1 Department of Nephrology and Rheumatology, Heinrich-Heine-University Düsseldorf, 2 Dialysis Center, Düsseldorf and 3 Dialysis Center, Mettmann, Germany
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Abstract |
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Methods. Thirty-nine chronic haemodialysis patients, 43 chronic peritoneal dialysis patients and 22 healthy controls were included in the study. Multifrequency BIA was performed using the Xitron BIS4000B device (frequencies from 5 to 500 kHz were scanned and fitted) in patients before and after haemodialysis. Peritoneal dialysis patients were measured after drainage of the dialysate. Plasma ANP and cGMP levels were measured in plasma using a 125I solid phase RIA. Serum albumin concentrations and serum osmolality were measured in all patients. The body fluid data were analysed in relation with the clinical findings.
Results. Total body water (TBW) was 0.471±0.066 l/kg before haemodialysis and 0.466±0.054 l/kg after haemodialysis. Peritoneal dialysis patients had a TBW (0.498±0.063 l/kg) that was greater than the before and after dialysis values of haemodialysis patients. The extracellular body fluid (Vecf) was increased pre-haemodialysis. It was even greater in peritoneal dialysis patients compared with patients both pre- and post-haemodialysis (pre 0.276±0.037 l/kg; post 0.254±0.034 l/kg; peritoneal dialysis 0.293±0.042 l/kg, P<0.05). However, plasma ANP concentrations (representing intravascular filling) in peritoneal dialysis patients were comparable with post-haemodialysis values (284±191 pg/ml vs 286±144 pg/ml). The correlation coefficient between sysRR and Vecf was r=0.257 in haemodialysis (P=0.057) and r=0.258 in peritoneal dialysis (P<0.05). A significant negative correlation was found between serum albumin and Vecf/TBW in peritoneal dialysis patients (r=-0.624).
Conclusion. Body fluid analysis by BIA demonstrated that TBW and Vecf were increased in peritoneal dialysis patients, and were comparable or even greater than values found before haemodialysis. However, plasma ANP levels indicated that intravascular filling was not increased in peritoneal dialysis. The ratio of Vecf to TBW was correlated to systolic pressure and negatively to serum albumin in peritoneal dialysis patients.
Keywords: ANP; bioimpedance analysis; body fluid; body water; cGMP; extracellular water; haemodialysis; hypertension; intravascular filling; peritoneal dialysis; serum albumin; total body water
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Introduction |
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The measurement of total body water (TBW) using an isotopic dilution method (for example using deuterium or 18O-labelled water) represents the gold standard [3], but is not practical in clinical routine. Deuterium requires an equilibration time of at least 3 h and necessitates subtle laboratory analysis. Multifrequency bioimpedance analysis (BIA) measurement has been shown to be a simple, safe, and inexpensive method to measure the different water compartments of the human body [4]. The method is based upon a model describing the human body as a circuit consisting of capacitors and resistors lying in an electric field [5]. BIA, when compared with standard isotopic dilution methods, has been shown to be a precise and reproducible technique for determining TBW and extracellular body fluid (Vecf) [5].
The aim of this study was to investigate and compare total body water and the extracellular fluid compartment, including intravascular filling, in patients treated with haemodialysis and peritoneal dialysis. As BIA cannot differentiate between interstitial and intravascular fluid within the extracellular space, we additionally measured atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP), which have been shown to be sensitive markers of changes in body fluid status in end-stage renal disease patients [6]. The release of ANP depends on right atrial wall tension and it is significantly correlated with central venous filling or central venous pressure [7]. cGMP is the second messenger of ANP and has also been used as a marker of venous filling [8].
A recent study with haemodialysis patients in Tassin (France) assessing fluid status by BIA supported the hypothesis that improved control of fluid volume (Vecf) was responsible for the low incidence of hypertension and was probably linked to the outstanding high survival rate of the Tassin patients [9]. Previous studies using biopsies or tracer dilution techniques (muscle biopsies, 18O-labelled water) to measure body fluid in dialysis patients showed that subjects receiving peritoneal dialysis were often chronically fluid overloaded [10]. However, there is a lack of data comparing body fluid between peritoneal dialysis patients and haemodialysis patients.
Hypoalbuminaemia and a high transport capacity of small solutes in the so-called peritoneal equilibration test (PET) have been correlated with patient survival in peritoneal dialysis [11]. Because hypoalbuminaemia may be linked to body fluid status, we also examined the relationship between serum albumin concentration and body fluid distribution in haemodialysis and peritoneal dialysis patients.
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Subjects and methods |
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To examine relationships between measured hydration data and clinical indicators of hydration, we performed further anaylsis on the PD group because they had a stable hydration status. These patients were subdivided into groups according to their fluid measurement data according to the limits of the Gaussian distribution: (i) below mean-1 SD low hydration; (ii) between mean-1 SD to mean+1 SD average hydration; and (iii) above mean+1 SD high hydration. These groups were then assessed for differences in oedema, blood pressure, residual diuresis, and the use of antihypertensives.
Body surface area of the patients was calculated according to the Boyd formula.
Instruments
Bioelectrical spectroscopy was carried out using the BIS4000B analyser (Xitron Technologies, San Diego, CA, USA). Four skin electrodes (Xitron) were placed on the dorsal surfaces of the left hand and foot. Measurements were made after the subjects had been supine for at least 20 min. Fifty frequencies were measured ranging from 5 to 500 kHz. Data were collected and analysed with software supplied by Xitron Technologies. The ColeCole model and the Hanai equation were used for computation [12]:
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Zobs is the observed complex impedance, RE, RI, and CM are the component values of the circuit, is frequency in radians/sec (=2
xfrequency).
TBW was calculated as:
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The urea distribution volume of one HD group is a well-established parameter for measuring TBW. In a closed dialysate tank system (e.g. GeniusTM dialysis system), it can easily be derived from the following equation:
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This technique was used to confirm the accuracy of BIA measuement. The BlandAltman analysis was used to compare the two methods. The coefficient of correlation showing the differences between methods (urea distribution volume measured in the dialysate tank system and TBW measured by BIA) and the mean of all methods was 0.081 with a bias of -1.5 l and a 95% confidence interval of -3.50 to 0.50 l, indicating that the values of BIA fell near the identity line.
Blood samples for ANP measurement were collected from the arterial line in HD group before and 15 min after haemodialysis. Plasma was separated in chilled EDTA tubes. ANP was extracted from plasma using Sep-pak-C18 columns and quantified with a 125I solid phase RIA (Laboserv GmbH, Giessen, Germany). cGMP levels were measured after acetylation with 125I RIA using a second antibody coupled to magnetic beads (lower detection limit 0.5 pmol/ml, Amersham Buchler, Braunschweig, Germany).
Serum albumin was measured by the BCT methods (Brominecresol purpure) on a Beckmann autoanalyzer. Osmolality was measured by freezing point depression (Knauer GmbH, Bad Homburg, Germany).
Peritoneal transport characteristics of the PD group were classified according to a 4 h standard PET test.
Statistics
Results are expressed as means±SD. Statistical analysis was performed using t-tests for unpaired or paired samples. An alpha error <0.05 was considered significant. Linear regression analysis was performed according to Spearman. A normal distribution of Vecf and TBW in dialysis patients was confirmed by the AndersonDarling normality test. Differences between more than two (sub)groups were analysed using ANOVA and post hoc Scheffé test (SPSS, v. 9.01, SPSS Inc., Chicago, IL, USA).
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Results |
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The ratio of Vecf/TBW was calculated to determine the relative degree of extracellular fluid expansion. This value was increased in the PD group (58.9±4.8%) compared with healthy controls (52.2±3.0%, P<0.005) (Figure 1). This ratio in PD patients corresponded with the findings in HD patients before dialysis (58.7±5.2%). Ultrafiltration in HD patients reduced the ratio of Vecf/TBW to 54.7±5.3% (P<0.001), which was significantly lower than in PD patients (P<0.005). But also in HD the post-haemodialysis Vecf/TBW fluid ratio, remained slightly elevated compared with normal controls (P<0.05).
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Parameters of intravascular filling
Plasma ANP concentration
Healthy volunteers had a mean supine plasma ANP concentration of 62±30 pg/ml that ranged from 28 to 139 pg/ml (Figure 2). In the dialysis patients, the lowest plasma ANP levels were measured after the haemodialysis session (286±144 pg/ml). Before haemodialysis, ANP concentrations were markedly higher (536±324 pg/ml, P<0.005). Plasma ANP levels were clearly decreased by ultrafiltration but remained unchanged in patients with isovolaemic haemodialysis. In the subgroup of HD patients showing signs of heart failure, higher plasma ANP levels were found (pre-HD 623±354 pg/ml; post-HD 218±72 pg/ml) compared with HD patients without heart failure (pre-HD 421±245 pg/ml; post-HD 384±168 pg/ml, n.s.). The mean plasma ANP concentration in the PD group was 284±191 pg/ml, and it fell to a level near that of HD patients after dialysis. The subgroups of PD patients with and without signs of heart failure were comparable with the HD patient subgroups after dialysis. There was a significant correlation between plasma ANP levels and the ratio of Vecf/TBW both in HD and PD patients (r=0.372, P<0.005 and r=0.469, P<0.001).
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Plasma cGMP concentration
Healthy controls had a mean plasma cGMP level of 4.8±2.3 pmol/l. As with ANP, the highest cGMP plasma levels were found before haemodialysis (HD group 29.6±12.8 pmol/l). After haemodialysis, cGMP dropped to 12.4±4.0 pmol/l (P<0.001). In PD patients, cGMP levels were intermediate to the values found before and after haemodialysis (24.9±7.8 pmol/l). However, post-haemodialysis cGMP levels underestimated the true volume status because cGMP itself (a small molecule) was partly removed by dialysis. In contrast to ANP, cGMP markedly decreased in patients with isovolaemic HD. As found for ANP, there was a significant correlation between cGMP levels and Vecf/TBW ratio (r=0.565, all patients).
TBW and Vecf related to clinical signs of overhydration
Pre-dialysis mean arterial blood pressure (MAP) was 105.5±14.9 mmHg in PD patients and 100.5±11.1 mmHg in HD patients (n.s.), systolic pressure was 146.2±22.0 mmHg in PD and 143.5±18.1 mmHg in HD patients, and diastolic pressure was 85.1±14.0 and 79.0±10.4 mmHg (P<0.05) respectively. The rank correlation coefficient between systolic pressure and Vecf was significant in PD patients (r=0.258, P<0.05) and was r=0.257 (P=0.057) in HD patients. There were more classes of antihypertensive drugs prescribed for PD patients than for HD patients (1.9±1.1 vs 1.1±0.9, P<0.005). The ratio of Vecf/TBW was negatively correlated to the amount of residual diuresis in the PD group (r=-0.323, P<0.05).
As described in the methods section, the PD group was subdivided into three groups according to body fluid compartment measurements (from a low to high extracellular hydration status). Arterial pressure, antihypertensive medication, and the incidence of clinical signs of overhydration (oedema and/or increased jugular vein filling and/or increased interstitial pulmonary fluid according to chest X-ray) were evaluated. Of these parameters, the ratio of Vecf/TBW revealed the most clinically significant findings (Table 2). Measurements of single body fluid compartments showed a higher degree of variation and less significance.
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Relation between body fluid distribution, serum albumin concentration and peritoneal transport properties
Serum albumin concentration did not differ between the HD and PD groups (PD 3.8±0.8 g/dl; pre-HD 3.7±0.3 g/dl; post-HD 3.9±0.4 g/dl).
A negative correlation between serum albumin levels and Vecf/TBW was found in PD patients (r=-0.624, P<0.001) (Figure 3), but not in the HD group (r=-0.099). PD patients with serum albumin levels below 3.5 g/dl had significantly higher ratios of Vecf/TBW compared with patients having serum albumin above 3.5 g/dl (60.5±4.2 vs 57.1±4.9%, P<0.05). A negative correlation between serum albumin level and plasma ANP was also revealed (r=-0.367, P<0.05).
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Serum osmolality was lower in PD patients compared with HD patients after dialysis (PD 265.1±22.4 mosmol/kg; pre-HD 277.8±25.8 mosmol/kg; post-HD 281.0±14.2 mosmol/kg, P<0.05). Serum osmolality was not correlated with TBW, Vecf, or Vecf/TBW in either group.
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Discussion |
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However, variation in results may occur because of a lack of standardization, the type of device used, the skin electrodes used, and the mathematical model applied for curve fitting and computation. An individual control or set-up for each centre is, therefore, recommendable. To evaluate the accuracy of BIA, we compared TBW measured by BIA with the urea distribution volume calculated in HD patients from the dialysate and plasma urea concentration in a closed system (Genius® tank dialysis system). The BlandAltman analysis showed that the bias was small with BIA values falling close to the identity line. A recent study called into question the accuracy of intradialytic volume changes assessed by BIA because of orthostatically (pre-HD) induced spurious volume changes during haemodialysis [13]. To minimize this effect we performed all measurements after the subjects had been supine for at least 20 min. Indeed, we found that the acute changes in TBW during ultrafiltration haemodialysis were more difficult to detect than shifts within the extracellular space. The correlation coefficient between weight loss on haemodialysis and the change in Vecf was 0.72 (data not shown). In a recent study, Zhu et al. [14] demonstrated similar findings when comparing TBW and
Vecf with the actual ultrafiltration volume in dialysis patients. The extracellular fluid, which is mostly represented by an Ohm resistance is probably measured with higher accuracy by BIA than TBW measurement which is deduced from an Ohm and a capacitive resistance. An additional modified method, the so-called segmental BIA, found even higher correlations between
Vecf and ultrafiltration volume than with whole body BIA [14]. The discrepancy in results between whole body BIA and segmental BIA has been attributed to the large difference in extracellular resistance in different segments of the body [14]. According to Zhu et al. [14], the limbs account for more than 90% of whole body resistance; however, they contribute to only 28% of total Vecf. We used whole body BIA as it is the more common method, and because it is simple to use and less time consuming. Reliable comparisons of single body fluid compartments between individuals should be normalized for body weight, body surface area, or fat distribution. However, to avoid these calculations, it is possible to use the ratios of different compartments. The ratio of Vecf/TBW is a dimensionless value that sensitively reflects extracellular fluid expansion. This measure was best correlated to clinical signs of overhydration in our study.
While multifrequency BIA can measure extracellular water, it cannot differentiate between the interstitial and intravascular compartments. It has been shown that the plasma concentration of ANP that depends on right atrial wall tension correlates with intravascular volume and central venous pressure [7]. However, as a biochemical parameter, ANP only allows a relative estimation of central venous filling and is also dependent on cardiac function. Nevertheless, we found in previous studies very sensitive ANP responses to ultrafiltration and to intermediate changes in dry weight [6]. ANP can, therefore, be helpful to assess the filling state of the intravascular space [6].
Before haemodialysis, the extracellular fluid space was increased in HD. PD patients had both higher TBW and Vecf compared with controls. PD patients had TBW which was even greater than in HD patients before dialysis. The increase in TBW in PD patients was also reflected by an expansion of the extracellular fluid space with a Vecf/TBW ratio that surpassed the values of HD patients after dialysis and was in the range of the pre-haemodialysis values. Rottembourg [15] found a higher mean pulmonary artery pressure in CAPD patients compared with HD patients [15]. Lameire et al. [16] described a considerable fall in dry weight after transfering CAPD patients to haemodialysis.
PD patients, having a more constant level of hydration were subdivided into three groups according to their hydration status in order to study correlations between BIA and clinical findings. As mentioned previously, the ratio of Vecf/TBW focuses attention on extracellular volume expansion. This ratio was better correlated with clinical findings of overhydration than with single body fluid compartments. Prevalent oedema, increased jugular vein filling, and interstitial pulmonary fluid indicated by X-ray were correlated with this quotient. Increased systolic blood pressure in PD patients was correlated with the ratio of Vecf/TBW. The use of antihypertensive drugs tended to be more frequent in the group showing BIA indicated extracellular fluid overload. Even in the group having the highest Vecf/TBW ratio there were still 12.5% of patients that did not demonstrate any clinical signs of overhydration. This illustrates the insensitivity of standard clinical parameters for estimating body fluid status. It has been demonstrated that with an increasing extracellular fluid space blood pressure slowly increases over weeks to months [17]. However, short-term changes in extravascular and intravascular filling did not actually change blood pressure. In a follow-up investigation, Katzarski and Charra et al. [9] have demonstrated that reductions in dry weight were accompanied by slow decreases in blood pressure over several months. This finding in dialysis patients supports the concept that not hypervolaemia per se but a rise in peripheral vascular resistance may trigger the induction of hypertension. The biochemical or pathophysiological links between Vecf and peripheral vascular resistance, however, are still unclear.
Plasma ANP levels were significantly elevated in all dialysis patients, and they were even increased at post-haemodialysis. Contrary to Vecf in PD patients, which was slightly above the level in HD patients before haemodialysis, plasma ANP concentrations in PD patients corresponded to post-haemodialysis values. This supports the concept that extracellular fluid expansion in PD patients occurs predominantly in the interstitial space whereas intravascular filling is not increased to the same degree.
In the PD group, cGMP increased to a similar degree as did ANP. Contrary to the ANP findings, cGMP in PD patients surpassed the post-haemodialysis values in the HD group. However, the rather low post-haemodialysis cGMP levels can be attributed to the significant diffusional removal of this small molecule during haemodialysis. Plasma cGMP consecutively decreases also during isovolaemic haemodialysis and thereby underestimate post-dialysis hydration [18].
Metabolic changes during dialysis may be related to fluid status. We found a significant negative correlation between serum albumin levels and the Vecf/TBW ratio in PD patients. No such correlation was found in the HD group, which may be a result of the more intermittent type of dialysis. Lower serum albumin levels may result from extracellular dilution in cases of overhydration. Whether a low serum albumin concentration per se favours extracellular fluid expansion, especially in the interstitial space, is a matter of debate. Because the effective oncotic pressure gradient does not change between the intravascular and interstitial spaces during hypalbuminaemia (as a result of albumin equilibration between both compartments) an oncotic mechanism is unlikely to cause fluid expansion. Interestingly extracellular fluid status, serum albumin, and arterial pressure have been linked in previous studies. In clinical trials, dialysis patients with refractive hypertension that were treated with longer dialysis sessions or with daily haemodialysis at home showed a fall in dry weight, an increase in serum albumin levels and reductions in mean arterial blood pressure [19]. However, the role of solute clearance and the time factor in dialysis need further clarification to understand their link to hydration status in this setting.
The large prospective CANUSA study indicated that increased mortality in PD patients might be attributed to high peritoneal transport rates [11]. It was speculated that high transporters produced more rapid reductions in dialysate osmotic pressure, causing reduced ultrafiltration in CAPD with the risk of subsequent fluid overload. Hypertension and left ventricular hypertrophy could then develop resulting in increased mortality. In the present study, we did not detect differences in body fluid distribution in patients having low (<75%) or high (>75%) peritoneal transport rates. We found no correlation between the D/P ratio of creatinine in the peritoneal equilibration test and Vecf, TBW, or Vecf/TBW. This finding may be explained by fact that we closely adapted the dialysis regimen to changes in ultrafiltration. High transporters having a loss of ultrafiltration were typically switched to regimes with shorter dwell times using automated peritoneal dialysis. In a retrospective analysis that included 238 patients from our centre, we did not find a negative impact of high peritoneal transport rate on patient or system survival [20]. However, when reduced ultrafiltration because of high peritoneal transport is not adequately compensated by the dialysis regime, overhydration may occur thereby worsening patient outcome.
The current body fluid distribution findings in dialysis patients support a more general use of BIA for the assessment and repetitive control of dry weight, especially in PD patients. The data highlighted the links between extracellular fluid expansion and elevated systolic pressure in PD patients. Closer monitoring of dry weight and an adaptation of dialysis regimen may, therefore, be key for the improvement of long-term survival.
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Notes |
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References |
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