REVIEW J Am Soc Nephrol 10: 392–403, 1999

Assessment of Dry Weight in Hemodialysis: An Overview

JACK Q. JAEGER and RAVINDRA L. MEHTA Division of , Department of Medicine, University of California, San Diego, California.

Abstract. is an integral component of hemodial- information on the effect of on fluid shifts in the ysis treatments to prevent under- or overhydration, both of extracellular and intracellular fluid spaces. It is evident that a which have been demonstrated to have significant effects on better understanding of both interdialytic fluid status and fluid intradialytic morbidity and long-term cardiovascular compli- changes during hemodialysis is required to develop a precise cations. Fluid removal is usually achieved by ultrafiltration to measure of fluid balance. This article describes the current achieve a clinically derived value for “dry weight.” Unfortu- status of dry weight estimation and reviews emerging tech- nately, there is no standard measure of dry weight and as a niques for evaluation of fluid shifts. Additionally, it explores consequence it is difficult to ascertain adequacy of fluid re- the need for a marker of adequacy for fluid removal. moval for an individual patient. Additionally, there is a lack of

Fluid removal to achieve fluid balance is an important com- What is Dry Weight? ponent of hemodialysis (HD) treatment for end-stage renal The standard HD prescription targets fluid removal to a disease (ESRD), as both under- or overhydration are associated clinically derived estimate of dry weight. Dry weight is cur- with deleterious consequences. Despite considerable advances rently defined as the lowest weight a patient can tolerate in assessment of adequacy with respect to solute re- without the development of symptoms or hypotension (1). moval, there is at present no measure of adequacy for fluid Since physiologic dry weight is that weight resulting from removal. The majority of HD treatments incorporate a pre- normal renal function, vascular permeability, serum protein scription for fluid removal targeted to a patient’s “dry weight.” concentration, and body volume regulation, dry weight in HD In most centers, dry weight is clinically determined and usually should theoretically be lower than physiologic to prophylax reflects the lowest weight a patient can tolerate without intra- interdialytic weight gains. In most instances, dry weight is dialytic symptoms and hypotension in the absence of overt estimated by trial and error, and the degree of imprecision is fluid overload (1).This trial-and-error method is imprecise and reflected in the development of intradialytic symptoms or does not account for changes in nutritional status and lean body chronic volume overload with poor control of BP (2,3). From a clinical standpoint, the aim of HD is to normalize the milieu mass. As a consequence, it is difficult to determine whether an interior as much as possible. The healthy human body at steady individual patient is over- or underhydrated. Additionally, the state is composed of several fluid and solid compartments dry weight is used to calculate ultrafiltration (UF) volume and (Table 1) (4), which are maintained within tight boundaries. An rates for each dialysis treatment. It is well recognized that accurate assessment of a patient’s volume status requires intradialytic complications are influenced by the balance be- knowledge of three factors: (1) the capacity of body compart- tween ultrafiltration rates and plasma refilling. UF rates in ments (e.g., [ECF] and intracellular fluid excess of plasma refilling capacity predispose to dialysis- [ICF]); (2) the amount of water in each compartment; and (3) induced hypotension. It is evident that better methods of de- the solute content (e.g., sodium), which may affect fluid shifts termining volume changes during HD are required for defining between compartments, interdialytic weight gain, and have an the goal for fluid removal and to develop strategies for safer effect on the success of fluid removal during HD. Compart- dialysis treatments. This article describes the current status of ment size, amount of water, and content of solutes can be dry weight estimation and reviews emerging techniques for independently estimated by different techniques (as discussed evaluation of fluid shifts. Additionally, it explores the need for below), however, all three must be considered in the definition a marker of adequacy for fluid removal. 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- Received April 29, 1998. Accepted August 14, 1998. ferred to above. 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] Problems Associated with an Inaccurate 1046-6673/1002-0392$03.00/0 Assessment of Dry Weight Journal of the American Society of Nephrology At initiation of dialysis, most patients have typically been Copyright © 1999 by the American Society of Nephrology catabolic for several months due to chronic illness. At the same J Am Soc Nephrol 10: 392–403, 1999 Assessment of Dry Weight in Hemodialysis: An Overview 393

Table 1. Body fluid compartmentsa portant to note that in Vertes’ study of 40 patients, an early benchmark study of this concept, only five were truly hyper- Percent of Total Body Weight reninemic, all of them responding adversely to volume deple- Percent of tion and favorably to bilateral nephrectomy (7). Also, in Compartment Total Normal Normal Charra’s group of patients treated with long, slow hemodialy- Adult Adult Man Woman sis, less than 2% remained hypertensive off antihypertensive agents, thus deemphasizing -dependent mechanisms of Intracellular fluid 55 33 27.5 hypertension in the general dialysis population (11). Indeed, Extracellular fluid 45 27 22.5 Fishbane et al. used plasma atrial natriuretic peptide (ANP), a Interstitial fluid 20 12 10 marker of intravascular hypervolemia, to show that dialysis- Plasma 7.5 4.5 3.75 resistant hypertensive patients were actually volume over- Bone 7.5 4.5 3.75 loaded at the end of dialysis (8). Others have confirmed that Connective tissue 7.5 4.5 3.75 removing excess salt and water during maintenance hemodial- Transcellular 2.5 1.5 1.25 ysis normalizes BP in at least 70% of cases (9), while it has Total body water 100 60 50 also been shown that postdialytic BP correlates with total body water by bioimpedance spectroscopy (10). Although other non- a Adapted from Edelman and Leibman, 1959 (4). volume-related mechanisms for dialysis-resistant hypertension have been forwarded, such as sympathetic nervous system hyperactivity (14,15), endothelins (16), and , the time, adequate excretion of salt and water has given way to preponderance of evidence points toward chronic volume over- progressive dropout. This altered bodily fluid physi- load as the major cause of hypertension in the ESRD and ology results in a shrunken body cell mass with a relatively dialysis population. expanded extracellular space. As dialysis improves the uremic Hypertension and Excess Death in Hemodialysis Pa- state, an increase in lean body mass may occur undetected due tients. According to the U.S. Renal Data System (USRDS) to a coincident reduction in extracellular volume. Similarly, a (17), cardiovascular disease and stroke are the most prevalent reduction in lean body mass and a consequent increase in the causes of morbidity and mortality in dialysis patients, which in extracellular fluid may go unnoticed during an acute illness. turn have been linked to markers of volume overload. These Complicating this issue further is the fact that, barring a large markers include hypertension, left ventricular dysfunction, and interdialytic weight gain, a dialysis patient may not have left ventricular hypertrophy. In the general nonuremic popula- achieved their dry weight, yet still suffer intradialytic hypoten- tion, hypertension is a major cause of cardiovascular and sive episodes routinely for various nonvolume reasons. Con- cerebrovascular morbidity and mortality (18,19). As would be versely, they may arrive at and leave dialysis normotensive, expected, hypertension has been linked to excess cardiovascu- nonedematous, and without any other overt signs of fluid lar and cerebrovascular adverse events in dialysis patients as overload, yet remain quite above their true dry weight. Ambu- well (20). Indeed, in an analysis of iliac artery biopsies at time latory BP monitoring has been, to this point, the only way to of transplant in 50 nondiabetic hemodialysis patients, the pres- diagnose this silent hypervolemia, which may lead to the ence of atherosclerosis was found to be independent of lipid development of hypertension as late as 12 h after leaving the abnormalities and duration on dialysis, but correlated almost dialysis unit (5,6). Recognition of these changes is an integral exclusively with the presence of hypertension (21). Others component of the clinical acumen of the nephrologist. How- have agreed that BP control is essential for prolonged survival ever, the appropriate adjustment of dry weight may not always (22). And while Charra et al.’s (11) cohort of patients are be timely or precise as reflected by the complications of over- younger, narrowly representative of the general dialysis pop- and underhydration and intradialytic morbid events, which are ulation, and uncontrolled for other unknown beneficial effects discussed further. of long, slow hemodialysis, their 75% 10-yr survival rate associated with excellent dry weight control of BP remains the Overestimation of Dry Weight most compelling evidence for the beneficial effects of BP Hypertension. Studies have shown that at least 80% of all control (23). It is thus evident that if dry weight is the major hypertension in dialysis patients is due to chronic hypervol- component of hypertension, and hypertension is a major pre- emia (5,7–11). Early animal studies by Langston and Guyton in dictor of death in dialysis patients, we should be focusing on 1963 and 1969 (12) suggested that chronic volume overload dry weight. led to secondarily increased peripheral vascular resistance, Cardiac Dysfunction. Although it is difficult to separate even in nephrectomized dogs. At the same time, a subset of cause and effect when discussing the various cardiac disorders dialysis-resistant hypertensive patients with high serum renin in hemodialysis patients, it seems that an excessive dry weight activity were described, which led to the dichotomous descrip- is a sufficient risk factor allowing the final expression of tion of hypertension in dialysis patients: salt-water dependent cardiac dysfunction and indirectly, sudden death. In 1836, and renin-dependent (7). Some studies have categorized up to Bright first noted autopsy findings of left ventricular hypertro- half of their hypertensive patients as dialysis-resistant, imply- phy in patients dying of ESRD (24). As discussed previously, ing a renin-dependent mechanism (5,13). However, it is im- the majority of patients are hypertensive at presentation to 394 Journal of the American Society of Nephrology J Am Soc Nephrol 10: 392–403, 1999 dialysis, largely due to impaired salt and water excretion, and Underestimation of Dry Weight given the known association of chronic hypervolemia and Underestimation of dry weight is more likely to be recog- hypertension, and hypertension and left ventricular hypertro- nized due to its immediate consequences of intradialytic mor- phy (LVH) (25), it is no surprise that most ESRD patients bidity. It usually occurs when there is a failure to adjust the present to dialysis with LVH as well (26–29). LVH addition- ultrafiltration prescription to account for increases in either ally has been shown to be deleterious to hemodialysis patients lean body mass or fat mass over time. A previously stable for several reasons: (1) similar to nonuremic patients, it is patient becomes frequently hypotensive during hemodialysis, predictive of an increased incidence of myocardial infarction but the change in ultrafiltration prescription is often delayed (30), congestive heart failure (31), and sudden death (32); and either due to physician reluctance to change the dry weight, or (2) LVH can lead to diastolic dysfunction, which has been to efforts to investigate other more threatening etiologies of linked to an increased incidence of intradialytic morbid events hypotension. This situation, one of patients’ most frequent (33). Indeed, Parfrey et al. showed that 40% of their cohort of complaints (37), leads to patient dissatisfaction with the dial- dialysis patients with congestive heart failure had hypertrophic ysis prescription, early withdrawal from dialysis, failure to changes, 43% had either LV dilation or systolic dysfunction, arrive at the dialysis unit, and frequent interrupted sessions, all and only 16% had normal echocardiograms upon presentation of which lead to reduced solute removal. The resulting inade- to dialysis (31). LVH was thought to be due to chronically quate solute removal leads to decreased appetite, poor intake, increased afterload, while dilation and systolic dysfunction and subsequently to poor nutritional status, which have their were thought to be due to chronic hypervolemia. Although own adverse effects on dialysis outcome. On the other hand, these changes did not regress over the 17-mo follow-up, there not knowing the true dry weight of a patient, one might attempt was no intervention to lower the clinically derived dry weight. to mitigate frequent hypotensive events due myocardial is- Both forms of left ventricular abnormalities were associated chemia, pericardial effusion, cardiac arrythmia, or other disor- with a markedly poor median survival from 38 to 56 mo. As ders by increasing the dry weight goal, thus missing the diag- stated above, however, it is probable that both types of ven- nosis of a more serious underlying condition. tricular abnormality are volume-related. LV dilation and sys- tolic dysfunction are probably a form of burnt-out hypertensive Measuring Dry Weight heart disease due to an imbalance between appropriate hyper- It is obvious from the above discussion that clinical assess- trophy and cell death and fibrosis. Other studies have shown ment of dry weight is crude and often imprecise. Recently, the link between chronic hypervolemia and the development of several different techniques have been used to derive a more LVH in dialysis patients as well (34). standard method of assessing dry weight (38–41). However, It is obviously important to recognize that other risk factors no single method has emerged as a gold standard, as there is no for the development of LVH are increased age, diabetes mel- clear-cut definition of what constitutes dry weight. The follow- litus, anemia, and possibly hyperparathyroidism, and for LV ing section reviews these methods as they have been devel- dilation, anemia, ischemic heart disease, and hypoalbumine- oped, and offers a critical appraisal of their use. mia. Likewise, these disorders are present at the initiation of dialysis, and have not been shown to be reversible in hemodi- Biochemical Markers alysis patients. However, regression of LV dilation and LVH Atrial Natriuretic Peptide. ANP is a peptide hormone has been shown in studies in normal populations (35), and synthesized, stored, and released in atrial tissue in response to perhaps most intriguing are studies showing regression of LVH changes in atrial transmural pressure. The hormone follows the in hypertensive ESRD patients started on continuous ambula- usual cleavage synthesis pathway as a prepro-, pro-, and a tory peritoneal dialysis (36). It is therefore possible that ag- biologically active 28 amino acid peptide. It is rapidly de- gressive control of volume may lead to regression of left graded, primarily by the kidney, but also by other organs, with ventricular abnormalities, which are surrogate markers for poor a serum half-life of 2 to 4 min. Its end-organ effects and role survival in hemodialysis patients. in maintenance of salt and water homeostasis, which are well Missing Changes in Lean Body Mass. There is also the characterized elsewhere (42), as well as its short half-life and occasional patient who has achieved their so-called dry weight, somewhat minimal by hemodialysis, initiated excite- but over time subtle negative changes in lean body mass occur ment about its possible role in determining fluid status in due to inadequate dialysis prescription, inadequate dialysis hemodialysis patients. Rascher et al. were the first to suggest delivery, comorbid illness, depression, or other causes. This its use as an indicator of volume status in hemodialysis (43). In change might not be reflected in serum albumin or kinet- this and subsequent studies (44,45), ANP levels were found to ics studies, and failure to adjust dry weight results in a greater be elevated in hemodialysis patients, before dialysis, relative to proportion of their body weight becoming ECF. An increase in control subjects, and levels were significantly lower after both BP with recognition of lean body mass change and consequent hemofiltration (45) and hemodialysis (44). Plasma ANP levels adjustment of dry weight may occur. Alternatively, there may correlated with BP, and although ANP levels changed signif- be no BP response to this ECF expansion, a failure to adjust icantly during HD, in most studies postdialysis levels remained dry weight downward, and henceforth failure to identify this significantly higher than controls (43,44). Others (46–48) have subtle change in nutritional status. Such small changes in established marked interpatient variability and persistent post- nutritional status might be significant for the patient. dialysis elevation. Additionally, ANP levels have been shown J Am Soc Nephrol 10: 392–403, 1999 Assessment of Dry Weight in Hemodialysis: An Overview 395 to be persistently elevated after HD in patients with altered left central blood volume were first undertaken by Natori et al. in atrial hemodynamics compared to those with normal left atrial 1979 (55). They showed that supine measurements of caval hemodynamics (49), making ANP levels difficult to interpret diameter taken during expiration and its inspirational decrease in this setting. As discussed previously, Fishbane et al.’s (8) in diameter correlated well with central venous pressure. Ando cohort of persistently hypertensive patients had high plasma et al. (1985) were the first to quantify VCD changes during ANP, and were not believed to be at their dry weight, raising hemodialysis (56). In 1989, Cheriex et al. attempted to use this the possibility that the persistent postdialysis ANP elevations technique to assess dry weight in hemodialysis patients, show- in the previously mentioned studies might have been due to ing that postdialysis measurement of inferior caval diameter inadequate dry weight achievement or the presence of altered taken subdiaphragmatically correlated with right atrial pressure left atrial hemodynamics. Kojima et al. (46) showed that and circulating blood volume (57). Linear regression to right plasma ANP levels were still routinely elevated after hemodi- atrial pressure defined overhydration as a caval diameter alysis even when patients are determined to be clinically at greater than 11 mm/m2 body surface area or a collapsible index their dry weight. But in this study, ANP also correlated well (Expiratory caval diameter Ϫ Inspiratory caval diameter/Expi- with BP. A possible explanation for the persistently elevated ratory diameter ϫ 100%) as less than 40%. Underhydration levels of ANP in this study may be that these patients were was defined as a caval diameter of less than 8 mm/m2 and a really not at their dry weight as evidenced by the persistent collapsible index of greater than 75%. Nearly two-thirds of hypertension. Because of these uncertainties, a serum level at their patients who had met clinical criteria for dry weight were which ANP should be predictive of dry weight in a dialysis actually hypervolemic, according to these criteria. Those who patient is a matter of considerable controversy. In summary, were considered underhydrated by these criteria had greater plasma ANP is sensitive for detecting overhydrated patients, increases in heart rate and stroke volume, and greater decreases but not specific. Concordantly, it often remains elevated in dry in BP during dialysis when compared to their normally or individuals and hence is not sensitive in detecting underhy- overhydrated counterparts. Others have not been able to con- drated patients. A low ANP value’s specificity for detecting firm these findings. Mandelbaum et al. found a wide range of underhydration is unknown. caval diameters in their dialysis population, and they were not Cyclic Guanidine Monophosphate (cGMP). cGMP is correlated to age, height, weight, or body surface area of the generated when ANP activates membrane-bound guanylate patients (58), thus rejecting the “nomogram”-based generali- cyclase, and hence was predicted to be an indicator of volume zation of this measurement to the general dialysis population. status in dialysis patients (50). This biochemical marker was Franz et al. divided their patients into three groups of hydration perhaps best systematically studied by Lauster et al. status based on Cheriex et al.’s criteria above and showed that (40,51,52). Because cGMP is more stable in serum at room mean cGMP levels were higher in the hypervolemic group temperature than ANP (53), and the RIA for cGMP is some- compared with the normovolemic and underhydrated patients, what less arduous, it was believed that cGMP would poten- but there was no statistically significant linear correlation be- tially be a better marker than ANP for the routine assessment tween caval size and cGMP level (54). In their study, as would of fluid status. Their studies determined: (1) that cGMP levels be expected, a major limitation of this technique was measur- of 20 pmol/L immediately postdialysis correlated with achieve- ing volume status in patients with heart failure. The presence of ment of clinical dry weight; (2) the majority of those with tricuspid insufficiency requires its own criteria for assessment postdialysis levels greater than 20 pmol/L had evidence of fluid of volume status via vena caval diameter (59). On the other overload or congestive heart failure; (3) that reductions in dry hand, Katzarski et al. used VCD to confirm the volume hy- weight in these remaining patients were associated with both a pothesis of hypertension in hemodialysis patients (60). They reduction in cGMP levels to approximately 20 pmol/L and studied two cohorts of hypertensive and normotensive patients clinical resolution of the fluid overloaded state; and (4) those and showed that caval diameter was significantly larger post- whose levels could not be lowered beyond this point had left dialysis in their group of hypertensive patients. Leunissen et al. ventricular dysfunction. However, these measurements were (61) and Kouw et al. (62) have subsequently shown that not validated against other objective parameters, and others postdialysis VCD measurements reliably predict hemodynamic have not confirmed these findings. Franz et al. found that 28% changes during dialysis. In summary, while interpatient and of their patients had postdialysis cGMP levels of greater than interoperator variability and the presence of right-sided failure 20 pmol/L, the majority of which were in sinus rhythm, had no limit its use, VCD may be better suited than the biochemical evidence of congestive heart failure, and were not believed to markers for prediction of the underhydrated state. be fluid overloaded (54). As with ANP, the meaning of a low level is unknown, and cGMP levels are influenced by cardiac Bioimpedance Analysis and Bioimpedance or valvular dysfunction, thus limiting its clinical utility in this Spectroscopy setting. Single or Dual Frequency Bioimpedance Analysis. The basic principles of bioimpedance were initially described by Vena Cava Diameter Thomassett in 1963 (63), but the technique first gained prom- Because echocardiographic examination of the inferior vena inence in the early 1970s when Nyboer reported that the cava diameter (VCD) is simple, quick, and noninvasive, efforts impedance of the body to an alternating current roughly cor- to standardize its dimensional characteristics in relationship to related with changes in blood volume (64). These measure- 396 Journal of the American Society of Nephrology J Am Soc Nephrol 10: 392–403, 1999 ments are based on the basic principle that the electrical im- measurement differences. (2) Intuitively, extrapolation of data pedance of a cylinder is directly proportional to its length and to zero and infinite frequencies is probably more accurate than inversely proportional to its cross-sectional area multiplied by arbitrarily choosing a single frequency for analysis, for the its specific resistivity. Application of simple multiplication and same reasons as above. rearrangement resulted in the equation for volume V ϭ L2/Z, A few studies have compared the techniques. Ho et al. found where V is specific resistivity, L is length, and Z is the mea- that both techniques correlated very well with TBW by deute- sured impedance. Operating on the assumption that the human rium space (74). However, multifrequency modeling of TBW body is a sum of homogeneous cylinders, and that current was slightly more precise than the linear equation (6.2 versus would pass only through ion- and water-containing media, in 6.7%, respectively). And while multifrequency bioimpedance 1969 Hoffer was the first to attempt to measure total body tended to consistently underestimate TBW, the linear equation water by this method (65). In his and subsequent analyses (66), both over- and underpredicted TBW with more scatter along Height2/Impedance at a frequency of 50 kHz indeed showed the line of identity. Another study revealed that modeled bio- the best-fit regression to deuterium water space with a corre- impedance spectroscopy (BIS) and dual frequency resistances lation coefficient of 0.92. Subsequent multiple equations based showed very little intermeasurement differences (Ϯ 0.04), thus on variations of this principal, usually with the addition of confirming the underling Cole modeling scheme of BIS (75). gender-specific dummy variables or anthropometric parame- Whether one uses single, dual, or multiple frequency modeling, ters have been derived (67–70). Although this technique is one could make the argument that there is no need to extrap- simple and remains valid for the measurement of total body olate these resistances to volume terms, since (1) resistivity water, single frequency analysis is unable to distinguish be- constants (or components therein) are derived in a linear man- tween intracellular and extracellular compartments. Based on ner from nonuremic populations, and (2) their calculation the assumption that a low frequency current would transgress involves the use of Hanai mixture theory, which has not been only the extracellular space, Jenin et al. in 1975 first used a low validated in whole organisms (76). 1-kHz frequency paired with a 100-kHz frequency to estimate Bioimpedance and Dry Weight: Clinical Utility. Bioim- ECF volume and ICF volume separately (71). In 1988, pedance analysis has proven to be a useful tool in assessment Lukaski, using a single frequency method and a regression of dry weight in hemodialysis patients. We have shown that equation including reactance, improved the correlation to bro- BIS measurements during HD track ECF volume change and mide space to 0.83 (70). Standard error of estimate for both show excellent correlation to ultrafiltrate removed and change single and double frequency methods ranges from 1.5 to 3.5 L. in weight (77). Kouw et al. (78), using multiple frequencies, Bioimpedance Spectroscopy, the Multifrequency Ap- compared ECF and ICF in 29 hemodialysis patients and 31 proach. Multiple frequency analyzers were developed to control subjects. Compared with control subjects, hemodialysis take advantage of the dielectric theory of electrical conduction patients had markedly expanded ECF compartments predialy- through mixed, emulsified bodies (72). In this theory, conduc- sis, which were reduced to control values after dialysis. Pa- tion of current through the intracellular space is modeled as tients classified as underhydrated by comparison to control flow through innumerably different parallel circuits consisting subjects experienced more hypotension and greater blood vol- of a capacitance and a resistance in series, while parallel flow ume changes adjusted for ultrafiltration. In a later study (79), through the extracellular space is limited only by the resistance they were able to show that gradually increasing dry weight in to flow through ion and water. The result is that at low these underhydrated patients resulted in gradual reductions in frequencies, current cannot bridge the cell membrane (capac- the intradialytic change in blood volume and better hemody- itor) and will flow only through the extracellular space, while namic tolerance of ultrafiltration. Fisch and Spiegel, using at increasingly higher frequencies the cell membrane capaci- resistive index (L2/R) to bone mineral content or lean body tors will offer less and less reactance. As reactance approaches mass ratios and multifrequency analysis confirmed that fluid is zero, impedance is purely resistance, and resistance at this removed primarily from the extracellular compartment during frequency reflects the resistance of total body water (TBW). hemodialysis (80). Katzarski et al. were later able to show that Current analyzers offer frequency ranges from 1 kHz to 1 when their patients were divided into two groups based on the MHz, plot impedance loci at these frequencies, and extrapolate presence or absence of hypertension, those with hypertension reactance to zero along the locus via curve fitting at infinite had larger TBW and ECF expressed as a percentage of body extremes of frequency. What results are imaginary-real resis- weight (81). Gradual reductions in body weight in these pa- tances where true resistance for ECF (Re) and resistance for tients were followed by concordant changes in volume by BIS TBW values should theoretically lie (Resistance of ICF [Ri] is and BP. Thus, even when used singularly, bioimpedance anal- computed from the component circuit). These resistance values ysis is useful for detecting and managing both the over- and and the patient’s height, weight, gender, and Hanai mixture underhydrated state in hemodialysis. equations are used to extrapolate to volume (73). The potential The limitations of this tool, however, are multiple. As dis- advantages of this approach over linear single and double cussed previously, extrapolation of Re and Ri into volumetric frequency measurements are: (1) Complex impedance at any terms is based on resistivity constants derived by regression single frequency (characteristic frequency) may be different against bromide or deuterium space from a nonuremic patient from patient to patient or from time to time. Thus, curve fitting population. Hence, hydric volumes estimated for dialysis pa- and extrapolation may help smooth out these interpatient and tients from these equations must be interpreted with caution J Am Soc Nephrol 10: 392–403, 1999 Assessment of Dry Weight in Hemodialysis: An Overview 397

Table 2. Comparison of methodsa

Technique Benefits Limitations References

Biochemical markers Ease of use Difficult to use in heart Benefits: 40,43,45,46,51,52 No additional labor cost failure, tricuspid/mitral Limitations: 44,47–49 Highly sensitive for the valve disease volume overloaded state Cannot detect the Reflective of intravascular “underhydrated” state volume status “Normal” range? Meaning of low value? Vena cava diameter Widely available Difficult to use in heart Benefits: 60–62 Reflective of intravascular failure Limitations: 53,54,57,58,59 volume status Overestimates degree of Change in size correlates well dehydration postdialysis with ultrafiltration volume/ Interoperator error hemodynamic parameters Highly variable/difficult to normalize to population Bioimpedance Hydric volumes correlate well Postdialysis measurements Benefits: 74,77–79,81 with isotope dilution of ECF often Limitations: 76,82–84 methods underestimate Ease of use, immediate ultrafiltration volume results Underestimates volume Reproducible/repeatable removed from trunk Measurement of interstitial Accurate measurement of space and ICF ICF confounded by Immediate assessment of temperature and ion nutritional status effect Has potential to be readily Accurate measurement of normalized ECF confounded by effect Continuous/hemodynamic and of recumbancy static/dry weight utility Sensitive in detecting the underhydrated state Blood volume monitoring Ease of use and Continuous plasma volume Benefits: 93–95 understanding dependent on numerous Limitations: 89 Allows for concomitant factors other than prevention of hypotension hydration of the May be useful to screen for interstitial space an inappropriately high or Measures relative volumes low dry weight only Interpatient variability

a ECF, extracellular fluid; ICF, intracellular fluid. until more data are available. There has been some concern that are not finding this to be the case. Indeed, in these studies (84) changes in electrolyte composition and hematocrit may alter ECF change as measured by bioimpedance pre- and posthe- the conducting properties of both the extracellular and intra- modialysis often underestimates UF volume by as much as cellular fluid and thereby alter measurement of TBW (82). 30%. There are several possible explanations for this error, but Sinning et al. (83), using a single frequency bioimpedance the most likely is the following: During cumulative ultrafiltra- analysis measurement, did not find any correlation between tion, according to Daugirdas’ regional blood flow theory (85), changes in electrolytes during the course of HD, whereas a larger fraction of ultrafiltration is occurring from high flow changes in hematocrit and protein (reflecting reduction in low resistance flow circuits in the body. That is, as dialysis blood volume [BV]) had a high correlation to measured resis- proceeds, progressively more and more fluid is taken from the tance. Another concern is timing of the measurement. Al- trunk. The ability of bioimpedance to detect changes in volume though initial studies showed that ECF change during hemo- is roughly proportional to the resistance to current flow through dialysis tracked well with UF volume, other investigators (84) that volume bed. Since the trunk contributes only 5% or 20 398 Journal of the American Society of Nephrology J Am Soc Nephrol 10: 392–403, 1999

Figure 1. Comparison of extracellular fluid volume (VECF) and blood volume (BV) changes during dialysis. A decrease in BV is associated with a decrease in VECF. At the end of ultrafiltration, BV is repleted while VECF continues to decline. VECF versus %BV total (up to 154 min; r ϭ 0.718; P Ͻ 0.006); VECF versus %BV at the end of dialysis (ultrafiltration [UF] stopped to end; r ϭ 0.962; P Ͻ 0.001). ohm to total body resistance due to its large cross-sectional used this device to monitor changes in BV in dialysis patients area, removal of fluid from this segment escapes detection by and confirmed these observations, and demonstrated that in whole body bioimpedance techniques. Unfortunately, there is hypotension-prone patients, intradialytic symptoms are usually no simple solution to this problem, since accurate measurement preceded by a consistent and predictable change in BV (93). of resistance to current flow through the trunk would require Further investigation in this area suggests that it may be pos- large, cumbersome electrodes, and the heterogeneous nature of sible to identify a threshold for each patient below which trunk contents might make measured resistances unpredictable. intradialytic complications are likely (94). We have further Recently, Levin and Schneditz et al. used “sum of segmental demonstrated that this method can be used to target non- resistances” to confirm this hypothesis (86). And while dry constant ultrafiltration and reduce complications (95). weight, and hence ECF, should be assessed postdialysis, ICF As an isolated technique for determination of dry weight, must be measured predialysis. Measurement of high frequency however, BV measurement has its limitations. The difficulty impedance is greatly affected by temperature and ion changes that arises in standardization of this technique is that different that occur during hemodialysis. The result is the possible patients and disease states dictate different levels of vascular overestimation of intracellular fluid volume after hemodialysis. refilling from the interstitial compartment, and thus it is a Despite its limitations, bioimpedance is a convenient, safe, and nonquantifiable method of measurement. For example, there is noninvasive tool that, unlike the biochemical markers and little agreement on whether rate of change, absolute change, or VCD (which are markers of intravascular volume), can addi- absolute level of blood volume is or are predictive of hypo- tionally determine interstitial and intracellular fluid status. tension. Different patients respond to different patterns, and their own pattern usually must be established over a period of Blood Volume Monitoring trial and error. In fact, some patients tolerate as much as 20% Ultrafiltration during dialysis removes fluid from the intra- change in blood volume, whereas others (e.g., the elderly, vascular compartment and results in a progressive decline in diabetic patients, and patients with pulmonary hypertension BV (87). However, this decrease is limited by refilling from the and congestive heart failure) cannot tolerate even the slightest interstitial space (88). It is recognized that plasma refilling change. That said, in general, a flat blood volume line through- capacity is influenced by several factors including the tissue out dialysis in a patient who tolerated that session well hemo- hydration state (89). As long as plasma refilling can keep pace dynamically suggests that that patient is not yet at his or her dry with ultrafiltration, hypovolemia can be avoided and intradia- weight. On the other hand, multiple early rapid changes in BV lytic complications reduced. Several investigators have ex- accompanied by symptoms are generally predictive of under- plored the use of noninvasive methods to monitor BV changes estimation of dry weight. A hypotensive episode in a patient during dialysis (90,91). In general, all of these methods are with a flat blood volume curve might be predictive of a serious based on measuring the change in hematocrit or protein con- underlying problem not related to hydration status, but this centration during HD. The increase in hematocrit and protein is remains to be proven. inversely proportional to the change in BV (91). Thus, it is possible to assess the change in BV in real time during a Combination and Cross Validation of the Techniques hemodialysis treatment. Steuer et al. (91,92) have described Because each of the aforementioned techniques has its lim- the use of an optical method to measure hematocrit that is itations (Table 2), several studies have been done in an attempt simple, practical, and reliably tracks changes in BV. We have to cross-validate the methods, or use them in combination in J Am Soc Nephrol 10: 392–403, 1999 Assessment of Dry Weight in Hemodialysis: An Overview 399

Figure 2. Postdialysis volume shifts from extracellular fluid (ECF) compartment as tracked by bioimpedance spectroscopy and simultaneous blood volume monitoring. At the end of dialysis, there is a shift of fluid from the extravascular (interstitial fluid) compartment, which includes a redistribution to the intravascular space and a compartmental shift to the intracellular space. There is a continued decline in ECF up to 30 min postdialysis (as evaluated in these experiments). The influence of dialysate sodium concentration on the compartmental shifts has not been evaluated. VECF, extracellular fluid volume; VICF, intracellular fluid volume; PV, plasma volume. hopes of better defining fluid shifts during dialysis and deter- ultrafiltration rate reflects the plasma refilling rate. Our data mining dry weight. show that there is a good correlation between interstitial fluid Determination of Fluid Shifts. As changes in BV are volume and plasma refilling (99). De Vries et al. (79) have proportional to the balance between ultrafiltration rates and further used both techniques to adjust dry weights in hemodi- plasma refilling, in the absence of ultrafiltration it is possible to alysis patients and thereby reduced the frequency of hypoten- determine plasma refilling rates and absolute BV (96). Addi- sive episodes. tionally, if BIS measurements are combined with BV monitor- Determination of Dry Weight. Kouw et al. measured ing during dialysis, changes in the ECF and intravascular routine hemodynamic parameters noninvasively during dialy- compartments can be determined, permitting an estimate of sis and then stratified patients as over- or underhydrated based plasma refilling (97–99). We have used both of these tech- on posthemodialysis measurements of caval diameter, conduc- niques simultaneously and extended measurements for approx- tivity (lower extremity, single frequency [bioimpedance anal- imately 1 h after dialysis (Figure 1). Our data show that both ysis], ECF), cGMP levels, and ANP levels (62). They found BIS (ECF) and hematocrit measurements (BV) have an excel- that caval diameter and conductivity correlated well with ul- lent correlation with the volume of fluid removed (97). Bo- trafiltration volume, the dehydrated state, and each other, both gaard et al. (98) had similar findings using a single frequency pre- and posthemodialysis. There was a weak correlation be- BIS measurement and an optical method of hematocrit deter- tween postdialysis cGMP levels, change in blood volume, and mination. These authors used the ratio between change in BV hemodynamic parameters, indicating that cGMP is less valu- and the volume of ultrafiltrate as a reflection of plasma refilling able in assessing dry weight than either conductivity or caval and found that there were significant differences in the rate of diameter. When patients were separated by ANP levels, there change in BV in dehydrated, normally hydrated, and overhy- was no correlation with change in hemodynamics, caval diam- drated patients. We have calculated absolute plasma volume eter, or conductivity, indicating that it provides no value in and plasma refilling rates at the end of dialysis and have shown defining dry weight in their study. Notably, caval diameter that at the end of dialysis there is a continued decline in ECF routinely underestimated dry weight, whereas conductivity associated with plasma refilling. This suggests that the inter- overestimated dry weight. Both measurements were taken im- stitial fluid compartment contributes fluid for plasma refilling mediately after dialysis, raising the question as to whether and may replenish the intracellular space (99) (Figure 2). We enough time had elapsed to allow refilling of the plasma from have subsequently calculated absolute plasma volume for dif- the interstitium. Note that this is a slightly different mechanism ferent time points during dialysis and, in conjunction with the of overestimation of postdialysis ECF volume than stated in the ECF measurements done simultaneously, have computed the above discussion of bioimpedance. Another study by the same volume of interstitial fluid. The difference in change in BV and group that year compared bioimpedance and BV monitoring. 400 Journal of the American Society of Nephrology J Am Soc Nephrol 10: 392–403, 1999

They stratified patients as underhydrated, normal, or overhy- gestive heart failure, left ventricular disorders, diabetic auto- drated based on previously developed conductivity criteria nomic neuropathy, severe hypoalbuminemia, or other condi- taken postdialysis and then measured blood volume changes tions predisposing to hypotension in dialysis. On the other and hemodynamic parameters in these three groups (94). They hand, physiologic dry weight might be an appropriate goal for found that in the underhydrated group, there was significantly patients with persistent large interdialytic weight gains or the greater change in overall blood volume corrected for ultrafil- above conditions that predispose to hypotension. Furthermore, tration volume and more hypotensive episodes compared with the use of nonlinear ultrafiltration may assist dry weight normal or overhydrated patients. Conversely, Lopot et al. achievement in these patients (95). Because of this complexity, recently stratified patients based on blood volume profiles it is easy to recognize that objective tools used for estimating characterized as overhydrated, normal, and underhydrated, and dry weight are necessary. However, the individual techniques then compared these profiles with conductivity measurements each have limitations or are inherently insufficient for singular and VCD (100). Those with blood volume profiles indicative use in dry weight assessment (Table 2). Therefore, some com- of overhydration had larger postdialysis values of ECF and bination of these tools will need be used to achieve this goal. VCD. Likewise, those characterized as underhydrated on the Furthermore, dry weight assessment might further be stratified basis of rapid changes in blood volume had smaller postdialy- into two major categories: (1) the interdialytic measurement of sis ECF and VCD values. This is perhaps the only study static dry weight and body composition and (2) intradialytic utilizing and confirming the blood volume method as a screen- assessment of online data or comparison of pre- and posthe- ing tool to detect an inappropriately high dry weight. In the modialysis data. Either might be used on a monthly or other third part of Katzarski et al.’s study showing hypertension as periodic basis as a means of following dry weight and deriving dependent on bioimpedance-determined volume (81), they ad- an index of adequacy for fluid removal (101). ditionally showed that ECF and VCD decreased in tandem We have extensively reviewed the technologic methods for during dialysis and correlated well postdialysis. Thirty minutes actual measurement of volume status in dialysis patients as postdialysis, VCD increased markedly, likely indicative of they have developed thus far, as well as addressed their limi- plasma refilling from the interstitial space. However, ECF tations. Further development of these techniques is necessary values remained stable. We believe that this might be due to for attaining an easily derived and utilized index for adequacy refilling of plasma volume from more easily accessible fluid of fluid removal. The development of this index should be sites not measured by bioimpedance due to the peripheral undertaken whereby both interdialytic and intradialytic meth- arrangement of electrodes in this study. ods will be described and utilized on a periodic basis. Pending further research and development, the interdialytic measure- ment of dry weight and body composition will perhaps be best Beyond Dry Weight? An Index for Adequacy of accomplished with bioimpedance spectroscopy, because of its Fluid Removal unique ability to provide insight into nutritional status as well. From the above discussion, it is evident that contemporary Intradialytic methods will arise out of further interrogation of management of fluid in the dialysis patient is largely dependent fluid shifts that occur during dialysis. At some point, these on a clinically derived estimate of dry weight. Clinical assess- technologies might be incorporated into dialysis machines ment of dry weight inevitably leads to both overestimation and whereby volumetric control of ultrafiltration will take on a new underestimation of dry weight. Overestimation of dry weight meaning and result in profiled dialysis. It is obvious that we leads to hypertension, stroke, and congestive heart failure, have a long way to go, however, it is our belief that recognition which are the main causes of excess death in dialysis. Under- of the need for this process is an initial step that will hopefully estimation leads to persistent hypotensive episodes, alienating result in further investigation in this field. dialysis patients from their caretakers, and affecting delivery of prescribed dialysis. Moreover, the current focus on Kt/V as an Acknowledgment index for adequacy of dialysis in terms of solute removal We thank Dr. Robert Steiner for his recommendations and assis- ignores the contribution of volume as an independent factor tance in preparation of this manuscript. influencing outcome. Unfortunately, despite this recognition we have not attempted to rectify this problem in any systematic References way. It is our belief that a possible approach to this problem is 1. Henderson LW: Symptomatic hypotension during hemodialysis. the development of an index for adequacy for fluid manage- Kidney Int 17: 571–576, 1980 ment. 2. Diamond SM, Henrich WL: Hypertension in dialysis patients. 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