Cognitive Impairment Starts Early, Ups Death Risk in Patients With CKD

Cognitive impairment in patients with chronic kidney disease (CKD) is associated with a host of health problems, new research shows. The connections between kidney and brain health are actively being investigated. What’s becoming clear is that even children and younger adults with CKD are at risk, as are patients with acute kidney injury (AKI). There is a pressing need to conduct more research in this area and discover workable solutions.

Adverse Outcomes

Among more than a half million patients with stage 3-5 CKD in the TriNetX database, investigators propensity-score matched 8184 patients who had pre-existing cognitive impairment (ie, vascular dementia, Alzheimer disease, and mild cognitive impairment) up to 5 years before their CKD diagnosis and 8184 patients who did not.

At 10 years after CKD diagnosis, all-cause mortality occurred in a significantly higher proportion of the group with vs without cognitive impairment: 18.5% vs 12.6%, Lino Merlino, a PhD student at the University of Manchester in the UK, and colleagues reported in Clinical Kidney Journal.¹ The cognitive impairment group had a significant 63% increased risk for early death.

Cognitively impaired patients also had significantly higher rates of cerebrovascular disease (11.3% vs 6.9%), transient cerebral ischemic attacks (2.7% vs 1.6%), arrhythmia (14.5% vs 13.3%), hypotension (16.5% vs 12.5%), and AKI (19.5% vs 17.0%).

With respect to neurologic and psychiatric conditions, the cognitive impairment group more frequently displayed encephalopathy (9.9% vs 5.0%), mood disorders (13.6% vs 9.7%), psychosis (9.8% vs 4.6%), and epilepsy (4.3% vs 1.5%). They were more likely to take antidepressants (26.3% vs 16.3%), anticonvulsants (19.5% vs 15.1%), antipsychotics (18.6% vs 9.1%), anticholinesterase (5.6% vs 0.1%), and benzodiazepines (30.6% vs 26.6%).

Partly due to poor self-care, cognitively impaired patients had higher rates of malnutrition (6.7% vs 4.0%), urinary infections (13.2% vs 9.3%), and pneumonia (10.7% vs 7.9%).

According to Merlino’s team, “most research has centered on older patients or those approaching dialysis, leaving a gap in understanding the cumulative risk associated with [cognitive impairment] in younger patients with milder CKD.”

This study, they added, addresses this gap, demonstrating that even a short history of cognitive impairment can increase death risk by nearly 50% in younger adult patients (mean age 60.5 years) with milder CKD (estimated glomerular filtration rate [eGFR] of 52.9 mL/min/1.73 m² ) in a 2-year time frame.

The investigators noted the close connections between kidney and brain health. Brain damage, for example, may affect kidney function. Shared genetic pathways influence both the onset of CKD and cognitive impairment, particularly genes related to vascular health, inflammation, oxidative stress, and the renin-angiotensin system. In addition, some risk factors such as aging, diabetes, cardiovascular disease, and hypertension are common to both conditions.

“The study underscores the importance of a comprehensive cognitive assessment in CKD patients to identify the most vulnerable cohort at the earliest possible stage,” Merlino’s team wrote.

They also observed: “Nephrologists must increase their confidence in managing therapies linked to cognitive decline in the context of CKD, and cooperation with psychiatry or neurology specialists should be encouraged to guarantee better care and quality of life in patients with CKD.”

Kidney-Brain Connections

In a study published in Alzheimer’s & Dementia that included 15,897 adults aged 40-69 years from the CARTaGENE cohort, lower eGFR was specifically associated with reduced reasoning and memory performance and slower reaction times, which influence attention and executive functions.² Brain regions associated with eGFR were enriched for mitochondrial and inflammatory-related genes and correlated with changes in brain structure observable on MRI.

“Notably, eGFR mediated the relationship between reasoning and brain morphology,” Shady Rahayel, PsyD PhD, of Hôpital du Sacré-Coeur de Montréal in Quebec, Canada, and colleagues wrote. “Imaging transcriptomic analysis revealed that lower eGFR was associated with transcriptomic patterns resembling those seen in tauopathies and synucleinopathies.”

Midlife Adults and Children Affected

In a study of 22,435 Black and White adults aged 45 years and older who were free from cognitive impairment at baseline, the odds of later experiencing cognitive impairment were significantly increased 90% at midlife (aged 45 years or more but less than 65 years) for those with an eGFR less than 45 vs 90 mL/min/1.73m² or more, investigators reported  in the Journal of General Internal Medicine.³ Midlife patients with albuminuria had steeper declines in memory function. A previous study published in Scientific Reports likewise concluded that patients with CKD at midlife were at risk.

Even children and adolescents with CKD appear at risk for cognitive impairment, Lyndsay Harshman, MD, of the University of Iowa Hospitals and Clinics in Iowa City, and colleagues reported in JAMA Network Open.⁴ In a comparison of 37 patients with CKD and 87 healthy patients aged 6 to 21 years, the CKD group had worse age-related changes in cerebellar gray matter (β = -0.10) and white matter (β = -0.09). The findings point to abnormal growth trajectories of the cerebellum in pediatric CKD, even before dialysis or transplantation. Further, lower cerebellum volume correlated with lower kidney function and executive functioning deficits, such as attention regulation and planning. The investigators also found a negative association between amygdala volume and monitoring, another executive function component. Executive function worsens with longer CKD duration and the development of metabolic acidosis and hypertension. The investigators acknowledged that even isolated congenital anomalies of the kidney and urinary tract may affect brain development.

Acute Kidney Injury and Cognitive Impairment

Acute kidney injury (AKI) can also contribute to dementia, data suggest. Among 8148 older adults at high cardiovascular risk in the Systolic Blood Pressure Intervention Trial (SPRINT), the risk for probable dementia and a composite of mild cognitive impairment and probable dementia was significantly increased 72% and 43%, respectively, for those with vs without AKI, Kristen L. Nowak, PhD, MPH, of the University of Colorado at Aurora, and colleagues reported in Kidney Medicine.⁵ AKI was generally mild and reversible in SPRINT, the investigators noted. The most common AKI causes were dehydration and/or intravascular volume depletion, followed by hypotension. CKD was present in 28% of the cohort.

“It is plausible that a bout of inflammatory stimuli from AKI increases the risk of [mild cognitive impairment] and dementia years later, rather than via progression of AKI to CKD increasing risk of adverse cardiovascular endpoints,” according to Dr Nowak’s team. They urged monitoring of cognitive function after AKI in this patient population.

Cognitive Impairment in Dialysis Population

Dialysis-dependent patients have twice the risk of cognitive impairment compared with the age-matched general population, LaTonya J. Hickson, MD, of Mayo Clinic Nephrology and Hypertension in Jacksonville, Florida, and colleagues pointed out in a review article published in the Journal of the American Society of Nephrology.¹⁰ Lower kidney clearance of uremic toxins is associated with worse performance on cognitive measures. Indoxyl sulfate and p-cresyl sulfate are the most commonly studied, but there are many others.

Potential therapeutic interventions for the dialysis population under investigation include AST-120 [indoxyl sulfate absorbent], CH-223191 [aryl hydrocarbon receptor antagonist], TRAM34 [Kca3.1-specific inhibitor], anakinra [IL-1R inhibitor], marimastat, exercise, supplements, and kidney transplantation, according to the authors.

Research Priorities

Clara Bohm, MD, MPH, and colleagues convened panels of researchers, clinicians, and patients who identified 27 critical research questions about cognition in CKD. The top questions by consensus centered on preventing cognitive impairment and maintaining cognition in patients, including those on dialysis and children. Panelists also wondered whether clearance of uremic toxins via hemodialysis reduces the risk of impaired cognition. Dialysis is ineffective at removing larger, protein-bound metabolites such as phosphate and indoxyl sulfate implicated in cognitive impairment, the authors noted in Kidney360.⁶ They also pointed out that kidney transplantation is not an option for everyone.

In the Journal of Nephrology, Carmine Zoccali, MD, of Renal Research Institute in New York, New York, and colleagues urged dedicated research on genetic markers of cognitive dysfunction and dementia in CKD.⁷ According to the current literature, genetic markers that may be relevant to the CKD population include apolipoprotein E (APOE; a known risk factor for Alzheimer disease), complement receptor 1 (CR1), clusterin (CLU), sortilin-related receptor 1 (SORL1), catechol-O-methyltransferase (COMT), and brain-derived neurotrophic factor (BDNF). These genes play roles in lipid metabolism, inflammation, Aβ clearance, and neuronal function, and have been associated with cognitive dysfunction and dementia in other populations.

Interventions

A small study published in the Journal of Clinical Medicine found that cognitive impairment was tied to a greater likelihood of a sedentary lifestyle both in patients on dialysis (88% vs 48% without cognitive impairment) and kidney transplant recipients (45% vs 9%).⁸

A separate trial (ClinicalTrials.gov: ACTRN12618000851268) tested lifestyle modifications to prevent cognitive impairment in adults without CKD. In the trial, investigators randomly assigned 6104 dementia-free Australians aged 55-77 years with modifiable dementia risk factors to online coaching targeting physical activity, nutrition via a Mediterranean diet, cognitive activity and depression or anxiety (Maintain Your Brain program) or to a control group that received education only. Approximately a third had baseline hypertension, and less than half had high cholesterol. One in 5 had a history of depression and/or anxiety.

At 3 years, global cognitive composite z scores increased more in the intervention than control group: 0.28 vs 0.10, Henry Brodaty, MB BS, DSc, director of the Dementia Centre for Research Collaboration and co-director of the Centre for Healthy Brain Ageing at UNSW Sydney in New South Wales, Australia, and colleagues reported in Nature Medicine.⁹ Complex attention (0.16), executive function (0.07), and learning and memory (0.19) domain scores also increased significantly more in the intervention group.

The intervention group had higher adherence to a Mediterranean diet, more minutes of moderate to high-intensity aerobic training per week, 1 more day of strength training per week, and less psychological distress as measured by Kessler Psychological Distress Scale.

The Mind Your Brain program modestly lowered prospective dementia risk based on the ANU-ADRI-SF11 score by 0.53. Greater engagement and adherence were associated with better cognitive outcomes. Whether these results would extend to patients with CKD remains to be seen.

Trial-related adverse event rates were very low but affected more of the intervention group: 0.60% vs 0.03%.

“As these interventions can be conducted unsupervised through a web-based application, it has the potential to provide a realistic path toward community-based interventions for older people,” Dr Brodaty’s team wrote.

Disclosure: Please see the original references for a full list of authors’ disclosures.