Fig. 11.1
Possible mechanisms of stroke based on the medical records of Case #1
Risk of Stroke in Chronic Kidney Disease Patients
Stroke is common in patients with end-stage kidney disease (ESKD), both in patients undergoing hemodialysis [2] and those undergoing peritoneal dialysis [3]. The risk of stroke in dialysis patients has been found to be four to ten times higher than that in the general population [4]. In addition to the point that ESKD is a typical end result of arteriosclerosis, special characteristics unique to dialysis, including drastic hemodynamic change and consequent high variability of blood pressure, dialysate, anticoagulants, vascular access, dialysis amyloidosis, vascular calcification, and dialysis vintage can be triggers of both ischemic and hemorrhagic strokes [5]. In addition, milder chronic kidney disease (CKD) not requiring dialysis therapy also contributes to the risk and severity of stroke [6, 7].
CKD is primarily defined as a reduced glomerular filtration rate (GFR) or the presence of proteinuria [8]. Kidney disease and stroke share traditional cardiovascular risk factors, such as aging, diabetes, hypertension, dyslipidemia, obesity, and smoking. Both the kidney and brain are known to be target organs of arteriosclerotic insults. However, large-scale meta-analyses have demonstrated that CKD is a risk factor for stroke independent of known cardiovascular risk factors [9, 10]. In a meta-analysis including 284,672 people experiencing 7,863 stroke events, the risk of incident stroke increased by 43 % (95 % confidence interval [CI] 31–57 %) in subjects with an estimated GFR (eGFR) below 60 mL/min/1.73 m2 [9]. In 11 of 33 studies included in the meta-analysis, the risk estimate after adjustment for sex, age, and other cardiovascular risk factors was 1.45 (95 % 1.26–1.68). In a meta-analysis involving 140,231 people experiencing 3,266 stroke events, subjects with proteinuria had a 71 % (95 % CI 39–110 %) greater risk of stroke compared to those without proteinuria [10]. The risk remained significant after adjustment for known cardiovascular risk factors. These findings indicate the existence of nontraditional risk factors as contributors to the excess risk of stroke in CKD patients [6, 7] (Table 11.1). In addition, CKD is strongly associated with subclinical cerebrovascular abnormalities, including white matter lesions, silent infarcts, cerebral microbleeds, and carotid atherosclerosis, as well as cognitive impairment [7, 11–14].
Table 11.1
Risk factors common to stroke and kidney disease
Traditional risk factors: aging, hypertension, diabetes, dyslipidemia, obesity, smoking |
Risk factors unique to chronic kidney disease that increase stroke risk: chronic inflammation, asymmetric dimethylarginine, oxidative stress, sympathetic nervous system overactivity, thrombogenic factors, extravascular coagulation, hyperhomocysteinemia, maladaptive arterial remodeling |
Risk factors unique to advanced chronic kidney disease: uremic toxins, fluid retention, anemia, malnutrition, Ca2+and PO4 2− abnormalities, hyperparathyroidism, decreased Klotho protein expression |
Risk factors unique to end-stage kidney disease and dialysis procedures: drastic hemodynamic changes, dialysate, anticoagulants, vascular access, dialysis amyloidosis, vascular calcification, dialysis vintage |
CKD is also indicative of stroke severity and poor clinical outcomes after stroke. In the Fukuoka Stroke Registry involving 3,778 patients with first-ever ischemic stroke, of whom 1,320 (34.9 %) had CKD, CKD patients had a 49 % (95 % CI 17–89 %) greater risk of neurological deterioration during hospitalization, defined as a ≥2 point increase in the National Institutes of Health (NIH) Stroke Scale score, a 138 % (95 % CI 61–257 %) greater risk of in-hospital mortality, and a 25 % (95 % CI 5–48 %) greater risk of a modified Rankin Scale (mRS) score of 2 or more at discharge than non-CKD patients, after adjustment for potential confounding factors, including initial stroke severity [15]. The Fukuoka Stroke Registry also showed a 73 % (95 % CI 3–190 %) greater risk of recurrence of non-cardioembolic stroke in CKD patients [16]. In a post hoc analysis of the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) Trial, involving 18,666 patients with recent ischemic stroke, patients with reduced eGFR below 60 mL/min/1.73 m2 had a 16 % (95 % CI 4–31 %) greater risk of recurrent stroke after multivariate adjustment for confounders [17]. Studies of intracerebral hemorrhage showed that renal dysfunction (eGFR below 60 mL/min/1.73 m2, proteinuria, or serum creatinine ≥1.5 mg/dL) was associated with larger baseline hematoma volume, lower tendency to direct discharge to home and a high percentage of discharge to nursing homes, and death or disability at 1 year [18–20].
Management of Stroke in Chronic Kidney Disease Patients
Limitations of stroke therapies in CKD patients seem to be a reason for the poor stroke outcomes of CKD patients. The dilemma is that CKD patients have both high thromboembolic risk and high bleeding risk, and it is often difficult to maintain the balance of the risk and benefit of antithrombotic therapy in CKD patients. For example, in the Danish national registries involving 132,372 patients with nonvalvular atrial fibrillation, patients with non-end-stage CKD, as well as those with ESKD, had an increased risk of stroke and an increased bleeding risk compared with patients with normal renal function [21]. Thus, special care to prevent bleeding complications is needed for anticoagulation in patients having both CKD and atrial fibrillation. There is conflicting evidence on the benefit of stroke prevention from warfarin, especially in dialysis patients. In the above Danish national registries, warfarin significantly decreased the risk of stroke and significantly increased the risk of bleeding for both patients with non-end-stage CKD and those with ESKD. In contrast, other studies reported that warfarin increased all of bleeding risk, ischemic stroke risk, and mortality in atrial fibrillation patients on dialysis [22, 23]. Warfarin for dialysis patients also increases vascular calcification [22]. Thus, routine use of warfarin in ESKD patients seems to be often limited to those at very high risk for stroke and is performed with close monitoring of the international normalized ratio. Although non-vitamin K antagonist oral anticoagulants (otherwise, novel oral anticoagulants) may be safer and more beneficial for patients with nonvalvular atrial fibrillation than warfarin, they are contraindicated for patients with advanced renal dysfunction due to reduced clearance.
Although intravenous thrombolysis for hyperacute ischemic stroke is not contraindicated for patients with ESKD or advanced CKD, renal dysfunction seems to affect clinical outcomes after thrombolysis [24, 25]. In a meta-analysis of three studies involving 344 patients with reduced eGFR and 504 patients without, reduced eGFR was significantly associated with early symptomatic intracerebral hemorrhage, high mortality, and low percentage of patients with mRS score 0-2 at the subacute or chronic stage [26, 27]. Similarly, revascularization by endovascular therapy for CKD patients has several problems, such as limited use of contrast agents and difficulty in catheterization due to carotid calcification.
Emerging Risk Factors
Case Presentation (#2)
A 53-year-old, normotensive, ex-smoker developed 3 strokes over 5 months, and he was admitted to our hospital for the third stroke. After the death of his wife 4 years previously, he lived alone and often dined on box lunches and noodles. The first stroke was an ischemic event in the left corona radiata, with resulting right hemiparesis. One month later, he noticed right hemiparesis again due to an infarct in the left basal ganglia. Oral aspirin was started after the first stroke, and ticlopidine was added after the second. Four months after the second stroke, he noticed dysesthesia of the right side of his body. MRI revealed a fresh hematoma in the left thalamus. MRA did not show stenosis of any arteries. Blood tests showed an increased level of homocysteine (22.5 μmol/L). Among the serum vitamins, B12 (320 ng/L) and folate (3.3 μg/L) were within normal levels, and B6 was slightly decreased (5.9 μg/L). Methylenetetrahydrofolate reductase TT genotype was documented on polymerase chain reaction DNA amplification using whole blood lymphocytes. Oral supplementation of vitamin B6, vitamin B12, and folate brought the homocysteine level down to normal. The complete details of this case have been described elsewhere [28].
Young-Onset Strokes and Causes for Premature Atherosclerosis
Stroke in young adults is often associated with risk factors other than the traditional vascular risk factors. The differential diagnosis of ischemic stroke in young adults is listed in “Caplan’s Stroke” [29]. Here, the table is revised with some additional diseases (Table 11.2). The pathologic states in the table are indicative of uncommon causes of stroke, and stroke patients with such pathologic states are sometimes diagnosed as having cryptogenic stroke because these states are often underdiagnosed. Some of the causes are introduced in other chapters of this textbook.
Table 11.2
Causes of ischemic stroke in young adults
Migraine |
Arterial dissection |
Drugs, especially cocaine and heroin |
Premature atherosclerosis: dyslipidemia (familial hyperlipidemia), hypertension, diabetes, smoking, sleep disorders, insulin resistance, metabolic syndrome, hyperhomocysteinemia |
Female hormone-related (oral contraceptives, pregnancy, puerperium): eclampsia, dural sinus occlusion, peripartum cardiomyopathy, peripartum vasculopathy |
Hematologic: deficiency of antithrombin III, protein C, protein S, factor V Leiden, prothrombin gene mutations, fibrinolytic system disorders, deficiency of plasminogen activator, antiphospholipid antibody syndrome, increased factor VIII, cancer, thrombocytosis, polycythemia, thrombocytopenic purpura, disseminated intravascular coagulation |
Rheumatic and inflammatory: systemic lupus erythematosus, rheumatoid arthritis, sarcoidosis, Sjögren’s syndrome, scleroderma, polyarteritis nodosa, cryoglobulinemia, Crohn’s disease, ulcerative colitis |
Cardiac: intra-atrial septal defect, patent foramen ovale, mitral valve prolapse, mitral annulus calcification, myocardiopathies, arrhythmias, endocarditis |
Penetrating artery disease (lacunes): hypertension, diabetes |
Genetic: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), Fabry’s disease, homocystinuria (hyperhomocysteinemia) |
Others: Moyamoya syndrome, Behçet’s syndrome, neurosyphilis, Takayasu’s disease, Sneddon’s syndrome, fibromuscular dysplasia, Cogan’s disease |
In this chapter, causes of premature atherosclerosis are discussed. In addition to traditional risk factors for cardiovascular disease, including dyslipidemia, hypertension, diabetes, and smoking, emerging risk factors such as hyperhomocysteinemia, sleep disorders, insulin resistance, and metabolic syndrome are briefly introduced.
Homocysteine is a sulfurous amino acid that is an intermediary biosynthesized during the conversion of methionine to cysteine. A high serum level of homocysteine results from vitamin deficiencies due to lifestyle factor-related insufficiencies and wasting diseases, as shown in Case #2, CKD (vitamin deficiencies), and hereditary abnormalities of the metabolism of methionine (homocystinuria). Homocysteine causes endothelial cell injury and initiates the process of premature atherosclerosis. Meta-analyses indicate the association of hyperhomocysteinemia with an increased risk of ischemic stroke [30, 31]. Hyperhomocysteinemia predisposes to large-artery atherosclerosis stroke subtypes, including carotid stenosis [32, 33]. However, patients with small-artery infarction are also reported to have higher serum homocysteine levels than control patients [33]. Methylenetetrahydrofolate reductase serves as an enzyme for conversion of dietary folate to 5-methyltetrahydrofolate, and a methyl donor requires the remethylation of homocysteine to methionine in vivo. Methylenetetrahydrofolate reductase TT genotype seems to be an independent risk factor for silent brain infarction and white matter lesions in the general Japanese population [34]. Hyperhomocysteinemia may be a potential risk factor for stroke including small-artery infarctions and hemorrhage for relatively young patients with lifestyle factor-related insufficiencies. Hyperhomocysteinemia is a treatable disorder, but the effectiveness of lowering serum homocysteine for stroke prevention is not yet proven. In the Vitamin Intervention for Stroke Prevention (VISP) trial involving 3,680 patients with ischemic stroke, mean 2 μmol/L more reduction of serum homocysteine level by administration of high-dose folic acid, pyridoxine, and cobalamin as compared to low-dose administration did not decrease recurrent stroke during 2-year follow-up [35]. Similarly, daily administration of B vitamins did not reduce major vascular events including recurrent stroke as compared to placebo in the VITAmins TO Prevent Stroke (VITATOPS) trial [36].
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