Clinical demographics and long-term prognosis after stroke in patients on chronic haemodialysis

Kunitoshi Iseki, Koshiro Fukiyama and The Okinawa Dialysis Study (OKIDS) Group

Dialysis Unit and Third Department of Internal Medicine, University of The Ryukyus, and The Okinawa Dialysis Study (OKIDS) Group, Okinawa, Japan



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Stroke is one of the leading causes of death in chronic dialysis patients. However, few epidemiological studies have reported on the demographics and long-term prognosis after stroke.

Methods. We have observed the occurrence of stroke in the chronic dialysis population for the past 10 years in Okinawa, Japan. Definite cases of stroke were registered and categorized as cerebral haemorrhage (CB), cerebral infarction (CI), and subarachnoid hemorrhage (SAH).

Results. Among 3741 chronic dialysis patients (2073 men, 1668 women), 271 patients (164 men, 107 women) had strokes (CB 162, CI 97, SAH 12) at least once during the study period from 1 April 1988 to 31 March 1998. The total duration of observation was 15£748.8 patient-years (males 8990.5, females 6758.3). The incidence of stroke per 1000 patient-years was 17.2 overall, 10.3 for CB, 6.2 for CI, and 0.8 for SAH. Twenty-four per cent of stroke cases occurred within 1 year of starting dialysis therapy, and 57.7% occurred within 5 years after the beginning of therapy. The mean (SD) age at onset of stroke was 59.8 (13.0) years overall, 57.2 (12.6) for CB, 65.0 (12.1) for CI, and 53.6 (13.0) years for SAH. The survival rates after stroke were 53.4% at 1 month, 43.5% at 6 months, 35.7% at 12 months, and 23.2% at 60 months. Patients with diabetes mellitus (DM) had higher incidence of CI and a poorer prognosis than those without DM.

Conclusion. Incidence of stroke was high (17.2 per 1000 patient-years) in the dialysis population of our area and the long-term prognosis after stroke was poor.

Keywords: cerebral haemorrhage; cerebral infarction; dialysis; subarachnoid haemorrhage



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Several studies have shown that the stroke incidence and death rate due to stroke are higher in the dialysis population than in the general population [14]. Stroke is one of the leading causes of death, accounting for 12.6% of total deaths recorded in the recent Japanese registry [5]. Even if patients survive a stroke, they suffer difficulties in daily activities and may therefore have problems achieving adequate dialysis therapy. Long-term prognosis after stroke is not well described in dialysis patients. Recently, survival after acute myocardial infarction was reported as very poor in this population [6].

Okinawa, located in the southernmost part of Japan, consists of many sub-tropical islands. The population was 1.2 million in 1990 and 1.3 million in 1998. All chronic dialysis cases have been filed in the computer registry, and patient outcomes, especially the occurrence of stroke and acute myocardial infarction, are carefully recorded [1,7,8]. The aims of the present study were to document the characteristics of stroke in the chronic dialysis population over 10 years (1988–1997), and to investigate the differences in clinical demographics and prognosis between dialysis patients and the general population.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patients
The cases of 3741 chronic dialysis patients (2073 men, 1668 women) were prospectively reviewed for occurrence of stroke during the study period from 1 April 1988 to 31 March 1998 (10 years). At the start of the time period, 977 patients (593 men, 384 women) were on chronic haemodialysis, and another 2764 patients (1480 men, 1284 women) began dialysis therapy during the study period. All chronic dialysis patients who are Okinawa residents and who started regular dialysis treatment and survived at least 1 month have been registered in the Okinawa Dialysis Study (OKIDS) registry since the beginning of dialysis therapy in 1971. The demographics of this registry were reported previously [7,8]. Briefly, the registry includes the name of the patient, sex, birth date, start date of dialysis, and primary renal disease. The dialysis regimen in Okinawa does not differ from that in other parts of Japan [5]. More than 83% of the patients were dialysed three times weekly. The duration of dialysis per session was 3.0–3.5 h in 5.2%, 3.5–4.0 h in 57.0%, 4.0–5.0 h in 10.0%, and >5.0 h in 27.8%. The dialyser membrane area used was less than 1.0 m2 in 4.8%, 1.0–1.4 m2 in 34.9%, 1.5–1.9 m2 in 43.0%, and >2.0 m2 in 17.3%. The median blood flow rate was 200 ml/min. Bicarbonate solution was used as the dialysate in all units. The dialyser was not re-used because that is not permitted in Japan. The mean body height and weight were about 1.56 metres and 53.0 kg in the relevant patients on January 1991 [8]. Other pertinent clinical and laboratory data were collected in the relevant patients on January 1991 (n=1243). This information was obtained with the collaboration of all dialysis units in Okinawa. The number of dialysis facilities on the islands was 27 in 1990; it increased to 39 in 1998, including nine public hospitals, 16 private hospitals, and 14 private clinics. All patients' outcomes were documented and confirmed. Characteristics of the study patients are shown in Table 1Go. Mean age at start of dialysis and sex were not different between those who had a stroke and those who remained stroke free during the study period. Primary renal diseases were grouped into six types: chronic glomerulonephritis, diabetes mellitus (DM), hypertensive nephrosclerosis, polycystic kidney disease, lupus nephritis, and others. Causes of death were classified into six categories: infection, withdrawal, cardiac, vascular, sudden death, and others. Vascular death included death directly related to stroke, ruptured aneurysm, aortic dissection, and other non-cardiac ischaemic events.


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Table 1. Demographics of study patients who developed stroke (Yes) and those who did not develop stroke (No) during the study period

 

Stroke
Stroke was clinically diagnosed as sudden onset of focal and global disturbance of cerebral function lasting 24 h or longer or likely to result in death with no apparent cause other than that of vascular origin [9]. Most patients suffering a stroke underwent a computed tomography (CT) brain scan. To obtain accurate case updates, we regularly visited all dialysis units in Okinawa. Medical records were reviewed and registered according to previously reported diagnostic criteria [1,2]. Briefly, diagnosis of stroke, cerebral haemorrhage (CB), cerebral infarction (CI), and subarachnoid haemorrhage (SAH) was based on clinical symptoms and CT brain scan, which was performed within 48 h of onset and was repeated if necessary. Occurrences of stroke after renal transplantation were not considered. In cases of multiple strokes, we registered only the first in each patient during the study period. The incidence of stroke was calculated as the total number of stroke cases divided by the total observation period per 1000 patient-years. The observation period was defined as the duration of dialysis during the study period. Thus the observation period was calculated from the beginning of the study period on 1 April 1988 until death, renal transplantation, patient transfer outside of the Okinawa area, or the end of the study on 31 March 1998.

To learn more about the characteristics of stroke in the dialysis population, we compared stroke data from the dialysis population with stroke data from the general population in Okinawa [10]. The Co-operative Study Group of Morbidity and Mortality of Cardiovascular Diseases in Okinawa (COSMO) registry filed every hospital case of stroke that occurred in Okinawa during the 3 years between 1 April 1988 and 31 March 1991: the cases of 4523 patients (2463 men, 2060 women) were registered over the study period.

Statistical analysis
Student's t-test, Welch's test, and a chi-squared test were performed to compare data of dialysis patients who had strokes with data of patients who did not have strokes. The survival curve and the cumulative incidence of stroke were determined by the Kaplan–Meier method. Cox proportional hazard analysis was done to compare the survival rate after onset of CB, CI, and SAH. In this analysis, risk ratio and 95% confidence interval were determined with adjustment of sex, age at onset of stroke, and presence of DM. SAS package was used for statistical calculations. Data are expressed as mean±SD.



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Clinical demographics
The calculated observation period was 15 748.8 patient-years (men 8990.5, women 6758.3). The mean (SD) age at start of dialysis was 54.0 (16.9) years in all patients (n=3741), 52.2 (16.5) years in men (n=2073), and 56.2 (17.5) years in women (n=1668). Primary renal diseases were distributed as follows: chronic glomerulonephritis (n=1862, 49.8%), DM (n=1065, 28.5%), hypertensive nephrosclerosis (n=337, 9.0%), lupus nephritis (n=87, 2.3%), polycystic kidney disease (n=90, 2.4%), and others (n=300, 8.0%). During the study period, 141 (3.8%) patients underwent renal transplantation, 49 (1.3%) left Okinawa, and 1232 (32.9%) died. The death rate was 78.2 per 1000 patient-years. The overall survival rate was 91.6% at 1 year, 74.2% at 5 years, 58.3% at 10 years, and 48.3% at 15 years from the start of dialysis. The causes of death were cardiac (n=284, 23.0%), withdrawal (n=282, 22.9%), infection (n=230, 18.7%), vascular (n=165, 13.4%), sudden death (n=65, 5.3%), and others (n=206, 16.7%).

Stroke cases
Among the 271 patients (164 men, 107 women) who suffered stroke during the study period, 162 (103 men, 59 women) had CB, 97 (58 men, 39 women) had CI, and 12 (three men, nine women) had SAH. Eight patients (six men, two women) had stroke twice (CB 3, CI 5), and one patient had three episodes of CB during the study period. Table 2Go shows the mean (SD) age at onset of each subtype of stroke in both sexes. Among the subtypes of stroke, age at onset of stroke was not significantly different between men and women. In both sexes, mean age at the onset of CI was significantly older than that of CB. The overall incidences of stroke, CB, CI, and SAH were 17.2, 10.3, 6.2, and 0.8 per 1000 patient-years respectively. The number of patients and the incidence of stroke and each subtype of stroke over time are shown in Table 3Go. In both sexes, incidence of CI increased recently, whereas those of CB and SAH did not. SAH occurred predominantly in women. Table 4Go shows that the incidence of stroke by age in both sexes increased sharply. In the general population, stroke incidence in men is 0.04 at <=29 years, 0.24 at 30–39 years, 0.97 at 40–49 years, 3.22 at 50–59 years, 5.57 at 60–69 years, and 10.27 at >=70 years; among women the incidence is 0.02 at <=29 years, 0.18 at 30–39 years, 0.65 at 40–49 years, 1.73 at 50–59 years, 2.73 at 60–69 years, and 6.32 at >=70 years [10].


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Table 2. The mean (SD) age at onset of stroke with subtypes: cerebral haemorrhage, cerebral infarction, and subarachnoid haemorrhage

 

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Table 3. Incidence of stroke and subtypes (cerebral haemorrhage, cerebral infarction, and subarachnoid haemorrhage) expressed as number of cases per 1000 patient-years during the study period

 

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Table 4. Incidence of stroke in each age-group expressed as number of cases per 1000 patient-years. Patient numbers are in parentheses

 
To examine the relationship between the duration of haemodialysis and the occurrence of stroke, we calculated the cumulative incidence of stroke from the beginning of dialysis therapy. One-year and 5-year cumulative incidence of stroke was 24.4 and 57.7% respectively. The 1-year cumulative incidence was 22.2% for CB, 27.8% for CI, and 25.0% for SAH; the 5-year cumulative incidence was 56.2% for CB, 63.9% for CI, and 33.3% for SAH. (Figure 1Go).



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Fig. 1. Cumulative incidence of cerebral haemorrhage (CB), cerebral infarction (CI), and subarachnoid haemorrhage (SAH) by the duration of dialysis.

 
One hundred and ninety (70.1%) of 271 patients died after stroke. The overall survival rate from the start of dialysis therapy was 84.0% at 1 year, 59.4% at 5 years, and 34.7% at 10 years. The causes of death were vascular (n=141, 74.2%), infection (n=15, 7.9%), withdrawal (n=11, 5.8%), cardiac (n=9, 4.7%), sudden death (n=1, 0.5%), and others (n=13, 6.8%). The overall survival rate after the onset of stroke was 53.4% at 1 month, 43.5% at 6 months, 35.7% at 12 months, and 23.2% at 60 months. Survival curves after the onset of stroke were different among the subgroups (Figure 2Go). If we take CB as standard (1.00), the adjusted risk ratio of death (95% confidence interval) in CI is 0.66 (0.48–0.91) and that of SAH is 0.87 (0.46–1.92). If we take SAH as standard (1.00), the adjusted risk ratio (95% confidence interval) of CI is 0.41 (0.18–0.97). Therefore, survival after CI is significantly greater than that of CB and SAH. If we take the survival rate after staring dialysis therapy, the curves appear similar among stroke subtypes (Figure 3Go). This is mainly due to the differences in mean age at the onset of stroke (Table 2Go).



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Fig. 2. Survival rate after the onset of cerebral haemorrhage (CB), cerebral infarction (CI), and subarachnoid haemorrhage (SAH).

 


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Fig. 3. Survival rate with the duration of dialysis in patients with cerebral haemorrhage (CB), cerebral infarction (CI), and subarachnoid haemorrhage (SAH).

 
Patients with and without DM were compared for incidence of stroke subtypes. DM patients have a higher incidence of CI than non-DM patients (P=0.0025, chi-square test).



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The results of the present study confirmed and extended our previous findings [1,2]. The stroke mortality rate in our study, 12.1 per 1000 patient-years, was similar to that of recent data from the USA, 11.1 per 1000 patient-years [11]. Compared to the general population, chronic dialysis patients have higher incidence of CB, CI, and SAH. They contract stroke earlier than the general population [10,12]. SAH occurred predominantly in female dialysis patients, which is also the case in the general population [10].

We previously reported a gradual increase in stroke incidence after the introduction of erythropoietin in 1990 [13]. Before the era of erythropoietin, the annual incidence of stroke was 12.5 (1988) and 10.5 (1989) per 1000 patient-years. However, whether erythropoietin use caused this increase is unclear: A higher number of women, aged patients, and DM patients are erythropoietin users in Okinawa [unpublished observation]. The haematocrit achieved with erythropoietin therapy varies. In our registry, the target haematocrit is set empirically at approximately 30–35% before the haemodialysis session. The current increase in CI in our registry may reflect changes in patient demographics [7,14]. Among both our dialysis population (Table 5Go) and in the general population [15], DM patients have a relatively high tendency to suffer CI.


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Table 5. Comparison of stroke subtypes in those with and without diabetes mellitus (DM)

 
There was an early risk of stroke associated with the start of dialysis, with 24.4% of strokes occurring within 1 year and 57.7% occurring within 5 years after the initiation of dialysis (Figure 1Go). Whether this is directly related to dialysis procedure or simply reflects pre-existing comorbid conditions such as long-standing hypertension, atherosclerosis, and malnutrition is not clear. Use of heparin as an anticoagulant for haemodialysis may exacerbate CB. The size of a haematoma tends to be larger in dialysis patients than in the general population [1,2,16]. However, heparin's effect on the occurrence of bleeding is not certain. It usually takes several months before the dialysis patients reach their ideal ‘dry weight’. Therefore it is possible that in the early phase of chronic dialysis, control of hypertension is poor [17].

The presence of hypertension is the only risk factor of stroke [2]. The impact of other potential risk factors such as DM, dyslipidaemia, and smoking is smaller than that of hypertension. Mean levels of blood pressure were significantly high, especially in young dialysis patients, compared with levels in the general population [18]. A recent infection may precede an ischaemic stroke [19], and high serum C-reactive protein (CRP) is also a mortality risk factor in chronic dialysis patients [20].

There is little data on long-term prognosis after stroke among patients on chronic dialysis. In our dialysis patients, the acute death rate 30 days after stroke was 46.6% overall: 56.2% for CB, 27.9% for CI, and 66.7% for SAH. In the general population, the overall death rate was 12.3%, 17.3% for CB, 6.5% for CI, and 32.7% for SAH in Okinawa [10]. A recent long-term survival after CB and CI in the general population in our area reported 50% survival after CB at 6.4 years in women and 8.6 years in men, and 50% survival after CI at 7.5 years in women and 8.0 years in men [21]. In the general population, the mean age at onset was 66.6 years for stroke, 63.4 for CB, 69.9 for CI, and 59.1 for SAH [10]. Although the mean age at onset was younger in the dialysis population, mortality rates were higher in dialysis patients than in the general population. Very few patients survive more than 20 years on dialysis (Figure 3Go).

Renal transplantation may be another strategy to reduce the risk of stroke in dialysis patients. We observed a relatively low incidence of stroke in patients who received renal transplantation compared with those who were not transplanted [22]. Dialysis patients have higher incidence of stroke even when they are not hypertensive [2].

In Japan, the stroke mortality rate in the general population has dropped dramatically from 1960s to 1990s, and in general Japanese live longer. The exact reasons are not yet clear. Social and economic success may have contributed to the improvements in nutritional status and the reduction of infection. However, stroke death rate in our dialysis population is similar to or even worse than that of the general population in the 1960s. The nutritional status is poor in chronic dialysis patients, and they often show hypoalbuminaemia [8]. Hypoalbuminaemia directly affects red cell deformability and possible endothelial function, and therefore it would be an additional risk factor of death [23]. In the general population, low serum cholesterol, which is often associated with malnutrition, is inversely related to the incidence of CB [24].

There are several limitations to this study. First, we registered only those who presented with neurological symptoms suggesting stroke [9] and whose diagnosis was confirmed by CT brain scan. We did not use cerebral magnetic resonance image (MRI), which is much more sensitive than CT and can detect ‘asymptomatic cerebrovascular disease.’ Using this technique, Suzuki et al. [25] reported a very high prevalence of T2-weighted high intensity in patients with pre-dialysis end-stage renal disease. Asymptomatic stroke could easily be missed and not registered. Our data may underestimate the true incidence of stroke. At the facilities in our registry, physicians and co-medical staff are attentive to the possible occurrence of stroke [10]. Dialysis patients receive much more intensive medical attention than the general population. Thus, even slight symptoms in these patients stand a better chance of detection than those in the general population [1]. CT brain scan is easily accessible, if needed, within 1 h in every dialysis unit in Okinawa. CT brain scan was performed in 98.4% of all first-ever stroke cases in the general population [26]. Secondly, we did not determine the exact causes of sudden death (n=65). Autopsies were rarely performed in these cases. Thirdly, the present study did not differentiate between causes of ischaemic stroke such as thrombosis and emboli. Atrial fibrillation is a common precursor of embolic stroke in the general population. We had four cases of CI in which the patients later developed bleeding (haemorrhagic infarction). Lastly, the effect of dialysis regimen on the occurrence of stroke and the treatment strategy after stroke was not examined in this study. Important clinical issues remain unanswered. In both the general population and dialysis patients, low blood pressure may be hazardous, particularly for those suffering an ischaemic stroke. In the general population there is a non-linear (J-shaped) association between blood pressure levels and the risks of recurrent events [27]. Prospective studies are needed on the effect and treatment of hypertension in dialysis patients. The role of heparin in patients with CB or SAH and the role of surgery to remove haematomata also need to be elucidated.

We conclude that patients on dialysis who have strokes have high rates of acute death related to stroke and a poor prognosis for long-term survival. Stroke is a leading cause of withdrawal from dialysis and of long-term hospitalization. Our data provide support for more aggressive strategies for the prevention and treatment of stroke in patients on dialysis.



   Acknowledgments
 
Part of this study was supported by grants from the Ministry of Health and Welfare to Dr K. Iseki. Authors thank all the co-medical staff of the OKIDS affiliated dialysis units. Physicians of the registry are as follows: Dr T. Minei, Dr F. Miyasato, Dr K. Nishime, Dr H. Uehara, Dr K. Tokuyama, Dr S. Toma, Dr Y. Shiohira, Dr H. Henzan, Dr K. Kinjo, Dr O. Shiranezawa, Dr T. Taminato, Dr K. Afuso, Dr M. Nakayama, Dr T. Asato, Dr S. Kiyuna, Dr T. Mekaru, Dr M. Yamazato, Dr S. Miyagi, Dr M. Ikemura, Dr T. Sunagawa, Dr T. Yonaha, Dr M. Itokazu, Dr A. Higa, Dr K. Shimoji, Dr T. Oyama, Dr K. Uchima, Dr S. Nakazato, Dr T. Funakoshi, Dr H. Ogimi, Dr Y. Chinen, Dr H. Momozono, Dr T. Higa, Dr T. Asato, Dr K. Yoshihara, Dr S. Terukina, Dr T. Oura, Dr M. Arakaki, Dr K. Nagata, Dr K. Nakamura, Dr A. Hokama, Dr T. Wake, Dr H. Sunagawa, Dr I. Kyan, Dr Y. Uezu, Dr Y. Oshiro, Dr T. Kowatari, Dr S. Yoshi, and Prof. Y. Ogawa. The authors are grateful to Dr O. Morita and Mrs C. Iseki for the analysis and data processing.



   Notes
 
Correspondence and offprint requests to: Dr Kunitoshi Iseki MD, Dialysis Unit, University Hospital of The Ryukyus, 207-Uehara, Okinawa 903–0215, Japan. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 28.12.99
Revision received 19. 5.00.