CKD is a substantial public health problem. On the basis of the French national renal data system, it has been estimated that between 1.75 and 2.5 million people in France have CKD1 and that nearly 40,000 of the latter are undergoing dialysis. In the United States, similar results have been observed: Almost 8% of the population has CKD and 571,000 patients receive treatment for ESRD.2 Although the incidence of CKD is increasing in all age groups, this is particularly true in the elderly.3 Older adults are at a greater risk of developing cognitive disorders and dementia, and a major determinant of the quality of life in the elderly is the level of cognitive function.4 Recent data in this regard suggest that individuals at all stages of CKD may have a higher risk of developing dementia and cognitive impairment than those without CKD.5–7 Given the increase in life expectancy and the aging of the population in industrialized countries, the cognitive disorder burden associated with CKD is expected to worsen.
Prevalence and Characteristics of Cognitive Impairment in CKD
Patients with Stage 5 CKD
In hemodialysis patients, the prevalence of cognitive impairment has been estimated at 30%–60%6,8–10—at least twice the values observed in age-matched controls.11Table 1 summarizes the characteristics of the main studies assessing the prevalence of cognitive impairment in hemodialysis patients. One main limitation of these early studies concerns the cognitive assessment. Initially, cognitive impairment was based on short screening tests, such as the Mini-Mental State Examination (MMSE)12 and the 3MS (an extension of the MMSE with four additional subtests and a maximum score of 100 points instead of 30 points). The limited sensitivity of short screening tests of cognitive impairment in general and vascular cognitive impairment in particular13 probably led to an underestimation of the prevalence of cognitive impairment in CKD. In a cross-sectional study, Murray et al. compared 338 hemodialysis patients age 55 years and older with age-matched controls.14 Although only 3% of the patients had a documented history of cognitive impairment, further neuropsychological testing showed that the true prevalence of mild to severe cognitive impairment was as high as 87%. This finding was emphasized by another study by Kurella et al.15 According to data collected from a large, international sample of hemodialysis patients with a mean age of 60, only 4% of patients had a previously documented diagnosis of dementia. This value is lower than the prevalence reported in the general population age 65 or older.16,17
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Table 1: Prevalence of cognitive disorders and dementia in hemodialysis patients
Another important limitation in the interpretation of study data concerns study design, which differs from one study to the other. Some investigators did not report the proportion of nonevaluated patients or provide information on confounding factors, such as sociocultural demographic characteristics, the presence of depressive syndrome, vascular risk factors, and prior cerebrovascular events (such as stroke).
Lastly, most of the cognitive tests were administered during a hemodialysis session. Recently, Murray et al. showed that global cognitive function varies significantly over the course of the dialysis session; performance is worst during the session itself and best shortly before the session or on the day after.18 In patients undergoing peritoneal dialysis, the few available data suggest that the prevalence of cognitive impairment might be lower than in hemodialysis patients.19,20 However, this apparent discrepancy may reflect selection bias (because the dialysis procedure will depend on the patients’ characteristics and thus cognitive function before the introduction of dialysis21) rather than the procedure’s characteristics per se.
Patients with Mild to Moderate CKD
Cognitive impairment in CKD is not limited to patients with stage 5 CKD. Several cross-sectional studies have suggested its occurrence in earlier stages of kidney disease (Table 2). Thus, estimated GFR (eGFR) was inversely related to global performance in global cognitive function tests.6,22,23 Yaffe et al. confirmed this observation by applying a more detailed battery of neuropsychological tests.24 They reported that an inverse relation between eGFR and global cognitive function was observed for most cognitive domains, but the pattern of cognitive impairment differed from one CKD subgroup to another. Patients with advanced CKD (defined as eGFR<30 ml/min per 1.73 m2) were more likely to have cognitive impairment as revealed by tests evaluating global cognition, naming, attention, executive function, and delayed memory, but not tests assessing fluency and immediate memory, compared with patients with mild or moderate CKD (defined as an eGFR 45–59 ml/min per 1.73 m2).
Table 2: Main studies of association between mild to moderate CKD and cognitive impairment
The results of longitudinal studies also suggest that CKD is an independent risk factor for cognitive impairment because lower eGFR at study enrollment is associated with a more rapid rate of cognitive decline.25–28 In the Cardiovascular Health Cognition Study, the first study devoted to this topic, Seliger et al. reported that after adjustment for potential confounders, moderate kidney failure is associated with a 37% increase in the risk for dementia.28 In a population of 3034 community-dwelling older adults, Kurella et al. also showed that CKD, defined as an eGFR<60 ml/min per 1.73 m2, is associated with an increased risk for cognitive impairment. Furthermore, the risk for cognitive impairment in this population varied according to the severity of CKD, suggesting a causal relation.27 This association has been confirmed by other recent studies.25,26
However, two other studies failed to show an association between CKD at baseline and the risk for cognitive decline.29,30 In the first, a prospective, cohort study of 5529 healthy older men, Slinin et al. found an independent association between mild to moderate reductions in kidney function and executive function at baseline but not at the end of the follow-up period.30 Recently, data from the 3C population-based cohort study, which included 7839 patients older than age 65 with 7 years of follow-up and baseline eGFR<60 ml/min per 1.73 m2, were not associated with an increased risk for incident dementia or cognitive decline.29 However, in this latter study, the percentage of participants with CKD was relatively low (12% with a baseline eGFR<60 ml/min per 1.73 m2). Furthermore, the patients had a relatively low cardiovascular risk profile, in line with the low prevalence of CKD. This precludes generalization of the study findings to patient populations with more advanced CKD.
Brain Imaging in CKD Patients
Clinically Evident Stroke and Subclinical Cerebrovascular Disease in CKD Patients
Patients with CKD display a high prevalence of stroke. According to the U.S. Renal Data System, the prevalence is 17% for patients undergoing long-term hemodialysis, 10% for patients with mild to moderate CKD, and 4% in the non-CKD population, after accounting for age, sex, and race.2 A history of stroke doubles the risk for dementia in both CKD and non-CKD populations.2 Furthermore, CKD patients have an increased prevalence of subclinical cerebrovascular disease, with silent brain infarcts (SBIs), cerebral infarcts detected by brain imaging in the absence of clinical symptoms, more white matter lesions (WMLs), and more microbleeds (Figure 1).31
Figure 1: Subclinical brain lesions in CKD patients. (A) Axial fluid-attenuated inversion recovery magnetic resonance image showing silent brain lacunar infarct (arrow). (B) Axial gradient-echo magnetic resonance imaging sequence showing multiple microbleeds (small foci of hypointensity, arrows) located in the right cerebral hemisphere. Moderate (C) and severe (D) white-matter lesions in the centrum ovale.
Brain Lesions in CKD Patients
Brain lesions in CKD patients were first described in computed tomography–based studies (Table 3). More than 30 years ago, Passer et al. reported a high prevalence of cerebral atrophy in patients undergoing long-term hemodialysis.32 It was subsequently shown in such patients that the lesions were prominent in the frontal lobes and were correlated with the duration of hemodialysis.33,34 Other markers or risk factors for potential cerebrovascular disease, such as SBIs, have also been reported. Cusmano and Savazzi showed that 10% of CKD patients, most of whom were undergoing hemodialysis, had SBIs.35 More recently, we found a strong association between eGFR and intracranial artery calcification in patients hospitalized for stroke or nonvascular neurologic disorders.36 This is not surprising, given that CKD is associated with an accelerated, active vascular calcification process.37
Table 3: Main brain imaging studies in CKD patients
Magnetic resonance imaging (MRI) has allowed a considerable increase in the rate of detection of subclinical cerebrovascular damage in CKD patients. It has been estimated that approximately half of the patients with advanced CKD stages have SBIs, whereas the prevalence in the general population ranges from 8% to 28%.38 SBIs are associated with an increased risk for stroke, cognitive decline, and incident dementia in CKD patients.39 Furthermore, a small, prospective cohort study showed that SBIs were an independent prognostic factor for the progression of kidney disease in patients with CKD, independently of other established risk factors.40
Likewise, the prevalence of WMLs is high (up to 70%) in both CKD patients and stroke patients.9,41,42 This is not surprising, given that WMLs are thought to be symptomatic of a progressive, irreversible process that follows on from arteriolosclerosis.43 Most cross-sectional, population-based studies show a strong association between eGFR on one hand and white matter volume and WMLs on the other.44–46 Only Martinez-Vea et al. failed to report a statistically significant relationship between vascular nephropathy and WMLs in a multivariate analysis.47 This absence suggests that the elevated number of WMLs in CKD patients is a marker of systemic vascular disease. As with SBIs, WMLs are predictors of an increased incidence of stroke, dementia, and death.48 Other markers strongly associated with cerebral small vessel disease (microbleeds or microhemorrages) have been studied less extensively.
The incidence of cerebral microbleeds is higher in patients undergoing hemodialysis49 and also in patients with a more moderate decrease in renal function.50 In two other studies performed in patients with ischemic stroke, similar associations between chemical markers of CKD and cerebral microbleeds have been observed.51,52 Interestingly, Watanabe also found a high incidence of microbleeds in patients undergoing maintenance hemodialysis but failed to find any correlation between the duration of hemodialysis and the prevalence of microbleeds. The author concluded that the high proportion of patients with microbleeds in this population was caused by other risk factors, possibly arterial hypertension and uremic toxins, rather than maintenance hemodialysis per se.53 However, one must bear in mind that most of the above studies were performed in Asian persons—an ethnic group whose patterns of clinically evident and subclinical cerebrovascular disease greatly differs from that in other populations. This point was recently emphasized by the results of a meta-analysis by Lee et al. in which the presence of low eGFR was a marker for increased risk for stroke, with the highest risk being observed in Asian populations.54
Potential Causes of Cognitive Impairment in Patients with CKD
The Vascular Hypothesis of Cognitive Impairment
Figure 2 presents the possible causes of cognitive impairment in patients with CKD. The brain and the kidneys have many common anatomic and vasoregulatory features; they are low resistance end organs exposed to high-volume blood flow and thus are susceptible to vascular damage.55 Hence, impaired cerebral hemodynamics, as evaluated by transcranial Doppler ultrasonography, may reveal interesting information on the association between altered cerebrovascular hemodynamics and cognitive impairment.56 Indeed, previous transcranial Doppler studies show a positive correlation between hemodynamic impairment and cognitive impairment—suggesting that microvascular damage contributes to the cognitive changes observed in the early stages of dementia.57,58 Additionally, the prevalence of traditional vascular risk factors, such as arterial hypertension, is higher in patients with CKD than in the general population.2 This might explain the association between CKD and cerebrovascular disease because the latter plays the largest role in the pathogenesis of cognitive impairment in CKD patients.
Figure 2: Schematic representation of potential causes of cognitive impairment in patients with CKD.
Furthermore, it has been suggested that vascular disease is a more likely cause of cognitive impairment than is Alzheimer’s disease in this population. This hypothesis is supported by recent published data from the 3C study: Faster eGFR decline (>4 ml/min per 1.73 m2 during the first 4-year period of follow-up) was associated with global cognitive decline and incident dementia with a vascular component.29 The contribution of cerebral vascular lesions to cognitive impairment in CKD patients is also supported by the pattern of cognitive disorders; the prominent impairment of executive functions and psychomotor speed resembles the situation in stroke.59 However, the results of a neuropathologic study indicates that patients with small-vessel cerebrovascular disease present broader cognitive impairment, which can also include memory deficits. These findings thus challenge the utility of executive impairment as a diagnostic marker for vascular cognitive impairment or dementia.60
Nontraditional vascular risk factors, such as hyperhomocysteinemia, hypercoagulable states, inflammation, and oxidative stress, have also been linked to cognitive impairment.61 These factors could accelerate the progression of atherosclerosis and vascular endothelial dysfunction, both of which are associated with dementia risk.62,63 Interestingly, elevated homocysteine levels are present in 85% of dialysis patients but only 10% of the general population.64 In a prospective cohort study, plasma homocysteine was an independent risk factor for dementia.65
There are several possible mechanisms through which elevated homocysteine levels may cause cognitive impairment. First, hyperhomocysteinemia has a direct prothrombotic effect on the vascular system and thus may lead to both large- and small-vessel disease.66 Elevated homocysteine levels are also associated with the number of WMLs and progression—possibly through direct endothelial damage or stimulation of an endothelial inflammatory response.65,67,68 Second, hyperhomocysteinemia could impair neuronal pathways because elevated homocysteine has a direct, neurotoxic effect by activating the N-methyl-D-aspartate receptor or by conversion into homocysteic acid, leading to cell death.69 Furthermore, clinical studies show that elevated plasma homocysteine concentrations are associated with an increased risk for Alzheimer disease.70 However, lowering homocysteine levels in dementia patients does not appear to reduce global cognitive decline.71
The Neurodegenerative Hypothesis of Cognitive Impairment
The vascular risk factors and brain abnormalities mentioned above can only partly explain the high frequency of vasculopathy-related cognitive disorders observed in CKD patients. Hence, other disease mechanisms are necessarily involved. First, chronic hypertension and numerous vascular risk factors are associated with an increased risk for Alzheimer disease.72 Conversely, the results of observational studies and clinical trials suggest that antihypertensive drugs may decrease age-related cognitive decline and dementia, although longitudinal studies have provided inconsistent findings.73 In 2001, the Rotterdam study showed that antihypertensive treatment was associated only with a lower risk for vascular dementia.74 However, the Systolic Hypertension in Europe (Syst-Eur) and Syst-Eur 2 trials showed a significant, 50% reduction in the incidence of both vascular and neurodegenerative dementia.75,76 During the past decade, most studies have focused on the observation that beneficial effects of various antihypertensive drugs in preventing cognitive decline and dementia are apparently not correlated with their BP-lowering activity.77
It has been suggested that angiotensin-converting enzyme inhibitors might have deleterious effects on cognition (because they prevent angiotensin-converting enzyme–mediated conversion of Aβ42 into Aβ40, which is less amyloidogenic and less toxic), whereas angiotensin AT1-receptor blockers might exert a protective effect on cognition due to their activation of AT2 and AT4 receptors. Moreover, the accumulation of uremic toxins may cause cerebral endothelial dysfunction and contribute to cognitive disorders in CKD.78 Various uremic toxins have been implicated in the pathogenesis of cognitive impairment.79 DeDeyn et al. reported that cerebrospinal fluid and brain levels of some guanidine compounds, such as creatinine, guanidine, guanidinosuccinic acid, and methylguanidine, are substantially elevated in uremic patients.80 Interestingly, these high toxin concentrations (up to 10-fold higher in CKD patients than in controls) were found in brain regions that play a determinant role in cognition, such as the thalamus, the mammillary bodies, and the cerebral cortex.80 It is well known that these uremic guanidine compounds are neuroexcitatory agents and have convulsant activity in animal studies.81 However, it is still not clear whether uremic toxins are directly responsible for cognitive impairment. The involvement of guanidines in cognitive disorders could also be indirect because it has been shown that these compounds favor an elevation of serum homocysteine.82 Lastly, Yaffe et al. showed that community-resident elderly individuals with elevated levels of cystatin-C (an inhibitor of cysteine proteases that co-localizes with β-amyloid in the brain of patients with Alzheimer disease) had lower cognitive test scores and were more likely to experience a decline in cognitive function during a 7-year follow-up period—even after adjustment for vascular risk factors.83 Despite the absence of brain MRI data, it is possible that cystatin-C has a direct effect on the risk of developing Alzheimer disease.
Conclusion
The pathophysiologic link between brain and kidney injury is strong and complex. The cognitive disorders observed in CKD patients are probably explained by the common susceptibility of brain tissue to vascular injury. Brain MRI should be systematically performed in CKD patients with cognitive impairment because the frequency of both clinically apparent and silent cerebrovascular lesions is strikingly increased compared with that in the general population. In addition to cerebrovascular causes, other potential mechanisms, such as direct neuronal toxicity of the uremic state, could also be involved in CKD patients with cognitive disorders, especially in the absence of obvious cerebrovascular disease. Understanding the pathophysiologic interactions between renal impairment and brain function in CKD patients is important in order to minimize the risk for future cognitive impairment. Attempt to reach this goal would benefit from collaboration between neurologists and nephrologists.
Disclosures.
None
Published online ahead of print. Publication date available at www.jasn.org.
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