To the Editor:
Cognitive impairment, including dementia, affects up to 70% of individuals receiving
maintenance hemodialysis,
1
a prevalence that exceeds that of the elderly general population by 3- to 7-fold.
2
Cardiometabolic risk factors for dementia, such as diabetes, hypercholesterolemia,
hypertension, and vascular disease, are highly prevalent in end-stage kidney disease.
3
However, the rate of new-onset dementia is higher among hemodialysis patients compared
with peritoneal dialysis patients,
4
suggesting that aspects of the hemodialysis procedure may contribute to the development
of dementia.
Imaging studies show that hemodialysis can cause significant circulatory stress via
ultrafiltration-induced hypoperfusion of vital vascular beds, including the brain.
5
Maintenance of adequate cerebral perfusion during dialysis is dependent on intradialytic
blood pressure and the brain’s intrinsic ability to preserve relatively constant blood
flow despite changes in perfusion pressure. Hemodialysis patients may be particularly
susceptible to the neurologic consequences of dialysis-induced blood pressure declines
due, in part, to diminished autoregulatory capacity from autonomic and endothelial
dysfunction.6, 7 It is thus plausible that repeated exposure to intradialytic hypotension
(IDH) and associated cerebral hypoperfusion may increase dementia risk. In fact, general
population data indicate that orthostatic hypotension
8
as well as cerebral hypoperfusion
9
are associated with accelerated cognitive decline and a higher risk of new-onset dementia.
Although a recent study found an association between IDH and reversible cognitive
decline in the immediate post-dialysis period,
10
the relationship between long-term, cumulative IDH exposure and the development of
dementia in the hemodialysis population has not been established.
The objective of our study was to examine the association between the cumulative exposure
to frequent IDH and the 5-year risk of new-onset dementia among elderly individuals
initiating maintenance hemodialysis at a large U.S. dialysis organization. After a
30-day lag period following hemodialysis initiation, we determined if patients experienced
frequent IDH in successive 90-day exposure intervals (Supplementary Figure S1). Within
a given exposure interval, we classified an individual as having frequent IDH if he
or she experienced a nadir intradialytic systolic blood pressure <90 mm Hg in at least
30% of hemodialysis treatments. This IDH definition has been associated with all-cause
mortality, an important competing event in our analysis.
11
We evaluated the association between the time-updated, cumulative number of exposure
intervals with frequent IDH after dialysis initiation and new-onset dementia using
marginal structural Fine and Gray proportional subdistribution hazards models. All-cause
death was treated as a competing event.
A total of 31,055 individuals initiated maintenance hemodialysis from June 1, 2005,
to October 1, 2013, and met study selection criteria (Supplementary Table S1). The
study cohort had an average age of 76.0 ± 6.6 years, 46.2% were women, 19.9% were
black, 8.7% were Hispanic, and the most common cause of end-stage kidney disease was
diabetes (43.7%). Baseline cardiovascular comorbid conditions were common: 39.9% of
the cohort had an arrhythmia or conduction disorder, 59.2% had heart failure, 56.0%
had ischemic heart disease, 29.1% had peripheral arterial disease and 18.8% had a
history of stroke (Table 1 and Supplementary Table S2).
Table 1
Select characteristics of the study cohort at baseline
Characteristic
Total study population (N = 31,055)
Age at dialysis initiation, yr
76.0 ± 6.6
Female
14,359 (46.2)
Race
Black
6179 (19.9)
White
23,356 (75.2)
Other
1520 (4.9)
Hispanic
2705 (8.7)
Cause of end-stage kidney disease
Diabetes
13,565 (43.7)
Hypertension
11,636 (37.5)
Glomerular disease
1742 (5.6)
Other
4112 (13.2)
Current smoker at dialysis initiation
1090 (3.5)
Inpatient dialysis initiation
13,054 (42.0)
Vascular access
Catheter
22,398 (72.1)
Fistula
6580 (21.2)
Graft
2077 (6.7)
Arrhythmia or conduction disorder
12,393 (39.9)
Diabetes
20,379 (65.6)
Dyslipidemia
9972 (32.1)
Heart failure
18,370 (59.2)
Ischemic heart disease
17,398 (56.0)
Peripheral arterial disease
9046 (29.1)
Stroke
5834 (18.8)
Valvular disease
2464 (7.9)
Pre-dialysis systolic blood pressure, mm Hg
≤130
8475 (27.3)
131–150
12,240 (39.4)
151–170
7736 (24.9)
≥171
2604 (8.4)
Values are given as number (percent) for categorical variables and as mean ± SD for
continuous variables. Baseline covariates, including demographics, comorbid conditions,
and health care utilization metrics were obtained in the 365 days preceding dialysis
initiation. Baseline laboratory and dialysis treatment-related covariates were obtained
in the 30 days immediately after dialysis initiation. The complete list of study cohort
baseline characteristics is displayed in Supplementary Table S2.
The cohort was followed for a total of 64,982 person-years and had an average follow-up
duration of 2.1 ± 1.6 years. During the 5-year follow-up period, 4991 individuals
developed all-cause dementia (incidence rate = 7.7 cases of new-onset dementia/100
person-years) and 11,037 individuals died (incidence rate = 17.0 deaths/100 person-years).
Greater cumulative exposure to frequent IDH after hemodialysis initiation was incrementally
associated with a higher 5-year risk of new-onset dementia (Figure 1). Individuals
who experienced frequent IDH in ≥ 7 (vs. zero) 90-day exposure intervals across time
had the highest 5-year risk of new-onset dementia (hazard ratio [95% confidence interval] =
1.36 [1.20–1.48]).
Figure 1
Association between time-updated, cumulative exposure to frequent intradialytic hypotension
and the 5-year risk of new-onset dementia. We used marginal structural Fine and Gray
proportional subdistribution hazard models, treating death as a competing event, to
estimate association between the time-updated, cumulative exposure to frequent intradialytic
hypotension and the 5-year risk of new-onset dementia. Within a given 90-day exposure
interval, we classified an individual as having frequent intradialytic hypotension
if he or she experienced a nadir intradialytic systolic blood pressure <90 mm Hg in
at least 30% of hemodialysis treatments. Supplementary Table S3 contains outcome and
competing event definitions. We used inverse probability of exposure weighting to
adjust for baseline and time-updated covariates listed in Supplementary Table S4.
CI, confidence interval; HR, hazard ratio.
We provide initial evidence linking cumulative IDH exposure to new-onset dementia
among individuals receiving maintenance hemodialysis. Prior mechanistic studies have
shown that hemodialysis-induced circulatory stress may contribute to the development
of cerebral ischemic injury, but these studies were not powered to consider clinical
outcomes. For example, in a cross-sectional study of 12 elderly hemodialysis patients
from the Netherlands, Polinder-Bos et al.
5
demonstrated that hemodialysis induces a significant reduction in global and regional
cerebral blood flow. In a pilot study of 58 prevalent hemodialysis patients from the
United Kingdom, MacEwen et al.
12
found that more pronounced declines in intradialytic mean arterial pressure associated
with a higher incidence of intradialytic cerebral ischemic episodes. Furthermore,
in a prospective cohort study of 32 nondiabetic, Japanese hemodialysis patients, Mizumasa
et al.
13
noted that the number of IDH episodes (defined as a fall in systolic blood pressure
>50 mm Hg within 30 minutes of starting hemodialysis plus associated symptoms of hypoperfusion)
across time was weakly correlated with greater cerebral frontal lobe atrophy.
Our findings extend this mechanistic evidence by linking frequent IDH to the clinical
outcome of new-onset dementia. Dementia is associated with a range of adverse outcomes,
including lower quality of life
14
and treatment nonadherence,
15
as well as higher hospitalization and mortality rates.16, 17 Therefore, identification
of effective interventions that reduce dementia risk is needed to improve patient
outcomes. One promising hemodialysis-based intervention may be the use of cooled dialysate.
Cooled dialysate reduces intradialytic hemodynamic instability,
18
likely via cold-induced vasoconstriction and associated improvements in systemic vascular
resistance during ultrafiltration. In a randomized controlled trial of 73 incident
hemodialysis patients from the United Kingdom, Eldehni et al.
19
found that hemodialysis with cooled dialysate (0.5°C below core body temperature)
versus standard temperature dialysate (37°C) led to preservation of brain white matter
microstructure at 1 year. This relatively low-risk intervention may be a viable, low-cost
neuroprotective treatment strategy for individuals initiating hemodialysis. Other
potential IDH reduction strategies include treatment time extension, more frequent
dialysis, and ultrafiltration profiling, but supporting data, particularly with regard
to the latter, are limited.
In conclusion, we found that increased cumulative exposure to frequent IDH after dialysis
initiation was incrementally associated with a higher 5-year risk of new-onset dementia
in a cohort of more than 30,000 elderly hemodialysis patients. Interventional studies
are needed to determine if IDH mitigation reduces dementia risk among individuals
receiving maintenance hemodialysis.
Disclosure
MMA and JEF received investigator-initiated research funding from the Renal Research
Institute, a subsidiary of Fresenius Medical Care, North America. JEF received speaking
honoraria from American Renal Associates, American Society of Nephrology, Dialysis
Clinic, Incorporated, National Kidney Foundation, and multiple universities; consulting
fees from Fresenius Medical Care, North America; and serves on the medical advisory
board to NxStage Medical. LW declared no competing interests.