In a cohort of more than 850 community-dwelling older adults without dementia, decreased level of eGFR or the presence of impaired kidney function at baseline was associated with a more rapid rate of cognitive decline. This association between impaired kidney function and cognitive decline persisted after excluding participants with severely impaired function (eGFR <30 mL/min/1.73 m2). The association of kidney function and cognition persisted even after controlling several potential confounders. Further analyses showed that kidney function was related to specific cognitive abilities, including episodic memory, semantic memory, and working memory, but not perceptual speed or visuospatial abilities. These findings suggest that there are common pathophysiologic processes between kidney dysfunction and brain dysfunction in the elderly. From our studies, we cannot distinguish between the existence of a pathophysiologic process affecting both brain and kidney and a mechanism of brain injury that is initiated by kidney disease.
Although there is a well-known association between severe kidney disease and cognitive impairment, until recently less severe kidney dysfunction has not been considered a risk factor for cognitive impairment in the elderly. Rather, it was thought that cardiovascular risk factors and diseases accounted for many of the adverse health consequences that occur concurrently with mild kidney dysfunction.22–26
However, accumulating evidence suggests that after controlling for traditional vascular risk factors, impaired kidney function is associated with lower cognitive function.7–9
Cross-sectional studies have observed a link between kidney function and cognition; however, there are conflicting reports about the course of cognitive decline with impaired kidney function. Several longitudinal studies have reported that moderate kidney disease is associated with cognitive decline, but one recent study did not find an association between kidney function and cognitive decline over 5 years.10,11,27
The current study supports findings from prior studies reporting a link between kidney function and cognitive decline in elders.10,27
Although the optimal screening for and staging of kidney function in the elderly remain controversial, more than half of the participants in the current study had decreased kidney function.28,29
Further, the association between kidney function and cognition was robust and persisted in analyses using both a continuous and a dichotomized measure of kidney function as well as after adjusting for chronic disorders and medications known to affect kidney and cognitive functions. Given the paucity of modifiable risk factors for age-related cognitive decline, these results have important public health implications because they suggest that impaired kidney function is a risk factor for cognitive decline in old age.
Importantly, previous studies that have examined the association of kidney function with cognition have used different cognitive screening instruments. A novel feature of the current study is the availability of a detailed cognitive battery that allows for an examination of the association of kidney function with decline in 5 different cognitive systems.13
Some previous studies have suggested that kidney dysfunction may preferentially affect executive cognitive function.11
In the current study, kidney function was related to decline of semantic memory and working memory. Thus, these results provide some support for the association of executive cognitive abilities and kidney function, because working memory is a component of executive function, and semantic memory supports executive function. However, in this study, kidney function was not related to the rate of change in perceptual speed. Further, kidney function was related to change in episodic memory, often the earliest sign of AD. Taken together, these findings may suggest a more generalized association between kidney and cognitive function in old age. Subclinical vascular disease in the kidney and brain may account for the association of cognitive dysfunction and decreased kidney function. These results underscore the need to elucidate the biology underlying the association of kidney function and cognition in our aging population.
The basis for the relationship between kidney function and cognition is uncertain. Although kidney function may represent a true risk factor for cognitive decline, declining kidney function and cognition in the elderly may also derive from a common pathogenesis. Kidney dysfunction is associated with the prevalence of traditional cardiovascular risk factors such as elevations in homocysteine30,31
and inflammatory and procoagulant biomarkers,32
which are important biomarkers or mediators of cerebrovascular disease which leads to impaired cognition.33
This is particularly true for executive cognitive functions and working memory, but infarcts also are associated with episodic memory impairments.34
Further kidney dysfunction is associated with white matter hyperintensities and silent infarctions and, although our results persisted after adjustment for vascular risk factors and diseases, it is possible that subclinical cerebrovascular disease underlies the association of kidney function and cognition in this study.35,36
Because impaired kidney function is associated with anemia, this may imply some degree of cerebral hypoxia, which can also lead to decreased cognition.37
Erythropoietin has been reported to have neuroprotective effects, so lower levels of erythropoietin in impaired kidney function may lead to degeneration in cognitive pathways.38
Finally, kidney dysfunction is associated with metabolic abnormalities such as hyperparathyroidism, which may also contribute to cognitive dysfunction.39
Further studies are needed to determine the biologic basis for the association of kidney function and cognition.
The current study has some limitations. First, we did not have measures of inflammatory markers, direct measures of kidney function, or measures of nutritional status. Although we adjusted for common health conditions, there is a possibility that subclinical disease may also have contributed to cognitive decline. Finally, our results are based on a selected cohort that may differ in important ways from the general population, underscoring the need to investigate these findings in other cohorts. However, confidence in these findings is enhanced by several factors. Participants included a large number of older persons initially free of dementia who were examined annually via detailed evaluations for up to 6 years, with more than 90% follow-up participation in survivors. Annual cognitive assessments included multiple tests that allow for composite measures of global cognition, 5 cognitive systems, and investigation of cognitive change over time.