Dry Weight in Hemodialysis

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REVIEW Assessment of Dry Weight in Hemodialysis: An Overview JACK Q. JAEGER and RAVINDRA L. MEHTA Division of Nephrology, Department of Medicine, University of California, San Diego, California. Abstract. Fluid balance is an integral component of hemodial- ysis treatments to prevent under- or overhydration, both of which have been demonstrated to have significant effects on intradialytic morbidity and long-term cardiovascular compli- cations. Fluid removal is usually achieved by ultrafiltration to achieve a clinically derived value for “dry weight.” Unfortu- nately, there is no standard measure of dry weight and as a consequence it is difficult to ascertain adequacy of fluid re- moval for an individual patient. Additionally, there is a lack of information on the effect of ultrafiltration on fluid shifts in the extracellular and intracellular fluid spaces. It is evident that a better understanding of both interdialytic fluid status and fluid changes during hemodialysis is required to develop a precise measure of fluid balance. This article describes the current status of dry weight estimation and reviews emerging tech- niques for evaluation of fluid shifts. Additionally, it explores the need for a marker of adequacy for fluid removal. Fluid removal to achieve fluid balance is an important com- ponent of hemodialysis (HD) treatment for end-stage renal disease (ESRD), as both under- or overhydration are associated with deleterious consequences. Despite considerable advances in assessment of dialysis adequacy with respect to solute re- moval, there is at present no measure of adequacy for fluid removal. The majority of HD treatments incorporate a pre- scription for fluid removal targeted to a patient’s “dry weight.” In most centers, dry weight is clinically determined and usually reflects the lowest weight a patient can tolerate without intra- dialytic symptoms and hypotension in the absence of overt fluid overload (1).This trial-and-error method is imprecise and does not account for changes in nutritional status and lean body mass. As a consequence, it is difficult to determine whether an individual patient is over- or underhydrated. Additionally, the dry weight is used to calculate ultrafiltration (UF) volume and rates for each dialysis treatment. It is well recognized that intradialytic complications are influenced by the balance be- tween ultrafiltration rates and plasma refilling. UF rates in excess of plasma refilling capacity predispose to dialysis- induced hypotension. It is evident that better methods of de- termining volume changes during HD are required for defining the goal for fluid removal and to develop strategies for safer dialysis treatments. This article describes the current status of dry weight estimation and reviews emerging techniques for evaluation of fluid shifts. Additionally, it explores the need for a marker of adequacy for fluid removal. What is Dry Weight? The standard HD prescription targets fluid removal to a clinically derived estimate of dry weight. Dry weight is cur- rently defined as the lowest weight a patient can tolerate without the development of symptoms or hypotension (1). Since physiologic dry weight is that weight resulting from normal renal function, vascular permeability, serum protein concentration, and body volume regulation, dry weight in HD should theoretically be lower than physiologic to prophylax interdialytic weight gains. In most instances, dry weight is estimated by trial and error, and the degree of imprecision is reflected in the development of intradialytic symptoms or chronic volume overload with poor control of BP (2,3). From a clinical standpoint, the aim of HD is to normalize the milieu interior as much as possible. The healthy human body at steady state is composed of several fluid and solid compartments (Table 1) (4), which are maintained within tight boundaries. An accurate assessment of a patient’s volume status requires knowledge of three factors: (1) the capacity of body compart- ments (e.g., extracellular fluid [ECF] and intracellular fluid [ICF]); (2) the amount of water in each compartment; and (3) the solute content (e.g., sodium), which may affect fluid shifts between compartments, interdialytic weight gain, and have an effect on the success of fluid removal during HD. Compart- ment size, amount of water, and content of solutes can be independently estimated by different techniques (as discussed below), however, all three must be considered in the definition of dry weight. Although different terminologies have been used in the literature to express the state of volume deficit or excess, we have used the term hydration status in this article to encompass the three components of volume measurement re- ferred to above. Problems Associated with an Inaccurate Assessment of Dry Weight At initiation of dialysis, most patients have typically been catabolic for several months due to chronic illness. At the same Received April 29, 1998. Accepted August 14, 1998. Correspondence to Dr. Ravindra L. Mehta, UCSD Medical Center, 200 West Arbor Drive #8342, San Diego, CA 92103. Phone: 619-294-6083; Fax: 619- 291-3353; E-mail: [email protected] 1046-6673/1002-0392$03.00/0 Journal of the American Society of Nephrology Copyright © 1999 by the American Society of Nephrology J Am Soc Nephrol 10: 392– 403, 1999

Transcript of Dry Weight in Hemodialysis

Page 1: Dry Weight in Hemodialysis

REVIEW

Assessment of Dry Weight in Hemodialysis: An Overview

JACK Q. JAEGER and RAVINDRA L. MEHTADivision of Nephrology, Department of Medicine, University of California, San Diego, California.

Abstract.Fluid balance is an integral component of hemodial-ysis treatments to prevent under- or overhydration, both ofwhich have been demonstrated to have significant effects onintradialytic morbidity and long-term cardiovascular compli-cations. Fluid removal is usually achieved by ultrafiltration toachieve a clinically derived value for “dry weight.” Unfortu-nately, there is no standard measure of dry weight and as aconsequence it is difficult to ascertain adequacy of fluid re-moval for an individual patient. Additionally, there is a lack of

information on the effect of ultrafiltration on fluid shifts in theextracellular and intracellular fluid spaces. It is evident that abetter understanding of both interdialytic fluid status and fluidchanges during hemodialysis is required to develop a precisemeasure of fluid balance. This article describes the currentstatus of dry weight estimation and reviews emerging tech-niques for evaluation of fluid shifts. Additionally, it exploresthe need for a marker of adequacy for fluid removal.

Fluid removal to achieve fluid balance is an important com-ponent of hemodialysis (HD) treatment for end-stage renaldisease (ESRD), as both under- or overhydration are associatedwith deleterious consequences. Despite considerable advancesin assessment of dialysis adequacy with respect to solute re-moval, there is at present no measure of adequacy for fluidremoval. The majority of HD treatments incorporate a pre-scription for fluid removal targeted to a patient’s “dry weight.”In most centers, dry weight is clinically determined and usuallyreflects the lowest weight a patient can tolerate without intra-dialytic symptoms and hypotension in the absence of overtfluid overload (1).This trial-and-error method is imprecise anddoes not account for changes in nutritional status and lean bodymass. As a consequence, it is difficult to determine whether anindividual patient is over- or underhydrated. Additionally, thedry weight is used to calculate ultrafiltration (UF) volume andrates for each dialysis treatment. It is well recognized thatintradialytic complications are influenced by the balance be-tween ultrafiltration rates and plasma refilling. UF rates inexcess of plasma refilling capacity predispose to dialysis-induced hypotension. It is evident that better methods of de-termining volume changes during HD are required for definingthe goal for fluid removal and to develop strategies for saferdialysis treatments. This article describes the current status ofdry weight estimation and reviews emerging techniques forevaluation of fluid shifts. Additionally, it explores the need fora marker of adequacy for fluid removal.

What is Dry Weight?The standard HD prescription targets fluid removal to a

clinically derived estimate of dry weight. Dry weight is cur-rently defined as the lowest weight a patient can toleratewithout the development of symptoms or hypotension (1).Since physiologic dry weight is that weight resulting fromnormal renal function, vascular permeability, serum proteinconcentration, and body volume regulation, dry weight in HDshould theoretically be lower than physiologic to prophylaxinterdialytic weight gains. In most instances, dry weight isestimated by trial and error, and the degree of imprecision isreflected in the development of intradialytic symptoms orchronic volume overload with poor control of BP (2,3). Froma clinical standpoint, the aim of HD is to normalize the milieuinterior as much as possible. The healthy human body at steadystate is composed of several fluid and solid compartments(Table 1) (4), which are maintained within tight boundaries. Anaccurate assessment of a patient’s volume status requiresknowledge of three factors: (1) the capacity of body compart-ments (e.g., extracellular fluid [ECF] and intracellular fluid[ICF]); (2) the amount of water in each compartment; and (3)the solute content (e.g., sodium), which may affect fluid shiftsbetween compartments, interdialytic weight gain, and have aneffect on the success of fluid removal during HD. Compart-ment size, amount of water, and content of solutes can beindependently estimated by different techniques (as discussedbelow), however, all three must be considered in the definitionof dry weight. Although different terminologies have beenused in the literature to express the state of volume deficit orexcess, we have used the term hydration status in this article toencompass the three components of volume measurement re-ferred to above.

Problems Associated with an InaccurateAssessment of Dry Weight

At initiation of dialysis, most patients have typically beencatabolic for several months due to chronic illness. At the same

Received April 29, 1998. Accepted August 14, 1998.Correspondence to Dr. Ravindra L. Mehta, UCSD Medical Center, 200 WestArbor Drive #8342, San Diego, CA 92103. Phone: 619-294-6083; Fax: 619-291-3353; E-mail: [email protected]

1046-6673/1002-0392$03.00/0Journal of the American Society of NephrologyCopyright © 1999 by the American Society of Nephrology

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time, adequate excretion of salt and water has given way toprogressive nephron dropout. This altered bodily fluid physi-ology results in a shrunken body cell mass with a relativelyexpanded extracellular space. As dialysis improves the uremicstate, an increase in lean body mass may occur undetected dueto a coincident reduction in extracellular volume. Similarly, areduction in lean body mass and a consequent increase in theextracellular fluid may go unnoticed during an acute illness.Complicating this issue further is the fact that, barring a largeinterdialytic weight gain, a dialysis patient may not haveachieved their dry weight, yet still suffer intradialytic hypoten-sive episodes routinely for various nonvolume reasons. Con-versely, they may arrive at and leave dialysis normotensive,nonedematous, and without any other overt signs of fluidoverload, yet remain quite above their true dry weight. Ambu-latory BP monitoring has been, to this point, the only way todiagnose this silent hypervolemia, which may lead to thedevelopment of hypertension as late as 12 h after leaving thedialysis unit (5,6). Recognition of these changes is an integralcomponent of the clinical acumen of the nephrologist. How-ever, the appropriate adjustment of dry weight may not alwaysbe timely or precise as reflected by the complications of over-and underhydration and intradialytic morbid events, which arediscussed further.

Overestimation of Dry WeightHypertension. Studies have shown that at least 80% of all

hypertension in dialysis patients is due to chronic hypervol-emia (5,7–11). Early animal studies by Langston and Guyton in1963 and 1969 (12) suggested that chronic volume overloadled to secondarily increased peripheral vascular resistance,even in nephrectomized dogs. At the same time, a subset ofdialysis-resistant hypertensive patients with high serum reninactivity were described, which led to the dichotomous descrip-tion of hypertension in dialysis patients: salt-water dependentand renin-dependent (7). Some studies have categorized up tohalf of their hypertensive patients as dialysis-resistant, imply-ing a renin-dependent mechanism (5,13). However, it is im-

portant to note that in Vertes’ study of 40 patients, an earlybenchmark study of this concept, only five were truly hyper-reninemic, all of them responding adversely to volume deple-tion and favorably to bilateral nephrectomy (7). Also, inCharra’s group of patients treated with long, slow hemodialy-sis, less than 2% remained hypertensive off antihypertensiveagents, thus deemphasizing renin-dependent mechanisms ofhypertension in the general dialysis population (11). Indeed,Fishbaneet al. used plasma atrial natriuretic peptide (ANP), amarker of intravascular hypervolemia, to show that dialysis-resistant hypertensive patients were actually volume over-loaded at the end of dialysis (8). Others have confirmed thatremoving excess salt and water during maintenance hemodial-ysis normalizes BP in at least 70% of cases (9), while it hasalso been shown that postdialytic BP correlates with total bodywater by bioimpedance spectroscopy (10). Although other non-volume-related mechanisms for dialysis-resistant hypertensionhave been forwarded, such as sympathetic nervous systemhyperactivity (14,15), endothelins (16), and prostaglandins, thepreponderance of evidence points toward chronic volume over-load as the major cause of hypertension in the ESRD anddialysis population.

Hypertension and Excess Death in Hemodialysis Pa-tients. According to the U.S. Renal Data System (USRDS)(17), cardiovascular disease and stroke are the most prevalentcauses of morbidity and mortality in dialysis patients, which inturn have been linked to markers of volume overload. Thesemarkers include hypertension, left ventricular dysfunction, andleft ventricular hypertrophy. In the general nonuremic popula-tion, hypertension is a major cause of cardiovascular andcerebrovascular morbidity and mortality (18,19). As would beexpected, hypertension has been linked to excess cardiovascu-lar and cerebrovascular adverse events in dialysis patients aswell (20). Indeed, in an analysis of iliac artery biopsies at timeof transplant in 50 nondiabetic hemodialysis patients, the pres-ence of atherosclerosis was found to be independent of lipidabnormalities and duration on dialysis, but correlated almostexclusively with the presence of hypertension (21). Othershave agreed that BP control is essential for prolonged survival(22). And while Charraet al.’s (11) cohort of patients areyounger, narrowly representative of the general dialysis pop-ulation, and uncontrolled for other unknown beneficial effectsof long, slow hemodialysis, their 75% 10-yr survival rateassociated with excellent dry weight control of BP remains themost compelling evidence for the beneficial effects of BPcontrol (23). It is thus evident that if dry weight is the majorcomponent of hypertension, and hypertension is a major pre-dictor of death in dialysis patients, we should be focusing ondry weight.

Cardiac Dysfunction. Although it is difficult to separatecause and effect when discussing the various cardiac disordersin hemodialysis patients, it seems that an excessive dry weightis a sufficient risk factor allowing the final expression ofcardiac dysfunction and indirectly, sudden death. In 1836,Bright first noted autopsy findings of left ventricular hypertro-phy in patients dying of ESRD (24). As discussed previously,the majority of patients are hypertensive at presentation to

Table 1. Body fluid compartmentsa

CompartmentPercent ofTotal Body

Water

Percent of TotalBody Weight

NormalAdultMan

NormalAdult

Woman

Intracellular fluid 55 33 27.5Extracellular fluid 45 27 22.5Interstitial fluid 20 12 10Plasma 7.5 4.5 3.75Bone 7.5 4.5 3.75Connective tissue 7.5 4.5 3.75Transcellular 2.5 1.5 1.25

Total body water 100 60 50

a Adapted from Edelman and Leibman, 1959 (4).

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dialysis, largely due to impaired salt and water excretion, andgiven the known association of chronic hypervolemia andhypertension, and hypertension and left ventricular hypertro-phy (LVH) (25), it is no surprise that most ESRD patientspresent to dialysis with LVH as well (26–29). LVH addition-ally has been shown to be deleterious to hemodialysis patientsfor several reasons: (1) similar to nonuremic patients, it ispredictive of an increased incidence of myocardial infarction(30), congestive heart failure (31), and sudden death (32); and(2) LVH can lead to diastolic dysfunction, which has beenlinked to an increased incidence of intradialytic morbid events(33). Indeed, Parfreyet al. showed that 40% of their cohort ofdialysis patients with congestive heart failure had hypertrophicchanges, 43% had either LV dilation or systolic dysfunction,and only 16% had normal echocardiograms upon presentationto dialysis (31). LVH was thought to be due to chronicallyincreased afterload, while dilation and systolic dysfunctionwere thought to be due to chronic hypervolemia. Althoughthese changes did not regress over the 17-mo follow-up, therewas no intervention to lower the clinically derived dry weight.Both forms of left ventricular abnormalities were associatedwith a markedly poor median survival from 38 to 56 mo. Asstated above, however, it is probable that both types of ven-tricular abnormality are volume-related. LV dilation and sys-tolic dysfunction are probably a form of burnt-out hypertensiveheart disease due to an imbalance between appropriate hyper-trophy and cell death and fibrosis. Other studies have shownthe link between chronic hypervolemia and the development ofLVH in dialysis patients as well (34).

It is obviously important to recognize that other risk factorsfor the development of LVH are increased age, diabetes mel-litus, anemia, and possibly hyperparathyroidism, and for LVdilation, anemia, ischemic heart disease, and hypoalbumine-mia. Likewise, these disorders are present at the initiation ofdialysis, and have not been shown to be reversible in hemodi-alysis patients. However, regression of LV dilation and LVHhas been shown in studies in normal populations (35), andperhaps most intriguing are studies showing regression of LVHin hypertensive ESRD patients started on continuous ambula-tory peritoneal dialysis (36). It is therefore possible that ag-gressive control of volume may lead to regression of leftventricular abnormalities, which are surrogate markers for poorsurvival in hemodialysis patients.

Missing Changes in Lean Body Mass. There is also theoccasional patient who has achieved their so-called dry weight,but over time subtle negative changes in lean body mass occurdue to inadequate dialysis prescription, inadequate dialysisdelivery, comorbid illness, depression, or other causes. Thischange might not be reflected in serum albumin or urea kinet-ics studies, and failure to adjust dry weight results in a greaterproportion of their body weight becoming ECF. An increase inBP with recognition of lean body mass change and consequentadjustment of dry weight may occur. Alternatively, there maybe no BP response to this ECF expansion, a failure to adjustdry weight downward, and henceforth failure to identify thissubtle change in nutritional status. Such small changes innutritional status might be significant for the patient.

Underestimation of Dry WeightUnderestimation of dry weight is more likely to be recog-

nized due to its immediate consequences of intradialytic mor-bidity. It usually occurs when there is a failure to adjust theultrafiltration prescription to account for increases in eitherlean body mass or fat mass over time. A previously stablepatient becomes frequently hypotensive during hemodialysis,but the change in ultrafiltration prescription is often delayedeither due to physician reluctance to change the dry weight, orto efforts to investigate other more threatening etiologies ofhypotension. This situation, one of patients’ most frequentcomplaints (37), leads to patient dissatisfaction with the dial-ysis prescription, early withdrawal from dialysis, failure toarrive at the dialysis unit, and frequent interrupted sessions, allof which lead to reduced solute removal. The resulting inade-quate solute removal leads to decreased appetite, poor intake,and subsequently to poor nutritional status, which have theirown adverse effects on dialysis outcome. On the other hand,not knowing the true dry weight of a patient, one might attemptto mitigate frequent hypotensive events due myocardial is-chemia, pericardial effusion, cardiac arrythmia, or other disor-ders by increasing the dry weight goal, thus missing the diag-nosis of a more serious underlying condition.

Measuring Dry WeightIt is obvious from the above discussion that clinical assess-

ment of dry weight is crude and often imprecise. Recently,several different techniques have been used to derive a morestandard method of assessing dry weight (38–41). However,no single method has emerged as a gold standard, as there is noclear-cut definition of what constitutes dry weight. The follow-ing section reviews these methods as they have been devel-oped, and offers a critical appraisal of their use.

Biochemical MarkersAtrial Natriuretic Peptide. ANP is a peptide hormone

synthesized, stored, and released in atrial tissue in response tochanges in atrial transmural pressure. The hormone follows theusual cleavage synthesis pathway as a prepro-, pro-, and abiologically active 28 amino acid peptide. It is rapidly de-graded, primarily by the kidney, but also by other organs, witha serum half-life of 2 to 4 min. Its end-organ effects and rolein maintenance of salt and water homeostasis, which are wellcharacterized elsewhere (42), as well as its short half-life andsomewhat minimal clearance by hemodialysis, initiated excite-ment about its possible role in determining fluid status inhemodialysis patients. Rascheret al. were the first to suggestits use as an indicator of volume status in hemodialysis (43). Inthis and subsequent studies (44,45), ANP levels were found tobe elevated in hemodialysis patients, before dialysis, relative tocontrol subjects, and levels were significantly lower after bothhemofiltration (45) and hemodialysis (44). Plasma ANP levelscorrelated with BP, and although ANP levels changed signif-icantly during HD, in most studies postdialysis levels remainedsignificantly higher than controls (43,44). Others (46–48) haveestablished marked interpatient variability and persistent post-dialysis elevation. Additionally, ANP levels have been shown

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to be persistently elevated after HD in patients with altered leftatrial hemodynamics compared to those with normal left atrialhemodynamics (49), making ANP levels difficult to interpretin this setting. As discussed previously, Fishbaneet al.’s (8)cohort of persistently hypertensive patients had high plasmaANP, and were not believed to be at their dry weight, raisingthe possibility that the persistent postdialysis ANP elevationsin the previously mentioned studies might have been due toinadequate dry weight achievement or the presence of alteredleft atrial hemodynamics. Kojimaet al. (46) showed thatplasma ANP levels were still routinely elevated after hemodi-alysis even when patients are determined to be clinically attheir dry weight. But in this study, ANP also correlated wellwith BP. A possible explanation for the persistently elevatedlevels of ANP in this study may be that these patients werereally not at their dry weight as evidenced by the persistenthypertension. Because of these uncertainties, a serum level atwhich ANP should be predictive of dry weight in a dialysispatient is a matter of considerable controversy. In summary,plasma ANP is sensitive for detecting overhydrated patients,but not specific. Concordantly, it often remains elevated in dryindividuals and hence is not sensitive in detecting underhy-drated patients. A low ANP value’s specificity for detectingunderhydration is unknown.

Cyclic Guanidine Monophosphate (cGMP). cGMP isgenerated when ANP activates membrane-bound guanylatecyclase, and hence was predicted to be an indicator of volumestatus in dialysis patients (50). This biochemical marker wasperhaps best systematically studied by Lausteret al.(40,51,52). Because cGMP is more stable in serum at roomtemperature than ANP (53), and the RIA for cGMP is some-what less arduous, it was believed that cGMP would poten-tially be a better marker than ANP for the routine assessmentof fluid status. Their studies determined: (1) that cGMP levelsof 20 pmol/L immediately postdialysis correlated with achieve-ment of clinical dry weight; (2) the majority of those withpostdialysis levels greater than 20 pmol/L had evidence of fluidoverload or congestive heart failure; (3) that reductions in dryweight in these remaining patients were associated with both areduction in cGMP levels to approximately 20 pmol/L andclinical resolution of the fluid overloaded state; and (4) thosewhose levels could not be lowered beyond this point had leftventricular dysfunction. However, these measurements werenot validated against other objective parameters, and othershave not confirmed these findings. Franzet al. found that 28%of their patients had postdialysis cGMP levels of greater than20 pmol/L, the majority of which were in sinus rhythm, had noevidence of congestive heart failure, and were not believed tobe fluid overloaded (54). As with ANP, the meaning of a lowlevel is unknown, and cGMP levels are influenced by cardiacor valvular dysfunction, thus limiting its clinical utility in thissetting.

Vena Cava DiameterBecause echocardiographic examination of the inferior vena

cava diameter (VCD) is simple, quick, and noninvasive, effortsto standardize its dimensional characteristics in relationship to

central blood volume were first undertaken by Natoriet al. in1979 (55). They showed that supine measurements of cavaldiameter taken during expiration and its inspirational decreasein diameter correlated well with central venous pressure. Andoet al. (1985) were the first to quantify VCD changes duringhemodialysis (56). In 1989, Cheriexet al.attempted to use thistechnique to assess dry weight in hemodialysis patients, show-ing that postdialysis measurement of inferior caval diametertaken subdiaphragmatically correlated with right atrial pressureand circulating blood volume (57). Linear regression to rightatrial pressure defined overhydration as a caval diametergreater than 11 mm/m2 body surface area or a collapsible index(Expiratory caval diameter2 Inspiratory caval diameter/Expi-ratory diameter3 100%) as less than 40%. Underhydrationwas defined as a caval diameter of less than 8 mm/m2 and acollapsible index of greater than 75%. Nearly two-thirds oftheir patients who had met clinical criteria for dry weight wereactually hypervolemic, according to these criteria. Those whowere considered underhydrated by these criteria had greaterincreases in heart rate and stroke volume, and greater decreasesin BP during dialysis when compared to their normally oroverhydrated counterparts. Others have not been able to con-firm these findings. Mandelbaumet al. found a wide range ofcaval diameters in their dialysis population, and they were notcorrelated to age, height, weight, or body surface area of thepatients (58), thus rejecting the “nomogram”-based generali-zation of this measurement to the general dialysis population.Franzet al.divided their patients into three groups of hydrationstatus based on Cheriexet al.’s criteria above and showed thatmean cGMP levels were higher in the hypervolemic groupcompared with the normovolemic and underhydrated patients,but there was no statistically significant linear correlation be-tween caval size and cGMP level (54). In their study, as wouldbe expected, a major limitation of this technique was measur-ing volume status in patients with heart failure. The presence oftricuspid insufficiency requires its own criteria for assessmentof volume status via vena caval diameter (59). On the otherhand, Katzarskiet al. used VCD to confirm the volume hy-pothesis of hypertension in hemodialysis patients (60). Theystudied two cohorts of hypertensive and normotensive patientsand showed that caval diameter was significantly larger post-dialysis in their group of hypertensive patients. Leunissenet al.(61) and Kouw et al. (62) have subsequently shown thatpostdialysis VCD measurements reliably predict hemodynamicchanges during dialysis. In summary, while interpatient andinteroperator variability and the presence of right-sided failurelimit its use, VCD may be better suited than the biochemicalmarkers for prediction of the underhydrated state.

Bioimpedance Analysis and BioimpedanceSpectroscopy

Single or Dual Frequency Bioimpedance Analysis. Thebasic principles of bioimpedance were initially described byThomassett in 1963 (63), but the technique first gained prom-inence in the early 1970s when Nyboer reported that theimpedance of the body to an alternating current roughly cor-related with changes in blood volume (64). These measure-

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ments are based on the basic principle that the electrical im-pedance of a cylinder is directly proportional to its length andinversely proportional to its cross-sectional area multiplied byits specific resistivity. Application of simple multiplication andrearrangement resulted in the equation for volumeV 5 L2/Z,whereV is specific resistivity,L is length, andZ is the mea-sured impedance. Operating on the assumption that the humanbody is a sum of homogeneous cylinders, and that currentwould pass only through ion- and water-containing media, in1969 Hoffer was the first to attempt to measure total bodywater by this method (65). In his and subsequent analyses (66),Height2/Impedance at a frequency of 50 kHz indeed showedthe best-fit regression to deuterium water space with a corre-lation coefficient of 0.92. Subsequent multiple equations basedon variations of this principal, usually with the addition ofgender-specific dummy variables or anthropometric parame-ters have been derived (67–70). Although this technique issimple and remains valid for the measurement of total bodywater, single frequency analysis is unable to distinguish be-tween intracellular and extracellular compartments. Based onthe assumption that a low frequency current would transgressonly the extracellular space, Jeninet al. in 1975 first used a low1-kHz frequency paired with a 100-kHz frequency to estimateECF volume and ICF volume separately (71). In 1988,Lukaski, using a single frequency method and a regressionequation including reactance, improved the correlation to bro-mide space to 0.83 (70). Standard error of estimate for bothsingle and double frequency methods ranges from 1.5 to 3.5 L.

Bioimpedance Spectroscopy, the Multifrequency Ap-proach. Multiple frequency analyzers were developed totake advantage of the dielectric theory of electrical conductionthrough mixed, emulsified bodies (72). In this theory, conduc-tion of current through the intracellular space is modeled asflow through innumerably different parallel circuits consistingof a capacitance and a resistance in series, while parallel flowthrough the extracellular space is limited only by the resistanceto flow through ion and water. The result is that at lowfrequencies, current cannot bridge the cell membrane (capac-itor) and will flow only through the extracellular space, whileat increasingly higher frequencies the cell membrane capaci-tors will offer less and less reactance. As reactance approacheszero, impedance is purely resistance, and resistance at thisfrequency reflects the resistance of total body water (TBW).Current analyzers offer frequency ranges from 1 kHz to 1MHz, plot impedance loci at these frequencies, and extrapolatereactance to zero along the locus via curve fitting at infiniteextremes of frequency. What results are imaginary-real resis-tances where true resistance for ECF (Re) and resistance forTBW values should theoretically lie (Resistance of ICF [Ri] iscomputed from the component circuit). These resistance valuesand the patient’s height, weight, gender, and Hanai mixtureequations are used to extrapolate to volume (73). The potentialadvantages of this approach over linear single and doublefrequency measurements are: (1) Complex impedance at anysingle frequency (characteristic frequency) may be differentfrom patient to patient or from time to time. Thus, curve fittingand extrapolation may help smooth out these interpatient and

measurement differences. (2) Intuitively, extrapolation of datato zero and infinite frequencies is probably more accurate thanarbitrarily choosing a single frequency for analysis, for thesame reasons as above.

A few studies have compared the techniques. Hoet al. foundthat both techniques correlated very well with TBW by deute-rium space (74). However, multifrequency modeling of TBWwas slightly more precise than the linear equation (6.2versus6.7%, respectively). And while multifrequency bioimpedancetended to consistently underestimate TBW, the linear equationboth over- and underpredicted TBW with more scatter alongthe line of identity. Another study revealed that modeled bio-impedance spectroscopy (BIS) and dual frequency resistancesshowed very little intermeasurement differences (6 0.04), thusconfirming the underling Cole modeling scheme of BIS (75).Whether one uses single, dual, or multiple frequency modeling,one could make the argument that there is no need to extrap-olate these resistances to volume terms, since (1) resistivityconstants (or components therein) are derived in a linear man-ner from nonuremic populations, and (2) their calculationinvolves the use of Hanai mixture theory, which has not beenvalidated in whole organisms (76).

Bioimpedance and Dry Weight: Clinical Utility. Bioim-pedance analysis has proven to be a useful tool in assessmentof dry weight in hemodialysis patients. We have shown thatBIS measurements during HD track ECF volume change andshow excellent correlation to ultrafiltrate removed and changein weight (77). Kouwet al. (78), using multiple frequencies,compared ECF and ICF in 29 hemodialysis patients and 31control subjects. Compared with control subjects, hemodialysispatients had markedly expanded ECF compartments predialy-sis, which were reduced to control values after dialysis. Pa-tients classified as underhydrated by comparison to controlsubjects experienced more hypotension and greater blood vol-ume changes adjusted for ultrafiltration. In a later study (79),they were able to show that gradually increasing dry weight inthese underhydrated patients resulted in gradual reductions inthe intradialytic change in blood volume and better hemody-namic tolerance of ultrafiltration. Fisch and Spiegel, usingresistive index (L2/R) to bone mineral content or lean bodymass ratios and multifrequency analysis confirmed that fluid isremoved primarily from the extracellular compartment duringhemodialysis (80). Katzarskiet al.were later able to show thatwhen their patients were divided into two groups based on thepresence or absence of hypertension, those with hypertensionhad larger TBW and ECF expressed as a percentage of bodyweight (81). Gradual reductions in body weight in these pa-tients were followed by concordant changes in volume by BISand BP. Thus, even when used singularly, bioimpedance anal-ysis is useful for detecting and managing both the over- andunderhydrated state in hemodialysis.

The limitations of this tool, however, are multiple. As dis-cussed previously, extrapolation of Re and Ri into volumetricterms is based on resistivity constants derived by regressionagainst bromide or deuterium space from a nonuremic patientpopulation. Hence, hydric volumes estimated for dialysis pa-tients from these equations must be interpreted with caution

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until more data are available. There has been some concern thatchanges in electrolyte composition and hematocrit may alterthe conducting properties of both the extracellular and intra-cellular fluid and thereby alter measurement of TBW (82).Sinning et al. (83), using a single frequency bioimpedanceanalysis measurement, did not find any correlation betweenchanges in electrolytes during the course of HD, whereaschanges in hematocrit and protein (reflecting reduction inblood volume [BV]) had a high correlation to measured resis-tance. Another concern is timing of the measurement. Al-though initial studies showed that ECF change during hemo-dialysis tracked well with UF volume, other investigators (84)

are not finding this to be the case. Indeed, in these studies (84)ECF change as measured by bioimpedance pre- and posthe-modialysis often underestimates UF volume by as much as30%. There are several possible explanations for this error, butthe most likely is the following: During cumulative ultrafiltra-tion, according to Daugirdas’ regional blood flow theory (85),a larger fraction of ultrafiltration is occurring from high flowlow resistance flow circuits in the body. That is, as dialysisproceeds, progressively more and more fluid is taken from thetrunk. The ability of bioimpedance to detect changes in volumeis roughly proportional to the resistance to current flow throughthat volume bed. Since the trunk contributes only 5% or 20

Table 2. Comparison of methodsa

Technique Benefits Limitations References

Biochemical markers Ease of useNo additional labor costHighly sensitive for the

volume overloaded stateReflective of intravascular

volume status

Difficult to use in heartfailure, tricuspid/mitralvalve disease

Cannot detect the“underhydrated” state

“Normal” range?Meaning of low value?

Benefits: 40,43,45,46,51,52Limitations: 44,47–49

Vena cava diameter Widely availableReflective of intravascular

volume statusChange in size correlates well

with ultrafiltration volume/hemodynamic parameters

Difficult to use in heartfailure

Overestimates degree ofdehydration postdialysis

Interoperator errorHighly variable/difficult to

normalize to population

Benefits: 60–62Limitations: 53,54,57,58,59

Bioimpedance Hydric volumes correlate wellwith isotope dilutionmethods

Ease of use, immediateresults

Reproducible/repeatableMeasurement of interstitial

space and ICFImmediate assessment of

nutritional statusHas potential to be readily

normalizedContinuous/hemodynamic and

static/dry weight utilitySensitive in detecting the

underhydrated state

Postdialysis measurementsof ECF oftenunderestimateultrafiltration volume

Underestimates volumeremoved from trunk

Accurate measurement ofICF confounded by

temperature and ioneffect

Accurate measurement ofECF confounded by effect

of recumbancy

Benefits: 74,77–79,81Limitations: 76,82–84

Blood volume monitoring Ease of use andunderstanding

Allows for concomitantprevention of hypotension

May be useful to screen foran inappropriately high orlow dry weight

Continuous plasma volumedependent on numerousfactors other thanhydration of theinterstitial space

Measures relative volumesonly

Interpatient variability

Benefits: 93–95Limitations: 89

a ECF, extracellular fluid; ICF, intracellular fluid.

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ohm to total body resistance due to its large cross-sectionalarea, removal of fluid from this segment escapes detection bywhole body bioimpedance techniques. Unfortunately, there isno simple solution to this problem, since accurate measurementof resistance to current flow through the trunk would requirelarge, cumbersome electrodes, and the heterogeneous nature oftrunk contents might make measured resistances unpredictable.Recently, Levin and Schneditzet al. used “sum of segmentalresistances” to confirm this hypothesis (86). And while dryweight, and hence ECF, should be assessed postdialysis, ICFmust be measured predialysis. Measurement of high frequencyimpedance is greatly affected by temperature and ion changesthat occur during hemodialysis. The result is the possibleoverestimation of intracellular fluid volume after hemodialysis.Despite its limitations, bioimpedance is a convenient, safe, andnoninvasive tool that, unlike the biochemical markers andVCD (which are markers of intravascular volume), can addi-tionally determine interstitial and intracellular fluid status.

Blood Volume MonitoringUltrafiltration during dialysis removes fluid from the intra-

vascular compartment and results in a progressive decline inBV (87). However, this decrease is limited by refilling from theinterstitial space (88). It is recognized that plasma refillingcapacity is influenced by several factors including the tissuehydration state (89). As long as plasma refilling can keep pacewith ultrafiltration, hypovolemia can be avoided and intradia-lytic complications reduced. Several investigators have ex-plored the use of noninvasive methods to monitor BV changesduring dialysis (90,91). In general, all of these methods arebased on measuring the change in hematocrit or protein con-centration during HD. The increase in hematocrit and protein isinversely proportional to the change in BV (91). Thus, it ispossible to assess the change in BV in real time during ahemodialysis treatment. Steueret al. (91,92) have describedthe use of an optical method to measure hematocrit that issimple, practical, and reliably tracks changes in BV. We have

used this device to monitor changes in BV in dialysis patientsand confirmed these observations, and demonstrated that inhypotension-prone patients, intradialytic symptoms are usuallypreceded by a consistent and predictable change in BV (93).Further investigation in this area suggests that it may be pos-sible to identify a threshold for each patient below whichintradialytic complications are likely (94). We have furtherdemonstrated that this method can be used to target non-constant ultrafiltration and reduce complications (95).

As an isolated technique for determination of dry weight,however, BV measurement has its limitations. The difficultythat arises in standardization of this technique is that differentpatients and disease states dictate different levels of vascularrefilling from the interstitial compartment, and thus it is anonquantifiable method of measurement. For example, there islittle agreement on whether rate of change, absolute change, orabsolute level of blood volume is or are predictive of hypo-tension. Different patients respond to different patterns, andtheir own pattern usually must be established over a period oftrial and error. In fact, some patients tolerate as much as 20%change in blood volume, whereas others (e.g., the elderly,diabetic patients, and patients with pulmonary hypertensionand congestive heart failure) cannot tolerate even the slightestchange. That said, in general, a flat blood volume line through-out dialysis in a patient who tolerated that session well hemo-dynamically suggests that that patient is not yet at his or her dryweight. On the other hand, multiple early rapid changes in BVaccompanied by symptoms are generally predictive of under-estimation of dry weight. A hypotensive episode in a patientwith a flat blood volume curve might be predictive of a seriousunderlying problem not related to hydration status, but thisremains to be proven.

Combination and Cross Validation of the TechniquesBecause each of the aforementioned techniques has its lim-

itations (Table 2), several studies have been done in an attemptto cross-validate the methods, or use them in combination in

Figure 1.Comparison of extracellular fluid volume (VECF) and blood volume (BV) changes during dialysis. A decrease in BV is associatedwith a decrease in VECF. At the end of ultrafiltration, BV is repleted while VECF continues to decline. VECFversus%BV total (up to 154min; r 5 0.718;P , 0.006); VECFversus%BV at the end of dialysis (ultrafiltration [UF] stopped to end;r 5 0.962;P , 0.001).

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hopes of better defining fluid shifts during dialysis and deter-mining dry weight.

Determination of Fluid Shifts. As changes in BV areproportional to the balance between ultrafiltration rates andplasma refilling, in the absence of ultrafiltration it is possible todetermine plasma refilling rates and absolute BV (96). Addi-tionally, if BIS measurements are combined with BV monitor-ing during dialysis, changes in the ECF and intravascularcompartments can be determined, permitting an estimate ofplasma refilling (97–99). We have used both of these tech-niques simultaneously and extended measurements for approx-imately 1 h after dialysis (Figure 1). Our data show that bothBIS (ECF) and hematocrit measurements (BV) have an excel-lent correlation with the volume of fluid removed (97). Bo-gaardet al. (98) had similar findings using a single frequencyBIS measurement and an optical method of hematocrit deter-mination. These authors used the ratio between change in BVand the volume of ultrafiltrate as a reflection of plasma refillingand found that there were significant differences in the rate ofchange in BV in dehydrated, normally hydrated, and overhy-drated patients. We have calculated absolute plasma volumeand plasma refilling rates at the end of dialysis and have shownthat at the end of dialysis there is a continued decline in ECFassociated with plasma refilling. This suggests that the inter-stitial fluid compartment contributes fluid for plasma refillingand may replenish the intracellular space (99) (Figure 2). Wehave subsequently calculated absolute plasma volume for dif-ferent time points during dialysis and, in conjunction with theECF measurements done simultaneously, have computed thevolume of interstitial fluid. The difference in change in BV and

ultrafiltration rate reflects the plasma refilling rate. Our datashow that there is a good correlation between interstitial fluidvolume and plasma refilling (99). De Vrieset al. (79) havefurther used both techniques to adjust dry weights in hemodi-alysis patients and thereby reduced the frequency of hypoten-sive episodes.

Determination of Dry Weight. Kouw et al. measuredroutine hemodynamic parameters noninvasively during dialy-sis and then stratified patients as over- or underhydrated basedon posthemodialysis measurements of caval diameter, conduc-tivity (lower extremity, single frequency [bioimpedance anal-ysis], ECF), cGMP levels, and ANP levels (62). They foundthat caval diameter and conductivity correlated well with ul-trafiltration volume, the dehydrated state, and each other, bothpre- and posthemodialysis. There was a weak correlation be-tween postdialysis cGMP levels, change in blood volume, andhemodynamic parameters, indicating that cGMP is less valu-able in assessing dry weight than either conductivity or cavaldiameter. When patients were separated by ANP levels, therewas no correlation with change in hemodynamics, caval diam-eter, or conductivity, indicating that it provides no value indefining dry weight in their study. Notably, caval diameterroutinely underestimated dry weight, whereas conductivityoverestimated dry weight. Both measurements were taken im-mediately after dialysis, raising the question as to whetherenough time had elapsed to allow refilling of the plasma fromthe interstitium. Note that this is a slightly different mechanismof overestimation of postdialysis ECF volume than stated in theabove discussion of bioimpedance. Another study by the samegroup that year compared bioimpedance and BV monitoring.

Figure 2.Postdialysis volume shifts from extracellular fluid (ECF) compartment as tracked by bioimpedance spectroscopy and simultaneousblood volume monitoring. At the end of dialysis, there is a shift of fluid from the extravascular (interstitial fluid) compartment, which includesa redistribution to the intravascular space and a compartmental shift to the intracellular space. There is a continued decline in ECF up to 30min postdialysis (as evaluated in these experiments). The influence of dialysate sodium concentration on the compartmental shifts has not beenevaluated. VECF, extracellular fluid volume; VICF, intracellular fluid volume; PV, plasma volume.

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They stratified patients as underhydrated, normal, or overhy-drated based on previously developed conductivity criteriataken postdialysis and then measured blood volume changesand hemodynamic parameters in these three groups (94). Theyfound that in the underhydrated group, there was significantlygreater change in overall blood volume corrected for ultrafil-tration volume and more hypotensive episodes compared withnormal or overhydrated patients. Conversely, Lopotet al.recently stratified patients based on blood volume profilescharacterized as overhydrated, normal, and underhydrated, andthen compared these profiles with conductivity measurementsand VCD (100). Those with blood volume profiles indicativeof overhydration had larger postdialysis values of ECF andVCD. Likewise, those characterized as underhydrated on thebasis of rapid changes in blood volume had smaller postdialy-sis ECF and VCD values. This is perhaps the only studyutilizing and confirming the blood volume method as a screen-ing tool to detect an inappropriately high dry weight. In thethird part of Katzarskiet al.’s study showing hypertension asdependent on bioimpedance-determined volume (81), they ad-ditionally showed that ECF and VCD decreased in tandemduring dialysis and correlated well postdialysis. Thirty minutespostdialysis, VCD increased markedly, likely indicative ofplasma refilling from the interstitial space. However, ECFvalues remained stable. We believe that this might be due torefilling of plasma volume from more easily accessible fluidsites not measured by bioimpedance due to the peripheralarrangement of electrodes in this study.

Beyond Dry Weight? An Index for Adequacy ofFluid Removal

From the above discussion, it is evident that contemporarymanagement of fluid in the dialysis patient is largely dependenton a clinically derived estimate of dry weight. Clinical assess-ment of dry weight inevitably leads to both overestimation andunderestimation of dry weight. Overestimation of dry weightleads to hypertension, stroke, and congestive heart failure,which are the main causes of excess death in dialysis. Under-estimation leads to persistent hypotensive episodes, alienatingdialysis patients from their caretakers, and affecting delivery ofprescribed dialysis. Moreover, the current focus on Kt/V as anindex for adequacy of dialysis in terms of solute removalignores the contribution of volume as an independent factorinfluencing outcome. Unfortunately, despite this recognitionwe have not attempted to rectify this problem in any systematicway. It is our belief that a possible approach to this problem isthe development of an index for adequacy for fluid manage-ment.

Peritoneal dialysis provides the ideal model for achievingdry weight, since slow continuous peritoneal ultrafiltrationpermits physiologic or perhaps subphysiologic dry bodyweight control of BP. The goal for fluid removal in HD is toattain a lower than physiologic dry weight immediately post-dialysis, allowing a time-averaged physiologic dry weight inthe interdialytic period. This would be particularly true forpatients without large interdialytic weight gains (,2 L), con-

gestive heart failure, left ventricular disorders, diabetic auto-nomic neuropathy, severe hypoalbuminemia, or other condi-tions predisposing to hypotension in dialysis. On the otherhand, physiologic dry weight might be an appropriate goal forpatients with persistent large interdialytic weight gains or theabove conditions that predispose to hypotension. Furthermore,the use of nonlinear ultrafiltration may assist dry weightachievement in these patients (95). Because of this complexity,it is easy to recognize that objective tools used for estimatingdry weight are necessary. However, the individual techniqueseach have limitations or are inherently insufficient for singularuse in dry weight assessment (Table 2). Therefore, some com-bination of these tools will need be used to achieve this goal.Furthermore, dry weight assessment might further be stratifiedinto two major categories: (1) the interdialytic measurement ofstatic dry weight and body composition and (2) intradialyticassessment of online data or comparison of pre- and posthe-modialysis data. Either might be used on a monthly or otherperiodic basis as a means of following dry weight and derivingan index of adequacy for fluid removal (101).

We have extensively reviewed the technologic methods foractual measurement of volume status in dialysis patients asthey have developed thus far, as well as addressed their limi-tations. Further development of these techniques is necessaryfor attaining an easily derived and utilized index for adequacyof fluid removal. The development of this index should beundertaken whereby both interdialytic and intradialytic meth-ods will be described and utilized on a periodic basis. Pendingfurther research and development, the interdialytic measure-ment of dry weight and body composition will perhaps be bestaccomplished with bioimpedance spectroscopy, because of itsunique ability to provide insight into nutritional status as well.Intradialytic methods will arise out of further interrogation offluid shifts that occur during dialysis. At some point, thesetechnologies might be incorporated into dialysis machineswhereby volumetric control of ultrafiltration will take on a newmeaning and result in profiled dialysis. It is obvious that wehave a long way to go, however, it is our belief that recognitionof the need for this process is an initial step that will hopefullyresult in further investigation in this field.

AcknowledgmentWe thank Dr. Robert Steiner for his recommendations and assis-

tance in preparation of this manuscript.

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