Abstract
Rationale & Objective
Acute kidney injury (AKI) causes biochemical changes in the brain in animal models and is associated with adverse neurological complications in hospitalized patients. The objective of this study was to test the association between AKI and incident dementia in a community-based cohort.
Study Design
Prospective cohort study.
Setting & Participants
Adult participants in the Atherosclerosis Risk in Communities study who experienced hospitalized AKI, compared to participants with hospitalization for other reason (primary analysis, mean follow-up 4.3 years) or participants without hospitalized AKI (secondary analysis).
Predictors
Incident AKI, defined by ICD codes from hospital records.
Outcome
Incident dementia, diagnosed based on a combination of neurocognitive testing, informant interviews, ICD codes, and death certificates.
Analytical Approach
In the primary analysis, we estimated the propensity for hospitalized AKI and matched these participants to those hospitalized for another reason to examine the association of AKI with subsequent onset of dementia (N=1708). In secondary analysis, we estimated the association between time-varying hospitalized AKI and subsequent onset of dementia using multivariable Cox proportional hazards regression models, adjusted for age, sex, race/center, education, smoking status, BMI, baseline estimated glomerular filtration rate (eGFR), baseline urine albumin-to-creatinine ratio (ACR), systolic blood pressure, coronary heart disease (CHD), diabetes, hypertension, Apolipoprotein E (APOE) ε4 genotype, and C-reactive protein (CRP).
Results
Mean (SD) age in the propensity-matched cohort was 76.1 (6.5) years and 53.2% of participants were women. People who were hospitalized with AKI had a higher risk of dementia (HR: 1.25, 95% CI: 1.02–1.52, p=0.03) compared to those without a hospitalization for AKI. Associations were slightly stronger in the time-varying analysis (HR: 1.69, 95% CI: 1.48–1.92, p<0.001). Other risk factors for dementia included older age, male sex, higher albuminuria, diabetes, current smoker status, and presence of the APOE risk alleles.
Limitations
Observational study, with AKI identified through diagnosis codes.
Conclusions
Participants who experienced a hospitalization for AKI were at increased risk of dementia.
PLAIN LANGUAGE SUMMARY
Dementia is a major public health concern in the United States. While there is no known cure, early detection remains one of the most important factors in positive outcomes for both patients and families. Acute kidney injury (AKI) is a common condition that may impair the function of other organs, such as the brain. Using data from a community-based cohort of participants enrolled in the Atherosclerosis Risk in Communities study, we found that participants with hospitalizations for AKI were at higher risk of dementia than those without such hospitalizations.
INTRODUCTION
Dementia is a major public health concern in the United States. In 2020, over 5 million Americans had Alzheimer’s disease and other related dementias, a figure expected to more than double by 2050.1 In 2020, care for patients with dementia cost the U.S. $305 billion; by mid-century, costs could be as high as $1.1 trillion.2 Identifying risk factors for dementia is important in order to target high-risk patients and provide earlier diagnosis. Early diagnosis may benefit patients and their families by motivating risk factor modification and, when treatments become available, early intervention.3 Some potentially actionable risk factors for dementia include hearing loss, hypertension, diabetes, physical inactivity, heavy alcohol consumption, and smoking.4
Acute kidney injury (AKI) is a common condition that may impair distant organ function, including that of the brain. Animal models have demonstrated that renal ischemia increases levels of cytokines and chemokines in the brain, leading to dysfunction of coagulation pathways and atherogenic processes.5,6 Accumulation of cytokines may initiate inflammatory responses that disrupt the blood-brain barrier.7 Additionally, AKI may result in increased retention of neurotoxins, many of which are shown to lead to cognitive impairment.8 Studies have also examined how neurotransmitters may play a role. In animal models, bilateral renal ischemia reperfusion injury was associated with a decrease in dopamine turnover, as well as a decrease in motor activity.9
Previous clinical studies suggest that AKI may be associated with higher risk of developing dementia, even in those who have undergone complete renal recovery. One propensity-score matched cohort suggested a three-fold higher risk of dementia among patients with a history of AKI.10 Another study based in Taiwan found that participants with dialysis-requiring AKI had twice the risk of developing dementia (HR: 2.01, 95% CI: 1.19–3.39, p=0.01) compared to a healthy control group.11 The Atherosclerosis Risk in Communities study provides a unique opportunity to expand upon these results with carefully collected markers of kidney function, availability of APOE genotype, active follow-up for AKI, and rigorous assessment of cognitive function and dementia development. Additionally, 21% of the study population is African American, thereby enhancing the diversity of previously studied populations. Using this community-based cohort, we tested the hypothesis that hospitalization with AKI was associated with increased risk of incident dementia, independent of APOE genotype and other dementia risk factors.
METHODS
Study Population
The Atherosclerosis Risk in Communities Study (ARIC) is a prospective cohort study with 15792 participants, ages 45 to 64 years, from four U.S. communities (Washington County, MD; Forsyth County, NC; Jackson, MS; and suburban Minneapolis, MN). The Washington County and Minneapolis centers included primarily White participants (>99% for both centers); the Jackson site included only Black participants; and the Forsyth County site included both Black and White participants. Thus, because of small sample size at the Washington County and Minneapolis centers, Black participants from these sites were excluded along with participants who were neither Black nor White. The first study visit took place in 1987–1989 with follow-up visits in 1990–1992 (Visit 2), 1993–1995 (Visit 3), 1996–1998 (Visit 4), 2011–2013 (Visit 5), 2016–2017 (Visit 6), 2018–2019 (Visit 7), and 2020 (Visit 8).12 For inclusion in the current study, we required follow-up for AKI and dementia from Visit 4 and no previous history of stroke, AKI, end-stage kidney disease, or dementia, as well as measures for estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (ACR) at Visit 4. There were 11,074 eligible participants who were followed until December 31, 2019 (Figure S1). This study was approved by the institutional review boards at the study sites, and all participants gave written informed consent.
Exposure: AKI
Vital status and intervening hospitalizations for ARIC participants were determined by semi-annual telephone follow-up and through active, ongoing surveillance of community hospital discharge lists, local newspaper obituaries, state death lists, and death certificates. International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) or Tenth Revision, Clinical Modification (ICD-10-CM) codes were recorded from hospital discharge billing or death certificate.13 Incident AKI was defined by codes 584.5 to 584.9 in ICD-9-CM and codes N17.0 to 17.9 in ICD-10-CM.
Outcome: Incident Dementia
The primary outcome was onset of dementia, defined using the ARIC Neurocognitive Study validated definition which combines data from multiple sources.12 Dementia was actively ascertained using ICD codes from hospitalizations and death certificates, as well as a cognitive assessment administered at Visit 4 and more detailed assessments performed in-person or by telephone at Visit 5 (2011–2013), Visit 6 (2016–2017), and Visit 7 (2018–2019).
The cognitive assessment administered at Visit 4 included three tests evaluating memory, learning ability, psychomotor performance, and other cognitive skills. The in-person cognitive assessments at Visits 5, 6, and 7 were administered as part of the ARIC Neurocognitive Study. For these assessments, trained nurses and other personnel evaluated each participant through a series of examinations, interviews, and questionnaires. Detailed descriptions of the assessments performed at Visits 4, 5, 6, and 7 are included in Item S1. The visit-based definition of dementia is described in Item S2. For those who could not be seen in person, an instrument that can be used during phone visits to ascertain cognitive status called the modified (TICS-m) was administered.
Covariates
Most covariates used in the models were assessed at Visit 4 baseline, except for education, which was assessed at Visit 1. The covariates included the following: age (years), sex, race/center (White, Forsyth County; Black, Forsyth County; Black, Jackson; White, Minneapolis; White, Washington County), education level (less than high school, high school graduate or GED, beyond high school), smoking status (current smoker, former smoker, never smoked), BMI (kg/m2), eGFR (mL/min/1.73m2, estimated using the CKD-EPI 2021 equation), log-transformed urine albumin-to-creatinine ratio (μg/mg), systolic and diastolic blood pressure (mmHg), coronary heart disease (defined as self-reported prevalent CHD at Visit 1 or any of the following occurring before Visit 4 as adjudicated by ARIC physicians: hospitalized MI, cardiac procedure, or ECG MI), diabetes (defined as fasting glucose level ≥ 126 mg/dL after a ≥ 8 hourfast or non-fasting glucose level ≥ 200 mg/dL, self-reported diagnosis of diabetes by a physician, or use of medication for diabetes/high blood sugar), hypertension (defined as ≥ 140 mmHg with averaged 1st and 2nd systolic BP readings and ≥ 90 mmHg averaged 1st and 2nd diastolic BP readings, or use of medication for high blood pressure), APOE genotype (0, 1, or 2 ε4 alleles), and C-reactive protein (mg/L). For the propensity matched cohort, covariates for age, stroke, CHD, diabetes, hypertension, atrial fibrillation, and age were updated to the time of hospitalization.
Statistical Analysis
All statistical analyses were performed using Stata Version 15 (StataCorp LLC, College Station, TX, USA). Continuous variables were described using mean and standard deviation and compared across groups using t-tests. For categorical variables, chi-squared tests were used.
In the primary analysis, we compared the risk of incident dementia in a propensity-matched cohort of participants who had a hospitalization with AKI and participants who had hospitalizations without an AKI diagnosis. Propensity scores for AKI hospitalization were constructed using age, sex, race, number of previous hospitalizations since Visit 4, smoking status, CHD, atrial fibrillation, diabetes, hypertension, stroke, eGFR, urine albumin-to-creatinine ratio, systolic and diastolic blood pressures, C-reactive protein, and APOE genotype for each hospitalization for all participants. Participants who were free of dementia were considered for matching with any hospitalization without AKI until their first AKI hospitalization. In other words, a participant with an AKI hospitalization in a later time point could be matched to an AKI participant at an earlier time point. Matching was performed using a caliper of 0.0001. Only the first AKI hospitalization with a suitable match (e.g., non-AKI hospitalization with a propensity score within the designated caliper) were included. Cause-specific hazard ratios were estimated for AKI hospitalization compared with hospitalization for another cause using Cox proportional hazard models without accounting for matching.14 Time at risk for both groups started at the time of the matched hospitalization and continued until dementia, death, administrative censoring (December 31, 2019), or withdrawal from the study. Cumulative incidence curves were plotted accounting for the competing risk of death. Analyses were also repeated using death as the outcome of interest.
In secondary analysis, we evaluated risk from Visit 4, treating AKI as a time-varying covariate. Multivariable Cox proportional hazard regression models were used to determine the cause-specific hazard ratios (HRs) in order to quantify the association between time-varying AKI and incident dementia, as well as to detail additional independent risk factors for dementia. Evaluated covariates included the demographics, BMI, systolic and diastolic blood pressure, eGFR, albuminuria, CHD, diabetes, C-reactive protein, hypertension, education, smoking status, and APOE genotype. Time at risk began at Visit 4 and continued until incident dementia, death, administrative censoring (December 31, 2019), or withdrawal from the study.
RESULTS
Participant Characteristics
Among the 11074 study participants, the mean (SD) age was 62.8 (5.7) years at visit 4. Over half (56.2%) of participants were female and 21.6% of participants were Black. The average eGFR among the participants was 88.0 (14.8) mL/min per 1.73 m2, and the median urine albumin-to-creatinine ratio was 3.7 (IQR: 1.8–7.7) mg/g. Overall, 1297 (11.7%) had chronic kidney disease (CKD), as defined by either eGFR < 60 mL/min/1.73 m2 or ACR > 30 mg/g (Table S1). In total, there were 1411 cases of AKI in patients without a history of diagnosed dementia, 2458 cases of incident dementia, and 5,365 deaths over a mean follow-up of 17.4 years. Propensity-matching found suitable matches for 854 AKI cases. All covariates were well balanced between the cases and controls (Figure 1).
Figure 1:
Covariate balance before and after propensity matching.
Participant characteristics in the propensity-score matched cohort at the time of AKI or corresponding matched hospitalization reflected the time between Visit 4 and hospitalization: average age was 76.1 (6.5) years (Table 1). There were 993 deaths and 392 cases of dementia over a follow-up of 4.3 years. The most common primary reason for hospitalization for the control participants by ICD codes were ischemic heart disease (5.6%), osteoarthrosis (4.9%), cardiac dysrhythmia (4.6%), pneumonia (4.5%), and myocardial infarction (2.6%).
Table 1.
Characteristics of propensity-score matched cohort.
| Variable | Overall | No AKI | AKI | SMD |
|---|---|---|---|---|
| N | 1708 | 854 | 854 | |
| Age, years (SD) | 76.1 (6.5) | 76.3 (6.4) | 76.0 (6.6) | −4 |
| Female, n (%) | 908 (53.2%) | 454 (53.2%) | 454 (53.2%) | 0 |
| Black, n (%) | 294 (17.2%) | 147 (17.2%) | 147 (17.2%) | 0 |
| Body Mass Index, kg/m2 (SD) | 29.4 (6.0) | 28.8 (5.9) | 30.0 (6.0) | 20 |
| Systolic Blood Pressure, mmHg (SD) | 129.4 (19.3) | 128.9 (19.0) | 129.9 (19.6) | 5 |
| Diastolic Blood Pressure, mmHg (SD) | 70.5 (10.6) | 70.4 (10.6) | 70.7 (10.6) | 3 |
| Urine Albumin-to-Creatinine Ratio, mg/g (SD) | 4.3 (1.8 – 9.7) | 4.2 (1.8 – 9.6) | 4.4 (1.9 – 10.0) | 10 |
| eGFR, mL/min/1.73 m2 (SD) | 86.1 (16.5) | 86.7 (15.4) | 85.6 (17.4) | −7 |
| C-Reactive Protein, mg/L (SD) | 5.0 (6.4) | 4.8 (6.9) | 5.3 (5.9) | 7 |
| Prevalent Coronary Heart Disease, n (%) | 519 (30.4%) | 258 (30.2%) | 261 (30.6%) | 1 |
| Hypertension, n (%) | 740 (43.4%) | 361 (42.3%) | 379 (44.4%) | 5 |
| Diabetes, n (%) | 606 (35.5%) | 285 (33.4%) | 321 (37.6%) | 9 |
| eGFR < 60 mL/min/1.73 m^2, n (%) | 146 (8.5%) | 62 (7.3%) | 84 (9.8%) | 9 |
| ACR > 30 mg/g, n (%) | 202 (11.8%) | 91 (10.7%) | 111 (13.0%) | 7 |
| Chronic Kidney Disease, n (%) | 303 (17.7%) | 138 (16.2%) | 165 (19.3%) | 8 |
| Apolipoprotein E ε4 Genotype | ||||
| TT, 0 Risk Alleles, n (%) | 1251 (73.2%) | 625 (73.2%) | 626 (73.3%) | 0 |
| CT, 1 Risk Allele, n (%) | 421 (24.6%) | 214 (25.1%) | 207 (24.2%) | −2 |
| CC, 2 Risk Alleles, n (%) | 36 (2.1%) | 15 (1.8%) | 21 (2.5%) | 5 |
| Smoking Status | ||||
| Current Smoker, n (%) | 350 (20.5%) | 175 (20.5%) | 175 (20.5%) | 0 |
| Former Smoker, n (%) | 966 (56.6%) | 483 (56.6%) | 483 (56.6%) | 0 |
| Never Smoked, n (%) | 1316 (77.0%) | 658 (77.0%) | 658 (77.0%) | 0 |
| Education Level | ||||
| Education Level < High School, n (%) | 355 (20.8%) | 167 (19.6%) | 188 (22.0%) | −4 |
| Education Level = High School or GED, n (%) | 738 (43.2%) | 378 (44.3%) | 360 (42.2%) | −1 |
| Education Level > High School, n (%) | 615 (36.0%) | 309 (36.2%) | 306 (35.8%) |
Association of AKI with Incident Dementia
The cumulative incidence of dementia was 31.6% at 10 years in the propensity-matched cohort; the cumulative incidence of death (including death after dementia) over the same time period was 68.3%. Participants hospitalized for AKI had a 25% higher risk of dementia (cause-specific HR: 1.25, 95% CI: 1.02–1.52, p=0.03) than participants hospitalized for another reason (Figure 2). Participants hospitalized for AKI also had a 40% higher risk of death (HR: 1.40, 95% CI: 1.24–1.59, p<0.001).
Figure 2:
Cumulative incidence for dementia among patients with and without AKI hospitalization in the propensity-matched analysis. Analysis time 0 is the time of hospitalization.
Association Between AKI and Dementia when Accounting for AKI as a Time-Varying Risk Factor
In the 11,704 participants followed for AKI and dementia from visit 4, an episode of AKI also conferred higher risk of subsequent dementia (Table 2). In the fully adjusted model accounting for AKI as a time-varying exposure, participants with AKI had a 69% higher risk of dementia (HR: 1.69, 95% CI: 1.48–1.92, p<0.001) compared to those who did not. APOE genotype status was also a strong risk factor for dementia. For participants with one ε4 risk allele, the hazard of dementia was 1.85 (95% CI: 1.69–2.02, p<0.001) and in participants with two ε4 risk alleles, the hazard was 4.26 (95% CI: 3.54–5.14, p<0.001), compared to those with no risk alleles. Other risk factors included older age ((HR: 1.16, 95% CI: 1.15–1.17, p<0.001) per year older)), higher albumin/creatinine ratio ((HR: 1.17, 95% CI: 1.09–1.27, p<0.001) per ten-fold increase), the presence of diabetes (HR: 1.33, 95% CI: 1.19–1.50, p<0.001), and current smoker status (HR: 1.42, 95% CI: 1.24–1.63, p<0.001). Higher education level was protective (HR: 0.81, 95% CI: 0.76–0.86, p<0.001).
Table 2.
Risk factors for incident dementia: fully adjusted Cox regression model.
| Variable | Fully Adjusted HR (95% CI) | p-value | Demographics Adjusted HR (95% CI) | p-value | Unadjusted HR (95% CI) | p-value |
|---|---|---|---|---|---|---|
| AKI | 1.69 (1.48 – 1.92) | <0.001 | 1.95 (1.73 – 2.20) | <0.001 | 2.31 (2.05 – 2.61) | <0.001 |
| Age, years | 1.16 (1.15 – 1.17) | <0.001 | 1.16 (1.15 – 1.17) | <0.001 | ||
| Female | 0.89 (0.81 – 0.98) | 0.014 | 0.94 (0.87 – 1.02) | 0.140 | ||
| White participants, Forsyth Co. | ||||||
| White participants, Minneapolis | 0.99 (0.87 – 1.12) | 0.838 | 0.99 (0.88 – 1.11) | 0.848 | ||
| White participants, Washington Co. | 1.03 (0.91 – 1.16) | 0.648 | 1.13 (1.01 – 1.27) | 0.033 | ||
| Black participants, Forsyth Co. | 1.12 (0.83 – 1.51) | 0.461 | 1.32 (0.99 – 1.76) | 0.056 | ||
| Black participants, Jackson | 1.46 (1.26 – 1.68) | <0.001 | 1.90 (1.69 – 2.14) | <0.001 | ||
| BMI, per 5 kg/m2 | 1.01 (0.97 – 1.05) | 0.724 | ||||
| Systolic Blood Pressure. per 10 mmHg | 1.03 (1.00 – 1.07) | 0.035 | ||||
| Diastolic Blood Pressure. per 10 mmHg | 0.96 (0.91 – 1.01) | 0.096 | ||||
| Estimated Glomerular Filtration Rate (eGFR), per 10 ml/min/1.73m2 | 1.01 (0.98 – 1.04) | 0.598 | ||||
| log10 (Albumin/Creatinine Ratio, ug/mg) | 1.17 (1.09 – 1.27) | <0.001 | ||||
| Coronary Heart Disease (CHD) | 1.14 (0.97 – 1.34) | 0.121 | ||||
| Diabetes (Fasting Glucose Level >= 126 mg/dl) | 1.33 (1.19 – 1.50) | <0.001 | ||||
| C-reactive protein (CRP), mg/l | 1.01 (1.01 – 1.02) | <0.001 | ||||
| Hypertension | 1.07 (0.96 – 1.18) | 0.230 | ||||
| Education Level | 0.81 (0.76 – 0.86) | <0.001 | ||||
| Never Smoker | reference | |||||
| Former Smoker | 0.94 (0.85 – 1.03) | 0.159 | ||||
| Current Smoker | 1.42 (1.24 – 1.63) | <0.001 | ||||
| APOE genotype CT (0 Risk Alleles) | reference | |||||
| APOE genotype CT (1 Risk Allele) | 1.85 (1.69 – 2.02) | <0.001 | ||||
| APOE genotype CT (2 Risk Alleles) | 4.26 (3.54 – 5.14) | <0.001 |
DISCUSSION
Understanding the long-term consequences of AKI and the potential risk factors for dementia is vital in the context of public health. In this study of participants from the ARIC study, we observed that a hospitalization with AKI was associated with a higher risk of developing dementia. Associations were consistent when propensity-matching participants with an AKI hospitalization to those with another type of hospitalization and when evaluating AKI as a time-varying covariate. Other risk factors for dementia were older age, higher albumin/creatinine ratio, diabetes, lower education level, current smoker status, and APOE genotype. Associations also remained consistent when incorporating the risk of death and when using a propensity-matching strategy to identify a control group. This study suggests that persons hospitalized for AKI may constitute a high-risk population that warrants greater monitoring with the hope that early diagnosis may lead to better outcomes.
The current study expands upon the existing literature on the association between AKI and dementia. In a study of 1041 primarily white patients who recovered from AKI and matched with controls, those with a history of recovered AKI had a three-fold higher risk of developing dementia (HR: 3.4, 95% CI: 2.14–5.40), and 1.6-fold risk after accounting for the competing risk of death.10 A Taiwanese study involving 2905 participants with a history of AKI requiring dialysis followed by full recovery found that those who had AKI had twice the risk of developing dementia (HR: 2.01, 95% CI: 1.19–.39, p=0.01).11 The current study confirms these associations using a research cohort that actively followed participants for hospitalizations and onset of dementia using a validated definition.
The relationship between AKI and dementia may reflect shared risk factors, such as vascular dysfunction, or a causal role of AKI in dementia development. While the mechanisms are not yet well-understood, AKI has known effects on the central nervous system and other distant organs. In animal models, AKI causes changes in the brain, including decreased dopamine turnover, alterations in the blood-brain barrier, and increased levels of cytokines.15 In humans, AKI has been shown to cause central nervous system dysfunction with effects such as irritability, attention deficits, hyperreflexia, postural tremor, decreased mental status, seizures, and death. Recent papers suggest that oxidative stress may also play a role.16 Further, and similar to CKD, AKI may cause accumulation of prescribed medications due to decreased renal clearance, which may have cognitive impact. Other kidney-associated mechanisms may include impaired cerebral blood flow, suppressed lymphatic clearance of neurotoxins, or alkaline phosphatase-promoted binding of tau to receptors in the hippocampus.17
In considering our results, it is important to note the strengths and limitations of the study. The propensity score matched population was relatively small and relied on ICD codes for AKI, which may have identified individuals with greater severity of AKI. The time-varying analysis was limited by the length of time between Visit 4 and Visit 5, which may have resulted in missed dementia cases that did not require hospitalization. Notwithstanding these limitations, the study also has several strengths. The main strength is the large population-based sample from the ARIC study, with representation from four communities of Black and White individuals. Additionally, the study has a long observation period with 20 years of follow-up with carefully collected data on cognitive function. As a research cohort, clinical characteristics are collected in a standardized manner, including that of eGFR and albuminuria, with the latter being an important risk factor for both AKI and dementia.18 ARIC also provides characterization by APOE genotype, a known risk factor for Alzheimer’s disease.
Our findings add to existing literature regarding the complex outcomes of AKI in the long-term. The study demonstrates that there is an increased risk of dementia in patients with AKI-related hospitalizations and may suggest that patients recovering from AKI constitute a high-risk population that should be closely monitored for cognitive impairment.
Supplementary Material
Item S1: Cognitive tests performed at each visit.
Item S2: Dementia definition.
Table S1. Characteristics of study participants at Visit 4 baseline (1996–1998) stratified by AKI status at the end of follow-up.
Figure S1: Flow diagram of study participants starting at Visit 4 baseline (1996–1998).
Support:
The Atherosclerosis Risk in Communities Study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I and HHSN268201700004I). Neurocognitive data were collected with support by grants U01 2U01HL096812, 2U01HL096814, 2U01HL096899, 2U01HL096902, 2U01HL096917 from the National Institutes of Health (National Heart, Lung, and Blood Institute, with support from the National Institute of Neurological Disorders and Stroke, National Institute on Aging, and National Institute on Deafness and Other Communication Disorders) and with previous brain MRI examinations funded by R01-HL70825 from the National Heart, Lung, and Blood Institute. MG is supported by K24HL155861 and R01DK124399. The funders did not play a role in study design, data collection, analysis, reporting, or the decision to submit for publication.
Footnotes
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Financial Disclosure: MG declares that she has no other relevant financial interests. The other authors declare that they have no relevant financial interests.
REFERENCES
- 1.Olivari BS, French ME, McGuire LC. The Public Health Road Map to Respond to the Growing Dementia Crisis. Innov Aging. 2020;4(1):igz043. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Alzheimer’s Association. 2020 Alzheimer’s Disease Facts and Figures. Alzheimers Dement; 2020;16(3):391–460. [Google Scholar]
- 3.Rasmussen J, Langerman H. Alzheimer’s Disease - Why We Need Early Diagnosis. Degener Neurol Neuromuscul Dis. 2019;9:123–130. Published 2019. Dec 24. doi: 10.2147/DNND.S228939 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet. 2020;396(10248):413–446. doi: 10.1016/S0140-6736(20)30367-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Liu M, Liang Y, Chigurupati S, Lathia JD, Pletnikov M, Sun Z, Crow M, Ross CA, Mattson MP, Rabb H. Acute kidney injury leads to inflammation and functional changes in the brain. J Am Soc Nephrol. (7):1360–1370 2008. MED: 18385426 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Wilson CJ, Finch CE, Cohen HJ. Cytokines and cognition--the case for a head-to-toe inflammatory paradigm. J Am Geriatr Soc. 2002;50(12):2041–2056. doi: 10.1046/j.1532-5415.2002.50619.x [DOI] [PubMed] [Google Scholar]
- 7.Malek M Brain consequences of acute kidney injury: Focusing on the hippocampus. Kidney Res Clin Pract. 2018;37(4):315–322. doi: 10.23876/j.krcp.18.0056 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Vanholder R, Pletinck A, Schepers E, Glorieux G. Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update. Toxins (Basel). 2018;10(1):33. Published 2018. Jan 8. doi: 10.3390/toxins10010033 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Adachi N, Lei B, Deshpande G, et al. Uraemia suppresses central dopaminergic metabolism and impairs motor activity in rats. Intensive Care Med. 2001;27(10):1655–1660. doi: 10.1007/s001340101067 [DOI] [PubMed] [Google Scholar]
- 10.Kendrick J, Holmen J, Srinivas T, You Z, Chonchol M, Jovanovich A. Acute Kidney Injury Is Associated With an Increased Risk of Dementia. Kidney Int Rep. 2019;4(10):1491–1493. Published 2019. Jul 27. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Kao CC, Wu CH, Lai CF, et al. Long-term risk of dementia following acute kidney injury: A population-based study. Ci Ji Yi Xue Za Zhi. 2017;29(4):201–207. doi: 10.4103/tcmj.tcmj_40_17 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Knopman DS, Gottesman RF, Sharrett AR, et al. Mild Cognitive Impairment and Dementia Prevalence: The Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS). Alzheimers Dement (Amst). 2016;2:1–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Grams ME, Waikar SS, MacMahon B, Whelton S, Ballew SH, Coresh J. Performance and limitations of administrative data in the identification of AKI. Clin J Am Soc Nephrol. 2014;9(4):682–689. doi: 10.2215/CJN.07650713 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Stuart EA. Matching methods for causal inference: A review and a look forward. Stat Sci. 2010;25(1):1–21. doi: 10.1214/09-STS313 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Grams ME, Rabb H. The distant organ effects of acute kidney injury. Kidney Int. 2012;81:942–948. [DOI] [PubMed] [Google Scholar]
- 16.Tanaka S, Okusa MD. Crosstalk between the nervous system and the kidney. Kidney Int. 2020;97(3):466–476. doi: 10.1016/j.kint.2019.10.032 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Viggiano D, Wagner CA, Martino G, et al. Mechanisms of cognitive dysfunction in CKD. Nat Rev Nephrol. 2020;16(8):452–469. doi: 10.1038/s41581-020-0266-9 [DOI] [PubMed] [Google Scholar]
- 18.Scheppach JB, Coresh J, Wu A, et al. Albuminuria and Estimated GFR as Risk Factors for Dementia in Midlife and Older Age: Findings From the ARIC Study. Am J Kidney Dis. 2020;76(6):775–783. doi: 10.1053/j.ajkd.2020.03.015 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Schneider AL, Sharrett AR, Gottesman RF, et al. Normative data for 8 neuropsychological tests in older blacks and whites from the atherosclerosis risk in communities (ARIC) study. Alzheimer Dis Assoc Disord. 2015;29(1):32–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–198. [DOI] [PubMed] [Google Scholar]
- 21.Wilkinson GS. Wide Range Achievement Test 3–administration manual. Wilmington, DE: Jastak Associates;1993. [Google Scholar]
- 22.Atherosclerosis Risk in Communities Study. Collaborative Studies Coordinating Center Home and Field Center Procedures Manual 2. ARIC Visit 5 and NCS Study Protocol. https://sites.cscc.unc.edu/aric/sites/default/files/public/manuals/Manual%202%20Home%20and%20Field%20Center%20Procedures.pdf. Accessed July 28, 2021. [Google Scholar]
- 23.Wechsler D Wechsler Adult Intelligence Scale Revised Manual. Psychological Corp, 1981. [Google Scholar]
- 24.Kaplan E, Goodglass H, Weintraub S. The Boston Naming Test. Lea & Febiger; Philadelphia: 1983. [Google Scholar]
- 25.Weintraub S, Salmon D, Mercaldo N, et al. The Alzheimer’s Disease Centers’ Uniform Data Set (UDS): the neuropsychologic test battery. Alzheimer Dis Assoc Disord. 2009;23(2):91–101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Morris JC. Clinical dementia rating: a reliable and valid diagnostic and staging measure for dementia of the Alzheimer type. Int Psychogeriatr. 1997;9 Suppl 1:173–178. [DOI] [PubMed] [Google Scholar]
- 27.Pfeffer RI, Kurosaki TT, Harrah CH Jr, Chance JM, Filos S. Measurement of functional activities in older adults in the community. J Gerontol. 1982;37(3):323–329. [DOI] [PubMed] [Google Scholar]
- 28.Kaufer DI, Cummings JL, Ketchel P, et al. Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci. 2000;12(2):233–239. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Item S1: Cognitive tests performed at each visit.
Item S2: Dementia definition.
Table S1. Characteristics of study participants at Visit 4 baseline (1996–1998) stratified by AKI status at the end of follow-up.
Figure S1: Flow diagram of study participants starting at Visit 4 baseline (1996–1998).