Cerebrovascular Response during Acute Exercise in Kidney Transplant Recipients

Despite well-known benefits of kidney transplantation, the risk of stroke and cognitive impairment (1) remain higher in transplant recipients than the general population. Underlying mechanisms may not be solely related to eGFR (2), and altered cerebral blood flow (3) and possibly cerebrovascular response may contribute. Middle cerebral artery blood velocity (MCA_V) response to exercise quantifies the physiologic increase in cerebral blood flow with exercise and determines the ability to maintain cerebral blood flow through physiologic stresses; it is measured by the increase in MCA_V from rest to steady-state exercise (4,5). We hypothesized that kidney transplant recipients have a blunted MCA_V response and impaired MCA_V kinetics response profile with exercise.

In this cross-sectional, observational study, we compared MCAv response and MCA_V kinetics response profile with exercise in 50 kidney transplant recipients to 50 age- and sex-matched healthy controls without CKD using transcranial Doppler ultrasound during an acute bout of moderate-intensity exercise. We enrolled transplant recipients from our transplant clinic, and healthy controls from the community by word-of-mouth and flyers. All experimental procedures were approved by the Human Subjects Committee, and all participants gave informed consent. Inclusion criteria were: age 20–85 years, ≥3 months since transplantation, stable kidney function, a serum creatinine <3 mg/dl, and ability to perform moderate-intensity exercise. Patients were excluded if they had a dual organ transplant, acute stroke, concussion, traumatic brain injury, Parkinson’s disease, dementia, multiple sclerosis, severe pulmonary disease or dependency on supplemental oxygen, or if they were using antipsychotics or antiepileptics. Participants were excluded from the analysis if study staff were not able to acquire MCA signal using transcranial Doppler ultrasound. All transplant recipients were on calcineurin inhibitors per institutional protocol.

The experimental protocol used was identical to our prior work (4,5). Briefly, beat to beat heart rate (HR), mean arterial pressure, MCA_V, and end-tidal carbon dioxide (P_ETCO₂) were measured at rest and at steady state moderate-intensity exercise defined as 45%–55% of HR reserve calculated using the Karvonen formula. Participants completed two exercise bouts and data points were averaged to optimize signal-to-noise ratio. Our primary outcome, MCAv response to exercise, was calculated as the change in mean beat to beat MCA_V from rest to steady-state moderate-intensity exercise. Our secondary outcome, MCA_V kinetics response profile, was measured using 3-second time-binned means over the entire rest and exercise bout with a mono-exponential model:

$${\text{MCA}}_{\mathrm{V}}\left(\mathrm{t}\right)=\text{BL}+\text{Amp}\left(1-{\mathrm{e}}^{-\left(\mathrm{t}-\text{TD}\right)/\tau )}\right)$$

where MCA_V(t) is the MCA_V at any point in time, BL is the baseline resting MCA_V prior to starting exercise, TD is the time delay preceding the exponential increase in MCA_V, Amp is the peak amplitude of the response, and tau (τ) is the time constant.

Demographic characteristics, MCAv response to exercise, and MCA_V kinetics response profile are presented in Table 1. Baseline mean arterial pressure and HR were higher in the transplant recipients. There was no difference in resting MCA_V between transplant recipients and controls (P=0.31), likely because the two groups were age-matched (4). P_ETCO₂ monitoring did not reveal hyperventilation. Both groups reached moderate-intensity exercise. However, transplant recipients reached a similar HR at a lower work rate, likely indicating that they were more “deconditioned” than the controls. Transplant recipients had a blunted MCAv response to exercise (P=0.003). There was no association between MCAv response to exercise and duration of dialysis or time since transplantation. Because of poor model fit (i.e., nonexponential response), three transplant recipients were excluded from the MCA_V kinetics response profile analysis. Transplant recipients achieved target HR at lower work rates (P<0.001) with a shorter time delay (P<0.001) and a lower amplitude (P=0.003) but similar τ (P=0.52).

Table 1.

Participant characteristics, cerebrovascular response, and middle cerebral artery kinetics response during acute bout of moderate-intensity exercise

Patient Characteristics	Healthy Controls (n=50)	Transplant Recipients (n=50)	P Value
Participant demographics
Age, yr, mean ± SD	52±15	51±12
Male, n (%)	31 (62)	31 (62)
Race, n (%)
White	40 (80)	43 (86)
Black	1 (2)	3 (6)
Asian	7 (14)	1 (2)
Other	2 (4)	3 (6)
Comorbid conditions, n (%)
Coronary artery disease	4 (8)	7 (14)
Diabetes mellitus	1 (2)	11 (39)
Hypertension	7 (14)	46 (92)
Stroke	0 (0)	0 (0)
Smoking	1 (2)	4 (8)
Arrhythmias		3 (6)
Depression		10 (20)
Transplant recipient–specific characteristics
Cause of kidney failure, n (%)
Diabetes mellitus		2 (4)
Hypertension		5 (10)
ADPKD		15 (30)
Other		28 (56)
Dialysis modality prior to transplant, n (%)
Not on dialysis		17 (34)
In-center hemodialysis		21 (42)
Home hemodialysis		2 (4)
Peritoneal dialysis		10 (20)
Duration of dialysis prior to transplant, d, mean±SD		572±750
Time since transplant, d, mean±SD		2389±2125
eGFR ml/min per 1.73 m2, mean±SD		62±3
Cerebrovascular response and middle cerebral artery velocity kinetics response, mean±SD
Resting MAP, mm Hg	76±13	96±21	<0.001
Resting HR, bpm	69±10	75±12	0.006
Resting PETCO2, mm Hg	34±4	32±3	0.002
Resting MCAv, cm/s	53.1±9.2	55.7±14.6	0.31
MCAv response to exercise, cm/s	12.4±5.7	9.1±4.9	0.003
Work rate, Wa	115.3±29.5	83.6±16.1	<0.001
Time delay, sa	51±31	23±41	<0.001
Amplitude, cm/sa	12.2±5.7	9.3±4.3	0.003
Time constant, τ, sa	36±26	43±40	0.52
Steady-state MAP, mm Hga	100±19	120±22	<0.001
Steady-state HR, bpma	113±13	111±20	0.58
Steady-state PETCO2, mm Hg	40±6	36±4	<0.001

Baseline demographics of kidney transplant recipients and heathy controls are compared using descriptive statistics. For categorical variables, nonparametric Fisher exact test and chi-squared test of independence were used. For continuous variables, parametric (Welch t test) and nonparametric tests (Mann–Whitney U test) as appropriate following Shapiro–Wilk tests were used. Multiple linear regression analyses were used to assess the effect of duration of dialysis and time since kidney transplantation on MCAv response to exercise. Statistical significance was evaluated at α=0.05. ADPKD, autosomal polycystic kidney disease; eGFR, estimated glomerular filtration rate; MAP, mean arterial pressure; HR, heart rate; bpm, beats per minute; P_ETCO₂, end tidal carbon dioxide; MCAv, middle cerebral artery velocity,

^aThe MCAv kinetics profile, i.e., work rate, time delay, amplitude, time constant, steady-state MAP, steady-state heart rate, and steady-state P_ETCO₂ were reported for 47 kidney transplant recipients and 47 healthy controls as three kidney transplant recipients did not have a detectable change in MCAv.

Thus, even after restoration of kidney function with transplantation, MCAv response to exercise remains blunted. This inability to adequately increase MCA_V with exercise might explain the higher risk of cerebrovascular events, cognitive impairment, and dementia in transplant recipients. The blunted MCAv response to exercise could be related to vascular stiffness because of long-standing hypertension and other comorbidities associated with CKD (independent of kidney function) and/or possible role of calcineurin inhibitors leading to persistent cerebrovascular dysregulation post-transplant.

Few prior studies have evaluated MCAv response to exercise in CKD, and none have evaluated MCA_V kinetics response profile. MCAv response to exercise is blunted with aging (4), and with stroke (5). However, time delay does not decrease with age. A shorter time delay represents a faster change in MCA_V with exercise and could represent a high basal metabolic need, an impaired regulatory response, or a lower cerebral reserve where the MCA_V has to increase sooner to meet the metabolic demands.

Our study has limitations. The use of transcranial Doppler ultrasound assumes a constant MCA diameter for MCA_V to be used as a direct proxy for cerebral blood flow. We are unable to model the dynamic response of P_ETCO₂ as postprocessed data for MCA_V are beat to beat and for P_ETCO₂ data are breath by breath.

In summary, kidney transplant recipients have a blunted MCAv response and altered MCA_V kinetics response profile with exercise. Future longitudinal studies can help understand the cause and prognostic significance of the blunted MCAv response to exercise in kidney transplantation and CKD.

Disclosures

A. Gupta reports consultancy agreements with Novartis Pharmaceuticals; receiving research funding from the National Institutes of Health, Novartis, and Veloxis; receiving honoraria from UpToDate; and serving on the regional medical advisory board for the National Kidney Foundation and on the editorial board of Kidney Medicine. All remaining authors have nothing to disclose.

Funding

This work was supported by National Institutes of Health grant K23 AG055666 (to A. Gupta), an investigator-initiated grant from Novartis Pharmaceuticals (to A. Gupta), and an investigator-initiated grant from Veloxis Pharmaceuticals (to A. Gupta). The data collected were not shared with Novartis and Veloxis pharmaceuticals, and Novartis and Veloxis pharmaceuticals were not involved in the conduct of the study, data collection, analysis, or interpretation.