Bioimpedance Measurement in the Kidney Disease Patient

1.1 The problematic of hydration status in the kidney disease patient Dry weight corresponds to the body weight of a person with normal extracellular fluid volume [1]. In the context of hemodialysis, dry weight is the weight reached at the end of the dialysis session by patients who will remain free of orthostatic hypotension or hypertension until the next session. Clinicians are thus obliged to estimate the appropriate dry weight each individual patient should reach at the end of a dialysis session. If this weight is underestimated, the patients are at risk of various incidents ranging from simple yawning to death. Low dry weight also carries a permanent risk of hypotension, cramps, nausea, vomiting or ischemia. If this weight is overestimated, chronic hyperhydration can cause acute events including pulmonary edema, or hypertension, but also long-term consequences affecting cardiovascular morbidity and mortality [2]. This important notion of dry weight is however quite problematic because it corresponds to a transient state, making it necessary to anticipate weight gain between two dialysis sessions and thus to reach a certain degree of dehydration at the end of each hemodialysis session. The many methods proposed for measuring dry weight and body composition are still under investigation. The difficulty encountered in establishing a reliable comparative tool for measuring these parameters arises from inevitable physiological, anatomical and physical variability. Most approaches remain empirical, relying on feedback from trial and error [3]. In practice, dry weight is estimated clinically [4]. Physical examination is a classic but limited tool. Solid evidence-based analysis of specific physical findings such as systolic blood pressure, orthostatic blood pressure, or the presence or not of edema is lacking. Such clinical symptoms can also be related to conditions other than a dry weight or body composition problem. Several tests have been proposed to assess the dry weight of hemodialysis patients [5]. Echocardiographic inferior vena cava diameter and biochemical markers are available but results exhibit high variability and poor correlation with extracellular volume; there are also unserviceable in detecting volume depletion. Bioimpedance spectroscopy measurement has been demonstrated as a potentially useful method to determine the physiological status of living tissues [6]. Disease-related alterations are associated with variations in essential tissue parameters such as physical structure or ionic composition that can be detected as changes in passive electrical properties.


Basic principles of bioimpedance spectroscopy 1.2.1 Physical principles
The bioelectrical properties of the human body depend on the nature of the biological tissues composing it and their relative conductivities. These properties lead to the notion of impedance of a biological medium which varies as a function of the frequency of an electrical current applied across it. This in turn leads to the notion of bioimpedance spectroscopy. Impedance is a complex quantity (Z) describing, in compliance with Ohm's law (assuming sinusoidal voltage), the relationship between the voltage difference across the medium and the amplitude of the electrical current. Because of the capacitive nature of biological media, all impedance measurements of the human body involve a phase shift between the voltage and the current, yielding complex values. Biological media are weak conductors due to the dissipation (or loss) of energy in the media and can be considered as energy-loosing dielectrics. The quantities of interest can thus be defined using a schematic representation of a biological suspension placed between two electrodes (Fig. 1). U I Electrodes Biological medium The impedance of a biological medium is thus the relationship between the voltage difference across the medium and the current amplitude as described by Ohm's law: U = Z I where Z is the complex impedance expressed in Ohms (). In Cartesian form this gives Z = R + jX where R is the resistance, X is the reactance, both expressed in Ohms, and j the imaginary unit, j = 1  Setting Z = 22 RX  and  = arctg (X/R) gives the polar form Z = Z e j  The bioelectric impedance Z describes the inertia of a biological medium opposing passage of a sinusoidal current with intensity I and pulsation  (rad/s). Along the lines of the electrical current, this impedance generates a difference of potential U. Bioelectrical impedance can be represented in a complex plane. It is perfectly defined by knowledge of either its real and imaginary components (R and X), or by its module and its argument, Z and . For an isotropic, homogeneous, linear medium, impedance is a function of the medium's electrical properties, conductivity and permitivity, but also depends on the geometric features of the measurement cell. This so-called bioimpedance is a well-known tool for characterizing different physiological water compartments [7]. Because of the complexity and highly heterogeneous nature of living tissues, a global approach is used, considering the whole body as a suspension of cells in water and electrolytes [8].

Biological basis
Biological tissues cannot be considered as ideal conductors. They are ionic conductors with heterogeneous structures. If we limit our considerations to the sole electrical aspect of interest here, biological tissues can very schematically be considered as a combination of two components: i) a free water medium called the extracellular fluid, within which are suspended ii) cells surrounded by a membrane containing and thus limiting a volume of intracellular fluid (Fig. 2). The cell concentration can vary greatly, depending on the nature of the tissue. The fluid components (extracellular fluid, plasma and intracellular fluid) can be considered as electrolytic suspensions of ions whose concentration, electrical charge and mobility, taking into account the viscosity of the medium, will essentially determine the impedance of the suspension, mainly arising from resistive type resistance. Cell membranes however constitute a more complex component. Cole demonstrated that cell membranes can be likened to capacitors [9,10,11]. This divides biological media into two basic components, resistors (R) and capacitors (C), which when connected in parallel produce an electrical equivalent model as described by Fricke [13] (Fig. 2). This simplified model (R e , R i and C are not ideal) enables an interpretation of observed biophysical phenomena. Theoretically, tissue impedance, like any electric impedance, can be measured. The mass of tissue to study simply has to be delimited and linked to a measurement device via a system of electrodes. In practice however, measuring the electrical characteristics of biological tissues raise many specific problems. It is useful to recognize the electrical properties of www.intechopen.com Technical Problems in Patients on Hemodialysis 168 biological tissues and their components because of their interest both in medicine, where many diagnostic methods are based on electrical principles, and in fundamental physiology, where these same properties contribute to the structural analysis of cell organization, the study of cell excitation mechanisms, or to the analysis of protein molecules. Debye, Cole-Cole and Maxwell-Wagner models have been developed to represent the theoretical interpretations of these phenomena. These models can be used to demonstrate important factors characterizing biological tissues [12].  Capacitance and resistance can be combined either in series or in parallel, leading to several variants of the Fricke model. Resistivity (charge accumulation) and conductivity (conduction of electrical current) are however two independent processes for which the parallel model has been found to be more representative. Formulas used for biological tissues are thus all based on the Fricke model [13]. Applying these models to bioimpedance spectroscopy curves allows a quantification of value differences corresponding to the intracellular fluid and the extracellular fluid and thus their corresponding masses. The interest for hemodialysis is obvious.

Usefulness of bioimpedance for the kidney disease patient
Much research has been devoted to the determination of body hydration status and fluid compartments, particularly in hemodialysis patients [14]. Work has focused on various physiological parameters with different modalities to study individual segments of the body or the whole body [15,16,17] using multiple or unique frequencies [18]. One of the goals is to improve predictive equations and to identify the effect of different parameters on the measures obtained [19,20]. In dialysis for example, it has been shown that fluid is removed predominantly from the extracellular and peripheral (arms, legs) compartments [21]. Thus, different biofluid models have been proposed to describe the whole body or individual organs. Basically, applying the bioimpedance method to determine body composition consists in placing electrodes conveniently on the arms and legs in order to impose an electrical current and measure the voltage it induces across the body. For a reasonable current density, the behavior is linear so that Ohm's law remains valid. Intra-and extracellular fluids are mainly resistive, whereas cell membranes act as an insulator between these two compartments. Rare bioimpedance spectroscopy studies conducted in kidney graft recipients have shown a trend towards improved hydration after transplantation. We have been unable to find any study evaluating hydration changes in patients with acute kidney disease.

Theoretical and experimental models 2.1 Principles of bioimpédance in hemodialysis
Many different instruments have been marketed using algorithms based on different equations predicting body composition from impedance measurements [22,23,24,25]. The validity of these different equations remains a question of debate since most have been established empirically. Moreover, the equations actually used by the algorithms of commercial microcomputers are not readily accessible, making it rather difficult to discuss their validity or make necessary corrections. The voltage produced by the current is measured to calculate the impedance. The relationships between impedance and other variables such as body water volume have been established using statistical correlations observed in specific populations rather than on a real biophysical basis. Actually, the theoretical basis can be summarized by the following statement: the human body is a complex conductive volume composed of heterogeneous tissues and intra-and extracellular compartments in perpetual movement. Basically, the algorithms applied are based on regression laws used as a tool predictive of the relationship between two or more body variables constituting a database. Thus for total body water (TBW) the regression equation is written as [26](with H: Height): TBW is measured in a large population using a gold standard, e.g. isotopic dilution (Fig. 3). The statistical software then uses regression analysis to establish the best fitting equation describing the relationship between TBW and the different measurements, e.g. height, weight, age, gender, resistance… For subsequent resistance measurements, a software inserts the recorded data into the accepted formula and delivers the results as TBW (Fig. 4).

Historical background
One of the most commonly cited relationship is the cylinder model where the volume of a conductive cylinder is function of its length (L) and its resistance (R). High frequency current penetrates into the cell and runs across body fluids. A TBW value can thus be obtained by modeling the human body as a sum of cylinders. Devices applying this method are calibrated by dilution techniques. These devices rely on the following relationship:

Theories used
Three techniques are generally described, using multiple frequencies, high and low frequencies, and a unique 50 kHz frequency. The multifrequency mode is the most widely studied. It is based on the Cole-Cole model and allows differentiation between intra-and extra-cellular volumes. But the relationship between resistance and water volume is not linear, so that the multifrequency mode is associated with Hanaï theory, which takes into account the non-conductive element, connected in a parallel, to distinguish the different compartments. The parallel model described by Fricke takes into account the conductive elements exhibiting a certain degree of resistance connected in parallel and isolated by a cell membrane. This method has been validated by Van Loan [29,30,31]. At high and low frequencies, the Hanaï theory takes into account the presence of non-conductive elements connected in parallel. The measurement improvement mainly concerns the extracellular compartment [32,33]. At the unique 50 kHz frequency, the theory enables a measurement of TBW (and lean body mass) [28]. Many different formulas have been published, using the term: H²/R 50 , where H is the subject's height in cm and R 50 the wrist-ankle resistance. These methods have not been validated and generally cannot detect small volume changes. This limitation may be related to the relative uniformity of tissue elements considered in the formulas which do not take into consideration changes in tissue composition. Simple calculations allow extrapolations for extracellular water [34]. These different theories can then be applied to measure body segments or the whole body [35,36,37,38]. For segmental measures, the mathematical models remain empirical and actual measures remain dependent on electrode position. Differences appear in comparison with whole body measures with a trend to underestimate water loss during a dialysis session compared with a segmental measurement, particularly in the event of hypotension [39]. One advantage is that the segmental technique would be less sensitive to changes in patient position from one measure to the next [40].

From theory to measure
The problem is then to transform a resistance measurement into a calculation of body composition. Geometry plays an important role. As seen in Figure 6, three objects with a constant height exhibit the same resistance from top to bottom, despite their different volumes [41].

Technical Problems in Patients on Hemodialysis
Thus in many models, the human body is considered to be the sum of five compartments (Fig. 7) (the four limbs and the trunk), with a dimension homogeneity factor K b.
Then, by calculating the volume of the cylinder, and separating, arms, legs and trunk, the following formula is established with l for leg, t for trunk and a for arm: This formula, together with the classical formula for the volume of a cylinder, yields the dimension homogeneity constant, K B , which represents a characteristic anthropometric parameter independent of the electrical parameters. (

Formula validity and limitations
When these formulas are applied to measure body composition, the result is always significantly different from gold standard measurements. Thus Fenech [43] and Jaffrin [44] proposed a direct calculation of TBW using the same method as for extracellular water, assuming that TBW is a homogeneous quantity of fluid. The mean resistivity of this TBW was validated by comparison with body composition data obtained using the DEXA method. Jaffrin then raised the question of extrapolating total body resistance from the resistance value measured at 50 kHz [45], using a proportional intermediary multiplier.
Finally, the superiority of multifrequency impedance over the monofrequency impedance has not been demonstrated. Similarly no one formula has been found superior to the others.

Available clinical applications
Several studies have been conducted in hemodialysis patients. Three approaches have been particularly fruitful, the nomovolemia/hypervolemia curves established by Chamney [46,47,48,49], the resistance/reactance curves by Piccoli [50,51,52] and Zhu's continuous curves [53,54]. Although essential, these approaches will not be detailed here. Readers may usefully refer to the cited references.

Changes of body position
It has been shown that resistance/reactance curves are modified reversibly by changes in body position (reclining, sitting, upright position). Physical studies have demonstrated a modification in the lines of current passing through the body with changes in body position. In addition, length and resistance measures vary [55]. In the healthy subject, comparison of whole body and segmental measures shows an increase in resistance in all sectors (peripheral and central compartments) when moving from the upright to the reclining position [56,57]. This is logical for the peripheral sector, related to the decrease in water in this sector which is redistributed to the central sector by cancelation of the gravity effect. However, surprisingly, resistance increases in the trunk, despite the increase in water. One explanation is that impedancemetry poorly evaluates the central sector. In the dialysis patient, and using the segmental mode, resistances vary with electrode position. The volumes calculated using the segmental mode are much higher than with the whole body mode and than with the anthropometric formulas [58]. In conclusion, segmental measures are insufficient to eliminate artifacts related to changes in body position.

Underestimation of extracellular volume variations in dialysis patients
These calculations are made from variations in plasma sodium content, accepting the hypothesis of zero sodium exchange between intra-and extra-cellular compartments or with the dialysis solute (obviously a false assumption). These results show that the contribution of the extracellular volume is superior to that measured by impedancemetry, with certain aberrant results [59,60]. Conductivity variability is well known in dialysis and is most likely responsible for these problems of fluctuating resistivity for different compartments during dialysis.

Tanita (TBF-300)
Tanita (TBF-300) is a device for measuring body impedance between the two legs. It is simple to use and does not require electrodes. Manufactured in Japan, the devise presents as a weight scale with a built-in body composition analyzer which calculates TBW, total body fat and fat-free body mass [61]. The National Institute of Health has not validated the results. For these measurements, the person stands barefoot on a four-point platform. Impedance measurements are made using a high frequency (50kHz) and low intensity (500 µA) current between the feet. (formula are not known)

Body composition monitor
The body composition monitor (BCM) was developed by Fresenius® Medical Care. BCM is a rapid non-invasive 4-electrodes method for monitoring body composition by measuring the electrical impedance response to a multifrequency signal (50 frequencies from 5 kHz to 1 MHz). The Cole-Cole model is applied, with Hanaï mixture theory, to distinguish extracellular water (ECW), intracellular water (ICW) and total body water. Integrated software can also display over-hydration status. The device has been validated in healthy people, in comparison with reference methods (isotopic dilution). The advantage of this device is to provide a quantitative diagnosis of over-hydration. The model is based on tissue hydration constants observed in the healthy individual which can then be applied to quantify excess water in kidney disease patients. The validation study, based on gold standard methods (bromide dilution for the extracellular compartment, deuterium dilution for TBW, potassium dilution for intracellular compartment and DEXA for fat mass), included 500 healthy subjects. The measures were then compared with the hemodialysis patient, before and after dialysis. This technique assumes that intracellular water, fat-free mass, and fat mass remain unchanged during the course of the dialysis session despite the ultrafiltration [62]. The novel aspect of this model is the introduction of a third compartment corresponding to the excess fluid (Fig. 8) or over-hydration (OH) in comparison with the healthy individual. This over-hydration is considered to concern the extracellular compartment exclusively. Lean body mass contains exactly 73.2% water and includes the intra-and extra-cellular compartments, the intracellular compartment predominating. Lean body mass includes protein (muscles) and mineral (bone) matter. The sum of the intracellular compartment plus the protein mass defines the cell mass. Adipose tissue mass, or fat mass, contains 26.8% water, the extracellular compartment predominates. The notion of a third compartment avoids the problems related to the fact that the ratio between the extracellular and intracellular water is not constant. Comparing total and extracellular water measurements obtained in the healthy population and in the dialysis population defines the notion of overhydration. Time-course curves of the different compartments provide a picture of the evolving state of hydration. In Figure 9, the notion of hydration status in the dialysis patient is combined with systolic blood pressure. Four sectors are defined. I: over-hydration and hypertension, II: normohydration and hypertension, III: normo-hydration and normo-tension IV: over-hydration and normo-or hypo-tension. Trends can be plotted.

Elaborating a dry-weight index using Tanita
We first used the Tanita TBF-300 analyzer to obtain bioimpedance measures in 238 hemodialysis sessions. The mean total body water (TBW) was 41.9±7.9 kg before sessions and 39.6±7.3 kg after sessions. Mean body weight was 76.6±18.2 kg before and 74.2±17.1 kg after. Statistically, body weight remained stable during this study and was thus valid for assessing reliability. This enabled the definition of patient populations used to hypothesize the pathophysiology of hyperhydration, dehydration and normohydration state based on a body-weight index (Fig.10). Change in weight (W) and TBW (TBW) was noted and compared with ultrafiltration. In theory, these three variables should be similar, because during dialysis sessions, the ultrafiltration applied corresponds to a subtraction of water, and consequently to the change in w or TBW before and after the water depletion. But net ultrafiltration and W correlated poorly (c=0.62) with TBW. This led to the definition of a dry-weight index,  It was hypothesized that this Index would be 0 when patients reach their dry weight: I = W-TBW

Body composition monitoring of the elderly hemodialysis patients
Body composition was monitored for a 1.5-month period under standardized conditions in 10 hemodialysis patients aged over 80 years with the BCM. The data collected (Table 1) showed that these elderly patients exhibited a different water distribution pattern during ultrafiltration and also different refilling behavior. Thus ultrafiltration did not fully reflect changes in over-hydration. The only valid and clearly coherent measures were those recorded before the dialysis session. While the Cole-Cole model remained valid, implanted devices or specific clinical situations such as heart failure affected the impedance results. Pacemaker behavior (patient n° 8) was unaffected by the very small current used, but the presence of conductive metal (orthopedic prosthesis in patient 10) modified the bioimpedance measures. In such patients, change in weight and ultrafiltration followed a similar pattern, but TBW recordings were obviously incorrect in light of the weight loss (Table 1) and the over-hydration diagnosis ( Four patient profiles could be identified from the data presented in Table 1.  Patients 1, 2 and 9 exhibited good correlation between weight loss, applied ultrafiltration, and TBW variation during dialysis sessions.  Patients 3, 5, 6 and 10 exhibited a different type of behavior. The decline in TBW from the beginning to the end of the dialysis session was underestimated as compared with the variation in weight or applied ultrafiltration.  Inversely, for patients 4 and 8, the decline in TBW during dialysis was overestimated, compared with the very similar variations in weight or ultrafiltration.  In one patient (n° 7), ultrafiltration and TBW correlated well with each other, but not with weight loss. As expected, dialysis-related water depletion mainly involved a reduction of the extracellular compartment compared with the intracellular compartment. This well-known phenomenon is called refilling. In three patients (n° 5, 6 and 7), the bioimpedance measures predicted fluid overload in the intracellular compartment, with a smaller fall in TBW than in extracellular water. This might be related to a "reverse refilling" phenomenon. For patient The over-hydration data presented in Table 2 show that, according to the BCM findings, all patients except two (n° 8 and 10), were over-hydrated at dialysis onset and underhydrated at dialysis end. Comparing the clinical diagnosis of over-hydration established by the nephrologist programming the ultrafiltration at the beginning of the session (Table 1) with the over-hydration status diagnosis established by BCM before dialysis (Table 2) revealed different trends. The nephrologist tended to overestimate over-hydration before dialysis while the BCM tended towards an underestimation. At the end of the ultrafiltration six of the patients were dehydrated, but not far from their dry weight, with a difference of ≤0.5 liters from normo-hydration.

Body composition monitoring in living-donor transplant recipients
We prospectively studied five transplanted patients who had received a living-donor graft after a period of hemodialysis. These five patients had exhibited particularly rapid recovery of normal renal function after transplantation. We took bioimpedance measures before surgery and several times during a mean 2-months period after transplantation. Our findings produced a bell-shaped curve showing weight gain with increasing over-hydration followed by weight loss with normo-hydration, in correlation with the normalization of kidney graft function (Table 3).
BCM diagnosis Day 1 post-transplantation Day 50 post-transplantation Over-hydration 1.04±0.7 liters 0.56±0.3 liters Table 3. Over-hydration after kidney transplantation Clinically, the patients' blood pressure improved and edema disappeared. For example, one patient weighed 48.4 kg on day 4 post-transplantation and 47.3 kg on day 10. There was a reduction of the hyperhydration, the Cole-Cole curves shifting to the right (Fig. 11), and an increase in maximal reactance (X) (from 50.6 to 62.5 Ohm). The frequency at which this reactance reached its maximum also declined from 60 kHz to 50 kHz, a frequency which is commonly observed in normo-hydration subjects.

Body composition monitoring in acute kidney failure
We studied three patients with acute reversible kidney disease. Body composition monitoring was started at the time of the acute disease and continued to the recovery period. Results (impedance, reactance, phase shift, Cole-Cole curve) showed an overhydration period that disappeared with the normalization of kidney function. The time course of improved hydration status in this patient is represented in Figure 12. Overhydration and weight variations followed the same pattern, rising and declining in parallel.    Figure 13 also shows that the Cole-Cole curves shifted to the right as hydration status returned to normal. This right shift being the expression of lesser hyperhydration. On day 1, the resistance levels at 0 and ∞ frequency went from 450 to 370 Ohms with a maximum reactance of 26 for a resistance of 410. By day 11, the curves had shifted to the right, corresponding to lesser hyperhydration, weight loss, and a diagnosis of lower overhydration. These values ranged from 590 to 480 Ohms and maximal reactance of 37.7 with a corresponding resistance at 540 (Table 4). These physical elements also corresponded to clinical reality since blood pressure levels returned to normal with involution of lower limbs edema.

Conclusion
Bioimpedance is an easy-to-use tool providing a useful evaluation of patients' dry weight. The method remains limited due to the lack of standards of normality. Moreover, changes in electrolytes, red cells, protein, body temperature or implanted devices affect bioimpedance measures, further compromising use of bioimpedance for determining the dry weight or normal hydration level of hemodialysis patients. Nevertheless, measurable values such as impedance, reactance, or phase shift enable the identification of patient groups and the description of trends. Impedance, reactance and phase shift can be used to identify population groups with similar behavior patterns useful for determining dry weight or detecting hydration disorders. Analysis of correlations between physical data and clinical findings is another point of interest discussed in this chapter.