NDT Advance Access published online on May 2, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn176
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Longitudinal relationships between fluid status, inflammation, urine volume and plasma metabolites of icodextrin in patients randomized to glucose or icodextrin for the long exchange
1 University Hospital of North Staffordshire, Stoke-on-Trent, UK 2 Karolinska Institutet, Stockholm, Sweden 3 Leeds Teaching Hospitals Trust, Leeds, UK 4 Cardiff and Vale NHS Trust, Cardiff, UK 5 Klinik für Nephrologie, Düsseldorf, Germany 6 Addenbrookes Hospital, Cambridge, UK 7 University Hospital of Malmö, Malmo, Sweden 8 Otto-von-Guericke-Universität, Magdeburg, Germany 9 University Hospital of Lund, Sweden 10 Royal Free Hospital, London, UK 11 Baxter S.A, Brussels, Belgium
Correspondence and offprint requests to: Simon J. Davies, Department of Nephrology, North Staffordshire Hospital, Princes Road, Hartshill, Stoke-on-Trent, ST4 7LN, UK. Tel: +44-01782-554164; Fax: +44-01782-620759; E-mail: simondavies1@compuserve.com
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Abstract |
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Background. Randomized trials have shown that icodextrin reduces the volume of extra-cellular fluid (ECFv) with variable effects on residual renal function. To explore this fluid shift and its possible mechanisms in more detail, prospectively collected data from one such trial, including measures of inflammation (C-reactive protein, tumour necrosis factor-
, albumin and low and high molecular weight hyaluronan) ANP (atrial naturetic peptide), an indirect marker of intra-vascular volume, plasma concentrations of icodextrin metabolites and -amylase activity were analysed. Methods. 50 patients were randomized to either 2.27% glucose or icodextrin (n = 28) for a long exchange following a month run in. Blood samples were obtained at –1, 0, 3 and 6 months, coincident with measurements of urine volume and fluid status.
Results. In both randomized groups, a significant correlation between the fall in ECFv and the decline in urine volume was observed (P = 0.001), although the relative drop in urine volume for patients randomized to icodextrin tended to be less. At baseline, ANP was higher in patients with proportionately more ECFv for a given body water or height. Icodextrin patients had non-significantly higher ANP levels at baseline, whereas by 3 (P = 0.026) and 6 months (P = 0.016) these differed between groups due to divergence. There was a correlation between increasing ANP and reduced ECF at 3 months, r = –0.46, P = 0.007, in patients randomized to icodextrin, but not glucose. There were no relationships between fluid status and any inflammatory markers at any point of the study, with the exception of albumin at baseline, r = –0.39, P = 0.007. Amylase activities at –1 month and baseline were highly correlated, r = 0.89, P < 0.0001. Within patients, concentrations of icodextrin metabolites were highly correlated; the only predictor of between-patient variability on multivariate analysis was body weight. There was no relationship between plasma concentrations of icodextrin metabolites and any of the other clinical parameters, including change in daily ultrafiltration, urine volume, fluid or inflammatory status.
Conclusions. This analysis supports observational data that changes in fluid status are associated with changes in urine volume. Icodextrin was not associated with a greater fall in urine output despite its larger effect on ECFv. Changes in fluid status could not be explained or did not appear to influence systemic inflammation. Nor can they be explained by individual variability in plasma concentrations of icodextrin that are in turn inversely proportional to the volume of distribution.
Keywords: amylase; bioimpedance; fluid status; inflammation; icodextrin
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Introduction |
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Icodextrin has been shown to alter fluid status by reducing the extra-cellular fluid volume (ECFv) [1–3]. This has not always translated into associated changes in blood pressure (BP), however, and the impact on residual urine volume has also varied, with one study showing a fall, others a relative preservation of urine volume [1–4]. Possible explanations might include trial design leading to variable fluid status at baseline, differences in the incremental changes in fluid removal or good BP control at baseline leading to changes in medication during the course of the study that might have masked any clear effect. Alternatively, the relationship between fluid removal, ECFv and urine volume may differ between all glucose regimes and those including icodextrin.
We undertook further analysis of prospectively collected data and samples from a randomized, double-blind placebo-controlled trial designed to evaluate the effects of icodextrin on fluid status in order to try and answer the following questions: (i) Was there a relationship between changing fluid status and urine volume and if so, was this the same for glucose and icodextrin? (ii) Was there indirect evidence of a change in intra-vascular volume as judged by plasma atrial naturetic peptide (ANP), and could this be related to changing fluid status? (iii) Was there a relationship between fluid status changes and inflammatory status? (iv) Could the variability in response to icodextrin be explained by differences in the plasma concentrations of icodextrin metabolites?
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Study design
A detailed description of the randomized trial has been published previously [1]. Briefly, important inclusion criteria were (a) either untreated hypertension (BP > 140/90), treated hypertension or a dialysis prescription with a daily average glucose concentration of 2.27% or greater; (b) high or high-average peritoneal solute transport (corrected 4-h D/P creatinine ratio
0.65) and (c) urine output 
750 ml/day. Following a run-in period of 1 month during which subjects used glucose 2.27% in the long exchange (34% patients were on APD), 28 of the 50 were randomized to icodextrin 7.5%. The groups were well balanced for age, comorbidity, membrane function and peritoneal dialysis (PD) modality. Weight, body composition, urine volume and blood samples for the measurement of atrial natiuretic peptide (ANP), high-sensitivity C-reactive protein (CRP), tumour necrosis factor- (TNF-), total high molecular weight (HMW-HA) and low molecular weight hyaluronan (LMW-HA), amylase, osmolality and icodextrin metabolites were taken at –1, 0 (baseline), 3 and 6 months. The main findings of the study were a reduction in weight and ECFv in the icodextrin group compared to the glucose group; there were no significant changes in BP at 3 or 6 months and no reported adverse events related to hypotension or volume depletion. Diuretic doses were not altered during the study but there were multiple changes in BP medication that were difficult to analyse, although icodextrin use tended to be associated with more frequent reductions. No clear relationship between changing fluid status and BP was observed.
Clinical and laboratory measurements
The ECFv and total body water volume (TBWv) were determined using multiple frequency bioelectrical impedance analysis performed with the Hydra 4200 analyser (Xitron Technologies, San Diego, CA, USA). TBWv was also determined independently from deuterium (D) dilution as described. In the primary analysis, longitudinal changes in the ECFv correlated with changes in TBWv when determined from D dilution. Residual urine volume was determined from a 24-h collection.
Laboratory measurements
Plasma samples were put on ice after collection and stored at –80°C. Analyses were performed centrally. CRP was determined from a high-sensitivity assay. TNF- was determined by immunometric assay (Immulite, DPC, Siemens, California), and both HMW- and LMW-HA were determined by high-sensitivity, proteoglycan-dependent time-resolved immunoassay [5]. ANP was extracted from plasma using Sep-pak-C18 columns and quantified with an 125I solid-phase RIA (Laboserv GmbH, Giessen, Germany) [6]. Plasma -amylase activity was measured using an adapted routine method using p-nitrophenol maltoheptaoside as a substrate [7]. Plasma icodextrin metabolites were measured using gel filtration high-performance liquid chromatography as described [8]. The concerntrations of G8 to G10 are estimated as no commercial standards are available.
Statistics
Between-group and longitudinal within-group analyses were made using unpaired and paired tests, respectively, employing parametric and non-parametric tests where appropriate and Bonferroni's correction for multiple comparisons. Correlations between the changes in urine and ECF volumes and other measures were performed using Pearson's or Spearman's coefficients having first checked for linearity. A mixed-model repeated measures ANOVA (SAS) was used to investigate whether there was a relationship between changing fluid status and urine volume and if so whether or not it was the same for glucose and icodextrin. Multiple regression was performed where multiple correlations were observed, e.g. when determining factors associated with baseline fluid status and concentrations of plasma icodextrin metabolites. Where appropriate, data were first log transformed.
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Relationship between changes in ECFV and urine volume
Following randomization at both 3 and 6 months, there was a significant relationship between the longitudinal change in ECFv and the change in urine volume in both treatment groups. In each case, a reduction in ECFv was associated with a reduction in urine volume and vice versa (see Figure 1a and b), repeated measures ANOVA P < 0.001. At 3 months, for glucose the correlation was r = 0.44, P = 0.037, and for icodextrin r = 0.5, P = 0.013. At 6 months, for glucose the correlation was r = 0.63, P = 0.02, and for icodextrin r = 0.6, P = 0.003. The effect of treatment group in the repeated measures ANOVA was not significant (P = 0.39), although there was if anything a tendency for a greater fall in urine volume for a given change in ECFv in those treated with glucose in the long dwell (see Figure 1).
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, dashed regression line). At both time points for both solutions, there was a significant negative relationship (see the text for details). The relative reduction in urine volume for a given fall in ECFv appears less in the icodextrin group.Relationship between fluid status, fluid removal and ANP
The hydration state of patients on PD can be expressed as the ECFv/TBWv ratio, obtained from bioimpedance measurements. Using this ratio as the dependent variable, multivariate linear regression was used to identify factors that correlated with fluid status at baseline (n = 50), see Table 1. Two factors were found to have a significant relationship, peritoneal fluid removal and plasma ANP, which were decreased or increased with increasing hydration, respectively. ECFv/height, another approach to assessing fluid ECFv excess, also correlated with ANP, r = 0.52, P < 0.001. Following randomization, no such relationship was found with any of the clinical variables and hydration. Prior to the intervention, patients who were subsequently randomized to icodextrin had a non-significantly higher plasma ANP than the glucose group; following randomization, there was a divergence in the ANP concentrations such that they became significantly different, see Table 2. In the icodextrin-treated patients, the fall in ECFv correlated with an increase in ANP, r = –0.46, P = 0.007, whereas no such relationship was observed in the glucose-treated group.
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Relationship between fluid status, urine volume and inflammation
CRP correlated at each time point with total HA (range of r values: 0.33–0.45, P < 0.035), due to correlations with HMW-HA only and inversely with plasma albumin (r = –0.34, P = 0.028). On initial analysis, there was a positive correlation between TNF-
and total HA at each of the time points during the study. This was due to a single outlying patient with an underlying diagnosis of systemic lupus, with a normal CRP, whose TNF- and HA levels were an order of magnitude higher than that of the remaining patients. When this patient was excluded from further analysis, there were no between-group or within-group longitudinal differences in TNF- during the course of the study Table (2). At each time point, there was a significant but weak negative correlation between LMW-HA and urine volume, with r values ranging between –0.2 and –0.37, P < 0.05, but not with HMW-HA. Within each group total, LMW- and HMW-HA increased with time during the study; this was more significant in the icodextrin-treated group, especially for HMW-HA, but this difference was already seen in the month prior to randomization. There were no relationships observed between fluid status (either ECFv/TBW or ECFv/height) and inflammatory markers, with the exception of plasma albumin at baseline on univariate analysis (r = –0.39, P = 0.007), although this disappeared on multivariate analysis (Table 1).
Relationship between changes in fluid status, plasma amylase activity and concentrations of icodextrin metabolites
Prior to randomization, there was a wide range in plasma amylase activity observed (mean 80, range 35–200 U/l) with apparent stability within individuals as evidenced by a high degree of correlation between –1 month and baseline (r = 0.88, P < 0.001) (Figure 2). There was no relationship between plasma amylase and weight, BSA, age or urine volume on log-transformed linear regression. Following randomization there was, as expected, a very significant and sustained fall in plasma amylase in patients using icodextrin (see Table 2). At 3 and 6 months following commencement of icodextrin, plasma metabolites ranging from G2 (maltose) through to G10 were detected in decreasing concentrations with an increasing molecular weight (see Figure 3). A wide range of variability between subjects was observed, but the concentrations of the metabolites correlated significantly with each other. Factors associated with plasma icodextrin metabolite concentrations were weight and to a lesser extent urine volume (Table 3). No correlations with height, gender or amylase concentrations either before or after randomization were observed. There were no correlations observed between plasma icodextrin metabolites and any of the observed changes in weight, ultrafiltration, sodium removal, urine volume, plasma albumin or fluid status as measured either by BIA and D dilution.
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Discussion |
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The further analysis of this prospective randomized controlled trial lends further support to previous observations that fluid status is an important factor in the preservation of residual renal function in PD patients. In both of the patient groups, there was a significant longitudinal relationship between changes in ECFv and urine volume. Although these are only associations, the likelihood of a cause and effect relationship is high. The changes in ECFv were intended in the icodextrin group, being the primary objective of the study. In the glucose group ECFv changes resulted from an increased prescription of glucose, driven by clinical need. The published literature also supports this interpretation, and the finding of a reduction in urine output associated with volume depletion is easy to explain. Observational data from the NECOSAD study found that episodes of volume depletion were an independent risk factor for the loss of RRF [9]. This was also the price paid when strict salt restriction combined with increased ultrafiltration was used to control BP without anti-hypertensive drugs in another study of CAPD patients [10]. More recently, in a similar controlled trial where there was a loss of RRF observed in patients randomized to icodextrin for the long exchange [2], secondary analysis indicated that this was due to frank volume depletion in four of the patients [11]. This trial differed in one important respect from the present study in that the comparator solution was glucose 1.36% rather than 2.27%. Because the use of glucose 1.36% in the long exchange is generally associated with net fluid reabsorption, the relative change in fluid removal and thus the potential for unintentional volume depletion is greater. Taken together, these observations indicate that control of fluid status in PD is a two-way street. Overhydration is associated with many problems, but excessive volume depletion might put residual urine volume, a valuable commodity to any dialysis patient, at risk. Less easy to explain is an increase in the urine volume with increasing ECFv (unless of course the patients were previously volume depleted). This observation has been made before in haemodialysis patients when an increase in the urine volume GFR and fractional excretion of sodium was observed in the intra-dialytic period [12]. The concept of a pressure natriuresis has been proposed to explain this phenomenon although its mechanism is poorly understood.
The initial analysis of this trial clearly showed that by 6 months, urine volume was significantly better preserved in the icodextrin-treated patients despite their greater fall in ECFv [1]. The present analysis would also suggest that the change in urine volume for a given reduction in ECFv is less in patients treated with icodextrin. One possible explanation for this would be that the change in ECFv is achieved whilst protecting the patient from intravascular volume contraction. Assessing volume status in PD patients is undoubtedly difficult. There is considerable evidence that they are frequently volume loaded when compared to either normal subjects or haemodialysis patients [6], but it is less clear whether this extra fluid is predominantly in the intravascular or extravascular, interstitial space. At baseline in this study, there was an association between increased ANP levels and ECF excess, whether expressed as a ratio of the TBW or as a function of height that could not be explained by variations in residual renal function. ANP may not be an ideal measure of intravascular volume in patients with renal failure, although there is evidence to suggest it is an indirect indicator of atrial filling in patients without serious cardiac problems [13, 14]. N-terminal brain natriuretic peptide, which was not measured in this study for technical reasons, has recently been shown to predict cardiac failure in PD patients [15]; however this might be more a marker of structural cardiac injury than fluid status in this context. The observation that if anything ANP levels tended to increase, especially in patients who had the greatest reduction in their ECFv was, therefore, surprising, but raises the possibility that there is a relative preservation of intravascular volume when using icodextrin explained by osmotic or oncotic pressures induced by icodextrin metabolites. The present study however would not suggest that this is a function of plasma osmolarity or between-patient differences in LMW icodextrin metabolites. Low concentrations of HMW icodextrin in plasma could potentially influence oncotic pressures and are difficult to measure but it must be remembered that starch derivatives are routinely used as plasma expanders. This hypothesis requires testing, but the recent report of increasing natriuretic peptides with icodextrin use in diabetic patients undergoing CAPD shows that this is not an isolated observation [16].
Previous studies have indicated that increased systemic inflammation is associated with an expanded ECFv in PD patients [17,18]. There was some evidence for such an association at baseline in this study, but not longitudinally. This might reflect either a selection bias of relatively healthy patients or a lack of statistical power. Another weakness of the study was the failure to measure interleukin-6. The multivariate analysis disguises the fact that a higher CRP and lower albumin are associated with increasing age and both of these factors can be been linked to expanded ECFv both here and in previous studies [6,19,20]. Previous reports of the changes in systemic inflammatory markers when using icodextrin have been variable [21,22], but the present study did not find any between-group differences or within-group changes in either CRP, in agreement with the only other study randomizing patients to a fluid status intervention (2), or TNF-. The lack of a significant change in fluid status leading to an improvement in inflammatory markers is against a causal relationship in this direction. At first sight it appears that the icodextrin group tended to have a more marked longitudinal increase in plasma HA concentrations compared to the glucose group. However, this difference was already present in the month before randomization, indicating that this was a pre-existing feature of these patients. Furthermore, there were no between-group differences at any of the study time points. In view of this observation we chose to measure the high and low molecular weight components of HA. Previous studies in normal individuals have shown that daily turnover of HA, 95% of which resides in the interstitial space, is approximately one-third of its total mass [23]. Increased turnover, and thus plasma levels, may occur in response to inflammatory stimulus, such as increased TNF-, or due to physical propulsion associated with fluid movement from the extracellular into the intravascular space, e.g. after exercise or feeding [24,25]. The pathway and fate of HA depends on its molecular size, with HMW-HA being transported by the lymphatics and metabolized by the reticulo-endothelial system, and LMW-HA excreted by the kidneys [23]. This explains the relationship observed in this study between LMW-HA levels and residual urine volume.
The only important predictor of plasma icodextrin metabolite concentrations identified here was the weight, or more precisely the volume of distribution. This is in keeping with single-exchange kinetics in which the peak plasma concentration was closely correlated to weight [26]. The failure to find any correlation with the plasma amylase activity, either before or after commencing icodextrin, would suggest that the between-patient variability in amylase—which is significant and relatively stable—is not contributing to the between-patient differences in icodextrin metabolite concentrations. This is a little surprising as amylase is considered to be the principal enzyme responsible for cleaving icodextrin metabolites and may suggest that this process occurs in the peritoneal interstitial tissues where there is tissue-bound amylase and not just the plasma compartment. The marked reduction in plasma amylase activity following commencement of icodextrin has been described previously; initially thought to be an artefact due to the interference by metabolites of the amylase assay, this has been shown not to be the case with the method used here [7].
This study found no relationship between the efficacy of icodextrin in changing ultrafiltration, fluid status or the relative preservation of residual urine volume with the concentration of plasma icodextrin metabolites. This is in keeping with previous observations that there is no relationship between metabolite concentrations and net ultrafiltration achieved with icodextrin [27].
In summary, this analysis provides further evidence for the important relationship between ultrafiltration, fluid status and preservation of urine volume in PD patients. Existing as well as future guidelines should take this into account. Icodextrin has the potential to reduce ECFv without endangering the urine volume provided care is taken to avoid excessive fluid depletion. Inflammation appears to have some role in determining fluid status but there is no clear evidence for a reverse causal relationship.
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Acknowledgments |
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This study was funded by Baxter Healthcare Corporation, who also manufactured the double-blind product.
Conflict of interest statement. B.L., A.T. and J.C.D.F are employees of Baxter Healthcare. The data have been published in part previously in an abstract form only and presented at the 2004 meeting of the International Society of Peritoneal Dialysis—EuroPD in Amsterdam, 2005 EuroPD meeting in Prague and the ASN in Philadelphia. S.J.D. has received research funding and acts in an advisory capacity to Baxter Healthcare. Particular thanks go to Clive Richards and Louise Phillips for their excellent logistic support. High and low molecular weight hyaluronan fractions were analysed by Andreas Rössler (University of Graz, Austria). Tony Qureshi (Karolinska Institutet, Sweden) undertook the mixed-model repeated measures analysis.
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[Abstract/Free Full Text]
Accepted in revised form: 6. 3.08
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