t)N or simply Kp,t/V. Typical KtN,,,, values for chronic peritoneal dialysis range from 0.21 to 0.32/d or 1.5 to 2.25/wk. It is more common to express Kt/V on a weekly basis. The daily method, however, may be more useful for prescriptive purposes.

Standardization of KtN Values Kt/V values generally are expressed for a sin-

gle hemodialysis treatment. Studies correlating

Kt/V values with morbidity and mortality have been based on hemodialysis treatment schedules of three times per week. In the future, it is possible that hemodialysis treatments may be performed at different frequencies. It is important to indicate, therefore, the frequency of hemodialysis treatments when expressing the Kt/V. It is recommended that a value for a weekly Kt/V also be given. Similarly, chronic peritoneal dialysis is not always performed with the same dialysis dose each day; thus, expressing Kt/V for peritoneal dialysis on a weekly basis is generally preferable for peritoneal dialysis as well. Expression of Kt/ V for both hemodialysis and peritoneal dialysis on a weekly basis also allows for much easier comparisons between these two dialysis treatments.

Prescribed KtN Versus Delivered KtN There is much evidence indicating that the pre-

scribed Kt/V is not delivered in the majority of clinical dialysis treatments.8” Thus, research or quality assurance data concerning the effects of actual dialysis treatments should refer only to the delivered Kt/V:

Weekly Creatinine Clearance

Weekly creatinine clearance, the urinary and dialysis creatinine clearance, is expressed in liters per week and is usually normalized to 1.73 m2 of BSA. This index of dialysis dose has been developed for chronic peritoneal dialysis on em- pirical grounds, and a minimum value of 40 to 50 L/week is recommended. Kb, is calculated as for urea by multiplying the volume of drained (24 hours) dialysate by the dialysate to plasma/ serum water concentration ratio and adding the amount contributed by renal function (if any). Since creatinine is at most a minor toxin, its clearance, per se, is not of particular interest, except as a marker for the clearance of other solutes, particularly those that are somewhat larger than urea. Renal tubular secretion of creatinine accounts for a substantial fraction of renal creatinine clearance in patients with renal failure. Thus, an accurate estimate of GFR, rather than total renal creatinine clearance, should be used to estimate the renal contribution so that clearance of other molecules in this molecular weight range is not overestimated. It may be more appropriate to use plasma water concentrations rather

978 KOPPLE ET AL

than plasma concentrations in this calculation, as discussed above. Weekly creatinine clearance for an individual with BSA is normalized to 1.73 m’, as shown in below:

Kb,(normalized to 1.73 m*) = Kb; 1.73/BSA

(28)

It has been shown that for peritoneal dialysis there is a high correlation between Kt/V,,, and the weekly creatinine clearance, as long as the residual renal contribution is correctly measured. The choice between Kt/V,,. and weekly creatinine clearance as indices of the dose of peritoneal dialysis therapy may therefore be a personal one. However, the advantage of using urea as a marker of adequacy is that the same measurements also can be used to calculate UNA and PNA. In addition, laboratory measurements of creatinine in drained dialysate are complicated by the requirement for an appropriate dextrose correction.

ACKNOWLEDGMENT

That authors thank Baxter Healthcare Corporation, and especially Stephen Garchow, for providing administrative support for this project. In addition, discussions with Dr A. Ro- berto Frisancho regarding anthropometric standards were most helpful.

APPENDIX 1: MEASUREMENT OF ELBOW BREADTH

Measurement of elbow breadth has been described by Fri- sancho.” Briefly the subject’s right arm is raised forward to a horizontal position and then the forearm is bent to a 90- degree angle at the elbow with the palm facing the body. The examiner then measures the greatest width between the lateral and medial epicondyles using either a broadfaced sliding caliper (Bicondylar Calipers; Seritex, Calstadt, NJ) or a Frameter (distributed by Health products, Ann Arbor, MI). The latter instrument requires less expertise and is less subject to errors in locating the proper anatomical landmarks or in positioning the caliper jaws.

APPENDIX 2: SELECTION OF A REFERENCE BODY WEIGHT

It is recommended that, in general, the NHANES data”-19 rather than the data in the Metropolitan tablesZaz’ be used as a reference standard for body weight for the following reasons:

1. The NHANBS reference values are based on data obtained from all major races and ethnic groups in the United States. The Metropolitan data are derived from a more afflu- ent segment of Americans, with a skewed representation toward males and certain races and ethnic groups (ie, those

who purchased life insurance in the 1950s through the 1970~“~‘) and are thus less representative.

2. The age range for adults in the NHANES data is 25 to 74 years; for the Metropolitan data, the age range is more limited, 2.5 to 59 years.

3. It is not known whether the DBWs reported in the Metropolitan tables are associated with greater longevity for races and ethnic groups that are not well represented in the Metropolitan tables or for chronically ill individuals, such as maintenance dialysis patients.

4. The NHANES data were frequently collected by health care professionals trained and committed to obtain accurate weights, heights, and frame sizes. With regard to the Metro- politan tables, these data generally were obtained by persons who were not specifically trained in the techniques of anthropometric data collection. Approximately 10% of the Metro- politan data were self-reported.”

5. The classification of individuals according to frame size is more scientifically based in the NHANES data than in the Metropolitan tables.

6. In addition to body weights, there are other anthropometric data obtained from the same individuals for the NHANES data that are available for comparison’7-‘9; this is not the case for the Metropolitan data.

7. The anthropometric data in the Metropolitan tables were obtained at one point in time. There is no information concerning how subsequent changes in body weight will affect the risk of mortality.

8. There are bodies of data similar to the NHANES data in other countries that can be used for comparisons; in con- trast, the type of data reported in the Metropolitan tables is largely confined to the United States.

APPENDIX 3: CALCULATION OF V AND UREA NITROGEN APPEARANCE FROM THE

VARIABLE VOLUME SINGLE-POOL MODEL THAT INCLUDES THE INFLUENCE OF K, AND

UREA NITROGEN APPEARANCE ON UREA MASS BALANCE

During hemodialysis, the rate of decline of body content of urea nitrogen reflects the balance between the rate of removal of urea nitrogen by the dialyzer and residual renal function and the UN’A. The solution of the differential equation reflecting this balance is given below:

+(4+yeQ”f).(1 -$F) (1)

where C, and CZ are predialysis and postdialysis serum urea nitrogen concentrations, respectively, V, and VZ are predialysis and postdialysis volumes of urea distribution, respectively, I<d and K, are dialyzer and renal clearances, respectively, and Qur is the rate of ultrafiltration determined as the weight change during dialysis. I& is measured during dialysis, either from SUN concentrations at the dialyzer inlet and outlet or from outlet dialysate concentrations (see section on Clear-


ance). K, is determined by collecting urine between dialyses and measuring the volume and urea nitrogen concentration in this collected urine. V, is calculated as follows:

V, = VZ + Qur.b (2)

where b is the duration of dialysis. Between hemodialyses, the rate of accumulation of urea

nitrogen in the body reflects the balance between the UNA rate and removal by residual renal function. Solution of the differential equation expressing this mass balance yields the following formula:

(3)

where C, and C, are postdialysis and the next predialysis serum urea nitrogen concentrations, respectively, V, and V, are the corresponding volumes of urea distribution, and Qw is the rate of weight gain between dialyses. Vz is calculated as follows:

V, = Vr + Qw.t, (4)

where t is the duration between the two dialyses. C,, C2. and C, are measured by appropriate blood sampling. Qu is measured from the weight change between dialyses. The two remaining unknowns are UNA and V,. Equations 1 and 3 can he solved for these two unknowns.

REFERENCES

1. Sargent J, Gotch FA, Borah M, Piercy L, Spinozzi N, Schoenfeld P, Humphreys M: Urea kinetics: A guide to nutritional management of renal failure. Am J Clin Nutr 3 1: 1696- 1702, 1978

2. Gotch FA, Sargent JA: A mechanistic analysis of the National Cooperative Dialysis Study (NCDS). Kidney Int 28526-534, 1985

3. Keshaviah PR, Nolph KD, Prowant B, Moore H, Pon- ferrada L, Van Stone J, Twardowski ZJ, Khanna R: Defining adequacy of CAPD with urea kinetics. Adv Petit Dial 6: 173- 177, 1990

4. Teehan BP, Schleifer CR, Brown JM, Sigler MH, Rai- mondo J: Urea kinetic analysis and clinical outcome on CAPD. A five year longitudinal study. Adv Petit Dial 6: 18 l- 185, 1990

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a proposed glossary for dialysis kinetics

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