1First Department of Medicine, Faculty of Medicine, Semmelweis University, Budapest and 2EuroCare Nephrological Network, Hungary
Correspondence and offprint requests to: Dr András Tislér, First Department of Medicine, Semmelweis University, 2/a. Korányi S., H-1083 Budapest, Hungary. Email: atisler{at}axelero.hu
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Abstract |
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Methods. During a 10 month run-in period in 1998, 77 patients with f-IDH (10 hypotensive events/10 months, responding only to medical intervention) and 101 patients with o-IDH (1 or 2 events/10 months) were identified among all 958 patients of a dialysis network. Eighty-five patients who had no hypotensive episodes (no-IDH) during this run-in phase served as controls. Patients were followed for a median of 27 months (range: 0.337) and survival of patients in the three groups was compared by log-rank test. Independent association of f-IDH and o-IDH with survival, compared with no-IDH, was assessed by a proportional hazards model that included patient demographics, laboratory data and antihypertensive medication as well as comorbidity.
Results. Forty-five patients (58%) with f-IDH, 47 (47%) with o-IDH and 33 (39%) with no-IDH died during the follow-up. Mortality rates (deaths/100 patient years) were 37 (log-rank P = 0.013 vs no-IDH), 26 (log-rank P = 0.375 vs no-IDH) and 21 in the three groups, respectively. This indicates significantly decreased survival in patients with f-IDH as compared to those with no-IDH. In multivariate proportional hazards regression, however, where age, sex, time spent on dialysis, presence of coronary heart disease, diabetes, Kt/V, albumin level and use of ß-blockers, calcium-channel blockers and long-acting nitrates has been adjusted for, neither f-IDH nor o-IDH was associated with survival.
Conclusions. Mortality in patients with f-IDH is significantly higher than in those without such events. After adjustments for covariates, however, there is no independent effect of frequent or occasional episodes of IDH on mortality.
Keywords: clinical study; cohort study; comorbidity; haemodialysis-complication; hypotension; survival
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Introduction |
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While the occurrence of IDH is undoubtedly distressing to the patient and disruptive to the unit, its main clinical significance lies in its potential association with patient morbidity and mortality. The mechanisms that could cause and underlie such an association are coronary and cerebral ischaemic syndromes, arrhythmia and lower dialysis dose delivered to the patient [13]. While there is accumulating evidence that low pre- and post-dialytic systolic blood pressure [14,15] is associated with increased cardiovascular mortality, there are no previous studies that looked at the direct effects of frequent or occasional IDH on mortality in chronic haemodialysis patients.
In this study, therefore, our objective was to assess the effects of frequent and occasional IDH on the mortality of chronic haemodialysis patients and to determine whether such an association was independent of patient comorbidity.
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Subjects and methods |
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After the run-in phase, patients in the three groups were followed for an average of 27 months (range: 0.337 months) and all-cause mortality was considered as the primary outcome. Data were censored at transplantation, leaving haemodialysis, transfer to another dialysis unit or at the end of follow-up. During the follow-up patients received standard thrice-weekly haemodialysis using a bicarbonate bath and, almost exclusively, substituted cellulose and synthetic membranes.
Patient-related characteristics (demographics, comorbidity, biochemistry and medication) were extracted from patient charts by their treating physician at the beginning of the run-in phase as part of a survey at the network. Coronary artery disease was considered to be present if the patient had a history of myocardial infarction, angina, coronary revascularization or had significant ST segment depression on resting electrocardiogram as assessed by the treating physician. Liver disease refers to >50% elevation of liver enzyme levels, including -glutamyltransferase. Laboratory data are the mean of three monthly bloodworks at the beginning of the run-in phase. The data extraction for patient characteristics was performed in an unbiased fashion, i.e. before the patients hypotensive status was determined. Single-pool Kt/V was calculated according to Daugirdas [16] at the beginning of the run-in period. Reported Kt/V values were corrected to include residual renal function according to Gotch and Keen [17], assessed from 44 h interdialytic urine collections. Pre-dialysis blood pressure and ultrafiltration values for the f-IDH and o-IDH groups were derived from those dialysis sessions that were complicated by IDH. For those patients with no-IDH the mean values of 10 dialysis sessions from the beginning of each month of the run-in phase were calculated.
During the main analysis KaplanMeier survival curves were constructed for the three groups and comparison of the curves was performed by log-rank test. The independent association of f-IDH and o-IDH with survival was assessed by Coxs proportional hazards model using the no-IDH group as reference. The covariates to be included in the model were decided a priori: age, sex, time spent on haemodialysis before the run-in phase and those variables that show an association with survival in univariate models. The analyses were performed using SAS statistical software release 6.11. Tests that resulted in two-sided P-values of <0.05 were considered statistically significant. Relative hazards (RH) are presented with 95% confidence interval (CI) in brackets.
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Results |
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Demographic, clinical and biochemical data of the patients from the three groups are presented in Table 1. Patients with f-IDH were older and there were more females among them as compared to those with o-IDH (P < 0.001 for the age and P < 0.05 for the gender comparison) or no-IDH (P < 0.001 for both comparisons). More patients with f-IDH had coronary artery disease than patients in the other two groups (P < 0.05 vs o-IDH; P < 0.001 vs no-IDH). Serum phosphorus level was significantly higher in the group with f-IDH (P < 0.01 vs both o-IDH and no-IDH). Calcium-channel blocker use was less frequent in patients with f-IDH and significantly more no-IDH patients were treated with a diuretic than patients in the other two groups. Long-acting nitrate use was most frequent in patients with f-IDH.
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Discussion |
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IDH continues to be a common problem complicating a substantial proportion of haemodialysis sessions [1]. Besides factors directly related to the dialysis procedure itself (e.g. ultrafiltration rate, meal during dialysis, temperature, etc.) several patient characteristics increase the risk of IDH, such as older age, diabetes, left ventricular hypertrophy, coronary artery disease and autonomic neuropathy [29]. These risk factors may contribute to IDH by interfering with the haemodynamic cardiovascular mechanisms that counterbalance the decrease in plasma volume during dialysis, such as plasma refilling, arterial tone and venous capacitance, cardiac filling and sympathetic nerve activity [24]. The presence of these risk factors was confirmed in our study as patients with f-IDH were generally older and there was more coronary artery disease among them compared to those with no-IDH; the data lying in between for those with o-IDH.
While distressing to the patient and disruptive to the unit, the main clinical significance of IDH may relate to its potential association with patient morbidity and mortality. There are several, not mutually exclusive, mechanisms by which IDH could link to increased mortality. First, IDH could be directly causal in increasing the risk of death, independent of other classical risk factors, through myocardial ischaemia, ischaemic stroke or arrhythmias triggered by the drop in blood pressure during dialysis. Support to this hypothesis may come from results of studies indicating lower survival among those chronic haemodialysis patients with low pre- and post-dialysis blood pressure values [14,15]. Furthermore, alterations in endothelial function, arterial wall composition and blood rheology, seen in end-stage renal disease, may create an environment that promotes the occurrence of morbid events, independent of classical risk factors [13]. Alternatively, f-IDH may result in lower dialysis dose delivered to the patient with consequent increased mortality. Third, IDH may be a marker of the presence of risk factors that increase the risk of both IDH as well as mortality, such as age, diabetes and coronary artery disease. In this case, however, IDH is not expected to be associated with mortality once these covariates are accounted for in multivariate analysis. Of course, a combination of the above possibilities is also plausible.
In our study, survival of patients with f-IDH was significantly lower compared to those with no-IDH, while survival of the patients with o-IDH was not significantly different from that of controls. The high mortality observed in patients with f-IDH suggests that f-IDH may be considered as a warning sign for patients being at high risk of death. In multivariate analysis, however, neither f-IDH nor o-IDH showed an independent association with survival once age, comorbidities, medications and laboratory values were adjusted for. Our data, therefore, do not provide evidence that the first of the above three possibilities would hold true and our findings suggest that IDH may not directly be associated with survival.
As indicated above, lower delivered dose of dialysis may be the result of f-IDH; therefore, we recalculated our data without the inclusion of Kt/V in the multivariate model. Our conclusion has not been altered by the result of this analysis, suggesting that factors other than Kt/V, probably the older age and the high prevalence of comorbidities in patients with f-IDH, might explain for the apparent lack of an independent association of f-IDH with survival.
In our study, higher Kt/V was associated with improved survival independent of other risk factors. This contradicts the results of the recently published HEMO study [18] that found no difference in survival of patients on standard dose or high dose haemodialysis. It is to be considered, however, that the unequilibrated Kt/V values in our study were lower than those in either groups of the HEMO study and that our reported Kt/V values included the urea clearance contributed by the residual renal function.
It should be noted that the sample size of our study may limit the applicability of our conclusion. The wide confidence interval for the adjusted RH for death among those with f-IDH indicates that we might have failed to identify an independent association between f-IDH and survival. Furthermore, it is also plausible that f-IDH indeed contributes to increased mortality, but its ill effects occur primarily among those who are older or have diabetes or coronary artery disease, i.e. among those with less reserve capacity to compensate for a decrease in vital organ perfusion [19,20]. Our data did not allow us to explore this possibility and perhaps a different design and meticulous analysis of the temporal relationship of events could address this alternative. Further limitation of our study to be acknowledged is that these were prevalent patients who, in addition, had to survive the run-in period to enter the follow-up. The possibility of survival bias, therefore, may limit the generalizability of our results. Finally, we did not collect information on IDH episodes after the run-in phase in either of the groups. As no specific interventions were implemented, it is unlikely that significant crossing over had occurred among the groups. If, however, this was the case it would have biased our results towards no association between IDH and survival.
Based on the findings of our study on survival of patients with IDH, we conclude that f-IDH should be viewed as an indicator of significantly increased risk of mortality as compared with no-IDH. Our data, however, did not provide us with evidence that f-IDH in itself, independent of patient age and comorbidities, is causal in the chain of events leading to increased risk of death in these patients.
Conflict of interest statement. All authors except for A. Tislér are employed part-time or full-time as nephrologists by the EuroCare Nephrological network.
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References |
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