Interventions to Preserve Cognitive Functioning Among Older Kidney Transplant Recipients

Abstract

Purpose of Review:

To summarize the research on effective interventions for preserving cognitive function and prevent cognitive decline in patients with end-stage kidney disease (ESKD) who are undergoing dialysis and/or kidney transplantation (KT).

Recent Findings:

Among ESKD patients undergoing hemodialysis, exercise training has been administered through home-based and intradialytic interventions. Additionally, one pilot study identified intradialytic cognitive training, electronic brain games, as an intervention to preserve cognitive function among patients undergoing hemodialysis. Fewer studies have investigated interventions to preserver cognitive function among KT recipients. To date, the only randomized controlled trial in this population identified B-vitamin supplements as an intervention to preserve cognitive function. The evidence from these trials support a short-term benefit of cognitive and exercise training as well as B-vitamin supplementation among patients with ESKD. Future studies should: 1) replicate these findings, 2) identify interventions specific to KT candidates, and 3) investigate the synergistic impact of both cognitive and exercise training.

Summary:

Cognitive prehabilitation, with cognitive and/or exercise training, may be novel interventions for KT candidates that not only reduces delirium risk and long-term post-KT cognitive decline but also prevents dementia.

INTRODUCTION

Aging Patients with End-Stage Kidney Disease (ESKD)

Older adults bear a higher burden of end-stage kidney disease (ESKD). In the US, there has been a steady increase in the number of older adults (age ≥65 years) initiating hemodialysis such that in 2014, 49.6% of patients initiating HD were older adults.¹ In the last two decades, kidney transplantation (KT) has become a common treatment option for older patients with ESKD; approximately 19% of all KT recipients occurring among older adults. Furthermore, these patients live longer with a functioning graft, resulting in more older adults with a history of KT.² Consequently, many transplant centers have begun to recognize the importance of screening for age-related vulnerability, and 75% of centers reported that screening for cognitive impairment was very important.³ Below we summarize: 1) the epidemiology of cognitive impairment in ESKD patients, 2) the tools used to screen for cognitive function and their applicability to ESKD patients, and 3) what interventions may apply to KT candidates and recipients for prevention and/or treatment.

Global Cognitive Function

Dialysis patients have a high burden of global cognitive impairment even at younger ages,^4–6 and hemodialysis patients of all ages have worse cognitive function than individuals of the same ages in the general population.^7,8 In a cohort study of 324 adults aged ≥18 years (mean age=55) initiating HD, the mean Modified Mini-Mental State Exam (3MS) score, a measure of global cognitive function, was 89.8 (SD=7.6).⁸ Based on normative data among older adults, these 3MS scores signify that these patients of all ages are particularly vulnerable.⁹ By dialysis initiation, many patients already experience impaired cognition.^10–12 Global cognitive function continues to decline while undergoing dialysis.^4,13–15 Strikingly, about 13% of patients undergoing hemodialysis were found to have normal cognition.¹⁶ Cognitive impairment, and particularly declining cognitive function, is often overlooked by clinicians among those undergoing HD¹⁷ or KT;¹⁸ physicians were only able to accurately identify HD patients and KT recipients with cognitive impairment 57%¹⁷ and 66%¹⁸ of the time, respectively. Peritoneal dialysis patients have been found to have better cognitive functioning compared to those undergoing hemodialysis,¹⁹ however, more cognitively robust patients may be the ones who are selected for this form of renal replacement therapy. This is evident by the fact that patients living with chronic kidney disease and concurrent cognitive impairment are less likely to initiate peritoneal dialysis.²⁰

In small, single-center studies that included the Montreal Cognitive Assessment (MoCA), another measure of global cognitive function, 38% of Hispanic and Native American KT candidates,²¹ and 58%²² of KT recipients were identified as having cognitive impairment. KT recipients who have global cognitive impairment have been found to be at an increased risk of all-cause graft loss after KT.²³ After KT and the restoration of kidney function, recipients experience improvements in global cognitive function, particularly within the first year.^24–30 However, these improvements are not universal among KT recipients; a study of 4 year post-KT cognitive trajectories among recipients of all ages found that frail KT recipients experience declines in global cognitive function between 1 and 4 years post-KT.³⁰ In fact, by 4 years their cognitive levels had declined to levels lower than their pre-KT average.³⁰

Executive Function

Of all the cognitive domains, patients living with ESKD are most often impacted by declines in executive function:³¹ the domain responsible for set shifting, mental flexibility and complex problem solving. Severe impairment in executive function is problematic as it impedes patients’ ability to comply with their dialysis schedule, diet, and complicated medication regimens. Additionally, this impairment leads to greater risk of dependence,^32–34 difficulty making informed clinical decisions, and difficulty adhering to the necessary fluid and dietary restrictions,¹⁷ which often can lead to death.^6,35 This is a particular concern for KT recipients, as executive function will likely impact their ability to manage daily maintenance immunosuppression regimens.

In the cohort study of patients initiating hemodialysis (described above), executive function was measured and calculated by subtracting the Trail Making Test Part A for psychomotor speed from the Trail Making Test Part B (TMTB-TMTA). For this measure of executive function, longer times to complete this test are indicative of worse cognitive function. The mean time it took for patients undergoing hemodialysis to finish these tests was 55 seconds (SD=29) and 161 seconds (SD=83), respectively.⁸ These mean times are significantly lower than the mean times for these tests among community-dwelling adults.³⁶ Furthermore, executive function is the cognitive domain that is most impacted by the initiation of hemodialysis.⁵ Patients undergoing hemodialysis are 3-fold more likely to experience impairments in executive function compared to similar aged adults in the general population.^6,37 Previous studies have found that 38% of patients of all ages undergoing hemodialysis actually have severe impairments in executive function.³⁸ One small study (n=90) found that among KT recipients, the mean times for the Trail Making Test Part A was 29.0 seconds and for Trail Making Part B was 69 seconds.³⁹

Causes of Cognitive Impairment

The major clinical contributors to cognitive impairment for patients with ESKD include subclinical cerebrovascular disease, a history of stroke, arterial stiffness and central pressure.^6,40–42 Patients undergoing hemodialysis experience a greater burden of white matter disease as well as cerebral atrophy than their healthy counterparts,⁴³ and executive function is further impacted by hemodialysis.⁵ In fact, the transition from CKD to dialysis was associated with a profound loss of executive function.⁵ The treatment of hemodialysis leads to deficits in executive function through incomplete removal of uremic toxins^25,44 and by inducing recurrent cerebral ischemia.^6,45 However, it is not just executive function that is impacted; deficits in multiple domains of cognition are often concurrent.⁴⁶

In addition, health behaviors also contribute to declines in cognitive function while undergoing hemodialysis. Patients undergoing evaluation for KT who were treated with hemodialysis often spend the 4–6 hours of their dialysis session doing less cognitively challenging activities. One study found that patients reported sleeping (72.4%) and watching TV (87.9%), which leads to the self-report of poor mental HRQOL.⁴⁷ In addition, among KT candidates, cognitive impairment is highly associated with limited health literacy; patients with cognitive impairment are more than 3-fold more likely to report limited health literacy.⁴⁸ And finally KT candidates who have a visual, hearing, physical, or walking impairment are more likely to also have cognitive impairment (9.7% vs. 5.5%).⁴⁹ These all contribute to the loss of cognitive function while undergoing hemodialysis.

Consequences of Cognitive Impairment

As in the general population, cognitive impairment clearly has implications among patients with ESKD. First, patients with cognitive impairment before hemodialysis initiation are less likely to maintain functional status after dialysis initiation.⁵⁰ Second, executive function impairment in patients with ESKD may represent an early sign of future dementia. This dementia is likely to be vascular dementia,^51,52 and in many cases may also include Alzheimer’s disease and related dementia.^53,54 Using national registry data linked to Medicare claims (n=356,668 older patients initiating hemodialysis), the age-adjusted risk of being diagnosed with dementia (accounting for the competing risk of death, dialysis withdrawal, and switch to peritoneal dialysis) was 13% for older men and 16% for older women in the 5-years after hemodialysis initiation; the corresponding risks for Alzheimer’s disease diagnosis were 2.0% for men and 2.6% for women.⁵⁵ As expected, these older patients were at a 2-fold higher risk of mortality after a diagnosis of dementia (including Alzheimers’ disease).

Furthermore, cognitive impairment, measured by the MoCA, has been identified as a barrier to listing for KT as was indicated in a study of KT candidates referred for transplant evaluation.⁵⁶ One study of 154 KT candidates found that 1 point increase in MoCA associated with a 10% increase likelihood of being listed.²¹ Furthermore, cognitive impairment was not only associated with listing but additionally, with an increased risk of waitlist mortality and a decreased transplant rate among 3,360 KT candidates; these associations were primarily observed among those without diabetes (Chu, AJKD, in press).

Interestingly, older KT recipients are comprised of a group of ESKD patients who are selected to be free of dementia and particularly of Alzheimer’s disease. However, older KT recipients also have a higher burden of cognitive impairment⁵⁷ as well as dementia and Alzheimer’s disease compared to their community-dwelling counterparts.⁵⁸ Dementia rates are as high as 6.7% in the 10 years after KT.⁵⁸ Among older KT recipients, a diagnosis of dementia or Alzheimer’s disease are both associated with a 2.4-fold risk of graft loss and 1.3-fold risk of mortality.⁵⁸

Cognitive impairment is a well-recognized risk factor for mortality among community-dwelling older adults.^59,60 More recent studies have demonstrated that ESKD patients of all ages with cognitive impairment are at a 1.7- to 2.5-fold increased risk of mortality.^35,61 Even after KT, the long-lasting impact of cognitive impairment are evident. For example, cognitive impairment at the time of admission for KT is associated with a 3 to 5-fold higher risk of all-cause graft loss.⁶² Furthermore, KT recipients are at unique risk of the surgical complication of delirium,⁶³ which is a known risk factor for cognitive decline and dementia among older adults in the general population.^64,65

How to Measure Cognitive Function among Patients with ESKD

The study of cognitive function among patients with ESKD is relatively new and often includes younger adults with ESKD.⁶⁶ As such, no cohort studies to date have measured multiple cognitive domains, including attention, visuospatial ability, memory, language, and executive function. Global cognitive function is often assessed in these studies using one of the brief screening tools.^8,18,30,31 One of the most commonly studied tools to measure global cognitive function in older adults and in patients with ESKD is the Modified Mini-Mental State Exam (3MS). It is a validated tool to measure global cognitive function^67–69 and it includes components like temporal and spatial orientation, multi-stage commands, and recall. 3MS scores range from 0 to 100, where lower scores indicate worse cognitive function. More recently, the Montreal Cognitive Assessment (MoCA) became available as an alternative brief screening tool of global cognitive function. It is increasingly being recognized as a more sensitive tool in detecting mild cognitive impairment compared to the 3MS, especially among higher functioning individuals; however, it has only recently been studied in ESKD patients and KT recipients.^18,61 In the US, 8% of transplant centers report using the MoCA as part of pre-transplant screening.³ However, it is critical to recognize that interpretations of cognitive tests in populations with ESKD should not be based exclusively on normative data generated from healthy community-dwelling adults, particularly if these tools will be used to select transplant candidates. MoCA scores of <24 have been used as a threshold for cognitive impairment in KT patients, which is less than the threshold for community-dwelling older adults. However, interpretations should account for educational attainment, age, and timing around the dialysis cycle for those who are dialysis-dependent, given that cognitive performance often declines during treatment.

Interventions to Prevent Cognitive Impairment in Community-Dwelling Older Adults

In community-dwelling older adults, exercise training, has been identified as a an effective non-pharmacological intervention that specifically targets global cognitive function,^70–72 and has been found to have the greatest impact on preserving executive function.^73–78 The impact of exercise training begins even before improvements in strength and physical functioning are observed.⁷⁹ Exercise training has been found to preserve executive function among community dwelling-older adults⁷⁸ through 4 potential mechanisms: 1) increased cerebral blood flow;^80,81 2) more brain volume in the prefrontal cortex and hippocampus;^82–84 and 3) higher brain-derived neurotrophic factor.^85–89 Furthermore, exercise is an integral way to reduce inflammation and impacts inflammatory markers, like C-reactive protein, interleukin-6, and tumor necrosis factor alpha. This reduced inflammation results in better brain plasticity and improved executive function.^86,90 Strikingly, a single exercise training session changes neurophysiology and subsequently improves executive function.^91–93

Additionally, among community-dwelling older adults, cognitive training^71,94,95 has been identified as another non-pharmacological intervention to prevent cognitive decline. Cognitive training has been found to prevent declines in multiple domains of cognitive function, such as executive function, and can impact working memory, abstraction, verbal reasoning, and inhibition.^{32,33,96–102} It is thought that they impact cognitive function by improving neural structures.^103–105 Therefore, multi-domain approaches to cognitive training are preferred over memory training alone. This approach has been associated with broad benefits in cognitive function and provides lasting gains that extend to everyday life activities up to 10 years post-intervention,⁹⁸ among community-dwelling older adults.^100,106,107 Cognitive training has also been combined with exercise training for community-dwelling older adults, and this multi-model approach has been found to be more effective than either intervention alone,^85,103 especially for executive function.^79,85,99,108 One possible reason that combining cognitive and exercise training effectively impacts cognitive function is that these interventions enhance synaptic connections between brain cells and are thought to improve brain plasticity.^109,110

Exercise Interventions in Patients Undergoing Hemodialysis

In the past three decades, research has identified exercise as an important intervention for patients undergoing dialysis because it improves physical function.^111–113 Furthermore, this intervention produces many other beneficial results including decreases in treatment-related symptoms,¹¹⁴ improvement in dialysis efficacy,¹¹⁵ reductions in inflammation,¹¹² improvement in bone mineral density,^112,116 elevations in quality of life,¹¹⁷ improvements in peak oxygen consumption,^118,119 reductions in anxiety,¹²⁰ and improvements in exercise capacity.^121,122 Patients undergoing hemodialysis are most compliant and adherent when the exercise interventions are delivered during the dialysis session.^123,124

Exercise as an Intervention to Preserve Cognitive Function in Patients Undergoing Dialysis

To date, three trials have explored exercise as an intervention to preserve and improve cognitive function among patients undergoing dialysis. The first was the Exercise Introduction to Enhance Performance in Dialysis (EXCITE) trial, a 6-month randomized, controlled, multicenter trial of adult patients of all ages on dialysis.¹²⁵ The goal of this trial was to test whether home-based, personalized exercise interventions improve functional status and this study additionally collected self-reported cognitive function. This trial found that exercise improved self-reported cognitive function scores from Kidney Disease Quality of Life Short Form (KDQOL-SF).¹²⁵ In a secondary analyses, this trial tested the impact and tolerance of the exercise program on older (aged 65 years and older) dialysis patients. Exercise preserved self-reported cognitive function in this older population; those randomized to the control arm experienced declines in self-reported cognitive function, on average.¹²⁶

Two pilot randomized controlled trials have studied intradialytic exercise as an intervention to preserve cognitive function.^81,127 The first pilot randomized controlled trial of 30 adult (aged 18 years and older) patients undergoing hemodialysis tested the impact of a 4-month exercise intervention of intradialytic cycling. They tested whether this aerobic exercise affected cerebral blood flow and cognitive function, and found that those randomized to the exercise group (N=15) had improved cognitive function, a greater proportion of arteries with increased flow velocity, and improved basilar maximum blood flow velocity compared to a control group (N=15).⁸¹ The second pilot randomized controlled trial of 20 adult (aged 18 years and older) patients undergoing hemodialysis tested whether 3 months of intradialytic cognitive training (tablet-based brain games) (N=7), exercise training (foot peddlers) (N=6), or standard of care (N=7) preserved cognitive function.¹²⁷ Cognitive function was directly measured using the 3MS and TMTA/B. While those patients randomized to the standard of care arm experienced decline in psychomotor speed and executive function at 3 months of follow-up, those randomized to either the exercise or cognitive training arms had preserved cognitive function. More recently, this pilot trial was expanded to a 2-by-2 factorial randomized controlled trial; the goal of this new trial is to test whether 3 months of cognitive and exercise training have a synergistic effect on executive function (Clinicaltrials.gov # NCT03616535).

These three trials suggest that exercise and cognitive training may be important interventions for KT candidates who are undergoing hemodialysis while waiting for KT.

Dialysis Modality Interventions to Preserve Cognitive Function for ESKD patients

To our knowledge, only one study has assessed the effect of a dialysis modality on cognitive function in patients with ESKD. Leveraging the Frequent Hemodialysis Network (FHN) randomized clinical trials, including 218 participants from the Daily Trial and 81 participants from the Nocturnal Trial, investigators assessed whether more frequent hemodialysis (6-times per week) improved cognitive function compared to 3-times per week. The study found that frequent hemodialysis did not improve executive function or global cognitive function compared to the recommended thrice weekly hemodialysis in either trial,¹²⁸ suggesting that switching dialysis modality may not be an effective intervention strategy for preserving or improving cognitive function among patients with ESKD prior to transplantation.

Interventions to Preserve Cognitive Function for KT Recipients

Only one study has sought to identify interventions to preserve or improve cognitive function among KT recipients.¹²⁹ The FAVORIT trial was a randomized controlled trial of high-dose B vitamins among 584 KT recipients with elevated total homocysteine levels in the US. They found that processing speed and memory scores were higher among KT recipients who were randomized to B-vitamin supplements.¹²⁹ This is a novel study that may open new pathways to improve cognitive function beyond the non-pharmacological interventions that were found to be effective in pilot studies of patients undergoing hemodialysis.

FUTURE RESEARCH

Few studies have specifically identified interventions to preserve cognitive function among KT candidates and recipients. However, insight from the few published trials of patients undergoing dialysis and KT recipients suggest that exercise and cognitive training, as well as supplementation, may be components of a multimodal approach to preserve cognitive function. One gap in this emerging field of research is whether pre-transplant interventions preserve cognitive function among advanced, non-dialysis dependent patients with chronic kidney disease or among patients with ESKD waiting for KT, and whether this preserved cognitive function reduces the risk of post-KT delirium, cognitive decline, Alzheimer’s disease, and long-term mortality. Furthermore, it is unclear whether tailoring induction and/or maintenance immunosuppression would impact post-KT cognitive decline. Cognitive screening should be a standard part of KT evaluation and may help identify those KT candidates who may benefit most from exercise and/or cognitive training before and potentially after KT.^130,131

CONCLUSIONS

Among patients with ESKD, KT candidates, and KT recipients, cognitive impairment is common. Executive function, a domain that often declines prior to vascular dementia, is most often impaired in this population. Transition to maintenance dialysis marks the start of cognitive decline likely due to recurrent cerebral ischemia, retention of uremic toxins, and high burden of inactivity during each session. This cognitive decline likely continues while waiting for KT. The long-term adverse consequences of cognitive impairment go beyond dementia and mortality, and include decreased access to KT. Patients regain some global cognitive function in the first year after KT, yet the most vulnerable and frail still experience long-term cognitive decline. Potential interventions to preserve cognitive function this population include home-based and intradialytic exercise training, cognitive training, and B-vitamin supplementation. The long-term impact of these interventions among KT candidates and recipients remains an open area of research.

Figure 1.

Conceptual Framework of Non-pharmacologic Intradialytic Cognitive Interventions on Short- and Long-term Outcomes Among Kidney Transplant Recipients.