Association of cardiovascular structure and function with cerebrovascular changes and cognitive function in older patients with end-stage renal disease

Introduction

Cardiovascular diseases and cognitive impairment are frequent and increasingly prevalent, especially in older patients and patients with end-stage renal disease (ESRD) [1–4]. Both chronic kidney disease, especially ESRD, and cardiovascular diseases have been identified as independent risk factors for the development of microvascular damage and cerebral small vessel disease, which can lead to structural cerebrovascular changes and cognitive impairment [5–9]. It is, however, unknown how cardiovascular structure and function associates with brain structure and function in older patients with ESRD.

In ESRD nephrogenic factors as uremic toxins, anaemia and inflammation, are potential underlying mechanisms for the development of cerebrovascular changes and cognitive impairment [9]. Furthermore, cardiovascular risk factors can lead to microvascular damage in both the brain and kidney [9, 10]. The association between cardiovascular structure and function with both cerebrovascular changes and cognitive impairment can be divided into two possible mechanisms in the general population, namely increased arterial stiffness and impaired systolic heart function. Arterial stiffness can cause microvascular damage in the brain due to an increased impact of pulsatility on the microvasculature, which possibly alters brain structure or cognitive functioning [11–13]. Furthermore, impaired systolic heart function could cause cerebral ischemia because of hypoperfusion in the brain due to decreased cardiac output [14–17]. To what extent an altered cardiac structure and function play a role in cerebrovascular changes and cognitive impairment in older patients with ESRD remains unclear.

Figure 1 shows the hypothesis of the current study as well as the potential underlying mechanisms. The aim of this study was to investigate the association of cardiovascular structure and function with cerebrovascular changes and cognitive function in older patients with ESRD.

Figure 1. The heart-kidney-brain axis. Hypothesis of the current study and the potential underlying pathophysiological mechanisms in the heart-kidney-brain axis.

Results

Of the 157 patients included in the ‘The Cognitive decline in Older Patients with End stage renal disease’ (COPE) study, cardiac magnetic resonance imaging (MRI) scans were available for 85 participants, see the flowchart in Figure 2. Baseline characteristics of all patients are shown in Table 1. Mean±standard deviation (SD) of age was 75.6±6.9years and 56 (66%) patients were male. Mean±SD eGFR at time of inclusion was 15.8±4.2ml/min/1.73m². The origin of primary kidney disease was non-vascular in 36% and vascular (mainly diabetes and hypertension) in 64% of all patients. Median [interquartile range (IQR)] pulse wave velocity (PWV) was 9.6m/s [7.8-13.0], ejection fraction (EF) 62% [51–66] and cardiac index (CI) 2.5l/min/m² [2.1-3.0]. Global cognition in the total population was not impaired, measured by the MMSE with median [IQR] 28 [27–30] out of 30 points and also clock drawing with a median [IQR] of 12 [11–13]. Differences in baseline characteristics for each subgroup of PWV, EF and CI are shown in Supplementary Tables 1–3.

Figure 2. Flowchart study population. Inclusion and exclusion criteria of the COPE (The Cognitive decline in Older Patients with End stage renal disease) study.

Table 1. Baseline characteristics total population (n=85).

Male gender, n (%)	56 (65.9)
Age, years; mean ± SD	75.6 ± 6.9
Race, Caucasian, n (%)	75 (88.2)
Higher educational level, n (%)	32 (37.6)
Primary kidney disease, n (%)
Non-vascular cause	30 (35.7)
Vascular cause	54 (64.3)
Comorbidity, n (%)
Diabetes mellitus	32 (37.6)
Peripheral vascular disease	16 (18.8)
Cerebral vascular accident	23 (27.1)
Heart failure	7 (8.2)
Coronary heart disease	18 (21.2)
Atrial fibrillation	17 (20.5)
Alcohol consumption, n (%)	45 (52.9)
Current smoking, n (%)	14 (16.5)
History of smoking, n (%)	49 (57.6)
Medication use, n (%)
Polypharmacy (the use of ≥5 medications)	75 (88.2)
Antihypertensive medication	79 (92.9)
Beta-blockers	44 (51.8)
Diuretics	50 (58.8)
Objective measures, mean ± SD
Blood pressure (mmHg)
Systolic	150.3 ± 22.2
Diastolic	81.6 ± 11.8
eGFR (ml/min/1.73m2)	15.8 ± 4.2
Urea (mg/dL)	21.3 ± 6.3
Phosphate (mmol/L)	1.32 ± 0.29
Albuminuria (mg/24 hours)	771 ± 882
Troponin (ng/L)	0.052 ± 0.070
NT-proBNP (ng/L)	879 ± 1208
Cardiovascular function, measured by MRI, median [IQR]
Pulse wave velocity (m/s)	9.6 [7.8-13.0]
Ejection fraction (%)	62 [51–66]
Cardiac index (l/min/m2)	2.5 [2.1-3.0]
Cerebrovascular changes, measured by MRI, n (%) or mean ± SD
Presence of microbleeds
Non-lobar	18 (21.2)
Lobar	32 (37.6)
Presence of lacunes*	39 (45.9)
Total white matter hyperintensities	16.1 ± 8.0
Cognitive function performance, mean ± SD or median [IQR]
Global cognition
Mini-Mental State Examination (points)	28 [27–30]
Visuoconstruction
Clock drawing	12 [11–13]
Memory
15-WVLT immediate recall	32.3 ± 10.1
15-WVLT delayed recall	6.3 ± 3.0
Visual Association Test	12 [11–12]
Executive function
TMT-B (sec)	157.0 ± 72.5
SCWT III (sec)	166.0 ± 90.0
SCWT III corrected for SCWT II (sec)	84.0 ± 81.6
Psychomotor Speed
LDST (correct in 60 sec)	22.9 ± 7.1
TMT-A (sec)	62.0 ± 39.0
SCWT II (sec)	82.5 ± 33.7
*Lacunes; both gliotic and hemorrhagic parenchymal defects subcortical, in brain stem and basal ganglia. Abbreviations: 15-WVLT, 15-Word Verbal Learning Test; eGFR, estimated glomerular filtration rate; LDST, Letter Digit Substitution Test; NT-proBNP, N-terminal pro b-type natriuretic peptide; SD, standard deviation; SCWT, Stroop Color and Word Test; TMT, Trail Making Test.

Cerebrovascular changes

Table 2 shows the association between cardiac parameters and cerebrovascular changes. No statistically significant associations were observed between cardiac parameters and cerebrovascular changes. Patients with a high PWV, and therefore high aortic stiffness, more often than with low PWV, had more structural cerebrovascular changes, including more microbleeds (both non-lobar and lobar) and lacunes, and a higher mean total white matter hyperintensities (WMH), although differences were of unknown clinical relevance and not statistically significant. Similar non-significant results were seen for patients with a low compared to high EF and a low compared to high CI. A sensitivity analysis based on median PWV, EF and CI and a sensitivity analysis excluding patients with a history of CVA yielded similar results.

Table 2. Association of cardiovascular function parameters and cerebrovascular changes.

	Better cardiovascular function	Worse cardiovascular function
	Pulse wave velocity ≤10m/s n = 45	Pulse wave velocity >10m/s n = 38	p-value
			Crude	Adjusted
Presence of microbleeds, %
Non-lobar	7 (16.7)	11 (28.9)	0.189	0.575
Lobar	13 (31.0)	18 (47.4)	0.132	0.105
Presence of lacunes, %	18 (42.9)	19 (50.0)	0.522	0.616
Total WMH, mean ± SE	15.5 ± 1.2	16.6 ± 1.4	0.561	0.438
	Ejection fraction ≥50% n = 65	Ejection fraction <50% n = 19
Presence of microbleeds, %
Non-lobar	13 (20.6)	5 (27.8)	0.520	0.563
Lobar	22 (34.9)	10 (55.6)	0.114	0.121
Presence of lacunes, %	29 (46.0)	10 (55.6)	0.476	0.767
Total WMH, mean ± SE	15.8 ± 0.9	16.9 ± 2.4	0.609	0.778
	Cardiac index >2.2l/min/m2 n = 56	Cardiac index ≤2.2l/min/m2 n = 27
Presence of microbleeds, %
Non-lobar	13 (23.6)	5 (20.0)	0.718	0.457
Lobar	23 (41.8)	8 (32.0)	0.403	0.382
Presence of lacunes, %	28 (50.9)	10 (40.0)	0.365	0.443
Total WMH, mean ± SE	17.0 ± 1.2	14.2 ± 1.3	0.151	0.166
P-values are assessed using linear or logistic regression models, unadjusted and adjusted for age and sex, comparing low versus high pulse wave velocity, ejection fraction and cardiac index.
Lacunes include both gliotic and hemorrhagic parenchymal defects subcortical, in brain stem and basal ganglia.
Abbreviations: SE, standard error; WMH, white matter hyperintensities.

Cognitive function

Table 3 shows the association between cardiac parameters and cognitive function in three different domains, namely memory, executive function and psychomotor speed. The scores of all cognitive function tests were worse for patients with a high compared to low PWV in all three domains, statistical significance was reached for the Trail Making Test B (TMTB) with a difference of 39 seconds (p=0.009), for Trail Making Test A (TMTA) with a difference of 23 seconds (p=0.008) and for the Letter Digit Substitution Test (LDST) with a difference of 4 correct answers in 60 seconds (p=0.021). After adjustment for age, sex and education, only the TMTA, measuring psychomotor speed, remained statistically significant (p=0.030). No clinically relevant nor statistically significant associations were found in cognitive function comparing patients with low compared to high EF. Patients with a low compared to high CI had a worse memory function (both immediate and delayed recall), which remained statistically significant for delayed recall after adjustment (p=0.003). No statistically significant differences were found in executive function or psychomotor speed. A sensitivity analysis based on median PWV, EF and CI and a sensitivity analysis excluding patients with a history of CVA yielded similar results.

Table 3. Association of cardiovascular function parameters and cognitive function.

	Better Cardiovascular function	Worse Cardiovascular function
	PWV ≤10m/s n=45	PWV >10m/s n=38	p-value
			Crude	Adjusted
Memory
15-Word Verbal Learning Test immediate recall ↓	33.3 ± 1.2	31.6 ± 2.0	0.455	0.899
15-Word Verbal Learning Test delayed recall ↓	6.6 ± 0.4	5.9 ± 0.6	0.307	0.719
Executive function
Trail Making Test B (sec) ↑	140.6 ± 9.6	179.3 ± 12.2	0.009	0.184
SCWT III (sec) ↑	158.3 ± 15.6	173.5 ± 11.8	0.439	0.339
SCWT III corrected for SCWT II (sec) ↑	80.5 ± 14.0	87.6 ± 11.1	0.692	0.148
Psychomotor speed
Letter Digit Substitution Test (correct in 60 sec) ↓	24.6 ± 0.9	20.9 ± 1.3	0.021	0.179
Trail Making Test A (sec) ↑	51.6 ± 2.5	74.6 ± 8.7	0.008	0.030
Stroop Color and Word Test II (sec) ↑	77.8 ± 3.9	87.0 ± 6.7	0.241	0.361
	EF ≥50% n=65	EF <50% n=19
Memory
15-Word Verbal Learning Test immediate recall ↓	32.1 ± 1.2	32.5 ± 2.8	0.881	0.621
15-Word Verbal Learning Test delayed recall ↓	6.4 ± 0.4	5.7 ± 0.8	0.426	0.664
Executive function
Trail Making Test B (sec) ↑	160.4 ± 8.9	153.4 ± 19.2	0.809	0.728
SCWT III (sec) ↑	166.7 ± 11.7	164.8 ± 19.1	0.940	0.669
SCWT III corrected for SCWT II (sec) ↑	86.4 ± 10.3	75.9 ± 19.8	0.633	0.392
Psychomotor Speed
Letter Digit Substitution Test (correct in 60 sec) ↓	23.4 ± 0.8	21.3 ± 1.9	0.265	0.383
Trail Making Test A (sec) ↑	59.2 ± 4.4	73.4 ± 12.3	0.186	0.274
Stroop Color and Word Test II (sec) ↑	80.9 ± 3.2	88.9 ± 12.8	0.377	0.459
	CI >2.2 l/min/m2 n=56	CI≤2.2 l/min/m2 n=27
Memory
15-Word Verbal Learning Test immediate recall ↓	33.2 ± 1.4	30.1 ± 1.9	0.207	0.219
15-Word Verbal Learning Test delayed recall ↓	6.9 ± 0.4	4.9 ± 0.5	0.004	0.003
Executive function
Trail Making Test B (sec) ↑	149.6 ± 8.7	176. ± 16.6	0.156	0.191
SCWT III (sec) ↑	164.5 ± 13.1	171.4 ± 15.6	0.748	0.978
SCWT III corrected for SCWT II (sec) ↑	85.1 ± 12.9	84.3 ± 10.0	0.966	0.712
Psychomotor Speed
Letter Digit Substitution Test (correct in 60 sec) ↓	23.4 ± 0.9	21.5 ± 1.5	0.266	0.349
Trail Making Test A (sec) ↑	59.9 ± 4.4	68.1 ± 10.1	0.384	0.414
Stroop Color and Word Test II (sec) ↑	80.2 ± 4.6	87.1 ± 6.5	0.387	0.428
Values are mean ± SE. ↓↑ indicates that a higher (↑) or lower (↓) score means a worse cognitive function.
P-values are assessed using linear regression models, unadjusted and multivariate adjusted for age, sex and education, comparing low versus high pulse wave velocity, ejection fraction and cardiac index.
Abbreviations: CI, cardiac index; EF, ejection fraction; PWV, pulse wave velocity

Abbreviations

15-WVLT: 15-Word Verbal Learning Test, immediate and delayed; BMI: body mass index; CI: cardiac index; COPE: Cognitive decline in Older Patients with End stage renal disease; EF: ejection fraction; eGFR: estimated glomerular filtration rate; ESRD: end-stage renal disease; IQR: interquartile range; LDST: Letter Digit Substitution Test; MMSE: Mini-Mental State Examination; MRI: magnetic resonance imaging; PWV: pulse wave velocity; SCWT: Stroop Color and Word Test; SD: standard deviation; SE: standard error; TMTA/TMTB: Trail Making Test A&B ; VAT: Visual Association Test ; WMH: white matter hyperintensities.

Author Contributions

Laurien E. Zijlstra, Conception and design of the study; analysis and interpretation of data; drafting of the manuscript; providing intellectual content of critical importance to the work described; final approval of the manuscript, Stella Trompet, Conception and design of the study; analysis and interpretation of data; revising of the manuscript; providing intellectual content of critical importance to the work described; final approval of the manuscript, J. Wouter Jukema, Conception and design of the study; analysis and interpretation of data; revising of the manuscript; providing intellectual content of critical importance to the work described; final approval of the manuscript, Lucia J.M. Kroft, Conception and design of the study; analysis and interpretation of data; revising of the manuscript; providing intellectual content of critical importance to the work described; final approval of the manuscript, Jeroen de Bresser, Conception and design of the study; analysis and interpretation of data; revising of the manuscript; providing intellectual content of critical importance to the work described; final approval of the manuscript, Matthias J.P. van Osch, Conception and design of the study; analysis and interpretation of data; revising of the manuscript; providing intellectual content of critical importance to the work described; final approval of the manuscript, Sebastiaan Hammer, Conception and design of the study; analysis and interpretation of data; revising of the manuscript; providing intellectual content of critical importance to the work described; final approval of the manuscript, Marie-Noëlle Witjes, Revising of the manuscript; providing intellectual content of critical importance to the work described; final approval of the manuscript, Marjolijn van Buren*, Conception and design of the study; analysis and interpretation of data; revising of the manuscript; providing intellectual content of critical importance to the work described; final approval of the manuscript, Simon P. Mooijaart*, Conception and design of the study; analysis and interpretation of data; revising of the manuscript; providing intellectual content of critical importance to the work described; final approval of the manuscript. * Van Buren and Mooijaart (shared last authors) contributed equally to this work.

Conflicts of Interest

M.J.P. van Osch reports receiving research support from Philips. No other competing conflicts of interest, financial or otherwise, are declared by the other authors.

Funding

This study was supported by a grant of Roche Nederland BV. The sponsor did not play a role in the preparation of this article.

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