Effect of the duration of dialysis on survival in a cohort of chronic haemodialysis patients
Kunitoshi Iseki,
Masahiko Tozawa and
Shuichi Takishita
Dialysis Unit and Third Department of Internal Medicine, University of The Ryukyus, Okinawa, Japan
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Abstract
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Background. Atherosclerosis and vascular calcification are common in chronic haemodialysis (HD) patients, and usually progress with time. Whether the length of dialysis treatment in chronic HD patients is a significant independent risk factor of death is not clear.
Methods. A cohort of chronic HD patients from the Okinawa Dialysis Study, n=1243 (720 men, 523 women), was followed from January 1991 to December 2000, and their survival rates were compared against the duration of HD, which was calculated in months from the start of dialysis therapy to January 1991. A Cox proportional hazards regression analysis was done to examine the influence of the duration of dialysis on survival, after adjusting for other factors such as age, sex, serum albumin concentration and diastolic blood pressure. The hazards ratio and 95% confidence interval (CI) were calculated in both diabetic and non-diabetic patients.
Results. The mean duration of dialysis was 61.9 months and ranged from 1 to 233 months. The numbers of patients who died, underwent renal transplantation or were transferred outside Okinawa were 568 (45.7%), 61 (4.9%) and 14 (1.1%), respectively, during the study. The hazards ratio (95% CI) was 1.002 (1.0001.004, P=0.0245) for non-diabetic patients and 1.006 (1.0011.011, P=0.0214) for diabetic patients, suggesting that the longer the duration of dialysis, the greater the risk of death.
Conclusions. This study shows that prolonged dialysis is a significant predictor of death in chronic HD patients, in particular diabetic patients. Whether this is related to the progression of the atherosclerotic process or to uraemic conditions remains to be shown.
Keywords: dialysis duration; haemodialysis; serum albumin; survival
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Introduction
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The prognosis for patients on chronic haemodialysis (HD) is poor, owing mainly to uncontrolled hypertension, malnutrition and pre-dialysis comorbidity. By the time of renal transplantation, it is common to see severe atherosclerosis and coronary artery calcification, especially in patients on long-term dialysis [1]. Therefore, it is reasonable to assume that dialysis accelerates atherosclerosis [1]. It is difficult, however, to assess the effect of the duration of dialysis on survival, since patients often become candidates for renal transplantation and are transferred to other dialysis units or registries. Our dialysis population is almost free of renal transplantation or transfer; therefore, it is suitable for examining the effect of the duration of dialysis on survival.
We and other researchers [2] have observed an inverse relationship between the duration of dialysis and death; as the duration of dialysis increases, the incidence of death tends to decrease. Although this outcome is counterintuitive, it could reflect a selection bias or survivor bias inherent in every dialysis registry. Survivors of long-term dialysis often begin dialysis at a young age and have had no opportunity for renal transplantation. Young and healthy dialysis patients who are considered good candidates for renal transplantation would actually have survived longer without having transplants. It was shown recently that prolonged dialysis prior to renal transplantation is associated with the poor survival of renal transplants [3]. These observations suggest relentless progression of atherosclerosis and uraemic complications in chronic HD patients. There are several problems in interpreting the effect of dialysis duration on survival in chronic dialysis patients [4,5]. The aim of this study was to examine the relationship between the duration of dialysis and survival in a large cohort of chronic HD patients.
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Subjects and methods
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Subjects
All chronic HD patients in Okinawa, Japan, alive on 1 January 1991, were considered for the study, and the patients were followed until 31 December 2000. The demographics of this cohort (n=1243) were published previously [6]. Briefly, patients with end-stage renal disease who survived at least 1 month on dialysis were registered as chronic dialysis patients in the Okinawa Dialysis Study (OKIDS) registry. Approvals from institutional ethics committees and the administrative personnel or physicians in charge were obtained for the registry data collection. Bicarbonate solution was the dialysate used in all units (the reuse of a dialyser is not permitted in Japan). The prevalence of cupurophane membrane usage was
30% at the start of the study. The mean endotoxin level was
29.3 EU/l in Okinawa (data of the Japanese Society for Dialysis Therapy, 1998). Baseline laboratory and clinical data, which were obtained for each patient before the first dialysis session in January 1991, included: body weight, height, blood pressure, blood urea nitrogen, serum creatinine, total cholesterol, triglyceride, total protein, serum albumin and uric acid. Body height was measured within 6 months of the start of the study. Body mass index was defined as the ratio of weight in kilograms to height in metres squared (kg/m2). Data for the delivered dialysis dose and urea reduction rate were available in a subgroup of the cohort (n=615). Patient records had been updated at least twice a year for medical events such as death, renal transplantation and transfer outside Okinawa. All patients were followed until a major medical event or 31 December 2000, and we verified outcomes with the collaboration of physicians and paramedical staff of all dialysis units in Okinawa.
The duration of dialysis was calculated from the date of the start of dialysis to 1 January 1991, and was categorized as
12, 1360, 61120 and
121 months. Outcomes were known and confirmed for all patients.
Statistical analysis
Data are shown as mean (SD). The unpaired t-test or chi-square test was used to compare values and ratios between groups according to the duration of dialysis and the presence of diabetes mellitus. Survival curves were estimated by the KaplanMeier method, and a log-rank test was used to compare groups according to the duration of dialysis. Cox proportional hazards analysis was done to examine the influence of various durations of dialysis on survival after adjusting for age, sex, serum albumin concentration and diastolic blood pressure. Hazards ratios and 95% confidence intervals (CIs) are shown. The SAS software package (SAS Institute, Cary, NC, USA) was used for the statistical analyses. A P-value of <0.05 was considered significant.
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Results
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A total of 1243 patients (720 men, 523 women) were receiving chronic HD as of 1 January 1991, when the study began. In 1041 (83.7%) of these patients, dialysis was performed three times per week, and in 708 (57.0%) the dialysis time was 3.54.0 h per session. The mean (SD) duration of dialysis in the total study population was 61.9 (49.4) months, ranging from 1 to 233 months, and the age of patients at the start of the study was 52.2 (14.1) years, and ranged from 13 to 91 years. The durations of dialysis are shown for all 1243 patients in Figure 1
. The duration of dialysis was more than 10 years at the time of the start of the study in
16% of our subjects.
The baseline demographics and the clinical characteristics of the subjects are summarized according to the duration of dialysis in Table 1
. In long-term HD patients (HD
121 months), age was lower and the dose of HD was greater than in patients on dialysis for a relatively short duration (HD
12 months). Dialysis doses both prescribed and delivered showed an increase with the duration of dialysis (Table 2
). Baseline laboratory data categorized according to the duration of dialysis are summarized in Table 3
. Systolic blood pressure was lower in long-term dialysis patients (HD
121 months) than in short-term dialysis patients (HD
12 months), despite the use of fewer anti-hypertensives drugs in the long-term patients.
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Table 1. Baseline demographics and clinical characteristics of study patients shown according to the duration of HD
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Table 2. Prescribed and delivered dose of dialysis according to the duration of HD at the start of the study (January 1991)
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Overall, the number of deaths, renal transplants and transfers outside Okinawa were 568 (45.7%), 61 (4.9%) and 14 (1.1%), respectively. Half of the deaths (n=284), renal transplants (n=30) and transfers (n=7) occurred at 32, 35 and 27 months, respectively, from the start of the study. The 5 and 10 year survival rates were 0.713 and 0.523, in all patients, respectively. Survival curves are shown according to the duration of dialysis in Figure 2
. The longer the duration of dialysis, the better the survival (P<0.001 by log-rank test). However, according to the multivariate proportional hazards analysis, survival rates decreased with longer periods of dialysis. The hazards ratio (95% CI) of HD was 1.029 (1.0041.054, P=0.0228) for non-diabetics and 1.073 (1.0071.142, P=0.0284) for diabetics under extended dialysis every year (Table 4
). The relative risks of death for each period of dialysis are shown for non-diabetics in Figure 3
and for diabetic patients in Figure 4
, the reference period being a HD duration of
12 months. Outcomes, death rates and causes of death are summarized in Table 5
.
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Table 4. Results of Cox proportional hazards analysis of mortality according to the duration of HD in non-diabetics and diabetics (study period January 1991 to December 2000)
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Fig. 3. Relative risk (95% CI) for the various durations of HD in non-diabetics. HD of 112 months was taken as reference. *P<0.025 vs HD duration of 112 months.
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Fig. 4. Relative risk (95% CI) for the various durations of HD in patients with diabetes mellitus. HD of 112 months was taken as reference. *P<0.042 vs HD duration of 112 months.
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Discussion
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This study showed the significant influence of the duration of dialysis on survival in chronic HD patients, an influence that was independent of age, serum albumin level and diastolic blood pressure (Table 3
). Our results were compatible with those of Chertow et al. [4] who showed that mortality risk increased by 6% with each year on dialysis therapy. They also showed a significant decline in all measured nutritional parameters, which is different from our results. The mean dialysis duration was 3.8 years in their study, which was shorter than that of ours of 5.2 years. The effect of vintage may not be straightforward. Okechukwu et al. [5] showed that the adjusted mortality risk increased until
68 years, but decreased after 8 years. In their study, patients in their first year of dialysis (compatible to the <12 months group in our study) were excluded. In both studies, follow-up periods were as short as 2 years.
In cross-sectional analysis, the HD
121 months patients compared with the HD
12 months patients seemed to be better nourished and their blood pressures better controlled with less use of anti-hypertensives. This probably reflects the selection of patients who survived under dialysis therapy. It takes 612 months of treatment to attain dry weight and control of blood pressure [7] and to increase fat mass [8], especially in patients who are malnourished at the start of dialysis. The demographics of the incident dialysis patients are changing, therefore, we cannot exclude the possibility of selection bias. In a subgroup of the cohort (n=615), we estimated the creatinine clearance at the start of dialysis therapy by the formula of Cockroft and Gault. Mean estimated creatinine clearance was 5.0 ml/min at the beginning of dialysis. Although the data for residual renal function were not available, there was a certain percentage of patients who had significant residual renal function, in particular those with shorter durations of HD (Table 2
).
The mechanisms responsible for the untoward effect of long-term dialysis on survival remain speculative. Retention of metabolic substances such as ß2-microglobulin [9] and advanced glycation end products [10], is often seen in long-term dialysis patients; and they may induce inflammatory responses. Dialysis patients are in a chronic inflammatory state, and a high serum C-reactive protein (CRP) level points to a poor prognosis [11]. Atherosclerosis itself is closely related to inflammation [12]. The influence of the duration of dialysis on the risk of death was greater in diabetic patients than in non-diabetic patients. The 10 year survival rate was as low as 0.20 in diabetic patients [13]. The reasons for this difference remain speculative. A recent study [14] has shown that coronary artery calcification worsens with prolonged dialysis and that it progresses at a faster rate in HD patients than in the general population. Dialysis patients with diabetes mellitus have increased aortic stiffness, which contributes to increased all-cause and cardiovascular mortality rates, in comparison with non-diabetic dialysis patients [15].
Cosio et al. [3] showed that pre-transplant dialysis has a significant effect on patient survival after transplantation. In their study, increased time on dialysis prior to renal transplantation was associated with decreased survival of renal transplants. They suggested the presence of heart disease and immunosuppression in long-term dialysis patients. Although serum albumin concentrations were higher in our long-term HD patients than in shorter-term dialysis patients (HD
12 months), mean body mass index was slightly less in the long-term dialysis patients (Table 2
). This may suggest the presence of malnutrition or uraemic myopathy in long-term dialysis patients.
Our findings do not downplay the importance of blood pressure control and nutritional support. The best survival in dialysis patients is obtained through the control of both nutritional status and blood pressure [16]. Recently, we showed the significance of pulse pressure in predicting overall mortality rates in non-diabetic patients [17].
There are some limitations in the present study. The mean duration of HD in this study was
60 months, so, many high-risk patients may have died without an opportunity to participate in the study. Our inclusion criterion for the registry is survival for at least 1 month on scheduled dialysis. The factor responsible for the greatest risk of cardiovascular death may be dialysis for <4 years [18]. The incidence and prevalence of dialysis differ between countries [19] and even within individual countries [20]. Of the regions in Japan, Okinawa has the highest incidence and prevalence of dialysis. Therefore, our results may not apply to other registries. However, the prognosis for dialysis patients is better in Okinawa than in other parts of Japan. The impact of renal transplantation was not measured since the number of transplant patients equalled only 4.9% of the total patient population. Renal transplantation offers better survival than HD, but elderly patients receive less survival benefit from it. Given the recently noted increases in age and multiple comorbid conditions at the start of dialysis in Japan [13,20], improving the survival of patients on HD therapy is necessary; in this regard, there has been a slight but significant improvement in survival among diabetic dialysis patients. Finally, the arterial system in dialysis patients undergoes remodelling very similar to changes that occur with ageing; however, several features of arterial remodelling observed in the presence of chronic uraemia differ from those of the natural ageing process. Anaemia has a significant relation to the pathogenesis of arterial disorders. Unfortunately, data pertaining to haematocrit, haemoglobin and doses of erythropoietin were not available for our cohort.
In conclusion, our study showed that the risk of death increased with increases in the duration of dialysis, especially in diabetic patients. The longest duration of dialysis treatment in Japan is
35 years [20]. The life expectancy of chronic dialysis patients between the ages of 20 and 40 years is 1520 years less than that of individuals of the same age in the general population. Renal transplantation is recommended even in a well rehabilitated HD patient. Mechanisms associated with the influence of the duration of dialysis on survival remain to be studied. Early detection of signs of malnutrition such as appetite loss, losing weight, hypoalbuminaemia and high CRP may be helpful to identify patients at risk of death.
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Acknowledgments
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The authors are grateful for the collaboration of the physicians and co-medical staff of all dialysis units in Okinawa. A list of these physicians appears in Iseki et al. [13]. The authors are grateful to Dr O. Morita and Ms C. Iseki, who helped with the data processing and statistical analysis. Parts of this study were supported by grants from the Ministry of Health and Welfare.
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Notes
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Correspondence and offprint requests to: Dr Kunitoshi Iseki, MD, Dialysis Unit, University of The Ryukyus, 207 Uehara, Okinawa 903-0215, Okinawa, Japan. Email: chihokun{at}med.u-yukyu.ac.jp 
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Received for publication: 20. 5.02
Accepted in revised form: 12. 9.02