Stroke In The Kidney: What's The Connection?

Stroke is a leading cause of morbidity and mortality worldwide. Renal failure is a potent risk factor for stroke, with the risk of stroke being 5–30 times higher in patients with chronic kidney disease (CKD), especially on dialysis. CKD patients have a higher risk of both ischemic and hemorrhagic strokes. CKD in combination with other cardiovascular risk factors accelerates atherosclerosis and increases stroke risk in the predialysis stages. Medial calcifications occur frequently in patients with CKD, independent from the intima calcifications caused by atherosclerosis. Endothelial dysfunction and arteriosclerosis each are enhanced by water and sodium retention, uremic toxins, abnormal electrolytes and hyperparathyroidism.

Risk factors for stroke in CKD patients

The risk of stroke is 5–30 times higher in patients with chronic kidney disease (CKD), especially on dialysis. The heightened risk of stroke in CKD represents the interplay of the vascular co-morbidities that occur with renal impairment and factors specific to renal failure.

Non-modifiable risk factors

• Older age
• Diabetes
• Male gender
• Non-Caucasian/Asian ethnicity
• Positive family history

Modifiable risk factors

• Hypertension
• Atherosclerotic risk factors such as smoking, hyperlipidemia, and atrial fibrillation (AF)
• The co-existence of several vascular risk factors in patients with CKD, including hypertension, diabetes mellitus, dyslipidemia, and proteinuria
• Factors specific to CKD include accelerated atherosclerosis, vascular calcification, the effect of uremic toxins, prothrombotic tendency, and impaired cerebral autoregulation
• Initiation of dialysis
• Anemia
• Hypoalbuminemia and malnutrition
• Uremia-induced accelerated atherosclerosis
• Anticoagulation during dialysis and uremic bleeding diathesis
• Renal transplant
• Hyperhomocysteinemia

Clinical relationship between CKD, stroke and stroke outcomes

Chronic kidney disease (CKD) is an independent risk factor for stroke, including both hemorrhagic and ischemic subtypes. The risk of stroke is 5–30 times higher in patients with CKD, especially on dialysis. The heightened risk of stroke in CKD represents the interplay of the vascular co-morbidities that occur with renal impairment and factors specific to renal failure such as malnutrition-inflammation-atherosclerosis complex, the effect of uremic toxins, dialysis techniques, vascular access, and the use of anticoagulants to maintain flow in the extracorporeal circuit.

The risk factors for stroke include non-modifiable risk factors such as older age, diabetes, male gender, non-Caucasian/Asian ethnicity, and a positive family history. Hypertension continues to be the major modifiable risk factor for both ischemic and hemorrhagic stroke with risk increasing with worsening systolic and diastolic blood pressure control. Atherosclerotic risk factors such as smoking, hyperlipidemia as well as atrial fibrillation (AF) increase the risk of ischemic stroke. The prevalence of AF in CKD patients is more than twice that in the general population and confers a greater thromboembolic risk.

The co-existence of several vascular risk factors in patients with CKD has been postulated as the reason for the observed association of renal dysfunction with stroke. Hypertension, diabetes mellitus, dyslipidemia, and proteinuria are all highly prevalent in the CKD population. Moreover, factors specific to CKD include accelerated atherosclerosis, vascular calcification, effect of uremic toxins, prothrombotic tendency, and impaired cerebral autoregulation. Intracranial arterial calcification, which is associated with stroke risk in the general population, increases in prevalence in patients with CKD.

CKD is an independent risk factor for both ischemic and hemorrhagic stroke. In addition, renal impairment is associated with a greater neurological deficit following ischemic stroke, a poor functional outcome, and greater mortality. Following acute ischemic stroke, advanced CKD has been associated with a higher risk of hemorrhagic transformation. In patients with hemorrhagic stroke, moderate-to-severe CKD has been associated with a larger hematoma volume.

The occurrence of stroke in CKD patients, especially the manifold increased risk in ESRD patients, is an expression of increased and accelerated atherosclerosis in this group. However, in comparison to cardiac disease, this has been relatively understudied. It is, therefore, important to understand the risks as well as benefits of established therapy for stroke management and prevention and apply them judiciously in all stages of CKD.

Functional brain damage in CKD patients

Functional brain damage in patients with chronic kidney disease (CKD) is a result of the interplay of cerebrovascular disease and cognitive impairment. CKD patients are at a heightened risk of cerebrovascular disease, including both hemorrhagic and ischemic subtypes. This is due to a multitude of mechanisms linking nephropathy with altered cerebral perfusion, cerebral neurovascular coupling, and blood vessel integrity. CKD patients are at a higher risk of developing cognitive impairment, which has been linked to poor compliance with medications, and is associated with greater morbidity and mortality.

CKD patients are at a higher risk of cerebrovascular disease due to several factors. Firstly, CKD patients are at a higher risk of developing hypertension, which is a major modifiable risk factor for both ischemic and hemorrhagic stroke. Secondly, CKD patients are more likely to have impaired cerebral autoregulation, which can lead to hypoperfusion at low levels of systemic blood pressure and hyperperfusion at high levels. Thirdly, CKD patients are more likely to have endothelial dysfunction, which can lead to accelerated arteriosclerosis and impaired cerebral autoregulation. Finally, CKD patients are more likely to have increased arterial stiffness and dilatation, which can lead to increased blood flow and strain on the downstream cerebral vasculature.

CKD patients are also at a higher risk of developing cognitive impairment. This is due to several factors, including endothelial dysfunction, vascular calcification, and impaired cerebral autoregulation. Additionally, CKD patients are more likely to have anemia, which can impair oxygen delivery to the brain and affect brain metabolism. CKD patients are also more likely to have a higher prevalence of white matter lesions, which can lead to cognitive impairment. Finally, CKD patients are more likely to have a higher prevalence of cerebral atrophy, which can lead to executive dysfunction.

Neuroimaging and brain lesions in CKD

Neuroimaging modalities such as magnetic resonance imaging (MRI) are used to non-invasively study the neurobiological underpinnings of cognitive dysfunction in CKD. MRI studies have shown that CKD is associated with cerebral atrophy, decreased cerebral density in both white and grey matter, and more white matter lesions.

CKD is associated with a higher risk of stroke, with patients on dialysis having an eight- to ten-fold greater incidence of stroke compared to the general population. The risk of stroke is also higher in patients with CKD who are not on dialysis, with a study reporting that patients with an eGFR <60 ml/min/1.73 m2 had a 43% independent risk of stroke.

CKD is associated with both ischemic and hemorrhagic stroke subtypes. CKD increases the risk of intracerebral hemorrhage (ICH) and cerebral microbleeds. CKD also increases the risk of large vessel stroke, as well as small vessel ischemic stroke.

MRI studies have shown that CKD is associated with cerebral atrophy, decreased cerebral density in both white and grey matter, and more white matter lesions. These brain lesions include white matter lesions, silent cerebral infarcts, and brain atrophy.

CKD is associated with a higher risk of stroke, with patients on dialysis having an eight- to ten-fold greater incidence of stroke compared to the general population. The risk of stroke is also higher in patients with CKD who are not on dialysis, with a study reporting that patients with an eGFR <60 ml/min/1.73 m2 had a 43% independent risk of stroke.

CKD is associated with both ischemic and hemorrhagic stroke subtypes. CKD increases the risk of intracerebral hemorrhage (ICH) and cerebral microbleeds. CKD also increases the risk of large vessel stroke, as well as small vessel ischemic stroke.

CKD is also associated with a greater neurological deficit following ischemic stroke, a poor functional outcome, and greater mortality. CKD patients with ischemic stroke were more likely to die in the hospital and have an unfavorable discharge functional status.

Therapies and interventions for stroke prevention in CKD

Hypertension Management

Hypertension is a major modifiable risk factor for stroke, and controlling blood pressure is the most important aspect of stroke prevention. The initiation of dialysis is associated with a heightened risk of stroke, and rapid control of blood pressure is an important factor in reducing CV risk.

Lipid-lowering Therapy

Some studies suggest that reduction of LDL cholesterol may be beneficial in secondary stroke prevention among individuals with reduced kidney function. However, the role of statins as prophylactic agents remains a matter of debate.

Anaemia Management

Anaemia has been shown to increase the risk of stroke in CKD patients. Recombinant erythropoietin is indicated to correct this condition, with a target haemoglobin level of ≥11.0 g/dl. Higher haemoglobin targets of >13.0 g/dl have been associated with a greater risk of stroke.

Antiplatelet Therapy

Antiplatelet therapy is recommended for the presence of ischemic stroke, and there is evidence supporting its efficacy in patients with non-dialysis CKD. However, the risk of bleeding with prophylactic antiplatelet agents is increased in ESRD, and they should be used with caution.

Anticoagulants

Oral anticoagulants are recommended for patients with AF with a CHADS score ≥2. However, the hazards of anticoagulation may outweigh the benefits in ESRD patients. Newer non-vitamin K-dependent oral anticoagulants have a prolonged half-life in CKD patients, resulting in an increased bleeding risk, and should be used cautiously.

Dialysis Modalities

The choice of dialysis modality may impact stroke risk. For example, patients on peritoneal dialysis (PD) have been found to have a lower risk of hemorrhagic stroke compared to those on hemodialysis (HD).

Frequently asked questions