Part Ⅰ： Kidney Disease And Risk Of Dementia: A Danish Nationwide Cohort Study
Apr 10, 2023
Abstract
Objectives
It is currently unclear whether kidney disease is a risk factor for dementia. We investigated the relationship between kidney disease and the risk of future dementia.
Design and setting
Danish National Historical Register Cohort Study, based on data from January 1, 1995, to December 31, 2016.
Participants
All patients diagnosed with kidney disease and a matched general population cohort without kidney disease (age, sex, and year of kidney disease diagnosis matched 1:5).
Primary and secondary outcome measures
All-cause dementia and its subtypes: Alzheimer's disease, vascular dementia, and other specific or unspecified dementias. We used Cox regression analysis to calculate the 5-year cumulative incidence (risk) and hazard ratios (HRs) for the outcomes.
Results
The study cohort included 82,690 patients with kidney disease and 413,405 individuals from the general population. The 5- and 10-year mortality rates were twice as high in patients with kidney disease as in the general population. The 5-year risk of all-cause dementia was 2.90% (95% confidence interval: 2.78% to 3.08%) in patients with kidney disease and 2.98% (2.92% to 3.04%) in the general population. Compared with the general population, corrected HRs for all-cause dementia in patients with kidney disease were 1.06 (1.00 to 1.12) during the 5-year follow-up and 1.08 (1.03 to 1.12) over the entire study period. Risk estimates for dementia subtypes varied widely, with lower estimates for Alzheimer's disease and higher estimates for vascular dementia.
Conclusions
Patients diagnosed with kidney disease have a slightly increased incidence of dementia, primarily caused by vascular dementia. In addition, patients with kidney disease may not be diagnosed with dementia due to high mortality and other prioritized comorbidities.
Keywords
Kidney disease; dementia; Cistanche supplements.
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Introduction
Dementia is a common, progressive age-related neurological disorder diagnosed when acquired cognitive impairment is severe enough to impair social and/or occupational functioning Although the incidence of dementia has declined slightly over the past 30 years, the prevalence of dementia is on the rise globally, likely due to increased life expectancy This imposes significant costs on affected individuals and families, as well as on healthcare and society.
Kidney disease is another disease with a high (nearly 10%) and increasing prevalence, partly due to the aging of the population and the increasing incidence of hypertension and diabetes.
Kidney disease and dementia share common risk factors such as aging, hypertension, diabetes, hyperlipidemia, and the pathophysiology of small vessel disease. A potential link between kidney disease and dementia may be the common susceptibility of kidney and brain tissue to vascular injury kidney disease is associated with oxidative stress, chronic inflammation, and altered coagulation, and may also affect the brain or cerebral vasculature indirectly or directly through metabolic disturbances and uremic toxins.
A previous population-based study in Taiwan found a hazard ratio (HR) of 1.41 for all-cause dementia in patients diagnosed with kidney disease (N=37049) compared to the general population (N=74098. However, these findings may not apply to European populations and the Taiwanese study did not examine potential differences between dementia subtypes. Furthermore, in previous studies defining renal disease as persistent proteinuria or an estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m2, different results were reported. Therefore, it is uncertain whether renal disease is associated with the risk of dementia. We investigated all-cause dementia and dementia subtypes (Alzheimer's disease, vascular dementia, and other dementias) in a national cohort study.
Methods
We followed the Guidelines for Enhancing the Reporting of Observational Epidemiologic Studies on Epidemiologic Cohort Studies.
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Study cohort
During the study period from January 1, 1995, to December 31, 2016, we conducted a nationwide cohort study including all Danish hospital-diagnosed patients with kidney disease and a matched general population comparison cohort without kidney disease.
The flow chart of the study cohort is shown in Figure 1. During the study period, we identified 122,670 patients with a first diagnosis of kidney disease. Next, we excluded patients who died (N=32196) or did not live in Denmark (N=465) within one year after the diagnosis of renal disease. Further exclusion criteria were a diagnosis of dementia (N=1909) and prodromal symptoms of dementia, i.e. mild cognitive impairment and amnesic syndrome (N=303) prior to the diagnosis of renal disease. In addition, we excluded patients diagnosed with dementia (N=1300) and prodromal symptoms of dementia (N=156) within one year of the diagnosis of renal disease, as a diagnosis of dementia during this period is unlikely to be a consequence of renal disease. Finally, we limited the cohort to adult patients aged 18 years and older. The remaining 82,690 patients comprised our renal disease cohort. For each patient in the kidney disease cohort, 5 individuals from the general population without a kidney disease diagnosis prior to the index date were randomly selected and matched on the basis of age (year of birth), sex, and calendar year of the index date (i.e., date of kidney disease diagnosis). Matching was performed as individual matching to replace the general population comparison cohort consisting of 413,405 patients who did not have dementia, mild cognitive impairment, amnesic syndrome, or renal disease prior to study entry.
Figure 1:Flow chart of the study. individuals in the cohort of patients who developed kidney disease during 1995-2016 and the matched general population comparison cohort.
Diagnoses
Diagnoses of renal disease (exposure), dementia (outcome), mild cognitive impairment, amnesic syndrome, and covariates were based on diagnoses obtained from the Danish National Patient Registry and/or the Danish Central Research Registry of Psychiatry. These registries covered all hospitals in Denmark and recorded hospital admissions since 1977 and 1969, respectively, and outpatient specialist visits since 1995. We used all primary and secondary discharge diagnoses for all inpatient and outpatient visits but excluded emergency room visits (because diagnoses in such cases may be tentative and therefore less valid). Diagnoses were determined according to the World Health Organization's International Classification of Diseases, Revision 8 (ICD-8), until the end of 1993, followed by Revision 10 (ICD-10). We used the date of hospitalization or the start of outpatient follow-up as the date of all diagnoses.
Kidney disease
In the primary analysis, we used an expanded definition of kidney disease that included chronic kidney disease as well as several other persistent kidney diseases, dialysis treatment, and kidney transplantation. Importantly, this extended definition of renal disease did not include acute and/or potentially reversible kidney injury. In sensitivity analyses, we used only chronic kidney disease (limited to ICD-8 792 and ICD-10 N18) as the exposure for all-cause dementia. Kidney Disease Improving Overall Prognosis (KDIGO) defines chronic kidney as persistent (3 months) eGFR 60 mL/min/1.73 m2 or renal impairment, usually determined by the presence of proteinuria.
Dementia
The validity of all-cause dementia was high, with a positive predictive value of 86% of dementia subtypes registered in Denmark being mutually exclusive, and we used only the first coded dementia subtype: Alzheimer's disease, vascular dementia, and other (specified or unspecified) dementia, the latter constituting the majority of dementia diagnoses. Because approximately one-third of other unspecified dementia cases may be attributable to Alzheimer's disease,19 we also included the combined outcome of Alzheimer's disease and other dementias.
Covariates
We included cardiovascular disease (CVD), CVD risk factors, (any) cancer, and socioeconomic status as potential confounders because of their association with kidney disease and dementia. All covariates were assessed prior to study entry. the CVD covariates were angina pectoris, myocardial infarction, stroke, peripheral arterial disease, venous thromboembolism, heart failure, heart valve disease, and atrial fibrillation. The covariates associated with CVD risk factors were hypercholesterolemia, hypertension, obesity, diabetes mellitus, and chronic obstructive pulmonary disease (smoking.) CVD risk factors were based on diagnoses from the Danish National Patient Registry, in addition to prescriptions for lipid-lowering and anti-hypertensive drugs from the Danish National Prescription Registry, which contains detailed individual data on all outpatient prescriptions since 1995.
The covariates associated with socioeconomic status are highest educational attainment, total personal income, and employment status, which were obtained from the Labor Market Research Comprehensive Database established in 1981. Educational attainment is categorized as low (elementary school only), medium (high school and/or college professional degree), and high (bachelor's, master's, or higher degree). Total personal income is categorized by quartiles. Employment status was categorized as employed, retired, and unemployed. We used employment status 12-24 months prior to entry into the study because employment status in the year prior to the diagnosis of kidney disease may underestimate peak employment status.
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Statistical analysis
We compared the cumulative incidence of death (risk) and all-cause dementia (taking into account competing risks of death) in the renal disease and comparison cohorts. HRs for all-cause dementia and dementia subtypes and their corresponding 95% CIs were calculated using Cox regression analysis using the study time as the time scale. proportional risk assumptions were graphically tested by log-log plots, and no violations were detected. In the unadjusted Cox model, age, sex, and calendar year of index date have been controlled for, as these were the matching criteria. However, to account for the matching method, matches could not be fully retained due to built-in selection bias, so the adjusted Cox model included age, gender, and calendar year of the index date, as well as other potential confounders. Participants with missing values (1% of total personal income and 11% of employment status and education level) were excluded from the adjusted analysis. 1 year from the index date until December 31, 2016 diagnosis of dementia or screening, immigration, or death, whichever came first. The minimum follow-up period was 1 year and the maximum was 22 years. Because all diagnoses and life and immigration status were registered in the National Registry, we had no loss of follow-up. We performed predefined stratified analyses for age (18-49, 50-59, 60-74, 75-84, and 85 years), sex, index date calendar year (1995-2003 or 2004-2016), cardiovascular disease, cardiovascular disease risk factors, socioeconomic factors, and duration of follow-up (1-5, 1-10, and 1-22 years).
Finally, to assess whether all-cause dementia risk was associated with kidney disease severity, we stratified the kidney disease cohort according to the presence or absence of kidney failure. All analyses were performed using SAS V.9.4 (SAS Institute).
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Alisa D Kjaergaard 1,2. Benjamin R Johannesen 2. Henrik T Sørensen 2,3. Victor W Henderson 2,4. Christian F Christiansen 2
1. Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark
2. Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
3. Excellence Research Center, Stanford University, Stanford, California, USA
4. Departments of Epidemiology and Population Health and of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA
