Part Ⅱ: Kidney Disease And Risk Of Dementia: A Danish Nationwide Cohort Study
Apr 10, 2023
Results
The study cohort consisted of a kidney disease cohort of 82,690 patients with kidney disease and a comparison cohort of 413,405 matched individuals from the general population without kidney disease. The median age was 69 years (IQR: 56-78 years). Females comprised 41% of all participants, with 71% enrolled between 2004 - 2016 and the remaining 29% enrolled between 1995 - 2003. CVD and CVD risk factors were diagnosed much more frequently in the renal disease cohort compared to the comparison cohort. In addition, the renal disease cohort had lower income, higher unemployment, and lower educational attainment. The follow-up time was shorter in the kidney disease group than in the control group, with a median of 3.7 and 5.2 years, respectively. This difference reflects the higher mortality rate in the kidney disease group than in the control group:5-year and 10-year mortality rates were twice as high in patients with kidney disease as in the general population (Figure 2). During the study period, 466,071 (94%) died, 78,555 (95%) in the renal disease cohort, and 387,516 (94%) in the comparison cohort.
Figure 2 Cumulative incidences of (A) death and (B) all-cause dementia in patients with kidney disease (kidney disease cohort) and individuals in a matched population without kidney disease (comparison cohort).
Kidney disease and risk of developing dementia
During follow-up, 3462 (4.19% of 82,690) patients with kidney disease and 21,879 (5.29% of 413,405) patients in the comparison cohort developed dementia, most of which were classified as other dementia. Alzheimer's disease was more common in the comparison cohort and vascular dementia was more common in the renal disease cohort.
The 5-, 10- and 22-year risk of all-cause dementia was lower in patients with kidney disease than in the general population:2.90% (95% CI 2.78% to 3.08%), 4.96% (4.79% to 5.14%) and 7.05% (6.70% to 7.41%) in the kidney disease group and 2.98% (2.92% to 3.04%), 6.03% (5.94% to 6.12%) and 10.39% (10.17% to 10.60%) (Figure 2).
The dementia subtype of Alzheimer's disease had the lowest estimated value and vascular dementia had the highest estimated value.
The adjusted HR (aHR) for all-cause dementia remained stable over time. 1.06 (1.00 to 1.12) at up to 5 years of follow-up, 1.08 (1.03 to 1.13) at up to 10 years of follow-up, and 1.08 (1.03 to 1.12) at up to 22 years of follow-up. When we limited the nephropathy exposure to chronic kidney disease, the aHR for all-cause dementia was 1.04 (0.98 to 1.10) over up to 22 years of follow-up and very similar for shorter follow-up
In analyses stratified by age, HRs for all-cause dementia decreased progressively with age:1.14 (0.78 - 1.67), 1.32 (1.09 - 1.61), 1.16 (1.08 - 1.24), 1.01 ( 0.95 - 1.08) and 0.90 (0.77 - 1.04). There were no differences in the prevalence of all-cause dementia by sex, calendar year of the index date, or socioeconomic factors. Renal disease was also associated with elevated HR for dementia in most CVD subgroups (myocardial infarction, stroke, peripheral artery disease, venous thromboembolism, heart failure, and heart valve disease) and CVD risk factors (atrial fibrillation, hypertension, obesity, and diabetes), but estimates were imprecise. Results for dementia subtypes showed consistent results.
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Kidney disease severity and risk of developing dementia
In the kidney disease cohort, fewer patients with end-stage renal disease developed dementia during follow-up compared with patients with other kidney diseases: 3.3% (61 of 1866) of patients treated with dialysis or kidney transplantation and 4.2% (3401 of 80,982) of patients who did not receive these interventions.
Discussion
In this national study involving nearly 500,000 participants, we found that being diagnosed with kidney disease was associated with a slightly increased risk of developing dementia in the future. This association was similar when we restricted exposure to chronic kidney disease only.
We found a much smaller estimate compared to the only previous population-based study, where researchers in Taiwan found an HR of 1.41 for all-cause dementia in patients with kidney disease compared to the general population (1.32 to 1.50) This may be due in part to differences between Asian and European populations, differences in study design, or both. Our study included more recent data, 5 times more participants, more precise age matching, and a longer follow-up period. In addition, we included dialysis treatment, kidney transplantation, and hypertensive nephropathy in our definition of kidney disease, and we did not exclude participants based on other kidney-related diagnoses. In contrast, the Taiwanese study excluded these patients and several other kidney-related diagnoses. Thus, our study may have included a relatively large number of patients with severe kidney disease in the kidney disease cohort and patients with mild kidney disease in the comparison cohort. Finally, although we excluded patients diagnosed with dementia within 1 year of the diagnosis of kidney disease, which was not done in the Taiwan study, the incidence rate ratio in this population with less than 2 years of follow-up was significantly higher than the incidence rate ratio with 2 or more years of follow-up.
A meta-analysis of cross-sectional and cohort studies including over 50,000 participants showed an association between renal disease (eGFR < 60 mL/min/1.73 m2) and cognitive impairment The cognitive domains primarily affected (i.e., orientation, attention, concept formation, and reasoning) differ from those affected by dementia, suggesting that renal disease and other cognitive impairments association may be stronger than the association with dementia. Unfortunately, we do not have data on cognitive performance.
Interestingly, studies that primarily included eGFR measurements in the normal range showed a stronger association between proteinuria and dementia than between eGFR and dementia. This finding suggests that proteinuria may be a better marker of advanced kidney disease than eGFR. Unfortunately, we have no data on proteinuria or eGFR.
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The lack of a strong association between kidney disease and dementia may be due in part to the high mortality rate of patients with kidney disease and therefore the existence of a survivorship bias that dementia increases with age and that patients with kidney disease may not live long enough to develop dementia. In fact, a lower proportion of patients with severe kidney disease were diagnosed with dementia than those with mild kidney disease (3.3% of patients treated with dialysis or kidney transplantation and 4.2% of patients who did not receive these interventions). This finding may reflect survivorship bias or may indicate that clinicians are more likely to underdiagnose dementia in the presence of life-threatening disease and reduced life expectancy (detection bias). This inference is further supported by our stratified analysis, suggesting that risk estimates are lower in the presence of cardiovascular disease (e.g., myocardial infarction), a cardiovascular disease risk factor known to be associated with increased mortality In contrast, a previous Danish study matching 314911 patients with myocardial infarction to 1573193 individuals in the general population reported that myocardial infarction was associated with a high risk of vascular dementia associated with all-cause dementia or risk for other subtypes Taken together, these findings suggest that clinicians may be more likely to diagnose vascular dementia in patients with dementia, kidney disease, or myocardial infarction and less likely to diagnose Alzheimer's disease than in patients without these disorders, and therefore there may be a misclassification bias for dementia subtypes.
Because HRs may vary over time, the modest association observed between kidney disease and dementia may be limited to the first few years after kidney disease diagnosis. On the other hand, period-specific HR managers are prone to inherent selection bias in our study, which translates into prioritizing the review of patients, due to death, for follow-up from the start of the renal disease cohort. As follow-up time increases, this may lead to a relative increase in the proportion of dementia-susceptible individuals in the comparison cohort, thus explaining why unadjusted HRs diminish with increasing follow-up time. Because of this built-in selection bias, matches could not be retained, so we included matching covariates in the adjusted analyses. This may explain why unadjusted hr diminish with increasing follow-up time, whereas HRs do not diminish with increasing follow-up time.
The main strength of our study is its design: A large national registry cohort study with individual-level data and complete follow-up of a matched general population comparison cohort of all Danish patients with hospital-diagnosed kidney disease and without kidney disease during the study period 1995 to 2016.
Limitations of this study include selection bias, survival bias, and surveillance bias. Excluding participants with missing values may bias our estimates because we did not make multiple imputations for income, employment status, and education level. However, if the missing values are not random, this would only bias the estimates. If the missing values are associated with lower income, employment, and education levels, then the unbiased estimates may be larger. Further limitations are misclassification bias (kidney disease, dementia, and covariates), unmeasured or residual confounding, coding quality, and diagnostic validity. A positive predictive value of 100% for renal disease coded in the Danish National Patient Registry was reported, whereas completeness may be only 37%; that is, not all patients with renal disease were captured. Although the positive predictive values for all-cause dementia and Alzheimer's disease in the Danish National Patient Registry were 86% and 81%, respectively, the positive predictive values for other dementia subtypes were lower.
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Therefore, results regarding dementia subtypes should be interpreted with caution. This caveat is particularly important because our results are consistent with the misclassification of the identification of dementia subtypes in patients with kidney disease, where vascular risk factors are particularly common and vascular risk is low in the general population. In addition, we used the date of admission or start of outpatient follow-up as the date of all diagnoses, as exact dates were not available. This may have led to bias, especially at the beginning of the follow-up. In addition, there is a variable lag time between the onset of dementia and the date of diagnosis. Finally, since all diagnoses are recorded by hospital physicians, mild kidney disease and mild dementia treated only by general practitioners would not be recorded unless they were also evaluated in the hospital or outpatient setting.
In conclusion, patients diagnosed with kidney disease are at a slightly increased risk of being diagnosed with future dementia. This association is primarily driven by the diagnosis of vascular dementia, which may be limited to the first few years after the diagnosis of kidney disease. On the other hand, patients with kidney disease may not be diagnosed with dementia due to high mortality and other higher-priority comorbidities, and the true risk of future dementia may be somewhat higher than our study suggests.
Standardized Cistanche is an excellent supplement for those who suffer from kidney disease or want to improve their kidney health. Its ability to improve kidney function, protect against oxidative stress, reduce inflammation, and have a mild diuretic effect make it a valuable tool in the fight against kidney-related conditions. As with any supplement, it is essential to consult with a healthcare professional before starting to take Cistanche.
The effects of Cistanche on Kidney
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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
