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Figure.
Flow Diagram Showing Cohort Assembly of Enrolled Patients Undergoing Hemodialysis
Flow Diagram Showing Cohort Assembly of Enrolled Patients Undergoing Hemodialysis
Table 1.  
Characteristics of Patients Undergoing Incident Hemodialysis Who Subsequently Developed Retinal Artery Occlusion (RAO) or Retinal Vein Occlusion (RVO) and Patients Undergoing Hemodialysis Without Ocular Disorders (WODs)
Characteristics of Patients Undergoing Incident Hemodialysis Who Subsequently Developed Retinal Artery Occlusion (RAO) or Retinal Vein Occlusion (RVO) and Patients Undergoing Hemodialysis Without Ocular Disorders (WODs)
Table 2.  
Cox Proportional Hazards Model for Mortality Among Patients Undergoing Incident Hemodialysis Who Subsequently Developed Retinal Artery Occlusion (RAO) or Retinal Vein Occlusion (RVO) and Patients Undergoing Hemodialysis Without Ocular Disorders (WODs)a
Cox Proportional Hazards Model for Mortality Among Patients Undergoing Incident Hemodialysis Who Subsequently Developed Retinal Artery Occlusion (RAO) or Retinal Vein Occlusion (RVO) and Patients Undergoing Hemodialysis Without Ocular Disorders (WODs)a
Table 3.  
Competing Risk Regression Model for Cerebrovascular Diseases in Patients Undergoing Incident Hemodialysis Who Subsequently Developed Retinal Artery Occlusion (RAO) or Retinal Vein Occlusion (RVO) and Patients Undergoing Hemodialysis Without Ocular Disorders (WODs)a
Competing Risk Regression Model for Cerebrovascular Diseases in Patients Undergoing Incident Hemodialysis Who Subsequently Developed Retinal Artery Occlusion (RAO) or Retinal Vein Occlusion (RVO) and Patients Undergoing Hemodialysis Without Ocular Disorders (WODs)a
Table 4.  
Competing Risk Regression Model for Cardiovascular Diseases in Patients Undergoing Incident Hemodialysis Who Subsequently Developed Retinal Artery Occlusion (RAO) or Retinal Vein Occlusion (RVO) and Patients Undergoing Hemodialysis Without Ocular Disorders (WODs)a
Competing Risk Regression Model for Cardiovascular Diseases in Patients Undergoing Incident Hemodialysis Who Subsequently Developed Retinal Artery Occlusion (RAO) or Retinal Vein Occlusion (RVO) and Patients Undergoing Hemodialysis Without Ocular Disorders (WODs)a
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Original Investigation
February 2016

Risk of Mortality and of Atherosclerotic Events Among Patients Who Underwent Hemodialysis and Subsequently Developed Retinal Vascular OcclusionA Taiwanese Retrospective Cohort Study

Author Affiliations
  • 1Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
  • 2Division of Nephrology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
  • 3Division of Nephrology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
  • 4Division of Nephrology, Department of Internal Medicine, Taipei Tzu Chi Hospital, Taipei, Taiwan
  • 5Division of Nephrology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
  • 6Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
JAMA Ophthalmol. 2016;134(2):196-203. doi:10.1001/jamaophthalmol.2015.5052
Abstract

Importance  Retinal vascular occlusion is considered a risk factor for cardiovascular diseases in the general population. However, the long-term outcomes of patients who undergo incident hemodialysis and subsequently develop retinal vascular occlusion have not been examined.

Objective  To determine the mortality rate and subsequent prevalence of systemic vascular diseases associated with retinal vascular occlusion among patients undergoing hemodialysis in Taiwan.

Design, Setting, and Participants  Data from the Taiwan National Health Institutes research database were used, and we identified 105 956 patients undergoing hemodialysis during the period from January 1997 to December 2008. In total, 113 patients with retinal artery occlusion and 463 patients with retinal vein occlusion were enrolled and matched for age, sex, and the duration of hemodialysis (at a 1:5 ratio) with patients without ocular disorders.

Main Outcomes and Measures  Mortality and atherosclerotic events. A multivariate Cox regression model for mortality and a competing risk regression model for atherosclerotic events were used for this population-based retrospective cohort study.

Results  Of 113 patients with retinal artery occlusion and 463 patients with retinal vein occlusion, 66 (58.4%) and 245 (52.9%) were females, respectively (ranging in age from ≤40 to 80 years). Our study showed there was a significant risk of mortality among patients undergoing hemodialysis who subsequently developed retinal artery occlusion or retinal vein occlusion compared with patients undergoing hemodialysis without ocular disorders. Patients with retinal artery occlusion had higher risks of ischemic stroke (adjusted hazard ratio [HR], 3.35 [95% CI, 2.00-5.59]; P < .001), coronary artery disease (adjusted HR, 1.70 [95% CI, 1.23-2.36]; P = .001), acute coronary syndrome (adjusted HR, 2.03 [95% CI, 1.24-3.33]; P = .002), and peripheral arterial occlusive disease (adjusted HR, 2.15 [95% CI, 1.26-3.66]; P = .002) than did patients without ocular disorders. Patients with retinal vein occlusion had higher risks of hemorrhagic stroke (adjusted HR, 2.54 [95% CI, 1.50-4.30]; P = .001), coronary artery disease (adjusted HR, 1.55 [95% CI, 1.31-1.83]; P < .001), and acute coronary syndrome (adjusted HR, 1.53 [95% CI, 1.14-2.06]; P = .002) than did patients without ocular disorders.

Conclusions and Relevance  Our data demonstrate that the risks of mortality and atherosclerotic events were increased among patients undergoing incident hemodialysis who subsequently developed retinal vascular occlusion.

Introduction

Patients undergoing hemodialysis often develop ocular disorders that may be due to underlying diseases, a poor uremic status, iatrogenic complications of hemodialysis, poor fluid homeostasis, or elevated calcium-phosphate products.1 Typical manifestations of ocular disorders in these patients include increased intraocular pressure, scratchy red eyes, band keratopathy, and retinal ischemia.2 Retinal ischemia can lead to serious deterioration of vision and a reduced quality of life, so it is important to understand the causes of these conditions in patients undergoing hemodialysis.

Recent studies35 indicated that chronic kidney disease is strongly associated with retinopathies, even in the absence of diabetes mellitus. Furthermore, the multicenter Chronic Renal Insufficiency Cohort study6 suggested that microvascular retinopathy can increase the risk of cardiovascular diseases (CVDs) in patients with chronic kidney disease who are not undergoing dialysis treatment. In addition, some studies79 showed that the presence of retinal vascular occlusion was associated with the progression of CVDs in the general population. Taken together, these studies39 show that retinal vascular occlusion may be considered a predisposed risk for progression of CVDs in the general population.

Taiwan has the highest incidence and prevalence of patients undergoing hemodialysis in the world.10,11 The Taiwan National Health Insurance (NHI) program has provided compulsory universal health insurance since 1995, and almost all citizens are enrolled in the program, so the data from this program make it ideal for longitudinal cohort studies.1217 Recently, the existence of retinal vascular diseases, such as retinal artery occlusion (RAO) and retinal vein occlusion (RVO), were reported in several studies7,9,18,19 to increase the risk of CVDs in the general population. According to those studies,7,9,18,19 retinal vascular occlusion may predispose one to CVDs. However, the long-term outcomes of patients undergoing incident hemodialysis who subsequently develop RAO or RVO have not been investigated to date. Thus, we used the NHI research database during the period from 1997 to 2008 to examine subsequent outcomes of RAO or RVO among patients undergoing incident hemodialysis and the effects of these outcomes on mortality and the incidences of hemorrhagic stroke, ischemic stroke, coronary artery disease (CAD), acute coronary syndrome (ACS), and peripheral arterial occlusive disease (PAOD).

Box Section Ref ID

At a Glance

  • Retinal vascular occlusion is considered a risk factor for cardiovascular diseases in the general population.

  • However, the long-term outcomes of patients who undergo incident hemodialysis and subsequently develop retinal vascular occlusion have not been examined.

  • Our data demonstrate that the risks of mortality and atherosclerotic events were increased among patients who underwent incident hemodialysis and subsequently developed retinal vascular occlusion.

Methods
Data Sources

All data were from the NHI research database, which is produced by the Taiwan National Health Research Institute. The NHI program has provided compulsory universal health insurance since 1995, and more than 99% of the citizens of Taiwan are enrolled. This database provides clinical data for population-based longitudinal cohort investigations in Taiwan. All dialysis patients with catastrophic illness registration cards are enrolled in the NHI program because it provides free dialysis treatment. The NHI research database is one of the highest-quality databases of its kind in the world and has been widely used for longitudinal cohort studies,1217,20 including our previous reports.1517,20

All data in the NHI research database are encrypted to protect the privacy of individuals. The database provides the patient identification number; birth date; sex; names of medical institutions where care was given; diagnostic codes according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM); prescription use; procedure codes; health care costs; dates of admission and discharge; date of death; outpatient and inpatient claims data; and related information. All data sets can be interlinked through each individual’s unique identification number.

Study Cohort and Patient Selection

Our study received prior approval from the Ethics Committee and Human Subjects institutional review board of Tzu Chi Hospital in Hualien, Taiwan (institutional review board number 101-126). Informed consent was waived because the data were deidentified. A total of 105 956 patients who received dialysis between January 1, 1997, and December 31, 2008, were initially enrolled in our study (Figure). Patients were excluded if they had received dialysis for less than 3 months (n = 9078), had received a renal transplant before or after initiation of dialysis (n = 3248), had received peritoneal dialysis rather than hemodialysis (n = 1711), or had both RAO and RVO (n = 713). The 91 206 remaining patients undergoing hemodialysis for whom follow-up data were available were assigned to 1 of 2 groups: 59 059 case patients with ocular disorders (ICD-9-CM codes 360-379, which include retinal disorders, glaucoma, cataract, cornea disorders, conjunctiva disorders, disorders of refraction and accommodation, and visual disturbances) and 32 147 control patients without ocular disorders.

Finally, the case and control patients were enrolled in a 1:5 ratio, matched by age and sex, and then compared in the following 3 ways: (1) 113 patients with RAO were compared with a first group of 565 patients without ocular disorders, (2) 463 patients with RVO were compared with a second group of 2315 patients without ocular disorders, and (3) the 113 patients with RAO were compared with the 463 patients with RVO (Figure). The index date was defined as the onset date of RAO or RVO. The study time of follow-up began from the onset date of RAO or RVO. To avoid confounding from the effect of hemodialysis, each control patient in each group of patients without ocular disorders was matched with a case patient in the RAO or RVO group who had the same duration of hemodialysis between the initiation of hemodialysis and the onset date of RAO or RVO. For example, the 2 groups of patients without ocular disorders are matched by duration of hemodialysis (defined as the time from the initiation of hemodialysis to the onset date of RAO or RVO among patients undergoing hemodialysis with retinal vascular occlusion) and then followed up. If the enrolled case patient had 1 year of hemodialysis and experienced an atherosclerotic event 2 years after RAO or RVO diagnosis, then the follow-up for a patient without ocular disorders would begin 1 year after initiation of hemodialysis to match the duration of hemodialysis between the initiation of hemodialysis and the index date (ie, the control patients without ocular disorders were followed up for 3 years after initiation of hemodialysis).

Outcomes Measures

The study end points were mortality and atherosclerotic events, including ischemic stroke, hemorrhagic stroke, CAD (defined as acute myocardial infarction, old myocardial infarction, angina pectoris, subacute ischemic heart disease, and chronic ischemic heart disease), ACS (defined as acute myocardial infarction and subacute ischemic heart disease), and PAOD.

ICD-9-CM Codes

The ICD-9-CM codes and prescription use are interlinked by patient identification numbers in the NHI databases. Dialysis patients were defined as those who had catastrophic illness registration cards for end-stage renal disease (ICD-9-CM code 585) and received hemodialysis or peritoneal dialysis for more than 3 months of renal replacement therapy. The ICD-9-CM codes for study patients were as follows: ocular disorders (codes 36X.X-37X.X), RAO (codes 362.31-362.34), and RVO (codes 362.35-362.37). The ICD-9-CM codes of traditional risk factors for CVDs were as follows: diabetes mellitus (codes 250-250.3 and 250.7), hypertension (codes 401.X-405.X, 437.2, and 362.11), and hyperlipidemia (code 272.X). The ICD-9-CM codes of the end points were as follows: acute myocardial infarction (codes 410-410.9), other acute and subacute forms of ischemic heart disease (code 411), old myocardial infarction (code 412), angina pectoris (code 413), other forms of chronic ischemic heart disease (code 414), hemorrhagic stroke (codes 430-432.X), ischemic stroke (codes 433.X-438.X), and PAOD (codes 440-444, 447, 451-453, and 557). The definition and analyzed measurement of the Charlson comorbidity index (CCI) were derived from Charlson et al,21 whose index is commonly used to analyze the effect of comorbidities on mortality.22

Statistical Analysis

Patient demographic data included age, sex, duration of hemodialysis, hypertension, hyperlipidemia, diabetes, and the CCI score. Age was entered as a categorical variable (≤40, 41-50, 51-60, 61-70, and 71-80 years). A χ2 test was used to compare the differences in demographic characteristics between the groups. A Cox proportional hazards model was used to assess the adjusted hazard ratio (HR) and 95% CI of mortality. With respect to the outcomes of cerebrovascular diseases and CVDs, the frameworks of competing risk models were conducted since we censored individuals who died before the event happened or before the end of the study observation period (December 31, 2008). SAS statistical software (SAS System for Windows, version 9.3; SAS Institute Inc) was used for the statistical analysis. All statistical tests were 2-sided, and P < .003 (ie, 0.05/18 = 0.0027) was considered statistically significant for a total of 18 comparisons of outcome measures based on the Bonferroni multiple-adjustment method.

Results

Table 1 presents the clinical and demographic characteristics of all 3 groups of patients undergoing hemodialysis. Patients with RAO or RVO had higher CCI scores than did the control patients without ocular disorders. Furthermore, the percentages of patients with hyperlipidemia, diabetes with or without complications, and congestive heart failure were higher in the group of 113 patients with RAO than in the first group of 565 patients without ocular disorders. The 463 patients with RVO were associated with higher percentages of hypertension, hyperlipidemia, congestive heart failure, peptic ulcers, chronic pulmonary disease, and liver disease than were the second group of 2315 patients without ocular disorders. Compared with the group of 463 patients with RVO, the group of 113 patients with RAO had higher percentages of old patients and patients with hyperlipidemia and diabetes with or without subsequent complications and higher CCI scores.

Table 2 shows the results of the multivariate Cox proportional analysis of mortality. After adjusting for age, sex, duration of hemodialysis, hypertension, hyperlipidemia, diabetes, and CCI score, we found that both the patients undergoing hemodialysis with RAO and the patients undergoing hemodialysis with RVO were associated with higher mortality than were the patients undergoing hemodialysis in the 2 groups without ocular disorders (adjusted HR of 2.46 [95% CI, 1.70-3.55]; P < .001 and 2.79 [95% CI, 2.23-3.48]; P < .001, respectively). Higher CCI scores resulted in greater risk of mortality regardless of vascular occlusion in the comparisons of patients with RAO vs patients without ocular disorders and patients with RVO vs patients without ocular disorders. In addition, both RVO status and a duration of hemodialysis of more than 3 years significantly increased mortality risk between the group of patients with RVO and the second group of patients without ocular disorders. Moreover, the adjusted HRs for mortality (among patients with RAO vs patients without ocular disorders and among patients with RVO vs patients without ocular disorders) by calendar year are shown in eTable in the Supplement.

Table 3 shows the results of the competing risk regression model for ischemic stroke and hemorrhagic stroke. The 113 patients with RAO had a higher risk for ischemic stroke than did the first group of 565 patients without ocular disorders (adjusted HR, 3.35 [95% CI, 2.00-5.59]; P < .001). The 463 patients with RVO had a higher risk of hemorrhagic stroke than did the second group of 2315 patients without ocular disorders (adjusted HR, 2.54 [95% CI, 1.50-4.30]; P = .001).

Table 4 presents the results of the competing risk regression model for major CVDs (CAD, ACS, and PAOD). Both the patients undergoing hemodialysis with RAO and the patients undergoing hemodialysis with RVO had a significantly increased risk of CAD (adjusted HR of 1.70 [95% CI, 1.23-2.36] P = .001 and 1.55 [95% CI, 1.31-1.83]; P < .001, respectively) compared with the 2 groups of patients undergoing hemodialysis without ocular disorders. Both the patients undergoing hemodialysis with RAO and the patients undergoing hemodialysis with RVO had a significantly increased risk of ACS (adjusted HR of 2.03 [95% CI, 1.24-3.33]; P = .002 and 1.53 [95% CI, 1.14-2.06]; P = .002, respectively) compared with the 2 groups of patients undergoing hemodialysis without ocular disorders. Compared with the first group of patients without ocular disorders, the patients with RAO had a significantly increased risk for PAOD (adjusted HR, 2.15 [95% CI, 1.26-3.66]; P = .002).

Discussion

The long-term outcomes of patients undergoing incident hemodialysis with RAO or RVO are unknown. Our study examines the long-term outcomes of patients undergoing incident hemodialysis with RAO or RVO using the Taiwan NHI research database. After multivariate adjustment, the major findings of our study were that (1) patients undergoing hemodialysis with RAO had significantly higher risks of mortality, ischemic stroke, CAD, ACS, and PAOD than did patients undergoing hemodialysis without ocular disorders and (2) patients undergoing hemodialysis with RVO had significantly higher risks of mortality, hemorrhagic stroke, CAD, and ACS than did patients undergoing hemodialysis without ocular disorders.

Mortality among patients with RAO or RVO has rarely been investigated and has yet to be clarified. For example, in the general population, a cross-sectional study23 showed that the survival of 151 patients with RAO did not significantly differ from that of an age- and sex-matched group of patients without RAO (P = . 29). However, a population-based cohort study24 of 1 784 960 patients older than 70 years of age showed that elderly patients with RVO had a significantly higher risk of all-cause mortality (adjusted HR, 1.09 [95% CI, 1.02-1.17]). In our population-based longitudinal cohort, the analysis of survival indicated that the risks of mortality among patients undergoing hemodialysis were related to the risks of mortality among patients with RAO and also patients with RVO. The reason may be because the risks of RAO and RVO are also the risks of cerebrovascular diseases and CVDs, and thus they are associated with higher mortality among patients undergoing hemodialysis.

Previous studies25,26 of general populations demonstrated that patients with RAO were positively associated with risk of ischemic stroke. For example, analysis of the data of 1 million randomly selected beneficiaries among Taiwan’s 23 million residents indicated that patients with RAO had a higher percentage of ischemic strokes (19.6%) than did controls (10.1%) during a 3-year follow-up period (P < .001).25 Furthermore, the results of our longitudinal study demonstrated that patients undergoing hemodialysis with RAO have a higher risk of ischemic stroke.

Our study showed that patients undergoing hemodialysis with RVO had a higher risk of hemorrhagic stroke than did patients undergoing hemodialysis without ocular disorders. An animal study26 demonstrated that RVO (which causes subsequent retinal hemorrhage) and hemorrhagic cerebral infarct were related because of their similar pathogeneses of arteriolar flow insufficiency and the stress that was placed on the longstanding capillaropathy, which precedes the hemorrhagic phase of these diseases.

Our results showed that the presence of RAO increased the risk of CVDs (such as CAD, ACS, and PAOD) in patients undergoing hemodialysis. This result is consistent with the results of studies7,9 in general populations, indicating that RAO is a predictor of CVDs. Previous studies7,9,27 of general populations showed a high prevalence of CVDs in patients with RAO, and indicated that RAO increased the risk for systemic vascular disease. Similarly, our study showed that the patients undergoing hemodialysis with RVO had higher risks of CAD and ACS. Some previous studies18,28 also showed that CAD was more prevalent with RVO in the general population.

The main strength of our study is that the NHI research database is one of the largest and most reliable databases of its kind reported in the literature.1417,2932 Nevertheless, there are some limitations to our study. First, the NHI research database protects patients’ privacy, and therefore we were unable to obtain information on body weight, educational level, occupation, physical activity, personal lifestyle, use of tobacco and alcohol, and family history. Second, laboratory data could not be obtained, and so we did not know the adequacy of dialysis and did not have basic biochemical data. Third, the cause of death was not available from the NHI research database; therefore, we could not compare the cause of death between patients with and patients without retinal vascular occlusion.

Conclusions

Our analysis of the Taiwan NHI research database indicated that patients undergoing hemodialysis with RAO had increased risks of mortality, ischemic stroke, CAD, ACS, and PAOD compared with patients undergoing hemodialysis without ocular disorders. Compared with the patients undergoing hemodialysis without ocular disorders, the patients undergoing hemodialysis with RVO had significantly increased risks of mortality, hemorrhagic stroke, CAD, and ACS. Our nationwide cohort study reports that the risks of mortality and atherosclerotic events were increased among patients undergoing incident hemodialysis who subsequently developed retinal vascular occlusion. Thus, it is mandatory to pay attention to the mortality rate and the number of atherosclerotic events among patients undergoing incident hemodialysis who subsequently developed retinal vascular occlusion.

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Article Information

Submitted for Publication: July 27, 2015; final revision received October 10, 2015; accepted October 18, 2015.

Corresponding Author: Te-Chao Fang, MD, PhD, Division of Nephrology, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, 111, Section 3, Hsing-Long Road, Taipei 116, Taiwan (fangtechao@yahoo.com.tw).

Published Online: December 17, 2015. doi:10.1001/jamaophthalmol.2015.5052.

Author Contributions: Drs Hsieh and Fang had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Fang.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Hsieh, Chou, Kuo, Lai, Lin, Fang.

Critical revision of the manuscript for important intellectual content: Hsieh, Chou, Chen, Y.-C. Wang, C.-H. Wang, Fang.

Statistical analysis: Hsieh.

Obtained funding: Fang.

Administrative, technical, or material support: C.-H. Wang.

Study supervision: Fang.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This study was supported by grant TCRD 101-12 from Tzu Chi General Hospital in Hualien, Taiwan.

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The interpretations and conclusions contained herein do not represent those of the Bureau of NHI, the Department of Health, or the National Health Research Institutes.

Previous Presentation: This paper was presented at the Annual Meeting of the Taiwan Society of Nephrology; December 7, 2013; Taipei, Taiwan.

Additional Information: This study was based in part on data from the NHI research database, which is provided by the Bureau of NHI and the Department of Health and managed by the National Health Research Institutes.

References
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