Association between acute kidney injury and risk of Parkinson disease

European Journal of Internal Medicine 36 (2016) 81–86

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European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim

Association between acute kidney injury and risk of Parkinson disease Shih-Yi Lin a,b, Cheng-Li Lin c,d, Wu-Huei Hsu a,e, Hung-Chieh Yeh a,b, Cheng-Chieh Lin a,f, Chih-Hsueh Lin a,f, Chun-Hung Tseng a,g,⁎ a

Graduate Institute of Clinical Medical Science, College of Medicine, China Medical University, Taichung, Taiwan Division of Nephrology and Kidney Institute, China Medical University Hospital, Taichung, Taiwan Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan d College of Medicine, China Medical University, Taichung, Taiwan e Division of Pulmonary and Critical Care Medicine, China Medical University Hospital and China Medical University, Taichung, Taiwan f Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan g Department of Neurology, China Medical University Hospital, Taichung, Taiwan b c

a r t i c l e

i n f o

Article history: Received 1 August 2016 Received in revised form 24 August 2016 Accepted 18 September 2016 Available online 1 October 2016 Keywords: Acute kidney injury Movement disorder Neurodegenerative disease Parkinson disease

a b s t r a c t Backgrounds: Worldwide, the incidence of acute kidney injury (AKI) has been increasing. However, information on the long-term incidence of Parkinson disease (PD) in patients with AKI has not been reported. Methods: A total of 9380 patients with AKI and 37,484 age- and sex-matched patients who did not have AKI were identified during 2003–2011. All patients were tracked until a diagnosis of PD, death, or the end of 2011. Cumulative incidences and hazard ratios (HRs) were calculated. Results: The mean follow-up time for PD was 6.89 (SD = 3.30) years in the AKI cohort and 6.78 (SD = 3.29) years in the non-AKI cohort. The overall incidence densities of PD were significantly higher in the AKI cohort than in the non-AKI cohort (6.04 vs. 3.99/1000 person-years), with an adjusted HR of 1.47 (95% confidence interval [CI] = 1.18–1.83). Compared with the patients in the non-AKI cohort aged ≤64 years, the relative risk (95% CI) of PD was 2.17 (1.12–4.18), 14.1 (9.16–21.8), and 14.1 (8.43–23.6) for the patients in the AKI cohort aged ≤ 64, 65–79, and ≥80 years, respectively. Conclusion: Patients with AKI were associated with a higher long-term risk of PD. © 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

1. Introduction Parkinson disease (PD), affecting approximately 1%–2% of the population worldwide, is the second most common neurodegenerative disorder after Alzheimer disease [1]. PD has a broad spectrum of symptoms such as progressive motor dysfunction and psychiatric disturbances, which gradually reduce a patient's ability of self-care [2]. The onset of PD typically occurs in the sixth decade, and its prevalence increases with age. Approximately 77% of patients have a poor outcome 10 years after the diagnosis of PD [3]. With the worldwide phenomenon of population aging [4], PD is expected to impose an increasing economic and social burden on medical care systems. In patients with PD, the proposed pathologic mechanisms of selective dopaminergic neuron loss in the substantia nigra are mitochondrial dysfunction, oxidative stress, and protein mishandling [5]. The susceptibility genes PARK 1–15 have been identified to play a role in the pathogenesis of PD. Over the decades, epidemiologic studies have reported that nongenetic factors (occupational exposure, dietary factors, and inflammation) [6] and disease (diabetes [7], abnormal heart rate variability [8], end⁎ Corresponding author at: Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. E-mail address: [email protected] (C.-H. Tseng).

stage renal disease [9], hypertension [10], and depression [11]) are associated with the risk of PD development. Acute kidney injury (AKI), of which the incidence proportionately increased over the decades, is a common complication of medical illness and surgical procedures in hospitalized patients. [12,13]. Recent studies have revealed that the consequences of AKI are considerably broad and encompass short-term and long-term major organ damage in addition to kidney damage [14,15]. Studies on experimental animals have demonstrated that AKI leads to an increase in microvascular permeability in the brain, induces proinflammatory chemokines, and causes inflammation and functional changes of the blood–brain barrier [16]. Wu et al. reported that AKI is associated with a 1.25-fold higher risk of de novo stroke [17]. These findings suggest that AKI has remote effects on the central nervous system (CNS). However, whether AKI causes long-lasting neurodegenerative effects within the CNS remains unknown. Furthermore, the results of animal studies lack clinical relevance. Thus, the association between AKI and neurodegenerative disorders, such as PD, requires epidemiologic evidence obtained using a large-scale cohort study design. The Taiwan National Health Insurance (NHI) Research Database (NHIRD) provides longitudinal and comprehensive medical claims data on approximately 23 million people. Several studies have used the NHIRD to investigate AKI or PD, and the data are reliable [18–21]. We used data from the NHIRD to examine whether AKI is associated with the risk of long-term PD.

http://dx.doi.org/10.1016/j.ejim.2016.09.016 0953-6205/© 2016 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

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S.-Y. Lin et al. / European Journal of Internal Medicine 36 (2016) 81–86

2. Methods 2.1. Data source Data for the subjects sampled in this retrospective cohort study were obtained from the Longitudinal Health Insurance Database 2000 (LHID2000). On March 1, 1995, Taiwan implemented the NHI program and enrolled nearly 99% of all residents [22]. The LHID2000 consists of all original medical claims for a random sample of 1000,000 NHI beneficiaries from the 2000 Registry of Beneficiaries compiled using a systematic sampling method for research purposes. The details of the NHI program and LHID2000 have been previously described [23,24]. This study was approved by the Institutional Review Board of China Medical University (CMUH104-REC2-115). 2.2. Study population The AKI cohort was identified during January 1, 2000 to December 31, 2011. We included patients with newly diagnosed acute renal failure (ICD-9-CM codes 584.5–584.9) and set the index date as the date of AKI diagnosis. We used a 1-year period prior to the index date to identify preindex comorbidities and AKI. Patients with a history of chronic kidney disease (CKD; ICD-9-CM code 585), end-stage renal disease (ESRD; ICD-9-CM code 585), and PD (ICD-9-CM code 332) before the index date were excluded. The diagnosis of primary PD is based on

Table 1 Demographic characteristics and comorbidities in cohorts with and without acute kidney injury. Variable

Age, year ≤49 50–64 65–79 80+ Mean ± SD† Sex Female Male Urbanization level& 1 (Highest urbanization) 2 3 4(Lowest urbanization) Occupation Housekeeping White collar Blue collar Others‡ Comorbidity Diabetes Hypertension Hyperlipidemia Anxiety Depression Alcohol-related illness Obesity Bipolar disorder Schizophrenia Head injury Stroke Hypnotic medication Benzodiazepine Non-BZD Anti-psychotic medications

Acute kidney injury

p-value

No

Yes

N = 37,484

N = 9380

6268(16.7) 7544(20.1) 13,821(36.9) 9851(26.3) 67.0(16.7)

1567(16.7) 1886(20.1) 3453(36.8) 2474(26.4) 67.8(16.7)

15,173(40.5) 22,311(59.5)

3797(40.5) 5583(59.5)

10,306(27.5) 10,038(26.8) 6504(17.4) 10,636(28.4)

2281(24.3) 2536(27.0) 1624(17.3) 2939(31.3)

10,364(27.7) 8298(22.1) 12,876(34.4) 5946(15.9)

2785(29.7) 1571(16.8) 3368(35.9) 1656(17.7)

5265(14.1) 19,646(52.4) 10,220(27.3) 3608(9.63) 2021(5.39) 1277(3.41) 391(1.04) 130(0.35) 114(0.30) 2318(6.18) 3224(8.60)

3025(32.3) 6351(67.7) 3025(32.3) 968(10.3) 755(8.05) 1106(11.8) 152(1.62) 73(0.78) 77(0.82) 900(9.59) 2221(23.7)

b0.001 b0.001 b0.001 0.04 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001 b0.001

14,620(39.0) 4425(11.8) 3294(8.79)

4055(43.2) 1584(16.9) 1154(12.3)

b0.001 b0.001 b0.001

0.99

0.001 0.99

b0.001

ICD-9 code (332 except 332.1), while the diagnosis of secondary PD is based on ICD-9 code (332.1). The non-AKI cohort, comprising patients without any kidney disease (ICD-9-CM codes 580–589), was randomly identified from the LHID2000 during the same period of 2000–2011, with exclusion criteria identical to those applied to the AKI cohort. With each AKI patient, 4 non-AKI subjects were frequency-matched by age (every 5-year span), sex, and the year of the index date. The patients in both cohorts were followed until PD was diagnosed, they were censored for withdrawal from the NHI program, or December 31, 2011. 2.3. Variables of interest The sociodemographic variables used in this study comprised age, sex, urbanization level, and occupation. Urbanization level and occupation were defined in detail in a previous paper [25]. The comorbidities included in this study were diabetes (ICD-9-CM code 250), hypertension (ICD-9-CM codes 401–405), hyperlipidemia (ICD-9-CM code 272), anxiety (ICD-9-CM code 300.00), depression (ICD-9-CM codes 296.2, 296.3, 300.4, and 311), alcohol-related illness (ICD-9-CM codes 291, 303, 305, 571.0, 571.1, 571.2, 571.3, 790.3, A215, and V11.3), obesity (ICD-9-CM code 278), bipolar disorder (ICD-9-CM code 296), schizophrenia (ICD-9-CM code 295), head injury (ICD-9-CM codes 850–854 and 959.01), and stroke (ICD-9-CM code 430–438), identified at the baseline. In addition, benzodiazepine (BZD) use, non-BZD use, and antipsychotic medication use were compared between the AKI and non-AKI cohorts. Temporary dialysis was defined on the basis of the procedure code (ICD-9-CM procedure 39.95). 2.4. Statistical analysis The distributions of the sociodemographic data, comorbidities, and medications of the AKI and non-AKI cohorts were compared using the chi-square test to examine categorical variables and Student's t test to examine continuous variables. The Kaplan–Meier method was used to estimate the cumulative incidence of PD in both cohorts, with significance based on the log-rank test. The follow-up period in personyears was used to estimate incidence density rate of PD among different risk factors and stratified by age, sex, urbanization level, occupation, comorbidity, and medication. Univariable and multivariable Cox proportional hazard regression models were used to evaluate hazard ratios (HRs) and 95% confidence intervals (CIs) for PD. The variables in the multivariable model included age; sex; urbanization level; occupation; comorbidities of diabetes, hypertension, hyperlipidemia, anxiety,

b0.001

Chi-Square Test; †: T-Test. : Urbanization level was categorized according to the population density of the residential area into 4 levels, with Level 1 the most urbanized and Level 4 the least urbanized. ‡ Other occupations included primarily retired, unemployed, or low income populations. &

Fig. 1. Cummulative incidence comparison of Parkinson's disease for patients with (dashed line) or without (solid line) acute kidney injury (AKI).


depression , bipolar disorder, head injury, and stroke; and BZD, nonBZD, and antipsychotic medications. All of the confounding factors showed a significant difference in the univariable model. All analyses

83

were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). The level of significance was set at 0.05, and significance was evaluated using a 2-tailed test.

Table 2 Incidence and Hazard ratio for Parkinson's disease and Parkinson's disease-associated risk factor. Variable Acute kidney injury No Yes Age, year ≤64 65–79 80+ Sex Female Male Urbanization level& 1 (Highest urbanization) 2 3 4(Lowest urbanization) Occupation Housekeeping White collar Blue collar Others‡ Comorbidity Diabetes No Yes Hypertension No Yes Hyperlipidemia No Yes Anxiety No Yes Depression No Yes Alcohol-related illness No Yes Obesity No Yes Bipolar disorder No Yes Schizophrenia No Yes Head injury No Yes Stroke No Yes Hypnotic medication Benzodiazepine No Yes Non-BZD No Yes Anti-psychotic medications No Yes

Event

PY

Rate#

Crude HR (95% CI)

Adjusted HR& (95% CI)

629 102

157729 16883

3.99 6.04

1.00 1.51(1.22, 1 .86)***

1.00 1.47(1.18, 1.83)***

47 437 247

76172 65964 32477

0.62 6.62 7.61

1.00 10.8(7.97, 14.5)*** 12.5(9.13, 17.1)***

1.00 8.08(5.85, 11.2)*** 8.91(6.33, 12.5)***

318 413

71151 103462

4.47 3.99

1.00 0.89(0.77, 1.03)

1.00 −

186 165 143 237

48352 47074 30154 49032

3.85 3.51 4.74 4.83

1.10(0.89, 1.35) 1.00 1.35(1.08, 1.69)** 1.38(1.13, 1.68)**

1.11(0.90, 1.37) 1.00 1.30(1.04, 1.63)* 1.10(0.88, 1.36)

256 52 275 148

46773 40646 59753 27440

5.47 1.28 4.60 5.39

4.26(3.16, 5.74)*** 1.00 3.59(2.67, 4.82)*** 4.20(3.06, 5.76)***

1.30(0.95, 1.77) 1.00 1.30(0.94, 1.79) 1.22(0.88, 1.71)

575 156

151825 22788

3.79 6.85

1.00 1.79(1.50, 2.14)***

1.00 1.18(0.98, 1.42)

179 552

89293 85320

2.00 6.47

1.00 3.22(2.72, 3.81)***

1.00 1.45(1.21, 1.75)***

495 236

130968 43645

3.78 5.41

1.00 1.42(1.22, 1.66)***

1.00 0.91(0.77, 1.08)

625 106

160946 13666

3.88 7.76

1.00 1.97(1.61, 2.43)***

1.00 1.19(0.95, 1.48)

651 80

166635 7977

3.91 10.0

1.00 2.55(2.02, 3.21)***

1.00 1.55(1.20, 2.02)**

705 26

168951 5662

4.17 4.59

1.00 1.09(0.73, 1.61)

1.00 −

724 7

172982 1631

4.19 4.29

1.00 1.02(0.48, 2.14)

1.00 −

723 8

174037 576

4.15 13.9

1.00 3.32(1.66, 6.66)***

1.00 2.12(1.03, 4.36)*

729 2

173969 644

4.19 3.11

1.00 0.74(0.19, 2.96)

1.00 −

665 66

165662 8950

4.01 7.37

1.00 1.81(1.41, 2.34)***

1.00 1.33(1.03, 1.72)*

621 110

162019 12594

3.83 8.73

1.00 2.26(1.84, 2.77)***

1.00 1.18(0.95, 1.46)

354 377

113648 60965

3.11 6.18

1.00 1.97(1.70, 2.28)***

1.00 1.09(0.93, 1.28)

599 132

158806 15806

3.77 8.35

1.00 2.20(1.82, 2.65)***

1.00 1.19(0.96, 1.47)

615 116

161694 12918

3.80 8.98

1.00 2.34(1.92, 2.86)***

1.00 1.38(1.11, 1.72)**

Rate#, incidence rate, per 1000 person-years; Crude HR, relative hazard ratio; Adjusted HR† : multivariable analysis including age, urbanization level, occupation and comorbidities of diabetes, hypertension, hyperlipidemia, anxiety, depression , bipolar disorder, head injury, stroke, and medications of benzodiazepine, non-benzodiazepine, and anti-psychotic; PY: per 1000 person years. & : Urbanization level was categorized according to the population density of the residential area into 4 levels, with Level 1 the most urbanized and Level 4 the least urbanized. ‡ Other occupations included primarily retired, unemployed, or low income populations. *p b 0.05, **p b 0.01, ***p b 0.001.

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3. Results We included 9380 patients in the AKI cohort and 37,484 patients in the non-AKI cohort; the age and sex distributions of the cohorts were similar (Table 1). The mean age of the AKI cohort was 67.8 years, and the mean age of the non-AKI cohort was 67.0 years. Most patients in the AKI and non-AKI cohorts were aged ≥ 65 years (63.2%), male (59.5%), living in urbanized areas (51.3% vs. 54.3%), and blue-collar workers (35.9% vs. 34.4%). The patients in the AKI cohort were more likely to have comorbidities and use BZD, non-BZD, and antipsychotic medications than those in the non-AKI cohort (P b 0.05). The mean follow-up time for PD was 6.89 (SD = 3.30) years in the AKI cohort and 6.78 (SD = 3.29) years in the non-AKI cohort. The cumulative incidence curves of PD showed that the AKI cohort had a significantly higher risk of PD than that of the non-AKI cohort (P b 0.001; log-rank test; Fig. 1). Table 2 demonstrated the incidence and hazard ratio for PD classified by various PD-associated risk factors. The overall incidence densities of PD were significantly higher in the AKI cohort than in the nonAKI cohort (6.04 vs. 3.99 per 1000 person-years), with an adjusted HR (aHR) of 1.47 (95% CI = 1.18–1.83; Table 2). Compared with patients who were ≤ 64 years old, the risk of PD was 8.08-fold higher in those aged 65–79 years (95% CI = 5.85–11.2) and was 8.91-fold higher in

those aged ≥80 years (95% CI = 6.33–12.5). Patients with AKI living in the third most urbanized area had a higher risk of PD compared with those living in the second most urbanized area (aHR = 1.30, 95% CI = 1.04–1.63). The risk of PD was higher for patients with hypertension (aHR = 1.45, 95% CI = 1.21–1.75), depression (aHR = 1.55, 95% CI = 1.20–2.02), bipolar disorder (aHR = 2.12, 95% CI = 1.03–4.36), and head injury (aHR = 1.33, 95% CI = 1.03–1.72). Antipsychotic medications (aHR = 1.38, 95% CI = 1.11–1.72) were also associated with PD. Table 3 showed Cox multivariate proportional hazards analysis of PD risk for AKI cohort and non-AKD cohort. AKI patients were 1.34-fold more likely to develop primary Parkinson's disease (95% CI = 1.02– 1.76) and 1.77-fold more likely to develop secondary Parkinson's disease (95% CI = 1.23–2.54) than the non-AKI cohort (Table 3). Agespecific analysis of the AKI and non-AKI cohorts showed that the aHR of PD was the highest for those 65–79 years of age (aHR = 1.49, 95% CI = 1.13–1.98). Gender-specific analysis showed that the aHR of PD was significant for both females (aHR = 1.56, 95% CI = 1.13–2.14) and males (aHR = 1.41, 95% CI = 1.05–1.90), but significance was higher for females, in a comparison of the AKI cohort with the nonAKI cohort. In a comparison of the AKI cohort with the non-AKI cohort, living in the third most urbanized area was associated with a significantly higher PD risk (aHR = 1.86, 95% CI = 1.18–2.94). The occupation-specific relative risk of PD for the AKI cohort relative to the

Table 3 Incidence of Parkinson's disease by age, sex, comorbidity and medications and Cox model measured hazards ratio for patients with acute kidney injury compared those without acute kidney injury. Acute kidney injury No

Yes

Variables

Event

PY

Rate#

Event

PY

Rate#

Crude HR⁎ (95% CI)

Adjusted HR& (95% CI)

Primary Parkinson's disease Secondary Parkinson's disease Age, years ≤64 65–79 80+ Sex Female Male Urbanization level& 1 (Highest urbanization) 2 3 4(Lowest urbanization) Occupation Housekeeping White collar Blue collar Others‡ Comorbidity$ No Yes Hypnotic medication Benzodiazepine No Yes Non-BZD No Yes Anti-psychotic medications No Yes

427 198

157729 157729

2.71 1.26

63 38

16,883 16,883

3.73 2.25

2.00(1.54, 2.59)*** 2.77(1.97, 3.88)***

1.34(1.02, 1.76)* 1.77(1.23, 2.54)**

35 375 219

67419 60396 29914

0.52 6.21 7.32

12 62 28

8752 5568 2563

1.37 11.1 10.9

2.67(1.39, 5.15)** 1.86(1.42, 2.44)*** 1.49(1.00, 2.21)*

1.77(0.88, 3.57) 1.49(1.13, 1.98)** 1.36(0.91, 2.04)

269 360

63802 93928

4.22 3.83

49 53

7349 9534

6.67 5.56

1.57(1.15, 2.13)** 1.44(1.08, 1.93)*

1.56(1.13, 2.14)** 1.41(1.05, 1.90)*

164 142 118 205

43732 42362 27355 44281

3.75 3.35 4.31 4.63

22 23 25 32

4620 4712 2800 4751

4.76 4.88 8.93 6.73

1.28(0.82, 2.00) 1.44(0.92, 2.23) 2.07(1.34, 3.19)** 1.43(0.98, 2.08)

1.21(0.76, 1.93) 1.42(0.90, 2.24) 1.86(1.18, 2.94)** 1.43(0.97, 2.10)

216 43 237 133

42137 36989 53871 24732

5.13 1.16 4.40 5.38

40 9 38 15

4636 3657 5882 2709

8.63 2.46 6.46 5.54

1.71(1.22, 2.40)** 2.10(1.02, 4.30)* 1.44(1.02, 2.03)* 1.04(0.61, 1.77)

1.64(1.15, 2.34)** 2.15(1.01, 4.60)* 1.38(0.97, 1.98) 1.10(0.64, 1.91)

92 537

64616 93114

1.42 5.77

5 97

3564 13,229

1.37 7.33

0.96(0.39, 2.35) 1.28(1.03, 1.58)*

1.65(0.67, 4.10) 1.52(1.22, 1.89)***

310 319

103493 54237

3.00 5.88

44 58

10,155 6728

4.33 8.62

1.44(1.05, 1.98)* 1.47(1.11, 1.95)**

1.36(0.98, 1.90) 1.53(1.15, 2.05)**

515 114

144293 13436

3.57 8.48

84 18

14,513 2370

5.79 7.60

1.62(1.29, 2.05)*** 0.89(0.54, 1.46)

1.60(1.26, 2.03)*** 1.01(0.61, 1.69)

534 95

146566 11163

3.64 8.51

81 21

15,128 1755

5.35 12.0

1.46(1.16, 1.85)** 1.41(0.88, 2.26)

1.46(1.14, 1.86)** 1.44(0.88, 2.36)

Rate#, incidence rate, per 1000 person-years; Crude HR, relative hazard ratio; Adjusted HR† : multivariable analysis including age, urbanization level, occupation and comorbidities of diabetes, hypertension, hyperlipidemia, anxiety, depression , bipolar disorder, head injury, stroke, and medications of benzodiazepine, non-benzodiazepine, and anti-psychotic; PY: per 1000 person years. Comorbidity$: Patients with any one of the comorbidities diabetes, hypertension, hyperlipidemia, anxiety, depression, bipolar disorder, head injury, and stroke, were classified as the comorbidity group. & : Urbanization level was categorized according to the population density of the residential area into 4 levels, with Level 1 the most urbanized and Level 4 the least urbanized. ‡ Other occupations included primarily retired, unemployed, or low income populations. *p b 0.05, **p b 0.01, ***p b 0.001.


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Table 4 Cox proportional hazards regression analysis for hazard ratio of Parkinson's disease-associated acute kidney injury with interaction of age, and hemodialysis. Variables Acute kidney injury

Age, year

No No No Yes Yes Yes

≤64 65–79 80+ ≤64 65–79 80+

Acute kidney injury

Temporary hemodialysis

No Yes Yes

No No Yes

N

Event

Rate#

Adjusted HR‡ (95% CI)

13,812 13,821 9851 3453 3453 2474

35 375 219 12 62 28

0.52 6.51 7.32 1.37 11.1 10.9

1(Reference) 9.42(6.61, 13.5)*** 10.7(7.36, 15.4)*** 2.17(1.12, 4.18)* 14.1(9.16, 21.8)*** 14.1(8.43, 23.6)***

37,484 7916 1464

629 94 8

3.99 6.15 4.97

1(Reference) 1.49(1.19, 1.86)*** 1.29(0.64, 2.62)

Rate#, incidence rate, per 1000 person-years; Crude HR, relative hazard ratio; Adjusted HR† : multivariable analysis including age, urbanization level, occupation and comorbidities of diabetes, hypertension, hyperlipidemia, anxiety, depression , bipolar disorder, head injury, stroke, and medications of benzodiazepine, non-benzodiazepine, and anti-psychotic; *p b 0.05, **p b 0.01, ***p b 0.001.

non-AKI cohort was significantly higher for housekeepers (aHR = 1.64, 95% CI = 1.15–2.34), and white collar workers (aHR = 2.15, 95% CI = 1.01–4.60). The aHR of PD was higher in the AKI cohort than in the non-AKI cohort in an analysis stratified by BZD use and the absence of non-BZD and antipsychotic use. To further evaluate the interactions between AKI and age and between AKI and temporary dialysis as well as their effect on PD development, the study subjects were classified into subgroups according to the presence or absence of individual parameters (Table 4). Compared with the patients in the non-AKI cohort aged ≤64 years, the relative risk (95% CI) of PD was 2.17 (1.12–4.18), 14.1 (9.16–21.8), and 14.1 (8.43–23.6) for the patients in the AKI cohort aged ≤ 64, 65–79, and ≥ 80 years, respectively. Compared with the patients in the non-AKI cohort not undergoing temporary dialysis, the relative risk (95% CI) of PD was 1.49 (1.19–1.86) for the patients in the AKI cohort not receiving temporary dialysis. The PD risk of the patients in the AKI cohort undergoing temporary dialysis was not significantly higher compared with that of the patients in the non-AKI cohort not receiving temporary dialysis (aHR = 1.29, 95% CI = 0.64–2.62).

4. Discussion This population-based cohort study revealed that AKI was associated with a 1.47-fold increased risk of PD, which is higher than the values obtained for previously identified risk factors of PD, including a 1.33-fold increased risk associated with head injury, a 1.38-fold increased risk associated with antipsychotic agent use, and a 1.45-fold increased risk associated with hypertension. PD is significantly more common in the ESRD population than in the non-ESRD population [9]. However, whether recovery from AKI has consequences on neurodegeneration remains unclear. Because this study excluded patients with CKD or ESRD before the diagnosis of PD, this study clearly demonstrated that AKI cohort had significantly higher risk of primary PD and secondary PD, compared with non-AKI cohort. Our finding suggests that AKI contributes to long-term degeneration of dopaminergic neurons in the substantia nigra. The possible pathogenic mechanism involves a burst of oxidative stress, hyperhomocysteinemia, inflammatory chemokines, and toxic metabolite leakage through a disrupted blood–brain barrier during an episode of AKI [26–29]. These pathogenic factors can directly cause the death of dopaminergic neurons in the substantia nigra. Alternatively, these factors can indirectly make dopaminergic neurons vulnerable to other harmful environmental toxins. These direct and indirect accumulating insults induce mitochondrial impairment, oxidative stress, proteasome dysregulation, and protein mishandling, thereby causing dysfunction and death

of neurons [30,31]. As prominent cell death of nigral dopaminergic neurons occurs with time, the symptoms of PD begin [32,33]. Age is the significantly strongest independent risk factor for PD, especially vascular PD [34]. After adjusting those traditional cardiovascular risk factors and stroke, our data revealed that people with AKI aged ≤64, 65–79, and ≥80 years had a higher PD risk compared with those without AKI in the same age category. While sub classified PD into primary PD and secondary PD, AKI cohorts had both significantly higher risk of the primary PD and secondary PD. Taken these results together, our data suggest there is an additive effect of AKI on aging in PD development, and the mechanism is complex which would encompass vascular changes in the brain and other neurodegenerative pathways. In patients aged ≥80 years with AKI, the PD risk is up to 14.1-fold higher compared with the risk of those without AKI aged ≤ 64. Thus far, PD treatment has entailed reducing the related symptoms, and no therapy can cure or slow the progression of PD [35]. Therefore, the effective strategy for reducing the burden of PD involves lessening any controllable and avoidable risk factors. We propose that lessening AKI episodes is a workable approach to reducing the risk of PD. In this study, AKI patients who did not require temporary dialysis had a higher PD risk compared with AKI patients requiring temporary dialysis. There are several explanations for this finding. First, patients with CKD and ESRD have a higher chance of developing PD. To alleviate such bias from CKD and ESRD, we excluded patients who developed CKD or ESRD subsequent to AKI before the diagnosis of PD. Among the excluded AKI patients, the proportion of those requiring dialysis, the rates of CKD and ESRD [36], and the risk of PD development are likely higher. Thus, the PD risk of this temporary dialysis AKI cohort may have been underestimated. Second, temporary dialysis reduces the burden of uremic metabolites and oxidative stress in patients with AKI. Thus, the remote hazard effects of AKI on dopaminergic CNS neurons are minimized after temporary dialysis in patients with AKI. This study has several limitations. First, information regarding the levels of creatinine, blood urea nitrogen, and blood pressure and the severity of AKI was not available in the claims dataset. Second, we have no detailed information on factors associated with the development of PD such as the family history of PD, environmental toxin exposure, diet preference, and smoking habits. Although we did not have any detailed information on these variables directly associated with PD risk, we believe that we controlled for most of the confounding variables for PD, including age, sex, occupation, urbanization, schizophrenia, bipolar disorder, anxiety, depression, antipsychotic agent use, hypnotic use, and head injury. In addition, the majority of PD cases are sporadic, whereas the prevalence of inherited PD is less than 10% [37]. AKI was significantly independent from these risk variables for subsequent PD.

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Our current study revealed that AKI was associated with an increased risk of PD, and the impact was similar to those of known risk factors of PD, including head injury, antipsychotic agent use, and hypertension. Elderly patients with AKI had the highest risk of PD (up to 14.1-fold). Preventing AKI episodes is an effective public health strategy for reducing the long-term PD risk. Physicians, particularly geriatrists, caring for elderly patients with AKI, even those who have recovered renal function, should keep this association in mind. Health care initiatives are required to closely monitor the appearance of early PD symptoms and to provide appropriate medications and education at the beginning of PD, because PD impairs patients' ability of self-care and quality of life, and increases mortality and morbidity. Author contributions All authors have contributed significantly, and all authors are in agreement with the content of the manuscript. Conception/Design: Shih-Yi Lin, Chun-Hung Tseng; Provision of study materials: Chun-Hung Tseng; Collection and/or assembly of data: All authors; Data analysis and interpretation: All authors; Manuscript writing: All authors; Final approval of manuscript: All authors. Conflict of interest All authors report no conflicts of interest. Acknowledgment This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW105TDU-B-212-133019), China Medical University Hospital, Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10501010037), NRPB Stroke Clinical Trial Consortium (MOST 104-2325-B-039-005), Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation, Taipei, Taiwan, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan; and CMU under the Aim for Top University Plan of the Ministry of Education, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. References [1] Lesage S, Brice A. Parkinson's disease: from monogenic forms to genetic susceptibility factors. Hum Mol Genet 2009;18:R48–59. [2] Khoo TK, Yarnall AJ, Duncan GW, Coleman S, O'Brien JT, Brooks DJ, et al. The spectrum of nonmotor symptoms in early Parkinson disease. Neurology 2013;80: 276–81. [3] Williams-Gray CH, Mason SL, Evans JR, Foltynie T, Brayne C, Robbins TW, et al. The CamPaIGN study of Parkinson's disease: 10-year outlook in an incident population-based cohort. J Neurol Neurosurg Psychiatry 2013;84:1258–64. [4] Lutz W, Sanderson W, Scherbov S. The coming acceleration of global population ageing. Nature 2008;451:716–9. [5] Dexter DT, Jenner P. Parkinson disease: from pathology to molecular disease mechanisms. Free Radic Biol Med 2013;62:132–44. [6] Schapira AH, Jenner P. Etiology and pathogenesis of Parkinson's disease. Mov Disord 2011;26:1049–55. [7] Sun Y, Chang YH, Chen HF, Su YH, Su HF, Li CY. Risk of Parkinson disease onset in patients with diabetes a 9-year population-based cohort study with age and sex stratifications. Diabetes Care 2012;35:1047–9. [8] Alonso A, Huang X, Mosley TH, Heiss G, Chen H. Heart rate variability and the risk of Parkinson disease: the atherosclerosis risk in communities study. Ann Neurol 2015; 77:877–83.

[9] Wang IK, Lin CL, Wu YY, Chou CY, Lin SY, Liu JH, et al. Increased risk of Parkinson's disease in patients with end-stage renal disease: a retrospective cohort study. Neuroepidemiology 2014;42:204–10. [10] Lee YC, Lin CH, Wu RM, Lin JW, Chang CH, Lai MS. Antihypertensive agents and risk of Parkinson's disease: a nationwide cohort study. PLoS One 2014;9, e98961. [11] Lin HL, Lin HC, Chen YH. Psychiatric diseases predated the occurrence of Parkinson disease: a retrospective cohort study. Ann Epidemiol 2014;24:206–13. [12] Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16:3365–70. [13] Lameire NH, Bagga A, Cruz D, De Maeseneer J, Endre Z, Kellum JA, et al. Acute kidney injury: an increasing global concern. Lancet 2013;382:170–9. [14] Coca SG, Yusuf B, Shlipak MG, Garg AX, Parikh CR. Long-term risk of mortality and other adverse outcomes after acute kidney injury: a systematic review and metaanalysis. Am J Kidney Dis 2009;53:961–73. [15] James MT, Ghali WA, Knudtson ML, Ravani P, Tonelli M, Faris P, et al. Associations between acute kidney injury and cardiovascular and renal outcomes after coronary angiography. Circulation 2011;123:409–16. [16] Liu M, Liang Y, Chigurupati S, Lathia JD, Pletnikov M, Sun Z, et al. Acute kidney injury leads to inflammation and functional changes in the brain. J Am Soc Nephrol 2008; 19:1360–70. [17] Wu VC, Wu PC, Wu CH, Huang TM, Chang CH, Tsai PR, et al. The impact of acute kidney injury on the long-term risk of stroke. J Am Heart Assoc 2014;3(4). [18] Sung CC, Lin CS, Lin SH, Lin CL, Jhang KM, Kao CH. Pyogenic liver abscess is associated with increased risk of acute kidney injury: a Nationwide population-based cohort study. Medicine 2016;95, e2489. [19] Lai TS, Wang CY, Pan SC, Huang TM, Lin MC, Lai CF, et al. Risk of developing severe sepsis after acute kidney injury: a population-based cohort study. Crit Care 2013; 17:R231. [20] Lai CY, Chou MC, Lin CL, Kao CH. Increased risk of Parkinson disease in patients with carbon monoxide intoxication: a population-based cohort study. Medicine 2015;94, e869. [21] Huang HC, Tsai CH, Muo CH, Lin KH, Lu MK, Sung FC, et al. Risk of Parkinson's disease following zolpidem use: a retrospective, population-based cohort study. J Clin Psychiatry 2015;76:e104–10. [22] database NHI. Background. Secondary background; 2015. [23] Shen TC, Lin CL, Wei CC, Chen CH, Tu CY, Hsia TC, et al. Bidirectional association between asthma and irritable bowel syndrome: two population-based retrospective cohort studies. PLoS One 2016;11, e0153911. [24] Lin SY, Lin CL, Chang YJ, Hsu WH, Lin CC, Wang IK, et al. Association between kidney stones and risk of stroke: a nationwide population-based cohort study. Medicine 2016;95, e2847. [25] Tu YF, Lin CL, Lin CH, Huang CC, Sung FC, Kao CH. Febrile convulsions increase risk of Tourette syndrome. Seizure 2014;23:651–6. [26] Himmelfarb J, McMonagle E, Freedman S, Klenzak J, McMenamin E, Le P, et al. Oxidative stress is increased in critically ill patients with acute renal failure. J Am Soc Nephrol 2004;15:2449–56. [27] Wei Q, Xiao X, Fogle P, Dong Z. Changes in metabolic profiles during acute kidney injury and recovery following ischemia/reperfusion. PLoS One 2014;9, e106647. [28] Sun J, Shannon M, Ando Y, Schnackenberg LK, Khan NA, Portilla D, et al. Serum metabolomic profiles from patients with acute kidney injury: a pilot study. J Chromatogr B Analyt Technol Biomed Life Sci 2012;893–894:107–13. [29] Grigoryev DN, Liu M, Hassoun HT, Cheadle C, Barnes KC, Rabb H. The local and systemic inflammatory transcriptome after acute kidney injury. J Am Soc Nephrol 2008; 19:547–58. [30] Greenamyre JT, Hastings TG. Parkinson's—divergent causes, convergent mechanisms. Science 2004;304:1120–2. [31] Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 2006;443:787–95. [32] Hirsch E, Graybiel AM, Agid YA. Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature 1988;334:345–8. [33] McCormack AL, Thiruchelvam M, Manning-Bog AB, Thiffault C, Langston JW, CorySlechta DA, et al. Environmental risk factors and Parkinson's disease: selective degeneration of nigral dopaminergic neurons caused by the herbicide paraquat. Neurobiol Dis 2002;10:119–27. [34] Reeve A, Simcox E, Turnbull D. Ageing and Parkinson's disease: why is advancing age the biggest risk factor? Ageing Res Rev 2014;14:19–30. [35] Connolly BS, Lang AE. Pharmacological treatment of parkinson disease: a review. JAMA 2014;311:1670–83. [36] Coca SG, Singanamala S, Parikh CR. Chronic kidney disease after acute kidney injury: a systematic review and meta-analysis. Kidney Int 2012;81:442–8. [37] Warner TT, Schapira AH. Genetic and environmental factors in the cause of Parkinson's disease. Ann Neurol 2003;53:S16–25.