1 Department of Medicine, Division of Nephrology, 2 Institute for Renal Outcomes Research and Health Policy, Duke University Medical Center, Durham, NC, 3 Fresenius Medical CareNorth America, Inc., Lexington, MA and 4 Baxter International Healthcare, Waukegan, IL, USA
Correspondence and offprint requests to: Lynda Anne Szczech, MD, MSCE, Duke University Medical Center, Department of Medicine, Division of Nephrology, 2400 Pratt Street, Room 7060, Durham, NC 27705, USA. Email: szcze001{at}mc.duke.edu
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Abstract |
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Methods. All patients receiving haemodialysis through Fresenius Medical CareNorth America during 1998 were included. The percentage reduction in weight or intradialytic weight loss (IDWL%) was defined as the difference between the average of pre- and post-dialysis weights from the last 3 months of 1997 expressed as a percentage of post-dialysis weight. Associations between IDWL% and clinical and demographic variables were estimated using linear regression. The association between mortality risk and IDWL% was estimated using Cox proportional hazards regression.
Results. Younger age, male gender, the presence of diabetes mellitus, decreasing cholesterol, post-dialysis weight and pre-dialysis blood pressure (systolic and pulse pressure) were associated with increased IDWL%. Increasing IDWL% was associated with increasing phosphorus, creatinine, albumin, potassium and urea reduction ratio. Increasing IDWL% was significantly associated with mortality at 1 year [hazard ratio (HR) = 1.07, P = 0.003]. Among patients with diabetes mellitus, increasing IDWL% was associated with a mortality HR of 1.03 (P = 0.02). Among patients without diabetes mellitus, increasing IDWL% was not associated with an increased mortality risk. Increasing IDWL% is associated with a greater mortality risk among patients with creatinine <7.26, which failed to remain significant for patients whose creatinine was 7.26 mg/dl. Increasing IDWL% is associated with a greater mortality risk among patients with greater post-dialysis weight, greater body mass index and lower serum sodium measurements.
Conclusions. This study confirms and extends the findings of the deleterious association between increasing IDWL% and mortality among patients with diabetes mellitus and among subgroups based on serum creatinine and body weight. The putative deleterious effect of dialysis-related volume expansion on mortality must be interpreted in the context of the patients diabetic and nutritional status.
Keywords: end-stage renal disease; haemodialysis; mortality; nutrition; weight
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Introduction |
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Competing with the putative increasing mortality risk of volume expansion is the association between increasing interdialytic weight gain and better nutrition as measured by normalized protein catabolic rate (nPCR) and serum albumin [5,7,8]. Patients with increasing albumin and nPCR have lower mortality rates [912]. Increased protein-calorie intake is usually accompanied by larger intake of foodstuffs and beverages reflected by a larger interdialytic weight gain. While patients with greater interdialytic weight gain have better serum albumin measurements [5,8] and greater nPCR [5,7], the impact of these nutritional factors on the mortality risk associated with interdialytic weight gain has not been fully explored. Given the positive associations between a greater interdialytic weight gain and laboratory surrogates of nutrition, the relationship between an elevated weight gain and mortality may be affected by an individual patients nutritional status. However, due to small sample size, earlier studies were limited by their inability to incorporate biochemical and anthropometric markers of nutritional status and so examine clinically relevant subgroups of patients [7]. Because intradialytic weight loss represents the component of each patients volume exposure over which health care providers have impact by ultrafiltration, this study was undertaken to explore the relationship between intradialytic weight loss (IDWL), nutritional parameters and survival.
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Subjects and methods |
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IDWL was defined as the difference between the average of pre-dialysis weights and the average of post-dialysis weights from each dialysis treatment received during the last 3 months of 1997. Relative intradialytic weight loss (IDWL%) was expressed as a percentage of IDWL relative to estimated dry weight as approximated by average post-dialysis weight. Pulse pressure was defined as the difference between pre-dialysis seated systolic and diastolic blood pressures. The presence or absence of diabetes mellitus was defined considering it as a co-morbid condition rather than as the cause of renal failure. Dialysis vintage was defined as the time period between initiation of renal replacement therapy and January 1, 1998. Because vintage was positively skewed, with the majority of patients clustered among lower values, the variable was transformed to a more normal distribution using its square root.
The mean and standard deviation for IDWL and IDWL% were calculated for groups of patients defined by categories of age, gender, race and presence or absence of diabetes mellitus. Differences between groups were compared using analysis of variance (ANOVA) and the Students t-test.
Associations between IDWL% and clinical and demographic variables were estimated using linear regression in both univariate and multivariable analyses. The fully adjusted, multivariable linear regression model was built using both forward and backward stepwise elimination methods. Variables tested for significance included case-mix variables (age, gender, race and the presence of diabetes mellitus), clinical variables (pre-dialysis systolic blood pressure, pre-dialysis pulse pressure and the difference between pre- and post-dialysis systolic blood pressure, dialysis vintage), post-dialysis weight (as a surrogate for estimated dry weight), biochemical markers of nutrition (creatinine, albumin, cholesterol), other laboratory measurements (sodium, phosphorus, haematocrit, glucose, haemoglobin A1c, potassium) and a measurement of dialysis adequacy (URR). Entry and elimination criteria were set at a value of P = 0.05.
Cox proportional hazards regression was used to estimate the association between IDWL% and mortality risk in both unadjusted and adjusted analyses. The model was built using both forward and backward stepwise elimination methods testing the variables described above. Interactions between IDWL% and nutritional markers such as albumin and creatinine as well as case-mix variables (age, gender, race, diabetes mellitus), serum sodium and anthropometric attributes (post-dialysis weight, body mass index) were tested in separate models. Additional analyses were performed stratifying on values of those variables that interacted significantly with IDWL% incorporating all variables found to be significantly associated with mortality in the full main effects model. For binomial variables (such as diabetes mellitus), the analysis was repeated stratified on the presence and absence of the condition represented by the variable. For continuous variables (such as creatinine), the analysis was stratified into groups divided by quartiles of the variable of interest. Because serum sodium was positively skewed, the analysis was stratified into the clinically significant groupings of 135 and
135 and
135 meq/l. Quartiles of patients based on selected variables provided subsamples with 80% power to detect the association between IDWL% and mortality demonstrated among the entire cohort.
All P-values reported are two-sided, and all confidence intervals (CIs) reported are 95% intervals. All analyses were performed using SAS (version 6.12, SAS Institute Inc., Cary, NC).
Results
The demographic and clinical characteristics of patients in this cohort are described in Table 1. The cohort was composed of 47.7% patients with diabetes mellitus, 51.4% were male, 50.4% were black, and they had a mean age of 60.2 years. IDWL and IDWL% for clinical subgroups defined by gender, age, race and the presence or absence of diabetes mellitus are shown in Table 2. Weight loss defined by both IDWL and IDWL% was greater among younger patients (P < 0.0001 and P < 0.0001) and among patients with diabetes mellitus (P = 0.04 and P < 0.0001). Weight loss was also greater among men as compared with women (P < 0.0001 and P < 0.0001) and among blacks as compared with whites (P = 0.009 and P < 0.0001).
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The association between increasing IDWL% and mortality among patients described by quartiles of creatinine, body mass index and post-dialysis weight are shown in Table 5. While patients in the lowest quartile (creatinine <7.26) showed a similar relationship between increasing IDWL% and mortality to the cohort overall (HR = 1.04, P = 0.002), patients whose creatinine was >7.26 mg/dl did not experience the same increased mortality risk associated with increasing IDWL%.
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Discussion
This study explores the interaction between IDWL% and nutrition and their effects on mortality. Consistent with prior research, patients with increasing IDWL% tended to be younger and have increasing biochemical markers suggesting better somatic nutrition, including higher serum creatinine concentration, and markers of greater protein-caloric intake, including phosphorus, potassium, glucose and cholesterol [15]. While increasing IDWL% was associated with an increase in mortality, this relationship was not homogeneous among clinical subgroups. Increasing IDWL% was associated with a much greater risk in mortality among patients with diabetes mellitus as compared with patients without diabetes mellitus. Additionally, the strength and significance of the mortality risk associated with increasing IDWL% declined among patients with increasing serum creatinine such that patients with the greatest serum creatinine values experienced no significant increase in death risk associated with increasing IDWL%. Interestingly, the association between IDWL% and mortality was also strongest among patients with the greatest weights and declined at lesser post-dialysis weights and among patients with lower serum sodium measurements.
Exposure to volume changes and the relative risk of mortality may be assessed and analysed in a number of ways. Weight gain has been reported as the percentage gain between dialysis treatments relative to estimated dry weight [5,7], weight gain greater than or less than 5.7% [6], weight gain greater than or less than 5.0% [16] and weight gain expressed in litres [5]. For the purposes of this analysis, we chose to express this concept as intradialytic weight loss. It is unclear which arithmetic expression most accurately reflects the risks and physiological responses to volume expansion and resultant ultrafiltration requirements. Clinical practice, however, is often driven by the pre- to post-dialysis weight change or ultrafiltration volume required for a particular dialysis treatment. In this manner, IDWL reflects a compromise between the clinicians perception of the patients volume exposure and their haemodynamic tolerance of its minimization.
Towards understanding the haemodynamic components reflected by IDWL, we included a number of measures of blood pressure to attempt to reflect the changes seen during ultrafiltration. These include pre-dialysis measure of pulse pressure, pre-dialysis systolic blood pressure and the fall in systolic blood pressure seen before and after dialysis. In models controlling for these factors, IDWL% continued to have an association with mortality. While these measures do not entirely describe the haemodynamic changes associated with ultrafiltration and how they vary based on cardiac function, their lack of significant interaction suggests that the effect of IDWL% on mortality is not entirely mediated by these mechanisms.
This is the first study to demonstrate the heterogeneous relationship between IDWL% and mortality among patients with increasing serum creatinine concentration. Increasing creatinine in the setting of adequate dialysis is thought to reflect a greater muscle mass and subsequently to be a somatic marker of better nutrition [12]. As a laboratory surrogate of somatic nutrition, increasing serum creatinine is associated with decreased mortality risk [12]. Patients with a greater serum creatinine experienced less of an association between IDWL% and mortality, suggesting that the ability to defend against decreasing intravascular volume status may be protected among patients with better nutrition. Alternatively, patients with better nutrition may have less co-morbid disease and subsequently are less affected by larger weight gains, or finally maintenance of better nutritional status mandates greater fluid removal. Counterintuitive was the finding that patients with both increasing post-dialysis weight and increasing body mass index experienced a stronger association between IDWL% and mortality risk. The difference between creatinine and both body mass index and weight may reflect the importance of body composition rather than size in the relationship between IDWL% and mortality.
While the relationship between albumin and mortality was similar to that previously reported [9,12,17], the effect of IDWL% on mortality did not vary based on a patients albumin measurement. This may reflect fluctuations in albumin related to intercurrent illness or other inflammatory states that limit the ability of albumin to represent only the nutritional state in the short term [18,19]. The relationship between IDWL% and mortality varied based on a patients serum sodium concentration. While serum sodium is affected by many factors including diet, dialytic parameters and residual renal function, the use of serum sodium may provide a measure to compare volume and nutritional status (hyponatraemia secondary to hypervolaemia).
These findings are consistent with prior reports demonstrating that the relationship between increasing IDWL% and mortality is different in the presence and absence of diabetes mellitus [7]. In a prospective study of 283 patients, Kimmel et al. [7] demonstrated that patients without diabetes mellitus did not experience an increased mortality risk with increasing IDWL%. While interpretation of this study is limited by its small sample size (n = 164 without diabetes mellitus), the finding that IDWL% is not significantly associated with an increased mortality risk among patients without diabetes mellitus was confirmed here using a cohort with greater power to examine this clinical subgroup. Among patients with diabetes mellitus, this association may be related to the relationship between increased IDWL% and poor glycaemic control, which portends a poorer survival [20]. Alternatively, patients with diabetes mellitus may also have a greater prevalence of cardiovascular disease and other co-morbidities, not assessed in this analysis, which may augment the risk associated with increasing IDWL%.
While the relationship between IDWL% and mortality is significant, the strength of this relationship relative to other predictors of mortality must be noted. The 2 for IDWL% is comparable with that of cholesterol and potassium and only slightly less than that of diabetes mellitus. Relative to the predictive power of albumin and age as assessed by the
2 term for each variable, IDWL% accounts for only a small amount of the variance in the model. Given this, clinical and research efforts should be directed toward those factors that may be, in some part, actionable, such as blood pressure, divalent cations and nutritional surrogates, to attempt to improve mortality risk.
While this study demonstrates heterogeneity in the association between IDWL% and mortality among patients with ESRD, its conclusions should be interpreted in the setting of certain limitations. As a retrospective cohort study, these associations cannot be ascribed a causeeffect relationship. Further research using a prospective, randomized design will be required to confirm this relationship. Additionally, while residual renal function may affect the weight gain between dialysis treatments, data reflecting individual urine outputs were not available for this or other similar analyses [5,6]. While the individual components of weight gain cannot be assessed by this and other studies [5,6], the combined effect of intradialytic oral intake and residual renal function is assessed periodically by the rounding nephrologist and is the net physiological effect examined here. Finally, the effect of classes of antihypertensive medications on this relationship between IDWL% and mortality was not assessed. Any protective or deleterious effect that may be conferred through a decrement in systemic vascular resistance or heart rate by the individual classes of antihypertensives will need to be explored in future prospective investigations.
The current study is the first to demonstrate that the association between IDWL% and mortality risk declines among patients with increasing serum creatinine concentrations. It further demonstrates that the association between IDWL% and mortality is different among patients with and without diabetes mellitus. Prospective investigations will be necessary to define the optimal IDWL% for each individual patient and whether a change in IDWL% subsequently will alter mortality risk. Clinical recommendations for suggested IDWL% should be made in the context of clinical factors reflective of nutrition and the presence of diabetes mellitus. With recent recognition that an expanded dialysis-associated volume can also reflect a greater state of nutrition, acute weight changes may not be a robust marker of non-compliance. The putative deleterious effect of dialysis-related volume exposure on mortality must be interpreted in the context of the patients nutritional status.
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Acknowledgments |
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References |
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