The Role of Anemia to Restless Legs Syndrome in Regular

Hemodialysis Patients in Haji Adam Malik

Medan General Hospital

Rasyidah Hasan Harahap

, Riri Andri Muzasti

Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera Utara/Haji Adam Malik General Hospital,

Medan, Indonesia

Division Nephrology and Hypertension, Department of Internal Medicine, Faculty of Medicine, Universitas Sumatera

Utara/Haji Adam Malik General Hospital, Medan, Indonesia

Corresponding author: Riri Andri Muzasti,

Division Nephrology and Hypertension, Department of Internal Medicine,

Faculty of Medicine, Universitas Sumatera Utara/Haji Adam Malik General Hospital, Medan, Indonesia

Jl. Bunga Lau No.17, Medan, Indonesia, Phone/facsimile:+62-61-8365742.

Keywords: anemia, restless legs syndrome, hemodialysis

Abstract: Background: Restless Syndrome (RLS) has a higher prevalence in hemodialysis (HD) patients compared

to the general population. Anemia as a cause of the high prevalence of RLS in HD is still unclear. Method:

This is a cross-sectional study conducted in October 2017 evaluated 106 regular HD patients in Haji Adam

Malik Medan General Hospital who had fulfilled inclusion and exclusion criteria. RLS diagnoses and

severity was done in face to face interview according to the International Restless Legs Syndrome Study

Group. Biochemical characteristics were measured. Bivariate and multivariate analysis was performed.

Results: Of the 106 patients who took part in this study, RLS was found in 32 patients (30.2%). Hb levels in

regular hemodialysis patients with RLS have a lower mean than patients without RLS. In the multivariate

analysis using multinomial regression it was found that age and TIBC levels were associated with RLS and

Hb as a protection factor for RLS OR 0.697 95% CI 0.496 ± 0.98. Conclusion: Anemia is one of the factors

that influence the occurrence of RLS in addition to age being a matter that must be considered in the

prevention and management of RLS in hemodialysis patients.

1 INTRODUCTION

Restless Legs Syndrome (RLS) is one of the most

common sleep disorders in dialysis patients with a

prevalence reaching 20% in patients with Chronic

Kidney Disease (CKD) (Scherer JS, et al., 2017).

Some literature shows an association between RLS

and quality of life and mortality of patients with HD

(what HD stand for?) (Neves, et al., 2017). Patients

with HD who have RLS, have a higher mortality rate

compared to patients without RLS (32.3% vs.

14.5%; p <0.04) with Hazard Ratio 1.39; 95% CI

1.08-1.79) (Scherer JS, et al., 2017).

Decreasing HD prevalence of RLS in patients

who have received kidney transplantation (4% vs.

11%; p <0.001) illustrates that kidney disease itself

plays a role in the occurrence of RLS (Scherer JS, et

al., 2017).

It was already known that one of the

complications of CKD is anemia (Suwitra, 2014). In

dialysis patients, anemia is considered to be the main

cause of RLS regardless of available iron reserves

(Menezes, et al., 2018). However, several studies are

not in line with this finding (Kim, et al., 2008).

The pathophysiology of anemia with the

occurrence of RLS in regular hemodialysis patients

is still unclear. Therefore, we were interested in

knowing the relationship of anemia with RLS in

regular HD patients. This is important to be used as

prevention and management of RLS in regular

hemodialysis patients. The aim of the study…..

Harahap, R. and Muzasti, R.

The Role of Anemia to Restless Legs Syndrome in Regular Hemodialysis Patients in Haji Adam Malik Medan General Hospital.

DOI: 10.5220/0009863702210226

In Proceedings of the 2nd International Conference on Tropical Medicine and Infectious Disease (ICTROMI 2019), pages 221-226

ISBN: 978-989-758-469-5

221

2 METHODS

2.1 Data Collection

This is an observational analytic study with cross-

sectional study design. Aim of this study is to

ascertain the relationship between anemia and RLS

in regular hemodialysis patients. The study was

conducted in October 2017 at the Adam Malik Haji

Hospital in Medan.

All patients undergoing hemodialysis therapy at

Adam Malik Haji Hospital in Medan and willing to

take part in the study and fulfill the inclusion and

exclusion criteria were included. Inclusion/exclusion

criteria: age 18 years old or older, patients who have

stably undergone hemodialysis more than 3 months,

not suffering or being treated from infection,

malignancy or drug / alcohol abuse, neurological

disorders, heart, lung and heart disease and have

complete data (what about blood transfusion?

Mostly HD with blood transfusion)

Data collected from primary data and secondary

data. Primary data is data obtained from interviews

for patient data and filling out questionnaires.

Secondary data obtained from medical records in the

form of laboratory results. (mention same result of

laboratory use for this research). Before data

collection from the sample is carried out, samples

that are in accordance with the inclusion and

exclusion criteria will be given a research

explanation and informed consent if agreed, the

hemodialysis patients can be used as research

samples. In this study, there were 106 patients who

participated in the study (How to calculate this 106

sample, How to choose the sample, for example,

consecutive sampling or convenience sampling the

author must write it )

Patients are diagnosed with RLS if they fulfill all

criteria by the International Restless Legs Syndrome

Study Group (IRLSSG). Patients who met the

criteria continued with interviews to determine the

degree of RLS based on the International RLS

Severity Scale (IRLS). What kind of research

instrument used in this research, what about ethical

clearance? Is valid and reliable? The author must

mention it clearly)

2.2 Statistical Analysis

All data were analyzed with statistical software

SPSS 22.0 using univariate, bivariate and

multivariate analysis with 95% confidence

interval.

Bivariate analysis was carried out using chi-square

to compare patients with and without RLS. Pearson

correlation examined the relationship between single

variables. Multinomial logistic regression was also

performed to investigate factors associated with

RLS, adjusting for covariates (more explanation

about using chi-square, person correlation, and

multivariate, what data using for each statistical

analytic).

3 RESULTS

Table 1. Of the 106 patients who attended the study,

all patients underwent HD 2 times a month. Men

have a higher prevalence than a woman (66% vs

34%). The Mean age of regular HD patients was

48.4 ± 13.29 with HD duration mean 24.2 ± 12.45.

Mean of hemoglobin level is 9.15 ± 1.47, SI 66.9 ±

33.7, TIBC 191.8 ± 58.8, transferrin saturation 37.3

± 19.61, ferritin levels 983.8 ± 932.86. The mean of

mineral level calcium is 8.13 ± 0.96, and phosphate

level is 5.6 ± 2.13. Of 32 patients (30.2%) with

respect to the severity of RLS, 4 patients classified

as mild (12.5%), 15 patients had moderate (46.9%),

9 had severe (28.1%) and 4 patients had very severe

(12.5%). 74 patients have no symptom of RLS.

(explanation the table used to after the table, not

before the table show).

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Table 1: Baseline characteristic regular hemodialysis patients in Haji Adam Malik General Hospital.

Variable n (%); Mean ± SD

Gender

Men 70 (66%)

Women 36 (34%)

Age (years) 48,4 ± 13,29

HD (month) 24,2 ± 12,45

Hb (gr/dL) 9,15 ± 1,47

SI (µg/dL) 66,9 ± 33,7

TIBC (µg/dL) 191,8 ± 58,8

Ferritin (µg/dL) 983,8 ± 932,86

ST (%) 37,3 ± 19,61

Ca (mg/dL) 8,13 ± 0,96

P (mg/dL) 5,6 ± 2,13

RLS

RLS 32 (30,2)

without RLS 74 (69,8)

RLS severity

Mild 4 (12,5)

Moderate 15 (46,9)

Severe 9 (28,1)

Very severe 4 (12,5)

Table 2: Characteristic of patients according to restless legs syndrome presence or absence

Tanpa RLS

(n = 74)

RLS

(n = 32)

P value

Gender 0,377

Men 51 (68,9) 19 (59,4)

Women 23 (31,1) 13 (40,6)

Age (years)

44,4  14,32 50,1  12,55

0,044*

HD (month)

25,2  12,76 23,8  12,08

0,604

Hb (gr/dL)

<10

>10

9,5 1,42

9,0 1,47

0,102

0,287

SI (µg/dL)

68,4  39,43 66,3  31,1

0,764

TIBC (µg/dL)

178,8  52,35 197,4  60,89

0,135

Ferritin (µg/dL)

893,3  952,94 1193  862,75

0,129

ST (%)

38,3  21,41 36,8  18,92

0,714

Ca (mg/dL)

8,3 0,84 8,1 1,01

0,251

P (mg/dL)

5,7  2,24 5,5 2,09

0,675

The Role of Anemia to Restless Legs Syndrome in Regular Hemodialysis Patients in Haji Adam Malik Medan General Hospital

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We found age was significantly associated with

the incidence (prevalence) of RLS with p = 0.044,

where the mean age at RLS (50.1 ± 12.55) was older

than without RLS (44.4 ± 14.32). In this study long

HD was not significantly different between RLS and

without RLS. Anemia profile showed lower Hb

levels (Hb averaged 9,0 ± 1.47 vs. 9.5 ± 1.42), lower

SI and TSAT ?? levels and higher of TIBC and

ferritin level in RLS than without RLS. There was

no statistically significant difference in calcium and

phosphate levels in this study between RLS and

without RLS.

Table 3. Variables that have a value of p <0.25

are included in the multivariate analysis. From the

results of multivariate analysis, it was found that

RLS was influenced by levels of TIBC, Hb and age.

Table 3: Multinomial logistic regression predicting the

presence/ absence of restless legs syndrome

Variable OR P Value 95% CI

TIBC 1,010 0,020

1,002  1,019

Hb 0,697 0,038

0,496  0,981

Age 1,040 0,025

1,005  1,076

4 DISCUSSION

In this study, the prevalence of RLS in regular HD

patients was 30.2%. This prevalence is in

accordance with previous research reports using

IRLSSG where the prevalence of RLS in dialysis

patients was around 20% -62% (Saraji, et al., 2017).

This was also in line with previous studies by Marta

et al (12-25%), Scherer JS et al (10-20%) (Scherer

JS, et al., 2017), Guo et al (20-30%) (Guo, et al.,

2017), Rohani et al (37.4%) (Rohani, et al., 2015).

Higher incidence of RLS in HD patients is also

supported by data from various other studies such as

in Sao Paolo on 101 dialysis patients found 29

patients (28.7%) with RLS (Kim, et al., 2008), the

study of Zamani et al in Mashad Iran found RLS

prevalence reached 31.7% (Saraji, et al., 2017), and

Al-Jahdali et al with RLS prevalence of 50.22%

(Higuchi, et al., 2015). The prevalence that is quite

varied in various regions can be caused by

differences in race, culture, socio-economic status,

or available health facilities (Takaki, et al., 2003).

In this study, there was no relationship between

sex and RLS. In this study, RLS was more common

in men than in women as in the study by Takaki et al

(Takaki, et al., 2003). Previous studies by Kim et al

also showed the same thing (Kim, et al., 2008).

Gender does not affect the occurrence of RLS in

dialysis patients (Kim, et al., 2008). Differences

from previous studies may be explained by

differences in proportions in each study (Saraji, et

al., 2017).

The existence of a relationship that was

statistically significant between age and the

incidence of RLS was found in this study. The

average age of patients with RLS is higher than the

group without RLS. Although different from the

study by Jeong Min Kim et al who found age did not

affect the occurrence of RLS (Kim, et al., 2008).

Secondary RLS usually occurs in patients over 40

years of age and is associated with various

neurological disorders (Guo, et al., 2017). The

previous study has concluded that the prevalence

and severity of RLS levels that increase with age

suggest that the neurodegeneration process plays an

important role in the occurrence of RLS (Kim, et al.,

2008) (Guo, et al., 2017).

This is in line with the study of Saraji et al on

dialysis patients who showed an increase in the

prevalence of RLS with age (p = 0.002) (Saraji, et

al., 2017) and a study by Ki et al. Which showed a

tendency of RLS with age (Ki, et al., 2010).

In a previous study by Kim et al and Araujo et

al, The duration of dialysis did not affect the

occurrence of RLS in dialysis patients (Kim, et al.,

2008) (Araujo, et al., 2010). This study also showed

no association between the duration of hemodialysis

and the occurrence of RLS. The duration of dialysis

is not proven to improve or worsen RLS complaints.

Significant relationship between Hb level and

RLS (OR 0.697 0.496 ± 0.981, p = 0.038) can be

seen in this study. This is in accordance with the

study by Takaki et al (OR 0.741 0.551-0.997, p =

0.0475) (Takaki, et al., 2003). Precil et al. Also

proved that there was a relationship between Hb

levels <9.8 g / dL and the occurrence of RLS (OR

1.84 1.03-2.79, p = 0.040) (Neves, et al., 2017).

Similarly, Araujo et al. proved the association of

RLS in dialysis patients and decreased Hb (p

<0.005) (Araujo, et al., 2010). Based on the results

of a Meta-analysis study of 23 previous studies Mao

et al found lower Hb levels than patients without

RLS (Menezes, et al., 2018). Along with decreased

kidney function, there will be a decrease in the

production of erythropoietin which is the main cause

of anemia in kidney disease (Babitt & Lin, 2012).

Decreasing erythropoietin will cause a decrease in

erythropoiesis where in a way that is still not fully

(Kim, et al., 2008)known, reduce iron transport to

the central nervous system (CNS) and medulla

(Menezes, et al., 2018). Several recent studies have

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shown that anemia, regardless of the iron content, is

a major cause of RLS (Menezes, et al., 2018).

However, several other studies are not in line with

this finding (Kim, et al., 2008).

Iron deficiency anemia is known to be one of the

risk factors for RLS (Kim, et al., 2008). Iron is

needed for recycling dopamine in the nervous

system and is the main cofactor for the regulation of

dopamine synthesis (eg Tyrosine hydroxylase)

(Scherer JS, et al., 2017). However, this is not very

clear in dialysis patients because of the use of iron

supplements in this population (Scherer JS, et al.,

2017). Iron deficiency in dialysis patients defined by

the Japanese Society for Dialysis Therapy (JSDT) is

serum ferritin levels <100ng / dL and TSAT <20%

(Higuchi, et al., 2015) (Yamamoto, et al., 2015). In

patients who meet the criteria will receive iron

supplementation both oral and intravenous (Kim, et

al., 2008). This, of course, can obscure the

relationship between serum iron and serum ferritin

and TSAT with RLS in this study (Kim, et al.,

2008). In this study, no significant association was

found between serum iron and TSAT with RLS in

line with Terumi et al (Higuchi, et al., 2015). In

addition, in some circumstances, RLS can be found

even though the serum iron value is normal

(Wijemanne & Ondo, 2017). This is because

peripheral iron values cannot describe the low iron

in the brain (Wijemanne & Ondo, 2017). Therefore a

neuropathological examination such as imaging

(MRI) and cerebrospinal fluid examination is needed

(Wijemanne & Ondo, 2017).

In this study, there was no association between

serum ferritin and TSAT in RLS patients and

without RLS. These results are in line with the study

by Terumi et al.who did not find any association

between serum ferritin and RLS (Higuchi, et al.,

2015). This is in contrast to the study of Guo et al.

who found an association of the degree of RLS with

ferritin values (Guo, et al., 2017). Mean serum

ferritin which tended to increase and lower TSAT in

RLS patients than patients without RLS showed that

ferritin values could not be used as deposit

predictors iron and can better describe iron status in

iron deficiency (Menezes, et al., 2018) (Saraji, et al.,

2017). In addition, iron supplementation also

obscures the relationship between them (Saraji, et

al., 2017). Ferritin levels can also be affected by

other factors such as inflammation and oxidative

stress (Higuchi, et al., 2015) (Babitt & Lin, 2012). In

this study, we have excluded patients in treatment,

infections, malignancies, and other factors that cause

inflammation based on interviews and physical

examinations. But this cannot rule out other

inflammatory factors. Therefore, in subsequent

studies, it is recommended to examine inflammatory

markers as monitoring.

From the bivariate analysis, we found a

significant relationship between the increase in

TIBC values and the occurrence of RLS. This is

something new in this study. Previous studies were

more likely to analyze hemoglobin, serum iron and

ferritin to see the iron status in the body (KDIGO,

2012). TIBC examinations to see as iron status

analysis are rare. Serum iron and TIBC comparison

values to see TSAT is more commonly found and

show insignificant results as in a study by Precil et al

and Terumi et al (Neves, et al., 2017) (Rohani, et al.,

2015) (Neves, et al., 2017) (Higuchi, et al., 2015).

Serum ferritin values that can be influenced by

factors such as inflammation also have a non-

significant relationship in RLS in this study.

Therefore, TIBC can be considered a marker for

assessing iron status in dialysis patients.

The relationship between phosphate levels to

RLS cannot be proven in this study. The calcium-

phosphate balance associated with RLS is

controversial (Saraji, et al., 2017). Study by Roberto

et al found an improvement in RLS complaints and a

decrease in phosphate levels after parathyroidectomy

(Menezes, et al., 2018), was not in line with other

studies by Filho et al., La manna et al, Terumi et al,

and Saraji et al. who also found no association

between phosphate and calcium levels with RLS

(Higuchi, et al., 2015) (Saraji, et al., 2017).

Of the 106 patients who took part in the study,

32 patients (30.2%) had RLS with mild severity of 4

patients (12.5%), moderate 15 patients (46.9%),

severe 9 patients (28,1%) and very severe 4 patients

(12.5%). Patients who did not experience RLS were

74 patients (69.8%). Based on the results of

statistical tests by comparing age, Hb levels and

TIBC values in light-to-moderate and severely

severe RLS patients no significant differences were

found between the two groups. The number of

samples and proportions may be the factors that

influence the results of the study. In addition, other

factors such as drug use and iron supplementation

can be biased.

This research is a cross-sectional study.

Therefore, the cause of the relationship cannot be

determined. There is limited research that has the

potential to be biased because of the limited sample

and data obtained from interviews such as medical

history, drug use (HD patients tend to consume more

drugs including benzodiazepines, gabapentin,

tricyclics) cannot play a role in RLS. Further

The Role of Anemia to Restless Legs Syndrome in Regular Hemodialysis Patients in Haji Adam Malik Medan General Hospital

225

research is needed to approach risk factors and

pathophysiology in RLS.

5 CONCLUSION

In this study, the prevalence of RLS in regular HD

patients is 30.2%. We found that RLS status was

influenced by Hb, TIBC, and age. RLS is often

found in HD patients but is still often undiagnosed

and untreated. RLS creates a disruption in quality of

life and increases mortality risk, therefore screening

for RLS is best done at health facilities that provide

services for renal replacement therapy especially

hemodialysis. The need for education about RLS for

HD patients to make it more routine for screening

(anemia) and prevention, especially for patients who

are older.

Pathophysiology of RLS is still unknown and

multifactorial, with the availability of complete data

and larger samples it is expected that other factors

related to RLS can be identified. In accordance with

the results of the study where low Hb levels and

high TIBC are significant risk factors, it is

recommended to correct anemia as prevention and

management of RLS.

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