Characteristics of cerebrovascular disease in patients with CKD
Effect of CKD on incident cerebrovascular disease
The prevalence of CKD in patients with cerebrovascular disease is 20–35 % and 20–46 %
in patients with brain infarction and brain hemorrhage, respectively. Recent prospective
studies have demonstrated that renal dysfunction and proteinuria are independent risk
factors for incident cerebrovascular disease 2]. In contrast to a decrease in brain hemorrhage, the proportion of brain infarction
is increasing. A possible reason for this finding could be developments in hemodialysis
that have led to expansion of the indications for hemodialysis among older patients
with multiple risk factors. In addition, use of erythropoiesis-stimulating agents
to treat anemia might, to some extent, have increased thromboembolic events. A possible
reason for the relative decrease in brain hemorrhage could be a decrease in heparin
dose during dialysis according to improvement in dialysis membranes. Additionally,
low-molecular weight heparin instead of unfractionated heparin has been used for patients
at high risk for hemorrhagic complications, although this has not frequently been
performed 3].
Effect of CKD on the severity of cerebrovascular disease
CKD is considered to affect not only the incidence of cerebrovascular disease but
also its severity. In the Fukuoka Stroke Registry Study, it was reported that patients
with CKD had significantly higher risks of neurological deterioration, in-hospital
mortality, and poor functional outcome 4], 5]. These reports also demonstrated that among the CKD components, a higher urinary
protein level was associated with an elevated risk of each outcome. Severity of cerebrovascular
disease is more prominent in dialysis patients compared to those with non-dialysis
dependent CKD, and brain hematoma after hemorrhagic stroke is larger and the prognosis
is poorer in hemodialysis patients 1], 2], 6].
Effect of a decrease in brain blood volume on cerebrovascular disease during and after
hemodialysis
Cerebral infarction often occurs within 6 h after the end of hemodialysis 7]. A decrease in blood pressure has been reported to be more pronounced in patients
who developed infarction soon after the end of dialysis than those who developed it
6 h or longer after the end of dialysis 1]. The mechanisms of hemodialysis-induced cerebral infarction include a reduction in
cerebral blood flow due to increased blood viscosity and a fall in blood pressure
associated with water removal or orthopedic hypotension following sitting up or standing
up after dialysis.
Elderly patients and those with diabetes mellitus (DM) have severe systemic atherosclerosis
and are prone to develop dialysis-related hypotension and orthostatic hypotension.
Hemodynamic brain infarction might be induced in these patients because of a damaged
brain autoregulation system 8]. To evaluate cerebral circulation during orthostasis in patients with DM, we examined
changes in mean blood flow velocity in the middle cerebral artery during 60° of head-up
tilt for 5 min in patients with DM by using transcranial Doppler sonography. We compared
our findings with those in hemodialysis patients without DM in the supine position
9]. We found a significant decrease in cerebral blood flow velocity during tilt of equal
magnitude in both groups before hemodialysis, despite differences in the level of
hypotension, whereas reduction in cerebral blood flow velocity and a decrease in mean
blood pressure were more marked in DM after hemodialysis (Fig. 1). Therefore, orthostasis can cause hemodynamically mediated brain damage after hemodialysis,
especially in patients with DM.
Fig. 1. Percentage of change in mean blood flow velocity of the middle cerebral artery during
tilt before and after hemodialysis. There are no significant differences in percentage
of change in mean blood flow velocity of the middle cerebral artery (gray bars) between DM and non-DM patients before hemodialysis, whereas percent reduction of
mean blood flow velocity of the middle cerebral artery after hemodialysis (black bars) in patients with DM is greater (approximately threefold) than that before hemodialysis
(P??0.01) and also greater than in non-DM patients after hemodialysis (P??0.01). Abbreviations: DM diabetes mellitus, %MCVm percentage of the change in the mean middle cerebral artery flow velocity. From Ishida
et al. 9]
Prevention of cerebrovascular disease
Anticoagulant therapy for hemodialysis patients with atrial fibrillation
Effect of atrial fibrillation on thromboembolic complications
Whether atrial fibrillation increases thromboembolic complications in hemodialysis
patients is controversial. Vázquez et al. 10], 11] reported that atrial fibrillation is relatively prevalent and its presence increases
mortality and the risk of ischemic stroke. However, Wiesholzer et al. 12] reported that atrial fibrillation itself is not associated with an increased risk
of stroke in patients on maintenance hemodialysis. Furthermore, Genovesi et al. 13] demonstrated that rates of stroke did not significantly differ by atrial fibrillation
status, although patients with atrial fibrillation were hospitalized more frequently
than those without atrial fibrillation.
Advantages and disadvantages of administration of warfarin
Whether warfarin should be administered to chronic hemodialysis patients with atrial
fibrillation is also controversial. Chan et al. 14] investigated the association between this medication and new stroke, mortality, and
hospitalization in a retrospective cohort analysis of 1671 incident hemodialysis patients
with preexisting atrial fibrillation. They showed that warfarin use was associated
with a significantly increased risk for new stroke. They also demonstrated that warfarin
users who received no international normalized ratio monitoring had the highest risk
for stroke compared with nonusers. Thereafter, similar, large-scale, observational
studies were conducted, and they concluded that warfarin use is not beneficial in
reducing the risk of stroke, but it is associated with a higher bleeding risk in patients
with atrial fibrillation undergoing dialysis 15]–17].
In contrast, only one large-scale study has recently shown usefulness of warfarin
in hemodialysis patients with atrial fibrillation. Olesen et al. 18] conducted a study using Danish national registries in which all 132,372 patients,
including 3587 with non-dialysis-dependent CKD and 901 with ESKD, were identified
to be discharged from the hospital with a diagnosis of non-valvular atrial fibrillation
between 1997 and 2008. They estimated the risk of stroke or systemic thromboembolism
and bleeding with the use of time-dependent Cox regression analyses and compared the
effects of treatment with warfarin, aspirin, or both in patients with or without CKD.
They showed that the risk of stroke or systemic thromboembolism was increased in patients
with CKD and ESKD compared with those without CKD, and such risk was decreased by
treatment with warfarin in both groups of patients with CKD and ESKD.
However, there were several limitations to this study. A larger proportion of dialysis
patients had unusually low HAS-BLED scores (HAS-BLED score 2–35 % (312/901); 0 or
1–43 % (390/901)). Contrary to Shah’s study and DOPPS, dialysis patients had a low
prevalence of diabetes mellitus (14 % (129/901)) and hypertension (54 % (486/901)).
It is possible that a selection bias of healthier patients undergoing dialysis could
explain the reason for the decreased risk of stroke with warfarin use in the study
by Olesen et al.
As described above, the usefulness of warfarin has not been established in hemodialysis
patients with atrial fibrillation in most recently reported large-scale, observational
studies (Fig. 2) 17]. In Japan, guidelines for management of cardiovascular disease in patients on chronic
hemodialysis published by the Japanese Society for Dialysis Therapy 1] suggest that warfarin therapy should not be routinely performed for atrial fibrillation.
However, if considered beneficial, such therapy is desirable to use by maintaining
the prothrombin time-international normalized ratio at 2.0. The Canadian Cardiovascular
Society Atrial Fibrillation Guidelines 19] also suggest that patients with an estimated glomerular filtration rate 15 mL/min/1.73 m
2
(on dialysis) should not routinely receive either oral anticoagulants or aspirin for
prevention of stroke in atrial fibrillation.
Fig. 2. Warfarin use and the risk for stroke in patients with atrial fibrillation undergoing
dialysis. Results of evidence from previous published studies of warfarin use and
the risk for stroke in patients with atrial fibrillation undergoing dialysis are shown.
Abbreviation: CI confidence interval. From Shah et al. 17]
Novel oral anticoagulants for patients with CKD
Recently, novel oral anticoagulants (NOACs), such as dabigatran, rivaroxaban, apixaban,
and edoxaban, were developed and clinically approved. These drugs are superior to
warfarin for prevention of ischemic stroke, systemic embolic events, intracranial
hemorrhage, and all-cause mortality 20].
Because these drugs are excreted from the body via the kidney, using these drugs in
patients with severe CKD is considered difficult. A systematic review of randomized,
controlled trials was conducted in patients with CKD and defined creatinine clearance
(Ccr) as 30–50 mL/min. This review demonstrated that the use of NOACs in select patients
with CKD is effective and safe, similar to warfarin 21].
Recently, the relationship between NOACs and activated partial thromboplastin time
(aPTT) has been focused in the careful monitoring. Shimomura et al. 22] analyzed plasma dabigatran concentration and aPTT at various time points following
administration of oral dabigatran in 149 patients with non-valvular atrial fibrillation.
They demonstrated that there was a significant correlation between plasma dabigatran
concentrations and aPTT and concluded that considering the pharmacokinetics of dabigatran,
aPTT can be used as an index for risk screening for excess dabigatran concentrations
in Japanese patients. However, they also showed that significantly higher dabigatran
concentrations were observed in samples from patients with reduced renal function
(Ccr 50 mL/min) compared with those with normal renal function (Ccr ?50 mL/min),
and the correlation was lower when plasma dabigatran concentrations were higher, suggesting
the difficulties for monitoring of dabigatran concentrations using aPTT in CKD patients.
The use of NOACs in dialysis patients is discouraged because these drugs can bioaccumulate
to precipitate inadvertent bleeding. However, in the USA, dabigatran and rivaroxaban
use in dialysis patients with atrial fibrillation has steadily risen to where 5.9 %
of anticoagulated dialysis patients are started on dabigatran or rivaroxaban. Chan
et al. 23] reported that in covariate-adjusted Poisson regression, dabigatran and rivaroxaban
were associated with a higher risk of hospitalization or death from bleeding compared
with warfarin. Additionally, the risk of hemorrhagic death was even larger with dabigatran
and rivaroxaban relative to warfarin, although there were too few events in the study
to detect meaningful differences in stroke and arterial embolism between the drug
groups 23].
Prevalence of cerebral microbleeds and risk of brain hemorrhage
Cerebral microbleeds appearing as low-signal-intensity areas by T2*-weighted magnetic
resonance imaging (MRI) are frequently detected in patients with hypertension and
those with a history of cerebrovascular disorders. Cerebral microbleeds are also frequently
observed in CKD patients, especially in ESKD patients 24], 25].
Cerebral microbleeds have been reported to affect the occurrence of cerebral hemorrhage
26]–29]. Naganuma et al. 29] performed cranial MRI, including T2*-weighted MRI, on 179 hemodialysis patients with
no past history of cerebrovascular events and followed them prospectively until death
or renal transplantation. They showed that intracerebral hemorrhage occurred in only
one of 134 (0.7 %) patients without cerebral microbleeds, whereas it occurred in 11
of 45 (24.4 %) patients with cerebral microbleeds during a median follow-up period
of 5.0 years. This finding suggests that hemodialysis patients with cerebral microbleeds
should be carefully monitored for future onset of intracerebral hemorrhage. However,
whether the risk of cerebral hemorrhage is increased by antithrombotic therapy is
unclear.
Hypotension during hemodialysis sessions
Hypotension during hemodialysis sessions might decrease brain blood flow and induce
brain infarction. In our previous study using MRI, we found a positive association
between the numbers of dialysis-related hypotension episodes, i.e., a sudden drop
in blood pressure during HD, was arbitrarily defined as a fall in systolic blood pressure
50 mmHg within 30 min of HD, associated with clinical symptoms such as fatigue, clouding
of consciousness, muscle cramps, or other symptoms associated with hypoperfusion of
the peripheral or central nervous system, identified from the medical records during
3 years with progression of frontal brain atrophy (Fig. 3) 30].
Fig. 3. Correlation of the changes in frontal brain atrophy and the number of sudden blood
pressure drops. The changes in frontal atrophy index correlates significantly with
the number of sudden blood pressure drops over 3 years (r?=?0.45, P??0.05). Abbreviation: ?FAI the change in frontal atrophy index. From Mizumasa et al. 30]
Therefore, reducing the ultrafiltration rate per hour during hemodialysis is important.
Consequently, education of patients on salt restriction is important to reduce intradialytic
weight gain. Administration of vasopressor drugs is available and effective to prevent
hypotension during and after hemodialysis sessions. We previously reported the effect
of vasopressor drugs, such as midodrine hydrochloride and droxidopa, against a decrease
in brain blood flow due to orthostatic hypotension after a hemodialysis session (Fig. 4) 31].
Fig. 4. Serial changes in %MCVm after head-up tilt test in patients treated with L-DOPS. The
serial changes in %MCVm during the 5-min head-up tilt test, before and after 4-week L-DOPS
treatment at each period are shown. L-DOPS improves %MCVm decrement throughout the
5-min head-up tilt test. Data are mean?±?SEM. *P??0.05 vs. before L-DOPS. Abbreviations: %MCVm percentage of the change in the mean middle cerebral artery flow velocity, L-DOPSL–threo-3,4-dihydroxyphenylserine. From Fujisaki et al. 31]
Carotid endarterectomy and carotid artery stenting for carotid artery stenosis
The prognosis after carotid endarterectomy (CEA) for severe carotid artery stenosis
in patients with CKD has been shown to be poor 32], while better effectiveness of CEA was reported in those patients compared with non-CKD
patients 33]. With regard to carotid artery stenting (CAS), poorer prognosis was also reported
in CKD patients compared with non-CKD patients 34].
Using the United States Renal Data System (USRDS) databases, Yuo et al. 35] examined the prognosis in 2131 dialysis patients (1805 CEA, 326 CAS) who underwent
CEA or CAS for asymptomatic disease from 2005 to 2008. They showed that the combined
stroke or death rate was 10.2 % at 30 days and 33.5 % at 1 year and concluded that
patients on dialysis have high perioperative and long-term stroke or death rates after
CEA or CAS for asymptomatic stenosis, with a median survival of 2.5 years, which is
less than that recommended by current guidelines 36]. This finding emphasizes the importance of a minimum life expectancy of at least
3 years for there to be a benefit in asymptomatic patients undergoing CEA. According
to these findings, the indications for these procedures must be carefully evaluated.
In contrast, Okawa et al. 37] demonstrated that of 12 hemodialysis patients with carotid artery stenosis undergoing
15 CEAs, none of them showed periprocedural complications, including stroke and myocardial
infarction. They concluded that CEA may be effective for prevention of stroke in hemodialysis
patients.
Treatment and management of cerebrovascular disease
Management of renal failure during the acute phase of cerebrovascular disease
Intracranial pressure autoregulation collapses immediately after the onset of brain
infarction 38], and the risk of expansion of hematoma is high within 24 h after the onset of cerebral
hemorrhage 39]. Therefore, avoiding dialysis on the day of onset is desirable. Consequently, the
need for dialysis should be carefully evaluated. If dialysis is performed, procedures
such as peritoneal dialysis, continuous hemodiafiltration, and hemodialysis with restricted
blood flow, which are less likely to increase intracranial pressure compared with
usual intermittent hemodialysis, are recommended as the dialysis techniques to be
used during the acute period. Rapid and massive removal of water should be avoided
because it exacerbates brain ischemia. Nafamostat mesilate is recommended to use as
an anticoagulant during hemodialysis if hemorrhagic stroke and hemorrhagic brain infarction
are concerned 1].
Thrombolytic therapy
In the last decade, thrombolytic therapy using recombinant tissue plasminogen activator
(rt-PA) has been applied in the clinical setting for patients with hyperacute phase
brain infarction. However, a worse prognosis with a higher mortality and incidence
of brain hemorrhage has been reported in patients with CKD compared with those without
CKD 40], 41].
Because thrombolytic therapy has not been contraindicated for hemodialysis patients,
it has been applied to hemodialysis patients in a few cases. Naganuma et al. 42] reported the effectiveness of rt-PA therapy in four stroke patients receiving maintenance
hemodialysis with a unique complication of ectopic cortical hematoma.
Tariq et al. 43] analyzed the data of 82,142 patients from the Nationwide Inpatient Sample for all
thrombolytic-treated patients presenting with acute ischemic stroke in the USA between
2002 and 2009. They showed a twofold higher likelihood of in-hospital mortality associated
with administration of intravenous thrombolytic therapy in 1072 dialysis patients,
requiring careful assessment of the risk-benefit ratio in this population. A systematic
review recently reported by Jung et al. 44] demonstrated that patients with CKD had a higher risk of symptomatic intracerebral
hemorrhage and mortality, and were likely to have an increased risk of poor functional
status.
In spite of high risk of thrombolytic therapy for ESKD patients on hemodialysis as
described above, this therapy is one of the important modality of treatment for patients
with hyperacute phase brain infarction. Thus, if a hemodialysis patient develops cerebrovascular
disease during or shortly after hemodialysis, the patient should be transported to
expert facilities early after the onset 1]. Accordingly, creating a system and preparing to be able to transport these patients
as soon as possible after the onset of are considered to be important in the hemodialysis
facilities.
Endovascular mechanical thrombectomy
Recently, mechanical thrombectomy has been applied for patients with ischemic stroke
who are invalid or contraindicated for thrombolytic therapy. More recently, randomized,
controlled trials showing the usefulness of mechanical thrombectomy for patients with
acute brain infarction due to intracranial major artery stenosis have been published
45]–49]. However, the effectiveness of mechanical thrombectomy in CKD patients is unknown
because all of these trials provided no or little information on renal function and
proteinuria in the participants.
Saeed et al. 50] analyzed 2313 dialysis patients with ischemic stroke using data from the Nationwide
Inpatient Sample including dialysis patients presenting with acute ischemic stroke
in the USA between 2005 and 2010. Among these, 1398 (60 %) received intravenous thrombolytic
therapy and 915 (40 %) were treated with endovascular mechanical thrombectomy. They
showed that endovascular mechanical thrombectomy was associated with lower in-hospital
mortality and moderate-to-severe disability, even after adjusting for age, sex, and
potential confounders. According to these findings, the preferential use of endovascular
mechanical thrombectomy might be warranted in this patient population.