Original Paper Received: October 21, 2013 Accepted: January 20, 2014 Published online: April 15, 2014
Neuroepidemiology 2014;42:204–210 DOI: 10.1159/000358921
Increased Risk of Parkinson’s Disease in Patients with End-Stage Renal Disease: A Retrospective Cohort Study I-kuan Wang a–c Cheng-Li Lin d, e Yi-Ying Wu f Che-Yi Chou c Shih-Yi Lin c Jiung-Hsiun Liu c Tzung-Hai Yen g, h Chiu-Ching Huang c Fung-Chang Sung d, e
Institute of Clinical Medical Science and b Department of Internal Medicine, China Medical University College of Medicine, c Division of Nephrology and d Management Office for Health Data, China Medical University Hospital, e Department of Public Health and f Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, g Division of Nephrology, Chang Gung Memorial Hospital, Taipei, and h Chang Gung University College of Medicine, Taoyuan, Taiwan
Key Words End-stage renal disease · Parkinson’s disease · Risk factors
Abstract Background: Studies on dyskinesia and Parkinson’s syndrome associated with chronic kidney disease or end-stage renal disease (ESRD) have been mainly limited to case reports or case series studies. This population-based study investigated the risk of Parkinson’s disease in patients with ESRD. Methods: From a universal insurance claims database of Taiwan, we established a cohort of 8,325 adults with newly diagnosed ESRD from 1997 to 2010 without a history of Parkinson’s disease. A control cohort of 33,382 insured subjects without a history of kidney disease or Parkinson’s disease was also selected, with frequency matched for age, sex and index date of the patients with ESRD. Both cohorts were followed up until the end of 2010. Results: The Parkinson’s disease incidence was 1.55-fold higher in the cohort with ESRD than in the comparison cohort (48.8 vs. 31.7 per 10,000 person-years) with an adjusted hazard ratio of 1.73 (95% confidence interval, 1.39–2.15). Sex-specific and age-specific analysis showed a higher relative risk for women and young-
© 2014 S. Karger AG, Basel 0251–5350/14/0424–0204$39.50/0 E-Mail [email protected] www.karger.com/ned
er patients with ESRD compared to the control cohort. Conclusions: ESRD is significantly associated with an increased risk of Parkinson’s disease. Close surveillance for Parkinson’s disease should be considered for patients with ESRD. © 2014 S. Karger AG, Basel
Introduction
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, characterized by movement disorders such as bradykinesia, resting tremor, rigidity, and postural instability [1]. The pathogenesis of the disease is associated with progressive loss of neurons in the substantia nigra and other brain structures [2]. The prevalence of PD increases with age, ranging from 1% to over 4% in the elderly [1, 3]. Epidemiological studies have demonstrated that PD reduces life expectancy with hazard ratios (HR) of mortality ranging from 1.5 to 2.7, compared with a population without the disease [1].
Conducting the statistical analysis: Cheng-Li Lin, MS.
Prof. Fung-Chang Sung, PhD, MPH Institute of Clinical Medical Science, China Medical University 91 Hsueh Shih Road Taichung 404 (Taiwan) E-Mail fcsung1008 @ yahoo.com
Downloaded by: University of Tokyo 157.82.153.40 - 5/14/2015 9:28:34 PM
a
Materials and Methods Data Sources This study used claims data retrieved from the National Health Insurance Research Database obtained from Taiwan’s National Health Insurance program. The insurance program provides health care to approximately 99% of 23.74 million people and has contracted with 97% of hospitals and clinics by the end of 2009. The National Health Insurance Research Database contains all reimbursement claim records from 1996 to 2010 for 1,000,000 persons randomly selected from all insured persons in Taiwan. Information available from the database included all registered medical facilities, ambulatory care, inpatient care, dental services, prescription drugs, and registration files with scrambled identifications. The diseases were identified according to the International Classification of Disease, 9th revision, Clinical Modification (ICD-9-CM). This retrospective observational study complied with the guidelines of the Declaration of Helsinki and was approved by the Research Ethics Committee of China Medical University (CMUREC-101-012). Since this study involved the retrospective review of existing data, the Institutional Review Board of China Medical University has specifically waived the need for consent. All data was deidentified and analyzed anonymously.
Outcome Measures Each study subject was followed until PD (ICD-9-CM codes 332) was diagnosed or censored because of kidney transplantation, death, loss to follow-up, termination of insurance, or December 31, 2010. The diagnosis of PD was made by neurologists with at least two successive records of diagnosis in the claims data. The comorbidities that might be associated with PD to be included in this study were coronary artery disease (ICD-9-CM codes 410– 413, 414.01–414.05, 414.8, and 414.9), congestive heart failure (ICD-9-CM codes 428, 398.91, 402.x1), stroke (ICD-9-CM codes 430–438), hyperlipidemia (ICD-9-CM codes 272), hypertension (ICD-9-CM codes 401–405), diabetes (ICD-9-CM codes 250), head injury (ICD-9-CM codes: 850–854, 959.01), identified at baseline. Statistical Analysis Our data analyses first compared the distribution of sociodemographic factors and comorbid conditions between the ESRD group and the control group. We used the χ2 test to examine categorical variables and the t test for continuous variables. The incidence density rates of PD were estimated in person-years for both groups. Univariate and multivariate Cox proportional hazards models were used to assess the risk of developing PD associated with ESRD, compared with the control cohort. HR and 95% confidence interval (CI) were estimated in the Cox models. The follow-up period was partitioned into two segments (≤1 year and >1 year), and multivariable Cox proportional hazard regression analysis was also used to assess whether the risk of PD changed over time. Kaplan-Meier analysis was performed to show the probability of persons remaining without PD, and the log-rank test was applied to examine the difference between the ESRD cohort and the control cohort. All statistical analyses were performed by SAS version 9.2 (SAS Institute Inc., Cary, N.C., USA) and the KaplanMeier survival curve was plotted using R software (R Foundation for Statistical Computing, Vienna, Austria). The level of statistical significance was set at p < 0.05.
Results
Study Subjects We identified 8,959 patients with newly diagnosed ESRD (ICD9-CM codes 585) during 1997–2010 from the Registry for Catastrophic Illness Patient Database, which included those who require long-term renal replacement therapy such as dialysis or kidney transplant. The date when ESRD was diagnosed was designated as the index date. Patients with a history of PD diagnosed before the index date (n = 481), with missing information on age or sex (n = 64), and aged less than 20 years were excluded (n = 89). The remaining 8,325 patients with ESRD were included in the ESRD group. For every ESRD patient, we randomly selected 4 insured subjects without any history of PD or kidney disease, matched for age, sex, and the month of the index day.
In this study, 8,325 patients with ESRD, including 7,902 hemodialysis patients and 423 peritoneal dialysis patients, and 33,382 controls without any kidney disease were enrolled (table 1). The mean follow-up periods were 2.56 ± 3.24 years in the ESRD cohort and 5.51 ± 3.81 in the control cohort. In addition, the follow-up periods for PD onset were 2.82 ± 2.48 years in the ESRD cohort and 4.12 ± 3.0 years in the control cohort. In both cohorts there was a predominance of men (53.2 vs. 46.8%) and subjects less than 65 years old. Compared to the control cohort, the ESRD cohort tended to live in higher urbanized areas (55.1% in urbanization levels 1 and 2), and comorbidities of coronary artery disease (28.2 vs. 13.2%), congestive heart failure (25.0 vs. 5.15%), stroke (39.1 vs. 20.7%), hypertension (80.2 vs. 43.5%), diabetes (51.4 vs. 16.3%), and head injury (3.21 vs. 2.45%) were more prevalent.
Parkinson’s Disease and End-Stage Renal Disease
Neuroepidemiology 2014;42:204–210 DOI: 10.1159/000358921
205
Downloaded by: University of Tokyo 157.82.153.40 - 5/14/2015 9:28:34 PM
Movement disorders also appear in uremic patients with symptoms of mainly asterixis, myoclonus and restless leg syndrome [4]. Asterixis and myoclonus seen in patients with uremic encephalopathy may reflect cortical involvement [4]. Restless leg syndrome is a common disorder not only in PD patients but also in patients with chronic kidney disease (CKD) with prevalence of at least 20% and response to dopaminergic treatment [4, 5]. It is therefore possible that there is an association between PD and CKD. However, limited case reports or case series studies have reported dyskinesia and Parkinson’s syndromes in association with the basal ganglion lesions in patients with CKD or end-stage renal disease (ESRD) [6–13]. Therefore, the present study aims to investigate the risk of PD in incident ESRD patients using population-based claim data derived from the Taiwan National Health Insurance program.
Discussion
Among the case studies of Parkinson’s syndrome in patients with ESRD, most were conducted in Asian populations [8–10, 12–16]. The present study accounted for 73% increased risk of PD for patients with ESRD. An additional validation analysis by excluding those aged more than 75 years also demonstrated 64% increased risk. The comorbidity-specific relative risk is even greater for ESRD patients without the comorbidity. Lin et al. [17] found recently that CKD patients were more vulnerable to parkinsonism, with a 1.81-fold higher risk than nonCKD patients. It is likely that the risk of PD associated 206
Neuroepidemiology 2014;42:204–210 DOI: 10.1159/000358921
Table 1. Demographic characteristics and comorbidities in the co-
hort with ESRD and the control cohort Variable Sex Female Male Age, mean ± SDb Age cohort ≤64 65–74 75+ Urbanizationc 4 3 2 1 Comorbidity CAD CHF Stroke Hyperlipidemia Hypertension Diabetes Head injury
Control, n (%) (n = 33,382)
ESRD, n (%) (n = 8,325)
p value
15,612 (46.8) 17,770 (53.2) 64.5±15.2
3,893 (46.8) 4,432 (53.2) 64.5±15.2
0.96
15,309 (45.9) 7,766 (23.3) 10,307 (30.9)
3,795 (45.6) 1,964 (23.6) 2,566 (30.8)
0.81
9,403 (28.2) 5,756 (17.2) 8,963 (26.9) 9,259 (27.7)
2,273 (27.3) 1,460 (17.5) 2,367 (28.4) 2,225 (26.7)
0.01a
4,417 (13.2) 1,720 (5.15) 5,039 (15.1) 6,904 (20.7) 14,536 (43.5) 5,423 (16.3) 819 (2.45)
2,347 (28.2) 2,083 (25.0) 2,459 (29.5) 3,251 (39.1) 6,676 (80.2) 4,280 (51.4) 268 (3.21)
Neuroepidemiology 2014;42:204–210 DOI: 10.1159/000358921
Increased Risk of Parkinson’s Disease in Patients with End-Stage Renal Disease: A Retrospective Cohort Study I-kuan Wang a–c Cheng-Li Lin d, e Yi-Ying Wu f Che-Yi Chou c Shih-Yi Lin c Jiung-Hsiun Liu c Tzung-Hai Yen g, h Chiu-Ching Huang c Fung-Chang Sung d, e
Institute of Clinical Medical Science and b Department of Internal Medicine, China Medical University College of Medicine, c Division of Nephrology and d Management Office for Health Data, China Medical University Hospital, e Department of Public Health and f Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, g Division of Nephrology, Chang Gung Memorial Hospital, Taipei, and h Chang Gung University College of Medicine, Taoyuan, Taiwan
Key Words End-stage renal disease · Parkinson’s disease · Risk factors
Abstract Background: Studies on dyskinesia and Parkinson’s syndrome associated with chronic kidney disease or end-stage renal disease (ESRD) have been mainly limited to case reports or case series studies. This population-based study investigated the risk of Parkinson’s disease in patients with ESRD. Methods: From a universal insurance claims database of Taiwan, we established a cohort of 8,325 adults with newly diagnosed ESRD from 1997 to 2010 without a history of Parkinson’s disease. A control cohort of 33,382 insured subjects without a history of kidney disease or Parkinson’s disease was also selected, with frequency matched for age, sex and index date of the patients with ESRD. Both cohorts were followed up until the end of 2010. Results: The Parkinson’s disease incidence was 1.55-fold higher in the cohort with ESRD than in the comparison cohort (48.8 vs. 31.7 per 10,000 person-years) with an adjusted hazard ratio of 1.73 (95% confidence interval, 1.39–2.15). Sex-specific and age-specific analysis showed a higher relative risk for women and young-
© 2014 S. Karger AG, Basel 0251–5350/14/0424–0204$39.50/0 E-Mail [email protected] www.karger.com/ned
er patients with ESRD compared to the control cohort. Conclusions: ESRD is significantly associated with an increased risk of Parkinson’s disease. Close surveillance for Parkinson’s disease should be considered for patients with ESRD. © 2014 S. Karger AG, Basel
Introduction
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, characterized by movement disorders such as bradykinesia, resting tremor, rigidity, and postural instability [1]. The pathogenesis of the disease is associated with progressive loss of neurons in the substantia nigra and other brain structures [2]. The prevalence of PD increases with age, ranging from 1% to over 4% in the elderly [1, 3]. Epidemiological studies have demonstrated that PD reduces life expectancy with hazard ratios (HR) of mortality ranging from 1.5 to 2.7, compared with a population without the disease [1].
Conducting the statistical analysis: Cheng-Li Lin, MS.
Prof. Fung-Chang Sung, PhD, MPH Institute of Clinical Medical Science, China Medical University 91 Hsueh Shih Road Taichung 404 (Taiwan) E-Mail fcsung1008 @ yahoo.com
Downloaded by: University of Tokyo 157.82.153.40 - 5/14/2015 9:28:34 PM
a
Materials and Methods Data Sources This study used claims data retrieved from the National Health Insurance Research Database obtained from Taiwan’s National Health Insurance program. The insurance program provides health care to approximately 99% of 23.74 million people and has contracted with 97% of hospitals and clinics by the end of 2009. The National Health Insurance Research Database contains all reimbursement claim records from 1996 to 2010 for 1,000,000 persons randomly selected from all insured persons in Taiwan. Information available from the database included all registered medical facilities, ambulatory care, inpatient care, dental services, prescription drugs, and registration files with scrambled identifications. The diseases were identified according to the International Classification of Disease, 9th revision, Clinical Modification (ICD-9-CM). This retrospective observational study complied with the guidelines of the Declaration of Helsinki and was approved by the Research Ethics Committee of China Medical University (CMUREC-101-012). Since this study involved the retrospective review of existing data, the Institutional Review Board of China Medical University has specifically waived the need for consent. All data was deidentified and analyzed anonymously.
Outcome Measures Each study subject was followed until PD (ICD-9-CM codes 332) was diagnosed or censored because of kidney transplantation, death, loss to follow-up, termination of insurance, or December 31, 2010. The diagnosis of PD was made by neurologists with at least two successive records of diagnosis in the claims data. The comorbidities that might be associated with PD to be included in this study were coronary artery disease (ICD-9-CM codes 410– 413, 414.01–414.05, 414.8, and 414.9), congestive heart failure (ICD-9-CM codes 428, 398.91, 402.x1), stroke (ICD-9-CM codes 430–438), hyperlipidemia (ICD-9-CM codes 272), hypertension (ICD-9-CM codes 401–405), diabetes (ICD-9-CM codes 250), head injury (ICD-9-CM codes: 850–854, 959.01), identified at baseline. Statistical Analysis Our data analyses first compared the distribution of sociodemographic factors and comorbid conditions between the ESRD group and the control group. We used the χ2 test to examine categorical variables and the t test for continuous variables. The incidence density rates of PD were estimated in person-years for both groups. Univariate and multivariate Cox proportional hazards models were used to assess the risk of developing PD associated with ESRD, compared with the control cohort. HR and 95% confidence interval (CI) were estimated in the Cox models. The follow-up period was partitioned into two segments (≤1 year and >1 year), and multivariable Cox proportional hazard regression analysis was also used to assess whether the risk of PD changed over time. Kaplan-Meier analysis was performed to show the probability of persons remaining without PD, and the log-rank test was applied to examine the difference between the ESRD cohort and the control cohort. All statistical analyses were performed by SAS version 9.2 (SAS Institute Inc., Cary, N.C., USA) and the KaplanMeier survival curve was plotted using R software (R Foundation for Statistical Computing, Vienna, Austria). The level of statistical significance was set at p < 0.05.
Results
Study Subjects We identified 8,959 patients with newly diagnosed ESRD (ICD9-CM codes 585) during 1997–2010 from the Registry for Catastrophic Illness Patient Database, which included those who require long-term renal replacement therapy such as dialysis or kidney transplant. The date when ESRD was diagnosed was designated as the index date. Patients with a history of PD diagnosed before the index date (n = 481), with missing information on age or sex (n = 64), and aged less than 20 years were excluded (n = 89). The remaining 8,325 patients with ESRD were included in the ESRD group. For every ESRD patient, we randomly selected 4 insured subjects without any history of PD or kidney disease, matched for age, sex, and the month of the index day.
In this study, 8,325 patients with ESRD, including 7,902 hemodialysis patients and 423 peritoneal dialysis patients, and 33,382 controls without any kidney disease were enrolled (table 1). The mean follow-up periods were 2.56 ± 3.24 years in the ESRD cohort and 5.51 ± 3.81 in the control cohort. In addition, the follow-up periods for PD onset were 2.82 ± 2.48 years in the ESRD cohort and 4.12 ± 3.0 years in the control cohort. In both cohorts there was a predominance of men (53.2 vs. 46.8%) and subjects less than 65 years old. Compared to the control cohort, the ESRD cohort tended to live in higher urbanized areas (55.1% in urbanization levels 1 and 2), and comorbidities of coronary artery disease (28.2 vs. 13.2%), congestive heart failure (25.0 vs. 5.15%), stroke (39.1 vs. 20.7%), hypertension (80.2 vs. 43.5%), diabetes (51.4 vs. 16.3%), and head injury (3.21 vs. 2.45%) were more prevalent.
Parkinson’s Disease and End-Stage Renal Disease
Neuroepidemiology 2014;42:204–210 DOI: 10.1159/000358921
205
Downloaded by: University of Tokyo 157.82.153.40 - 5/14/2015 9:28:34 PM
Movement disorders also appear in uremic patients with symptoms of mainly asterixis, myoclonus and restless leg syndrome [4]. Asterixis and myoclonus seen in patients with uremic encephalopathy may reflect cortical involvement [4]. Restless leg syndrome is a common disorder not only in PD patients but also in patients with chronic kidney disease (CKD) with prevalence of at least 20% and response to dopaminergic treatment [4, 5]. It is therefore possible that there is an association between PD and CKD. However, limited case reports or case series studies have reported dyskinesia and Parkinson’s syndromes in association with the basal ganglion lesions in patients with CKD or end-stage renal disease (ESRD) [6–13]. Therefore, the present study aims to investigate the risk of PD in incident ESRD patients using population-based claim data derived from the Taiwan National Health Insurance program.
Discussion
Among the case studies of Parkinson’s syndrome in patients with ESRD, most were conducted in Asian populations [8–10, 12–16]. The present study accounted for 73% increased risk of PD for patients with ESRD. An additional validation analysis by excluding those aged more than 75 years also demonstrated 64% increased risk. The comorbidity-specific relative risk is even greater for ESRD patients without the comorbidity. Lin et al. [17] found recently that CKD patients were more vulnerable to parkinsonism, with a 1.81-fold higher risk than nonCKD patients. It is likely that the risk of PD associated 206
Neuroepidemiology 2014;42:204–210 DOI: 10.1159/000358921
Table 1. Demographic characteristics and comorbidities in the co-
hort with ESRD and the control cohort Variable Sex Female Male Age, mean ± SDb Age cohort ≤64 65–74 75+ Urbanizationc 4 3 2 1 Comorbidity CAD CHF Stroke Hyperlipidemia Hypertension Diabetes Head injury
Control, n (%) (n = 33,382)
ESRD, n (%) (n = 8,325)
p value
15,612 (46.8) 17,770 (53.2) 64.5±15.2
3,893 (46.8) 4,432 (53.2) 64.5±15.2
0.96
15,309 (45.9) 7,766 (23.3) 10,307 (30.9)
3,795 (45.6) 1,964 (23.6) 2,566 (30.8)
0.81
9,403 (28.2) 5,756 (17.2) 8,963 (26.9) 9,259 (27.7)
2,273 (27.3) 1,460 (17.5) 2,367 (28.4) 2,225 (26.7)
0.01a
4,417 (13.2) 1,720 (5.15) 5,039 (15.1) 6,904 (20.7) 14,536 (43.5) 5,423 (16.3) 819 (2.45)
2,347 (28.2) 2,083 (25.0) 2,459 (29.5) 3,251 (39.1) 6,676 (80.2) 4,280 (51.4) 268 (3.21)
